1. No category

HEPATITIS C IN 2014
Lisa M. Chirch, M.D.
Assistant Professor of Medicine
University of Connecticut Health Center
A Local Performance Site of the New England AETC
Disclosures
• None
Objectives
•
•
•
Describe epidemiology, transmission,
and clinical presentation of Hepatitis C
infection
Understand and implement new testing
and screening recommendations
Apply relevant data from recent
publications regarding treatment of
chronic hepatitis C infection
Hepatitis C - Chapter 3 - 2012 Yellow Book | Travelers' Health | CDC
wwwnc.cdc.gov
Magnitude of the Problem
• Nearly 4 million persons in United States
infected
• Approximately 35,000 new cases yearly
• Acute infections on the rise since 2010
• <10% chronically infected patients are
treated
• Leading cause of




Chronic liver disease
Cirrhosis
Liver cancer
Liver transplantation
http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm.
“Silent Epidemic”
 NHANES survey: estimated unidentified
HCV infections – 43%
 May 2011: U.S. Viral Hepatitis Action
Plan
 Federal platform
 Educate providers and communities
 Increase awareness, testing and linkage to
care
 USPSTF has aligned with CDC on testing
recommendations – Grade B
Ronald Valdiserri – DHHS Deputy Assistant Secretary; The Liver Meeting 2013
Hepatitis C, a Silent Killer, Meets Its
Match
November 4, 2013
Sources of Infection with HCV
Indications for HCV screening?
• HIV
• IDU
• History of chronic HD, transfusion, blood
product or organ transplant prior to 1992
• Unexplained persistent elevation in ALT
(?RNA)
• and….
Hepatitis C: Screening guidelines
• CDC 2012:
• Recommendations for the Identification of
Chronic Hepatitis C Virus Infection Among
Persons Born During 1945–1965
• Recommendations and Reports, August 17,
2012
…one-time testing without prior ascertainment of
HCV risk for persons born during 1945 -1965, a
population with a disproportionately high prevalence
of HCV infection and related disease.
2013: Update of Guidance for
Clinicians and Laboratories
• MMWR May 2013
• Availability of rapid test for HCV antibody
(OraQuick)
– Fingerstick or venipuncture
– CLIA waiver by FDA in 2011
• Discontinuation of the RIBA HCV
• Recommended testing sequence:
MMWR May10, 2013
Question
 A 50 year old female with a history of HTN and
DM is referred to you after her primary care
physician performed hepatitis C antibody testing
as part of routine evaluation, which was positive.
She would like you to explain the chances that
she does NOT have chronic hepatitis C infection.
What do you tell her?





A) 0%
B) 15%
C) 50%
D) 75%
E) 99%
Answer
 A 50 year old female with a history of HTN
and DM is referred to you after her primary
care physician performed hepatitis C
antibody testing as part of routine
evaluation, which was positive. She would
like you to explain the chances that she
does NOT have chronic hepatitis C
infection. What do you tell her?





A) 0%
B) 15%
C) 50%
D) 75%
E) 99%
Hepatitis C Virus Infection
Natural History
Acute HCV
Resolved
15% (15%)
Chronic HCV
85% (85%)
Stable
80% (68%)
HCC, hepatocellular carcinoma
Cirrhosis
20% (17%)
Slowly
progressive
75% (13%)
HCC
Liver failure
25% (4%)
Hepatitis C Virus
Genotypes in the USA
Type 2
17%
Type 1
72%
McHutchinson JG, et al. N Engl J Med. 1998;339:1485-1492.
Type 3
10%
All others
1%
Management of Chronic HCV
Disease Severity
Response to Therapy
AST/ALT
Bilirubin
Albumin
Pro-time (INR)
Platelet count
Liver histology
Transient Elastography
ALT
HCV RNA
HCV genotype
Liver histology
IL28B
IL28B:gene coding for IFN-λ3, associated
with IFN sensitivity
–C/C genotype (vs C/T or T/T) associated with
favorable response to HCV treatment in pts
treated with PEG/ribavirin
Clark PJ, Am J Gastroenterol Oct 2010
HCV RNA and Liver Histology
Fibrosis
 Serum HCV RNA does not correlate with level of fibrosis
Log HCV RNA
(copies/mL)
8
Genotype
1
2
3
4
6
4
2
0
No
Portal Bridging Cirrhosis
Fibrosis Fibrosis Fibrosis
Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.
