Sameh W. Boktor, MD, MPH. Medical Epidemiologist. Pennsylvania Department of Health. Harrisburg, Pennsylvania. Disclosures. Off-label and/or investigational use of pharmaceuticals may be discussed in the presentation. This disclosure is to ensure participants in the activity may formulate their own.... ID: 681119
DownloadNote - The PPT/PDF document "Management of Patients with Chronic Hepa..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Management of Patients with Chronic Hepatitis C: The Route to Safe and Effective Care
Sameh W. Boktor, MD, MPH
Pennsylvania Department of Health
Off-label and/or investigational use of pharmaceuticals may be discussed in the presentation. This disclosure is to ensure participants in the activity may formulate their own judgments regarding the presentation.
Sameh Boktor, MD, has no financial interests/relationships or affiliations in relation to this activity.
This activity was independently
peer-reviewed by CME Peer Review. Neither of the independent reviewers had relevant financial relationships to disclose.Slide3
Evaluate the most recent clinical guidelines to improve screening
diagnosis of infection with hepatitis C virus (HCV)Optimize
current evidence-based components of chronic HCV therapy based on patient status, HCV genotype, comorbidities, and concomitant therapiesIntegrate methods to minimize toxicities and adequately manage treatment-related adverse effectsEvaluate the utility of investigational therapies for the treatment of HCVSlide4
Hepatitis C: Burden of Disease in the U.S.
About 5.2 million infected individuals in the United States currently (~2% of the population)
Leading cause for liver transplant and liver cancer
Number of patients with morbidity and mortality from chronic HCV increasing
Approximately 1.76 million persons with untreated chronic HCV infection will develop cirrhosis over the next 40 to 50 yearsThe projected incidence peak of end-stage liver disease will occur in 2030, with about 38,600 cases per year Transplants are expected to peak in 2032 to 2033 at level of 3200 HCV-related transplants per yearRein et al. Dig Liver Dis 2011;43:66-72. Zalesak et al. PLOS ONE 2013;8(5):e63959.Slide5
Chronic HCV Infection May Lead to Chronic Liver Disease or Liver
Chronic hepatitis occurs in 75-85% of infected individuals and can lead to fibrous scar within the liver
Over time, fibrosis can lead to severe scarring or cirrhosis in 10-20% patientsIn 1-4% patients, cancer of the liver will developDecompensated cirrhosis (5-year survival rate of 50%):
Spontaneous bacterial peritonitis
Davis et al.
Huffman et al.
Extrahepatic Manifestations of Chronic Hepatitis C
gammopathiesLymphoma (non-Hodgkin’s B cell)Anemia, thrombocytopenia, coagulopathyAutoimmune disordersAutoantibodiesAutoimmune hepatitisThyroid diseaseCardiacMyocarditisCardiomyopathyDermatologicPorphyria cutanea tardaLeukocytoclastic vasculitisLichen planusRheumatologicArthritisRenalMembranoproliferative glomerulonephritisMembranous nephropathyRenal failureEndocrineDiabetes mellitus
et al. The GERMIVIC 2000;79:47.Slide7
Gaps in Hepatitis C Screening and Treatment
National survey of PCPs revealed
73% of respondents reported seeing five or fewer patients with HCV per
year, 44% reported no experience with HCV
treatment, and only 59% actually screened for HCVDue to lack of awareness of the current advances in HCV, only ~50% of patients with HCV are referred for subspecialty evaluationMitchell et al. Hepatology 2010;51:729-33. Shehab et al. Journal of viral hepatitis 2001;8:377-83.Slide8
Identifying Patients With Chronic Hepatitis C
An estimated 40 to 85% of persons infected with HCV are unaware of their HCV infection
One study reported that
amongst HCV-infected injection drug users who were 15 to 30 years old, 72% were unaware of their HCV infection statusNHANES study conducted from 2001 through 2008 found that 50.3% of persons infected with HCV were unaware of their statusIn a study involving persons with access to medical care in four private health care organizations during the years 2006 to 2008, an estimated 43% were unaware of their HCV infection Armstrong et al. Ann Intern Med. 2006;144:705-14. Denniston MM et al. Hepatology 2012;55:1652-61. Denniston MM et al. Ann Intern Med. 2014;160:293-300.Slide9
Hepatitis C Testing in the U.S.
