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HIV & VIROLOGY NEWS
Issue 2 · 2015
DENMARK
ILC IN VIENNA · EFAVIRENZ: TOO MUCH OF A GOOD THING? · THE NEW DHHS GUIDELINES. FORGETTING
EVIDENCE, EMBRACING OPINION · NEW DRUGS FROM NEW CLASSES OF DRUGS · MONITORING THE
PERSISTENT HIV RESERVOIR IN THE ERA OF HIV CURE TRIALS · SYMPOSIUM ON THE SEARCH FOR A CURE
Beyond Ef ficacy
R ES I
Reasons
to rethink
first-line
treatment
in HIV
NVENIENCE
CO
STA N CE
ER AB I L I T Y
TOL
E F FICAC Y
Dolutegravir-based regimens delivered
SUSTAINED EFFICACY
up to 96 weeks in treatment-naïve patients1-4
In some markets, Atripla® is not licensed
for initial use in treatment-naïve patients.
Tivicay® (dolutegravir)
Indikation(er): Tivicay er indiceret i kombination med andre antiretrovirale lægemidler til behandling af humant
immundefektvirus (hiv)-inficerede voksne og unge over 12 år.
Dosering*: Voksne: Patienter inficeret med hiv-1 uden dokumenteret eller klinisk formodet resistens over for
integraseklassen: 50 mg (en tablet) oralt én gang daglig. Tivicay skal administreres 2 gange daglig i denne
population, når det gives samtidigt med visse lægemidler (f.eks. efavirenz, nevirapin, tipranavir/ritonavir eller
rifampicin). Patienter inficeret med hiv-1 med resistens over for integraseklassen (dokumenteret eller klinisk
formodet): 50 mg (en tablet) 2 gange daglig. Samtidig administration af Tivicay med visse lægemidler skal
undgås i denne population (f.eks. efavirenz, nevirapin, tipranavir/ritonavir eller rifampicin). Unge fra 12 år og
derover: Hos unge (fra 12 til 17 år og med en vægt på mindst 40 kg), der er inficeret med hiv-1 uden resistens
over for integraseklassen, er den anbefalede dosis af dolutegravir 50 mg én gang daglig. Kontraindikationer*:
Overfølsomhed over for det aktive stof eller over for et eller flere af hjælpestofferne. Administration samtidigt med
dofetilid. Forsigtighedsregler*: Beslutningen om at anvende dolutegravir ved resistens over for integraseklassen
skal tage højde for at aktiviteten af dolutegravir vurderes at være kompromitteret for virale stammer, der indeholder
Q148+≥ 2 sekundære mutationer fra G140A/C/S, E138A/K/T, L741. Der er rapporteret overfølsomhedsreaktioner
over for dolutegravir (udslæt, konstitutionelle fund og nogle gange organdysfunktion, herunder alvorlige
leverreaktioner). Dolutegravir og andre mistænkte stoffer skal omgående seponeres, hvis der udvikles tegn
eller symptomer på overfølsomhedsreaktioner. Det anbefales at monitorere biokemiske leverparametre hos
patienter, der er co-inficeret med hepatitis B- og/eller C-virus. Patienter i behandling med dolutegravir kan stadig
udvikle opportunistiske infektioner og andre komplikationer fra hiv-infektion. Undgå samtidig administration med
lægemidler, der reducerer dolutegravireksponering (f.eks. antacida indeholdende magnesium/aluminium, jernog calciumtilskud, multivitaminer og inducerende midler, tipranavir/ritonavir, rifampicin og visse antiepileptiske
lægemidler). Koncentrationen af metformin kan øges af dolutegravir. Interaktioner*: Alle faktorer, der reducerer
eksponering for dolutegravir skal undgås ved tilstedeværelse af resistens over for integraseklassen. Dolutegravir
elimineres overvejende gennem metabolisering via UGT1A1. Dolutegravir er også substrat for UGT1A3, UGT1A9,
CYP3A4, Pgp og BCRP; derfor kan lægemidler, der inducerer disse enzymer reducere plasmakoncentrationen
af dolutegravir og reducere den terapeutiske effekt af dolutegravir. Samtidig administration af dolutegravir og
andre lægemidler, der hæmmer disse enzymer kan øge plasmakoncentrationen af dolutegravir. Absorptionen
af dolutegravir reduceres af visse syreneutraliserende lægemidler. In vitro hæmmede dolutegravir den renale
transporter 2 af organiske kationer (OCT2) og multidrug og toksin ekstruderingstransporter (MATE) 1. In vivo blev
et 10-14 % fald i kreatininclearancen (sekretionsfraktion afhænger af OCT2 og MATE-1 transport) observeret
hos patienterne. In vivo kan dolutegravir øge plasmakoncentrationerne af lægemidler, for hvilke udskillelsen
afhænger af OCT2 eller MATE-1 (f.eks. dofetilid, metformin). In vitro hæmmede dolutegravir de renale
optagelsestransportere, organisk anion-transporterer (OAT1) og OAT3. Baseret på manglende effekt på in vivo
farmakokinetikken af OAT-substratet tenofovir, er in vivo hæmning af OAT1 usandsynlig. Hæmning af OAT3 er
ikke undersøgt in vivo. Dolutegravir kan øge plasmakoncentrationen af lægemidler, hvis udskillelse er afhængig
af OAT3. Graviditet og amning*: Der er utilstrækkelig mængde data fra anvendelse af dolutegravir til gravide
kvinder. Det er ukendt, om dolutegravir udskilles i human mælk. Det anbefales, at hiv-inficerede kvinder under
ingen omstændigheder ammer deres spædbørn, så overførsel af hiv undgås. Bivirkninger*: Meget almindelig:
Hovedpine, kvalme, diarré. Almindelig: Insomni, unormale drømme, svimmelhed, opkastning, flatulens, smerter
i øvre del af abdomen, abdominalsmerter, abdominalt ubehag, udslæt, pruritus, træthed, forhøjet niveau af
alaninaminotransferase (ALAT) og/eller aspartataminotransferase (ASAT), forhøjet niveau af kreatinfosfokinase
(CPK). Ikke almindelig: Overfølsomhed, immunrekonstitutionssyndrom, hepatitis. Overdosering*: Der er på
nuværende tidspunkt begrænset erfaring med overdosering af dolutegravir. Begrænsede data med højere
enkeltdoser (op til 250 mg hos raske personer) medførte ingen specifikke symptomer eller tegn ud over de tegn
og symptomer, der er anført som bivirkninger. Udlevering: BEGR. Ikke tilskud.
De med * mærkede afsnit er omskrevet og/eller forkortet i forhold til det af EMA godkendte produktresumé.
Fuldt produktresumé kan vederlagsfrit rekvireres hos den danske repræsentant for ViiV, GlaxoSmithKline
Pharma A/S, Nykær 68, 2605 Brøndby.
Bivirkninger, både kendte og nyopdagede, bedes indberettet hurtigst muligt til Sundhedsstyrelsen
(www.meldenbivirkning.dk) eller GlaxoSmithKline (dk [email protected]).
Dagsaktuelle priser findes på www.medicinpriser.dk
References:
1. Walmsley S et al. N Engl J Med. 2013;369(19):1807-1818.
2. Tivicay Summary of Product Characteristics
3. Clotet B et al. Lancet. 2014;383:2222-2231.
4. Molina J M et al. Lancet 2015; Published online March 10,
http://dx.doi.org/10.1016/S2352-3018(15)00027-2
DK/DLG/0012/15 maj 2015
Nykær 68
DK-2605 Brøndby
T +45 36 35 91 00
F +45 36 35 91 01
www.glaxosmithkline.dk
HIV & VIROLOGY NEWS
HIV & Virology News is a quarterly publication
with four issues per year.
The magazine is distributed free of charge to
all those specialists in the field of Infectious
diseases in 13 European countries including the
UK, the Netherlands, Belgium, Germany,
France, Spain, Italy, Sweden, Norway, Denmark,
Finland, Austria and Switzerland.
In this issue:
The magazine is in English with all content
being HIV and virology related. It also include
summaries of research results from the above
mentioned countries as well as consensus
relating from the fields of HIV and virology.
Also featured are educational programmes and
excerpts from seminars and conferences.
Editor in Chief:
Magnus Gisslén, MD, Ph.D
Professor of Infectious Diseases
Dpt of Infectious Diseases
Sahlgrenska University Hospital,
Gothenburg, Sweden
[email protected]
Editorial Board:
Graeme J. Moyle, MD, MB BS, Dip. GUM
Director of HIV Research Strategy
Chelsea & Westminster Hospital
London, United Kingdom
[email protected]
José Arribas, MD
Associate Professor of Medicine at
the Autonoma University School of Medicine in
Madrid and Research Director at the HIV unit of
La Paz Hospital, Madrid, Spain
[email protected]
Christine Katlama, Professor of Infectious
Diseases at University Pierre and Marie Curie
and Head of the AIDS Unit in the Department
of Infectious Diseases at the Pitié-Salpêtrière
Hospital in Paris, France
[email protected]
Heiner Wedemeyer, Prof. Dr.
Dept. of Gastroenterology, Hepatology and
Endocrinology
Hannover Medical School
Hannover, Germany
[email protected]
Advertising:
Advertising space within HIV and Virology News
is sold locally in each country.
As a result of placing an advertisement within
this magazine you will reach every specialist
in the field of infectious diseases in these
countries.
For questions concerning advertising contact:
Lars Lundblad
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Mediahuset i Göteborg AB, Sweden
Marieholmsgatan 10C,
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Production:
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www.mediahuset.se
Layout and cover picture:
Eva-Lotta Emilsdotter
[email protected]
Printing:
ÅkessonBerg, Emmaboda,
Sweden
ISSN 2000-8384 (print)
ISSN 2001-8193 (online)
Vienna
2
Letter from the Editor
3
ILC in Vienna
17
Efavirenz: too much of a good thing?
21
The new DHHS guidelines. Forgetting
evidence, embracing opinion
Magnus Gisslén
Per Lundblad
Jose R Arribas
Graeme Moyle
24
25
Topical Conferences
30
Monitoring the persistent HIV reservoir
in the era of HIV cure trials
34
Symposium on the search for a cure
38
Banishing B - going beyond management
41
Conquering C - going beyond cure
42
The new landscape in management of HCV
45
Notes 2015
New drugs from new classes of drugs
Christine Katlama
Ward de Spiegelaere and Linos Vanderkerckhove
Per Lundblad
Per Lundblad
Per Lundblad
Per Lundblad
Leo Flamholc
www.hivvirology.com
HIV & VIROLOGY NEWS 2 · 2015
1
Letter from the Editor
New guidelines
In this issue of HIV & Virology News you can read a critical review of the new US DHHS HIV treatment guidelines (https://
aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescenttreatment-guidelines/0) by Graeme Moyle (page 21).
I
t is easy to agree with many of Graeme’s objections to some
of the new recommendations. Several recommendations are
published on the same topic each year all over the world. The
DHHS guidelines are one of the latest presented. Making recommendations is not an easy task. The data on which the recommendations are based are the same for all guideline groups,
but the interpretations differ considerably among responsible
experts. Some of the recent guidelines on recommended first line
regimens for antiretroviral-naïve subjects are given in the figure
below: DHHS from the US; the European guidelines (EACS); the
British guidelines (BHIVA); and the Swedish guidelines. While
it may be expected that certain aspects of drugs and studies are
valued differently by various experts, in fact, it also gives one
some perspective and humility. Most recommendations are, in
fact, expert opinions (and not objective judgements) based on
the strength and quality of the evidence available at present.
Recommended drug regimens for ART-­‐naïve subjects
DHHS 2015
EACS 2014
BHIVA 2013 Swedish 2014
NNRTI-­‐based regimes:
EFV + ABC/3TC
EFV/TDF/FTC
RPV + ABC/3TC
RPV/TDF/FTC
PI/r-­‐based regimens:
AZV/r + ABC/3TC
AZV/r + TDF/FTC
DRV/r + ABC/3TC
DRV/R + TDF/FTC
INSTI-­‐based regimens:
EVG/c/TDF/FTC
DTG/ABC/3TC
DTG + TDF/FTC
RAL + ABC/3TC
RAL + TDF/FTC
One important question is the extent to which financial considerations should be taken into account in the treatment guidelines. My personal view is that this is an important responsibility
for the guideline authors. Financial resources are not unlimited
in providing health care. All regimens currently in use in Western Europe and the US are well-tolerated and very effective in
antiretroviral-naïve patients without resistance. Since there are
only small differences between drugs, one can argue that we
should use the cheapest possible combinations as the first line of
treatment. The regime can be changed in the minority of subjects
who experience side effects. Thus, the more expensive drugs can
be saved for specific situations, such as drug resistance, significant side effects, or risk for adverse reactions due to comorbidities, etc. This will be an even more important issue as more
generic drugs become available.
2
Magnus Gisslén
Editor
HIV & VIROLOGY NEWS 2 · 2015
ILC in Vienna
The annual International Liver Congress
(ILC) was in 2015 held in Vienna. It is the
European Association for the study of
the Liver (EASL) biggest event – and this
year in Vienna, EASL celebrated ILC’s
50th anniversary. Hepatitis C was one
of the topics at the core of the Congress
agenda.
I
n his welcoming address at the Opening
Ceremony, Prof Marcus Peck, The Secretary General of EASL, pointed out
that the development during these 50
years had been extraordinary.
– At our first Meeting in Marburg, Germany in 1966 at today’s date – the 23:rd
of April – there were perhaps 50 persons
present. Today we have 10,127 attendees
registered in Vienna. This is very close to
the 10,638 that came to ILC in London last
year – which was an all time high record,
he said.
High SVR12 rates in patients with advanced liver disease
Patients with chronic HCV infection and
advanced liver disease – especially those
with decompensated cirrhosis – have a
HIV & VIROLOGY NEWS 2 · 2015
poor prognosis and limited treatments options. Liver failure and hepatocellular carcinoma related to HCV infection are the
most common indications for liver transplantation in North America and Europe.
This was pointed out by Prof Michael
Manns in his lecture at the Opening Session. He presented a study that aimed to
evaluate the safety and efficacy of ledipasvir/sofosbuvir with ribavirin for 12 or 24
weeks in patients with HCV genotype 1 or
4 decompensated cirrhosis and/or those
with recurrent HCV post-transplantation.
Ledipasvir is a once-daily, oral NS5A
inhibitor, sofosbuvir is a once daily NS5B
inhibitor. The two has been combined in
ledipasvir/sofosbuvir fixed dose combination (FDC), a once daily single-tablet
regimen for HCV.
In the study 329 patients at 34 sites in 12
countries participated.
– They were 168 post-transplant patients with F0 - F3 fibrosis, or CPT A (=
early) cirrhosis and 160 patients with decompensated cirrhosis – 53 post-transplant. 1 patient was not treated, Prof
Manns said.
He reported that ledipasvir/sofosbuvir
with ribavirin resulted in high SVR12 rates in HCV patients with advanced liver
disease – irrespective of transplantation
status.
– For genotype 1 patients, the study
found no difference in SVR12 rates between 12 and 24 weeks. There were too
few genotype 4 patients for meaningful
comparisons.
Among patients with cirrhosis, virologic response was associated with improvements in MELD and CPT scores largely
due to decreases in bilirubin and improvement in synthetic function (e.g. albumin),
Prof Manns continued.
– Ledipasvir/sofosbuvir with ribavirin
for 12 - 24 weeks was generally safe and
well tolerated in patients with advanced
liver disease, pre- and post-liver transplantation, was Prof Manns conclusion.
A pressing need to educate the public
As many as half of the people infected
with viral hepatitis have suffered discrimination. One quarter of them admit that
family members have avoided physical
contact with them after finding out they
had the infection.
3
ILC in Vienna
This was revealed in patient survey presented at the Congress. Research conducted with the Ministry of Health in Brazil
questioned 1,217 people infected with hepatitis B or C in Europe and America using
an online survey tool. The aim of the research was to find out from those infected,
when, and with what intensity, stigma and
discrimination affect their quality of life.
– Few studies have evaluated the circumstances and the degree to which stigma and discrimination are present for
those living with viral hepatitis. This is
one of the first studies that listens to the
voice of the patient – in order to find out
from them the context and intensity of
stigma and discrimination that they experience, and how it affects their quality of
life, said Dr Marcelo Naveira, Viral Hepatitis Coordination, Secretariat for Disease
Surveillance Ministry of Health of Brazil,
at a press conference.
The survey revealed that nearly half
(49.6%) of those infected have suffered
some kind of discrimination. Of the 94.1%
who told their family they had the infection, a quarter (24.6%) said that relatives
started to avoid physical contact.
Marcus Peck
4
Marcelo Naveira
– Furthermore, of the 73.7% who told
friends about their condition, nearly half
(46.9%) said they suffered discrimination
and 23.8% said they were no longer invited to social events, Dr Naveira pointed
out.
The stigma and discrimination faced by
people living with hepatitis is all too often
based on misunderstandings about the virus and its transmission. Not only is this
damaging to people diagnosed with the
disease, but it may also discourage others
from getting tested and accessing treatment and support, Prof Peck commented
on the survey’s findings.
– There is a pressing need to educate
the general public about hepatitis, in order to erode this stigma and break down
barriers to timely testing, treatment and
care, Prof Peck concluded.
New combinations
One of the many parallel sessions given at
the Congress concerned HCV therapy. In
one of these, Dr Xavier Forns presented
interim data from the Phase II open-label
SATURN study.
The study investigated on-treatment
virologic response and tolerability of simeprevir, daclatasvir and ribavirin in
patients with recurrent HCV genotype
(GT)1b infection after orthotopic liver
transplantation (OLT).
– As you all know, simeprevir is a once
daily (QD) NS3/4A protease inhibitor
with antiviral activity against HCV GT 1,
2, 4, 5 and 6. It is approved in combination
with peginterferon/ribavirin for chronic
HCV GT 1 infection in the United States,
and GT 1 and 4 infection in the European
Union, Dr Forns said.
Daclatasvir is a QD pangenotypic NS5A
replication complex inhibitor.
– We found that simeprevir 150 mg +
daclatasvir 60 mg QD + ribavirin achieved
high rates of on-treatment response in
HCV GT 1b-infected post-OLT patients
on immunosuppressive therapy, Dr Forns
said.
The combination was generally safe and
well tolerated.
– The study is ongoing; data from the
primary efficacy analysis on SVR12 will be
reported later in 2015, Dr Forns stated.
Dr Eric Lawitz presented a study on
retreatment of patients who failed 8 or
12 weeks of ledipasvir/sofosbuvir-based
regimens with ledipasvir/sofosbuvir for
24 weeks. It was an open-label study on
previous failures.
– 71 % of patients who failed these regimens achieved SVR12 when retreated for
24 weeks, he said.
The presence of baseline NS5A resistance-associated variants – which was
more likely to develop with longer ledipasvir/sofosbuvir treatment – was associated with virologic failure. Emergence of
S282T mutation was observed in 3 of 12
virologic failure patients.
– Retreatment with ledipasvir/sofosbuvir is feasible in patients who have failed
prior ledipasvir/sofosbuvir regimens, was
Dr Lawitz conclusion.
Shortening therapy
Grazoprevir is a HCV NS3/4A inhibitor,
administered orally once-daily. Elbasvir
is a HCV NS5A once-daily, oral inhibitor.
Prof Fred Poordad presented a study
that aimed to combine three highly potent
direct-acting antivirals (grazoprevir + elbasvir + sofosbuvir), each with a different
mechanism of action, in order to explore
short duration therapy in the most common and difficult to cure genotypes – GT 1
and 3 – with and without cirrhosis.
– We found that this novel regimen
was able to shorten treatment duration
to 8 weeks or less among cirrhotic and
non-cirrhotic GT 1-infected patients, he
said.
GT 3 patients achieved high SVR12 rates with 8 - 12 weeks of therapy – including patients with cirrhosis, Prof Poordad
added.
– All virologic failures were due to relapse. Patients who relapsed were most
commonly infected with either wild-type
virus, or with resistance-associated variants already present at baseline. Generally
the regimen was safe and well tolerated,
he summarized the findings.
Prof Poordad’s conclusions were that
HIV & VIROLOGY NEWS 2 · 2015
ILC in Vienna
this proof-of-concept study had demonstrated the concept of shortening therapy
even in cirrhotic patients, and that retreatment of the virologic failures is ongoing.
Significant advances with new therapy
Dr Rajender Reddy presented more data
on grazoprevir + elbasvir combination.
It was the Phase III C-EDGE TN study
in treatment naive patients. This showed
that a 12-week oral regimen of once-daily
single tablet grazoprevir/elbasvir is effective and well-tolerated in treatment-naive
(TN) patients infected with HCV GT 1, 4
or 6, including those with compensated
cirrhosis.
Based on preliminary results from 316
recipients in the immediate treatment
arm, 299 (95 %) achieved STR12.
These initial results show that once-daily grazoprevir/elbasvir offers significant
advantages over older treatments, demonstrating the ideal combination of high
efficacy with good tolerability and convenience in treatment-naive patients infected with chronic HCV, Dr Reddy stated.
The study is an international, randomised, blinded, placebo-controlled, parallel-group trial.
– Newer antiviral regimens – such as
this combination – offer much hope to
people living with HCV. They have shown
great efficacy and tolerability for the treatment of this chronic infection, said EASL
Vice-Secretary Dr Laurent Castera (who
was elected as the new Secretary General
later at the Congress).
High response in CP-B patients
The combination of grazoprevir and elbasvir was also studied in HCV GT 1 infected patients with Child-Pugh class B
(CP-B) cirrhosis – the 2 C-SALT study. It
was presented by Prof Ira Jacobson.
– Currently, there is no approved treatment regimen for patients with CP-B cirrhosis, he started by saying.
In this open-label study, 30 patients
with HCV GT 1 infection and CP-B cirrhosis were given all oral 50 mg grazoprevir and 50 mg elbasvir. 10 non-cirrhotic
patients with HCV GT 1 infection were
enrolled for pharmacokinetic analysis.
They received 100 mg grazoprevir and
elbasvir. The drugs were administered as
separate entities.
– High rates of virologic response were
observed in CP-B patients. The regimen
was well tolerated with no evidence of hepatotoxicity, Prof Jacobsen reported.
Plasma grazoprevir exposure was
slightly higher in CP-B patients receiving
50 mg, compared to non-cirrhotic pa-
HIV & VIROLOGY NEWS 2 · 2015
tients receiving 100 mg. Elbasvir exposure
was similar in both groups.
– This regimen was highly effective
and well tolerated in a traditionally hardto-treat patient group with no currently
approved treatment options, was his conclusion.
DCV + SOF work across concomitant
cART regimens
HCV with HIV co-infection more than
triples the risk of HCV-related liver disease, liver failure and liver-related death.
Co-infection can also complicate the management of HIV infection.
In Vienna, Phase III results of the
ALLY-2 study were presented. It is a randomised, open-label study on once-daily
treatment with daclatasvir + sofosbuvir, and the data showed an overall 97 %
SVR12 post-treatment in patients with
HCV and HIV co-infection.
Importantly, due to their limited pharmacokinetic interactions with other
agents, daclatasvir + sofosbuvir are able
to work effectively across a broad range
Fred Poordad
Rajender Reddy
of concomitant cART regimens without
compromising HIV virologic control (98
% of patients were on cART).
A total of 98 % of patients completed
the study treatment. In GT 1 patients, SVR
was achieved by 96 % of treatment-naive
patients and 98 % of treatment-experienced patients after 12 weeks. These positive
results were also seen in GT 2, 3 and 4 patients, with SVR at post-treatment week
12 reaching 100 % for all these genotypes.
There were no treatment-related serious adverse events, and none of the pa-
5
ILC in Vienna
tients stopped treatments due to adverse
events. The results show that 12 weeks of
daclatasvir/sofosbuvir is a highly effective
and well-tolerated treatment regimen for
HCV in HIV co-infected patients, including cirrhotic patients.
“A ground breaking study”
The BOSON study demonstrate that
HCV-infected GT 3 patients, with and
without cirrhosis, receiving 24 weeks of
sofosbuvir in combination with ribavirin
and peginterferon achieved the highest
sustained virological response observed
in a PHASE III study to date, underlined
Prof Graham Foster.
– Sofosbuvir in combination with ribavirin and with or without peginterferon
have never been directly compared before to determine SVR12 after treatment.
This study highlights that sofosbuvir with
ribavirin and peginterferon should be
considered for interferon-eligible GT 3
patients – particularly for those with cirrhosis and/or prior treatment failure, Prof
Foster continued.
The study also evaluated the safety and
efficacy of sofosbuvir + peginterferon/
ribavirin for 12 weeks versus sofosbuvir
+ ribavirin for 16 or 24 weeks in treatment-experienced GT 2 HCV-infected
patients with cirrhosis. These patients
had high SVR12 rates in all arms: 87 % of
those receiving sofosbuvir + ribavirin for
16 weeks, 100 % of those receiving sofosbuvir + ribavirin for 16 weeks and 94 % of
those receiving sofosbuvir + peginterferon/ribavirin for 12 weeks.
– BOSON is a ground-breaking new study that provides information about how
we can ensure the best outcomes for both
GT 2 and GT 3 infected HCV-infected
patients. It has confirmed that 24 weeks
is the optimal duration for a sofosbuvir
+ ribavirin combination in GT 3 patients,
whilst also finding that sofosbuvir + ribavirin/peginterferon for 12 weeks resulted
in the highest SVR12 rates observed to
date in a Phase III study, said Prof Tom
Hemming Carlsen, Scientific Committee
Member of EASL.
Indications for treatment
One of the highlights of the Meeting is the
Session in which EASL recommendations
on treatment of hepatitis C are presented
and discussed. It was Prof Jean-Michel
Pawlotsky who did this in Vienna, and he
started by defining the goals of therapy.
– The goal is to eradicate HIV infection
to prevent cirrhosis, decompensation of
cirrhosis, HCC and death, Prof Pawlotsky
established.
6
The endpoint of therapy is undetectable
HCV RNA in a sensitive assay – i.e. less
than 15 IU/mL – 12 weeks (SVR12) and 24
weeks (SVR24) after the end of treatment.
He also talked about the heterogeneity
of countries in Europe, and how EASL
have to be aware of the differences.
– EASL’s statement on treatment indication is: All treatment-naive and treatment-experienced patients with compensated or decompensated chronic liver disease related to HCV, who are willing to
be treated and who have no contraindications to treatment, should be considered
for therapy, Prof Pawlotsky continued.
For HIV co-infected patients, indications for treatment are identical to those in patients with HCV monoinfection.
However, potential drug-drug interactions with antiretroviral drugs should be
taken into account.
– The drug interactions charts from the
University of Liverpool, which easily can
be accessed online at www.hep-druginteractions.org, is the tool that EASL recommends for this purpose.
Recommendation principles
Three direct acting antivirals (DAAs) was
approved in 2014: Sofosbuvir, a nucleotide,
all genotypes, simeprevir, a NS3/4A protease inhibitor GT 1 and 4 and daclatasvir, a NS5A-inhibitor, all genotypes.
– DAAs approved in 2015 are sofosbuvir/ledipasvir, for GT 1, 4, 5, and 6, ombitasvir/paritaprevir/ritonavir, for GT 1 and
4 and dasabuvir for GT 1, Prof Pawlotsky
said.
EASL recommendations are based on
evidence from existing publications and
presentations or – when no evidence is available – the panel members’ experience
and opinion. For each group of patients,
options are provided: These options are
considered equally valuable and their numbering does not indicate any prioritization.
– When subgroup delineation was felt
difficult in clinical practice, the panel opted for the most efficacious treatment regimen – in order to offer patients the best
chance to achieve a cure, Prof Pawlotsky
pointed out.
He stated that notwithstanding the respective costs, IFN-free regimens are the
best options when available because of
their virological efficacy, ease of use and
tolerability.
– But all patients with compensated or
decompensated cirrhosis and patients in
the post-liver transplant setting with no
contra-indications to ribavirin should be
treated with ribavirin, regardless of the
HIV & VIROLOGY NEWS 2 · 2015
dolutegravir/abacavir/
lamivudine
innerstrength
The only once daily single-pill regimen
built with DOLUTEGRAVIR
Indication: Triumeq (dolutegravir/abacavir/lamivudine) is
indicated for the treatment of Human Immunodeficiency Virus
(HIV) infected adults and adolescents above 12 years of age
weighing at least 40 kg1.
Screening for HLA-B*5701 allele should be performed before
prescribing Triumeq. Triumeq should not be used in patients
known to carry the HLA-B*5701 allele1.
Triumeq® (dolutegravir/abacavir/lamivudin)
Indikation(er): Triumeq er indiceret til behandling af humant immundefektvirus (hiv)-inficerede voksne og unge
over 12 år, som vejer mindst 40 kg. Før initiering af behandling med produkter, der indeholder abacavir, skal alle hivinficerede patienter, uanset raceoprindelse, screenes for om de skulle være bærer af HLA-B*5701-allelen.Abacavir bør
ikke anvendes til patienter, der er bærere af HLA-B*5701-allelen. Dosering*: Voksne og unge: Den anbefalede dosis
af Triumeq til voksne og unge er 1 tablet én gang daglig.Triumeq bør ikke administreres til voksne eller unge, der vejer
under 40 kg, eller patienter der har brug for dosisjusteringer, da det er en fastdosis-tablet, der ikke kan dosisreduceres.
I tilfælde hvor ophør med eller dosisjustering af en af de aktive substanser er indiceret, er separate præparater med
dolutegravir, abacavir eller lamivudin tilgængelige. I disse tilfælde bør lægen henvise til produktinformationen for
de individuelle lægemidler. Kontraindikationer: Overfølsomhed over for dolutegravir, abacavir eller lamivudin eller
over for et eller flere af hjælpestofferne. Samtidig administration med dofetilid. Forsigtighedsregler*: Både abacavir
og dolutegravir er forbundet med en risiko for udvikling af overfølsomhedsreaktioner (feber, udslæt, konstitutionelle
fund og påvirkede organer, heriblandt alvorlige leverreaktioner). Risikoen for at udvikle en overfølsomhedsreaktion
over for abacavir er signifikant større for patienter, der er testet positive for HLA-B*5701-allelen. Triumeq skal
omgående seponeres, hvis der opstår tegn eller symptomer på overfølsomhedsreaktioner. Forsinket ophør af
behandling med Triumeq efter indtrædelse af en overfølsomhedsreaktion, kan resultere i en livstruende reaktion.Der
bør udvises forsigtighed ved administration af nukleosidanaloger til patienter (specielt overvægtige kvinder) med
hepatomegali, hepatitis eller andre kendte risikofaktorer for leversygdomme og fedtinfiltration på leveren (herunder
visse typer medicin og alkohol), da behandlingen med Triumeq kan være forbundet med udvikling af laktacidose.
Patienter co-inficeret med hepatitis C-virus, som er i behandling med interferon alfa og ribavirin, kan være særligt
udsatte. Antiretroviral kombinationsbehandling er forbundet med omfordeling af legemsfedt (lipodystrofi) hos
hiv-patienter. Sikkerheden og virkningen af Triumeq hos patienter med betydelige underliggende leversygdom
er ikke klarlagt. Triumeq anbefales ikke til patienter med moderat til svært nedsat leverfunktion. Patienter med
kronisk hepatitis B eller C, behandlet med antiretroviral kombinationsbehandling, har større risiko for alvorlige og
potentielt fatale leverbivirkninger. Hos hiv-inficerede patienter med alvorlig immundefekt kan der på tidspunktet for
påbegyndelse af antiretroviral kombinationsbehandling (CART) opstå en inflammatorisk reaktion på asymptomatiske
eller tilbageværende opportunistiske patogener, som kan forårsage alvorlige kliniske tilstande eller forværring af
symptomer. Observationsstudier har vist en forbindelse mellem myokardieinfarkt og brugen af abacavir. I disse
studier omfattede patientgruppen primært patienter, der tidligere havde fået antiretroviral behandling. Patienter i
behandling med Triumeq kan stadig udvikle opportunistiske infektioner og andre komplikationer fra hiv-infektion.
Triumeq anbefales ikke til patienter der er i samtidig behandling med lægemidler indeholdende efavirenz, nevirapin,
rifampicin, tipranavir/ritonavir og emtricitabin eller andre lægemidler indeholdende dolutegravir, abacavir eller
lamivudin. Samtidig administration af Triumeq og etravirin (ETR) anbefales ikke, medmindre patienten også
samtidigt behandles med atazanavir + ritonavir (ATV + RTV), lopinavir + ritonavir (LPV + RTV) eller darunavir +
ritonavir (DRV + RTV).Triumeq bør administreres 2 timer før eller 6 timer efter indtagelse af calcium- eller jerntilskud
og bør ikke administreres med antacida. Interaktioner*: Samtidig administration af Triumeq og andre lægemidler,
der hæmmer UGT1A1, UGT1A3, UGT1A9, CYP3A4 og/eller Pgp, kan øge plasmakoncentrationen af dolutegravir.
Lægemidler, der inducerer disse enzymer eller transportere, kan reducere plasmakoncentrationen af dolutegravir og
reducere den terapeutiske effekt af dolutegravir. Absorptionen af dolutegravir reduceres af visse syreneutraliserende
lægemidler. Samtidig administration af UGT-enzym-induktorer eller -hæmmere eller af forbindelser, der elimineres
via alkoholdehydrogenase, kan ændre eksponeringen for abacavir. Samtidig administration af lamivudin og OCT2-
HIV & VIROLOGY NEWS 1 · 2014
og MATE-hæmmere kan muligvis øge eksponeringen for lamivudin. Graviditet og amning*: Der er ingen data
fra anvendelse af Triumeq til gravide kvinder. Det er påvist in vitro og in vivo, at nukleosid- og nukleotidanaloger
i forskellig udstrækning forårsager mitokondrieskader. Der foreligger rapporter om mitokondriel dysfunktion
hos hiv-negative spædbørn, som in utero og/eller efter fødslen har været eksponeret for nukleosidanaloger.
Lamivudin udskilles i human mælk og på basis af data fra dyr forventes det, at dolutegravir og abacavir også
udskilles i human mælk, selvom dette ikke er blevet bekræftet hos mennesker. Det anbefales, at hiv-inficerede
kvinder under ingen omstændigheder ammer deres spædbørn, så overførsel af hiv undgås. Bivirkninger*: Meget
almindelig: insomni, hovedpine, kvalme, diarré, træthed. Almindelig: overfølsomhed, anoreksi, abnormale drømme,
depression, mareridt, søvnforstyrrelser, svimmelhed, somnolens, svær udmatning, hoste, symptomer fra næse,
opkastning, flatulens, abdominalsmerter, smerter i den øvre del af abdomen, udspiling af abdomen, abdominalt
ubehag, gastroøsofageal refluxsygdom, dyspepsi, udslæt, kløe, hårtab, atralgi, muskelforstyrrelser, asteni, feber,
utilpashed, forhøjet niveau af CPK, forhøjet niveau af ALAT/ASAT. Ikke almindelig: neutropeni, anæmi, trombocytopeni,
immunrekonstitutionssyndrom, hypertriglyceridæmi, hyperglykæmi, hepatitis. Sjælden: pancreatitis, rabdomyolyse,
forhøjet niveau af amylase. Meget sjælden: ren erytrocytaplasi, perifer neuropati, paræstesi, erythema multiforme,
Stevens-Johnsons syndrom, toksist epidermal nekrolyse. Overdosering*: Der ikke identificeret nogen specifikke
symptomer eller tegn efter akut overdosering med dolutegravir, abacavir eller lamivudin.