How to Stage
Hepatitis C Virus Infection
Liver Biopsy
• Only test that can accurately assess
– Severity of inflammation
– Degree of fibrosis
• Determines
– Risk for developing cirrhosis in future
– Need for therapy
– Need for ongoing therapy when initial
treatment has failed
Sampling error of liver biopsy
Serum Markers of Liver Fibrosis
Fibroscan
Validity of Fibroscan Versus Biopsy
HCV Fibrosis Progression
Effect of Alcohol
Fibrosis Score
4.0
3.0
Alcohol intake
> 50 g/day*
< 50 g/day
2.0
1.0
0
< 10
11-20
21-30
31-40
Duration of Infection (Years)
*50 g is equal to approximately 3.5 drinks
Poynard T, et al. Lancet. 1997;349:825-832.
> 40
Cumulative Probability of
Fibrosis Progression (%)
Fibrosis Progression in HCV
Effect of Steatosis
Cumulative Probability of Fibrosis
According to Level of Steatosis
100
80
60
40
30%
0
18%
18%
20
2% 6%
< 5%
4%
33%
7%
5%-10% 11%-30%
> 30%
Percentage of Steatosis at Initial Biopsy
Fartoux L, et al. Hepatology. 2005;41:82-87.
Year 4
Year 6
Chronic Hepatitis C Virus
Extrahepatic Manifestations
• Nonspecific antibodies
• Essential mixed
cryoglobulinemia
• Glomerulonephritis
• Porphyria cutanea tarda
• Leukocytoclastic
vasculitis
• Mooren’s corneal ulcer
• Non-Hodgkin’s
lymphoma
• Autoimmune thyroiditis
• Diabetes mellitus
• Sjögren’s syndrome
HCV Treatment Goals
 Goals of treatment for chronic HCV
 Viral eradication (undetectable viral load)
 Delay progression of fibrosis
 Prevent decompensation, HCC, and death
 Best indicator of successful treatment is
sustained virologic response (SVR)
Sustained virologic response
 SVR: serum HCV RNA is undetectable based
on a quantitative HCV RNA assay with lower
limit of detection of 50 IU/mL or less at 24
weeks after treatment ends
 SVR 12: …12 weeks after treatment ends
 RVR
 EVR
Sustained Virologic
Response (%)
Treatment of Chronic HCV
Peginterferon and Ribavirin
100
80
60
PegIFN-2a/RBV
PegIFN-2b/RBV
40
20
0
1
2-3
Genotype
Fried MW, et al. N Eng J Med. 2002;347:975-982. Manns MP, et al. Lancet 2001;358:958-965.
Interferon
• Flu-like symptoms: fatigue, headache,
myalgias
• Dose-related myelosuppression
– Reversible with dose reduction (cost?)
– Use of G-CSF and erythropoietin
• Depression: risk assessment prior to
therapy initiation
– 35-40%
– Management with SSRIs and TCAs
Time Course of TreatmentAssociated Psychiatric Adverse
Effects
Incidence/Severity
100
80
Depression
60
Fatigue
40
20
Influenza-like
symptoms
0
0
1
2
3
4
Months
Dan A, et al. J Hepatol. 2006;44:491-498. Constant A, et al. J Clin Psychiatry. 2005;66:1050-1057.
Ribavirin
 Nucleoside analog
 Inhibits inosine monophosphate dehydrogenase
 Potentiates purine analogs, ie didanosine
 Immune modulator, shift from Th2 to Th1 response
 Teratogenic
 both men and women must use contraception
during and for 6 months after treatment
 Dose-dependent hemolytic anemia
 Increased risk for lactic acidosis
HCV Life Cycle and DAA Targets
Receptor binding
and endocytosis
Transport
and release
Fusion
and
uncoating
Translation
and
polyprotein
processing
NS3/4 protease
inhibitors
(+) RNA
ER lumen
LD
LD
Virion
assembly
LD
Membranous
web
ER lumen
NS5A* inhibitors
*Block replication complex formation, assembly
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
NS5B polymerase
RNA
replication
inhibitors
Nucleoside/nucleotide
Nonnucleoside
What Are the Key Elements of an
Ideal HCV Regimen?
