1. health and fitness
2. disease
3. aids and hiv

EU antiretroviral drug approvals:
1987–20091-5
Toxicity of antiretroviral
drugs
Nucleoside reverse transcriptase inhibitor
Non-nucleoside reverse transcriptase inhibitor
ETR
Protease inhibitor
30
DRV
MVC
RAL
Intergrase inhibitor
CCR5 antagonist / Entry inhibitor
ATV
FPV
25
TPV
FTC
ENF
Linos Vandekerckhove
APV
20
d4T
3TC
SQV
RTV
IDV
15
General Internal Medicine, Infectious
Diseases and Psychosomatic Medicine
University Hospital Gent
Belgium
5
ddC*
0
87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08
Efficacy outcomes 12 months after initiation of cART in naïve
patients has significantly improved over time
6
60
Deaths per 100 Person Years
50
% Patients on HAART
5
4
40
3
30
2
20
1
10
*p<0.001 across 3 study periods
100
90.6%
84.5%
1997
1998
1999
2000
2001
2002
2003
2004
60
40
20
0
197.5
176.5
175
80
0
1996
*p<0.001 across 3 study periods
200
92.6%
Median increase from baseline
in CD4+ cell count (cells/μL)
7
Percentage of patients with HIV-1
RNA viral load <50 copies/mL
8
80
Deaths per 100 Person Years
90
0
09
Years
1. Data available at: http://www.emea.europa.eu/htms/human/epar/a.htm. Last accessed February 2010. 2. HIVID PI update June 2006:
http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/ucm086099.pdf. Last accessed February 2010. 3. Retrovir US PI November
2009: http://us.gsk.com/products/assets/us_retrovir.pdf. Last accessed February 2010. 4. Videx US PI January 2010:
http://packageinserts.bms.com/pi/pi_videx_ec.pdf. Last accessed February 2010..
70
% of Patients on HAART
ddl
AZT
*Discontinued
Decrease in mortality associated with increase in use
of HAART
• Before the introduction of
effective antiretrovirals, 18% of
patients with HIV developed
AIDS after 42–48 months
follow up2
LPV
ABC
EFV
10
26 march 2010
• Prospective, multicentre,
observational cohort study of
6,945 patients with HIV followed
for a median of 39.2 months1
NFV
NVP
TDF
157.5
150
125
100
75
50
25
0
2000 – 2001 2002 – 2003 2004 – 2005
2000 – 2001
2002– 2003
2004 – 2005
Time
1. Palella FJ, et al. J Acquir Immune Defic Syndr 2006;43:27–34; 2. Rezza G, et al. AIDS 1989;3:87–90
Vo TT, et al. J Infect Dis 2008;197:1685–94
Improvement over time of virological failure with
second HAART
Systematic overview highlights efficacy of NNRTI- and
boosted PI-containing regimens
Relative risk
60
40
% Patients with HIV RNA
< 50 copies/mL at 48 weeks
100
80
1
0.5
20
80
• 55% of patients with viral load
<50 copies/mL at week 48;
this percentage increases
with later publication dates
60
Unboosted PI
40
NNRTI
NRTI
20
02
-2
00
3
20
04
-2
00
5
20
02
-2
00
3
20
04
-2
00
5
0
0
19
96
-1
99
7
19
98
-1
99
9*
20
00
-2
00
1
• Systematic overview of 53
trials that enrolled 14,264
patients into 90 treatment
arms
100
1.5
19
96
-1
99
7
19
98
-1
99
9*
20
00
-2
00
1
Incidence of virological failure
with 2nd HAART/100 patient-yrs
120
*Reference data
Deeks, S et al. 15th CROI Boston MA, 2008. Abstract 41
Boosted PI
20
0
5
10
15
20
Number of antiretroviral pills prescibed per day
25
The size of the bubble reflects the numbers of subjects.
Based on Bartlett JA, et al. AIDS 2006;20:2051–64
1
First-line HAART regimens are well-tolerated
Drug regimens
HIV-1 RNA
<50 copies/mL at
study end (%)
144 weeks
EFV + TDF + FTC
EFV + ZDV/3TC
64
56
5
11
KLEAN[2]
144 weeks
FPV/r + ABC/3TC
LPV/r + ABC/3TC
73
60
13
9
ARTEMIS[3]
96 weeks
DRV/r + TDF/FTC
LPV/r + TDF/FTC
79
71
4
9
CASTLE[4]
96 weeks
ATV/r + TDF/FTC
LPV/r + TDF/FTC
74
68
3
5
MERIT[5]
96 weeks
EFV + ZDV/3TC
MVC + ZDV/3TC
62
59
16
6
STARTMRK[6]
96 weeks
EFV + TDF/FTC
RAL + TDF/FTC
79
81
19
10
ACTG 5202[7]
96 weeks
EFV + TDF/FTC
ATV/r + TDF/FTC
EFV + ABC/3TC
ATV/r + ABC/3TC
90*
89*
85*
83*
ATV/r + TDF/FTC
NVP + TDF/FTC
65
67
ARTEN[8]
48 weeks
Discontinuations due
to AEs (%)
Hazard Ratio
ATV/r vs. EFV with:
ABC/3TC
HR 0.81 (95% CI 0.66, 1.0)
p=0.05
TDF/FTC
HR 0.91 (95% CI 0.72, 1.15)
p=0.44
ABC/3TC
HR 0.69 (95% CI 0.55, 0.86)
p=0.0008
TDF/FTC
HR 0.84 (95% CI 0.66, 1.07)
p=0.17
4
14
A high proportion of patients do not remain on
original treatment regimen 1 year after initiating
HAART
• Reasons for patients discontinuing
HAART 2002–2004
(EuroSIDA study [n=78])
off treatment
5.9%
Remain on treatment
70.2%
Mocroft A, et al. AIDS Res Hum Retroviruses 2005;21:527–36
2
There remains a high proportion of
patients with HIV who switch cART
unknown
7.7%
Other
16.7%
patient/
physician
choice
33.3%
treatment failure
7.7%
