HEPATITIS C
| NEW THERAPIES IN DEVELOPMENT —Paul J. Pockros, MD, Head, Division of Gastroenterology/Hepatology,
Scripps Clinic, La Jolla, CA
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| Viral life cycle: provides targets for therapy; 1) neutralizing antibodies that block viral entry into hepatocyte; monoclonal
and polyclonal antibodies that do this tested in transplant setting; 2) immunotherapeutic strategies, eg, interferon;
3) internal ribosome entry site-mediated translation initiation (antisense oligonucleotides; studies failed); 4)
RNA interference; 5) RNA-dependent protease and polymerase inhibitors most promising
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| Albinterferon alfa-2b (Albuferon): new interferon; made by combining human serum albumin gene with interferon-
α gene to make one large protein (86 kD; larger than largest pegylated interferon); 2-wk half-life could allow
patient to take drug every 2 wk, instead of weekly (not important unless side effects extinguished after 2 days and patient
has 12 days of good quality of life [QOL]); high enough dosing peak could make monthly injections possible
(speaker thinks this would be significant for QOL); dosing—good virologic response at 900 and 1200 µg (study in
phase 3 trials); second dose provides second drop in hepatitis C virus (HCV) RNA; since drug in system 2 to 4 wk, hematologic
adverse events (eg, neutropenia, thrombocytopenia) could be problem, especially since second injection already
given (data suggest viral load [VL] drops in first 2 wk, then stabilizes)
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| Replacing ribavirin: if left out, relapse rates high; replacement with inosine-5’-monophosphate dehydrogenase (IMPDH)
inhibitor proposed (developed but did not work); viramidine—ribavirin prodrug; enters red blood cell less often
than hepatocyte; thought that viramidine would not cause hemolytic anemia (major ribavirin side effect); however,
phase 3 trials found that conversion of viramidine to ribavirin in hepatocyte slows rate at which ribavirin effective; 2
other trials failed to show efficacy of viramadine equivalent to that of ribavirin, although anemia less with viramidine;
new study—hypothesis that weight-based dosing of viramidine will produce sustained viral response (SVR) rates
matching those of ribavirin with less anemia
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Drugs to Watch
| Direct antivirals: NS3 protease inhibitors and NSB5 polymerase inhibitors; study with pegylated interferon plus ribavirin
in genotype 1 patients found that if virus cleared by week 4, chance of SVR 91%; if cleared by week 12,
chance 60% to 70%; if cleared by week 24, chance 43% to 48%; but chance almost 0 if not cleared by week 24; direct
antivirals designed to put all patients into week-4 group with rapid virologic response (RVR) and SVR as long
as drug combination continued; protease inhibitor concept—give direct antiviral and decrease VL by 3 logs within
24 to 48 hr; works primarily in genotype 1 (new drugs being studied only in genotype 1)
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 | Protease inhibitors in development: SCH503034 (Schering-Plough)— NS3 inhibitor; studied in nonresponders (high
VL; no 2-log drop in HCV RNA in 12 wk when first treated); SCH503034 produced rapid 1.5- to 2.0-log drop that
was sustained until patients off drug; resistant strains developed rapidly (2-4 days); when drug combined with pegylated
interferon (peginterferon alfa-2b) and ribavirin left out, resistance developed, but 50% of patients HCV RNA-
negative within 2 wk; VX950—NS3 protease inhibitor; monotherapy produced robust drop in HCV RNA (≈4.5
logs in 2 wk); study that combined peginterferon alfa-2a, ribavirin, and VX950, found all 12 patients HCV RNA-
negative in first 2 wk; compared to standard pegylated interferon and ribavirin therapy in patients with genotype 1,
10-fold greater rate of HCV RNA negativity; unknown whether this will translate into 100% SVR rates (many patients
still on protocol, although some stopped at 24 wk); in Europe, genotype-1 patients on peginterferon alfa-2a
and ribavirin stop after 24 wk if RVR occurs (based on retrospective data); mechanism of response—suggested that
in genotype 1, protease inhibitors derepress interferon-stimulating genes repressed by virus, reconstituting immune
response and allowing patient’s own interferon to work; all protease inhibitors result in resistant strains because of
error-prone RNA-dependent RNA polymerase; data based on VX950 showed resistant variants sensitive to pegylated
interferon; as long as pegylated interferon given, resistant variants cannot replicate; new drugs developed on
this basis, not monotherapy; Food and Drug Administration (FDA) requires studies on protease inhibitors to include
pegylated interferon; in studies on polymerase inhibitors, FDA requires inclusion of ribavirin also
