hepatitis c in 2014
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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 | CDCwwwnc.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 PlanFederal platformEducate providers and communitiesIncrease 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 InfectionNatural History
Stable80% (68%)
HCCLiver failure25% (4%)
Slowlyprogressive75% (13%)
Resolved15% (15%)
Acute HCV
Cirrhosis20% (17%)
Chronic HCV85% (85%)
HCC, hepatocellular carcinoma
Hepatitis C VirusGenotypes in the USA
All others1%
Type 310%
Type 217%
Type 172%
McHutchinson JG, et al. N Engl J Med. 1998;339:1485-1492.
Management of Chronic HCV
Disease SeverityResponse to Therapy
AST/ALTBilirubinAlbuminPro-time (INR)Platelet countLiver histologyTransient Elastography
ALTHCV RNAHCV genotypeLiver 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 HistologyFibrosis
Genotype
NoFibrosis
PortalFibrosis
BridgingFibrosis
Cirrhosis
Serum HCV RNA does not correlate with level of fibrosis
0
2
4
6
8
Lo
g H
CV
RN
A(c
op
ies/
mL
)
1
2
3
4
Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.
How to Stage
Hepatitis C Virus InfectionLiver 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
Poynard T, et al. Lancet. 1997;349:825-832.
HCV Fibrosis Progression Effect of Alcohol
Alcohol intake> 50 g/day*< 50 g/day
*50 g is equal to approximately 3.5 drinks
< 10 11-20 21-30 31-40 > 40
Duration of Infection (Years)
4.0
3.0
2.0
1.0
0
Fib
rosi
s S
core
Fibrosis Progression in HCVEffect of Steatosis
2% 4% 7%
18%
6%18%
30% 33%
0
20
40
60
80
100
< 5% 5%-10% 11%-30% > 30%
Percentage of Steatosis at Initial Biopsy
Cu
mu
lati
ve P
rob
abil
ity
of
Fib
rosi
s P
rog
ress
ion
(%
)
Year 4
Year 6
Fartoux L, et al. Hepatology. 2005;41:82-87.
Cumulative Probability of Fibrosis According to Level of Steatosis
Chronic Hepatitis C VirusExtrahepatic 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
Treatment of Chronic HCVPeginterferon and Ribavirin
0
20
40
60
80
100
1 2-3
Genotype
Su
stai
ned
Vir
olo
gic
Res
po
nse
(%
)
PegIFN-2a/RBVPegIFN-2b/RBV
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
Months
Inci
den
ce/S
ever
ity
Depression
Fatigue
Influenza-like symptoms
Time Course of Treatment-Associated Psychiatric Adverse
Effects
1 2 3 400
20
40
60
80
100
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
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Receptor bindingand endocytosis
Fusion and
uncoating
Transportand release
(+) RNATranslation
andpolyprotein processing
RNA replication
Virionassembly
Membranousweb
ER lumen
LD
LDER lumen
LD
NS3/4 protease inhibitors
NS5B polymerase inhibitors
Nucleoside/nucleotideNonnucleoside
*Block replication complex formation, assembly
NS5A* inhibitors
Simple Regimen
Short duration, simple, straightforward stopping rules
What Are the Key Elements of an Ideal HCV Regimen?
Pan-Genotypic
Regimen can be used across all genotypes
Highly Effective
High efficacy in traditionally challenging
populations (ie, poor IFN sensitivity, cirrhosis)
Safe and Tolerable
Few or easily manageable adverse
effects
All Oral
PegIFN/RBV replaced with alternate backbone
with low chance of resistance
Easy Dosing
Once daily, low pill burden
HCV Therapy: Past, Present and Future
Interferon
Ribavirin
Pegylatedinterferons
Proof of concept
for DAA (PI)
Suppression of HCV with DAA combination
(PI + NI)
Telaprevir and
boceprevir
Curability of HCV without
interferon
Frequent curability of
diverse populations without IFN
Approval of simeprevir and sofosbuvir with IFN
First approved IFN-free therapy: SOF + RBV for GT2/3
IFN-free DAAcombinations (GT1)
Potential approval ofother DAAs
with IFN
1990 2000 2005 2010 2011 2012 2013 2014 2015-
Telaprevir - PROVE
McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
0
20
40
60
80
100
Wk 4
Pat
ien
ts (
%)
12-wk TVR + 48-wk pegIFN/RBV (n = 79)
12-wk TVR + 24-wk pegIFN/RBV (n = 79)
59*
Wk 12 Wk 24 Wk 48
12-wk TVR + pegIFN/RBV (n = 17)
Control (n = 75)
81*
11
81*
71 68
45
80
N/A
57 57
71
SVR Relapse
N/A
47
65
N/A
35
61†
41
67‡
33
2
23
6
Undetectable HCV RNAN/A, not applicable. *P < .001 vs control. †P = .02 vs control. ‡P = .002 vs control.