Patients with at least 1 encounter and no previous HCV
Percent tested for HCV13%Percent of patients who were positive for HCV5.1%Percent patients with ≥2 elevated ALT results tested for HCV43.9%Percent patients positive for HCV after ≥2 elevated ALT results8.2%2012 Kaiser study including HI, OR, MI, PA sites
PR et al.
Who Should be Tested: USPSTF Grade B Recommendations
Everyone born from 1945-1965 (one-time)
Past or present injection drug use
Sex with an IDU; other high risk sex
Blood transfusion prior to 1992Persons with hemophiliaLong-term hemodialysisBorn to an HCV-infected motherIncarcerationIntranasal drug useUnregulated tattooOccupational percutaneous exposureSurgery prior to universal precautionsSmith et al. Ann Intern Med 2012;157:817-822. Moyer et al. Ann Intern Med epub 25 June 2013.Slide11
HCV Screening IntervalPersons in the birth cohort and those who are at risk because of potential exposure before universal blood screening and are not otherwise at increased risk
need only be screened once.
with continued risk for HCV infection (injection drug users)
should be screened periodically. The USPSTF found no evidence about how often screening should occur in persons who continue to be at risk for new HCV infection.http://www.uspreventiveservicestaskforce.org/uspstf12/hepc/hepcfinalrs.htmSlide12
HCV Testing Algorithm
Rapid or lab-conducted assay
FALSE + TEST
TESTING AS INDICATED
CURRENT HCV INFECTION
HCV ANTIBODY TEST
HCV RNA TEST
Adapted from Centers for Disease Control and Prevention (CDC), 2013.
* For persons who might have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up testing for HCV antibody should be performed. For persons who are immunocompromised, testing for HCV RNA should be performed.Slide13
FDA-approved Commercially Available HCV Antibody Tests
Abbott HCV EIA 2.0AbbottEIA (Manual)Advia Centaur HCVSiemensCIA (Automated)ARCHITECT Anti-HCVAbbottCMIA (Automated)AxSYM Anti-HCVAbbottMEIA (Automated)
HCV Rapid Antibody
Ortho HCV Version 3.0 EIA
Anti-HCV = HCV antibody; EIA = enzyme immunoassay; CIA =
immunoassay; MEIA =
enzyme immunoassay; CMIA =
MG et al.
. 2009. 49: 1335-74
Confirmatory Testing for HCV Infection
(HCV quantitative test)
Nucleic acid testing
Not intended for diagnosis of acute hepatitis CAbbott Real Time HCV Detection range 12IUml-100 million IU/mlRoche COBAS Taq Man HCVDetection range 43IU/ml-69 million IU/mlGenotypic TestingTrugene 5NC HCV Genotyping kit (Siemens Healthcare Diagnostics Division, Tarrytown, NY)Versant HCV Genotyping Assay 2.0 (Siemens Healthcare Diagnostics Division, Tarrytown, NY)INNO-LiPa HCV II, (Innogenetics, Ghent, Belgium)Ghany MG et al. Hepatology. 2009. 49: 1335-74.Slide15
HCV Genotype Distribution in the United States
Data reported on https://www.labcorp.comSlide16
Next Steps in Evaluation of HCV Infected Individuals
Abstinence from alcohol and, when appropriate, interventions to facilitate cessation of alcohol
for other conditions that may accelerate liver fibrosis, including HBV and HIV infectionsEvaluation for advanced fibrosis is recommended using liver biopsy, imaging, or non-invasive markers to facilitate an appropriate decision regarding HCV treatment strategy and to determine the need for initiating additional screening measures (hepatocellular carcinoma [HCC] screening, variceal screening)Vaccination against hepatitis A and hepatitis BEducation on how to avoid HCV transmission to othersEvaluation by a practitioner who is prepared to provide comprehensive management including consideration of antiviral therapySlide17
Recommendations for Preventing Transmission
Avoid sharing toothbrushes, dental and shaving equipment and cover any bleeding wound.
Avoid obtaining tattoos and piercings at non-reputable, unlicensed facilities that do not sterilize equipment.
Avoid donating blood and discuss serostatus prior to donation of body organs, other tissue or semen.Use barrier protection for MSM with HIV infection and those with multiple sex partners. Others with HCV infection should be counseled that risk of sexual transmission is low and may not warrant barrier protection.http://www.hcvguidelines.orgSlide18
Decontaminate household surfaces and implements with visible blood from an HCV-infected person with dilution of 1 part household bleach:9 parts water. Wear gloves for cleaning.For
illicit drug users, stop using and enter substance abuse treatment. If drug use is continued,
avoid reusing or sharing syringes, needles, water, cotton and other drug preparation equipment. New sterile syringes, filters, and disinfected cookers should be used. Needles and syringes should be disposed of in safe, puncture-proof containers.