Easy Dosing
Once daily, low pill
burden
Highly Effective
All Oral
High efficacy in
traditionally challenging
populations (ie, poor
IFN sensitivity, cirrhosis)
PegIFN/RBV replaced
with alternate backbone
with low chance of
resistance
Simple Regimen
Short duration, simple,
straightforward
stopping rules
Pan-Genotypic
Regimen can be used
across all genotypes
Safe and Tolerable
Few or easily
manageable adverse
effects
HCV Therapy: Past, Present and
Future
Suppression of
HCV with DAA
combination
(PI + NI)
Ribavirin
Interferon
1990
Proof
of concept
for DAA (PI)
2000
2005
Pegylated
interferons
Telaprevir
and
boceprevir
2010
2011
IFN-free DAA
combinations (GT1)
Frequent
curability of
diverse
populations
without IFN
2012
Curability of
HCV without
interferon
Potential
approval of
other DAAs
with IFN
2013
2014
2015-
 Approval of simeprevir
and sofosbuvir with IFN
 First approved IFN-free
therapy: SOF + RBV for
GT2/3
Telaprevir - PROVE
12-wk TVR + pegIFN/RBV (n = 17)
12-wk TVR + 24-wk pegIFN/RBV (n = 79)
12-wk TVR + 48-wk pegIFN/RBV (n = 79)
Control (n = 75)
67‡
100
Patients (%)
80
81* 81*
80
71
71 68
60
65
59*
57
61†
57
47
45
41
40
35
23
20
0
33
11
N/A
Wk 4
2 6
N/A N/A
Wk 12
Wk 24
Undetectable HCV RNA
Wk 48
SVR
N/A, not applicable. *P < .001 vs control. †P = .02 vs control. ‡P = .002 vs control.
McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
Relapse
Summary of Key Conclusions
• 12-week course of TVR with 24 or 48 weeks of
pegIFN/RBV increased SVR rates in treatmentnaive patients infected with genotype 1 HCV vs 48
weeks of pegIFN/RBV alone
• TVR also resulted in higher rate of RVR and lower
relapse rate compared with pegIFN/RBV
• TVR increased rate of treatment discontinuation
due to adverse effects, predominantly anemia,
rash, rectal symptoms (FIARRHEA)
• Small subset experienced virologic breakthrough
with protease resistance mutations
McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
No Free Lunch
Treatment is more effective but much more
difficult
Jordan Feld, MD, MPH. Toronto Western Hospital Liver Centre
Other Issues With PI-Based
Therapy
Pill burden
Food requirement
Resistance
BOC = 12/day TVR = 6/day
RBV = 4-7/day RBV = 4-7/day
Drug-drug interactions
PI
CYP3A4
metabolites
20 grams of fat…
• Breakfast Ideas
– 2-egg omelet with 1 ounce shredded cheese; oatmeal with 1
ounce nuts and ½ tablespoon butter; toast with 2 tablespoons
unsalted peanut butter and glass of 2% milk; bagel with 2
tablespoons cream cheese and glass of whole milk 1 egg and 1-3
sausage links (check sausage label, need 15 g fat)
• Lunch / Dinner
– 6 ounces salmon; ½ box prepared macaroni and cheese; 3
tablespoons of 2 cups of canned chili with meat; sandwich with 3
slices bologna; 1½ beef hot dogs; 1 chicken leg and thigh with
skin; burrito with beans, cheese, and guacamole; 2 pork chops;
french fries, medium order; quarter-pound hamburger or double
cheeseburger
Drug–Drug Interactions a Clinical
Challenge With Current Therapy
 Several drugs contraindicated; many more require dose adjustment or
caution
Drug Class
Contraindicated With BOC[1]
Contraindicated With TVR[2]
Alpha 1-adrenoreceptor
antagonist
Alfuzosin
Alfuzosin
Anticonvulsants
Carbamazepine, phenobarbital,
phenytoin
N/A
Antimycobacterials
Rifampin
Rifampin
Ergot derivatives
Dihydroergotamine, ergonovine,
ergotamine, methylergonovine
Dihydroergotamine, ergonovine,
ergotamine, methylergonovine
GI motility agents
Cisapride
Cisapride
Herbal products
Hypericum perforatum (St John’s wort)
Hypericum perforatum
HMG CoA reductase inhibitors
Lovastatin, simvastatin
Lovastatin, simvastatin
Oral contraceptives
Drospirenone
N/A
Neuroleptic
Pimozide
Pimozide
PDE5 inhibitor
Sildenafil or tadalafil when used for tx
of pulmonary arterial hypertension
Sildenafil or tadalafil when used for tx of
pulmonary arterial hypertension
Sedatives/hypnotics
Triazolam; orally administered
midazolam
Orally administered midazolam,
triazolam
1Boceprevir [package insert]. November 2012. 2. Telaprevir [package insert]. October 2012.