Udlevering: B. Ikke tilskud.
De med * mærkede afsnit er omskrevet og/eller forkortet i forhold til det af EMA godkendte produktresumé.
Fuldt produktresumé kan vederlagsfrit rekvireres hos den danske repræsentant for ViiV, GlaxoSmithKline
Pharma A/S, Nykær 68, 2605 Brøndby.
Bivirkninger, både kendte og nyopdagede, bedes indberettet hurtigst muligt til Sundhedsstyrelsen
(www.meldenbivirkning.dk) eller GlaxoSmithKline ([email protected]).
Dagsaktuelle priser findes på www.medicinpriser.dk
Reference: 1. TRIUMEQ Summary of Product Characteristics September 2014.
DK/TRIM/0004/15 februar 2015
Nykær 68
DK-2605 Brøndby
T +45 36 35 91 00
F +45 36 35 91 01
www.glaxosmithkline.dk
9
Nucleoside
ILC
in Vienna
Free Zones
PRODUKTINFORMATION RETTET TIL
for nedsat nyrefunktion, er hyppigere monito- P gp, BCRP, OATP1B1 eller OATP1B3, kan føre malaci (manifesterer sig som knoglesmerter og
SUNDHEDSPERSONER
rering af nyrefunktionen nødvendig. Cobicistat til øgede plasmakoncentrationer af disse præ- i sjældne tilfælde medvirkende årsag til fraktuForkortet produktresumé for STRIBILD®
hæmmer den tubulære sekretion af kreatinin og parater, hvilket kunne øge eller forlænge deres rer), myopati*, nyresvigt (akut og kronisk), akut
filmovertrukne tabletter
kan forårsage moderat øgning af serumkreatinin terapeutiske virkning og bivirkninger. Samtidig tubulær nekrose, proksimal renal tubulopati, herElvitegravir, cobicistat, emcitrabin, tenofovir- og moderat nedsættelse af kreatininclerance administration af Stribild og lægemidler, der under Fanconis syndrom, nefritis (herunder akut
interferon-free regimen used. Inuden
patients
disoproxil
at påvirke nyrernes glomerulære funktion. hæmmer CYP3A, kan reducere clearance af interstitiel nefritis), nefrogen diabetes insipidus.
with ribavirin
contra-indications
– or who
Præsentation:
Hver filmovertrukket
tablet inde- Patienter
som oplever en bekræftet øgning i cobicistat og føre til øgede plasmakoncentrati- Bivirkninger markeret med* kan forekomme som
do 150
notmgtolerate
well
– treatment
dura- på over 26,5 µmol/l (0,3 mg/dl) oner af cobicistat. Stribild må ikke administreres resultat af proksimal renal tubulopati. Tilfælde af
holder
elvitegravir,it150
mg cobicistat,
serumkreatinin,
200tion
mg emtricitabin
og 245
mg tenofovirdisoshould be
doubled,
without ribavirin.
fra baseline, bør overvåges tæt for renale bivirk- samtidig med adefovirdipivoxil, lamivudin eller osteonekrose er rapporteret, specielt hos paproxil (svarende til 300 mg tenofovirdisoproxil- ninger. Hvis kreatininclearance på < 50 ml/min didanosin og lægemidler der indeholder teno- tienter med generelt anerkendte risikofaktorer,
fumarat
ellercontinued
136 mg tenofovir)
To be
kan bekræftes eller serumphophfat falder til < fovirdisoproxil (som fumarat). Elvitegravir er en fremskreden hiv sygdom eller langvarig CART.
Indikationer:
Behandling afproceeded
infektion med huProf Pawlotsky
with0,32
presenmmol/l (1,0 mg/dl) bør Stribild seponeres. moderat inducer af CYP2C9 og kan reducere Hyppigheden er ukendt.
mant
immundefekt
virus 1 (hivtreatment
1) hos voksne options
Det bør også
ting
the different
forovervejes at afbryde behandlingen plasmakoncentrationen af CYP2C9 substrater. Overdosering*: Såfremt der forekommer overi alderen
år og derover,
som accessed
er antiretrovi- from
med Stribild
can be
EASLi tilfælde af progressiv forværring af Lægemidler, der inducerer CYP3A-aktivitet, dosering, monitoreres for tegn på toksicitet. Der
2015.18They
ral-behandlingsnaive
inficerede med hivClick
nyrefunktionen,
homepage onellerwww.easl.eu.
on Re- når der ikke er identificeret an- forventes at øge clearance af elvitegravir, hvil- skal gives støttende standardbehandling efter
1 uden
kendte
mutationer
forbundet
med
redre
search in the top menu, then Clinicalårsager.
Prac-Stribild bør undgås ved samtidig an- ket fører til reducerede plasmakoncentrationer behov. Da elvitegravir og cobicistat i høj grad er
sistens over for nogle af de tre antiretrovirale vendelse med eller nylig brug af et nefrotoksisk af elvitegravir, hvilket kan forårsage svigtende bundet til plasmaproteiner, er det usandsynligt,
tice Guidelines and finally Recommendastoffer i Stribild.
lægemiddel
tions on treatment of Hepatitis C.
Directpå grund af øget risiko for renale terapeutisk virkning og udvikling af resistens. at elvitegravir og cobicistat i signifikant grad vil
Dosering og indgivelsesmåde*: Voksne: Én bivirkninger (med TDF-komponenten i Stribild). Samtidig administration af Stribild og nogle læ- fjernes ved hæmodialyse eller peritonealdialyse.
link is www.easl.eu/medias/cpg/HEPCtablet én gang dagligt, tages hel, oralt, med mad. Se produktresuméet for yderligere anbefalinger gemidler, der primært metaboliseres af CYP3A, Op til 30 % af emtricitabindosen og cirka 10 %
2015/Summary.pdf.
Børn: Sikkerhed og virkninger er ikke klarlagt mht. monitorering og seponering af behandling. kan føre til øgede plasmakoncentrationer af af tenofovirdosis kan fjernes ved hæmodialyse.
The
recommendations
are presented
hos børn
og unge
<18 år. Nedsat nyrefunktion:
Nyresvigt, nedsat nyrefunktion, forhøjet kreati- disse præparater, hvilket er forbundet med mu- Det vides ikke, om emtricitabin eller tenofovir
according to genotype,
and
Se systematically
afsnit ”Særlige advarsler”.
nin, hypophosphatæmi
og proksimal tubulopati ligheden for alvorlige og/eller livstruende reak- kan fjernes ved peritonealdialyse.
are
sorted
in
both
IFN-free
and
IFN-conKontraindikationer: Overfølsomhed over for (herunder Fanconis syndrom) er rapporteret ved tioner, såsom perifer vasospasme eller iskæmi. Farmaceutiske forholdsregler*: Opbevares
regimens.
de taining
aktive stoffer
eller over for et eller flere af brug af tenofovirdisoproxilfumarat i klinisk prak- Samtidig administration af Stribild og andre læ- i den originale emballage for at beskytte mod
He alsoSamtidig
discussed
challenging
hjælpestofferne.
administration
med sis.patient
Samtidig infektion: Hiv inficerede patienter, gemidler, der primært metaboliseres af CYP3A fugt. Hold beholderen tæt lukket.
such på
asgrund
patients
with advanced
de groups,
følgende lægemidler
af muligheden
der samtidig er inficeret med HBV eller HCV i er kontraindiceret. Samtidig administration af Pakninger och pris: Beholdere med 30
for liver
alvorligedisease,
og/eller livstruende
hændelser
eller antiretroviral
with renal
insufficiency
andbehandling har øget risiko for al- Stribild og nogle lægemidler, som inducerer CY- filmovertrukne tabletter. Vnr: 168038. For dagsReview
thataktuelle
documents
lack
of informasvigtende
virologisk
respons
og mulig
resistens vorlige
ting
viral hepatitis
disease
sur-reducerede
medicinpriser
se: www.medicinpriser.dk
P3A kan føre
til signifikant
plasmapotentielt
letalechronic
hepatiske bivirkninpatients
that
need
re-treatment.
Forogthe
overlatter
for Stribild:
Alfa 1 adrenoreceptorantagotion hvil- Tilskudsstatus: Ikke tilskudsberettiget.
cobicistat og elvitegravir,
assessing
burden ofaf disease
Seponering
behandling kan
associeres thekoncentrationer
group,
recommendationsger.are
ba- afveillance,
nister:
Antiarytmika:evidence
Amiodaron, quiniBEGR
(kun udlevering
ket kan forårsage
svigtende terapeutisk
virkning Udlevering:
med alvorlig,
eksacerbation
af hepatitis.
A systematic
review,
presented
bytil sygehuse)
Prof
measuring
the impact
of intervensedAlfuzosin.
on indirect
and subject
to akutand
din.change
Antikonvulsiva:
Carbamazepin,
phenobarbiMarkedsføringstilladelsesnummer:
og
udvikling
af
resistens.
Se
produktresuméet
Patienter
med
samtidig
infektioner
af
hiv/HBV
Jeffrey
Lazarus,
concluded
that
the
curtions,
according
to
a
study
presented
at
when more data become available.
tal, phenytoin.
Antimykobakterielle
EU/1/13/830/001
bør testing
monitoreres tætthe
i mindst
flere måneder efter for detaljer vedrørende lægemiddelinteraktioner
rent evidence
base on HBV and HCV tesILC.
The utility
of HCVlægemidler:
resistance
Rifampicin. Ergot-derivater: Dihydroergotamin, behandlingen med Stribild
af markedsføringstilladelsen:
antiinfektiva
og antimykotika,
HCV proteasympto- forthat
appearsIndehaver
to be lacking
in many EuroTheophører
studyforhighlights
less than
one ting
prior to treatment is unknown.
ergometrin, ergotamin. Stoffer, der fremmer ma- mer på alvorlig, akut eksacerbation af hepatitis. sehæmmere, makrolidantibiotika,pean
Gilead
Sciences
International Ltd, Granta Park,
inhalerede/
countries.
– Antiviral therapy is indicated in pa- third (27 %) of WHO European member
ve-tarm-motiliteten: Cisaprid. Naturlægemiddel: Behandlingen bør ikke seponeres hos patienter nasale kortikosteroider, antacida, kosttilskud, Abington, Cambridge, CB21 6GT, Storbritannien.
The results indicate that some hightients awaiting liver transplantation, states have national strategies in place
Prikbladet perikum (Hypericum perforatum). med fremskreden leversygdom. Leversygdom: orale antidiabetika, narkotiske analgetika, orale Produktinformationen er forkortet. Et fuldthat contain a surveillance component. risk populations have been studied much
because
it
prevents
graft
infection.
TreHMG Co A-reduktasehæmmere: Lovasta- Patienter med eksisterende nedsat leverfunkti- antikonceptiva, antiarytmika, antihypertensiva, stændigt produktresumé kan rekvireres hos
should
be initiated
as soon
as pos- Furthermore, only 64 % have a national more than others, but mostly in a small
tin,atment
simvastatin.
Neuroleptika:
Pimozid. PDE
on skal monitoreres. Afbrydelse eller seponering endothelin receptorantagonister, antikoagulan- indehaveren af markedsføringstilladelsen
for chronic hepatitis B (HBV) and number of countries. The results also apsible
in
order
to
complete
a
full
treatment
5-hæmmere: Sildenafil til behandling af pulmo- af behandling skal system
overvejes, hvis der er tegn på tia, inhaleret beta-agonist, HMG Co A-redukta- og yderligere information kan rekvireres hos
pear to show
median
testing
uptake
61 % for
chronic
C. PDE- 5-hæmmere, antidepressiva,
before transplantation.
nalcourse
arteriel hypertension.
Sedativa/hypnotika: forværring af leversygdom.
denhigh
danske
repræsentant:
Gilead
Sciences
Lipodystrofi
og hepatitis
me- sehæmmere,
levelsmidler
in Europe.
Main
areasbehandin which
governments
The nextmidazolam,
available
HCV therapies
will
Oralt administreret
triazolam.
Denmark ApS, Korskildelund 6, 2670 Greve,
immunosuppressiva,
sedativa/hypnotika,
tabolisme:
Kombination
af antiretroviral
However, Danmark
since almost
all36of91the
studies
would
like WHO’s
according to
be grazoprevir-elbasvir
combination,
asu-forbundet
Særlige
advarsler*: Stribild må ikke
admi- ling er blevet
Telefon: +45
50 50
mod podagra.
med lipodystrofi
hos hiv support,
show
methodologies
that
required
or enthe
study,
are
development
of
national
naprevir-daclatasvir-beclabuvir
nistreres
sammen med andre antiretrovirale combinaAfsnit
markeret
med
*
er
forkortet
i
forhold
til det
Fertilitet,
graviditet
og
amning*:
Anvendelsen
patienter. Måling af fastende serumlipider og
couraged
to undergo
viral hepatitis
prevention
præparater.
Det sofosbuvir-GS5816
bør ikke indgives samtidig med
tion and
combination.
af EMAparticipants
godkendte produktresumé.
af Stribild
skal ledsagesand
af anvendelse
af effek- study
blodglucose bør plans
overvejes for
og lipidændringer
andre –
lægemidler,
indeholder tenofovirdiso-arebør
testing,
highLÆS
median
testing uptake
(39 Andre:
%), estimation
of the national
PRODUKTRESUMÉET
FØRlevels
ORDINAhos kvindelige patienter
i den
behandles
relevant måde.
Lak- tiv kontraception
So thesom
recommendations
going
to på control
proxil
fumarat), lamivudin
eller adefovirdi-finished
are not
likely
toISÆR
be representative
of the
TION
MED HENSYN TIL BIVIRKNINhos mænd og kvinder.
Stribild
tatacidose,his
mitokondriel
dysfunktion,
immunre- (34fertile
burden
of hepatitis
%) alder
andsamt
surveillanbe(som
updated,
Prof Pawlotsky
pivoxil
(anvendes til behandling af virusinfektion aktiveringssyndrom,ceosteonekrose,
hvis den
GER,
ADVARSLER
OG KONTRAINDIKATIOoverall
testing
uptake
in most
populations.
(23 %). reduktion i bør kun anvendes under graviditeten,
presentation.
med hepatitis
B). discussion
Samtidig administration
af knoglemineraltæthed
potentielle fordel berettiger
risi-clear
og knogleanomalier
– se demonstrates
NER.
– It is
from our review that there
In
all, the study
a clearden potentielle
A panel
then ended
the SesStribild
og didanosin frarådes, da eksponering produktresuméet need
må ikke anvendes
under amning.
for anbefalinger
mht. disease
mo- ko. Det
Et fuldstændigt
produktresumé
findes
are crucial gaps
in our knowledge
onkan
HBV
for better
surveillance
and
sion.
for didanosin stiger betydeligt efter samtidig ad- nitorering og behandling.
Bivirkninger:
Meget
almindelige
(≥1/10):
HySjældne
tilfælde
af
på
EMAs
hjemmeside
improvements in the development of na- and HCV testing – we do not yet have
ministration af tenofovirdisoproxilfumarat, hvilket pankreatitis og laktatacidose, undertiden fatal, pophosphatæmi*, svimmelhed, hovedpine,
diarré,information
Dato for oprettelse
af produktinformation:
to effective
public
tional strategies to help prevent and con- enough
European countries are ill prepared
kan øge risikoen for didanosinrelaterede bivirk- er rapporteret Bør ikke anvendes til patienter kvalme, opkastning, udslæt, forhøjet kreatinki- Juli 2014
Many countries in the WHO European trol the spread of viral hepatitis in the health responses in Europe, Prof Lazarus
ninger. Selvom effektiv viral suppression med med arvelig galactoseintolerans, en særlig form nase og asteni. Almindelige (≥1/100, <1/10): Job Bag No: HIV/DK/13-07/PM/1794
commented.
Region are facing limitations in conduc- WHO European region.
antiretroviral behandling har vist sig at nedsætte af hereditær lactasemangel (Lapp Lactase De- Neutropeni, allergiske reaktioner, nedsat appe– Our research team is particularly conrisikoen væsentligt for seksuel overførsel, kan ficiency) eller glucose/galactosemalabsorption. tit, hyperglykæmi, hypertriglyceridæmi, insomni,
cernedopabout the low
numbersafofmarkedspublisVed godkendelse
residual risiko ikke udelukkes. Der skal derfor Kvinder i den fertile alder skal enten anven- unormale drømme, hovedpine, svimmelhed,
hed
studies
looking
at
migrants,
prison
føringstilladelsen,
er
dette
lægemiddel
træffes passende forholdsregler for at forebyg- de hormonelle antikonceptiva, der indeholder kastning, abdominalsmerter, abdominal distenløbende
underlagt
supplerende
oversex
with
men
inmates
and
men
who
have
ge risikoen for at overføre hiv til andre via seksu- mindst 30 µg ethinylestradiol og norgestimat sion, dyspepsi, forstoppelse, flatulens, forhøjet
vågning, som vist med den omvendte
– all populations
that
might
benefit
greatel kontakt eller kontaminering med blod. Ældre: som progestagenet eller de skal anvende en amylase herunder forhøjet pancreasamylase,
sorte trekant. Alle mistænkte bivirkninger
ly from
hepatitis
testing
interved brug
af Stribild skal
rapporteres
til
Stribild har begrænsede data hos patienter over anden sikker kontraceptionsmetode. Samtidig forhøjet serum lipase, forhøjet ASAT
og ALAT,targeted
Gilead via e-mail til: Nordics.SafetyMailventions,
65 år. Det er mere sandsynligt, at ældre patien- administration af Stribild og orale antikonceptiva, hyperbilirubinæmi, forhøjede transaminaser,
ud- he continued.
[email protected] eller på telefon
ter har nedsat nyrefunktion. Derfor skal der ud- der indeholder andre progestagener end norge- slæt, vesikulobulløst udslæt, pustuløst
Prof
Tom Hemming
udslæt,
+46 (8) 505Carlsen
718 00 ogadded:
/eller til Sundvises forsigtighed ved behandling af ældre pa- stimat er ikke undersøgt og bør derfor undgås. makulopapuløst udslæt, pruritus, urticaria,
mis– Viruses
that
affect the
liver – suchmed
as
hedsstyrelsen
i overensstemmelse
spontane
tienter med Stribild. Nyrefunktion: Patienter som Når patienter, som er dårlige til at metabolisere farvning af huden (øget pigmentering),
HBVforhøjet
and HCVdet
– nationale
can cause
realrapporteringssysproblems
tem. www.meldenbivirkning.dk
tidligere har stoppet behandling med TDF på CYP2B6, skiftes fra et behandlingsprogram, der kreatinin i blodet, smerter, asteniifognot
træthed.
identified
and treated early. We
grund af nyretoksicitet bør ikke behandles med indeholder efavirenz, til Stribild, er der mulighed Ikke almindelige (≥1/1,000, <1/100):
need Anæto raise awareness of the threat they
Stribild. Patienter bør have beregnet kreatinin- for en lavere eksponering over for elvitegravir mi, hypokaliæmi*, depression, selvmordstanker
pose and actively encourage testing across
clearance og målt glukose og protein i urinen før på grund af en langvarig CYP3A-induktion af og selvmordsforsøg (hos patienter med en
Europe. This is not only vital to diagnosis
start af behandling med Stribild. Stribild behand- efavirenz. Det anbefales at overvåge den virale eksisterende anamnese med depression eller
and treatment, but also to prevention – for
ling bør ikke startes hos patienter med kreatinin- belastning i løbet af den første måned efter be- en psykisk sygdom), pancreatitis, angioødem,
stopping the viruses spreading through
clearance under 70 ml/min. Kreatininclearance, handlingen skiftes.
rabdomyolyse*, muskelsvækkelse*, nyresvigt,
Panel discussion in the Session on EASL’s recommendations.
populations and generations to come!
serumphosphat, glukose og protein i urinen bør Interaktioner*: Samtidig administration af Stri- erhvervet Fanconis syndrom, og proteinuri.
monitoreres hver 4. uge i løbet af det første år og bild og lægemidler, som primært metaboliseres Sjældne (≥1/10,000, <1/1000): Lactatacidose,
derefter hver 3. måned. Hos patienter med risiko af CYP3A eller CYP2D6, eller er substrater for steatosis hepatis, hepatitis, angioødem, osteo- HIV/DK/15-02/PM/1120
8
HIV & VIROLOGY NEWS 2 · 2015
Powerful performance in HIV1–7
78-80% achieved virologic success
with STRIBILD® (E/C/F/TDF) through
144 weeks in naïve patients6,7
STRIBILD (E/C/F/TDF) is powered with
Truvada – because backbone matters8-10
References: 1. SmPC Stribild. 07/2014. Available at www.ema.europa.eu. 2. DeJesus E, et al. Lancet 2012; 379:2429–2438. 3. Sax
P, et al. Lancet 2012; 379:2439–2448. 4. Rockstroh J, et al. J Acquir Immune Defic Syndr 2013; 62:483-486. 5. Zolopa A, et al. J
Acquir Immune Defic Syndr 2013; 63:96-100. 6. Clumeck N, et al. J Acquir Immune Defic Syndr 2014; 65(3):e121-124. 7. Wohl D A,
et al. J Acquir Immune Defic Syndr 2014; 65(3):e118-120. 8. United States Department of Health & Human Services (DHHS).
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. November 2014. Available at www.aidsinfo.
nih.gov/guidelines. 9. Günthard HF, et al. JAMA 2014;312(4):410-425. 10. European AIDS Clinical Society (EACS) Treatment
Guidelines. November 2014 (Version 7.1). Available at www.eacsociety.org/Guidelines.
elvitegravir 150 mg/cobistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil 245 mg = (E/C/F/TDF)
Rethink Performance
Gilead Sciences Nordic Office | Hemvärnsgatan 9, SE-171 54 Solna, Sweden | Phone: + 46 (0)8 505 71 800 | Fax: + 46 (0)8 505 71 801
HIV & VIROLOGY NEWS 1 · 2015
9
PRODUKTINFORMATION RETTET TIL
SUNDHEDSPERSONER
Forkortet produktresumé for STRIBILD®
filmovertrukne tabletter
Elvitegravir, cobicistat, emcitrabin, tenofovirdisoproxil
Præsentation: Hver filmovertrukket tablet indeholder 150 mg elvitegravir, 150 mg cobicistat,
200 mg emtricitabin og 245 mg tenofovirdisoproxil (svarende til 300 mg tenofovirdisoproxilfumarat eller 136 mg tenofovir)
Indikationer: Behandling af infektion med humant immundefekt virus 1 (hiv 1) hos voksne
i alderen 18 år og derover, som er antiretroviral-behandlingsnaive eller inficerede med hiv
1 uden kendte mutationer forbundet med resistens over for nogle af de tre antiretrovirale
stoffer i Stribild.
Dosering og indgivelsesmåde*: Voksne: Én
tablet én gang dagligt, tages hel, oralt, med mad.
Børn: Sikkerhed og virkninger er ikke klarlagt
hos børn og unge <18 år. Nedsat nyrefunktion:
Se afsnit ”Særlige advarsler”.
Kontraindikationer: Overfølsomhed over for
de aktive stoffer eller over for et eller flere af
hjælpestofferne. Samtidig administration med
de følgende lægemidler på grund af muligheden
for alvorlige og/eller livstruende hændelser eller
svigtende virologisk respons og mulig resistens
over for Stribild: Alfa 1 adrenoreceptorantagonister: Alfuzosin. Antiarytmika: Amiodaron, quinidin. Antikonvulsiva: Carbamazepin, phenobarbital, phenytoin. Antimykobakterielle lægemidler:
Rifampicin. Ergot-derivater: Dihydroergotamin,
ergometrin, ergotamin. Stoffer, der fremmer mave-tarm-motiliteten: Cisaprid. Naturlægemiddel:
Prikbladet perikum (Hypericum perforatum).
HMG Co A-reduktasehæmmere: Lovastatin, simvastatin. Neuroleptika: Pimozid. PDE
5-hæmmere: Sildenafil til behandling af pulmonal arteriel hypertension. Sedativa/hypnotika:
Oralt administreret midazolam, triazolam.
Særlige advarsler*: Stribild må ikke administreres sammen med andre antiretrovirale
præparater. Det bør ikke indgives samtidig med
andre lægemidler, som indeholder tenofovirdisoproxil (som fumarat), lamivudin eller adefovirdipivoxil (anvendes til behandling af virusinfektion
med hepatitis B). Samtidig administration af
Stribild og didanosin frarådes, da eksponering
for didanosin stiger betydeligt efter samtidig administration af tenofovirdisoproxilfumarat, hvilket
kan øge risikoen for didanosinrelaterede bivirkninger. Selvom effektiv viral suppression med
antiretroviral behandling har vist sig at nedsætte
risikoen væsentligt for seksuel overførsel, kan
residual risiko ikke udelukkes. Der skal derfor
træffes passende forholdsregler for at forebygge risikoen for at overføre hiv til andre via seksuel kontakt eller kontaminering med blod. Ældre:
Stribild har begrænsede data hos patienter over
65 år. Det er mere sandsynligt, at ældre patienter har nedsat nyrefunktion. Derfor skal der udvises forsigtighed ved behandling af ældre patienter med Stribild. Nyrefunktion: Patienter som
tidligere har stoppet behandling med TDF på
grund af nyretoksicitet bør ikke behandles med
Stribild. Patienter bør have beregnet kreatininclearance og målt glukose og protein i urinen før
start af behandling med Stribild. Stribild behandling bør ikke startes hos patienter med kreatininclearance under 70 ml/min. Kreatininclearance,
serumphosphat, glukose og protein i urinen bør
monitoreres hver 4. uge i løbet af det første år og
derefter hver 3. måned. Hos patienter med risiko
10
for nedsat nyrefunktion, er hyppigere monitorering af nyrefunktionen nødvendig. Cobicistat
hæmmer den tubulære sekretion af kreatinin og
kan forårsage moderat øgning af serumkreatinin
og moderat nedsættelse af kreatininclerance
uden at påvirke nyrernes glomerulære funktion.
Patienter som oplever en bekræftet øgning i
serumkreatinin, på over 26,5 µmol/l (0,3 mg/dl)
fra baseline, bør overvåges tæt for renale bivirkninger. Hvis kreatininclearance på < 50 ml/min
kan bekræftes eller serumphophfat falder til <
0,32 mmol/l (1,0 mg/dl) bør Stribild seponeres.
Det bør også overvejes at afbryde behandlingen
med Stribild i tilfælde af progressiv forværring af
nyrefunktionen, når der ikke er identificeret andre årsager. Stribild bør undgås ved samtidig anvendelse med eller nylig brug af et nefrotoksisk
lægemiddel på grund af øget risiko for renale
bivirkninger (med TDF-komponenten i Stribild).
Se produktresuméet for yderligere anbefalinger
mht. monitorering og seponering af behandling.
Nyresvigt, nedsat nyrefunktion, forhøjet kreatinin, hypophosphatæmi og proksimal tubulopati
(herunder Fanconis syndrom) er rapporteret ved
brug af tenofovirdisoproxilfumarat i klinisk praksis. Samtidig infektion: Hiv inficerede patienter,
der samtidig er inficeret med HBV eller HCV i
antiretroviral behandling har øget risiko for alvorlige og potentielt letale hepatiske bivirkninger. Seponering af behandling kan associeres
med alvorlig, akut eksacerbation af hepatitis.
Patienter med samtidig infektioner af hiv/HBV
bør monitoreres tæt i mindst flere måneder efter
behandlingen med Stribild ophører for symptomer på alvorlig, akut eksacerbation af hepatitis.
Behandlingen bør ikke seponeres hos patienter
med fremskreden leversygdom. Leversygdom:
Patienter med eksisterende nedsat leverfunktion skal monitoreres. Afbrydelse eller seponering
af behandling skal overvejes, hvis der er tegn på
forværring af leversygdom. Lipodystrofi og metabolisme: Kombination af antiretroviral behandling er blevet forbundet med lipodystrofi hos hiv
patienter. Måling af fastende serumlipider og
blodglucose bør overvejes og lipidændringer
bør behandles på relevant måde. Andre: Laktatacidose, mitokondriel dysfunktion, immunreaktiveringssyndrom, osteonekrose, reduktion i
knoglemineraltæthed og knogleanomalier – se
produktresuméet for anbefalinger mht. monitorering og behandling. Sjældne tilfælde af
pankreatitis og laktatacidose, undertiden fatal,
er rapporteret Bør ikke anvendes til patienter
med arvelig galactoseintolerans, en særlig form
af hereditær lactasemangel (Lapp Lactase Deficiency) eller glucose/galactosemalabsorption.
Kvinder i den fertile alder skal enten anvende hormonelle antikonceptiva, der indeholder
mindst 30 µg ethinylestradiol og norgestimat
som progestagenet eller de skal anvende en
anden sikker kontraceptionsmetode. Samtidig
administration af Stribild og orale antikonceptiva,
der indeholder andre progestagener end norgestimat er ikke undersøgt og bør derfor undgås.
Når patienter, som er dårlige til at metabolisere
CYP2B6, skiftes fra et behandlingsprogram, der
indeholder efavirenz, til Stribild, er der mulighed
for en lavere eksponering over for elvitegravir
på grund af en langvarig CYP3A-induktion af
efavirenz. Det anbefales at overvåge den virale
belastning i løbet af den første måned efter behandlingen skiftes.
Interaktioner*: Samtidig administration af Stribild og lægemidler, som primært metaboliseres
af CYP3A eller CYP2D6, eller er substrater for
P gp, BCRP, OATP1B1 eller OATP1B3, kan føre
til øgede plasmakoncentrationer af disse præparater, hvilket kunne øge eller forlænge deres
terapeutiske virkning og bivirkninger. Samtidig
administration af Stribild og lægemidler, der
hæmmer CYP3A, kan reducere clearance af
cobicistat og føre til øgede plasmakoncentrationer af cobicistat. Stribild må ikke administreres
samtidig med adefovirdipivoxil, lamivudin eller
didanosin og lægemidler der indeholder tenofovirdisoproxil (som fumarat). Elvitegravir er en
moderat inducer af CYP2C9 og kan reducere
plasmakoncentrationen af CYP2C9 substrater.
Lægemidler, der inducerer CYP3A-aktivitet,
forventes at øge clearance af elvitegravir, hvilket fører til reducerede plasmakoncentrationer
af elvitegravir, hvilket kan forårsage svigtende
terapeutisk virkning og udvikling af resistens.
Samtidig administration af Stribild og nogle lægemidler, der primært metaboliseres af CYP3A,
kan føre til øgede plasmakoncentrationer af
disse præparater, hvilket er forbundet med muligheden for alvorlige og/eller livstruende reaktioner, såsom perifer vasospasme eller iskæmi.
Samtidig administration af Stribild og andre lægemidler, der primært metaboliseres af CYP3A
er kontraindiceret. Samtidig administration af
Stribild og nogle lægemidler, som inducerer CYP3A kan føre til signifikant reducerede plasmakoncentrationer af cobicistat og elvitegravir, hvilket kan forårsage svigtende terapeutisk virkning
og udvikling af resistens. Se produktresuméet
for detaljer vedrørende lægemiddelinteraktioner
for antiinfektiva og antimykotika, HCV proteasehæmmere, makrolidantibiotika, inhalerede/
nasale kortikosteroider, antacida, kosttilskud,
orale antidiabetika, narkotiske analgetika, orale
antikonceptiva, antiarytmika, antihypertensiva,
endothelin receptorantagonister, antikoagulantia, inhaleret beta-agonist, HMG Co A-reduktasehæmmere, PDE- 5-hæmmere, antidepressiva,
immunosuppressiva, sedativa/hypnotika, midler
mod podagra.
Fertilitet, graviditet og amning*: Anvendelsen
af Stribild skal ledsages af anvendelse af effektiv kontraception hos kvindelige patienter i den
fertile alder samt hos mænd og kvinder. Stribild
bør kun anvendes under graviditeten, hvis den
potentielle fordel berettiger den potentielle risiko. Det må ikke anvendes under amning.
Bivirkninger: Meget almindelige (≥1/10): Hypophosphatæmi*, svimmelhed, hovedpine, diarré,
kvalme, opkastning, udslæt, forhøjet kreatinkinase og asteni. Almindelige (≥1/100, <1/10):
Neutropeni, allergiske reaktioner, nedsat appetit, hyperglykæmi, hypertriglyceridæmi, insomni,
unormale drømme, hovedpine, svimmelhed, opkastning, abdominalsmerter, abdominal distension, dyspepsi, forstoppelse, flatulens, forhøjet
amylase herunder forhøjet pancreasamylase,
forhøjet serum lipase, forhøjet ASAT og ALAT,
hyperbilirubinæmi, forhøjede transaminaser, udslæt, vesikulobulløst udslæt, pustuløst udslæt,
makulopapuløst udslæt, pruritus, urticaria, misfarvning af huden (øget pigmentering), forhøjet
kreatinin i blodet, smerter, asteni og træthed.
Ikke almindelige (≥1/1,000, <1/100): Anæmi, hypokaliæmi*, depression, selvmordstanker
og selvmordsforsøg (hos patienter med en
eksisterende anamnese med depression eller
en psykisk sygdom), pancreatitis, angioødem,
rabdomyolyse*, muskelsvækkelse*, nyresvigt,
erhvervet Fanconis syndrom, og proteinuri.
Sjældne (≥1/10,000, <1/1000): Lactatacidose,
steatosis hepatis, hepatitis, angioødem, osteo-
malaci (manifesterer sig som knoglesmerter og
i sjældne tilfælde medvirkende årsag til frakturer), myopati*, nyresvigt (akut og kronisk), akut
tubulær nekrose, proksimal renal tubulopati, herunder Fanconis syndrom, nefritis (herunder akut
interstitiel nefritis), nefrogen diabetes insipidus.
Bivirkninger markeret med* kan forekomme som
resultat af proksimal renal tubulopati. Tilfælde af
osteonekrose er rapporteret, specielt hos patienter med generelt anerkendte risikofaktorer,
fremskreden hiv sygdom eller langvarig CART.
Hyppigheden er ukendt.
Overdosering*: Såfremt der forekommer overdosering, monitoreres for tegn på toksicitet. Der
skal gives støttende standardbehandling efter
behov. Da elvitegravir og cobicistat i høj grad er
bundet til plasmaproteiner, er det usandsynligt,
at elvitegravir og cobicistat i signifikant grad vil
fjernes ved hæmodialyse eller peritonealdialyse.
Op til 30 % af emtricitabindosen og cirka 10 %
af tenofovirdosis kan fjernes ved hæmodialyse.
Det vides ikke, om emtricitabin eller tenofovir
kan fjernes ved peritonealdialyse.
Farmaceutiske forholdsregler*: Opbevares
i den originale emballage for at beskytte mod
fugt. Hold beholderen tæt lukket.
Pakninger och pris: Beholdere med 30
filmovertrukne tabletter. Vnr: 168038. For dagsaktuelle medicinpriser se: www.medicinpriser.dk
Tilskudsstatus: Ikke tilskudsberettiget.
Udlevering: BEGR (kun udlevering til sygehuse)
Markedsføringstilladelsesnummer:
EU/1/13/830/001
Indehaver af markedsføringstilladelsen:
Gilead Sciences International Ltd, Granta Park,
Abington, Cambridge, CB21 6GT, Storbritannien.