1.0
1.0
2000-2001
2002-2003
2004-2005
0.8
0.6
0.4
0.2
0.0
0
Change of PI in 2-class regimens
Change of NNRTI in 2-class regimens
Any change in NRTI backbones
0.8
0.6
Probability of any
treatment change
• Twenty-four antiretrovirals have been
brought to market in the EU since 1987
• HAART has improved virological outcomes,
lowered mortality and is well tolerated by the
majority of patients
• The recent combination of efficacy,
tolerability
and simplicity of antiretroviral therapies has
heightened patients’ and physicians’
expectations
Change
treatment
23.9%
Favours
EFV
1
Daar, E. et al. 17th CROI, 2010. Presentation 59LB
Evolving expectations
• Patients with HIV starting
HAART after 1999
(EuroSIDA study [N=1198])
Tolerability (time to
change in treatment
regimen for any
reason)
Favours
ATV/r
0
Data from different studies can not be compared directly. *% without virological failure
1. Arribas JR, et al. J Acquir Immune Defic Syndr 2008;47:74–8; 2. Pulido F, et al. HIV Clin Trials 2009;10:76–87;
3. Mills A, et al. AIDS 2009 23:1679–88; 4. Molina JM, et al. ICAAC/IDSA 2008. Abstract 1250d; 5. Heera J, et al. 5th IAS 2009.
Abstract TUAB103; 6. Lennox J, et al. ICAAC 2009. Poster H924b; 7. Daar, E. et al. 17th CROI, 2010. Presentation 59LB;
8. Soriano V, et al. 5th IAS Congress 2009. Poster LBPEB07
Safety (time to
grade 3 or 4
symptoms or lab
toxicities)
Probability of any
treatment change
GS934[1]
Study
period
Log-rank test, p=0.17
Test for trend, p=0.15
2
4
6
8
10
0.4
0.2
0.0
0
12
Time since cART initiation, months
2
4
6
8
10
12
Time since cART initiation, months
Vo TT, et al. J Infect Dis 2008;197:1685–94
Major causes of discontinuation in a
cohort of ARV-naïve patients initiating
HAART 2003–2007
n=635
• A population-based cohort of
HIV-positive individuals in Italy
• Primary endpoints were
discontinuation of HAART for
drug toxicity and discontinuation
for virological failure
• The 1-year probability
(Kaplan-Meier estimate) of drug
discontinuation in the first
regimen was 41.2%
toxicities
34.6%
25
1-year probability of discontinuation (%)
Study
ACTG 5202: Safety and tolerability outcomes
of ATV/r vs EFV in combination with ABC/3TC
and TDF/FTC
20
20.8
15
10
10.5
7.6
5
3.4
0
Intolerence/
toxicity
Poor
Immunovirological Simplification
adherence
and
clinical failure
Cicconi P, et al. HIV Med 2010;11:104–13
2
Pregnancy
Age
Drug–drug
interactions
Virological
failure
Patient
desire
Adherence
difficulties
Poor CD4
response
Therapy not
meeting
current
recommendations
Trial end
point
Short-term
side effects
P
im rea ote
pr so nt
ov ns ial
e to
A
R
T
Management
of comorbidities
Long-term
toxicities
Regimen
simplificatio
n
What factors do you consider
for the patient in front of you?
EACS Guidelines, Clinical management and treatment of HIV infected adults in Europe
http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf. Accessed February 2010
Short-term
side effects
Side effects in the short
term
Gastrointestinal
effects
Nephrotoxicity
Rash
Hepatotoxicity
CNS
symptoms
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 2010
The most common side effects reported by
clinical trials are gastrointestinal side effects
• Group-based analysis was by
weighted, forward, stepwise,
linear regression
• The incidence of gastrointestinal side effects can
result from HIV infection and some antiretroviral
treatments
• Boosted PIs and certain NRTIs (e.g. zidovudine)
are associated with gastrointestinal side effects
30
Weighted mean incidence (%)
• Systematic review of initial ART
studies (64 randomised,
15 cohort)
29
25
25
20
18
15
Gastrointestinal side effects
15
13
10
– The most common gastrointestinal effect is diarrhoea
5
0
Diarrhoea
Headache
Nausea
Carr A, et al. AIDS 2009,23:343–53
Fatigue
Rash
Hill A, et al. AIDS Rev 2009;11:30–8
3
Different PIs are associated with different
frequencies of drug-related diarrhoea in
treatment-naïve patients at 96 weeks
20
KLEAN1
Grades 2–4
ARTEMIS2
20
20
Grades 2–4
CASTLE3
Short-term
side effects
Grades 2–4
Patients with diarrhoea (%)
16
15
15
15
10
10
5
5
0
0
Gastrointestinal
effects
12
11
11
4
5
2
mg
Anti-diarrhoeal use
Rash
0
LPV/r DRV/r
OD or 800/100
BD
OD
LPV/r FPV/r
400/100 700/100
BD
BD
NP
Nephrotoxicity
10
NP
NP
NP
22%
Hepatotoxicity
CNS
symptoms
LPV/r ATV/r
400/100 300/100
BD
OD
9%
Data in figures are from different studies and cannot be compared directly. NP = not provided
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 2010