Limited Efficacy With Telaprevir and
Boceprevir in Some Patient Groups
100
75-83[1,2]
SVR (%)
80
68-75[3,4]
42-62[3,4] 53-62[3,4]
60
40-59[1,2]
29-40[1,5]
40
20
0
14[6]*
Relapser
Naive
White/
Nonblack
Naive Naive Black Partial
Cirrhotic
Responder
Null
Responder
Cirrhotic
Null
Responder
*Pooled TVR arms of REALIZE trial.
1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 5.
Bronowicki J, et al. EASL 2012. Abstract 11. 6. Zeuzem S, et al. EASL 2011. Abstract 5.
Question
 A 44 year old male with a history of prior heroin abuse
(clean for 1 year +) is referred for hepatitis C therapy. His
HCV RNA level is 5.2 million IU/mL, genotype 1b, ALT 65,
and there are no stigmata or lab values to suggest ESLD.
He does have a history of depression and anxiety, requiring
mirtazapine and citalopram therapy. How should you
proceed?
 A) get a liver biopsy – this will help me decide
 B) He cannot receive therapy due to
comorbidities
 C) Treat with just IFN/ribavirin, he will not likely
tolerate a PI
 D) Treat with just telaprevir, he will not likely
tolerate IFN
 E) wait for something better
Answer
 A 44 year old male with a history of prior heroin abuse (clean
for 1 year +) is referred for hepatitis C therapy. His HCV RNA
level is 5.2 million IU/mL, genotype 1b, ALT 65, and there are
no stigmata or lab values to suggest ESLD. He does have a
history of depression and anxiety, requiring mirtazapine and
citalopram therapy. How should you proceed?
 A) get a liver biopsy – this will help me decide
 B) He cannot receive therapy due to comorbidities
 C) Treat with just IFN/ribavirin, he will not likely
tolerate a PI
 D) Treat with just telaprevir, he will not likely
tolerate IFN
 E) wait for something better
Standard of Care of Chronic HCV
Infection- October 2014
Genotype
Regimen
Duration
Considerations
1
Sofosbuvir +
Ledipasvir (FDC)
12 weeks (24 for
experienced
cirrhotics)
FDA approved,
not yet in
guidance
1
Sofosbuvir +
IFN/RBV
12 weeks
Minimal drug
interactions
1
Sofosbuvir +
Simeprevir +/RBV
12 weeks
Off label to date
For IFN ineligible
2
Sofosbuvir + RBV
12 weeks
3
Sofosbuvir + RBV
24 weeks
www.hcvguidelines.org
NEUTRINO: SVR12 With Sofosbuvir +
P/R According to Genotype and
Fibrosis Level
SVR12 According to
Fibrosis Level
SVR12 According to
Genotype
100
89
96
100
100
80
80
SVR12 (%)
80
SVR12 (%)
92
60
40
20
60
40
20
n/N = 261/292
27/28
7/7
252/273
43/54
No
Cirrhosis
Cirrhosis
0
0
GT 1
GT 4
GT 5,6
Lawitz E, et al. EASL 2013. Abstract 1411. N Engl J Med 2013; 368:1878-1887
COSMOS: SVR12 in Cohorts 1 and 2 by HCV
Subgenotype and Baseline Q80K
SVR12 (%)
GT1a without Q80K
GT1b
GT1a with Q80K
Cohort 1 (F0-F2 Nulls)*[1]
100 100
100100 100
100 100
Cohort 2 (F3-F4 Naives/Nulls)*[2]
100 100
100 100
100 100 100
100 100 100
100
89
89
89
100
100 93
100
100
95 96
88
88
83
80
60
40
20
4/ 7/ 8/
4 7 9
3/ 7/ 3/
3 7 3
6/ 12/ 8/
6 12 9
4/ 4/ 5/
4 4 6
7/ 30/ 24/
17 30 27
6/ 11/ 11/
6 11 11
4/ 7/ 4/
4 7 4
5/ 13/ 7/
5 14 8
3/ 7/ 3/
3 8 3
18/ 38/ 25/
18 40 26
SMV/SOF +
RBV
SMV/SOF
SMV/SOF+
RBV
SMV/SOF
SMV/SOF ±
RBV
SMV/SOF +
RBV
SMV/SOF
SMV/SOF +
RBV
SMV/SOF
SMV/SOF ±
RBV
0
24 Wks
12 Wks
Overall
24 Wks
12 Wks
*Excluding patients who discontinued for nonvirologic reasons.