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| RNA polymerase inhibitors: NM283—speaker’s study of nonresponders with genotype 1; unusual design (lead-in
period; no control group; several drug combinations, no ribavirin); arm with NM283 and peginterferon at higher doses
caused gastrointestinal toxicity (nausea and vomiting); redone at lower doses (200 mg), had 4-log drop in HCV RNA
and were HCV RNA-negative by 24 wk (68%), compared to historical control groups; R1626—first RNA polymerase
inhibitor to show efficacy equivalent to protease inhibitors, but caused anemia at higher doses
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| Cyclosporine: Japanese trial shows it works in hepatitis C; Novartis developed compound without cyclosporine toxicities;
studies ongoing
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| Goals: shorten duration of therapy in genotype-1 patients; show improved superiority with standard duration of therapy;
eliminate ribavirin if possible
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| Summary: pegylated interferon remains backbone of treatment; 5 direct antivirals with potent antiviral effect in phase
2 trials
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| THE NATURAL HISTORY OF UNTREATED HEPATITIS C—Robert J. Fontana, MD, Associate Professor, Department
of Internal Medicine, and Medical Director of Liver Transplantation, University of Michigan Medical School, Ann
Arbor
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| Introduction: significant worldwide problem; in United States, cohort effect; parenteral risk factors; seroprevalence
based on age; more morbidity and mortality as cohort ages
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| Clinical factors: abnormal alanine aminotransferase (ALT), history of intravenous (IV) drug use, or blood transfusion
before 1992 account for 85% of viremic patients; of 100 patients exposed to virus— 15% to 30% develop immunity,
ie, become antibody-positive and polymerase chain reaction (PCR)–negative; (provides hope for vaccine to prevent
primary infection); majority develop chronic infection, ranging from mild liver disease to moderate hepatitis to cirrhosis
in 20 to 30 yr; to prevent cirrhosis, important to identify early on patients at risk for disease progression
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| Clinical features of hepatitis C: acquisition— most patients do not know when exposure or acquisition of infection
occurred; <20% develop hepatitic illness with abdominal pain, malaise, or jaundice; 20% to 30% have normal
ALT and aspartate aminotransferase (AST; should not preclude testing for hepatitis C if parenteral risk factor present);
silent progression—mild or severe liver fibrosis often asymptomatic; rate of progression to cirrhosis 1% to 10% per
decade; extrahepatic manifestations—may be primary presentation; include porphyria cutanea tarda, skin rash, primary
cryoglobulinemia, membranoproliferative glomerulonephritis and other glomerular disease; develop in <1% of
chronically infected patients
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| Diagnosis: target high-risk patients with parenteral risk factors; evaluate patients with fatigue and abdominal pain;
screening tests—enzyme-linked immunosorbent assay (ELISA) antibody-generation test sensitive and specific; confirmatory
tests—to determine whether patient actively viremic, use qualitative or quantitative PCR assays; guide
counseling about disease transmission; antiviral treatment indicated if PCR positive
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| Hepatitis C staging: physical examination—stigmata of chronic liver disease usually absent; laboratory tests—
often normal in newly diagnosed patients; may see variable aminotransferase; look for hypoalbuminemia and prolonged
prothrombin time; bilirubin may be normal; platelet count decreases as fibrosis increases (indicator of severe
disease in asymptomatic patient); liver biopsy—gold standard; findings include periportal lymphoid follicle (typical
of hepatitis C; seen in ≈60% of patients), variable steatosis of liver lobule, bridging fibrosis, and nodular cirrhosis; scoring
fibrosis—Knodell system nonlinear and has 4 stages; Ishak system gives greater gradation of severity of fibrosis
(6 stages); limitations of biopsy—sampling artifact may cause difference of ≥1 stage; with smaller sample, more
likely to underestimate fibrosis; know scoring system used by hospital; fibrosis scores integers but not on linear scale,
eg, Ishak score of 4 does not mean twice as much fibrosis as score of 2
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| Progression factors: disease progression more likely with longer duration of chronic infection; genotype and VL do
not correlate with disease progression; host factors—age at exposure (patients exposed at younger age take longer to
develop significant fibrosis); men develop fibrosis more rapidly than women; HIV-coinfected and transplant patients
have accelerated fibrosis; fatty liver and insulin resistance drive fibrosis; diabetes associated with accelerated fibrosis;