1. Pulido F, et al. 47th ICAAC 2007. Abstract H-361; 2. Mills A, et al. AIDS 2009 23:1679–88;
3. Molina JM, et al. 48th ICAAC 2008. Abstract H-1250d
Division of AIDS gradations for
rash
Grade 1
Parameter
Rash
Mild
Localised macular
rash
Grade 2
Grade 3
Moderate
Diffuse macular,
maculopapular, or
morbilliform rash
OR
Target lesions
Severe
Diffuse macular,
maculopapular, or
morbilliform rash with
vesicles or limited
number of bullae OR
Superficial ulcerations
of mucous membrane
limited to one site
Rash and antiretrovirals
•
Grade 4
Potentially life
threatening
Extensive or generalised
bullous lesions OR
Stevens-Johnson
syndrome OR Ulceration
of mucous membrane
involving two or more
distinct mucosal sites
OR Toxic epidermal
necrolysis
DAIDS AE grading table. Available at:
http://www.ucdmc.ucdavis.edu/clinicaltrials/documents/DAIDS_AE_GradingTable_FinalDec2004.pdf. Accessed November 2009
Rash is common (~10–25% of patients) during the first 1–3 weeks of NNRTI
treatment, but is usually short-lived and self-limiting1-4
–
–
Only 8% of 122 patients who replaced NVP with EFV due to rash had the same
problem a median of 8 days later5
Rash was reported in 16% of NVP and 12% of ATV/r patients in the ARTEN study; no
patients on ATV/r discontinued due to rash compared with 5% of NVP6
•
NNRTI-associated rash is generally mild-to-moderate (Grade 1 or 2 macular or
maculopapular)1-4
•
Treatment may include antihistamines or corticosteroids1
•
More severe rashes (Grade 3 and 4), including Stevens-Johnson syndrome, are
rare (0.1–1.5% of cases)1-4
•
Approximately 5% of patients taking abacavir develop hypersensitivity reactions7
1. Viramune SmPC June 2009. Available at:http://www.ema.europa.eu/humandocs/Humans/EPAR/viramune/viramune.htm. Accessed February 2010;
2. Sustiva SmPC January 2010: http://www.ema.europa.eu/humandocs/PDFs/EPAR/Sustiva/H-249-en1.pdf . Accessed February 2010;
3. Katlama C, et al. AIDS 2009;23:2289–300; 4; Lazzarin A, et al. Lancet 2007;370:39–485; 5. Manosuthi W, et al. HIV Med 2006:7:378–82;
6. Soriano V, et al. 5th IAS Conference 2009. Poster LBPEB07; 7. Ziagen SmPC February 2010.
http://www.ema.europa.eu/humandocs/PDFs/EPAR/Ziagen/H-252-en1.pdf. Accessed February 2010
EFV is associated with mild,
transient CNS symptoms
Short-term
side effects
Gastrointestinal
effects
Nephrotoxicity
Rash
NVP 200 mg BD
<Week 6
>Week 6
(n=373)
(n=335)
45
31 (9.3%)
(12.1%)
EFV 600 mg OD
<Week 6
>Week 6
(n=376)
(n=313)
Total
CNS
sympto
ms
Grade 1
32 (8.6%)
14 (4.2%)
116 (30.9%)
15 (4.8%)
Grade 2
11 (2.9%)
12 (3.6%)
48 (12.8%)
14 (4.5%)
Grade 3
1 (0.3%)
3 (0.9%)
6 (1.6%)
8 (2.6%)
Grade 4
1 (0.3%)
2 (0.6%)
2 (0.5%)
1 (0.3%)
172 (45.7%)
38 (12.1%)
Hepatotoxicity
CNS
symptoms
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 2010
Kappelhoff BS, et al. Antiviral Therapy 2005;10:489−98
4
Improvement in neuropsychological score
maintained over
3 years, CNS symptoms transient
Incidence of CNS symptoms
decrease over time
50
Percentage of patients
with new-onset CNS symptoms
• Minimal increase in baseline EFV-associated symptoms
“of questionable clinical significance”
8
Median change in EFV-associated
symptom score
0.7
Median change in
*NPZ3 score
0.6
0.5
0.4
0.3
0.2
0.1
EFV regimen
Non-EFV regimen
0.0
-0.1
6
EFV regimen
Non-EFV regimen
4
2
12
24
30
20
10
0
0
-2
01 4
Mild
Moderate
Severe
40
184
01 4
12
Week
24
184
EFV Control
n=827 n=401
EFV Control
n=797 n=377
EFV Control
n=773 n=350
EFV Control
n=750 n=335
EFV Control
n=729 n=318
EFV Control
n=711 n=302
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Week
*NPZ3 score is a composite score from Trailmaking A and B and Digit Symbol tests
Johnson M, et al. 8th European Conference on Clinical Aspects and Treatment of HIV Infection 2001 Abstract 22
Clifford DB , et al. 13th CROI 2006:Poster 773
Hepatotoxicity and nephrotoxicity
Short-term
side effects
Gastrointestinal
effects
Nephrotoxicity
Rash
Hepatotoxicity
CNS
symptoms
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 2010
Gazzard BJ, et al. HIV Medicine 2008;9:563–608
Increased nevirapine levels are
associated with increased transaminase
levels
•
•
Case-control study of 70 patients
taking NVP classified into subjects
who developed hepatotoxicity and
subjects without transaminase
elevations
Peak transaminase levels among
the 33 subjects with hepatotoxicity
occurred at a median time of
6.1 months
Both higher NVP levels and HCV
seropositivity were found to be