1. Sulkowski M, et al. EASL 2014. Abstract O7. 2. Lawitz E, et al. EASL 2014. Abstract O165.
Overall
TURQUOISE II: SVR12 With 3 DAAs +
RBV in Cirrhotic Pts by HCV Subtype
GT1a
SVR12 (%)
100
93.3100
100 100
92.9
80.0
80
80
60
60
40
40
20
20
0

92.2 92.9
12 wks
24 wks 100
59/ 52/
64 56
Naive
14/ 13/
15 13
11/ 10/
11 10
40/ 39/
50 42
Relapse Partial
Null
Response Response
0
GT1b
100 100
100 100
85.7100
100 100
22/ 18/
22 18
25/ 20/
25 20
6/7 3/3
14/ 10/
14 10
Naive
Relapse Partial
Null
Response Response
Virologic failure in 17/380 pts (4.5%); relapse more frequent with 12-wk vs 24-wk
treatment (12 vs 1 pt), 7/12 relapsers by posttreatment Wk 12 were GT1a null responders
Poordad F, et al. EASL 2014. Abstract O163
Summary of Investigational HCV Agents
Class
Drug
Dosing
ABT-450/RTV
150/100 mg
NS3 protease inhibitor
Asunaprevir
200 mg BID
NS3/4A protease inhibitor
Faldaprevir
120 mg or 240 mg QD
NS3 protease inhibitor
GS-9451
200 mg QD
NS3/4A protease inhibitor
MK-5172
100 mg QD
NS3/4A protease inhibitor
Simeprevir*
150 mg QD
NS5B nonnucleoside polymerase inhibitor
ABT-333
400 mg BID
NS5B nonnucleoside polymerase inhibitor
BMS-791325
75 mg or 150 mg BID
NS5B nonnucleoside polymerase inhibitor
Deleobuvir
600 mg BID
NS5B nonnucleoside polymerase inhibitor
GS-9669
500 mg QD
Sofosbuvir*
400 mg QD
NS5A inhibitor
ABT-267
25 mg QD
NS5A inhibitor
Daclatasvir
30 mg BID or 60 mg QD
NS5A inhibitor
Ledipasvir**
90 mg QD
NS5A inhibitor
MK-8742
20 or 50 mg QD
NS5A inhibitor
PI-688
200 mg QD
NS3/4A protease inhibitor
NS5B nucleotide polymerase inhibitor
*FDA approved December 2013; **October 2014
Regimen
Genotype
Mechanism of Action
Approximate SVR
in naïve/relapsers
Daclatasvir + Sofosbuvir
+/- RBV
1,2,3
NS5A/NS5B polymerase
98/92/89%
ION-1,2,3:
Sofosbuvir + Ledipasvir
(FDC) +/- RBV
1, naïve
and
previously
treated
Polymerase / NS5A
97-99%
Sof/LDV + RBV or GS
9669
1
Polymerase / NS5A inhibitor +
non-nuc.
100/100%
SAPPHIRE-I and –II:
ABT-450/RTV +
ombitasvir + Dasabuvir
+ RBV
1
Protease/NS5A/NS5B
polymerase/ritonavir
>95%
1, cirrhosis
Protease/NS5A/NS5B
polymerase/ritonavir
92-96%
1
2nd gen protease, NS5A
90-100
N Engl J Med. 2014 Apr 11.
N Engl J Med 2014;370:17.
TURQUOISE-II:
ABT-450/RTV +
ombitasvir + Dasabuvir
+ RBV
N Engl J Med. 2014 Apr 11.
[Epub ahead of print]
C-WORTHY:
MK-5172/MK-8742 +/RBV
• Enter the Nonspecialist:
– Will Evolving Hepatitis C Therapies Reduce
the Need for Specialized Care?
– Graham R. Foster, FRCP, PhD - 10/8/2013
“A rapid expansion of patients and providers will mirror improving efficacies and
gentler adverse event profiles…the introduction of a single-tablet regimen for
HCV therapy—a development that will propel hepatitis C care to its future in
nonspecialist providers offices. Information will be the key to overcoming
preconceptions about adverse events and regimen complexities, finally allowing
nonspecialists to take a central role in caring for HCV-infected patients”.
Parting thoughts
 The last word…
 “Back to the Future”…? The future is
here.
 Liang and Ghany
 “The Costs of Success”
 Hoofnagle and Sherker
Connecticut Infectious Diseases Society Annual
Meeting, New Haven, CT. May 15, 2014