Recommendations for Preventing Transmissionhttp://www.hcvguidelines.orgSlide19
Eligibility Criteria for Chronic HCV Treatment
Age 18 years or older
etectable serum HCV RNA Liver biopsy with chronic hepatitis and significant fibrosis (historic criteria, not currently mandated)
Compensated liver diseaseAcceptable hematologic and biochemical indicesWilling to be treated and conform to treatment requirementsNo contraindications to treatmentNeed to consider additional factors such as: alcohol use, drug use, chronic kidney disease, prior liver transplantSlide20
Non-invasive Biomarkers of Fibrosis
Contraindications to Treatment with Peg-IFN
depressionSolid organ transplant (e.g., kidney, heart or lung)
Autoimmune hepatitis or other autoimmune condition Untreated thyroid diseasePregnant or unwilling to practice effective birth controlSevere accompanying diseases, such as very high blood pressure, heart failure, significant coronary disease, poorly controlled diabetes and chronic obstructive disease/emphysemaA parent of children younger than 2 years oldKnown allergies to the drugs used to treat HCVSlide22
Evolution of Hepatitis C Treatment
Proof of concept for DAAs (PI)
of HCV with DAA combination (PI + NI)
FDA approval of
Potential approval of other DAAs
Categories of Therapy Response
No previous treatmentRapid Virologic ResponseHCV undetectable at 4 weeks of treatmentEarly Virologic Response≥2log10 reduction in HCV RNA level compared to baseline
level or undetectable at week 12
HCV RNA undetectable
at week 12, 24 or 48 of treatment
Sustained Viral response
HCV RNA undetectable 24 weeks after end of treatment
Failure to clear HCV RNA after
24 weeks of treatment
Failure to decrease HCV
RNA by at least 2log
after 24 weeks of treatment
decrease in HCV RNA but still detectable
at week 24
Reappearance of HCV RNA while still on therapy
Reappearance of HCV RNA after therapy is discontinued
MG ,et al.
2009;49:1335-74. *Developed primarily for response-guided therapy.Slide24
Goal of Treatment
HCV RNA negativity 6 months post-treatment
Predicts 99% chance of remaining RNA negative long-term and considered a cure
Sustained viral response (SVR
Chronic HCV Therapy (Genotype 1): Advances in Raising Cure Rates
35%16%Schaefer EA et al. Gastroenterology. 2012;142:1340-1350. Ghany MG et al. Hepatology
Targets for Direct-Acting Antiviral Agents (DAAs)
Prevent viral entry
Polyclonal and monoclonal antibodies
Prevent translation of viral RNA
NS3/4 protease inhibitorsInhibit HCV-RNA polymeraseNucleoside analogue NS5B poly. inhibNon-nucleoside analogue NS5B poly inhibReplication complex inhibitorCyclophilin B inhibitorsViral assembly/releaseGlucosidase inhibitorPereira et al. Nat Rev Gastroenterol Hepatol. 2009;6:403-411. http://trialx.comSlide27
Selected Characteristics for Direct Acting Agents for Chronic Hepatitis C Infection
polymerase inhibitorsNon-nucleoside polymerase inhibitorsNS5A inhibitorsPotencyHigh(varies by HCV genotype)Moderate to high (consistent across genotypes, subtype)Variable (HCV genotypes)High(multiple HCV genotypes)Barrier to resistance
Potential for drug interactions
Low to moderate
Interactions (ART, RIBA)
generation PI’s (higher
barrier to resistance, pan-genotype)
active target site
Multiple antiviral MOA
Schaefer et al.