independent factors predicting
hepatic injury (OR 1.7, 95% CI
1.2–2.6, p=0.007 and OR 11.7,
95% CI
3.2–42.8, p=0.0002, respectively)
González de Requena D, et al. AIDS 2002;16:290–1
10
8
Median NVP plasma
concentration (μg/mL)
•
p=0.025
6
• Antiretrovirals have the potential to cause
hepatotoxicity
• Risk is increased two- to three-fold in the
presence of chronic liver disease caused by
hepatitis
• Patients should be monitored for hepatotoxicity
when HAART is started or switched
• Patients should have blood biochemistry and
urinalysis performed prior to initiating tenofovir
with regular monitoring throughout treatment
6.25
5.2
4
2
0
Transaminase
elevated group
Control
Side effects in the short term
• Short-term side effects are common and are a
major cause of discontinuation among patients
taking antiretrovirals
• Approximately 34.6% of patients discontinue
treatment due to toxicity1
• The most common side effects in the short term
are gastrointestinal, rash, CNS symptoms,
hepatotoxicity and nephrotoxicity
• Potential switch options may help manage shortterm side effects
5
Long-term
toxicities
Cardiovascular
disorders
Neurocognitive
impairment
Long-term toxicity
Metabolic
disorders
Vitamin D
deficiency
Bone mineral
density diseases
Renal disease
Hepatotoxicity
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 2010
Cardiovascular and metabolic
disorders and HIV
Patient factors
Lifestyle factors
• Age
• Smoking
• Family history
• Lack of exercise
Smoking increases risk of death from
CVD and non-AIDS malignancies in
patients with HIV
10
Adjusted rate ratio (95% Cl)
• Diet
• Hypertension
• Dyslipidaemia
• Obesity
HIV
• Cardiovascular diseases
Overall
AIDS
LIVER
CVD
Non-AIDS Malignancies
5
1
0.5
• Insulin resistance
0.1
• Dyslipideamia
Current smoker
Ex smoker
Unknown
smoker
• Antiretroviral therapy (PIs)
Denholm JT et al. Aust Fam Physician 2009;8:574–7
Never
(ref)
Smith C, et al. 16th CROI 2009. Oral presentation
Choice of regimen backbone affects lipid profile
Gallant JE, et al. N Eng J Med 2006;354:251–60
Lipid effects of TDF/FTC vs ZDV/3TC at Week 48
50
Mean change in lipids from
baseline to Week 48 (mg/dL)
• Prospective, multicentre,
open-label study of 517
naïve patients with HIV
randomised to
TDF/FTC/EFV or ZDV/3TC
in combination with EFV for
48 weeks
• Mean total limb fat was
significantly less in a
subgroup of 49 patients in
the ZDV/3TC group
compared with 51 patients
in the TDF/FTC group (6.9
kg vs 8.9 kg; p=0.03)
p<0.001
40
p=0.38
35
31
30
p=0.01
21
20
20
13
10
p=0.004
9
6
3
0
TC
LDL
TDF/FTC/EFV
HDL
TG
ZDV/3TC and EFV
Example Framingham Score : man 48 y / Smoker
Total Cholesterol 230 mg/dL / HDL 42 mg/dL /Systolic BP 14
(mmHg).
SCORE = 15 % of 10-year Hard Coronary Heart Disease Risk
1. D.A.D. Study Group. The Lancet 2008; 371 (9622): 1417 – 1426
6
Data on abacavir and possible increased risk of
myocardial infarction (MI) are inconclusive
Changes in Cardiovascular Biomarkers with
Abacavir: a Randomized, 96-Week Trial
A Humphries1, J Amin1, D Cooper1, A Carr2, A Kelleher3, M Bloch4, D Baker5, Sean Emery*1, and STEAL
Study Group
Study
Design
Event ascertainment
N of patients
- N of MI
D:A:D
Prospective observational cohort
Prospective, pre-defined
33,347 - 580
ANRS
(FHDB)
Case control in observational
cohort
Prospectively reported MI,
retrospectively validated
884 controls289 cases
SMART
RCT observational
Prospective pre-defined
2,752 -19
STEAL
RCT
Prospective
357 – 3
GSK analysis
54 trials (12 RCTs)
Retrospective database search
14,174 -11
ALLRT
ACTG 5001
LTFU from 5 RCTs
Retrospective by 2 independent
reviewers
3,205 – 27
HEAT
RCT
Assessment of CV biomarkers
688 – 0
Veterans
Administration
Retrospective observational cohort
Retrospective, AMI (& CVA)
identified via ICD-9 disease codes
19,424 - 278
Quebec
(QPHID)
Case control in observational
cohort
Retrospective, MI identified via
ICD-9 disease codes
1,084 controls
125 cases
BICOMBO
Retrospective sub-study of RCT
Assessment of CV biomarkers
80 - 0
Based on Reiss P. 16th CROI ; 8th-11th Feb 2009, Montreal. 152. with additional data from:
Smith KY et al. 17th IAC, 3rd-8th August 2008, Mexico City, Mexico. D:A:D Study Group. The Lancet 2008; 371 (9622):
1417 – 1426; Lang S, at al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 43LB.; Lundgren D et al. AIDS
2008, 22:F17–F24; Martin A et al. CID 2009; 49:1591–1601; Brothers C et al. JAIDS 2009;51:20–28 ; Benson CA et al.