Summary of Key Conclusions• 12-week course of TVR with 24 or 48 weeks of
pegIFN/RBV increased SVR rates in treatment-naive 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 LunchTreatment 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
CYP3A4PI metabolites
Drug-drug interactions
Resistance
BOC = 12/dayRBV = 4-7/day
TVR = 6/dayRBV = 4-7/day
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 cautionDrug 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
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.
0
20
40
60
80
100
SV
R (
%)
Relapser Naive White/
Nonblack
Null Responder
Naive Black Partial Responder
Cirrhotic Null
Responder
68-75[3,4]
53-62[3,4]
*Pooled TVR arms of REALIZE trial.
75-83[1,2]
40-59[1,2]
29-40[1,5]
14[6]*
42-62[3,4]
NaiveCirrhotic
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 decideB) He cannot receive therapy due to comorbiditiesC) Treat with just IFN/ribavirin, he will not likely
tolerate a PID) Treat with just telaprevir, he will not likely
tolerate IFNE) 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 decideB) He cannot receive therapy due to comorbiditiesC) Treat with just IFN/ribavirin, he will not likely
tolerate a PID) Treat with just telaprevir, he will not likely
tolerate IFNE) wait for something better
Standard of Care of Chronic HCV Infection- October 2014
www.hcvguidelines.org
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 dateFor IFN ineligible
2 Sofosbuvir + RBV 12 weeks
3 Sofosbuvir + RBV 24 weeks
NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and
Fibrosis Level
Lawitz E, et al. EASL 2013. Abstract 1411. N Engl J Med 2013; 368:1878-1887
SV
R12
(%
)
92
80
100
80
60
40
20
0No
CirrhosisCirrhosis
252/273 43/54
SVR12 According to Fibrosis Level
SV
R12
(%
)
8996
100100
80
60
40
20
0GT 1 GT 4 GT 5,6
261/292 27/28 7/7
SVR12 According to Genotype
n/N =
COSMOS: SVR12 in Cohorts 1 and 2 by HCV Subgenotype and Baseline Q80K
Cohort 1 (F0-F2 Nulls)*[1] Cohort 2 (F3-F4 Naives/Nulls)*[2]
1. Sulkowski M, et al. EASL 2014. Abstract O7. 2. Lawitz E, et al. EASL 2014. Abstract O165.
SMV/SOF ±RBV
SVR12 (%)
SMV/SOF +RBV
SMV/SOF+RBV
SMV/SOF SMV/SOF
24 Wks 12 Wks Overall
4/4
7/7
8/9
3/3
7/7
3/3
6/6
12/12
8/9
4/4
4/4
5/6
*Excluding patients who discontinued for nonvirologic reasons.
100 10093
8895
100 100
88
10096
SMV/SOF ±RBV
SMV/SOF +RBV
SMV/SOF +RBV
SMV/SOF SMV/SOF
24 Wks 12 Wks Overall
6/6
11/11
11/11
4/4
7/7
4/4
5/5
13/14
7/8
3/3
7/8
3/3
18/18
38/40
25/26
100 100 100 100 100100
80
60
40
20
0
100 100
89
100100 100 100 100
89
100 100
83
100 100
89
GT1b GT1a without Q80K GT1a with Q80K
30/30
7/17
24/27
TURQUOISE II: SVR12 With 3 DAAs + RBV in Cirrhotic Pts by HCV Subtype
12 wks24 wks 100 100
Naive Relapse
100 100 85.7100 100 100
PartialResponse
NullResponse
GT1b
Poordad F, et al. EASL 2014. Abstract O163
SV
R12
(%
)
Naive Relapse PartialResponse
NullResponse
GT1a
59/64
14/15
52/56
13/13
11/11
40/50
10/10
39/42
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
100
80
60
40
20
0
92.292.9 93.3100 100 100
80.0
92.9100
80
60
40
20
0
22/22
25/25
18/18
20/20
6/7 14/14
3/3 10/10
Summary of Investigational HCV AgentsClass Drug Dosing
NS3/4A protease inhibitor 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
NS5B nucleotide polymerase inhibitor 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
*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) +/- RBVN Engl J Med. 2014 Apr 11.
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 + RBVN Engl J Med 2014;370:17.
1 Protease/NS5A/NS5B polymerase/ritonavir
>95%
TURQUOISE-II:ABT-450/RTV + ombitasvir + Dasabuvir + RBVN Engl J Med. 2014 Apr 11. [Epub ahead of print]
1, cirrhosis Protease/NS5A/NS5B polymerase/ritonavir
92-96%
C-WORTHY:MK-5172/MK-8742 +/- RBV
1 2nd gen protease, NS5A 90-100
HALLMARK-DUAL: Daclatasvir + asuneprevir
1b NS5A / 2nd gen protease 73-91%
• 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