Produktinformationen er forkortet. Et fuldstændigt produktresumé kan rekvireres hos
indehaveren af markedsføringstilladelsen
og yderligere information kan rekvireres hos
den danske repræsentant: Gilead Sciences
Denmark ApS, Korskildelund 6, 2670 Greve,
Danmark Telefon: +45 36 91 50 50
Afsnit markeret med * er forkortet i forhold til det
af EMA godkendte produktresumé.
LÆS PRODUKTRESUMÉET FØR ORDINATION ISÆR MED HENSYN TIL BIVIRKNINGER, ADVARSLER OG KONTRAINDIKATIONER.
Et fuldstændigt produktresumé kan findes
på EMAs hjemmeside
Dato for oprettelse af produktinformation:
Juli 2014
Job Bag No: HIV/DK/13-07/PM/1794
Ved godkendelse af markedsføringstilladelsen, er dette lægemiddel
løbende underlagt supplerende overvågning, som vist med den omvendte
sorte trekant. Alle mistænkte bivirkninger
ved brug af Stribild skal rapporteres til
Gilead via e-mail til: [email protected] eller på telefon
+46 (8) 505 718 00 og /eller til Sundhedsstyrelsen i overensstemmelse med
det nationale spontane rapporteringssystem. www.meldenbivirkning.dk
HIV/DK/15-02/PM/1120
HIV & VIROLOGY NEWS 1 · 2015
ILC in Vienna
Powerful performance in HIV
HBV management has advanced significantly
Prof Geoffrey Dusheiko gave a talk about
the current situation and definitions of a
cure in chronic HBV infection.
– This is a dynamic field – there is a regenerated interest in HBV, he started by
saying.
He presented primary aims achieved
in antiviral therapy for HBV, and pointed
out that HBV can be prevented by vaccination.
– In the past three decades we have
seen improvement: With conventional
interferon, pegylated interferon and six
nucleotide analogues – lamviudine, adefovir, entecavir, telbivudine, tenofovir and
emtricitabine. But these are blunt instruments, even though they have been shown
to delay progression of cirrhosis.
Antiviral therapies also reduce – but do
not eliminate – the risk of hepatocellular
carcinoma (HCC).
– Existing therapy improves survival,
and reduces the need for liver transplantation. But for all these achievements, a
cure is still not available, Prof Dusheiko
continued.
He talked about the possibility to stop
nucleus analogues. The benefits of this
would be several – cost saving, making
younger patients more accepting of therapy, avoid adherence concerns and also
avoiding risk of resistance and potential
long term toxicities.
The question is what can be considered
as a defined cure. Do we mean a virological
cure, a functional cure or a disease cure?
– At some time we have to agree on this!
In his conclusions Prof Dusheiko stated
that chronic hepatitis B management has
advanced significantly. There are therapies that effectively suppress the virus
with no risk of resistance.
– Current research focus on examining
stopping agents and amplifying therapy.
And there are new direct agents or immunological measures on the horizon to cure
or control chronic infection!
1–7
78-80% achieved virologic success
with STRIBILD® (E/C/F/TDF) through
144 weeks in naïve patients6,7
STRIBILD (E/C/F/TDF) is powered with
Truvada – because backbone matters8-10
Of the respondents with known HCV
infection, the proportion with a high, intermediate and low probability of advanced fibrosis was 14.5 %, 40.3 % and 45.2 %,
respectively. In those with undiagnosed
HCV the results were 19.1 %, 30.9 % and
50.0 %, respectively.
The study highlights that even if people
are unaware they are infected with HCV,
the virus affects their liver in the same
way – resulting in advanced fibrosis. These results validate the current recommendation that screening for HCV – particularly among high-risk groups – is vital.
Combination of DAAs for patients with
kidney disease
Preliminary data from an ongoing study
revealed at the ILC suggest that a combination of three direct-acting antivirals is
well tolerated in patients with severe renal impairment or end-stage renal disease
when used with or without ribavirin.
In addition, the combination led to rapid HCV viral load suppression with no
virological failures seen in the preliminary data.
The study is called RUBY-1 and it is evaHCV screening essential to catch pa- luating ombitasvir/paritaprevir/ritonavir
in combination with dasabuvir in these
tients with advanced liver fibrosis
Most individuals with HCV remain a- patient categories.
Treatment-naive non-cirrhotic adults
symptomatic, which makes the diagnosis difficult. In a study presented at the with chronic HCV GT1 infection and
chronic
disease
(CKD) classified
Congress,
theStribild.
authors
used
theathypotheReferences:
1. SmPC
07/2014.
Available
www.ema.europa.eu.
2. DeJesuskidney
E, et al. Lancet
2012; 379:2429–2438.
3. Sax
as stage
or 5,2013;
received
12 weeks
P, et
Lancet individuals
2012; 379:2439–2448.
4. Rockstroh
et al. JdiAcquir Immune
Defic4Syndr
62:483-486.
5. Zolopa of
A, ettreatal. J
sisal. that
whose
HCV isJ, not
Acquir
Immune Defic
63:96-100.
6. Clumeck
N, et al. J Acquir
Immunewith
Defic Syndr
65(3):e121-124. 7.with
Wohl D A,or
ment
this2014;
combination
agnosed
areSyndr
less2013;
likely
to have
advanced
et al. J Acquir Immune Defic Syndr 2014; 65(3):e118-120. 8. United States Department of Health & Human Services (DHHS).
ribavirin.
There
wasat awww.aidsinfo.
24-week
fibrosis,
than
who
have
been diagGuidelines
for the
Use ofthose
Antiretroviral
Agents
in HIV-1-Infected
Adults without
and Adolescents.
November 2014.
Available
nih.gov/guidelines.
9. Günthard
HF, et al. JAMA
2014;312(4):410-425.
10. European AIDS follow-up
Clinical Society period.
(EACS) Treatment
As of
nosed. They
then compared
liver
fibrosis post-treatment
Guidelines.
November
2014 (Version of
7.1).National
Available at www.eacsociety.org/Guidelines.
between
respondents
Health February 18 2015, 17 of a planned 20 pain Cohort 1 had received treatment
and Nutrition
Survey
in the USA,
pa- tients
elvitegravir
150 mg/cobistat
150 mg/emtricitabine
200in
mg/tenofovir
disoproxil 245 mg = (E/C/F/TDF)
tients with diagnosed and undiagnosed and 6 had completed it. The combination
was well tolerated to date, with no treatHCV infection.
ment-related serious adverse events and
no premature discontinuation of directacting antivirals.
Limited data are available on the safety
for treating HCV infection in this category of patients; many of them currently go
untreated and are vulnerable to disease
progression.
Combination therapy for GT4 and 5
HCV GT4 is estimated to account for 8 13 % of all chronic HCV infections, and
GT5 for about 1 %. Clinical studies evaluating the treatment outcome with new direct-acting antivirals in GT4 and especially GT5 HCV infection have been limited
to date.
A study was presented that demonstrated that ledipasvir in combination with
sofosbuvir achieves SVR 12 of 93 % of patients with GT4, and in 95 % of patients
with GT5.
In the study, ledipasvir/sofosbuvir was
administrated as a once-daily fixed-dose combination for 12 weeks to treatment-naive and treatment-experienced
patients with and without cirrhosis. A total of 85 patients – of which 44 had GT4
and 41 had GT5 – were enrolled. SVR12
rates were similar across all patient types.
Adds to the evidence bank
Results from a retrospective study from
USA show that cancer rates in patients
with HCV were significantly increased,
compared to a non-HCV cohort. The researchers suggested that an extrahepatic
manifestation of HCV may be associated
with an increased risk of cancer.
Known cancer types associated with
HCV are non-Hodgkin’s lymphoma, renal
Rethink
Performance
and prostate
cancer
as well as liver cancer.
Gilead Sciences Nordic Office | Hemvärnsgatan 9, SE-171 54 Solna, Sweden | Phone: + 46 (0)8 505 71 800 | Fax: + 46 (0)8 505 71 801
HIV & VIROLOGY NEWS 2 · 2015
11
Nucleoside
ILC
in Vienna
Free Zones
The study authors recorded all cancer
diagnoses in patients over 18 years of age
with or without HCV during 2008 - 2012.
Within the timeframe of the study
145,210 patient years were included in the
HCV cohort, and 13,948,826 patient years
were included in the non-HCV cohort.
In the HCV cohort there were 2,213
cancer diagnoses (1,524/100,000) and
1,654 cancer diagnoses when liver cancer
was excluded (1,139/100,000).
In the non-HCV cohort there were
84,419 cancer diagnoses (605/100,000)
during the same period, and 83,795
(601/100,000) when liver cancer was excluded. When all cancers are considered
the rate is 2.5 times higher in the HCV
cohort – when liver cancers are excluded
the rate is still almost 2 times higher.
– The results suggest that cancer rates
are increased in the cohort of HCV patients versus the non-HCV patients, both
including and excluding liver cancers,
said Dr Lisa Nyberg, senior author of the
study.
12
She pointed out that these findings certainly points to the suggestion that HCV
may be associated with an increased risk
of cancer.
– However, the findings must be interpreted with caution, as the study also
showed confounding factors such as alcohol abuse, tobacco, obesity and diabetes
modified the results, Dr Nyberg added.
– These data adds to the evidence bank
linking HCV with an increased risk of
cancer, and highlights that there is still a
long way to go in order to fully understand
this complex and devastating disease, Dr
Laurent Castera commented.
An outstanding congress
At the Closing Ceremony, Prof Michael
Manns summarised the Congress in Vienna.
– We have now seen real-world data on
HCV treatment that are similar to those
presented from trials a year ago in London, he said.
He recapped several of the presenta-
tions that he thought will change and improve the management of patients with
HCV.
– In the future we will be able to treat
with shorter regimens. But obviously there is a barrier around week 6.
Prof Manns also mentioned the new developments of hepatitis D.
– There are 8 genotypes – and they were
presented at this Congress.
The new Secretary General of EASL, Dr
Laurent Castera, said that the 50th anniversary of ILC had been an outstanding
Meeting.
– I’d like to thank the Scientific Committee, the Reviewers and our own EASL
office who for the first time arranged the
entire Congress. I also look forward to
welcome all delegates next year!
The 51:st International Liver Congress
will take place in Barcelona April 13 – 17
2016. Reserve the date!
Per Lundblad
HIV & VIROLOGY NEWS 2 · 2015
Heiners article
FACULTY:
Annika Karlsson, Sweden
Arild Maeland, Norway
Pietro Lampertico, Italy
Jan Gerstoft, Denmark
Warner Greene, USA
Soo Aleman, Sweden
Philip Goulder, UK
Andrew Hill, UK
Steve Deeks, USA
Graham Foster, UK
Robert Siliciano, USA
Natasha Martin, USA
Helene Mens, Denmark
Giovanni Guaraldi, Italy
Michael Kazatchinke, Switzerland
For further information, registration and abstract submission please visit
www.hivnordic.se
HIV & VIROLOGY NEWS 2 · 2015
13
14
HIV & VIROLOGY NEWS 2 · 2015
HIV & VIROLOGY NEWS 2 · 2015
15
Nucleoside Free Zones
NeuroHIV
The
simplicity
patients
want
The
versatility
you
need
New once-daily REZOLSTA®
(darunavir 800mg/cobicistat 150mg) is now available!
Janssen is proud to introduce REZOLSTA® (darunavir 800mg/cobicistat 150mg) – boosted darunavir
REZOLSTA® (darunavir/cobicistat)
Lægemiddelform; Filmovertrukne tablet. Indikation: Rezolsta 800 mg/150 mg er indiceret til behandling af
humant immundefektvirus 1 (hiv-1)-infektion administreret i kombination med andre antiretrovirale lægemidler
hos voksne over 18 år. Dosering: Behandlingen skal påbegyndes af en læge, der har erfaring med håndtering af
hiv-infektion. Efter behandling med REZOLSTA er påbegyndt, må patienten ikke ændre doseringen eller
afbryde behandlingen undtagen efter aftale med lægen. ART-naive patienter En tablet en gang dagligt i
forbindelse med et måltid. ART-erfarne patienter En tablet en gang dagligt i forbindelse med et måltid kan
anvendes til patienter, der tidligere har været eksponeret for antiretrovirale lægemidler, men ikke har
mutationer associeret med darunavirresistens (DRV-RAM’s: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V,
I84V, L89V )*, og som har plasma-hiv-1 RNA < 100.000 kopier/ml og CD4+ celletal ≥ 100 x 106 celler/l. Hos alle
andre ART-erfarne patienter eller i tilfælde, hvor der ikke foreligger hiv-1-genotypebestemmelse, er REZOLSTA
ikke egnet. Særlige populationer Ældre REZOLSTA skal anvendes med forsigtighed til patienter over 65 år.
Nedsat leverfunktion Der foreligger ingen farmakokinetiske data vedrørende anvendelse af REZOLSTA til
patienter med nedsat leverfunktion. Nedsat nyrefunktion Behandling med REZOLSTA bør ikke initieres hos
patienter med kreatininclearance under 70 ml/min, hvis dosisjustering på basis af kreatininclearance er
nødvendig for et samtidigt administreret lægemiddel. På grund af cobicistats og darunavirs meget begrænsede
renale elimination kræves der ingen særlige forholdsregler eller dosisjusteringer af REZOLSTA hos patienter
med nedsat nyrefunktion. Pædiatrisk population Der foreligger ikke data om REZOLSTAs sikkerhed og virkning
hos patienter i alderen 3 til 17 år. REZOLSTA bør af sikkerhedsmæssige grunde ikke anvendes til pædiatriske
patienter under 3 år. Administration Oral anvendelse. Tabletten skal synkes hel inden for 30 minutter efter
indtagelse af et måltid. Kontraindikationer: Overfølsomhed over for de aktive stoffer eller over for et eller
flere af hjælpestofferne. Patienter med svært nedsat leverfunktion. Co-administration med følgende
lægemidler er kontraindiceret på grund af risikoen for tab af terapeutisk virkning: carbamazepin, phenobarbital,
phenytoin, rifampicin (antimykobakterielt lægemiddel), perikon (Hypericum perforatum). Co-administration
med følgende lægemidler er kontraindiceret på grund af risikoen for alvorlige og/eller livstruende bivirkninger:
alfuzosin (alfa-1-receptorantagonist), amiodaron, bepridil, dronedaron, quinidin, ranolazin, systemisk lidocain
(antiarytmika/midler mod angina pectoris), astemizol, terfenadin (antihistaminer), rifampicin
(antimykobakterielt lægemiddel), colchicin, ved anvendelse hos patienter med nedsat nyre- eller leverfunktion
(middel mod arthritis urica), sekalealkaloider (f.eks. dihydroergotamin, ergometrin, ergotamin,
methylergometrin), cisaprid (gastrointestinalt motilitetsmiddel), pimozid, quetiapin, sertindol (antipsykotika),
triazolam, midazolam administreret oralt (sedativa/hypnotika) (om forsigtighed ved parenteral administration
af midazolam, se produktresume), sildenafil til behandling af pulmonal arteriel hypertension, avanafil (PDE-5hæmmere), simvastatin og lovastatin (HMG-CoA-reduktasehæmmere), ticagrelor (trombocythæmmende
middel). Særlige advarsler og forsigtighedsregler vedrørende brugen. Regelmæssig kontrol af virologisk
respons anbefales. Ved manglende eller tab af virologisk respons bør patienten testes for resistens. Displacering
af lægemidler, der i udstrakt grad bindes til surt a1-glykoprotein, kan ikke udelukkes. REZOLSTA bør ikke
anvendes til behandlingserfarne patienter med en eller flere DRV-RAM’s, hiv-1 RNA ≥ 100.000 kopier/ml eller
CD4+ celletal < 100 x 106 celler/l . Der bør udvises forsigtighed ved behandling af ældre, der foreligger kun
begrænsede oplysninger om brug af REZOLSTA til patienter over 65 år. Der er rapporteret alvorlige
hudreaktioner hos 0,4 % af patienterne. DRESS og Stevens-Johnsons syndrom er rapporteret i sjældne tilfælde
så vel som toksisk epidermal nekrolyse og akut generaliseret eksantematøs pustulose. Ved symptomer på
alvorlige hudreaktioner skal REZOLSTA straks seponeres. REZOLSTA skal anvendes med forsigtighed hos
patienter med kendt sulfonamidallergi. Lægemiddelinduceret hepatitis er blevet rapporteret efter anvendelse
af darunavir/ritonavir. REZOLSTA anvendes med forsigtighed hos patienter med let eller moderat nedsat
leverfunktion, herunder kronisk aktiv hepatitis B eller C. Monitorering for forhøjet ASAT/ALAT bør overvejes
hos patienter med kronisk hepatitis eller cirrose og hos patienter med forhøjede aminotransferaser før
behandlingen – specielt i de første mange måneder af REZOLSTA-behandling. Ved nyopstået eller forværret
leverdysfunktion hos patienter, der tager REZOLSTA, skal det omgående overvejes midlertigt at afbryde eller
helt seponere behandlingen.Patienter med co-eksisterende tilstande: Patienter med hæmofili skal være
opmærksomme på risikoen for øget blødningstendens. Der er rapporter om nyopstået diabetes mellitus,
hyperglykæmi eller forværring af eksisterende diabetes mellitus hos patienter, der får antiretroviral behandling.
Der er rapporteret tilfælde af osteonekrose, især hos patienter med fremskreden hiv-sygdom og/eller
langvarig eksponering for antiretroviral kombinationsbehandling (CART). Hos hiv-inficerede patienter med
svær immuninsufficiens på tidspunktet for påbegyndelse af antiretroviral kombinationsbehandling (CART) kan
der opstå en inflammatorisk reaktion på asymptomatiske eller residuale opportunistiske patogener, som kan
forårsage alvorlige kliniske tilstande eller forværring af symptomer. Interaktioner med lægemidler Der er
indberettet livstruende og dødelige lægemiddelinteraktioner hos patienter, der blev behandlet med colchicin
og potente CYP3A- og P-glykoprotein (P-gp)-hæmmere farmakokinetisk forstærkning, da der ikke er fastsat
doseringsanbefalinger for en sådan kombination. REZOLSTA bør ikke anvendes sammen med præparater, der
indeholder ritonavir, eller regimer, der indeholder ritonavir eller cobicistat. Hvis der skiftes fra ritonavir til
cobicistat som farmakokinetisk forstærker, skal der udvises forsigtighed de første to uger af REZOLSTAbehandlingen. Interaktion med andre lægemidler og andre former for interaktion Der er ikke udført
interaktionsstudier med REZOLSTA. Da REZOLSTA indeholder darunavir og cobicistat, kan interaktioner, som
er identificeret med darunavir (i kombination med lavdosis ritonavir) og med cobicistat, muligvis forekommer
med REZOLSTA. Darunavir er en CYP3A-hæmmer, en svag CYP2D6-hæmmer og en P-gp-hæmmer. Cobicistat
er en mekanismebaseret CYP3A-hæmmer og en svag CYP2D6-hæmmer. REZOLSTA må ikke kombineres med
lægemidler, der er meget afhængige af CYP3A i forbindelse med clearance, og for hvilke øget systemisk
eksponering er forbundet med alvorlige og/eller livstruende bivirkninger. En fuldstændig interaktionstabel
med doseringsanbefaling kan findes i produktresuméet. Graviditet REZOLSTA bør kun anvendes under
graviditet, hvis den mulige fordel opvejer den mulige risiko. Amning Mødre må under ingen omstændigheder
amme, hvis de behandles med REZOLSTA. Virkning på evnen til at føre motorkøretøj og betjene maskiner
Der ses ingen eller kun i ubetydelig grad påvirkning af evnen til at føre motorkøretøj og betjene maskiner.
Bivirkninger Da REZOLSTA indeholder darunavir og cobicistat, kan der forventes de samme bivirkninger, der
er forbundet med de enkelte stoffer. Meget almindelig bivirkninger (≥ 1/10) hovedpine, diarré, kvalme, udslæt.
Almindelige bivirkninger (≥ 1/100 til < 1/10): (lægemiddel) overfølsomhed, lipodystrofi, anoreksi, diabetes
mellitus, hyperkolesterolæmi, hypertriglyceridæmi, hyperlipidæmi, unormale drømme, opkastning,
abdominalsmerter, abdominal distention, dyspepsi, flatulens, forhøjede pankreasenzymer, forhøjede
leverenzymer, angioødem, pruritus, urticaria, myalgi, osteonekrose, træthed, forhøjet kreatinin i blodet. Ikke
almindelige bivirkninger (≥ 1/1.000 til < 1/100): immunrekonstitutionsinflammatorisk syndrom (IRIS), akut
pankreatitis, hepatitis, cytolytisk hepatitis, gynækomasti, asteni. Sjældne (≥ 1/10.000 til < 1/1.000): Eosinofili og
systemiske symptomer som reaktion over for lægemidlet, Stevens-Johnsons syndrom Ikke kendt (hyppighed
kan ikke estimeres ud fra forhåndenværende data): toksisk epidermal nekrolyse, akut generaliseret
eksantematøs pustulose. Der henvises til produktresuméet for cobicistat for yderligere oplysninger. Dette
lægemiddel er underlagt supplerende overvågning. Læger og sundhedspersonale anmodes om at indberette
alle formodede bivirkninger via Sundhedsstyrelsen Axel Heides Gade 1 DK-2300 København S Websted: www.
meldenbivirkning.dk. E-mail: [email protected]. Overdosering. Der findes ingen specifik antidot mod REZOLSTA.
Behandling af overdosering med REZOLSTA består af generelle understøttende foranstaltninger, herunder
overvågning af vitale tegn og observation af patientens kliniske tilstand. Udlv.: (BEGR) Pakninger og priser:
800 mg 30 stk (VNR 141015). Dagsaktuelle priser kan ses på www.medicinpriser.dk. Produktinformationerne er
forkortet i forhold til produktresume godkendt af Det Europæiske Lægemiddelagentur (EMA) 19. november
2014. Produktresumeet kan vederlagsfrit rekvireres fra Janssen-Cilag A/S, Hammerbakken 19, 3460 Birkerød, Tlf
45948282, Fax 45948283, www.janssen-cilag.dk.Yderligere information om dette lægemiddel er tilgængelig på
EMEA’s hjemmeside http://www.emea.europa.eu/.
Janssen-Cilag A/S Hammerbakken 19, DK-3460 Birkerød, Denmark, Tel +45 4594 8282, Fax +45 4594 8283, www.janssen-cilag.dk
Janssen-Cilag A/S
16
HIV & VIROLOGY NEWS 2 · 2015
PHDEN/REZ/0315/0001
References: 1. Llibre JM, et al. AIDS Rev. 2013;15:112–21 2. Ortiz R, et al. AIDS 2009;22:1389–97 3. Mills AM, et
al. AIDS 2009;23:1679–88 4. Orkin C, et al. HIV Med. 2013;14:49–59 5. Cahn P, et al. AIDS 2011;25:929–39
6. Nelson M, et al. J Antimicrob Chemother. 2010;65:1505–9 7. REZOLSTA Summary of Product Characteristics.
Nov 2014
JC-150109-1
in one tablet. REZOLSTA® offers the proven versatility of darunavir1–6 with a booster for the first
time in the same tablet, simplifying the regimen for many of your adult patients.7
Efavirenz
Efavirenz: too much of a good thing?
The Food and Drug Administration approved efavirenz in 1998. To the surprise
of many the legendary 006 trial [1] proved that efavirenz was more efficacious
than indinavir, the preferred protease
inhibitor at the end of the last century.
Since then, efavirenz has been part of
the recommended regimens in expert
guidelines for almost two decades. During these years we have joked many times “efavirenz has never lost a beauty
contest”.
N
ew drugs came challenging efavirenz but results of the trials were
stubborn: at most, new drugs achieved non-inferiority and many times they were unable to match efavirenz
efficacy. This year, for the first time efavirenz is no longer a recommended regimen
in the HHS guidelines (see Dr. Moyle update of the guidelines in this issue) nor in
the Spanish Gesida guidelines [2,3].
Three recent clinical trials have shown
inferiority of efavirenz versus other
drugs. The double-blind STARTMRK trial [4] showed that after 5 years of follow
up, suppression rates were significantly
higher with tenofovir/emtricitabine and
raltegravir than with tenofovir/emtricitabine and efavirenz. Discontinuations
due to adverse events occurred in 5% of
patients receiving raltegravir and in 8.9%
of the patients treated with efavirenz.
The open-label STAR trial [5] compared
the fixed combinations tenofovir/emtri-
citabine/rilpivirine vs. tenofovir/emtricitabine/efavirenz. A statistically significant difference in efficacy favoring the rilpivirine combination was demonstrated
for participants with baseline viral loads
lower than 100,000 copies/ml. The main
reason for this difference was a higher
rate of discontinuations of efavirenz
(8.7%) than of rilpivirine (2.5%). In the
SINGLE study [6] dolutegravir combined
with abacavir/lamivudine proved for the
first time to have superior antiviral efficacy than efavirenz combined with tenofovir/emtricitabine in the primary endpoint
of the trial, regardless of the baseline viral
load. The main driver of this result was
Table 1. Baseline characteristics of patients included in ENCORE1.
HIV & VIROLOGY NEWS 2 · 2015
a significantly higher rate of discontinuations due to adverse events in the efavirenz arm (10% vs. 2%). In STARTMRK,
STAR and SINGLE as expected the most
common adverse events leading to discontinuation of efavirenz were related to
the central nervous system. These adverse
events have always been the Achilles’ heel
of efavirenz. However in prior trials efavirenz compensated this drawback thanks
to its very high antiviral efficacy.
One other important aspect that has
contributed to the “demotion” of efavirenz from the preferred category group of
regimens has been the finding of an association of efavirenz with a 2-fold increased hazard of suicidality compared with
a regimens not containing efavirenz. This
association was observed in an AIDS Clinical Trials Group cross-protocol analysis
[7]. Although other observational studies
have not replicated this association [8,9]
expert guidelines mention this issue as
one of the reasons not to recommend efavirenz as a preferred drug.
It appears that the era of efavirenz has
come to an end [10]. Has it really or is there any hope for a kinder, gentler form of
efavirenz? The answer to this question
has big implications. The World Health
Organization recommends tenofovir, lamivudine (or emtricitabine) and efavirenz as the preferred initial regimen for
adults and adolescents [11]. Therefore the
number of patients that could potentially
receive efavirenz is enormous (more than
26 millions).
17
Efavirenz
The ENCORE1 study is a randomised,
double blind, placebo-controlled, non-inferiority clinical trial that has compared
two doses of efavirenz in antiretroviral
naive patients: the usual 600 mg daily
versus an experimental lower dose of 400
mg daily. Results at 96 weeks have been
recently published [12]. The ENCORE1 is
a very large trial. It has enrolled 636 participants from high-income, middle-income, and low-income countries, a fact that
allows generalization of their findings
(Table 1). Results after two years of follow
up strengthen findings after 48 weeks [13]
and support the durability of the 400 mg
dose.
Is the 400 mg dose as efficacious as the
600 mg dose? At 96 weeks, 90% of the patients in the efavirenz 400 mg group and
90.6% in the efavirenz 600 mg group had
viral load below 200 copies/ml supporting
non-inferiority. Results did not change
using the 50 copies/mL cutoff. Baseline
viral load did not impact results. Of note,
one third or the patients entered the trial
with baseline viral loads above 100,000
copies/mL and one quarter had CD4 cell
counts lower than 200 cells/µL. Rates of
virological failure and development of
resistance did not differ by dosing group.
Overall this data clearly support the efficacy and durability of the 400 mg dose.
Is the 400 mg dose better tolerated than
the 400 mg dose? Let’s look at the data.
Proportions of patients reporting adverse events were exactly the same: 89% in
the 400 mg group and 89% in the 600 mg
group (p = 0.97). When we focus in adverse events that were definitely or probably
related to efavirenz there was a significant advantage in the lower dose group:
proportions were 38% and 48% in the 400
mg and 600 mg groups respectively (p =
0.01) Serious adverse events rates did not
differ between groups. Overall it appears
that there is a modest tolerability advantage of the lower dose. What about the CNS
adverse effects characteristic of efavirenz? Were they associated with the dose
used? The answer is not clear-cut. The
ENCORE1 trial included questionnaires
about quality of life, negative emotional
state, and efavirenz side-effects. There
were no significant differences between
treatment groups for this battery of tests,
suggesting that the lower dose did not
translate in a decrease in the CNS adverse
events of efavirenz (dizziness, abnormal
dreams) in the first (Figure 1) or second
year. Neuropsychiatric adverse events
were rare during the second year (5% in
the 400 mg group and 4% in the 600 mg
group).
An unexpected and interesting finding
is that recovery of CD4 cells was higher
in the lower dose group. After two years
the difference was 25 cells/µL in favor
of the 400 mg groups. This is difference
is not clinically relevant but add support
to the idea that efavirenz can have some
toxicity upon lymphocytes. It has been a
recurrent theme than in comparative trials of efavirenz versus protease inhibitors,
integrase inhibitors or maraviroc recovery
of CD4 has been persistently lower with
efavirenz.
Recently an interesting substudy of
ENCORE1 [14] looking at cerebrospinal
fluid exposure of efavirenz and its major
metabolites has been published. The substudy included 28 patients who consented
to have a lumbar puncture. Cerebrospinal
fluid concentrations were slightly lower
in patients who received the 400 mg
dose. Interestingly both doses of efavirenz
achieved cerebrospinal fluid concentrations considered to be adequate to inhibit
HIV replication. One metabolic product
of efavirenz is 8-hydroxy efavirenz. This
metabolite is virologically inactive but has
been associated with potential central nervous system toxicities. Concentrations of
this metabolite did not differ by dosing
group. The substudy provides reassuring
data about the ability of the 400 mg dose
to suppress HIV replication in the cerebrospinal fluid. However it does not appear that lowering the dose has a positive
impact in potentially toxic metabolites.
In my opinion results of ENCORE1 are
quite important to facilitate the access to
antiretroviral therapy worldwide. A 33%
reduction in the active pharmaceutical
ingredient translates in very large savings
in production costs. This is an impressive
achievement. It is important to emphasize that the 400 mg dose is not appropriate
in two scenarios: pregnancy and in patients who need to receive rifampicin for
the treatment of tuberculosis. These two
groups were excluded from ENCORE1
I do not think that the dose reduction
solves the issues of the central nervous
system adverse events of efavirenz. For
this reason I consider unlikely that just
by dose reduction efavirenz can regain its
position as a preferred drug in expert guidelines. In contrast with ENCORE1 when
raltegravir, rilpivirine and dolutegravir
have compared with efavirenz it has been
relatively easy to show and advantage in
terms of central nervous system.
DR. JOSÉ R ARRIBAS
Servicio de Medicina Interna,
Unidad VIH Hospital La Paz,
IdiPAZ. Madrid, Spain
References
1.
2.
Figure 1. Efavirenz adverse events during the first 48 weeks.
18
Staszewski S, Morales-Ramirez J, Tashima KT,
Rachlis A, Skiest D, Stanford J, et al. Efavirenz
plus zidovudine and lamivudine, efavirenz plus
indinavir, and indinavir plus zidovudine and
lamivudine in the treatment of HIV-1 infection
in adults. Study 006 Team. N Engl J Med 1999;
341:1865–1873.
Panel on Antiretroviral Guidelines for Adults
and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and
HIV & VIROLOGY NEWS 2 · 2015
Efavirenz
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
adolescents. Department of Health and Human
Services. Available at http://www.aidsinfo.nih.
gov/ContentFiles/AdultandAdolescentGL.pdf.
Panel de expertos de Gesida y Plan Nacional
sobre el Sida P. Documento de consenso de GeSIDA/Plan Nacional sobre el Sida respecto al
tratamiento antirretroviral en adultos con infección por el virus de la inmunodeficiencia humana (Actualización enero 2015). Available at
http://www.gesida-seimc.org/contenidos/guiasclinicas/2015/gesida-guiasclinicas-2015-tar.
pdf
Rockstroh JK, DeJesus E, Lennox JL, Yazdanpanah Y, Saag MS, Wan H, et al. Durable efficacy and safety of raltegravir versus efavirenz
when combined with tenofovir/emtricitabine
in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir
Immune Defic Syndr 2013; 63:77–85.
Cohen C, Wohl D, Arribas JR, Henry K, van
Lunzen J, Bloch M, et al. Week 48 results from a
randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults.
AIDS 2014; 28:989–997.
Walmsley SL, Antela A, Clumeck N, Duiculescu
D, Eberhard A, Gutierrez F, et al. Dolutegravir
plus Abacavir–Lamivudine for the Treatment of
HIV-1 Infection. N Engl J Med 2013; 369:1807–
1818.
Mollan KR, Smurzynski M, Eron JJ, Daar
ES, Campbell TB, Sax PE, et al. Association
between efavirenz as initial therapy for HIV-1
infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. ANNals of internal medicine
2014; 161:1–10.
Smith C, Ryom L, d’Arminio Monforte A, Reiss
P, Mocroft A, El-Sadr W, et al. Lack of association between use of efavirenz and death from
suicide: evidence from the D:A:D study. Journal of the International AIDS Society 2014; 17.
doi:10.7448/IAS.17.4.19512
Nkhoma L, Coumbis J, Farr A, Johnston S, Chu
B-C, Rosenblatt L. Using real world data to assess the risk of suicidality among patients initiating an efavirenz-containing regimen versus an
efavirenz-free antiretroviral regimen. IDWeek
2014. Philadelphia, October 8-12, 2014. Abstract
646.
Raffi F, Pozniak AL, Wainberg MA. Has the time
come to abandon efavirenz for first-line antiretroviral therapy? Journal of Antimicrobial Chemotherapy 2014; 69:1742–1747.
WHO. Consolidated guidelines on the use of
antiretroviral drugs for treating and preventing HIV infection. WHO 2013; Available at
http://www.who.int/iris/ bitstream/10665/
85321/1/9789241505727_eng.pdf?ua=1
ENCORE1 Study Group. Efficacy and safety of
efavirenz 400 mg daily versus 600 mg daily: 96week data from the randomised, double-blind,
placebo-controlled, non-inferiority ENCORE1
study. The Lancet Infectious Diseases Published Online First: 12 April 2015. doi:10.1016/
S1473-3099(15)70060-5
ENCORE1 Study Group, Puls R, Amin J, Losso M, Phanuphak P, Nwizu C, et al. Efficacy of
400 mg efavirenz versus standard 600 mg dose
in HIV-infected, antiretroviral-naive adults
(ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet
2014; 383:1474–1482.
Winston A, Amin J, Clarke A, Else L, Amara A,
Owen A, et al. Cerebrospinal Fluid Exposure of
Efavirenz and Its Major Metabolites When Dosed at 400 mg and 600 mg Once Daily: A Randomized Controlled Trial. Clinical Infectious
Diseases Published Online First: 11 December
2014. doi:10.1093/cid/ciu976
HIV & VIROLOGY NEWS 2 · 2015
19
NeuroHIV
SCIENTIFIC COMMITTEE
ANDREA ANTINORI, Rome, Italy
PAOLA CINQUE, Milan, Italy
STEVEN DEEKS, San Francisco, USA
MAGNUS GISSLEN, Goteborg, Sweden
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ADRIANO LAZZARIN, Milan, Italy
CARLO FEDERICO PERNO, Rome, Italy
RICHARD W. PRICE, San Francisco, USA
KEVIN ROBERTSON, Chapel Hill, USA
TOPICS
• Pathogenesis of HIV CNS invasion
and damage
• CNS HIV reservoirs in treated HIV infection
- characterization, evaluation and eradication
• Residual CNS inflammation in treated HIV
infection - characterization, evaluation
and mitigation
• Treating CNS HIV infection in 2015
• Biological classification of CNS HIV
infection & disease
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HIV & VIROLOGY NEWS 2 · 2015
The news DHHS guidelines
The new DHHS guidelines. Forgetting
evidence, embracing opinion
The recently updated Department of
Health and Human Services (DHHS) HIV
treatment guidelines were released on
April 8 2015. They contain considerable
change to recommendations and considerable confusion and conflict over who
to give what.