16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 721; Smith KY et al. AIDS 2009; 23:1547-1556; Bedimo R et
al. 5th IAS, 19th-22nd July 2009, Cape Town, SA. MOAB202; Durand M et al. 5th IAS, 2nd July 2009, Cape Town, SA.
Poster TUPEB175; Martinez E et al. AIDS e pub December 2009 ahead of publication, doi:
10.1097/QAD.0b013e32833562c5.
Abacavir and CVD — More Data but No
Consensus
•
Background: Abacavir has been implicated as a cause of cardiovascular
disease (CVD) in HIV, contributing to more than 10% of deaths.
The STEAL study was a prospective, controlled trial of participants randomised
to either abacavir/lamivudine (ABC/3TC; n = 179) or tenofovir/emtricitabine
(TDF/FTC; n = 178).
In this study an increased risk in CVD was reported (HR = 7.7, P =0.048) in
participants randomised to ABC/3TC compared to those who received
TDF/FTC. No lipid explanation was evident for this affect. The impact of
ABC/3TC treatment on a range of CVD and inflammatory biomarkers was
explored
•
Conclusions: This study did not reveal a consistent pattern of associations
between ABC/3TC and increased circulating levels of selected biomarkers of
inflammation and/or CVD.
New
Humphries et al. 17th CROI San Francisco, US, Feb. 2010, abs 718
NEW
Cumulative exposure to IDV and LPV/r associated with
increased risk of MI
Studies this year were evenly split, leaving patients and clinicians with few answers.
Nearly two years have passed since we first heard about a possible association between abacavir use
and increased risk for cardiovascular disease (CVD), but we still don't have any clear answers or even
a plausible mechanism. This is not for lack of effort.
In the past year alone, at least a dozen studies have been presented or published on the topic, including
two 96-week randomized trials that directly compared abacavir/3TC and tenofovir/FTC. Both trials
showed that the drugs were comparable in efficacy when taken as part of a larger antiretroviral
regimen, but the safety results were a draw: The HEAT study showed no difference in the safety
profiles of the two drugs (JW AIDS Clin Care Jul 20 2009). In contrast, in the STEAL study, the
abacavir group had a significantly higher rate of non-AIDS events, driven mainly by adverse
cardiovascular events, although the overall rate of such events was relatively low (JW AIDS Clin Care
Nov 23 2009). Notably, participants in the HEAT study were treatment-naive, whereas those in the
STEAL study were treatment-experienced.
RR/year 95% CI
1.2
The observational data that emerged this year were similarly split. Two studies — an updated analysis
from the DAD study (JW AIDS Clin Care Mar 9 2009) and a smaller study from Quebec (JW AIDS
Clin Care Aug 31 2009) — identified significant associations between abacavir use and increased
myocardial infarction (MI) risk, even after adjustment for cardiovascular risk factors and other
confounders. However, two other studies showed no association after control for confounders: The
French Hospital Database group initially reported a link between recent abacavir use and MI risk in a
case-control study (JW AIDS Clin Care Mar 9 2009) but then later reported that it was no longer
significant after adjustment for cocaine and injection-drug use. Similarly, in a large study from the
U.S. Veterans Affairs system, investigators found that an already-weak, nonsignificant link between
abacavir use and MI risk became even weaker after adjustment for traditional cardiovascular risk
factors and chronic renal disease, which increases risk for CVD (JW AIDS Clin Care Aug 31 2009).
1.13
1
0.9
Given these conflicting data, we find ourselves asking the same question we did 2 years ago, when the
issue was just arising: What is the role of abacavir? Aside from the cardiovascular concerns, abacavir
has a good safety record in HLA-B*5701–negative patients and thus remains a viable NRTI
component in many situations (e.g., in patients with renal dysfunction). However, patients with
moderate-to-high risk for CVD should be cautious about the use of abacavir and also focus on
managing their other CVD risk factors (e.g., smoking and diabetes).
PYFU:
MI:
Changes in blood lipids and
cardiovascular risk
LPV/r
37,136
150
SQV
44,657
221
New-onset diabetes increases with
cumulative exposure to cART
10
8
6
4
2
yr
s
yr
s
yr
s
6
>
56
45
yr
s
yr
s
23
34
yr
1
yr
s
0
<
Older age, male sex, greater BMI,
heterosexual or injection drug user,
black African and other ethnicities,
earlier calendar year, time-updated
total cholesterol, HDL cholesterol
and lipodystrophy were also
associated with increased risk
12
12
•
Significant association between
cumulative cART exposure and
new-onset diabetes (relative rate
per year 1.11, CI 95% 1.07–1.15
[p=0.0001])
14
Incidence (/1000 PYFU)
•
Prospective observational study of
33,389 patients with HIV
N
on
e
•
Friis-Møller N, et al. Curr Opin HIV AIDS 2008;3:220–225
NFV
56,529
197
Lundgren JD, et al. CROI 2009; Abstract 44LB
— Keith Henry, MD
• Combination ART, and PI-based therapy in particular, is
associated with an increased risk of cardiovascular disease. This
risk is probably mediated, in part, by changes in blood lipids
• Clinical outcome studies suggest that protease inhibitor-based
therapy is associated with an increased risk of cardiovascular
disease, with a consistent estimated increased risk of 1.16 to 1.17
for each additional year of protease inhibitor exposure
• ABC is associated with increased risk of MI in DAD and SMART,
however this was not confirmed in other study’s, justifying the
current EACS guidelines.