NS3/4A protease inhibitor FDA-approved November 2013
n combination with PR in G1 patients, can achieve overall SVR rate 75-85%Contraindications:
MonotherapySubstances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A)Pregnancy or a male whose female partner is pregnantNo dose adjustment needed for in any type of renal impairment or mild hepatic impairmentAdverse reactions: rash, photosensitivity, pruritus, nausea, myalgia, dyspneaUse not indicated in HIV/HCV co-infection, hepatocellular cancer, liver transplantJacobson I et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425.Manns M et al. J Hepatol. 2013;58(
1):S568. Abstract 1413.Slide29
Simeprivir + PR
Need to check Q80K polymorphism prior to treatment
150mg + weight-based PR Treatment-naïve and prior
relapsers (including cirrhotics): SIM + PR x 12 weeks + additional PR x 12 weeksTotal duration of therapy = 24 weeksPartial and null responders (including cirrhotics):SIM + PR x 12 weeks + additional PR x 36 weeksTotal duration of therapy = 48 weeksStop all treatment if: HCV RNA ≥25 IU/mL at either week 4, 12, or 24Slide30
Simeprivir + PR: SVR Rates
Pooled QUEST 1 and QUEST 2
SVR in treatment-naïve only, rates are lower in prior
, partial responders and null respondersOutcomesSimeprivir triple therapyP/R aloneOverall SVR12 (G1a and G1b)80%50% G1a75%47%
Outcomes for all patients without SVR12
Jacobson I, et al.
2013;58(suppl 1):S574. Abstract
M, et al.
1):S568. Abstract 1413.Slide31
polymerase inhibitor FDA-approved December 2013Contraindications:
MonotherapyP-gp inducers (St. John’s Wort, rifampin)Pregnancy or a male patient whose female partner is pregnantNo dose can be recommended in severe renal disease or end-stage liver diseaseAdverse reactions: headache, fatigue, nausea, insomnia, anemiaMay be used in HIV/HCV co-infection, hepatocellular cancer, those awaiting liver transplant Lawitz et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz
Sofosbuvir + PR
combination with PR (
pegIFN + RBV) for 12 weeks in genotypes 1, 4Off-label use
in genotypes 5, 6Can achieve overall SVR > 90%To be used in treatment-naïve patients onlyNo resistance detected, 1 relapse in patient who discontinued therapyWell-tolerated no additive effects of addition of sofosbuvir to PRLawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.Slide33
SVR12 Rates by Subgroups: NEUTRINO Study
E, et al.
J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
<0.001 vs historical SVR rate 60%
Sofosbuvir + Ribavirin
FDA-approved for genotypes 2, 3, 4
400mg + weight-based RBV Genotype 2: 12 weeksGenotype 3: 24
weeksGenotype 4: 24 weeksTreatment-naïve and experienced patientsAlternate therapy for interferon-intolerant G1 patientsGane E et al. J Hepatol. 2013;58(suppl 1);S3. Abstract 5. Lawitz E et al. N Engl J Med. 2013;368:1878-1887. Nelson ER, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368;1867-1877. Jacobson
IM, et a.
. 2013;58 (
1);S28. Abstract 61
SOF + RBV
PR12 WKS16 WKSOverall67% 67%
HCV RNA <6
HCV RNA >6
SOF + RBV: SVR12 Rates by Subgroup
E et al.
E et al.
ER, et al.
IM, et al.
IM, et a.
. 2013;58 (
1);S28. Abstract 61
Dose Adjustment: Ribavirin
Ribavirin Dose Modification Guideline for
Sofosbuvir + RBV: HCV/HIV Coinfection
400mg daily + weight-based RBV daily x 12 weeks
StudyTreatment naïve genotype 1-3Included compensated cirrhoticsStable HIV diseaseART was FTC/TDF plus either efavirenz (34%), atazanavir/r (17%), darunavir/r (18%), raltegravir (16%), rilpivirine (6%)SVR 76% (genotype 1, 24 weeks therapy), 88% (genotype 2, 12 weeks), 67% (genotype 3, 12 weeks)
1):313A-314. Abstract 212.Slide38
HCV RNA Monitoring: Sofosbuvir-based Regimens
Monitoring does not affect treatment course
99% achieved undetectable HCV RNA at week 4
8% treatment failure due to relapse
No official recommendation to check HCV RNA until after therapy Most providers check RNA level week 4 to document compliance and at end of treatment (week 12 or 24)Slide39
Effect of Illicit Drugs, Alcohol, and Marijuana on Treatment
Illicit drug use
No difference in SVR between users and non-users
sofosbuvir only included those on opiate replacement therapy and there was no difference in SVRDecision to treat on individual basisAlcohol useHigher viral loads in alcohol-users (blunts immune response)Rate and severity of liver damageRisk for hepatocellular cancerCessation leads to SVR rate of non-drinkersAlcohol treatment program or sober x 6 monthsMarijuana usePossible hepatic steatosis/fibrosis in daily usersSlide40
Emerging Therapies in Chronic HCV TreatmentSlide41
DAA + PR in Late-Stage Clinical Development
RBVFaldaprevir(genotype 1)PegIFNRBVSTARTVerso1 Trial: Phase 3, treatment-naïve, genotype 1
+ PR x 12 weeks + PR versus
+ PR for additional 12 weeks
% (Faldaprevir 120mg + PR)
240mg + PR
P et al.