M
ost critically, the authors fail to
emphasise the primacy of efficacy
in treatment choice, reduce the
ability of those actual read and
use the guidelines to individualise treatment, especially in the presence of specific risks or comorbidities, and have eliminated a whole NNRTI drug class from the
recommended list despite the class being
the No1 choice globally, including in the
WHO guidelines. This appears not simply a case of American exceptionalism, but
muddled thinking and, arguably, commercial bias, as only the most expensive
treatments regimens are recommended.
The guidelines are widely cited by pharmaceutical companies in their marketing
efforts and will be a welcome marketing
tool for these newer products. While the
guidelines list ‘costs’ as relevant to treatment choice they do not seem to take
this, and indeed the relatively imminent
loss of patent protection for some popular
agents, in to consideration. Thus, the guidelines provide poor value for money for
the US payers for healthcare and the US
government.
In the ”What to Start” section we now
have only five recommended regimens
down from nine (plus a restricted recommendation for TDF/FTC/rilpivirine) in
the previous guidelines. Four of the preferred regimens are integrase strand
transfer inhibitor (INSTI)-based. They include:
• Dolutegravir (DTG) plus abacavir
(ABC) plus lamivudine (3TC);
• DTG plus Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC);
• Elvitegravir/cobicistat (EVG/c) plus
TDF/FTC; and
• Raltegravir (RAL) plus TDF/FTC.
The fifth option and that is TDF/FTC
plus darunavir/ritonavir (DRV/r), now
HIV & VIROLOGY NEWS 2 · 2015
the only recommended ritonavir-boosted
protease inhibitor–based regimen. [1]
This is where the first confusion begins. The efficacy story is muddled, and
they are recommending an inferior agent
that has been demonstrably less good in
two large randomised controlled studies
when compared with other recommended regimens. DRV/r has been compared
against DTG in the Flamingo study and
was inferior at 48 weeks, mainly due to
higher rates of failure in high viral load
subjects but also some excess of adverse
event related discontinuation. In ACTG
5257, DRV/r was equivalent to RAL on
the virological efficacy endpoint as assessed by the ACTG statistical plan, but the
confidence intervals above 1 indicated it
was also inferior for this endpoint (but
this was not statistically tested by ACTG
statisticians as the upper band of the 95%
CI fell within the 10% equivalence band)
and inferior to RAL for safety/tolerability endpoints. There were 85 viral failures
on RAL and 115 on DRV/r (and 94 on ATV/r, see below) [2]. I know which groups I
would have rather been randomised to. So
the guidelines have recommended a PI/r
choice that is inferior to two recommended INSTI regimens. This makes no sense.
In a potential treatment course of 50 years
and with potentially serious consequences for failure, guidelines should not play
fast and loose with efficacy.
The confusion gets worse. Not on the
list of recommended regimens but dropped to the alternative section are TDF/
FTC or ABC/3TC with efavirenz and
TDF/FTC or ABC/3TC with atazanavir/
ritonavir. Both EFV and ATV/r regimens
have excellent virologic activity and have
been compared to recommended regimens. Indeed these represent the two
most well studied third agents in our armamentarium, having never been beaten
on efficacy, most notably in high viral load
and low CD4 subjects (which are especially poorly represented, along with women and non-whites, in both the EVG/c
and DTG development programme). In
comparison with these preferred INSTIs,
TDF/FTC/EFV was non-inferior in large randomised placebo controlled blin-
ded studies to both Elvitegravir/cobicistat (EVG/c) plus TDF/FTC in the GS102
study over 96 weeks and non-inferior to
Raltegravir (RAL) plus TDF/FTC (in the
StartMRK study) (at least over the first 3
years of planned analyses). The inferiority of TDF/FTC/efavirenz to ABC/3TC/
DTG in the SINGLE study was not due
to more virological failures but to an unusually high discontinuation rates in the
EFV arm (around twice the rate seen in
StartMRK or GS102), possibly due to the
use of questionnaires that focussed CNS
effects of EFV making participants interpret these events as adverse rather than
simply perverse. TDF/FTC/EFV also has
specific pharmacokinetic characteristics
of very long half-lifes of the active forms
of all agents that make this regimen very
forgiving of delayed or missed doses and
of course is presented as a single tablet
regimen that helps avoid partial non-adherence. So there is no efficacy basis on
which to drop TDF/FTC/EFV off the recommended list.
TDF/FTC plus atazanavir/ritonavir has
also been compared with multiple preferred regimens and remains the only PI/r
not to have ‘lost’ in an virological efficacy comparison despite being evaluated in
many more comparative studies in treatment naïve subjects than DRV/r. In ACTG
5202 in became the first and only PI to
be as effective as efavirenz regardless of
NRTI backbone and baseline characteristics. Subsequently, the virological outcomes of ACTG 5257 showed it was equivalent to RAL (albeit inferior on tolerability
outcomes) and equivalent to DRV/r but
with fewer defined virological failures (94
on ATV/r vs 115 on DRV/r) in the virological comparison [2]. It was also non-inferior to EVG/c in the blinded placebo
controlled GS103 study. More recently,
ATV/cobicistat was approved as the only
cobicistat boosted PI coformulation with
robust clinical trials data from the GS114
study and with full bioequivalence to ATV/r, including at the key trough concentration. This coformulation along with
DRV/c (which is bioequivalent to DRV/r
in area under the curve exposure but gives
substantially lower trough concentrations
21
The news DHHS guidelines
of DRV) are listed as alternative regimens.
As is characteristic of PI/r regimens (and
PI/c regimens), ATV/r demonstrates no
PI resistance and much lower rates of
NRTI resistance at failure relative to the
NNRTI and INSTI comparators in these
studies. So as with EFV, there is no efficacy basis on which to drop ATV/r from the
recommended list.
I am left wondering if the DHHS guidelines writers are implicitly downgrading the importance of virological efficacy
in HIV treatment (a process which began
with the listing of the demonstrably less
effective TDF/FTC plus rilpivirine regi-
men a few years back, a decision they have
now reversed, and continued with the listing of some ABC/3TC regimens that had
performed less well in ACTG 5202). This
is a rather odd implication given the seriousness of the disease we are treating and
the considerable consequences of failure
on future treatment options in a disease
requiring lifelong therapy.
The reason that the efavirenz and ATV/r are no longer in the ”recommended”
section is because of tolerability or safety.
With efavirenz-based regimens there are
concerns about central nervous system
toxicity and a possible association with
Recommended Regimen Options
(Drug classes and regimens within each class are arranged in alphabetical order.)
INSTI-Based Regimens:
•
•
•
•
DTG/ABC/3TC3 - only for patients who are HLA-B*5701 negative (AI)
DTG plus TDF/FTC3 (AI)
EVG/c/TDF/FTC - only for patients with pre-treatment estimated CrCI>70 mL/min (AI)
RAL plus TDF/FTC3 (AI)
PI-Based Regimens:
•
22
DRV/r plus TDF/FTC3 (AI)
suicidal ideation, what Americans now
call ‘suicidality’. With ATV/r it is primarily due to the results of the open-label study ACTG 5257 [2], which found that both
RAL and DRV/r were better tolerated. For
patients who are doing well on those regimens, there is no recommendation to
change, indeed the guidelines are explicit
about this.
Since EFV’s approval in 1996/7 the product label has included details of CNS
side effects including the possibility of
suicidal ideation at a rate of 0.3-0.7%.
The recent concerns have arisen due to
a small excess of this type of effect being
reported in several ACTG studies (5095,
5175, 5202, 5142) but which is countered
by large safety databases that have not
found the same associations. The effect
in the ACTG analysis was a hazard ration
of 2.28 (CI 1.27-4.2, p=0.006) for ideation,
attempted or completed suicide [3] relative to EFV-free comparators. The effect
size was similar in each study and only
significant for US subjects who made up
approximately 75% of participants. Additionally, subjects with no psychiatric history did not see a significant effect, nor did
subjects currently receiving antidepressants. The issue here may lie in the fact
that physicians in practice choose who to
prescribe EFV for, avoid its use in persons
with active mental health problems or significant past histories, whereas attendees
at ACTG sites who participate in clinical
may come from populations at higher risk
of mental health issues than average (the
uninsured) and get randomly allocated to
efavirenz in clinical trials. As the ACTG
analysis suggests selecting patients may
reduce any possible effects. Younger age
(<30yrs), history of IDU and psychiatric
history all had independent (and slightly larger) hazard ratios [3] than EFV use.
This outlines a simple screening list to limit the risk of EFV. In clinical practice we
don’t randomly assign to efavirenz (nor
indeed to ATV/r, see below) abrogating
risk through prudent choice. The ACTG
analysis data are refuted from several
clinical cohorts and databases that may
more accurately reflect clinical practice
approaches to the use of EFV. The FAERS
safety database [4], a public database developed to support post-marketing surveillance of medications by recording adverse events (AEs) reported by consumers
and healthcare professionals to the FDA
or manufacturers has reported an analysis
that does not support an association with
efavirenz or indeed other ART with suicide. Fluoxetine and sertraline, prescribed
to high risk individuals, were used as a
HIV & VIROLOGY NEWS 2 · 2015
The news DHHS guidelines
positive control [4]. Similarly, a US claims
database did not find an association with
suicidality, and indicated that in clinical
practice suicidality may be somewhat
more common on EFV-free regimens,
possibly suggesting an allocation bias
away from EFV in high risk subjects in
clinical practice [5]. Finally, the D:A:D safety study found no association with EFV
use and suicide, the risk factors identified
being older age, male, history of iDU and
lower current CD4 count [6]. In conclusion, the DHHS authors have selectively
evaluated the data on EFV to downgrade
it to alternative despite this drug being
an effective, cost-effective agent with nearly two decades of clinical experience,
with an endorsement from the WHO as
the global standard first agent and with
an established safety profile, that appears
well managed in clinical practice based on
multiple clinically derived safety databases. It rather defies logic.
The story with ATV/r is similar. The
dropping of this agent to alternative is based on the safety/tolerability outcomes in
ACTG5257, where ATV/r was inferior for
these analyses to RAL and DRV/r, the majority of discontinuations (for icterus, hyperbilirubinemia and GI upset) occurring
predominately in individuals with grade
3 or 4 hyperbilirubinemia [2]. Of note,
while bothersome to some individuals (as
rash, nausea, diarrhoea or hepatitis can be
with DRV), these are not life threatening
or life changing but rapidly reversible side
effects. The rates of adverse event discontinuations with ATV/r in ACTG 5257 was
4-8 times higher that multiple previous
studies conducted by the ACTG (5202),
Gilead (103, 114) and BMS (Castle). The
reasons for this differences is unclear.
Furthermore, risk factors for high grade
bilirubin are established from ACTG 5202
and 5257. Individuals with Gilbert’s syndrome, a variant in the UGT1A1 enzyme
in which ATV is partially metabolised,
have been shown be more likely to have
high grade bilirubin on study [7]. If high
grade bilirubin is a risk factor for ATV/r
discontinuation then it seems obvious to
limit or avoid ATV choice in persons with
Gilbert’s syndrome. Rather than a genetic
test (such as we have to do with Abacavir), simply looking at baseline bilirubin
is likely to be a reasonable screening tool.
Those with high baseline bilirubin are likely to go higher on ATV/r, so we should
use ATV with caution in people with baseline bilirubin at or above the upper limit
of normal. The second thing is to have management tools in place in case icterus occurs, in the same way we advise people to
HIV & VIROLOGY NEWS 2 · 2015
get antihistamines if they get a rash at the
start of DRV or EFV therapy. We published a study showing that co-administration of zinc (we used 100mg Zinc Sulphate, about 20mg of elemental zinc) leads
to immediate declines in bilirubin levels
of over 20% with a single dose and up to
28% with repeat dosing, via chelation of
gut bilirubin and some effect of lowering
ATV levels, which correlate with bilirubin levels [8]. An additional alternative if
the subject is on abacavir/lamivudine is
to drop the ritonavir and dose modify the
ATV to 400mg unboosted. As the INDUMA and ARIES studies showed, this leads to maintenance of viral efficacy and a
sharp decline in bilirubin levels. The final
contradictory thing to note is that ATV/r
is still a preferred regimen in the treatment naïve pregnant women (where it is
FDA approved) and is the only PI/r regimen that can be used with the oral contraceptive pill (at an adjusted oestrogen
dose). Thus, the guidelines appear to be
recommending treating specific groups of
women differently to the rest of the HIV
community, underlining their inconsistence. The DHHS writers have downgraded to alternative an effective drug with
predictable and manageable side effect
profile and established value in specific
populations.
Finally, while focussing on long known
and manageable side effects of EFV and
ATV/r as now being problematic, abacavir
has undergone somewhat of a renaissance
despite renewed concerns from the D:A:D
study group and, most recently, the Swiss
Cohort study [9] about cardiac safety. This
shift in attitude to ABC appears largely
due to the ability to prescribe the product
in a single tablet regimen with dolutegravir. Of note, the concerns regarding abacavir’s lower efficacy, which were seen
in the ACTG5202 study when partnered
with EFV or ATV/r, were not seen the
DTG development programme. However,
only the SINGLE study involved random
allocation to an ABC/3TC backbone, in
the other studies SPRING-2 and Flamingo
allocation to ABC/3TC or TDF/FTC was
non-random and at physician discretion.
Thus, the DTG programme did not have
the same statistical power as ACTG5202
to detect an efficacy effect and recruited few subjects with low (<200) CD4
counts and high (>100K) viral loads where ABC/3TC’s efficacy may be best tested.
So while being uncompromising on safety
concerns with EFV and ATV, the authors
throw relative caution to the wind on abacavir. A confusing narrative.
Other changes in the guidelines are less
controversial [1]. These include a section
on virologic failure that has been revised with a range of scenarios and a discussion on detecting viremia in the CNS.
There is a section on poor CD4 recovery
in the setting of virologic suppression, as
well as immune activation/inflammation
which conveys the message that there are
no proven interventions that can address
this hence it remains part of the research
agenda. There is also a revised section on
acute and early HIV infection, a section
on drug-drug interactions, and an expanded section discussing the drug-drug interactions with new HCV therapies. Finally,
the Monthly Average Wholesale Price of
Antiretroviral Drugs table will make fascinating reading for many Europeans.
GRAEME MOYLE
Associate Specialist in HIV Medicine
Chelsea and Westminster Hospital
London, United Kingdom
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
http://aidsinfo.nih.gov/guidelines/html/1/
adult-and-adolescent-treatment-guidelines/0
Landovitz RJ et al. Efficacy and tolerability of
atazanavir, raltegravir, or darunavir with FTC/
tenofovir: ACTG 5257. 21st CROI, 3-6 March
2014, Boston. Oral abstract 85
Association efavirenz as between initial therapy for HIV- infection and increased risk for
suicidal ideation and attempted or completed
suicide: an analysis of trial data Mollan, KR,
Smurzynski, M, Eron, J., et.al. Annals of Internal Medicine, 2014; 161:1-10
Napoli et al, J of Int AIDS Soc, 2014
Nkhoma et al, ID Week 2014; Oral Presentation 646
Smith C, et al, Oral presentation O315 HIV 12,
Glasgow 2014
Ribaudo HJ1, Daar ES, Tierney C, et al., Impact of UGT1A1 Gilbert variant on discontinuation of ritonavir-boosted atazanavir in AIDS
Clinical Trials Group Study A5202. J Infect
Dis. 2013 Feb 1;207(3):420-5.
Moyle G, Else L, Jackson A, et al. Coadministration of atazanavir-ritonavir and zinc sulfate: impact on hyperbilirubinemia and pharmacokinetics. Antimicrob Agents Chemother.
2013;57:3640-4.
Young J1, Xiao Y, Moodie EE, The effect of
cumulating exposure to abacavir on the risk of
cardiovascular disease events in patients from
the Swiss HIV Cohort Study. J Acquir Immune
Defic Syndr. 2015 Apr 28.
23
HIV News
Topical Conferences
August 5
Hepatitis C Management: State of the Art
New York, USA
www.hep2015.com
October 7-11
IDWeek 2015
San Diego, CA, USA
https://www.idweekinternational.com
July 18-19
Towards an HIV Cure Symposium
Vancouver, British Columbia, Canada
hivcure.ias2015.org
October 8-10
NeuroHIV 2015. 6th International Meeting
On HIV Infection and the Central Nervous System
Matera, Italy
http://www.neurohiv.com/
July 19-22
8th IAS Conference on HIV Pathogenesis,
Treatment and Prevention (IAS 2015)
Vancouver, Canada
www.ias2015.org
24
October 21-24
15th European AIDS Conference (EACS)
Barcelona,Spain
www.eacs-conference2015.com
September 17-21
ICAAC/ICC 2015
San Diego, CA, USA
www.icaac.org
November 13-17
AASLD - The Liver Meeting 2015
San Francisco, California, USA
http://www.aasld.org/
September 30 - October 2
HIV & Hepatitis Nordic Conference
Stockholm
www.hivnordic.se
December 8-11
7th International Workshop on
HIV Persistence during Therapy
Miami, USA
www.hiv-persistence.com
HIV & VIROLOGY NEWS 2 · 2015
HIV News
New drugs from new
classes of drugs
Although the growth of a single tablet
regime (STR) has made current treatment options better tolerated and
simpler to administer than in the past,
there is still a need to develop novel
antiretroviral drugs and regimens to
address the issues of maintaining viral
suppression, acceptable tolerability,
and long-term safety over decades of
therapy.
I
n the absence of remission of infection,
antiretroviral therapy (ART), according
to European experience, must be pursued for at least 3 or 4 decades by patients
who are commonly started on it in their
mid-thirties. The recommended regimen
at the present time consists of a multiple
drug combination taken in tablet form
once daily. A single tablet regimen (STR)
may contain four drugs, such as tenofovir/
emtricitabine/cobicistat/elvitegravir (Stibild®), or three drugs, as in Atripla® (TDF/
FTC/EFV), Eviplera® (TDF/FTC/RPV),
or Triumeq® (ABC/3TC/ DTG). The last
named is not yet available in Europe but
has been approved for use in the US.
These STRs represent a great improvement, especially in initiation strategies
with naïve patients who are able to adjust
much more easily to taking a single pill
once daily for a chronic disease they may
not fully understand; or for others who
underwent treatment in the past when
only complex regimens were available.
However, one disadvantage of STRs is tied
to their simplicity: they are fixed combinations of drugs at an invariable dosage,
whether or not their components are effective for an individual patient.
Many patients who were treated in the
2000s, and whose viremia has been suppressed for years, are receiving one of these
compact and easy-to-take STRs. However,
if one looks carefully at their history, a
considerable number who have been on
ART for the past ten to fifteen years or
more are found to harbor resistant viruses, most often with an M184V conferring
resistance to lamivudine or emtricitabine,
or even thymidine-associated mutations
that make tenofovir partially resistant. In
fact, most of the currently available STRs
HIV & VIROLOGY NEWS 2 · 2015
contain the first two drugs. The current
recommended ART strategies combine
drugs that belong to four classes: nucleoside reverse transcriptase inhibitors
(NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease
inhibitors (PIs), and integrase inhibitors.
Entry inhibitors are less commonly used,
although two such drugs have been licensed (maraviroc and enfuvirtide).
Few of these classes represent fully robust drugs with a high genetic barrier to
resistance. Thus, over a period of time,
even in the case of minimal failures with
short episodes of viral replication, viruses may escape control and patients may
develop resistance-associated mutations.
Moreover, in many Western countries patients with a cumulative time on therapy
of approximately ten years have shown
that, despite being virologically suppressed, they harbor archived resistance
mutations. Some HIV-positive patients,
particularly those who are treatment-experienced, may have limited treatment
options due to the presence of viral mutants that cause a) reduced antiretroviral
drug susceptibility, b) emergence of drug
toxicities from long-term ART, and c)
contraindications due to the need to manage concurrent infections.
Therefore, primarily because of the development of resistance to existing compounds, the need to improve long-term
drug safety and tolerability, the desire to
reduce the drug burden and eliminate
partially-resistant drugs, the search for
novel drugs that target different stages
of viral replication goes on. Currently several classes of drugs are under development. Some, such as entry, maturation,
and HIV latency inhibitors, traditionally
aim at inhibiting one step of the HIV lifecycle.
Entry inhibitors
The replication cycle of HIV-1 is a complex, multistep process leading to the
fusion of the virus into the cells through
membranes. First there is the entry of the
virus into host cells via attachment, then
the binding to the co-receptor, and finally
the fusion of HIV into the membrane.
These processes represent potential for
therapeutic intervention, and some pharmaceuticals have been approved and licensed for this purpose.
• Maraviroc prevents binding of HIV1 to the co-receptor C-C chemokine
receptor 5, although the use of maraviroc requires the determination of
the HIV tropism, limiting its use.
• Enfuvirtide, an injectable peptide,
inhibits the gp41-mediated fusion
of the host and viral cell membranes. However, enfuvirtide, which has
played an important role in salvage
therapy in the 2000s, has progressively disappeared from the armentorium given its need for parenteral
administration.1
Attachment inhibitors
HIV-1 attachment inhibitors (AIs) represent a novel class of small-molecule antiretroviral agents that bind to the HIV-1
envelope glycoprotein, gp120, and selectively inhibit the interaction between the
virus and its host receptor, CD4, thereby
preventing viral entry into the host cells.
BMS-488043: The first attachment inhibitor
The first AI, AI-488043, was developed
by Bristol-Myers Squibb (BMS). It was
evaluated in a proof-of-concept study that
consisted of an 8-day placebo-controlled
monotherapy study.1 Despite its potent
antiviral activity. AI-488043 was poorly
bioavailable. Consequently, its suboptimal
pharmacokinetics (PK) led to significant
variability in individual half-maximal effective concentration (EC50), which translated into the development of phenotypic
viral resistance (V68A, L116I, S375I/N,
and M426L). However, on the positive
side, safety and tolerability were good
over this very short period.2
BMS-663068 : The second attachment
inhibitor(fostemsavir)
The BMS scientists continued their efforts to develop a compound with a better
PK profile. BMS-663068 (fostemsavir) is a
pro-drug metabolized to the active moiety
BMS-626529, a first-in-class, potent HIV-
25
HIV News
1 AI that prevents the initial interaction
between virus and host cell by binding to
the viral envelope protein, gp120.3
Mode of action and resistance profile
By targeting the initial step in viral attachment and entry, BMS-626529 is not
affected by the co-receptor tropism and is
therefore active against CCR5-, CXCR4and dual-tropic (R5X4) strains of HIV-1.
Preliminary in vitro data show that HIV-1
viruses are generally susceptible to BMS626529, irrespective of subtype, with the
exception of subtype AE and Group O.
BMS-626529 has no in vitro cross-resistance to other classes of antiretrovirals.
(figure 1 and 2)
Figure 1. Conversion of BMS-663068
Figure 2. BMS-626529 attachment inhibitor: proposed mechanisms of action
Pharmacokinetics
BMS-663068 is delivered as an extended-release formulation, metabolized to
the active moiety BMS-626529 by alkaline
phosphatase in the gastrointestinal lumen
(Figure 2). The drug is rapidly absorbed
due to its efficient membrane permeability.3 BMS-626529 is a substrate of the
P-glycoprotein transporter and is predominately metabolized by an esterase-mediated hydrolysis pathway with contributions from a CYP3A4-mediated oxidative
pathway.
Clinical studies of BMS-663068
The first open pilot Phase IIA study (AI438006)3 included 50 treatment-naïve
and experienced subjects randomized to
one of five dose regimens of BMS-663068
in a 8-day monotherapy trial with the following groups:
1. 600 mg BMS-663068 plus 100 mg ritonavir every 12 hours (Q12H)
2. 1200 mg BMS-663068 plus 100 mg
ritonavir every night
3. 1200 mg BMS-663068 plus 100 mg
ritonavir Q12H
4. 1200 mg BMS-663068 Q12H plus 100
mg ritonavir every morning
5. 1200 mg BMS-663068 Q12H
Overall, there was a significant, rapid
decrease in plasma viral HIV-1 RNA over
7 days that ranged from –1.21 to –1.73 log10
c/mL. There was no safety signal in terms
of tolerability or side effects.
A Phase II study AI-438011 of fostemsavir (formerly BMS-663068) with the results at Week 24 was presented at CROI
20144 and again at CROI 2015.5 This ongoing Phase IIB AI-438011 has been designed to evaluate the efficacy, safety, and
response of several doses of BMS-663068
versus ritonavir-boosted atazanavir (ATV/r), each with tenofovir disoproxil fumarate (TDF) and raltegravir (RAL),
26
Figure 3. AI-438011: Study design
in HIV-1-infected, treatment-experienced patients. The study includes two
sub-studies: a monotherapy sub-study of
7 days of BMS-663068, and a main study
evaluating96 weeks of combined therapy
(cART).
Key entry criteria
Patients had to be:
• Treatment experienced with current
or previous exposure to at least 1 ARV
drug
• HIV RNA > 1000 cp/mL
• CD4 cells > 50/mm3
• HIV susceptible to TDF/ATV/RAL
• HIV susceptible to BMS-663068, as
determined by phenotypic assay
Patients were randomized 1:1:1:1:1 to:
• TDF + RAL + BMS-663068 400 mg
twice daily (BID), 800 mg BID, 600
mg once daily (QD), and 1200 mg QD
TDF + RAL + ATV/r 300/100 mg QD. (figure 3)
End points
The primary end point is the proportion
of patients achieving HIV RNA < 50 cp/
mL at Week 24 and the proportion of
patients discontinuing study treatments
due to side effects. Secondary end points
at Week 48 include the proportion of patients with HIV RNA < 50 cp/mL.
Outcome
A total of 251 patients were enrolled (approximately 50 in each arm). Sixty-two discontinued the study (48 in the BMS arms
and 14 in the ATV/r arm) for the following
reasons: 9 adverse events, 9 consent
withdrawals, 12 lost to follow-up, 8 poor
compliance, 13 for lack of efficacy). Baseline demographic and disease characteristics were broadly similar across all tre-
HIV & VIROLOGY NEWS 2 · 2015
HIV News
renal failure in the BMS-663068 arm, and
abdominal symptoms, including flatulence, nausea, or jaundice, in the ATV/r arm.
None were considered related to the attachment inhibitor.
Figure 4. Proportion of subjects achieving HIV-1 RNA < 50 c/mL through Week 48 (observed)
Figure 5. Proportion of subjects achieving HIV-1 RNA < 50 c/mL through Week 48 by baseline viral load
(observed)
atment groups. Patients were 60% male
(median age 39 years); two-thirds were
infected by subtype B. They had a median
viral load of 4.85 log10 c/mL and a median CD4 count of 229.5 cells/mL. In terms
of resistance profile, approximately 50%
of the subjects had ≥1 major PI, NRTI, or
NNRTI resistance-associated mutation at
baseline (M184V/I, 31%; K103N, 29%; thymidine analogue mutations, 13%; major PI
mutations, 2%).
ITT snapshot analysis: 61% to 82% on
BMS-663068 and 71% on ATV/r.
On treatment analysis: 69% to 91% on
BMS-663068 and 78% on ATV/r. (figure 4)
Despite the small number of subjects in
the study, if one breaks down the data according to baseline viral load, the performance of BMS-663068 remains substantial, with the best results being achieved
through dosing BID, rather than QD (see
figure 5).
Efficacy
As noted above, Week 24 results were presented at CROI 2014.4 In the mITT analysis the proportion of patients with maximal viral suppression were similar across
the different study arms. They ranged
from 69% to 80% in the BMS-663068
arms and were 75% in the ATV/r arm.
Results presented at CROI 2015 by Max
Lataillade again showed a response rate at
Week 48 that was very similar across different doses of the attachment inhibitor.6
Immunological effects
Following control of viral replication, the
increase in CD4 cell count was similar in
the BMS-663068 arms (+155 to +199 cells/
mm3) and the ATV/r arm (178 cells/mm3).
HIV & VIROLOGY NEWS 2 · 2015
Tolerability and safety
BMS-663068 is a safe drug, as suggested
by results at Week 24, which had no clinical or biological safety signal. The only
adverse effects (AEs) that led to discontinuation were one TDF-induced acute
BMS-663068 (fostemsavir) drug–drug
interactions
Because darunavir/ritonavir (DRV/r) and
etravirine (ETR) are commonly used in
HIV-positive patients who are treatment
experienced, it is of clinical importance
to understand potential drug–drug interactions between BMS-663068 and DRV/r and/or ETR.7 The first Phase I study
(n = 44) of BMS-663068 1200 mg BID/
single dose (SD), RTV 100 mg BID/SD,
and DRV 600 mg BID/SD in healthy subjects was terminated due to one episode
of anaphylaxis (Grade 3 rash and Grade 1 angiodema) in a subject receiving
BMS-663068 1200 mg + RTV 100 mg BID.
Even though RTV can be associated with
angioedema and severe rash, a possible
role of both RTV and BMS-663068 in the
events could not be excluded. Hence, the
interaction study was conducted again to
evaluate the safety profile of BMS-663068
when co-administered with DRV/r. BMS626529 is a substrate of the P-glycoprotein
transporter and predominately metabolized by an esterase-mediated hydrolysis
pathway, with contributions from a cytochrome P450 CYP3A4-mediated oxidative pathway. DRV and RTV are inhibitors
of CYP3A4, while ETR is an inducer of
CYP3A4. Therefore, co-administration
of DRV/r and/or ETR with BMS-663068
may affect BMS-626529 PK characteristics. Conversely, as BMS-626529 is not
an inhibitor or inducer of DRV/r or ETR
metabolism, no effect on their PK is anticipated.
Methods
Three cohorts of 14 healthy males and
females were used to evaluate the drug–
drug interactions between BSM-663068
(600 mg BID), then BMS-626529, in combination with DRV/r and ETR. (figure 6)
Effect of DRV/r on PK of BMS-626529
• Co-administration of DRV/r with
BMS-663068 increased peak plasma
concentration, AUC, and Cmin of
BMS-626529 by 52%, 63%, and 88%,
respectively. However, these increased concentrations were not associated with an increased incidence of
AEs or other safety signals potentially attributed to BMS-626529.
• Co-administration of BMS-663068
with ETR without a PI decreased
peak plasma concentration and syste-
27
HIV News
•
mic exposure of BMS-626529. However, this should not affect the efficacy of the combination, based on
the wide range of efficacy noted in
AI-438011 (with BMS-663068 doses
of 400 and 800 mg BID, 600 mg and
1200 mg QD). In the case of combinations with DRV/r and ETR, there
is an increase in BMS-626529 exposure.
Co-administration of BMS-663068
with DRV/r + ETR was generally safe
in healthy subjects; there were no
deaths or serious AEs. Skin rash was
consistent with ETR and DRV/r administration.
BMS-663068 and ATV alone or ATV/r
• Thirty-six healthy subjects were randomized 1:1:1:1 to receive one of four
treatment sequences in three consecutive treatments: BMS-663068 600
mg BID; BMS-663068 600 mg BID +
RTV 100 mg QD; ATV 300 mg QD +
RTV 100 mg QD (RTV-boosted ATV
[ATV/r]); or BMS-663068 600 mg
BID + ATV 300 mg QD + RTV 100 mg
QD.
• ATV/r increased BMS-626529 Cmax
and AUCtau by 68% and 54%, respectively.
• Similarly, co-administration of BMS663068 with RTV increased BMS626529 C max and AUCtau by 53%
and 45%, respectively. Compared
with ATV/r alone, ATV and RTV systemic exposures remained similar
following co-administration of BMS663068 with ATV/r
• There were no additional safety
signals in terms of frequency or severity of side effects. Therefore, administration of BMS-626529 with
ATV, whether boosted or not, should
require no dose adjustment when
co-administered.
Overall, despite a few drug–drug interactions with no clinical relevance, BMS663068 does not require dose adjustment
when administered with DRV, ETR, or
ATV.
Future prospects
The development of the BMS attachment
inhibitor is continuing with a Phase III
designed to enroll patients with treatment failure. It will be a randomized study comparing BMS-663068 to placebo
combined with optimized background
therapy (OBT). For patients who have no
treatment options, based on the results
of their genotypic resistance testing, there is an open-label, single-arm study of
28
Figure 6. BSM-663068 drug–drug interactions with DRV/r and ETR: Study design
Figure 7. BMS-955176 maturation inhibitor
BMS-663068 combined with OBT at the
investigator’s discretion.
Maturation inhibitors
Pharmaceutical companies know that one
should not stop after one’s first failure.
They are perseverant and this is good
for science. Some of us may remember a
drug named bevirimat, originally developed by Panacos, the first generation maturation inhibitor. Despite evidence of its
activity, development of the drug has been
halted—mainly because of an efficacy issue on HIV strains with Gag polymorphisms. At CROI 2015, the BMS research
team presented the clinical data on a second generation maturation inhibitor that
has overcome the problems of bevirimat.8
How does it work?
Maturation of HIV-1 requires the cleavage of the HIV Gag polyprotein by the HIV
protease. Unlike PIs, which also inhibit
virus maturation, inhibitors like bevirimat
and the second generation compound,
BMS-955176, bind to the Gag protein itself and not to the protease. Thus, they
prevent cleavage of Gag at their specific
binding site. BMS-955176 is active in vitro
against wild-type HIV and against variants that contain some of the cleavage site
polymorphism. (figure 7)
A flashback
Bevirimat was evaluated in a Phase IIB
proof-of-concept study in heavily experienced patients. The results were very
clear: whereas 45% of the patients had a
clear antiviral response with a decrease of
–1.26 log10, 55% (24/44) had no response
to therapy, that is, their decrease in HIV
RNA was < 0.5 log. The non-response
was associated with Gag polymorphisms
at positions 369, 370, or 371. Additionally,
protein binding on the potency of bevirimat significantly elevated the concentrations needed for efficacy, thus further
complicating the utility of the drug.
HIV & VIROLOGY NEWS 2 · 2015
Median change in HIV-1RNA from
baseline, log10 copies/mL
HIV News
1
0,8
0,6
0,4
0,2
0
-0,2
-0,4
-0,6
-0,8
-1
-1,2
-1,4
-1,6
-1,8
Dosing period
Placebo
5 mg
10 mg
20 mg
40 mg
80 mg
R
1
2
3
4
120 mg
5
6
7
8
9 10 11 12 13 14 15 17 19 24 25
Study days
CROI 2015 - Lataillade M et al., abstr. 114LB actualisé
Figure 8. BMS-955176: median change in HIV-1 RNA over time
BMS-955176 binds tightly and reversibly
to HIV-1 Gag. It interferes with protease
cleavage between the p24 capsid protein
and a smaller peptide in the Gag polyprotein, leading to the release of immature
virus particles that cannot complete their
life cycle and are not infectious. The drug
has a good PK profile with low protein
binding and a long half-life that supports
once daily dosing. BMS-955176 has been
tested in a classical Phase IB (or IIA) dose-ranging study in ART naïve HIV-1 infected individuals with HIV-1 subtype B,
a viral load > 5000 cp/mL, and CD4 cells
> 200/mm3.