IDV
68,469
298
De Wit S, et al. Diabetes Care 2008;31:1224–9
7
Renal and liver disease and HIV
Patient factors
Lifestyle factors
• Age
• Alcohol
Long-term
toxicities
Cardiovascular
disorders
Neurocognitive
impairment
• Ethnicity
• Co-morbidities
(hepatitis)
Metabolic
disorders
• Concurrent
nephro/hepatotoxic
agents
HIV
Vitamin D
deficiency
Bone mineral
density diseases
Renal disease
• Renal infection
Hepatotoxicity
• Antiretroviral therapy
Denholm JT et al. Aust Fam Physician 2009;38:574–7
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 2010
HIV-associated nephropathy
• HIV-associated nephropathy is an important cause of end-stage
renal disease among African American patients
• 16,834 patients with HIV in 8 UK clinics studied 1998–2004
– HIV-associated nephropathy prevalence in black patients was 0.93%
– HIV-associated nephropathy incidence in patients without renal disease at
baseline was 0.61 per 1000 person-years
– After a median of 4.2 years, 34 patients (56%) with HIV-associated
nephropathy had developed end-stage renal disease
– No additional renal benefit of early initiation of HAART or viral suppression
could be demonstrated
– Severity of kidney damage was the strongest predictor of renal outcome
ASSERT is examining renal
function in Kivexa and TDF /
FTC 1
Open Label ABC/3TC FDC QD
+
Open Label TDF/FTC FDC QD
Primary
endpoint:
Change from
eGFR (MDRD)
at week 48
+
Efavirenz 600mg QD (n=190)
ABC=abacavir 3TC=lamivudine
FTC=emtricitabine TDF=tenofovir
EFV=efavirenz
FDC= fixed dose combination
48 week
Primary analysis
eGFR=estimated glomerular filtration
rate
MDRD=Modification of Diet in Renal
Disease formula
Post FA, et al. Clin Infect Dis 2008;46:1282–9
Efavirenz 600mg QD (n=190)
HIV+
ART-naïve
VL > 1,000 c/mL
HLA-B*5701
neg
96 week
Final analysis
Randomisation stratified by:
• Screening GFR (MDRD) <90 or > 90mL/min/1.73m2
• Black or non-black race
• Body mass index <25 or > 25kg/m2
• Not stratified for viral load
1. Stellbrink HJ et al. 12th European AIDS Conference.
Cologne, Germany. November 11-14, 2009. PS10/1
The Swiss HIV Cohort Study
ASSERT 48 WK HJ Stellbrink
Secondary Endpoint: Renal Biomarkers
Week 48 as % of
Baseline
Ratio of
Changes from
BL (95% CI)
N
ABC/3TC
TDF/FTC
P-value
β2-microglobulin
/Creatinine Ratio
(Tubular dysfunction)
ABC/3TC = 100
TDF/FTC= 115
53%
124%
2.33
(1.71, 3.19)
<0.001
RBP/Creatinine Ratio1
(Tubular dysfunction)
ABC/3TC = 129
TDF/FTC= 142
100%
150%
1.50
(1.28, 1.76)
<0.001
Albumin/Creatinine
Ratio (General kidney
damage)
ABC/3TC = 129
TDF/FTC= 142
87%
94%
1.08
(0.90, 1.29)
0.4237
NAG/Creatinine Ratio2
(Tubular damage)
ABC/3TC = 129
TDF/FTC= 142
87%
92%
1.05
(0.91, 1.22)
0.5084
TDF & PI use are associated with an increased
prevalence of proximal renal tubular dysfunction
Cross sectional analysis (n=1202 unselected patients treated within the
SHCH)
4 parameters with following threshold for pathology
measured (fasting state)
Fractional excretion of phosphate
(FE_p)
p/creat(urine) / p/creat(serum)
Fractional excretion of uric acid
>20% / >10% of
hypophosphatemic
> 10%
UA/creat(urine) / UA/creat(serum)
Urine protein / creatine ratio
Euglycaemic glucosuria
> 0.1
> 0.6 mmol/L
No discontinuations due to renal dysfunction
1.
2.