1):S569-S570. Abstract 1416.Slide42
Multiple DAA + PR in Late Stage Clinical Development
Polymerase InhibitorsNS5A Replication Complex InhibitorsPegIFNRBVDanoprevirMericitabinePegIFNRBVAsunaprevirDacalatasvirPegIFNRBV
+ PR in G1
(partial responders) and
breakthrough related to
Regimens were safe and well-tolerated
Feld JJ et al.
4):231A-232A. Abstract 81.
+/- PR in G1
in quad arms
Adverse effects included headache, diarrhea, fatigue, insomniaSlide43
IFN-free Regimens in Late Stage Clinical Development
InhibitorsNon-nucleoside Polymerase InhibitorsNS5A ReplicationComplex InhibitorsRibavirinSofosbuvirLedipasvir±RBVSimeprivirSofosbuvir
Sofosbuvir + Ledipasvir:
FDA APPROVAL FOR THIS COMBINATION FILED FEB. 10,
ION-1 Trial: Phase 3, N=865, N Engl J Med 2014; 370:1483-149Ledipasvir also an NS5A inhibitorCombination tablet of Ledipasvir 90 mg/Sofosbuvir 400 mg once daily + RBV bidCombo tablet 12 weeks – SVR 99%Combo tablet + RBV 12 weeks – SVR 97%Combo tablet 24 weeks – SVR 98%Combo tablet + RBV 24 weeks – SVR 99%3 had virologic failure: 1 suspected non-adherence, 2 relapsedNo benefit with RibavirinSlide45
Sofosbuvir + Ledipasvir:
Trial: Phase 3, patients previously treated with PR +/- protease inhibitor, N=440,
N Engl J Med 2014; 370:1483-1493Combination tablet of Ledipasvir 90 mg/Sofosbuvir 400 mg once daily + RBV bidSVR measured at 12 weeks post-treatment completionCombo tablet 12 weeks – SVR 94%Combo tablet + RBV 12 weeks – SVR 96%Combo tablet 24 weeks – SVR 99%Combo tablet + RBV 24 weeks – SVR 99%No drop-outs for side effectsNo significant benefit with RBVSlide46
Sofosbuvir + Simeprivir ± RBV
study: Open-label, G1, prior PR null responder, non-
and cirrhoticsSIM + SOF qd vs SIM + SOF + RBV qd x 12 or 24 weeksInterim resultsJacobson IM et al. Hepatology. 2013;58(suppl 1):73A. Abstract LB-3.Slide47
ABT-450/R/ABT-267 + ABT-333 + RBV: Treatment-experienced G1
: Phase 3, placebo-controlled, 12 week regimen, non-cirrhotic, N=394
ABT-450 150mg + ritonavir 100mg + ombitasvir 25mg +
dasabuvir 250mg bid + RBV 1000-1200mgOverall SVR12 – 96%Relapsers SVR12 – 95%Partial responders SVR12 – 100%Null responders SVR12- 95%2.4% relapse rateZeuzem S et al. EASL abstract O1. J Hepatology 2014;60(suppl 1):S1.Slide48
It is important to recognize patients who should be screened for hepatitis C infection
There are many factors that contribute to treatment decisions
The decision to treat depends on the patient’s risk for progression of disease and anticipated efficacy of the drug combinationSVR decreases liver-related complications and all-cause mortality
Treatment options are rapidly changingTraditional prognostic factors becoming obsoleteNot all patients need to be urgently treatedSlide49
Results from phase 3 trials for all-oral agents are excellent, with well tolerated regimens and high SVR rates
Interferon-free regimens with high SVR rates are possible in a variety of populations, including difficult-to-treat patients
Ribavirin and IL28B status important for DAA + PR regimens
Further study needed in:Cirrhosis, HIV coinfection, liver transplant recipients, genotype 4, patients who fail therapy with newer DAA’sSlide50
Resources for Patientswww.hepmag.com