Six doses QD were evaluated : 5 mg, 10
mg, 20 mg, 40 mg, 80 mg, 120 mg, or pla-
cebo (8 patients and 2 placebo per arm)
over 10 days, after which patients were
followed up to 24 days. Patients were
mostly white males with a CD4 count of
approximately 450 to 500/mm3 and a low
viral load of about 10,000 cp/mL. The three highest doses, 40, 80, and 120 mg QD,
produced a 1.5 to 1.7 log10 (30- to 50-fold)
decline in HIV RNA over a 10 day period. According to baseline Gag polymorphisms, there was no difference in antiviral
activity, unlike the case with bevirimat.
Some HIV RNA suppression persisted after the drug was discontinued, consistent
with its long half-life. No safety signals
were apparent over the short period of the
drug’s administration. (figure 8)
Thus, BMS-955176 has overcome serum
binding and Gag polymorphism issues,
and has proven itself to be an effective
drug in this small pilot study. It had a 1.5
log decrease over a brief period of administration, with a plateau between 40 and
120 mg QD. It is suitable for use in co-formulation. A Phase IIB study is in preparation.
GSK-2578999 and 2828232 maturation
inhibitors
Glaxo-Smith-Kline (GSK) also has maturation inhibitors in development. Although promising details on GSK 2578999
were presented at the Drug Resistance
Workshop9 this compound is not going
forward and preclinical information on
a second compound, GSK 2828232 were
presented in a poster at CROI 2015.10
GSK 2828232 had an IC50 of 0.8–4.3
nM against a broad spectrum of 26 isolates covering a range of genotypes, and is
not affected by previous PI-experience.
Multiple-dose Phase I studies in HIV negative volunteers looking at food and drug
interactions and safety have either already
been conducted or are ongoing.
HIV & VIROLOGY NEWS 2 · 2015
Conclusion
The present projection that HIV treatment strategies will have to extend over
decades calls for further investment in
developing new drugs belonging to new
class of drugs. We have seen how prolonged time on therapy results in the accumulation of resistance mutations that are archived. The constant need to control the
virus requires a large portfolio of active
drugs. Attachment and maturation inhibitors represent two promising options for
expanding the antiretroviral armentorium needed to carry patients through a full
life span.
CHRISTINE KATLAMA
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Nettles RE, Schürmann D, Zhu L, et al. Pharmacodynamics, safety, and pharmacokinetics of
BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infected subjects. J Infect Dis 2012;
206: 1002–11.
Zhou N, Nowicka-Sans B, Zhang S, et al. In vivo
patterns of resistance to the HIV attachment
inhibitor BMS-488043. Antimicrob Agents
Chemother 2011; 55: 729–37.
Lalezari J, Latiff GH, Brinson C, et al. Safety
profile of HIV-1 attachment inhibitor prodrug
BMS-663068 in antiretroviral-experienced
subjects: Week 24 analysis. J Int AIDS Soc 2014;
17: 19530.
Lalezari J, Latiff GH, Brinson C, Echevarria J,
et al. HIV-1 attachment inhibitor prodrug in antiretroviral-experienced subjects: Week 24 analysis. CROI, 3–6 Mar 2014, Boston, MA.
Savant Landry I, et al. HIV-1 Attachment inhibitor prodrug BMS-663068: model-based dose
selection. CROI, 23–26 February 2015, Seattle,
WA. Poster abstract 509.
Thompson M, et al. Attachment inhibitor
prodrug BMS-663068 in ARV-experienced subjects: Week 48 analysis. CROI, 23–26 February
2015, Seattle, WA. Poster abstract 545.
Savant Landry I, et al. HIV-1 attachment inhibitor prodrug BMS-663068: interactions with
DRV/r and/or ETR. CROI, 23–26 February
2015, Seattle, WA. Poster abstract 523.
Carey H, et al. CROI, 23–26 February 2015, Seattle, WA. Oral abstract 114 LB
Tang J, et al. GSK2578999, an HIV-1 maturation
inhibitor with improved virology profile against
Gag polymorphisms. XXIV International Drug
Resistance Workshop, 21–22 February 2015, Seattle, WA. Oral abstract 63.
Jeffrey J, et al. GSK2838232, a second generation HIV-1 maturation inhibitor with an optimized virology profile. CROI, 23–26 February
2015, Seattle, WA. Poster abstract 538.
29
The persistent HIV reservoir
Monitoring the persistent HIV
reservoir in the era of HIV cure trials
HIV infection can be suppressed by suppressive combination antiretroviral treatment (cART). However, despite long
term cART a latent pool of replication
competent viral DNA persists and prevents the establishment of an HIV cure.
Current research to an HIV cure focuses
on eliminating this viral reservoir. Because of these efforts, there is a growing
need for relevant biomarkers that can
predict the successful elimination of the
HIV reservoir.
I
n current clinical practice, plasma HIV
RNA load is the most important virological measure. This marker has been
useful in assessing viral replication and
subsequent viral suppression by ART.
Plasma viral load continuous to be an effective marker to monitor treatment failure in the form of viral rebound. However,
this marker is no longer useful to monitor
the reservoir, as most patients on cART
have undetectable levels with clinically
validated viral load assays, regardless of
their viral reservoir. In search for novel
biomarkers, the different HIV RNA and
DNA populations that may represent discrete steps in the HIV life cycle (figure 1)
are being investigated to characterize the
state of the viral reservoir in patients on
suppressive cART (1).
Quantifying the reservoir size
The first choice of a biomarker to monitor
HIV persistence would be a marker that
estimates the size of the reservoir. Consequently, HIV DNA quantification is being
considered as such a marker. However,
one needs to take into account that quantifying HIV DNA leads to an overestimation of the true amount of replication
competent virus (2). Most of the chromosomally integrated HIV DNA sequences
are replication defective because of deleterious mutations introduced by specific
antiviral host defense mechanisms or by
the error prone HIV reverse transcription.
In the framework of an HIV cure, the relevant HIV reservoir is restricted to only
those integrated HIV DNA sequences that
remain capable of producing infective
virions. Hence, PCR-based markers that
30
Figure 1: Illustration of the HIV replication cycle in an infected cell showing the different forms of HIV
RNA and DNA. Plasma HIV RNA is present in free virions. Upon infection, viral RNA is transcribed to cDNA
and enters the nucleus. Here it either integrates in the host cells’ chromosome, or fails to integrate and
recombines to form episomal 1 or 2 LTR circles. Proviral transcription of integrated HIV DNA gives rise to
spliced and unspliced mRNA which are necessary for the production of viral proteins and for the viral
RNA genome.
quantify total or integrated HIV DNA may
not be adequate to monitor changes in the
size of the replication competent viral reservoir.
As alternatives to DNA quantification
tools, cell culture based methods are investigated as promising assays to specifically measure this replication competent
reservoir. These models activate patient
derived CD4+ T-cells ex vivo and induce reactivation of the latent HIV. Viral
spread is facilitated by co-culturing the
patient cells with cells from uninfected
donors in so-called viral outgrowth assays (VOA). Consequently, only latent
virus that is replication competent is quantified. Although promising, this method
comes with specific drawbacks. First, the
VOA is labor intensive, costly and time
consuming (1-3 weeks). Secondly, recent
data indicate that the VOA is not able to
reactivate all inducible proviral DNA.
Almost 12% of the proviral DNA that is
not induced during ex vivo stimulation is
composed of an intact HIV genome and
may thus be replication competent (3). At
least a part of this non-induced provirus is
replication competent as shown by a follow-up experiment using two consecutive
rounds of activation of the same cells. This
experiment revealed a subset of latently
infected cells that did not respond to the
first round of activation, but did produce
virus upon the second activation. Hence,
the viral reservoir is likely larger than predicted by ex vivo stimulation methods (3).
At the IAS Conference in Melbourne,
2014, Nicolas Chomont described a novel
method, called TILDA (Tat/Rev Induced
Limiting Dilution Assay). This method
quantifies viral transcription after ex
vivo stimulation. TILDA is more sensitive compared to the VOA as it does not
require HIV replication in co-cultured
cells. However, this aspect indicates that
TILDA cannot discern replication com-
HIV & VIROLOGY NEWS 2 · 2015
The persistent HIV reservoir
petent from replication deficient virus,
which may still transcribe RNA but may
harbor mutations preventing new rounds
of infection.
With HIV DNA quantification overestimating and the VOA underestimating the
viral reservoir, the question rises which
method correlates best with the actual
replication competent reservoir. Comparisons of different methods indicate that
total HIV DNA measures correlates poorly with the VOA outcome (2). These comparisons show that either, or both of these
markers fail to correlate with the replication competent reservoir. To this date,
we do not have clinical data that indicates
which of both methods is most relevant.
Hence, there is an urgent need for clinical
data from cure trials and preferably from
treatment interruption trials where both
methods are assessed for their correlations with viral rebound or time to viral
rebound.
Clinical data with treatment interruption studies are only available from a few
clinical trials that performed treatment
interruption. These trials indicate that total HIV DNA is associated with an improved suppression and an increased time to
viral rebound (4, 5). However, due to the
high variability in total HIV DNA loads
between patients, total HIV DNA markers
may only be relevant in a clinical setting
if measured longitudinally. Decreases in
HIV DNA as a result of HIV cure therapies may then provide evidence of reservoir clearance. Unfortunately, there are no
clinical data available on the VOA in treatment interruption studies.
Quantifying residual viral transcription
or replication
Measuring the activation status of the
viral reservoir is considered as an alternative method to estimate the potency of
the reservoir to form replication competent virus. Residual viral production has
been observed by ultrasensitive techniques which detect single copies of viral
RNA in the blood of patients on long term
cART (6). However, residual plasma virus
is only observed in a small number of patients, preventing accurate quantification.
Moreover, HIV plasma RNA is quickly degraded in the blood and may not be indicative for long term dynamics of the viral
reservoir.
Cell associated (CA) unspliced viral
mRNA (usRNA) transcripts are being investigated as markers for viral transcription. Although not all mRNA transcripts
result in the production of replication
Figure 2: Schematic representation of the HIV reservoir markers in relation to the actual replication competent reservoir (green). This replication competent reservoir forms a small part of the intact HIV DNA
sequences (yellow) which on their turn form a minor part of all HIV DNA sequences that are integrated.
The VOA (orange) is only able to reactivate a part of this replication competent reservoir. The TILDA assay
(purple) can reactivate more, but may also reactivate viral transcription from replication incompetent
virus. Finally, it is unknown to which extent the CA RNA measures (grey) cover the entire replication
competent reservoir (?) and if ongoing transcription may also originate from dead-end integrated HIV
DNA (??).
HIV & VIROLOGY NEWS 2 · 2015
competent virus, the existence of these
transcripts indicate active transcription
and may be useful as marker to estimate
the replication competence of the viral
reservoir. CA usRNA levels are associated
with a higher chance of viral rebound in
patients on treatment (7).
In addition to viral RNA, episomal
2LTR circles are considered as markers
for viral replication. When HIV infects
new cells, it frequently fails to integrate
and the unintegrated HIV DNA that remains in the nucleus recombines at the
long terminal repeats (LTR) and forms
circular DNA (8). These 2LTR circles are
unstable DNA forms, which are eventually degraded. Hence, the presence of these
2LTR circles is considered as a marker for
recent events of viral production and infection events.
Markers for reservoir activation may be
hampered because of their low abundancy in patients. However, they may form interesting markers to assess treatment efficacy of new cure compounds. Especially
for the so-called shock and kill strategies,
which aim to purge the reservoir by first
reactivating the latent virus and consequently killing off all HIV producing cells (7,
9). Initial clinical trials using treatment
intensification of integrase inhibitors
have shown transient increases in HIV
2LTR circles after intensification (10, 11).
In addition, increased expression of CA
HIV usRNA has been observed in several
cure trials using histone deacetylase inhibitors (HDACi) to reactivate latent virus
in patients (12, 13).
Unanswered Questions:
Despite extensive research, we are still
unable to define which marker is optimal
to monitor the replication competent reservoir (figure 2). Future research should
focus on a comprehensive analysis of different markers to assess whether a combination of these may be more relevant compared to any of the tested markers alone.
In addition, longitudinal profiling of individual patients may be more useful for
monitoring changes in the viral reservoir
compared to cross sectional assessments,
which are hampered by the large inter patient variability. In addition, future research should focus on structured interruption trials facilitating direct comparisons
of viral markers and viral rebound or the
time to rebound in patients off cART.
Finally, two recent treatment interruption studies indicate that viral markers
alone, may not be sufficient to predict
functional cure. In these studies, HIV was
suppressed to nearly undetectable levels
by a bone marrow transplant or early tre-
31
The persistent HIV reservoir
atment initiation in the Boston patients
or the Mississippi baby respectively (14).
These patients rebounded after a substantial time (between 3 to 27 months) of
HIV remission (15). From these studies,
we learn that as few as one latent provirus
may be enough to reactivate viral infection. Hence, viral biomarkers should be
complemented with immunological markers, which to monitor the fitness of the
immune system to handle low level viral
reactivation events.
References
1.
2.
3.
4.
5.
6.
7.
WARD DE SPIEGELAERE AND
LINOS VANDEKERCKHOVE
Professors in Internal Medicine,
FHIV Translational Research Unit,
Department of Internal Medicine,
Faculty of Medicine and Health Sciences,
Ghent University and Ghent University
Hospital, Ghent, Belgium
32
8.
9.
10.
Lewin SR, Rouzioux C. HIV cure and eradication: how will we get from the laboratory to
effective clinical trials? Aids. 2011;25(7):885-97.
Eriksson S, Graf EH, Dahl V, Strain MC, Yukl
SA, Lysenko ES, et al. Comparative Analysis of
Measures of Viral Reservoirs in HIV-1 Eradication Studies. PLoS Pathog. 2013;9(2):e1003174.
Ho YC, Shan L, Hosmane NN, Wang J, Laskey
SB, Rosenbloom DIS, et al. Replication-Competent Noninduced Proviruses in the Latent
Reservoir Increase Barrier to HIV-1 Cure. Cell.
2013;155(3):540-51.
Azzoni L, Foulkes AS, Papasavvas E, Mexas AM,
Lynn KM, Mounzer K, et al. Pegylated Interferon alfa-2a monotherapy results in suppression
of HIV type 1 replication and decreased cell-associated HIV DNA integration. J Infect Dis.
2013;207(2):213-22.
Williams JP, Hurst J, Stohr W, Robinson N,
Brown H, Fisher M, et al. HIV-1 DNA predicts
disease progression and post-treatment virological control. eLife. 2014:e03821.
Doyle T, Geretti AM. Low-level viraemia on
HAART: significance and management. Curr
Opin Infect Dis. 2012;25(1):17-25.
Pasternak AO, Lukashov VV, Berkhout B.
Cell-associated HIV RNA: a dynamic biomarker
of viral persistence. Retrovirology. 2013;10(1):41.
Sharkey M. Tracking episomal HIV DNA: implications for viral persistence and eradication
of HIV. Curr Opin HIV AIDS. 2013;8(2):93-9.
Archin NM, Margolis DM. Emerging strategies
to deplete the HIV reservoir. Curr Opin Infect
Dis. 2014;27(1):29-35.
Buzon MJ, Massanella M, Llibre JM, Esteve A,
Dahl V, Puertas MC, et al. HIV-1 replication and
immune dynamics are affected by raltegravir
intensification of HAART-suppressed subjects.
Nat Med. 2010;16(4):460-5.
11.
12.
13.
14.
15.
Hatano H, Strain MC, Scherzer R, Bacchetti P,
Wentworth D, Hoh R, et al. Increase in 2-Long
Terminal Repeat Circles and Decrease in D-dimer After Raltegravir Intensification in Patients
With Treated HIV Infection: A Randomized,
Placebo-Controlled Trial. J Infect Dis. 2013.
Elliott JH, Wightman F, Solomon A, Ghneim K,
Ahlers J, Cameron MJ, et al. Activation of HIV
Transcription with Short-Course Vorinostat in
HIV-Infected Patients on Suppressive Antiretroviral Therapy. PLoS Pathog. 2014;10(11).
rasmussen T, Tolstrup M, Brinkman C, Olesen
R, Erikstrup C, Solomon A, et al. Panobinostat,
a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on
suppressive antiretroviral therapy: a phase 1/2,
single group, clinical trial. The Lancet HIV.
2014;1(1):e13-e21.
Luzuriaga K, Gay H, Ziemniak C, Sanborn
KB, Somasundaran M, Rainwater-Lovett K,
et al. Viremic relapse after HIV-1 remission
in a perinatally infected child. N Engl J Med.
2015;372(8):786-8.
Henrich TJ, Hanhauser E, Marty FM, Sirignano
MN, Keating S, Lee TH, et al. Antiretroviral-Free
HIV-1 Remission and Viral Rebound After Allogeneic Stem Cell Transplantation Report of 2
Cases. Ann Intern Med. 2014;161(5):319-+.
HIV & VIROLOGY NEWS 2 · 2015
The persistent HIV reservoir
Beyond Ef ficacy
TO L
NV E N I E N C
E
Reasons
to rethink
first-line
treatment
in HIV
RE
EF F I C ACY
ER A B ILIT Y
CO
S I S TA N C E
Dolutegravir-based regimens deliver
A HIGH BARRIER TO RESISTANCE1-3
resistance to date
across 3 large treatment-naïve studies
0% treatment-emergent
1-3
Tivicay® (dolutegravir)
Indikation(er): Tivicay er indiceret i kombination med andre antiretrovirale lægemidler til behandling af humant
immundefektvirus (hiv)-inficerede voksne og unge over 12 år.
Dosering*: Voksne: Patienter inficeret med hiv-1 uden dokumenteret eller klinisk formodet resistens over for
integraseklassen: 50 mg (en tablet) oralt én gang daglig. Tivicay skal administreres 2 gange daglig i denne
population, når det gives samtidigt med visse lægemidler (f.eks. efavirenz, nevirapin, tipranavir/ritonavir eller
rifampicin). Patienter inficeret med hiv-1 med resistens over for integraseklassen (dokumenteret eller klinisk
formodet): 50 mg (en tablet) 2 gange daglig. Samtidig administration af Tivicay med visse lægemidler skal
undgås i denne population (f.eks. efavirenz, nevirapin, tipranavir/ritonavir eller rifampicin). Unge fra 12 år og
derover: Hos unge (fra 12 til 17 år og med en vægt på mindst 40 kg), der er inficeret med hiv-1 uden resistens
over for integraseklassen, er den anbefalede dosis af dolutegravir 50 mg én gang daglig. Kontraindikationer*:
Overfølsomhed over for det aktive stof eller over for et eller flere af hjælpestofferne. Administration samtidigt med
dofetilid. Forsigtighedsregler*: Beslutningen om at anvende dolutegravir ved resistens over for integraseklassen
skal tage højde for at aktiviteten af dolutegravir vurderes at være kompromitteret for virale stammer, der indeholder
Q148+≥ 2 sekundære mutationer fra G140A/C/S, E138A/K/T, L741. Der er rapporteret overfølsomhedsreaktioner
over for dolutegravir (udslæt, konstitutionelle fund og nogle gange organdysfunktion, herunder alvorlige
leverreaktioner). Dolutegravir og andre mistænkte stoffer skal omgående seponeres, hvis der udvikles tegn
eller symptomer på overfølsomhedsreaktioner. Det anbefales at monitorere biokemiske leverparametre hos
patienter, der er co-inficeret med hepatitis B- og/eller C-virus. Patienter i behandling med dolutegravir kan stadig
udvikle opportunistiske infektioner og andre komplikationer fra hiv-infektion. Undgå samtidig administration med
lægemidler, der reducerer dolutegravireksponering (f.eks. antacida indeholdende magnesium/aluminium, jernog calciumtilskud, multivitaminer og inducerende midler, tipranavir/ritonavir, rifampicin og visse antiepileptiske
lægemidler). Koncentrationen af metformin kan øges af dolutegravir. Interaktioner*: Alle faktorer, der reducerer
eksponering for dolutegravir skal undgås ved tilstedeværelse af resistens over for integraseklassen. Dolutegravir
elimineres overvejende gennem metabolisering via UGT1A1. Dolutegravir er også substrat for UGT1A3, UGT1A9,
CYP3A4, Pgp og BCRP; derfor kan lægemidler, der inducerer disse enzymer reducere plasmakoncentrationen
af dolutegravir og reducere den terapeutiske effekt af dolutegravir. Samtidig administration af dolutegravir og
andre lægemidler, der hæmmer disse enzymer kan øge plasmakoncentrationen af dolutegravir. Absorptionen
af dolutegravir reduceres af visse syreneutraliserende lægemidler. In vitro hæmmede dolutegravir den renale
transporter 2 af organiske kationer (OCT2) og multidrug og toksin ekstruderingstransporter (MATE) 1. In vivo blev
et 10-14 % fald i kreatininclearancen (sekretionsfraktion afhænger af OCT2 og MATE-1 transport) observeret
hos patienterne. In vivo kan dolutegravir øge plasmakoncentrationerne af lægemidler, for hvilke udskillelsen
afhænger af OCT2 eller MATE-1 (f.eks. dofetilid, metformin). In vitro hæmmede dolutegravir de renale
optagelsestransportere, organisk anion-transporterer (OAT1) og OAT3. Baseret på manglende effekt på in vivo
farmakokinetikken af OAT-substratet tenofovir, er in vivo hæmning af OAT1 usandsynlig. Hæmning af OAT3 er
HIV & VIROLOGY NEWS 2 · 2015
ikke undersøgt in vivo. Dolutegravir kan øge plasmakoncentrationen af lægemidler, hvis udskillelse er afhængig
af OAT3. Graviditet og amning*: Der er utilstrækkelig mængde data fra anvendelse af dolutegravir til gravide
kvinder. Det er ukendt, om dolutegravir udskilles i human mælk. Det anbefales, at hiv-inficerede kvinder under
ingen omstændigheder ammer deres spædbørn, så overførsel af hiv undgås. Bivirkninger*: Meget almindelig:
Hovedpine, kvalme, diarré. Almindelig: Insomni, unormale drømme, svimmelhed, opkastning, flatulens, smerter
i øvre del af abdomen, abdominalsmerter, abdominalt ubehag, udslæt, pruritus, træthed, forhøjet niveau af
alaninaminotransferase (ALAT) og/eller aspartataminotransferase (ASAT), forhøjet niveau af kreatinfosfokinase
(CPK). Ikke almindelig: Overfølsomhed, immunrekonstitutionssyndrom, hepatitis. Overdosering*: Der er på
nuværende tidspunkt begrænset erfaring med overdosering af dolutegravir. Begrænsede data med højere
enkeltdoser (op til 250 mg hos raske personer) medførte ingen specifikke symptomer eller tegn ud over de tegn
og symptomer, der er anført som bivirkninger. Udlevering: BEGR. Ikke tilskud.
De med * mærkede afsnit er omskrevet og/eller forkortet i forhold til det af EMA godkendte produktresumé.
Fuldt produktresumé kan vederlagsfrit rekvireres hos den danske repræsentant for ViiV, GlaxoSmithKline
Pharma A/S, Nykær 68, 2605 Brøndby.
Bivirkninger, både kendte og nyopdagede, bedes indberettet hurtigst muligt til Sundhedsstyrelsen
(www.meldenbivirkning.dk) eller GlaxoSmithKline (dk [email protected]).
Dagsaktuelle priser findes på www.medicinpriser.dk
References:
1. TIVICAY (dolutegravir) Summary of Product Characteristics
2. Molina J M et al. Lancet 2015; Published online March 10,
http://dx.doi.org/10.1016/S2352-3018(15)00027-2
3. Raffi F et al. Lancet Infect Dis. 2013;13(11):927-935.
DK/DLG/0013/15 maj 2015
Nykær 68
DK-2605 Brøndby
T +45 36 35 91 00
F +45 36 35 91 01
www.glaxosmithkline.dk
33
Search for a cure
Symposium on the search
for a cure
In March 2015, a Symposium on the
search for a cure for HIV was held in
Copenhagen. The scientific content of
the Meeting was organised by the Department of infectious diseases at Aarhus University Hospital in Denmark. The
Meeting was funded by an unrestricted
educational grant by Gilead Sciences
Nordic, as a service to medicine.
T
he first Speaker was Prof Mario Stevenson, who started by stating that
living with life-long therapy is not a
good option. Where does HIV-1 hide,
and why does it persist? This question
was also the title of his lecture.
Flip the question
Prof Stevenson talked about viral rebound
after HAART discontinuation.
– It is amazing how quick rebound comes, he said.
He continued by talking about the
mechanism of HIV persistence in latent
reservoir. How do we assess if the viral
reservoir that persists under suppressive
ART is static or dynamic?
– We could flip that question around:
What fuels viral recrudescence when antiretroviral suppression is interrupted?
Current consensus is that recrudescence
occurs following stochastic reactivation
of latently infected cells that drive exponential viral growth, Prof Stevenson said.
A latent infected cell has 9 more genes –
viral genes, he pointed out.
– Otherwise it is exactly like any other
cell, which makes it difficult to shine a
light at cells and decide if they are latently
infected or not.
It is debated if the time to rebound is
related to the size of the reservoir or not.
Viral recrudescence occurs in lymphatic
tissues at multiple anatomic sites simultaneously following treatment interruption.
Macrophages have a role in HIV infection
One theory is that ART interruption reveals focal sources of viral recrudescence.
Another theory is that ART interruption
coordinates removal of obstacle to viral
spread.
34
– This presents the question of how
transcriptional reactivation is coordinated. Are there reservoirs other than CD4+
T-cells, such as myeloid cells, that sustain
HIV-1 persistence in the face of ART?
Prof Stevenson told the audience that
his lab has had a long interest in myeloid
cells.
– Macrophages present unique obstacles to infection by primate lentiviruses. As a consequence, primate lentiviruses appear to have been evolutionary
pressed to evolve determinants to overcome these obstacles.
He ended his lecture by listing present
obstacles to cure. On top of this was the
reservoir of long-lived, latently infected
cells. Next item on the list was residual
replication and potential replenishment
of viral reservoirs.
– Large reservoirs of infected cells are
Mario Stevenson
Paul Denton
”primed” to ignite viral replication. The
reservoir may not be static – and that’s
actually encouraging!
Last on the list was the presence of virus in tissue macrophages. Whether such
cells constitute a long-live reservoir – and
whether such a reservoir poses unique
challenges for eradication – is unclear.
HIV & VIROLOGY NEWS 2 · 2015
Search for a cure
100% SVR 12 RATES IN ADVANCED FIBROSIS
EFFICACY IN
ADVANCED FIBROSIS
High SVR12 rates in genotypes 1 and 3 with advanced fibrosis
(≥F3 scores based on FibroTest data†) with Daklinza® daclatasvir
in combination with Sovaldi® sofosbuvir1,2
GENOTYPE 1
GENOTYPE 3
100%
100%
100%
n=41
n=20
n=5
Treatment Naive patients
12/24 wk treatment
PI-failures
24 wk treatment
Treatment Naive patients
24 wk treatment
Adapted from: Daklinza® daclatasvir Summary of Product Characteristics. Aug. 2014
† The Metavir score was derived from FibroTest Score and classified according to the manufacturer’s instructions [www.biopredictive.com]; patients with a score of F4 were required to have no evidence of cirrhosis.
References: 1. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211–221. 2. Daklinza®daclatasvir
Summary of Product Characteristics. Aug. 2014
Dette lægemiddel er underlagt supplerende overvågning. Læger og sundhedspersonale anmodes om at indberette alle mistænkte bivirkninger.
Produktinformation for DAKLINZA (DACLATASVIR) 30 mg og 60 mg filmovertrukne tabletter.
De med * markerede afsnit er omskrevet/forkortet i forhold til det af Sundhedsstyrelsen godkendte produktresumé dateret 17. september 2014.
Terapeutiske indikationer*: Behandling af kronisk hepatitis C virusinfektion (HCV) i kombination med andre lægemidler hos voksne.
Dosering og administration*: 60 mg oralt en gang dagligt. DAKLINZA skal administreres i kombination med andre lægemidler. Produktresuméerne for de andre lægemidler i behandlingen bør ligeledes konsulteres,
før behandling med DAKLINZA initieres. Anbefalede behandlinger og behandlingsvarighed: Til behandling af HCV Genotype 1 eller 4 uden cirrose med DAKLINZA + sofosbuvir er behandlingsvarigheden 12 uger.
Til behandling af HCV Genotype 1 eller 4 med kompenseret cirrose med DAKLINZA + sofosbuvir er behandlingsvarigheden 24 uger. Til behandling af HCV Genotype 3 med kompenseret cirrose og/eller tidligere
behandling er behanlingsvarigheden med DAKLINZA + sofosbuvir + ribavirin 24 uger. Til behandling af Genotype 4 med DAKLINZA + peginterferon alfa + ribavirin er behandlingsvarigheden 24 uger. Dosisjustering:
Anbefales ikke til håndtering af bivirkninger. Hvis det er nødvendigt at afbryde behandlingen med andre behandlingskomponenter på grund af bivirkninger, må DAKLINZA ikke gives som monoterapi. Administration:
Oral anvendelse. Skal synkes hel med vand, med eller uden føde. Kontraindikationer*: Overfølsomhed over for aktivt stof eller ét hjælpestof. Samtidig behandling med andre lægemidler, som er kraftige induktorer af
af cytochrom P450 3A4 (CYP3A4) og P-glycoprotein transporter (P-gp), da det kan medføre nedsat eksponering og nedsat virkning af DAKLINZA. Særlige advarsler og forsigtighedsregler vedrørende brugen*:
DAKLINZA må ikke administreres som monoterapi. DAKLINZA skal administreres i kombination med andre lægemidler til behandling af kronisk HCV infektion. Daklinza bør ikke anvendes under graviditeten og
til kvinder i den fertile alder, som ikke anvender sikker kontraception. Anvendelse af yderst sikker kontraception bør fortsætte i 5 uger efter ophør med behandling med DAKLINZA. Interaktioner*: Frarådes hos
patienter, der samtidig får systemisk behandling med kraftige hæmmere af både CYP3A4 og P-gp. Forsigtighed ved samtidig brug af kraftige CYP3A4- og P-gp-induktorer. Fertilitet, graviditet og amning*: Bør
ikke anvendes. Bivirkninger*: Meget almindelig(mere end 10%): Hovedpine. Kvalme. Træthed. Almindelig(1-10%): Anæmi. Nedsat appetit. Depression. Angst. Insomni. Svimmelhed. Migræne. Hedetur. Diarre.
Øvre abdominalsmerter. Obstipation. Flatulens. Gastoøsofagal reflukssygdom. Tør mund. Opkastning. Pruritus. Tør hud. Alopeci. Udslæt. Artralgi. Myalgi. Irritabilitet. Overdosering*: Ingen antidot. Påbegyndelse af
passende understøttende behandling. Pakninger og priser (ESP 29 10 2014): Filmovertrukne tabletter 30 mg: 28 stk: 102793,05 kr. Filmovertrukne tabletter 60 mg: 28 stk: 102793,05 kr. Se venligst dagsaktuel pris på
http://medicinpriser.dk. Tilskud: Nej. Udlevering: BEGR. Indehaver af markedsføringstilladelsen: Bristol-Myers Squibb Pharma EEIG, Uxbridge Business Park, Sanderson Road, Uxbridge UD8 1DH, Storbritannien.
Produktresumeet kan vederlagsfrit rekvireres fra den danske repræsentant: Bristol-Myers Squibb, Hummeltoftevej 49, 2830 Virum.
HIV & VIROLOGY NEWS 2 · 2015
35
Search for a cure
– But I think we now have sufficient
evidence that macrophages have a role in
HIV infection, Prof Stevenson finished his
talk.
The size of the reservoir matters
How large is the viral reservoir – and
what is the best way to measure it? This
question was the title of a talk from Prof
Linos Vandekerckhove (see also page 31 in
this issue of HIV & Virology News).
After defining the viral reservoir, he
presented three ways of measuring it. The
first was viral outgrowth assay (VOA).
– The frequency of HIV-1 latent infection of resting CD4+ T-cells can be measured using this assay. The technique is
limited by the fact that it is very expensive
and time-consuming. Therefore it is difficult to implement it in clinical trials, Prof
Vandekerckhove explained.
The second way is TILDA (Tat/Rev Induced Limiting Dilution Assay). It looks
for frequency of cells with multiply spliced HIV RNA.
– However, TILDA is not validated, he
continued.
The third way is PCR based assays to
quantify the reservoir. According to Prof
Vandekerckhove, this is the main method
used so far. It has been validated for functional cure.
On validation of total HIV DNA as a surrogate marker for functional cure, it has
been very nicely demonstrated that HIV-1
DNA predicts clinical progression in absence of ART, he continued.
– And this means that the size of the
reservoir has an effect on how quickly rebound takes place! What we lack is a study
where patient’s treatment is stopped based on the level of total HIV DNA.
There is no perfect assay
Prof Vandekerckhove continued by talking about how to improve assays. One
way is improving resolution.
– To which extent this will give us more
information is still to be proved. But it
looks promising!
What do we know about new PCR based assays?
– Limited dilution assays increase the
resolution to evaluate the reservoir, but
are expensive, not automated yet – and
the added value in clinical trials is still limited.
Integration site sequencing is a new
emerging tool to evaluate clonal expansion. Limited sampling might pose the
most important barrier to use these assays
in the cure field, he underlined.
In Prof Vandekerckhove’s conclusion
he pointed out that there is no ”perfect as-
36
say” and prospective trials are needed to
evaluate both PCR and VOA based assays.
Also that the size of the reservoir depends on the population we are evaluating.
– A combination of assays will most probably be needed to predict a functional
cure, he said.
A cure require novel combinations of
interventions
Prof Paul Denton talked about animal models, and what they can tell us about HIV
latency.
– Animal HIV models allow us to ethically overcome spatial, temporal and
combinatorial research challenges to gain
novel insights into HIV persistence. Spatial via analyses of multiple anatomical
compartments, temporal via careful timing of virus exposure and interventions
– and combinatorial via efficacy testing of
novel modality groupings, Prof Denton
explained.
Ole Søgaard
John Frater
The predominant animal models for
HIV persistence research are humanized
mice and non-human primates. He presented both pros and cons for the two.
Prof Denton summarised the findings in
each research challenge category.
– Spatial: Animal models have shown
that viral reservoirs persist throughout
the body in primary lymphoid tissues, secondary lymphoid tissues and other anatomical regions.
HIV & VIROLOGY NEWS 2 · 2015
Search for a cure
Under the headline temporal he said
that early ART (day 7) has showed reduced plasma viremia.
– But, initiating ART as early as day 3
did not cure the infection.
And under the final headline – combinatorial – the first statement was that a cure
for HIV will likely require novel combinations of interventions.
– Preclinical efficacy evaluations in animal models will help bring such combinations to the clinic.
Animal models have been of use to demonstrate in vivo efficacy and potential
design constraints on therapeutic vaccines and immunotherapies.
– Animal models can tell us a lot, Prof
Denton summarised his talk.
The shock and kill strategy
An overview on HIV curative interventions was presented by Prof Steven Deeks.
He began this by describing the mechanisms of HIV persistence: Long-lived
cellular reservoirs, ”homeostatic” T-cell
proliferation and inflammation/T-cell activation.
– The role of inflammation is still controversial, he underlined.
How does the immune system shape
the size, distribution and fate of the infected cell?
– Our work – and others – suggests that
total size of reservoir is correlated and
often enriched in cells. It also suggests
that HIV enriched in memory cells is programmed to persist indefinitely.
HIV is enriched in lymphoid-resident
Follicular helper T cells – especially in
lymph nodes, Prof Deeks continued.