Retinol Binding Protein
N-Acetyl-(D)-Glucosaminidase
Fux C et al., CROI 2009, Poster 743;
PRT was defined as > 3 / 4 pathological parameters
8
The Swiss HIV Cohort Study
TDF & PI use are associated with an increased
prevalence of proximal renal tubular dysfunction
Rates of PRT & pathological FE-p differed significantly between treatment
groups (p=0.006 for PRT; p<0.001 for FE-p)
EACS guidelines
• monitoring for renal disease in HIV
• eGFR (MDRD) every 3-6 months
• Urine dipstick annually
Logistical regression for proximal tubulopathy (PRT) & a pathological
fractional excretion of phosphate (path FE-p) according Tx
Treatment
OR (95%
CI) for PRT
p
OR (95%
CI) for FE-p
p
TDF - / PI -
1
-
1
-
TDF + / PI -
2.9
(0.9 – 6.7)
0.06
2.4
(1.6 – 3.6)
<0.001
TDF - / PI +
2.0
(0.6 – 7.3)
0.3
1.3
(0.8 – 2.2)
0.3
TDF + / PI +
7.1
(2.5 – 19.8)
<0.001
3.4
( 2.3 – 5.1)
<0.001
Fux C et al., CROI 2009, Poster 743;
EACS guidelines
• monitoring for tenofovir renal toxicity
Long-term
toxicities
Cardiovascular
disorders
Neurocognitive
impairment
Metabolic
disorders
Vitamin D
deficiency
Bone mineral
density diseases
Renal disease
Hepatotoxicity
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed November 2009
Hepatotoxicity of PIs and NRTIs
Drug
Incidence and risk factors
RTV
Most hepatotoxic of PIs when administered at full dose
IDV, SQV
Several cases of hepatotoxicity reported
NFV
Less hepatotoxic than other PIs analysed (RTV, IDV, SQV and APV) in study evaluating
1052 patients
Hepatotoxicity of PIs
Increasing
Caution
RTV*
ddI
d4T
AZT
LPV/r
Incidence of hepatotoxicity is low
ATV
Good safety profile
TPV
Appears to be more hepatotoxic, most probably because it is given with higher doses of
RTV
TPV
NVP
EFV
DRV
APV
ABV
TDF
ATV
LPV
3TC
FTC
SQV
NFV
NRTI
NNRTI
PI
T20
Entry
inhibitors
Hepatic safety profile of antiretroviral drugs. RTV, ritonavir (*at full doses, not when used as booster); ddI, didanosine; d4T, stavudine; AZT, zidovudine; ABV,
abacavir; TDF, tenofovir; 3TC, lamivudine; FTC, emtricitabine; NVP, nevirapine; EFV, efavirenz; TPV, tipranavir; APV, amprenavir; DRV, darunavir; ATV,
atazanavir; LPV, lopinavir; SQV, saquinavir; NFV, nelfinavir; T20, enfuvirtide; NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, nonnucleoside reverse
transcriptase inhibitors; PI, protease inhibitors.
Núñez M. J Hepatol 2006;44:S132–S139. Refer to slide 29 for further information on DRV and hepatotoxicity
Soriano V, et al. AIDS 2008;22:1-13.
9
Frequency of grade 3 or 4 increased liver
enzymes in patients treated with
efavirenz and nevirapine
2NN
NEFA
Sulkowski et al.
Long-term
toxicities
Cardiovascular
disorders
Martin-Carbonero et al.
Neurocognitive
impairment
25
20
Efavirenz
Nevirapine
% of cases
16
15
13
12
10
Metabolic
disorders
8
4
4
5
Vitamin D
deficiency
4
1
0
n=400 n=200
n=156 n=155
n=312 n=256
In addition to severe increased liver enzymes, nevirapine was more frequently associated with early
acute hepatitis than efavirenz
•
The most common risk factor for NNRTI-induced liver toxicity is Hepatitis C co-infection (2–7 fold
increased risk). Other risk factors include hepatitis B co-infection, concomitant use of PI and high
alcohol consumption
Adapted from Rivero A, et al. J Antimicrob Chemother 2007;59:342–6
Bone mineral
density diseases
Renal disease
n=400 n=200
•
Hepatotoxicity
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 2010
Bone mineral density and HIV
Lifestyle factors
Patient factors
• Smoking1,2
• Female1,2
Risk of osteoporosis in patients
with HIV
Study
Odds Ratio
(95% CI)
• HIV RNA levels5
Ameil (2004)
Brown (2004)
Bruera (2003)
Dolan (2004)
Huland (2002)
Knobel (2001)
Loiseau-Peres (2002)
Madeddu (2004)
Tebas (2000)
Telchman (2003)
Yin
(2005)
5.03
4.26
4.51
2.11
3.52
5.13
4.28
29.84
3.40
17.41
2.37
(91.47, 17.27)
(0.22, 82.64)
(0.26, 79.27)
(0.54, 8.28)
(0.15, 81.92)
(1.80, 14.60)
(0.46, 93.81)
(1.80, 494.92)
(0.19, 61.67)
(0.97, 313.73)
(1.09, 5.16)
• Antiretroviral therapy (PI and NRTI)3
Overall (95% CI)
3.68
(2.31, 5.84)
• Lack of exercise1,2
• Caucasian2
•
Alcohol1,2
• Family history1,2
• Falls risk2
• Medications – steroids1
HIV
• Length of HIV infection4
• Hypogonadism6
0.01
• Malnutrition – vitamin D deficiency / low BMI4
100
Odds ratio
1. NHS Your Health Your Choices Osteoporosis. Available at www.nhs.uk/Conditions/Osteoporosis/Pages/Causes.aspx. Accessed
February 2010; 2. National Osteoporosis Foundation. Available at http://www.nof.org/prevention/risk.htm. Accessed February 2010;
3. Brown TT, et al. AIDS 2006;20:2165–2174; 4. Bruera D, et al. AIDS 2003; 17:1917–23;
5. Fausto A, et al. Bone 2006;38:893–7; 6. Teichmann J, et al. Eur J Med Res 2009;14:59–64
Fracture prevalence according to
HIV status in women
Figure adapted from Brown TT, et al. AIDS 2006:20;2165–74
1. Duvivier C, et al. AIDS 2009; 27:817–24; 2. Woodward CL, et al. HIV Medicine 2009;10:482–7
EACS guidelines
Overall comparison p=0.002
7
Fracture prevalence/100 persons
1
• Higher prevalence of
bone loss in PI-treated
patients1
• Specific association
between NRTIs,
especially tenofovir,
and Fanconi syndrome2
HIV+
6
HIV5
4
3
2
1
0
30-39
40-49
50-59
60-69
70-79
Years
Triant VA, et al J Clin Endocrinol Metab 2008;93:3499–3504
10
Case No 2 – FRAX® score
Osteoporosis / osteopenia
Risk factors in HIV+ subjects – cross sectional studies:
- low weight / BMI1, 3-8
- length of HIV infection1, 2, 8
- older age3, 4, 7
- smoking1, 8
- non-black / Caucasian ethnicity6, 7
- steroids1
- female3
- HIV RNA3
- d4T use (+/- elevated lactate)4
- duration of NRTI8
1. Mondy K, et al. CID 2003; 36:482–490
2. Bruera D et al. AIDS 2003; 17:1917-23
3. Fausto A et al. Bone 2006;38:893-7
4. Carr A et al. AIDS 2001;15:703-9
5. Nolan D et al. AIDS 2001;15:1275-80
6. Arnsten JH et al. AIDS 2007;21:617-23
7. Arnsten JH et al. CID 2006;42:1014-20
8. Dolan SE et al. JCEM 2006;91:2938-45
Does ART play a role?
N = 112 men.
60 = ART with PI, 35 = no PI and naive and 17= HIV neg
Long-term
toxicities
Cardiovascular
disorders
Neurocognitive
impairment
Sites
Proximal femur BMD Z scores
4
Femoral neck
Trochanter
3
Ward’s triangle
2
1
Metabolic
disorders
¥
*
Vitamin D
deficiency
†
0
For comparisons with the no PI
group and healthy control group
* P = 0.08 (femoral neck)
†
P = 0.01 (trochanter)
¥ P = 0.09 (Ward’s triangle)
–1
–2
–3
PI + HIV +
No PI HIV +
Group
Bone mineral
density diseases
Renal disease
Hepatotoxicity
Controls
Tebas P, et al AIDS 2000; 14:F63–F67
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 2010
Vitamin D deficiency
• Vitamin D deficiencies have been associated with low CD4 cell
counts, an activated immune system, HIV disease progression1 and
type 2 diabetes mellitus2
• In one cohort of 252 patients with HIV studied in 2006, 29% had
vitamin D deficiency*1
• In a retrospective analysis of the Modena cohort (n=1811), 65.5% of
patients were found to have vitamin D deficiency†2
• Higher prevalence of vitamin D deficiency was observed
among patients taking NNRTIs compared with PIs
(37% and 23%, respectively)1
Long-term
toxicities
Cardiovascular
disorders
Neurocognitive
impairment
Metabolic
disorders
Vitamin D
deficiency
Bone mineral
density diseases
Renal disease
Hepatotoxicity
*<35 nmol/L from April to September and <25 nmol/L from October to March
†<20 ng/mL
1. Van Den Bout-Van Den Beukel CJ, et al. AIDS Res Hum Retroviruses. 2008;24:1375–82; 2. Szep Z, et al. Antiviral
Therapy 2008; 13(Suppl 4):A30 (Abstract P-10).
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 2010
11
• Mental illness
• Brain damage
• A systematic review of
cognitive development in
children with HIV revealed that
81% of studies report a
detrimental effect on
neurocognitive development1
• Data suggest that HIV in
ventricular cerebrospinal fluid
is partly recruited from the
circulation as HIV has rapid
exponential decay in the
cerebrospinal fluid2
HIV
• HIV RNA levels
• Antiretroviral therapy
• Optimising neurocognitive
recovery will require the
development of better
CNS- penetrating antiretroviral
regimens3
1. Sherr L, et al. Psychol Health Med 2009;14:387–404; 2. Eggers C, et al. Ann Neurol 2000;47:816–9;
3. Ellis R. Prog Neurobiol 2009 Oct 24. [Epub ahead of print]
Conflicting data exist regarding whether CSF
Penetrative Effectiveness is associated with
cognitive improvement
• 300 subjects with CSF HIV
RNA
<50 copies/mL
• 26% of subjects CSF+ and
plasma–
• Low level CSF HIV RNA
associated with lower CSF
Penetration Effectiveness
score
• Poorer neuropsychiatric
performance when HIV RNA
detected in CSF but NOT
plasma compared to subjects
with HIV RNA in CSF and
plasma
Adapted from Letendre S, et al. CROI 2009. Abstract 484b
HIV RNA in CNS >2 c/mL
Patient factors
Low levels of HIV RNA associated
with neurocognitive impairment
Relationship between antiretroviral CNS
penetration and HIV RNA in CSF
OR=1.7
p=0.03
50.8%
n=122
Yes
63.5%
n=178
No
0 0.40
0.45
0.50
0.55
0.60
0.65
0.70
CPE Rank, Proportion ≥1.5
9
Global rating
Neurocognitive impairment and
HIV
Neurocognitive function and HIV RNA in
CSF and plasma
7
5
3
+
+
p=0.006
1
Proportion
CSF >2 c/mL
Plasma >2 c/mL
26%
Yes
No
74%
Yes
Yes
Thank you
• CNS penetrating drugs are associated with reductions in CSF viral
load1
• In a cohort of 37 individuals with HIV-associated neurocognitive
disorder, cognitive improvement began soon after ARV initiation
(13.5% at week 12) in up to 41% of patients2
– Independent predictors of cognitive improvement were more severe
impairment at baseline and use of drugs with better CNS penetration index
• In 79 patients with advanced HIV starting/changing to a new potent
ARV regimen, good CNS penetration was more effective in
controlling CSF viral replication vs poorer penetration3
– However, ARVs with good CNS penetration were associated with poorer
neurocognitive performance
1. Letendre S, et al. Arch Neurol 2008;65:65–70; 2. Cysique LA, et al. Neurology 2009;73:342–8; 3. Marra CM, et al. AIDS
2009;23:1359–66.
12