– Massive and sustained (over years)
clonal expansion of infected T-cells
contributes to HIV persistence in many
individuals.
So how will HIV be eliminated or controlled in absence of ART? Prof Deeks talked about several approaches for this.
– By preventing latency via early ART,
by reversing latency – i.e. ”shock”, and
clearing virus-producing cells (i.e. ”kill”).
Also by modifying the immune system
to make it more ”harsh” for virus and by
using cell and gene therapy, he said.
An ambitious but feasible goal
The ”shock and kill” concept was described in more detail by Prof Deeks.
– Shock means to wake up latent cells,
he said and presented a study on panobinostat – a histone deacetylase inhibitor
for latent-virus reactivation in HIV patients on suppressive ART. It was a Phase
I and II single group, clinical trial. Accor-
HIV & VIROLOGY NEWS 2 · 2015
ding to Prof Deeks it represents an ”iconic
moment in the search for a cure”.
He continued by presenting another
study, this one on TLR7 agonist GS9620,
that was shown to increase CD8+ T-cell
activation in monkeys on ART.
– This was the most exciting news at
CROI 2015, he stated. (Read more of this
study in HIV & Virology News 1/15).
The concept of kill was illustrated by
Prof Deeks with a study on immune clearance of highly pathogenic SIV infection.
– CMV engineered as a live HIV/SIV
vaccine causes high levels of tissue-based ”killer” CD8+ T-cells that target novel
parts of the virus. These cells clear latency during early infection, resulting in first
clear documentation of a ”cure” in an animal model. Human studies are pending.
Curing HIV is an ambitious, but feasible
goal, he concluded.
– We need nimble funding that is targeted, goal-oriented and willing to support
”high-risk” science, not typically supported by National Institutes of Health. We
need multidisciplinary, and often international, teams and inclusive input from
academia, biotech/pharma, governments
and philanthropy.
It calls for effective leadership and organisation, and requires long-term commitment, Prof Deeks said and ended with
a quote:
– ”Science operates around a core of uncertainty, within which lies setbacks, but
also hope”.
Combining shocking agents
Vorinostat is a histone deacetylase
(HDAC) inhibitor with high potency against HDACs. It is FDA approved since
2006 for treatment of cutaneous T-cell
lymphoma. Vorinostat has repeatedly
shown to induce virus production in vitro
and ex vivo in the resting CD4+ T-cells
of aviremic HIV infected patients on
HAART.
This was pointed out by Dr Ole Søgaard,
who talked about the clinical experiences
of reversing HIV latency as a strategy to
purge the viral reservoir.
– A study on panobinostat found that it
provided the shock to reactivate HIV, Dr
Søgaard said.
After analytic treatment interruption,
all patients rebounded – but not at the
same time.
He continued by describing a non-randomised clinical trial on romidepsin iv
day 0, 7 and 14. The primary endpoints
were safety, as well as activation of HIV1 latency as determined by plasma HIV-1
RNA and cell-associated unspliced HIV-1
RNA in total CD4+ cells.
– The study showed proof-of-concept
that HDAC inhibitors can reverse latency
in vivo. But since all patients rebounded,
either the shock and/or the kill was insufficient, Dr Søgaard reported.
The path forward needs more potent
latency reversing agents (LRAs), he said.
– We need to combine LRAs to achieve a
synergetic effect – and combine them with
immunotherapeutics that permanently
enhance the clearence of virus-producing
cells.
Or we should combine LRAs with gene
therapy or other approaches that permanently protects uninfected cells from being infected, he summarised.
– Combining shocking agents – that
could be the future, Dr Søgaard stated.
The duration of ART matters
The last Speaker was Prof John Frater,
and the title of his talk was What predicts
long term HIV remission.
– I was given this title, and it’s interesting. There’s an assumption here – that
HIV can be in remission, he started by
saying.
A French study on people with primary, not chronic, infection found that two
years after treatment interruption 15.3 %
of patients had not rebounded.
– If you treat patients early, you can find
patients that do not rebound after discontinuation of ART. The duration of ART
at primary infection matters, Prof Frater
said.
He described the SPARTAC trial. A
sub-analysis found that 161 of 165 patients
rebounded after discontinuation of ART
after 48 weeks. A majority of these rebounded after 12 weeks.
– But not all! 14 % were still at undetectable levels after a year – which was
much more than expected. The duration
of ART definitely means something!
His conclusion was that – with the caveat that SPARTAC was not designed to
investigate the HIV reservoir or post-treatment control – they did find a close
association between HIV-1 DNA and
HIV-1-specific T-cell immunity.
– Only total HIV-1 DNA predicted rebound measured in treatment interruption. Three separate T-cell exhaustion/
”immune checkpoint” markers were associated with rebound – measured pre-ART.
And that’s an exciting thing to explore,
Prof Frater finished his lecture.
Per Lundblad
37
Banishing B
Banishing B - going beyond
management
Chronic infection with hepatitis B virus
(HBV) represents a major burden upon
health and economic resources in Europe. At a Satellite Symposium at the ILC
in Vienna, sponsored by Gilead, the remaining challenges and opportunities
when managing patients with HBV was
discussed – as well as milestones that
have been achieved to date.
P
rof Harald Hofer, who was the Chair,
pointed out in his talk that treatment
of HBV has made progress.
– We have achieved suppression of
HBV replication, decreased hepatic inflammation and fibrosis and managed to
prevent or reduce complications of cirrhosis, he said.
However, challenges remain. Now there
is a focus on cure, Prof Hofer said.
Good effect with tenofovir
The REVEAL study demonstrated the association between HBV DNA levels and
hepatocellular carcinoma, said Prof George Papatheodoridis.
– HBV DNA replication can be successfully controlled, with little or no resistance, he continued.
The effect of long-term tenofovir in patients with a high viral load are good, according to data.
He also presented data that showed two
approaches for rescue therapy in patients
with lamuvidine and entecavir refractory
chronic HBV infection
– 20 % of patients that had lamuvidine
+ adefovir rescue therapy had undetectable HBV DNA after 24 months. 88 % of
patients that switched to lamuvidine + tenofovir had undetectable HBV DNA after
6 months.
Treatment with tenofovir in patients
with chronic hepatitis B infection can result in regression of liver disease – liver
fibrosis regression and cirrhosis reversal.
HBsAg loss
Prof Papatheodoridis underlined the need
for patient’s adherence to therapy – and
reminded the audience that this may not
be as good as physicians expect.
– There are many reasons for poor ad-
38
Harald Hofer
herence. Factors associated with poor adherence are poor adherence to other medication, or a discrepancy between the
language spoken by the physician and the
patient.
His conclusion was that now is the time
to strive for HBsAg loss. Prof Papatheodoridis quoted EASL 2012 guidelines for
nucleoside analogues discontinuation.
– For HBeAg positive patients after
confirmed anti-HBe seroconversion (and
undetectable HBV DNA) after at least 12
months of consolidation. Then discontinuation can take place after confirmed
HBsAg loss and anti-HBs seroconversion.
For HBeAg negative patients, and cirrhotics, discontinuation can take place after
HBsAg loss and anti-HBs seroconversion.
Combination therapy an unmet need
Prof Jörg Petersen talked about the search
for a cure, and he agreed with Prof Papatheodoridis.
– Off-therapy HBsAg loss with – or even
without – anti-HBs seroconversion is the
ideal endpoint.
He reminded the audience that HBsAg
is a surrogate marker for covalently closed
circular DNA (cccDNA).
HBsAg loss is associated with a complete and definitive remission of chronic
HBV infection and improved long-term
survival.
– The ultimate goal would be achievement of HBsAg loss with a finite course of
oral antiviral therapy, Prof Petersen said.
He continued by describing several fu-
George Papatheodoridis
Jörg Petersen
ture HBV therapies – with new targets,
new drugs and new aims. One of the new
drugs investigated is the toll-like receptor
7 antagonist GS-9620, that acts by modulating the immune system.
In his conclusions Prof Petersen said
that EASL is considering combination
therapy in chronic HBV infection an unmet need, and is supporting ongoing assessment of safety and efficacy.
– The question is if HBsAg loss and potentially cccDNA silencing will be the ultimate goal of therapy in the future?
After the two lectures, a panel discussion on this and other questions ended the
Symposium.
Per Lundblad
HIV & VIROLOGY NEWS 2 · 2015
NeuroHIV
BE THE
ONE
WHO CAN CHANGE WHAT’S POSSIBLE
For your F0 to F4
compensated cirrhosis
GT1 patientsa:
CURE.
Up to 99% cure in HCV GT1 patients1,b,c
– Consistently high cure rates of 94-99% across phase 3
pivotal studies1
DON’T COMPROMISE.
99% completed regimens of up to 12 weeks1
– ≤1% of patients discontinued treatment with HARVONI
(ledipasvir/sofosbuvir) due to adverse events1
ONE pill, once a day1,d
– The first and only Single-Tablet Regimen for the majority
of HCV GT1 patients1,d
Albert Einstein used with permission of the HUJ/GreenLight
a
IFN free
As assessed by the Metavir fibrosis stage scoring system.
HARVONI (ledipasvir/sofosbuvir) is indicated for the treatment of chronic hepatitis C (CHC) in
adults. 99% cure rates were observed in the ION-1 study in previously untreated HCV GT1 patients
treated with HARVONI (ledipasvir/sofosbuvir) for 12 weeks. Across the ION studies, SVR rates
between 94-99% were observed in HCV GT1 patients treated with HARVONI (ledipasvir/sofosbuvir)
for 8-24 weeks. 99% of patients completed regimens of up to 12 weeks.1
b
c
RBV freed
PI free
NEW
EASL define cure as SVR12. 2
HARVONI (ledipasvir/sofosbuvir) offers a single-tablet, ribavirin-free regimen for the majority of
HCV GT1 patients, excluding those with decompensated cirrhosis, or who are pre- or post-liver
1
transplant.
HIV
& VIROLOGY NEWS 1 · 2015
d
39
AASLD 2014
Produktinformation rettet til sundhedspersoner
Forkortet produktresumé for Harvoni®
90 mg/400 mg filmovertrukne tabletter,
ledipasvir/sofosbuvir.
Præsentation: Hver filmovertrukken tablet
indeholder 90 mg ledipasvir og 400 mg sofosbuvir.
Indikationer: Harvoni er indiceret til behandling af kronisk hepatitis C (CHC) hos voksne.
For genotypespecifik aktivitet af hepatitis
C-virus (HCV) , se punkt 4.4 og 5.1 i produktresuméet.
Dosering og indgivelsesmåde*: Behandling
bør påbegyndes og overvåges af en læge
med erfaring i behandling af patienter med
CHC. Den anbefalede dosis er en tablet én
gang dagligt. Tabletten sluges hel sammen
med eller uden mad. Tabletterne bør ikke
tygges eller knuses. Patienter med genotype 1 eller genotype 4-CHC: Patienter uden
cirrose eller med kompenseret cirrose kan
behandles med Harvoni alene. Behandlingsvarighed varierer (se produktresuméet).
Patienter med dekompenseret cirrose, eller
før/efter en levertransplantation behandles
med Harvoni+ribavirin i 24 uger. Patienter
med genotype 3-CHC: Patienter med cirrose
og/eller tidligere behandlingssvigt behandles med Harvoni + ribavirin i 24 uger. Ved
kombinationsbehandling med ribavirin se
retningslinjer for dosismodifikation i produktresuméerne for både Harvoni og ribavirin.
Nedsat leverfunktion: Ingen dosisjustering
for patienter med let, moderat eller svært
nedsat leverfunktion. Sikkerhed og virkning
ved svært nedsat leverfunktion er undersøgt.
Pædiatrisk population: Sikkerhed og virkning
er ikke klarlagt hos børn og unge under 18 år.
Glemt dosis:. Hvis en dosis glemmes inden
for 18 timer fra det normale tidspunkt, tages
tabletten så snart som muligt, ellers skal der
ventes med den næste dosis til den sædvanlige tid. Hvis patienten kaster op inden for 5
timer efter dosering tages en ekstra tablet.
Kontraindikationer: Overfølsomhed over for
de aktive stoffer eller over for et eller flere
af hjælpestofferne. Samtidig administration
med rosuvastatin eller prikbladet perikon
(hypericum perforatum).
Særlige advarsler*: Harvoni må ikke administreres sammen med andre lægemidler, der
indeholder sofosbuvir. Genotypespecifik aktivitet: Angående anbefalede regimer med
forskellige HCV-genotyper, se doseringsafsnit i produktresuméet. De kliniske data, der
støtter brug af Harvoni hos patienter inficeret
med HCV-genotype 3 og 4 er begrænsede
(se produktresuméet pkt. 5.1). Ledipasvir/sofosbuvirs virkning er ikke blevet undersøgt
mod HCV-genotype 2, 5 og 6 og må derfor
ikke anvendes til patienter inficeret med disse
genotyper. Behandling af patienter med tidligere eksponering over for HCV direkte virkende antivirale midler: Patienter, hvor behandlingen med ledipasvir/sofosbuvir svigter, kan
være afhængige af andre lægemiddelklasser
med henblik på clearance af HCV-infektion.
Som følge heraf skal det overvejes at give
længere behandling for patienter med usikre
efterfølgende muligheder for genbehandling.
Nedsat nyrefunktion: Dosisjustering af Harvoni er ikke påkrævet ved en let eller moderat
nedsat nyrefunktion. Sikkerheden af Harvoni
er ikke blevet undersøgt ved en svært nedsat nyrefunktion. I kombination med ribavirin
i tilfælde af en kreatininclearance (CrCl) <50
ml/min. henvises også til produktresuméet
for ribavirin. Patienter med dekompenseret
cirrose og/eller som venter på en levertransplantation eller efter en levertransplantation:
Den relative virkning af 12 og 24 ugers be-
handling er ikke klarlagt. Derfor anbefales 24
ugers behandling. Behandling med Harvoni
bør vejledes af en vurdering af de mulige
fordele og risici for den individuelle patient.
Samtidig brug med kraftige P-gp-inducere,
som f.eks. rifampicin, carbamazepin og phenytoin kan nedsætte plasmakoncentrationen
af ledipasvir og sofosbuvir signifikant, hvilket
kan medføre en reduceret terapeutisk virkning. Derfor bør disse lægemidler ikke anvendes sammen med Harvoni. Samtidig brug
med visse hiv antiretrovirale regimer: Harvoni kan øge tenofovireksponeringen, især når
det bruges sammen med et hiv-regimen, der
indeholder tenofovirdisoproxilfumarat og en
farmakokinetisk forstærker (ritonavir eller
cobicistat). De mulige risici og fordele forbundet med administration af Harvoni med
fastdosis kombinationstabletter, der indeholder elvitegravir/cobicistat/emtricitabin/tenofovirdisoproxilfumarat eller tenofovirdisoproxilfumarat brugt sammen med en boostet
hiv proteasehæmmer (f.eks. atazanavir eller
darunavir) bør overvejes, især hos patienter
med øget risiko for nyredysfunktion. Patienter i denne kombinationsbehandling, bør
overvåges for tenofovirassocierede bivirkninger (se produktresuméerne for tenofovirdisoproxilfumarat, emtricitabin/tenofovirdisoproxilfumarat eller elvitegravir/cobicistat/
emtricitabin/tenofovirdisoproxilfumarat for
anbefalinger om nyreovervågning). Samtidig
brug med HMG-CoA reductasehæmmere og
Harvoni kan forhøje koncentrationen af statin
signifikant, hvilket øger risikoen for myopati
og rhabdomyolyse. Samtidig infektion med
HCV/HBV (hepatitis B-virus): Der foreligger
ingen data for anvendelsen af Harvoni hos
patienter med samtidig infektion med HCV/
HBV. Pædiatrisk population: Harvoni bør ikke
anvendes til børn og unge under 18 år. Hjælpestoffer: Indeholder azo-farvestoffet sunset
yellow FCF aluminiumpigment (E110), som
kan forårsage allergiske reaktioner. Indeholder lactose og bør derfor ikke anvendes til
patienter med arvelig galactoseintolerans,
en særlig form af hereditær lactasemangel (Lapp lactase deficiency) eller glucose/
galactosemalabsorption.
Interaktioner*: Da Harvoni indeholder ledipasvir og sofosbuvir kan alle interaktioner,
der er blevet identificeret med disse aktive
stoffer individuelt, forekomme med Harvoni
(se interaktioner, der kan have klinisk signifikans i tabel 3 i produktresuméet, tabellen er
dog ikke udførlig). Her nævnes følgende lægemiddelgrupper: Syrereducerende stoffer,
antiarytmika, antikoagulantia, antikonvulsiva,
antimykobakterielle midler, HCV-præparater. Hiv-antivirale stoffer: som f. eks. revers
transkriptasehæmmere eller hiv proteasehæmmere, eller integrasehæmmere. Naturmedicin, HMG-CoA reductasehæmmere,
narkotiske analgetika, immunosupprimerende midler, orale antikontraceptiva.
Fertilitet, graviditet og amning*:
Ved en kombineret behandling med ribavirin, skal der udvises ekstrem forsigtighed, så
graviditet undgås hos kvinder og hos mandlige patienters kvindelige partnere. Der er
vist signifikante teratogene og/eller embryocidale virkninger hos alle dyrearter, der blev
eksponeret for ribavirin. Der skal anvendes
en sikker kontraceptionsmetode i løbet af
behandlingen og i en periode efter behandlingen, som anbefalet i produktresuméet for
ribavirin.
Graviditet: Der er ingen eller utilstrækkelige
data fra anvendelse af ledipasvir, sofosbuvir
eller Harvoni til gravide kvinder. For en sikkerheds skyld bør Harvoni undgås under graviditeten.
References
1. HARVONI Summary of Product Characteristics, November 2014.
2. EASL Clinical Practice Guidelines. April 2014. Available at: http://www.easl.eu/–newsroom/latest-news
/easl-recommendations-on-treatment-of-hepatitis-c-2014.
32
Amning: Det er ukendt, om ledipasvir eller
sofosbuvir og dets metabolitter udskilles i
human mælk. En risiko for nyfødte/spædbørn kan ikke udelukkes, og derfor må Harvoni ikke anvendes under amning.
Fertilitet: Der foreligger ingen data fra mennesker om Harvonis indvirkning på fertiliteten. Ved en kombineret behandling med ribavirin -se produktresuméet for ribavirin.
Virkning på evnen til at føre motorkøretøj
og betjene maskiner: Ingen mærkning. Der
kan forekomme træthed som en mere almindelig bivirkning. Harvoni (administreret alene
eller i kombination med ribavirin) påvirker
ikke eller kun i ubetydelig grad evnen til at
føre motorkøretøj og betjene maskiner.
Bivirkninger*: Meget almindelige (≥1/10):
Træthed og hovedpine. Bivirkningerne i
kombineret behandling med ribavirin var ens
med den kendte sikkerhedsprofil for ribavirin,
uden øget hyppighed eller sværhedsgrad af
de forventede bivirkninger.
Overdosering*: Den højeste dosis af ledipasvir og sofosbuvir på hhv. 120 mg to gange
dagligt i 10 dage, og en enkeltdosis på 1.200
mg, viste ingen bivirkninger. Virkningen af
højere doser er ikke kendt. Der findes ingen specifik antidot. Behandling: Patienten
observeres for tegn på toksicitet. Ligeledes
overvåges de vitale tegn og patientens kliniske status. Det er ikke sandsynligt, at hæmodialyse fjerner ledipasvir i signifikant grad, da
ledipasvir i høj grad er bundet til plasmaprotein. Hæmodialyse er effektivt til at fjerne
den dominerende cirkulerende metabolit fra
sofosbuvir.
Pakninger: Tabletbeholdere med 28 filmovertrukne tabletter. Vnr: 573382
Pris: For dagsaktuel medicinpris se:
www.medicinpriser.dk
Tilskudsstatus: Ikke tilskudsberettiget.
Udlevering: BEGR (kun udlevering til sygehuse)
Markedsføringstilladelsesnummer:
EU/1/14/958/001
Indehaver af markedsføringstilladelsen:
Gilead Sciences International Ltd, Cambridge, CB21 6GT, Storbritannien.
Produktinformationen er forkortet. Et fuldstændigt produktresumé kan rekvireres hos
indehaveren af markedsføringstilladelsen
og yderligere information kan rekvireres
hos den danske repræsentant: Gilead Sciences Denmark ApS, Korskildelund 6, 2670
Greve, Danmark Telefon: +45 36 91 50 50
Afsnit markeret med * er forkortet i forhold til
det af EMA godkendte produktresumé.
LÆS PRODUKTRESUMÉET FØR ORDINATION ISÆR MED HENSYN TIL BIVIRKNINGER,
ADVARSLER OG KONTRAINDIKATIONER.
Et fuldstændigt produktresumé kan findes
på EMAs hjemmeside
Dato for oprettelse af produktinformation:
November 2014
Ved godkendelse af markedsføringstilladelsen, er dette lægemiddel løbende underlagt supplerende
overvågning, som vist med den
omvendte sorte trekant. Alle mistænkte bivirkninger ved brug af Harvoni
skal rapporteres til Gilead via e-mail
til: [email protected]
eller på telefon +46 (8) 505 718 00 og
/eller til Sundhedsstyrelsen i overensstemmelse med det nationale spontane rapporteringssystem.
www.meldenbivirkning.dk
Date of preparation:
December 2014
HAR/DK/14-12/PM/1138
Gilead Sciences Nordic Office | Hemvärnsgatan 9, SE-171 54 Solna, Sweden | Phone: + 46 (0)8 505 71 800 | Fax: + 46 (0)8 505 71 801
HIV & VIROLOGY NEWS 1 · 2015
Conquering C
Conquering C - going
beyond cure
During a Satellite Symposium sponsored by Gilead, an expert faculty discussed this new era of highly efficacious
agents and the challenges that remains
to overcome.
P
rof Stefan Zeuzem, who was the
Chair, began by presenting data proving that HCV-infected adults are at
increased risk of premature death.
– We now have direct-acting antivirals
(DAAs) that target different points in the
HCV lifecycle – delivering the possibility
of an interferon-free, and in some cases
ribavirin-free, future for patients, he said.
The challenge is to translate improvements in SVR into cure for all patients –
with improvements in liver function and
long-term outcomes.
Patients with liver disease
A greater understanding of the HCV lifecycle has provided a new toolbox of
highly effective interferon-free strategies,
Prof Jean-Michel Pawlotsky pointed out.
He continued by presenting the different
stages of severity of liver disease.
– Treatment solutions with high rates
of infection cure are now available for the
majority of HCV-infected patients. But a
majority is not all, he stated.
Challenges remain in special populations, including those who failed on interferon-free regimens and in implementation, was Prof Pawlotsky’s conclusion
Dr Marc Bourliére presented data that
showed that the risk of disease progression is linked to the stage of fibrosis. He
described the spectrum of advanced liver
disease with a worsening liver function.
– The new DAAs open up the possibility to treat more patients with advanced
disease, he pointed out.
Due to worsening fibrosis, there is a
need to treat patients early with drugs
that deliver the highest chance of a cure.
– The later you treat, the harder it is to
cure the liver disease
Short, well-tolerated direct-acting antivirals regimens will be available soon, and
this will increase the possibility to treat a
broad spectrum of patients with advanced
liver disease, he ended his talk.
HIV & VIROLOGY NEWS 2 · 2015
Jean-Michel Pawlotsky
Strategy for HCV in England
Prof Graham Foster talked about the new
EASL recommendations, and described
them as a ”manual for treating HCV”.
– But life gets in the way. There are
many factors you can’t change, such as access. What you can change is patient control. You want to pick a regimen that will
cause patients to be adherent, he said.
Treatment of all cirrhotic patients will
start soon, and treatment of non-cirrhotic
patients is scheduled to start in 2016, he
told the audience.
– We are working with NHS England to
maximise gains made with the new drugs,
Prof Foster continued.
If successful, all patients can be managed over the next 5 - 10 years.
– So where do we go next? After treating the cirrhotics, I suggest we go out of
the clinic – into the community, prisons,
i.v. drug users etc. This in order to treat
those that transmit the epidemic.
He summarised by stating that ongoing
exchange of real world experience is important in order to inform clinical decision-making in practice.
DAA therapy is cost-effective
Despite declining HCV infections, the
burden of HCV is still increasing in the
US, said Dr Nezam Afdhal.
– The number of individuals with late-stage liver disease is projected to increase, he explained.
With ongoing therapeutic advanceme-
Marc Bourliére
Nezam Afdhal
nts and screening policy changes, HCV in
a model-based prediction could become a
rare disease within the next 22 years, he
continued.
– But the question is: Will restrictions
on access and reimbursement mean that
these ideals are not achieved?
Dr Afdhal ended his talk by pointing
out that DAA therapy is cost-effective and
cost-efficient.
– Access programmes to bring the new
DAAs to more patients has the potential
to transform HCV management globally,
he concluded.
Per Lundblad
41
Management of HCV
The new landscape in
management of HCV
In a Satellite Symposium sponsored by
Bristol-Myers Squibb, recent evidence
taken to clinical practice was discussed.
Real-world data now prove to be very
similar those recorded in clinical trials.
The Symposium brought together an
international faculty to discuss up-todate evidence in the management of
HCV patients.
P
rof Heiner Wedemeyer, who was
the Chair, started by asking why we
are still aiming for new HCV treatments?
– Because people are dying from this
disease! Data shows that HCV complications will increase markedly over the next
5-10 years, he answered his own question.
Heiner Wedemeyer
Vincent Leroy
42
Three recent trials
We must keep in mind that HCV is not
only a liver disease. It causes many other
disorders, Prof Wedemeyer continued.
Improvements in IFN-free regimens
are substantially improving patient care.
But there are many tough decisions ahead:
When to start treatment, which drugs to
use and how long to treat.
– Also if to use ribavirin or not. What
about patients with advanced liver disease – and how to treat genotype (GT)
3? These are questions that need to be answered, he stated.
HCV GT 3 infection has a unique pathophysiology, with a higher mortality.
When it comes to burden of disease, 3 is
the second most prevalent GT.
– Currently approved IFN-free treatment choices in the European label for
patients with HCV GT 3 are: Daclatasvir
+ sofosbuvir + ribavirin, sofosbuvir /ledipasvir + ribavirin in a fixed dose combination and sofosbuvir + ribavirin – all for 24
weeks, Prof Wedemeyer continued.
He then presented the latest data from
three clinical trials, showing high sustained clinical response (SVR) rates without
ribavirin for non-cirrhotic GT 3 patients.
ALLY-3 (daclatasvir + sofosbuvir for 12
weeks) had 94 % of patients achieving
SVR. In ELECTRON-2 (LDV/SOF + ribavirin for 12 weeks) this figure was 89 %.
Finally, VALENCE (sofosbuvir + ribavirin
for 24 weeks) showed 87 % SVR.
Jürgen Rockstroh
GT 3 and co-infection patients
Then four speakers presented one patient
case each – which meant presenting data
from the real-world. Prof Vincent Leroy
began this with a case of a non-cirrhotic
GT 3-infected patient.
– GT 3 patients have an accelerated fibrosis progression, compared to other GTs,
he said.
He returned to the ALLY-3 study and
told the audience that they did choose to
treat the patient with daclatasvir + sofosbuvir without ribavirin.
– The patient achieved SVR12, and this
shows that real world experiences reflects
clinical trial data!
Prof Jürgen Rockstroh presented a case
with HCV/HIV co-infection, and he also
spoke about ALLY-2.
– The study demonstrates a high SVR12
rate (more than 97 %) in treatment-experienced and treatment-naive patients.
The patient was successfully treated
with daclatasvir + sofosbuvir for 12 weeks,
and this was well tolerated.
Cases with liver disease
The third case concerned a patient with
GT 3 and advanced cirrhosis. Dr Kosh
Agarwal told the audience that the patient
achieved SVR12 on a regimen of daclatasvir + sofosbuvir + ribavirin. Also an improvement of liver function with normalisation of clinical and biological indices,
was seen.
Prof Rafael Esteban finally described a
case of GT 1b Child-Pugh grade B patient.
The patient was treated with daclatasvir
+ sofosbuvir + ribavirin for 24 weeks, and
had HCV RNA undetectable at week 5.
– There was an improvement in liver
function, Child-Pugh grade A – and normal values. No clinically relevant adverse
events were found. Real-world data were
generally consistent with clinical trial results, he said.
A panel discussion between the four experts concluded the Symposium. In this, it
was pointed out that treatment options in
patients with very advanced disease may
need to be further optimised.
Per Lundblad
HIV & VIROLOGY NEWS 2 · 2015
FRI FOR HCV MED viekirax + exviera
Høj vished for helbredelsei
blandt GT1 patienter i robust
klinisk udviklingsprogram1,2
Viekirax + exviera +/- RBV i 12 eller 24 ugerii førte til konsistent høje helbredelsesrater i en
bred population af kronisk HCV GT1 patienter med lav forekomst af virologisk svigt eller relaps.
HØJE SVR12 FOR DE ANBEFALEDE
BEHANDLINGSREGIMER1
GT1
PATIENTER
(n=1.052/1.083)
GT1 UDEN CIRROSE
(n=870/894)
96%
(n=182/189)
viekirax
®
ombitasvir/ paritaprevir/
ritonavir filmovertrukne tabletter
GT1 MED KOMPENSERET
CIRROSE
exviera
®
dasabuvir
filmovertrukne tabletter
Viekirax med RBV er indiceret til behandling af GT4 uden cirrosei i 12 uger, og til behandling af GT4 med kompenseret cirrosei i 24 uger1
SVR12 var det primære effektmål for HCV helbredelsesraten i fase 3 kliniske forsøg og blev defineret som ikke-kvantificerbar eller ikke-detekterbar HCV RNA 12 uger efter afsluttet behandling.1,2
ii
Den anbefalede behandlingsvarighed for patienter med GT1a1,2 og kompenseret cirrose er 24 uger.
1
Produktresume for viekirax (ombitasvir/paritaprevir/ritonavir). AbbVie Ltd, Maidenhead, United Kingdom. 01/2015.
2
Produktresume for exviera (dasabuvir). AbbVie Ltd, Maidenhead, United Kingdom. 01/2015.
i
HIV & VIROLOGY NEWS 1 · 2015
33
DKHCV150154
97%
Forkortet produktresumé. Viekirax® (12,5 mg ombitasvir, 75 mg paritaprevir og 50 mg ritonavir) filmovertrukne tabletter. Farmakoterapeutisk klassifikation: Antivirale midler til systemisk brug; direkte virkende antivirale midler. ATC-kode: Ikke tildelt. Indikationer: Viekirax
er indiceret i kombination med andre lægemidler til behandling af kronisk hepatitis C (CHC) hos voksne. Dosering og administration*: Behandling med Viekirax skal påbegyndes og overvåges af en læge med erfaring i behandling af kronisk hepatitis C. Den anbefalede
orale dosis Viekirax er to 12,5 mg/75 mg/50 mg-tabletter én gang dagligt sammen med mad. Tabletterne skal sluges hele. Viekirax skal anvendes i kombination med andre lægemidler til behandling af HCV. Anbefalede samtidige lægemidler og anbefalet behandlingsvarighed
for Viekirax for hver patientpopulation: Genotype 1b, uden cirrose: Viekirax + dasabuvir i 12 uger. Genotype 1b, med kompenseret cirrose: Viekirax + dasabuvir + ribavirin i 12 uger. Genotype 1a, uden cirrose: Viekirax + dasabuvir + ribavirin** i 12 uger. Genotype 1a, med
kompenseret cirrose: Viekirax + dasabuvir + ribavirin** i 24 uger (se pkt. 5.1 i det fulde produktresumé). Genotype 4, uden cirrose: Viekirax + ribavirin i 12 uger. Genotype 4, med kompenseret cirrose: Viekirax + ribavirin i 24 uger. **Følg dosisanbefalingerne for genotype 1a
hos patienter med en ukendt genotype 1-undertype eller med en blandet genotype 1-infektion. Glemte doser: Hvis en dosis Viekirax glemmes, kan den ordinerede dosis tages op til 12 timer senere. Hvis der er gået mere end 12 timer siden det tidspunkt, hvor dosis normalt
tages, må den manglende dosis IKKE tages, og patienten skal vente til den efterfølgende dosis. Patienterne må ikke tage en dobbeltdosis. Særlige populationer: Samtidig HIV-1-infektion: Følg doseringsanbefalingerne i det fulde produktresumé. Patienter med
levertransplantat: Hos patienter med levertransplantat og HCV genotype 1-infektion anbefales det at give Viekirax og dasabuvir i kombination med ribavirin i 24 uger. Til patienter med genotype 4-infektion anbefales Viekirax i kombination med ribavirin. En lavere dosis
ribavirin kan være relevant ved opstart. Ældre: Det er ikke nødvendigt at justere dosis af Viekirax hos ældre patienter. Nedsat nyrefunktion: Det er ikke nødvendig at justere dosis af Viekirax hos patienter med let, moderat eller svært nedsat nyrefunktion. Nedsat
leverfunktion: Det er ikke nødvendigt at justere dosis af Viekirax hos patienter med let nedsat leverfunktion. Dosisjustering forventes ikke at være nødvendig ved moderat nedsat leverfunktion. Viekirax er kontraindiceret hos patienter med svært nedsat leverfunktion.
Pædiatrisk population: Sikkerhed og virkning hos børn og unge under 18 år er ikke klarlagt. Kontraindikationer*: Overfølsomhed over for de aktive stoffer eller over for et eller flere af hjælpestofferne. Patienter med svært nedsat leverfunktion. Brug af lægemidler med
ethinylestradiol som f.eks. kombinerede p-piller eller p-ringe. Lægemidler, der er meget afhængige af CYP3A ved clearance, og hvor forhøjede plasmaniveauer er forbundet med alvorlige hændelser, må ikke administreres samtidig med Viekirax. Administration af Viekirax med
eller uden dasabuvir og lægemidler, der er stærke eller moderate enzym-inducere må ikke ske samtidig. Administration af Viekirax med eller uden dasabuvir og lægemidler, der er stærke hæmmere af CYP3A må ikke ske samtidig. Særlige advarsler og forsigtighedsregler:
Generelt: Viekirax skal bruges i kombination med andre lægemidler til behandling af hepatitis C-infektion. Monoterapi anbefales ikke. Genotypespecifik aktivitet: Viekirax må ikke anvendes til behandling af patienter med HCV-genotype 2, 3, 5 og 6, da virkningen af Viekirax
ikke er klarlagt. Der foreligger ingen data for brugen af Viekirax og ribavirin hos patienter med HCV genotype 4-infektion og kompenseret cirrose, og den optimale behandlingsvarighed er ikke klarlagt, og derfor anbefales en konservativ behandlingsvarighed på 24 uger. Samtidig
administration af Viekirax og andre antivirale midler mod HCV: Sikkerheden ved og virkningen af Viekirax i kombination med dasabuvir og/eller ribavirin er klarlagt. Samtidig administration af Viekirax og andre antivirale midler er ikke undersøgt og anbefales derfor ikke. Gentaget
behandling: Virkningen af Viekirax hos patienter, der tidligere er blevet eksponeret for Viekirax eller for lægemidler af samme klasse som Viekirax er ikke undersøgt. Graviditet og samtidig brug af ribavirin: Når Viekirax anvendes i kombination med ribavirin, skal fertile kvinder
og deres mandlige partnere bruge en sikker form for prævention under behandlingen og i 6 måneder efter selve behandlingen. Forhøjet ALAT: I de kliniske studier af Viekirax og dasabuvir med eller uden ribavirin sås forbigående forhøjede niveauer af ALAT hos ca. 1% af
forsøgspersonerne (35 ud af 3.039). De forhøjede ALAT-niveauer var asymptomatiske og optrådte som regel i løbet af de første 4 uger af behandlingen, uden samtidig forhøjelse af bilirubin-niveauet, og de faldt igen i løbet af ca. 2 uger ved fortsat dosering af Viekirax og
dasabuvir med eller uden ribavirin. Forhøjet ALAT sås signifikant hyppigere i den undergruppe, der brugte ethinylestradiol-holdige lægemidler som f.eks. kombinerede p-piller eller p-ringe (6 ud af 25 forsøgspersoner). Patienter, der tager ethinylestradiol-holdige lægemidler, skal
skifte til en alternativ præventionsmetode, inden de starter behandling med Viekirax og dasabuvir. Selvom de forhøjede ALAT-niveauer i forbindelse med Viekirax og dasabuvir har været asymptomatiske, skal patienterne vide, at de skal være opmærksomme på tidlige tegn på
leverbetændelse og at de straks skal kontakte lægen, hvis de får disse symptomer på leverbetændelse. Rutinemæssig monitorering af leverenzymer er ikke nødvendig. Tidlig seponering kan medføre lægemiddelresistens, men betydningen for fremtidig behandling er ikke kendt.
Samtidig brug af fluticason eller andre inhalationsglukokortikoider, der metaboliseres af CYP3A, kan øge den systemiske glukokortikoid-eksponering, og der er indberettet tilfælde af Cushings syndrom og efterfølgende binyresuppression ved regimer, der indeholder ritonavir.
Interaktionen mellem Viekirax med eller uden dasabuvir og colchicin er ikke undersøgt. Det anbefales at nedsætte colchicin-dosen eller afbryde colchicin-behandlingen hos patienter med normal nyre- og leverfunktion, hvis behandling med Viekirax med eller uden dasabuvir er
nødvendig. Brug af colchicin samtidig med Viekirax med eller uden dasabuvir er kontraindiceret hos patienter med nedsat nyre- eller leverfunktion. Samtidig brug af statiner: Simvastatin, lovastatin og atorvastatin er kontraindicerede. Viekirax med dasabuvir forventes at øge
eksponeringen for rosuvastatin med mere end 3 gange. Hvis det er nødvendigt at give patienten rosuvastatin i behandlingsperioden, må den daglige rosuvastatin-dosis højst være 5 mg. Når rosuvastatin administreres sammen med Viekirax uden dasabuvir, øges rosuvastatineksponeringen i mindre udtalt grad. Hvis rosuvastatin administreres samtidig med Viekirax uden dasabuvir, må den daglige rosuvastatin-dosis højst være 10 mg. Det anbefales at afbryde behandlingen med pitavastatin/fluvastatin midlertidigt, så længe Viekirax-behandlingen
pågår. Hvis det er nødvendigt at give patienten statiner i behandlingsperioden, er det muligt at skifte til en reduceret dosis af pravastatin/rosuvastatin. Behandling af patienter med samtidig HIV-infektion: Lavdosis-ritonavir, der indgår i den faste kombinationsdosering sammen
med Viekirax, kan medføre PI-resistens hos patienter med samtidig HIV-infektion, der ikke er i antiretroviral behandling. Patienter med samtidig HIV-infektion, der ikke er i supprimerende antiretroviral behandling, må ikke få Viekirax. Hos patienter med samtidig HIV-infektion
skal der tages nøje højde for lægemiddelinteraktioner. Atazanavir kan bruges i kombination med Viekirax og dasabuvir ved samtidig administration. Kombinationen giver øget risiko for hyperbilirubinæmi. Darunavir 800 mg én gang dagligt kan bruges i kombination med Viekirax
og dasabuvir, hvis administration er på samme tid, og der ikke er udtalt PI-resistens. Andre HIV-proteasehæmmere end atazanavir og darunavir er kontraindiceret. Raltegravir-eksponeringen øges markant (med 2 gange). Rilpivirin-eksponeringen øges markant (med 3 gange),
når rilpivirin administreres i kombination med Viekirax og dasabuvir, og risikoen for QT-forlængelse øges som følge deraf. Hvis en HIV-proteasehæmmer tilføjes, kan rilpivirin-eksponeringen øges endnu mere; derfor anbefales dette ikke. Rilpivirin skal anvendes med forsigtighed
og under løbende EKG monitorering. Bortset fra rilpivirin er non-nukleosid revers transkriptase-hæmmere kontraindicerede. Samtidig infektion med HCV/HBV (hepatitis B-virus): Viekirax’ sikkerhed og virkning hos patienter med samtidig HCV/HBV-infektion er ikke klarlagt.
Pædiatrisk population: Viekirax’ sikkerhed og virkning hos børn og unge under 18 år er ikke klarlagt. Interaktioner*: Anbefalinger for samtidig administration af Viekirax med eller uden dasabuvir i forhold til en række lægemidler, der ofte ordineres samtidigt, er beskrevet
nedenfor. Hvis en patient under sin behandling med Viekirax med eller uden dasabuvir allerede tager eller begynder at tage et eller flere lægemidler, hvor der forventes potentiel lægemiddelinteraktion, skal dosisjustering af disse lægemidler eller klinisk overvågning overvejes.
Hvis dosisjustering af samtidigt administrerede lægemidler skyldes behandlingen med Viekirax eller Viekirax med dasabuvir, skal der ske fornyet dosisjustering, når behandlingen med Viekirax eller Viekirax med dasabuvir er afsluttet. Kendte eller potentielle interaktioner mellem
Viekirax med eller uden dasabuvir og andre hyppigt anvendte lægemidler: Samtidig brug er kontraindiceret: Alfa 1-antagonist: Alfuzosin. Antiarytmika: Amiodaron, quinidin. Antibiotika (systemisk administration.): Clarithromycin, telithromycin og fusidinsyre. Cytostatika:
Enzalutamid og mitotan. Antikonvulsive midler: Carbamazepin, phenobarbital og phenytoin. Antidiuretisk hormon: Conivaptan. Antimykotika: Ketoconazol, itraconazol, posaconazol, voriconazol. Midler mod urinsyregigt: Colchicin er kontraindiceret hos patienter med nedsat
nyre- eller leverfunktion. Antihistaminer: Astemizol, terfenadin. Lipidsænkende midler: Gemfibrozil med Viekirax med dasabuvir. Antibiotika med virkning på mykobakterier: Rifampicin. Antipsykotika: Pimozid, quetiapin. Midler til tromboseprofylakse: Ticagrelor. Præventionsmidler:
Ethinyl-estradiol/norgestimat (ethinylestradiol-holdige præventionsmidler). Sekalealkaloider: Ergotamin, dihydroergotamin, ergonovinmethylergometrin. Gastrointestinale midler: Cisaprid. Naturlægemidler: Prikbladet perikon. HIV-antivirale midler: Proteasehæmmere: Behandling
med atazanavir plus Viekirax uden dasabuvir anbefales ikke. Lopinavir/ritonavir, indinavir, saquinavir, tipranavir. Darunavir sammen med Viekirax plus dasabuvir anbefales ikke til patienter med udtalt PI-resistens. Behandling med darunavir plus Viekirax uden dasabuvir anbefales
ikke. HIV-antivirale midler: Non-nukleosid revers transkriptase-hæmmere: Efavirenz, nevirapin, etravirin. HIV-antivirale midler: Farmakokinetiske forstærkere: Cobicistat-regimer. HMG-CoA-reduktasehæmmer: Fluvastatin: Samtidig brug med fluvastatin og pitavastatin anbefales
ikke. Lovastatin, simvastatin, atorvastatin. Beta-agonister til inhalation: Salmeterol. Phosphodiesterase-5-hæmmere: Sildenafil (ved behandling af pulmonal arteriel hypertension). Sedativa/hypnotika: Oralt midazolam eller triazolam. Der bør udvises forsigtighed ved samtidig
brug: Aminosalicylater: Sulfasalazin. Antibiotika (systemisk administration): Erythromycin. Antikoagulantia: Warfarin 5 mg enkeltdosis med Viekirax med dasabuvir. Dabigatranetexilat. Antihistaminer: Fexofenadin. Klinisk overvågning og dosisjustering anbefales ved
samtidig brug: Angiotensin receptor blokker: Valsartan. Antiarytmika: Digoxin 0,5 mg enkeltdosis med Viekirax uden dasabuvir. Cytostatika: Imatinib. Antikonvulsive midler: S-mephenytoin. Antidepressiva: Trazodon. Calciumantagonister: Amlodipin, diltiazem, verapamil og
nifedipin. Diuretika: Furosemid. Immunosuppressiva: Ciclosporin, tacrolimus. Beta-celle stimulerende midler: Repaglinid. Thyroideahormoner: Levothyroxin. Sedativa/hypnotika: Alprazolam. Dosisjustering anbefales ved samtidig brug: Midler mod urinsyregigt: Colchicin:
Det anbefales at nedsætte colchicin-dosen eller afbryde colchicin-behandlingen hos patienter med normal nyre- og leverfunktion. HMG-CoA-reductasehæmmer: Pravastatin. Klinisk overvågning anbefales ved samtidig brug: Antiarytmika: Digoxin 0,5 mg enkeltdosis
med Viekirax med dasabuvir. Glukokortikoider (til inhalation): Fluticason. Samtidig brug af fluticason kan øge den systemiske eksponering af fluticason. HIV-antivirale midler: Non-nukleosid revers transkriptase-hæmmere: Rilpivirin: Samtidig administration af Viekirax og rilpivirin
én gang dagligt må kun overvejes hos patienter uden kendt QT-forlængelse, og som ikke får samtidig behandling med andre QT-forlængende lægemidler. Hvis Viekirax og rilpivirin administreres samtidig, skal der foretages løbende EKG-monitorering. Protonpumpehæmmere:
Omeprazol: Hvis det er klinisk indiceret, skal der bruges højere doser omeprazol. Esomeprazol, lansoprazol: Brug højere doser esomeprazol/lansoprazol, hvis det er klinisk indiceret. Dosisjustering er ikke nødvendig: Antidepressiva: Escitalopram, duloxetin. Lipidsænkende
midler: Gemfibrozil med Viekirax uden dasabuvir. Præventionsmidler: Norethindron (p-piller med progestin alene). HIV-antivirale midler: Proteasehæmmere: Atazanavir med Viekirax med dasabuvir. Darunavir (administreret samtidigt) med Viekirax med dasabuvir. HIV-antivirale
midler: HIV-integrase transfer-hæmmer: Raltegravir. HIV-antivirale midler: Nukleosid-hæmmere: Emtricitabin/tenofovir. HMG-CoA-reduktasehæmmer: Rosuvastatin højst 5 mg for Viekirax med dasabuvir, rosuvastatin højst 10 mg for Viekirax uden dasabuvir. Opioider: Metadon,
buprenorphin/naloxon. Sedativa/hypnotika: Zolpidem. Fertilitet, graviditet og amning: Der skal træffes skærpede forholdsregler for at undgå graviditet hos kvindelige patienter og hos mandlige patienters kvindelige partnere, når Viekirax administreres i kombination med
ribavirin. Ribavirin er kontraindiceret hos gravide kvinder og hos mænd, hvis partner er gravid. Fertile kvinder og deres mandlige partnere må ikke få ribavirin, medmindre de bruger en sikker præventionsmetode under behandlingen med ribavirin og i 6 måneder efter selve
behandlingen. Ethinylestradiol er kontraindiceret i kombination med Viekirax. Viekirax må ikke anvendes under graviditet. Hvis ribavirin administreres samtidig med Viekirax, gælder kontraindikationerne for brug af ribavirin under graviditet. Det er ukendt, om paritaprevir/ritonavir
og ombitasvir og deres metabolitter udskilles i human mælk. Farmakokinetiske data fra dyreforsøg viser, at det aktive stof og dets metabolitter udskilles i mælk. På grund af de potentielle bivirkninger for det diende barn skal det besluttes, om amning eller behandling med
lægemidlet skal ophøre. Hvis patienten samtidig får ribavirin, skal man også henholde sig til produktresuméet for ribavirin. Der foreligger ingen humane data om Viekirax’ indvirkning på fertiliteten. Bivirkninger*: Oversigt over sikkerhedsprofilen: Sikkerhedsprofilen er baseret
på samlede data fra kliniske fase 2- og fase 3-studier med over 2.600 patienter, der fik Viekirax og dasabuvir med eller uden ribavirin. Viekirax og dasabuvir med ribavirin (herunder forsøgspersoner med kompenseret cirrose): Hos de forsøgspersoner, der fik
Viekirax og dasabuvir med ribavirin, var de hyppigst indberettede bivirkninger træthed og kvalme (hos over 20%). Andelen af forsøgspersoner, der stoppede behandlingen permanent på grund af bivirkninger, var 0,2% (5/2.044). 4,8% (99/2.044) af forsøgspersonerne fik nedsat
ribavirin-dosis på grund af bivirkninger. Med undtagelse af øget hyppighed af forbigående hyperbilirubinæmi var sikkerhedsprofilen for Viekirax og dasabuvir med ribavirin hos forsøgspersoner med kompenseret cirrose den samme som hos forsøgspersoner uden cirrose. Viekirax
og dasabuvir uden ribavirin: Ingen forsøgspersoner ophørte permanent med behandlingen eller havde behandlingsafbrydelser på grund af bivirkninger. Bivirkninger, der er set ved Viekirax og dasabuvir med ribavirin: Meget almindelig: Søvnløshed, kvalme, pruritus, asteni,
træthed. Almindelig: Anæmi. Bivirkninger, der er set ved Viekirax i kombination med dasabuvir uden ribavirin: Almindelig: Pruritus. Andelen af forsøgspersoner, der stoppede behandlingen permanent på grund af bivirkninger, var 0,2%. Overdosering: I tilfælde af overdosering
anbefales det at overvåge patienten for tegn og symptomer på bivirkninger og straks iværksætte behandling af eventuelle symptomer. Særlige opbevaringsforhold: Ingen særlige forholdsregler vedrørende opbevaringen. Pakning og priser: Blisterpakninger fremstillet af
PVC/PE/PCTFE-aluminiumsfolie. 56 tabletter i multipakning med 4 æsker som hver indeholder 14 tabletter. Vnr.151250. Dagsaktuelle priser kan findes på medicinpriser.dk. Udlevering: Begr. Indehaver af markedsføringstilaldelsen: AbbVie Ltd, Maidenhead, SL6 4XE,
Storbritannien. Produktinformationen er forkortet i forhold til det af Den Europæiske Kommission godkendte produktresumé. De med * markerede afsnit i produktinformationen er forkortet og/eller omskrevet i forhold til det godkendte produktresumé.
Produktresuméet kan vederlagsfrit rekvireres hos AbbVie A/S, Emdrupvej 28 C, 2100 København Ø. Tlf.nr. 72302028. Fax nr. 72301047. Forkortet SPC i forhold til Kommissionens SPC af 15 jan 2015. DKHCV150034
HIV & HEPATITIS NEWS
Forkortet produktresumé. Exviera® (250 mg dasabuvir som natriummonohydrat) filmovertrukne tabletter. Farmakoterapeutisk klassifikation: Antivirale midler til systemisk brug; direkte virkende antivirale midler. ATC-kode: Ikke tildelt. Indikationer*: Exviera er indiceret
i kombination med andre lægemidler til behandling af kronisk hepatitis C (CHC) hos voksne. Dosering og administration*: Behandling med Exviera skal påbegyndes og overvåges af en læge med erfaring i behandling af kronisk hepatitis C. Den anbefalede orale dosis
Exviera er 250 mg (én tablet) to gange dagligt (morgen og aften) sammen med mad. Tabletterne skal sluges hele. Exviera må ikke gives som enkeltstofbehandling. Exviera skal anvendes i kombination med andre lægemidler til behandling af HCV. Anbefalede samtidige
administrerede lægemidler og anbefalet behandlingsvarighed ved administration sammen med Exviera + ombitasvir/paritaprevir/ritonavir for hver patientpopulation: Genotype 1b, uden cirrose: Exviera + ombitasvir/paritaprevir/ritonavir 12 uger. Genotype 1b, med kompenseret
cirrose: Exviera + ombitasvir/paritaprevir/ritonavir + ribavirin i 12 uger. Genotype 1a, uden cirrose: Exviera + ombitasvir/paritaprevir/ritonavir + ribavirin** i 12 uger. Genotype 1a, med kompenseret cirrose: Exviera + ombitasvir/paritaprevir/ritonavir + ribavirin** i 24 uger (se
pkt. 5.1 i det fulde produktresumé). **Følg dosisanbefalingerne for genotype 1a hos patienter med en ukendt genotype 1-undertype eller med en blandet genotype 1-infektion. Glemte doser: Hvis en patient glemmer at tage en dosis Exviera, kan den ordinerede dosis tages
op til 6 timer senere. Hvis der er gået mere end 6 timer siden det tidspunkt, hvor patienten normalt tager sin dosis Exviera, må den manglende dosis IKKE tages, idet patienten skal vente til den efterfølgende dosis i henhold til doseringsplanen. Patienterne skal have at vide, at
de ikke må tage en dobbeltdosis. Særlige populationer: Samtidig HIV-1-infektion: Følg doseringsanbefalingerne i det fulde produktresumé. Patienter med levertransplantat: Hos patienter med levertransplantat og HCV genotype 1-infektion anbefales det at give Exviera
og ombitasvir/paritaprevir/ritonavir i kombination med ribavirin i 24 uger. En lavere dosis ribavirin kan være relevant ved opstart. I post-levertransplantationsstudiet blev ribavirin-dosen justeret individuelt, og de fleste forsøgspersoner fik 600-800 mg pr. dag. Ældre: Det er ikke
nødvendigt at justere dosis af Exviera hos ældre patienter. Nedsat nyrefunktion: Det er ikke nødvendigt at justere dosis af Exviera hos patienter med let, moderat eller svært nedsat nyrefunktion. Nedsat leverfunktion: Det er ikke nødvendigt at justere dosis af Exviera hos
patienter med let nedsat leverfunktion. Dasabuvirs sikkerhed og virkning hos HCV-smittede patienter med moderat nedsat leverfunktion er ikke klarlagt. Dosisjustering forventes dog ikke at være nødvendig med henvisning til farmakokinetiske studier. Exviera må ikke anvendes
til patienter med svært nedsat leverfunktion. Pædiatrisk population: Dasabuvirs sikkerhed og virkning hos børn og unge under 18 år er ikke klarlagt. Der foreligger ingen data. Kontraindikationer*: Overfølsomhed over for de aktive stoffer eller over for et eller flere af
hjælpestofferne. Brug af lægemidler med ethinylestradiol som f.eks. de fleste kombinerede p-piller eller p-ringe. Samtidig administration af Exviera og lægemidler, der er stærke eller moderate enzym-inducere, forventes at nedbringe plasmakoncentrationen af dasabuvir og
nedsætte dasabuvirs terapeutiske virkning. Lægemidler, der er stærke CYP2C8-hæmmere, kan øge plasmakoncentrationen af dasabuvir og må ikke administreres samtidig med Exviera. Exviera skal bruges sammen med ombitasvir/paritaprevir/ritonavir. Særlige advarsler og
forsigtighedsregler*: Generelt: Det anbefales ikke at bruge Exviera som monoterapi; Exviera skal bruges i kombination med andre lægemidler til behandling af hepatitis C-infektion. Genotypespecifik aktivitet: Exvieras virkning hos patienter med andre HCV-genotyper end
genotype 1 er ikke klarlagt, og Exviera må derfor ikke bruges til behandling af patienter med andre genotyper end genotype 1. Samtidig administration af andre direkte virkende antivirale midler mod HCV: Sikkerheden ved og virkningen af Exviera i kombination med ombitasvir/
paritaprevir/ritonavir (sammen med eller uden ribavirin) er blevet klarlagt. Samtidig administration af Exviera og andre antivirale midler er ikke undersøgt og anbefales derfor ikke. Gentaget behandling: Virkningen af dasabuvir hos patienter, der tidligere har været eksponeret
for dasabuvir eller for lægemidler, der antages at indebære krydsresistens, er ikke undersøgt. Graviditet og samtidig brug af ribavirin: Når Exviera anvendes i kombination med ribavirin, skal fertile kvinder og deres mandlige partnere bruge en sikker form for prævention under
behandlingen og i 6 måneder efter selve behandlingen. Forhøjet ALAT: I de kliniske studier af Exviera og ombitasvir/paritaprevir/ritonavir med eller uden ribavirin sås forbigående forhøjet ALAT på over 5 gange den øvre normalgrænse hos ca. 1% af forsøgspersonerne (35 ud
af 3.039). De forhøjede ALAT-niveauer var asymptomatiske og optrådte som regel i løbet af de første 4 uger af behandlingen uden samtidig forhøjelse af bilirubin-niveauet, og de faldt igen inden for ca. 2 uger ved fortsat dosering af Exviera og ombitasvir/paritaprevir/ritonavir
med eller uden ribavirin. Forhøjet ALAT sås signifikant hyppigere i den undergruppe, der brugte ethinylestradiol-holdige lægemidler som f.eks. kombinerede p-piller eller p-ringe (6 ud af 25 forsøgspersoner). Til gengæld var forekomsten af forhøjet ALAT hos de forsøgspersoner,
som anvendte andre typer østrogener, herunder dem, der typisk anvendes i hormonerstatningsbehandling (dvs. estradiol til oral og topikal anvendelse samt konjugerede østrogener), den samme som hos de forsøgspersoner, der ikke brugte østrogenholdige lægemidler (ca. 1%
i hver gruppe). Patienter, der tager ethinylestradiol-holdige lægemidler (dvs. de fleste kombinerede p-piller og p-ringe), skal skifte til en alternativ præventionsmetode (f.eks. prævention med progestin alene eller ikke-hormonelle metoder), inden de starter behandling med Exviera
med ombitasvir/paritaprevir/ritonavir. Selvom de forhøjede ALAT-niveauer i forbindelse med Exviera og ombitasvir/paritaprevir/ritonavir har været asymptomatiske, skal patienterne have at vide, at de skal være opmærksomme på tidlige tegn på leverbetændelse, f.eks. træthed,
kraftesløshed, nedsat appetit, kvalme og opkastning, samt senere tegn som f.eks. gulsot og misfarvet afføring. De skal have at vide, at de straks skal kontakte lægen, hvis de får disse symptomer. Rutinemæssig monitorering af leverenzymer er ikke nødvendig. Tidlig seponering
kan medføre lægemiddelresistens, men betydningen for fremtidig behandling er ikke kendt. Samtidig brug af statiner: Rosuvastatin: Exviera med ombitasvir/paritaprevir/ritonavir forventes at øge eksponeringen for rosuvastatin med mere end 3 gange. Hvis det er nødvendigt at
give patienten rosuvastatin i behandlingsperioden, må den daglige rosuvastatin-dosis højst være 5 mg. Pitavastatin og fluvastatin: Der er ikke foretaget undersøgelser af interaktionen med pitavastatin og fluvastatin. Teoretisk set forventes dasabuvir med ombitasvir/paritaprevir/
ritonavir at øge eksponeringen for pitavastatin og fluvastatin. Det anbefales at afbryde behandlingen med pitavastatin/fluvastatin midlertidigt, så længe behandlingen med ombitasvir/paritaprevir/ritonavir pågår. Hvis det er nødvendigt at give patienten statiner i
behandlingsperioden, er det muligt at skifte til en reduceret dosis af pravastatin/rosuvastatin. Behandling af patienter med samtidig HIV-infektion: Exviera anbefales i kombination med paritaprevir/ombitasvir/ritonavir, og ritonavir kan medføre PI-resistens hos patienter med
samtidig HIV-infektion uden samtidig administration af et antiretroviralt middel. Patienter, der samtidig er HIV-smittede, og som ikke får supprimerende antiretroviral behandling, må ikke behandles med dasabuvir. Hos patienter med samtidig HIV-infektion skal der tages nøje
højde for lægemiddelinteraktioner. Atazanavir kan bruges i kombination med dasabuvir med ombitasvir/paritaprevir/ritonavir, hvis administration er på samme tid. Bemærk, at atazanavir skal tages uden ritonavir, da ritonavir 100 mg én gang dagligt indgår i den faste ombitasvir/
paritaprevir/ritonavir-dosis. Kombinationen giver øget risiko for hyperbilirubinæmi (herunder okulær ikterus), især når ribavirin indgår i hepatitis C-regimet. Darunavir i en dosis på 800 mg én gang dagligt kan bruges med ombitasvir/paritaprevir/ritonavir, hvis administration er
på samme tid, og der ikke er udtalt PI-resistens (reduceret eksponering for darunavir). Bemærk, at darunavir skal tages uden ritonavir, da ritonavir 100 mg én gang dagligt indgår i den faste ombitasvir/paritaprevir/ritonavir-dosis. For anvendelse af andre HIV-proteasehæmmere
end atazanavir og darunavir, se produktresuméerne for ombitasvir/paritaprevir/ritonavir. Raltegravir-eksponeringen øges markant (med 2 gange). Kombinationen blev ikke forbundet med nævneværdige problemer hos en begrænset gruppe patienter, der blev behandlet i 12-24
uger. Rilpivirin-eksponeringen øges markant (med 3 gange), når rilpivirin administreres i kombination med dasabuvir med ombitasvir/paritaprevir/ritonavir, og risikoen for QT-forlængelse øges som følge deraf. Hvis en HIV-proteasehæmmer tilføjes (atazanavir, darunavir), kan
rilpivirin-eksponeringen øges endnu mere; derfor anbefales dette ikke. Rilpivirin skal anvendes med forsigtighed og under løbende EKG-monitorering. Bortset fra rilpivirin er non-nukleosid revers transkriptase-hæmmere (efavirenz, etravirin og nevirapin) kontraindicerede. Samtidig
infektion med HCV/HBV (hepatitis B-virus): Dasabuvirs sikkerhed og virkning hos patienter med samtidig HCV/HBV-infektion er ikke klarlagt. Pædiatrisk population: Dasabuvirs sikkerhed og virkning hos børn under 18 år er ikke klarlagt. Der foreligger ingen data. Laktose: Exviera
indeholder laktose. Patienter med sjælden arvelig galaktoseintolerans, Lapp-laktase-mangel eller glukose-galaktose-malabsorption bør ikke behandles med dette lægemiddel. Interaktioner*: Dasabuvir skal altid administreres sammen med ombitasvir/paritaprevir/ritonavir.
Når disse stoffer administreres samtidig, har de en gensidig indvirkning på hinanden. Samtidig brug er kontraindiceret ved: Antibiotika med virkning på mykobakterier: Rifampicin. Antikonvulsiva: Carbamazepin, phenobarbital, phenytoin. Antimykotika: Ketoconazol. Cytostatika:
Enzalutamid, mitotan. HIV-antivirale midler: Non-nukleosid revers transkriptase-hæmmere: Samtidig brug af regimer med efavirenz, nevirapin, etravirin. HIV-antivirale midler: Proteasehæmmere: Lopinavir/ritonavir. Lipidsænkende midler: Gemfribrozil. Naturlægemidler: Prikbladet
perikon. Præventionsmidler: Ethinyl-estradiol/norgestimat (ethinylestradiolholdige præventionsmidler). Samtidig brug anbefales ikke ved: HMG-CoA-Reductasehæmmer: Fluvastatin, pitavastatin. Der bør udvises forsigtighed ved samtidig brug: Aminosalicylater: Sulfasalazin.
Antikoagulantia: Warfarin, dabigatranetexilat. Antikonvulsive midler: S-mephenytoin. Calciumantagonister: Amlodipin. Diuretika: Furosemid. Cytostatika: Imatinib. Immunosuppresiva: Ciclosporin, tacrolimus. HIV-antivirale midler: Non-nucleosid revers transkriptase-hæmmere:
Rilpivirin (bør kun overvejes hos patienter uden kendt QT-forlængelse, og som ikke får samtidig behandling med andre QT-forlængende lægemidler). HMG-CoA-Reductasehæmmer: Rosuvastatin, pravastatin. Jernchelerende midler: Deferasirox. Midler mod multipel (dissemineret)
sklerose: Teriflunomid. Protonpumpehæmmere: Omeprazol, esomeprazol, lansoprazol. Sedativa/Hypnotika: Alprazolam. Thyroideahormoner: Levothyroxin. Ingen dosisjustering nødvendig ved: Antiarytmika: Digoxin. Antidepressiva: Escitalopram, duloxetin. HIV-antivirale midler:
Proteasehæmmere: Atazanavir uden ritonavir med Exviera med ombitasvir/paritatprevir/ritonavir, darunavir, uden ritonavir ved samtidig administration med Exviera og ombitasvir/paritatprevir/ritonavir (dette regime kan anvendes, hvis der ikke er udtalt PI resistens).
Præventionsmidler: Norethindron (p-piller med progestin alene). HIV-antivirale midler: HIV integrase transfer-hæmmere: Raltegravir. HIV-antivirale midler: Nuklosid-hæmmere: Emtricitabin/tenofovir. Opioider: Metadon, buprenorphin/naloxon. Sedativa/Hypnotika: Zolpidem.
Pædiatrisk population: Lægemiddelinteraktionsstudier er kun udført hos voksne. Fertilitet, graviditet og amning*: Fertile kvinder/prævention hos mænd og kvinder: Der skal træffes skærpede forholdsregler for at undgå graviditet hos kvindelige patienter og hos mandlige
patienters kvindelige partnere, når Exviera administreres i kombination med ribavirin. Signifikante teratogene og/eller embryocidale virkninger er påvist hos alle dyrearter, der er blevet eksponeret for ribavirin, og derfor er ribavirin kontraindiceret hos gravide kvinder og hos
mænd, hvis partner er gravid. Fertile kvinder og deres mandlige partnere må ikke få ribavirin, medmindre de bruger en sikker præventionsmetode under behandlingen med ribavirin og i 6 måneder efter selve behandlingen. Ethinylestradiol er kontraindiceret i kombination med
Exviera. Graviditet: Der er meget begrænsede data fra anvendelse af Exviera til gravide kvinder. Dyreforsøg indikerer hverken direkte eller indirekte skadelige virkninger, hvad angår reproduktionstoksicitet. For en sikkerheds skyld bør Exviera undgås under graviditet. Hvis ribavirin
administreres samtidig med Exviera og ombitasvir/paritaprevir/ritonavir, gælder kontraindikationerne for brug af ribavirin under graviditet (se også produktresuméet for ribavirin). Amning: Det er ukendt, om dasabuvir og dets metabolitter udskilles i human mælk. De tilgængelige
farmakokinetiske data fra dyreforsøg viser, at dasabuvir og dasabuvirs metabolitter udskilles i mælk. På grund af de potentielle bivirkninger for det diende barn skal det besluttes, om amning eller behandling med Exviera skal ophøre, idet der skal tages højde for behandlingens
betydning for moderen. Hvis patienten får ribavirin, skal man også henholde sig til produktresuméet for ribavirin. Fertilitet: Der foreligger ingen humane data om dasabuvirs indvirkning på fertiliteten. Dyreforsøg indikerer ingen skadelige virkninger på fertiliteten. Bivirkninger*:
Oversigt over sikkerhedsprofilen: Sikkerhedsprofilen er baseret på samlede data fra kliniske fase 2- og fase 3-studier med over 2.600 patienter, der fik Exviera og ombitasvir/paritaprevir/ritonavir med eller uden ribavirin. Exviera og ombitasvir/paritaprevir/ritonavir med
ribavirin (herunder forsøgspersoner med kompenseret cirrose): Hos de forsøgspersoner, der fik Exviera og ombitasvir/paritaprevir/ritonavir med ribavirin, var de hyppigst indberettede bivirkninger træthed og kvalme (hos over 20%). Andelen af forsøgspersoner, der
stoppede behandlingen permanent på grund af bivirkninger, var 0,2% (5/2.044). 4,8% (99/2.044) af forsøgspersonerne fik nedsat ribavirin-dosis på grund af bivirkninger. Med undtagelse af øget hyppighed af forbigående hyperbilirubinæmi var sikkerhedsprofilen for Exviera
og ombitasvir/paritaprevir/ritonavir
med ribavirin hos forsøgspersoner med kompenseret cirrose den samme som hos forsøgspersoner uden cirrose. Exviera og ombitasvir/paritaprevir/ritonavir uden ribavirin: Ingen
ophørte
permanent
med behandlingen
HIVforsøgspersoner
& VIROLOGY
NEWS
2 · 2015
44
eller havde behandlingsafbrydelser på grund af bivirkninger. Bivirkninger, der er set ved Exviera i kombination med ombitasvir/paritaprevir/ritonavir med ribavirin: Meget almindelig: Søvnløshed, kvalme, pruritus, asteni, træthed. Almindelig: Anæmi. Bivirkninger, der er set ved
HIV & HEPATITIS NEWS
Notes 2015
Interaction to be aware of 1
A warning for the potential interaction between the directly acting anti-hepatitis C drug dasabuvir and clopidogrel was recently
issued. It has been found that clopidogrel is converted to a strong
inhibitor of P 450 CYP2C8 via glucoronidation. Dasabuvir is a
substrate of the same enzyme and the combination of the drugs
may lead to significant increase in exposure. An increased dasabuvir exposure may lead to increased risk of QT prolongation
and ventricular tachycardia that may be potentially fatal.
Stark, J. Clin Infect Dis. 2015 Mar 25. pii: civ246.
Comment: It is always a challenge to keep up with potential interactions in patients on multiple drugs. This is especially important with new drugs where we have limited experience. The
drug interaction charts from the University of Liverpool and similar sites are useful and should be used frequently to minimize
the risk of overlooking potentially harmful interactions.
Interaction to be aware of 2
FDA has issued a drug safety communication on the combination of sofosbuvir and the antiarrhythmic drug amiodarone. One
case of fatal cardiac arrest and three cases of severe bradycardia
requiring pacemaker placement to regulate their heart rhythms
have been described. The three patients recovered when treatment with sofosbuvir and/or amiodarone was discontinued. A
warning has been added to the drug labels of Sovaldi and Harvoni. The mechanism of the interaction is not yet known.
FDA Drug Safety Communication
Comment: Amiodarone has a very long half life and patients who
have discontinued amiodarone should be closely monitored for
bradycardia after initiating treatment with sofosbuvir.
Valacyclovir suppresses HIV
18 HIV-infected HSV-2 negative individuals with more than 500
CD4-cells not yet on ART were included in a double blind placebo-controlled crossover study of valacyclovir. Participants were
given valacyclovir 500 mg or placebo twice daily for 12 weeks.
This was followed by 2 weeks of washout and another 12 weeks
with placebo/valacyclovir. Valacyclovir treatment resulted in
an average decrease of viral load of 0.37 log10 copies/mL. The
authors conclude that the effects of valacyclovir on HIV-1 replication is due to a direct effect on HIV-replication and not and
indirect effect on HSV-2 mediated inflammation.
Vanpouille et al. Clin Infect Dis. (2015) 60 (11): 1708-1714.
Comment: The modest anti-HIV effect of valacyclovir in this
study is of statistical significance but it is difficult to see how this
modest effect will translate into clinical significance. In the preART era several attempts to use (val)acyclovir to slow the progression of HIV were done without any clinical benefit.
HIV & VIROLOGY NEWS 2 · 2015
Caffeine inhibits hepatitis C virus replication in
vitro
Coffee consumption has been associated with beneficial effects
on cirrhosis progression and cancer development in several
studies including chronic HCV infection. The in vitro effect of
caffeine on hepatitis C was evaluated in a Brazilian study. A full
length HCV 2 genome expressing luciferase was used in a human
hepatoma cell line. Caffeine in non-cytotoxic concentrations was
used. In summary caffeine was shown to have a dose dependant
inhibitory effect on HCV replication. The caffeine concentration
was much higher than what can be achieved by drinking coffee.
Batista et al.Arch Virol(2015) 160:339-407
Comment: Many studies have indicated that the consumption of
coffee has a beneficial effect on liver diseases. This in vitro study
confirms that caffeine has an in vitro inhibitory effect on HCV
replication. While we are waiting for the prices of the very effective and expensive DAA:s to get lower we may ask our patients
who are not yet offered treatment with DAA:s to enjoy good coffee as often and as much as they can!
Treatment as prevention in MSM
The “Opposites Attract study” is a prospective observational study in serodiscordant gay couples in Australia, Thailand and Brazil. Preliminary results were presented at CROI in February. By
December 2014, a total of 234 couples were enrolled in the study. The results included 150 couple years of follow up (CYFU)
of which 91 CYFU were without using condoms. 84.2 % of participants were on treatment at baseline with 82.9 % with viral
45
HIV & HEPATITIS NEWS
load < 200. Almost six thousand acts of anal intercourse without
condoms were reported. During the observation time there were
no cases of linked transmission.
Grulich et al. CROI 2015, Abstract 1019LB
Comment: It is reassuring that the results from the PARTNER-study are confirmed in this study although these data are
preliminary. As the focus for the moment is on PrEP it is important to emphasize the importance of diagnosing and treating as
many HIV-infected individuals as possible to stop the transmission through “treatment as prevention”
Dolutegravir as salvage therapy in HIV-2
Dolutegravir has shown in vitro activity against HIV-2. Thirteen
heavily pretreated HIV-2 infected French patients failing on a regimen including raltegravir were treated with combinations including dolutegravir in a dose of 50 mg BID. The patients had a
median duration of HIV-2 infection of 15 years and had received
16 previous antiretroviral regimens. Median baseline viral load
was 9544 copies per mL and median baseline CD4 count was 100
cells per µL. Resistance patterns included mutations in position
143, 148 and 155. Patients were given individualized optimized
background therapy based on resistance patterns together with
dolutegravir. The optimized background therapy conferred a genotypic score of 2 or less in 10 patients. At 3 and 6 months viral
load was undetectable in 6 of 13 and 4 of 12 patients. One patient
died from progressive multifocal leukoencephalopathy. The median CD4 increased to 161 after 3 months and 167 after 6 months.
Descamps et al.Clin Infect Dis(2015):60 (10): 1521-1527
Comment: There are no big RCT:s in the treatment of HIV-2.
Integrase inhibitors are active against HIV-2. Double dose dolutegravir seems to be a valuable addition in salvage therapy in
heavily pretreated patients with extensive resistance.
Occult hepatitis B in newborns
64 Egyptian infants born to HBsAg positive mothers received
vaccination and hepatitis B immunoglobulin within 48 hours after birth. At least one month after the last vaccination and not
earlier than at 6 months of age the infants were tested for HBV
serological profile and HBV-DNA. Median age for testing was
8 months. 98.4 % received more than 3 doses of vaccine. Only
40.6 % of the deliveries were vaginal. 92 % of the infants were
breastfed. Viral markers (HBsAg, anti-HBc and HBeAg) were
positive in one case and HBV-DNA in two cases. Mothers with
high viral loads received antiviral therapy during pregnancy (22
lamuvidine and 2 tenofovir). Of the 64 infants one showed immunoprophylaxis failure with positive HBsAg, HBeAg and antiHBc. In another infant an occult hepatitis B with persistent positive HBV-DNA without any serological markers except positive
anti-HBs at adequate titer. Both infants had received prophylaxis
with immunoglobulin and 4 doses of vaccine.
Foaud et al. Infection. 2015 Feb 10.
Comment: A case of occult hepatitis B with repeatedly positive
HBV-DNA, negative HBsAg and positive anti-HBs after routine
prophylaxis including full vaccination and immunoglobulin in
an infant is described. To diagnose occult hepatitis B under these
circumstances a sensitive HBV-DNA must be used which is not
routinely done. One may wonder how many such cases that are
missed?
Prevalence of opportunistic infections in HIV in
Africa
Almost six thousand HIV-positive individuals attending an HIV/
AIDS care program in Uganda from 2002 to 2013 were evaluated for the occurrence of five different opportunistic infections.
More than 200 000 monthly medical reports were analyzed.
During the study period HAART was gradually introduced in
Uganda. Mean annual occurrence decreased significantly for tuberculosis, herpes zoster, genital ulcer and oral candidiasis while
cryptococcal meningitis decreased non-significantly. The largest
decreases were observed in oral candidiasis that decreased from
173/1000 persons at risk in 2002 to 6.7/1000 in 2013 and tuberculosis that decreased from 76.9/1000 in 2002 to 11.0/1000 in 2013.
Rubalhayo et al.BMC Infectious Diseases (2015) 15:197
Comment: It is not mentioned in the paper whether INH-prophylaxis for tb was given or not. In any case the dramatic decrease
in tb incidence confirms that antiretroviral therapy by itself is an
effective tb prophylaxis.
Raltegravir in pregnancy
22 pregnant women received raltegravir at a standard dose of
400 mg BID in a non-randomized open label study. Raltegravir
was given in a number of different combinations with other antiretrovirals. 7 of the 22 women were on raltegravir prior to conception, 2 started therapy during first trimester, 6 during second
and 7 during third trimester. 4 were diagnosed with HIV during
pregnancy. 19/22 had viral load < 50 copies at the time of delivery. 3 women had detectable virus (144-290 copies/ml). None of
the children became HIV infected. Pharmacokinetic assessment
was performed during 3rd trimester and postpartum at least
46
HIV & VIROLOGY NEWS 2 · 2015
HIV & HEPATITIS NEWS
Produktinformation for REYATAZ (ATAZANAVIR) 150, 200 og 300 mg hårde kapsler. De med *markerede afsnit
er omskrevet/forkortede i forhold til det af Sundhedsstyrelsen godkendte produktresumé dateret april 2014.
Terapeutiske indikationer: REYATAZ, administreret sammen med en lav dosis ritonavir, er indiceret til behandling af
hiv-infektion hos voksne og børn fra 6 år og ældre i kombination med andre antiretrovirale lægemidler. På baggrund
af eksisterende virologiske og kliniske data for voksne patienter forventes der ikke gavnlig effekt hos patienter med
stammer, der er resistente over for flere proteasehæmmere (≥4 PI-mutationer). Data vedrørende børn i alderen fra 6
til 18 år er meget begrænsede. Valg af REYATAZ til behandlingserfarne voksne og pædiatriske patienter bør baseres på
en individuel, viral resistenstest og patientens behandlingsanamnese. Dosering*: Voksne: Anbefalet dosis REYATAZ
er 300 mg én gang dagligt sammen med 100 mg ritonavir én gang dagligt og i forbindelse med et måltid. Ritonavir
anvendes som farmakokinetisk booster for atazanavir. Pædiatriske patienter (fra 6 til 18 år): Doseringen af REYATAZ
bestemmes ud fra legemsvægten som vist i nedenstående tabel og bør ikke overskride den anbefalede dosis for voksne.
REYATAZ skal tages sammen med ritonavir og i forbindelse med et måltid.
Tabel 1: Dosering af REYATAZ-kapsler med ritonavir til pædiatriske patienter (fra 6 år til under 18 år)
Legemsvægt (kg)
REYATAZ en daglig dosis
Ritonavir en daglig dosisa
15 til under 20
150 mg
100 mgb
20 til under 40
200 mg
100 mg
mindst 40
300 mg
100 mg
a
Ritonavirkapsler, tabletter eller oral opløsning.
b
Ritonavir oral opløsning: ikke mindre end 80 mg og ikke mere end 100 mg kan anvendes til pædiatriske patienter
fra 15 kg til under 20 kg, der ikke kan synke ritonavirkapsler/tabletter. Tilgængelige data understøtter ikke brug af
REYATAZ i kombination med en lav dosis ritonavir hos pædiatriske patienter, der vejer mindre end 15 kg
Pædiatriske patienter (under 6 år): REYATAZ’ sikkerhed og virkning hos børn i alderen 3 måneder til 6 år er ikke klarlagt
og der kan ikke gives nogen anbefalinger vedrørende dosering til denne population. REYATAZ bør ikke anvendes til børn
under 3 måneder. Patienter med nedsat nyrefunktion: REYATAZ med ritonavir anbefales ikke til patienter i
hæmodialysebehandling. Patienter med nedsat leverfunktion: REYATAZ med ritonavir bør anvendes med forsigtighed til
patienter med let nedsat leverfunktion og må ikke anvendes til patienter med moderat til svært nedsat leverfunktion.
Graviditet og post partum: Graviditetens andet og tredje trimester: Da der findes begrænsede data samt på grund af
variabiliteten patienterne imellem under graviditet, kan det overvejes at anvende terapeutisk lægemiddelovervågning
(TDM Therapeutic Drug Monitoring) for at sikre tilstrækkelig eksponering. Når atazanavir administreres sammen med
lægemidler, der er kendt for at reducere dets eksponering forventes der en risiko for yderligere fald i eksponeringen. Post
partum: Eksponeringen for atazanavir kan muligvis øges i de første to måneder efter fødslen og derfor skal post partumpatienter monitoreres nøje for bivirkninger. Disse patienter skal følge samme dosisanbefalinger som ikke-gravide.
Administration: Kapslerne bør synkes hele. Kontraindikationer*: Overfølsomhed over for det aktive stof eller over for et
eller flere af hjælpestofferne. Patienter med moderat til svær leverinsufficiens. Samtidig administration af REYATAZ og
simvastatin eller lovastatin er kontraindiceret. Samtidig administration af kombination af rifampicin og REYATAZ og lavdosis ritonavir er kontraindiceret. Samtidig behandling med PDE5-hæmmeren sildenafil ved pulmonal arteriel
hypertension er kontraindiceret. REYATAZ med ritonavir må ikke anvendes i kombination med lægemidler, der er substrat
for CYP3A4 eller har et snævert terapeutisk vindue. REYATAZ må ikke anvendes i kombination med produkter, der
indeholder perikon. Særlige advarsler*: Selvom effektiv viral suppression med antiretroviral behandling har vist sig at
nedsætte risikoen væsentligt for seksuel overførsel, kan en residual risiko ikke udelukkes. Der bør træffes foranstaltninger
med henblik på at forebygge overførsel i overensstemmelse med nationale retningslinjer. Samtidig administration af
REYATAZ og ritonavir i doser over 100 mg én gang dagligt er ikke evalueret klinisk. Brug af højere doser ritonavir kan
ændre sikkerhedsprofilen for atazanavir (kardielle virkninger, hyperbilirubinæmi), og kan derfor ikke anbefales. Kun hvis
atazavir med ritonavir administreres sammen med efavirenz, kan det overvejes at øge dosis af ritonavir til 200 mg én
gang dagligt. Der bør udvises forsigtighed ved lægemidler, der vides at inducere PR-forlængelser. REYATAZ bør anvendes
med forsigtighed til patienter med allerede eksisterende overledningsproblemer (andengrads- eller højere
atrioventrikulær eller kompleks knude-grenblok), og kun såfremt fordelene opvejer risikoen. Der er rapporteret øget
blødning hos type A og B-hæmofile patienter, der har fået proteasehæmmere. Kombinationsbehandling med
antiretrovirale midler er forbundet med omfordeling af kropsfedt (lipodystrofi) hos hiv-patienter. Antiretroviral
kombinationsbehandling er forbundet med dyslipidæmi. Man bør derfor overveje at måle fastende serumlipider og
blodglukose. Der er rapporteret nyopstået diabetes mellitus, hyperglykæmi og forværring af eksisterende diabetes
mellitus hos patienter i behandling med proteasehæmmere. Der er set reversible forhøjelser i indirekte (ukonjugeret)
bilirubin relateret til hæmning af UDP-glucuronosyltransferase (UGT) hos patienter i behandling med REYATAZ. Patienter
i behandling med REYATAZ, som har forhøjede levertransaminaser og forhøjet bilirubin samtidig, bør evalueres for
alternative ætiologier. Der er rapporteret om cholelithiasis hos patienter behandlet med REYATAZ som i nogle tilfælde er
blevet forbundet med akut nyresvigt eller nyreinsufficiens. Der er rapporteret nephrolithiasis hos patienter behandlet
med REYATAZ. Hos hiv-inficerede patienter med svær immuninsufficiens kan der ved påbegyndelse af antiretroviral
kombinationsbehandling (CART) opstå inflammatorisk reaktion på asymptomatiske eller residuale opportunistiske
patogener, som kan forårsage alvorlige kliniske tilstande eller forværring af symptomer. Autoimmune lidelser (såsom
Graves sygdom) er også rapporteret i forbindelse med immunreaktivering. Udbrud kan optræde mange måneder efter
behandlingsstart. Der er rapporteret tilfælde af osteonekrose hos patienter med fremskreden hiv-sygdom og/eller
patienter i langvarig kombinationsbehandling med antiretrovirale lægemidler (CART). Udslæt er ofte lette til moderate
makulopapuløse huderuptioner, der optræder inden for de første 3 uger efter påbegyndelse af REYATAZ-behandling.
Stevens-Johnsons syndrom (SJS), erythema multiforme, toksiske huderuptioner og lægemiddelfremkaldt udslæt med
eosinofili og systemiske symptomer (DRESS-syndrom) har været rapporteret hos patienter i behandling med REYATAZ.
REYATAZ bør seponeres, hvis der udvikles alvorligt udslæt. Hvis patienten har udviklet SJS eller DRESS under REYATAZbehandling, bør REYATAZ-behandlingen ikke genoptages. Der bør udvises særlig forsigtighed ved ordinering af PDE5hæmmere (sildenafil, tadalafil eller vardenafil) til behandling af erektil dysfunktion hos patienter, der får REYATAZ
sammen med lav-dosis ritonavir, da denne kombination kan give PDE5-relaterede bivirkninger såsom hypotension,
synsforstyrrelser og priapisme. Samtidig administration af salmeterol og REYATAZ anbefales ikke, da dette kan resultere
i en øget risiko for salmeterolrelaterede kardiovaskulære bivirkninger. Absorptionen af atazanavir kan reduceres ved øget
pH-værdi i maven, uanset årsagen til dette. Samtidig administration af REYATAZ og protonpumpehæmmere frarådes.
Hvis kombinationen af REYATAZ og en protonpumpehæmmer ikke kan undgås, anbefales tæt klinisk monitorering af
patienten, samtidig med at dosis af REYATAZ øges til 400 mg med 100 mg ritonavir. Dosis af protonpumpehæmmere bør
ikke overstige dosis svarende til omeprazol 20 mg. Samtidig administration af REYATAZ/ritonavir og andre hormonelle
kontraceptionsmidler eller orale kontraceptionsmidler indeholdende andre gestagener end norgestimat bør undgås.
Patienter med arvelig galactoseintolerans, en særlig form af hereditær lactasemangel (Lapp Lactase deficiency) eller
glucose/galactosemalabsorption bør ikke tage dette lægemiddel. REYATAZ bør anvendes med forsigtighed til pædiatriske
patienter med allerede eksisterende overledningsproblemer. Interaktion med andre lægemidler og andre former for
interaktion*: Ved samtidig administration af REYATAZ og ritonavir kan ritonavirs metaboliske lægemiddelinteraktionsprofil
dominere, idet ritonavir er en mere potent CYP3A4-hæmmer end atazanavir. REYATAZ med ritonavir er derfor
kontraindiceret med lægemidler, der er substrater af CYP3A4 eller har et snævert terapeutisk vindue: Astemizol,
terfenadin, cisaprid, pimozid, quinidin, bepridil, triazolam, oralt administreret midazolam og sekalealkaloider, især
ergotamin og dihydroergotamin. Ved samtidig administration af REYATAZ, ritonavir og voriconazol forventes nedsat
eksponering for både voriconazol og atazanavir. Hos et lille antal patienter uden en funktionel CYP2C19-allel forventes
signifikant øget voriconazoleksponering. Der er risiko for interaktion mellem REYATAZ og ritonavir og for en lang række
lægemidler, såsom proteasehæmmere (indinavir), non-nukleoside reverse transkriptasehæmmere (NNRTI’er) (efavirenz,
nevirapin), HCV-proteasehæmmere (boceprevir), antibiotika (clarithromycin), antimykotika (ketoconazol, itraconazol,
voriconazol), antimykobakterielle midler (rifabutin, rifampicin), antipsykotika (quetiapin), H2-receptorantagonister
(famotidin), tenofovir, protonpumpehæmmere, antacida og lægemidler indeholdende buffer, alfa 1-adrenerge
receptorantagonister (alfuzosin), antikoagulantia (warfarin), antiepileptika (carbamazepin, phenytoin, phenobarbital,
lamotrigin), antineoplastiske midler (irinotecan), immunsupprimerende midler (ciclosporin, tacrolimus, sirolimus),
antiarytmika (amiodaron, systemisk lidocain, quinidin), calciumantagonister (bepridil, diltiazem, verapamil),
kortikosteroider (fluticasonpropionat), PDE5-hæmmere (sildenafil, tadalafil, vardenafil), perikon, HMG-CoA
reduktasehæmmere (simvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin), beta-agonister til inhalation
(salmeterol), benzodiazepiner (midazolam, triazolam). Fertilitet, graviditet og amning*: Brug af REYATAZ kan overvejes
under graviditet, hvis den potentielle fordel opvejer den potentielle risiko. For at undgå overførsel af hiv anbefales det
generelt, at hiv-inficerede mødre ikke ammer deres spædbørn. Trafiksikkerhed*: Patienterne bør informeres om, at der
er indberettet svimmelhed ved behandling med regimer indeholdende REYATAZ. Bivirkninger*: Almindelig: Hovedpine,
okulær icterus, opkastning, diarré, abdominalsmerter, kvalme, dyspepsi, gulsot, udslæt, lipodystrofisk syndrom, træthed.
Ikke almindelig: Overfølsomhed, diabetes1, hyperglykæmi1, vægttab, vægtstigning, anoreksi, øget appetit, depression,
desorientering, ængstelse, søvnløshed, søvnforstyrrelser, abnorme drømme, perifer neuropati, synkope, amnesi,
svimmelhed, døsighed, dysgeusia, torsades de pointes1, hypertension, dyspnø, pankreatitis, gastritis, abdominal
distension, aftøs stomatitis, flatulens, tør mund, hepatitis, cholelithiasis1, kolestase1, erythema multiforme1, toksiske
huderuptioner1, lægemiddelfremkaldt udslæt med eosinofili og systemiske symptomer (DRESS-syndrom)1, angioødem1,
urticaria, alopeci, pruritus, muskelatrofi, artralgi, myalgi, nephrolithiasis1, hæmaturi, proteinuri, pollakisuri, interstitiel
nefritis, gynækomasti, brystsmerter, ubehag, pyreksi, asteni. Sjælden: QTc-forlængelse1, ødem, palpitation,
hepatosplenomegali, cholecystitis1, Stevens-Johnsons syndrom1, vesikulobulløst udslæt, eksem, vasodilatation, myopati,
nyresmerter, gangforstyrrelser. 1Disse bivirkninger blev identificeret under post-marketing-overvågning, men
hyppigheden er estimeret ud fra en statistisk beregning baseret på kliniske studier med REYATAZ. Overdosering*:
Behandling af overdosering med REYATAZ bør bestå af generelt understøttende tiltag, inklusive monitorering af vitale
tegn og elektrokardiogram (ekg) samt observation af patientens kliniske status. Hvis indiceret, kan udskillelse af
uoptaget atazanavir opnås ved opkastning, maveskylning eller administration af aktivt kul. Der findes ingen specifik
antidot for overdosering med REYATAZ. Det er usandsynligt, at dialyse i signifikant grad kan bidrage til fjernelse af dette
lægemiddel. Pakninger og priser (ESP 29-10-2014): Hårde kapsler 150 mg, 60 stk: 5035,40 kr. Hårde kapsler 200 mg,
60 stk: 5035,40 kr. Hårde kapsler 300 mg, 30 stk: 5035,40 kr. Se venligst dagsaktuelle priser på www.medicinpriser.dk.
Tilskud: Nej. Udlevering: BEGR. Indehaver af markedsføringstilladelsen: Bristol-Myers Squibb Pharma EEIG,
Uxbridge Business Park, Sanderson Road, Uxbridge UB8 1DH, Storbritannien. Produktresumeet kan vederlagsfrit
rekvireres fra den danske repræsentant: Bristol-Myers Squibb, Hummeltoftevej 49, 2830 Virum.
Bristol-Myers Squibb · Hummeltoftevej 49 · 2830 Virum · www.bms.dk
HIV & VIROLOGY NEWS 2 · 2015
47
687DK14PR09753-01
Anette Fog, Anette Lorentzen, Maiken Steenstrup, Inge Zimmermann, Kirsten Bødker
HIV & HEPATITIS NEWS
three weeks after delivery. Raltegravir was well tolerated. The
pharmacokinetic assessment showed extensive variability with
mean AUC 29 % lower and C12h 36 % lower during third trimester compared to postpartum. The authors concluded that the
observed decreased exposure during third trimester compared
to postpartum was of no clinical importance and that raltegravir
can be used in standard dose during pregnancy.
Blonk et al. Clin Infect Dis:Advance access published May 5, 2015
Comment: Raltegravir is not part of a “preferred regimen”
during pregnancy but is considered as an alternative. In patients
already on raltegravir who become pregnant or in patients who
are diagnosed with HIV late during pregnancy it may be a reasonable alternative.
Nucleoside-nucleotide combination to prevent
recurrent Hepatitis B after liver transplantation
The standard procedure to prevent the recurrence of hepatitis
B after liver transplantation in patients infected with hepatitis B
is the combination of a nucleoside or nucleotide with Hepatitis
B Immune globulin (HBIg). The use of HBIg is both expensive
and inconvenient. 26 patients who had undergone liver transplantation and were on continuous indefinite treatment with
a nucleoside or nucleotide and HBIg in combination and had
undetectable HBsAg were switched to a combination of a nucleotide and a nucleoside. Most patients were given lamuvidine
and tenofovir in combination but other combinations were also
used. The mean duration of follow up after switching to a nucleoside-nucleotide combination was 32 months. HBsAg became
detectable in two patients 7 and 9 months after the switch at low
titers. Both patients had undetectable HBV-DNA and normal
aminotransferase levels. HBIg was reinstituted and HBsAg became undetectable. In the remaining 24 patients non developed
detectable HBsAg and all patients continued to have normal aminotransferase levels and undetectable HBV-DNA.
Khemichian et al.Dig.Dis Sci;Published on line 05 May 2015
Comment: A safe switch away from HBIg reduces costs and improves convenience in liver transplanted patients with hepatitis
B. The observation time in the present study is quite long and the
2 patients who had detectable HBsAg could be safely switched
back to HBIg and resuppress HBsAg.
DR. LEO FLAMHOLC
Skåne University Hospital
Malmö, Sweden
48
HIV & VIROLOGY NEWS 2 · 2015
Produktinformation rettet til sundhedspersoner
Forkortet produktresumé for Truvada filmovertrukne
tabletter
Emtricitabin og tenofovirdisoproxil
Præsentation: Hver filmovertrukken tablet indeholder 200 mg
emtricitabin og 245 mg tenofovirdisoproxil (svarende til 300 mg
tenofovirdisoproxilfumarat eller 136 mg tenofovir)
Indikationer*: Truvada er indiceret i antiretroviral kombinationsbehandling af hiv 1-inficerede voksne i alderen 18 år og derover.
Påvisningen af den gavnlige effekt af kombinationen emtricitabin
og tenofovirdisoproxilfumarat i antiretroviral behandling er udelukkende baseret på studier udført med behandlingsnaive patienter.
Dosering og indgivelsesmåde*: Voksne: Én tablet én gang dagligt, tages hel, oralt, helst sammen med mad. Ved synkebesvær
kan tabletten opløses i ca. 100 ml vand. Børn og unge: Sikkerhed
og virkning er ikke klarlagt. Ældre (>65 år): Kun dosisjustering
ved tegn på nyreinsufficiens. Nedsat nyrefunktion: Truvada anvendes kun, hvis de potentielle fordele ved behandlingen anses
for at veje tungere end de potentielle risici. Frarådes ved svært
nedsat nyrefunktion (kreatininclearance < 30 ml/min) eller hos
dialysepatienter. Leverfunktion: Dosisjustering er ikke nødvendig.
Patienter med hiv/HBV: Hvis Truvada seponeres, monitoreres patienten for udvikling af hepatitis. Glemt dosis: Hvis en dosis glemmes inden for 12 timer fra det normale tidspunkt, tages tabletten
(med mad) så snart som muligt, ellers skal der ventes med den
næste dosis til den sædvanlige tid. Hvis patienten kaster op inden
for 1 timer efter indtagelse tages en ekstra tablet.
Kontraindikationer: Overfølsomhed over for de aktive stoffer eller over for et eller flere af hjælpestofferne.
Særlige advarsler*: Samtidig administration med didanosin frarådes, da det resulterer i 40-60 % stigning i systemisk eksponering
for didanosin, hvilket kan øge risikoen for didanosinrelaterede bivirkninger. Trestofsbehandling med nukleosider: Ved kombination
med lamivudin og abacavir eller nukleosider er der set manglende
virologisk effekt og resistensudvikling. Opportunistiske infektioner:
Kan forekomme hos patienter med hiv-associerede sygdomme,
hvorfor tæt observation er nødvendig. Overførsel af hiv: Risiko for
seksuel overførsel er reduceret, men passende forholdsregler for at
forebygge overførsel er stadig nødvendige. Nyrefunktion: Det anbefales at kreatininclearance beregnes hos alle patienter før start
af behandling med Truvada. Nyrefunktion (kreatininclearance og
serumphosphat) bør monitoreres efter 2 til 4–ugers behandling,
efter 3 måneders behandling og derefter hver 3. til 6. måned hos
patienter uden renale risikofaktorer. Hos patienter med risiko for
nedsat nyrefunktion er hyppigere monitorering af nyrefunktionen
nødvendig. Hvis kreatininclearance på < 50 ml/min kan bekræftes eller serumphosphat falder til < 1,0 mg/dl (0,32 mmol/l)
bør det overvejes at seponere behandlingen med Truvada. Afbrydelse af behandling med Truvada bør også overvejes i tilfælde
af progressivt aftagende nyrefunktion, når anden årsag hertil
ikke kan identificeres. Truvada bør kun bruges til patienter med
nedsat nyrefunktion, hvis de potentielle fordele ved behandlingen
vurderes at veje tungere end de potentielle risici. Til patienter med
kreatininclearance <50 ml/min, kræves justering af doseringsintervallet af Truvada, som nævnt i produktresuméet. Truvada
anbefales ikke til patienter med stærkt nedsat nyrefunktion (kreatininclearance <30 ml/min) eller til patienter, som har behov for
dialyse. Truvada bør undgås ved samtidig anvendelse med eller
efter nylig brug af et nefrotoksisk lægemiddel på grund af øget
risiko for renale bivirkninger. Tidligere antiretroviral-behandlede
hiv-patienter: Bør undgås hos patienter med K65R-mutationer.
Hiv patienter i antiretroviral behandling, der samtidig er inficeret med HBV eller HCV har øget risiko for alvorlige og potentielt
letale hepatiske bivirkninger. Seponering af Truvada kan medføre
akut eksacerbation af hepatitis. Disse patienter monitoreres tæt i
mindst flere måneder efter behandlingsophør. Behandlingen bør
ikke seponeres hos patienter med fremskreden leversygdom eller
levercirrose. Under antiretroviral behandling -behandling er der set
forhøjet forekomst af unormal leverfunktion. Lipodystrofi: Der er
forekommet lipodystrofi (omfordeling af fedtvæv) hos hiv patienter. Måling af fastende serumlipider og blodglucose bør overvejes
og lipidændringer bør behandles på relevant måde. Laktatacidose:
Risikoen er øget hos patienter med hepatomegali, hepatitis, steatosis hepatis og alkoholmisbrug, og hos patienter, som samtidig er
inficeret med hepatitis C og som behandles med alfa-interferon og
ribavirin, Tidlige symptomer som f.eks. hyperlaktatæmi, kvalme,
abdominalsmerter, utilpashed, hurtig vejrtrækning og motorisk
svaghed kræver seponering af behandlingen. Mitokondriel dysfunktion: Spædbørn, som har været udsat for nukleosidanaloger
in utero skal udredes med henblik på mulig mitokondriel dysfunktion, hvis de har eller får symptomer som anæmi, neutropeni,
hyperlaktatæmi, hyperlipasæmi og senere evt. kramper og hypertoni. I en antiretroviral behandling kan der ligeledes forekomme
immunreaktiveringssyndrom, osteonekrose (specielt hos patienter
med fremskreden hiv sygdom eller i en langvarig behandling),
reduktion i knoglemineraltæthed og knogleanomalier – (se produktresuméet for anbefalinger mht. monitorering og behandling af
disse symptomer). Hjælpestoffer: Truvada indeholder lactosemonohydrat. Bør ikke anvendes til patienter med arvelig galactoseintolerans, en særlig form af hereditær lactasemangel (Lapp Lactase
Deficiency) eller glucose/galactosemalabsorption.
Interaktioner*: Alle interaktioner, som er identificeret med Truvadas aktive stoffer individuelt, kan forekomme med Truvada.
Nefrotoksiske lægemidler: Samtidig brug bør undgås. Cytidinanaloger, emtricitabin- eller tenofovirdisoproxilfumarat: Truvada bør
ikke indgives sammen med lamivudin eller med andre lægemidler
indeholdende emtricitabin eller tenofovirdisoproxilfumarat. Bør
ikke indgives sammen med adefovirdipivoxil. Andre interaktioner:
Se detaljeret information om interaktioner med antiinfektiva og
NRTIér i produktresuméet (tabel 1).
Fertilitet, graviditet og amning*: Hvis indiceret, kan anvendelsen overvejes under graviditet. Emtricitabin og tenofovir udskilles
i human mælk. Bør ikke anvendes under amning. Dyreforsøg
indikerer ingen skadelige virkninger på fertiliteten.
Bivirkninger*: Meget almindelige (≥1/10): Hypophosphatæmi*, svimmelhed, hovedpine, diarré, kvalme, opkastning,
udslæt, forhøjet kreatinkinase og asteni. Almindelige (≥1/100,
<1/10): Neutropeni, allergiske reaktioner, hyperglykæmi*, hypertriglyceridæmi, insomni, unormale drømme, abdominalsmerter, abdominal distension, flatulens, forhøjet amylase herunder
forhøjet pancreasamylase, forhøjet serum lipase, opkastning,
dyspepsi, forhøjet ASAT og/eller ALAT, hyperbilirubinæmi, forhøjede transaminaser, vesikulobulløst udslæt, pustuløst udslæt,
makulopapuløst udslæt, pruritus, urticaria, misfarvning af huden
(øget pigmentering), smerter. Ikke almindelige (≥1/1,000,
<1/100): Anæmi, hypokaliæmi, pancreatitis, angioødem,
rabdomylose*, muskelsvækkelse*, øget kreatinin, proteinuri.
Sjældne (≥1/10.000, <1/1000): Lactatacidose, steatosis hepatis, hepatitis, osteomalaci (manifesterer sig som knoglesmerter
og i sjældne tilfælde medvirkende årsag til frakturer)*, myopati*,
nyresvigt (akut og kronisk), akut tubulær nekrose, proksimal
renal tubulopati, herunder Fanconis syndrom, nefritis (herunder
akut interstitiel nefritis), nefrogen diabetes insipidus. Bivirkninger
markeret med* kan forekomme som resultat af proksimal renal
tubulopati. Tilfælde af osteonekrose er rapporteret. Hyppigheden
er ukendt.
Overdosering*: Patienten monitoreres for tegn på toksicitet. Der
gives støttende standardbehandling efter behov. Op til 30 % af
emtricitabindosen og cirka 10 % af tenofovirdosis kan fjernes ved
hæmodialyse. Det vides ikke, om emtricitabin eller tenofovir kan
fjernes ved peritonealdialyse.
Trafik og arbejdssikkerhed: Ikke mærkning. Svimmelhed er
blevet indberettet som en bivirkning.
Pakninger: HDPE-flaske:1x 30 filmovertrukne tabletter
Pris: For dagsaktuel medicinpris se www.medicinpriser.dk
Udlevering: BEGR (kun udlevering til sygehuse)
Tilskudsstatus: Ikke tilskudsberettiget.
Markedsføringstilladelsesnummer: EU/1/04/305/001,
Indehaver af markedsføringstilladelsen: Gilead Sciences nternational Limited, Cambridge, CB21 6GT, Storbritannien.
Produktinformationen er forkortet. Et fuldstændigt produktresumé kan rekvireres hos indehaveren af markedsføringstilladelsen og yderligere information kan rekvireres hos den
danske repræsentant: Gilead Sciences Denmark ApS, Korskildelund 6, 2670 Greve, Danmark Telefon: +45 36 91 50 50
Afsnit markeret med * er forkortet i forhold til det af EMA godkendte produktresumé.
LÆS PRODUKTRESUMÉET FØR ORDINATION ISÆR MED
HENSYN TIL BIVIRKNINGER, ADVARSLER OG KONTRAINDIKATIONER.
Et fuldstændigt produktresumé kan findes på EMAs
hjemmeside
Dato for oprettelse af produktinformation: December 2014
29.01.2015
References:
1. United States Department of Health & Human Services
(DHHS). Guidelines for the Use of Antiretroviral Agents in HIV1-Infected Adults and Adolescents. November 2014. Available
at www.aidsinfo.nih.gov/guidelines.
2. Günthard HF, et al. JAMA 2014;312(4):410-425.
3. European AIDS Clinical Society (EACS) Treatment Guidelines.
November 2014 (Version 7.1). Available at www.eacsociety.
org/Guidelines.
4. FDA, approval of Truvada for PrEP, avaliable at
http://www.fda.gov/downloads/AdvisoryCommittees
CommitteesMeetingMaterials Drugs AntiviralDrugsAdvisory
Committee /UCM303216.pdf.
5. Truvada® SmPC, 12/2014. Available at
www.ema.europa.eu.
6. Raffi F, et al. Lancet 2013;381:735-43.
7. Molina J-M, et al. HIV Medicine 2014;15:57-62.
8. Rockstroh JK, et al. J Acquir Immune Defic Syndr
2013;63:77-85.
164/DK/15-02/PM/1009
Gilead Sciences Nordic Office | Hemvärnsgatan 9, SE-171 54 Solna, Sweden | Phone: + 46 (0)8 505 71 800 | Fax: + 46 (0)8 505 71 801
Sender: Mediahuset i Göteborg AB
Marieholmsg. 10 C
SE-415 02 Göteborg, Sweden
TRUVADA (emtricitabine/tenofovir/disoproxil)
– BECAUSE BACKBONE MATTERS1-3
®
• Tenofovir-based regimens have established long-term safety
profiles with over 9 million patient-years’ experience worldwide4
• TRUVADA® (emtricitabine/tenofovir/disoproxil) has a well
documented and manageable renal profile5
• NRTI backbone of choice in independent and non-Gilead
sponsored studies6-8