genetic polymorphisms, variation in cytokines, and ethnicity play role; environmental factors—alcohol use (minimize);
iron supplementation (avoid); antiviral therapy
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| Progression of fibrosis (Irish women’s cohort study): 363 young pregnant women followed after receiving HCV-contaminated
Rh factor; no immunosuppression, coinfection; no alcoholism; after mean of 17 yr of infection, biopsy
showed 49% had no fibrosis, 34% had mild fibrosis, and 17% had bridging fibrosis or cirrhosis; suggests young age
at infection associated with milder course; Seef study—followed infected Air Force recruits; morbidity and mortality
from HCV infection seen at ≥60 yr of age; liver clinic patients—infected at older age; showed more liver-related
morbidity and mortality; serial liver biopsies—done on patients with established hepatitis C; 4 studies, ≈100
patients each; 3-yr mean follow-up between biopsies without treatment; approximately one-third of patients progressed;
factors associated with progression included age, ALT, and liver inflammtion score
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| HCV cirrhosis: Fattovich study—384 patients; if they remained compensated, good 10-yr survival; if they decompensated,
50% survival over 5 yr
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| Hepatocellular carcinoma (HCC) vs decompensation: 3 cohorts followed 5 yr; rate of decompensation 3% to
4%, rate of HCC 2% to 3%; survival after decompensation ≈50% in next 5 yr; risk factors for liver cancer—
speaker’s study found risk increased 6-fold in heavy drinkers, 5-fold in smokers (>20 pack years), and 4-fold in obese
patients (body mass index >30); factors independent but synergistic when added; other risk factors include country
(risk greater in Japan), age, sex, long duration of infection, and hepatitis B
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| Projections: from National Health and Nutrition Examination Survey (NHANES) data—number of HCV infections
will decrease because of infection-control practices; cirrhosis will increase and drive more decompensation and more
HCC; HCV-related deaths will increase; antiviral treatments that clear virus in 50% of patients could affect morbidity
and mortality
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| LIVER TRANSPLANTATION IN THE SETTING OF CHRONIC HEPATITIS C—David R. Nelson, MD, Associate
Professor of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, and Director of Hepatology and Liver
Transplantation, University of Florida College of Medicine, Gainesville
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| Background: hepatitis C most common reason for liver transplantation; all patients have recurrence of hepatitis C after
transplantation, with accelerated rate of progression and compromise to survival of patient and graft; cases of fibrosing
cholestatic hepatitis that progress rapidly to liver failure; within 5 yr, 30% develop cirrhosis; within 1 yr of
developing cirrhosis, 50% decompensate, with 1-yr survival <50%
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| Factors potentially associated with disease recurrence after transplantation: host—older host does
worse; Rosen study showed host immune system critical; viral factors—pretransplant VL most important; donor
factors— older age; more ischemic time; living donor; steatosis; during transplantation—need for OKT3 monoclonal
antibody or recurrent steroid boluses has negative effect; clinical factors—biliary tract complications; cytomegalovirus
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| Viral replication: 10-fold higher after transplantation (virus more efficient at replicating); liver transplanted across
HLA class I and class II barriers; since adaptive immune response HLA class I- and class II-restricted, virus-specific T
cells cannot recognize infected liver cells; clinical factors—immunosuppression, steatosis, and ischemic time; all
cause inflammation, block intracellular immune response to virus, and contribute to reinfection
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| Immunosuppression in transplantation: patient will do worse if OKT3 or recurrent steroid boluses used; preventing
steroid resistance key; summary of literature—avoid too much immunosupression; avoid rapid steroid taper
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| Rejection: prevention key; treating for it increases risk for mortality; cyclosporine vs tacrolimus—speaker’s data
suggest advantage to cyclosporine
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| Prevent recurrence or treat it? posttransplant strategies —1) preemptively treat as soon as transplantation finished
(associated with poor tolerability); 2) target therapy to those with more advanced disease (most programs do
this; current recommendation to treat stage II fibrosis or significant inflammation); 3) do nothing (anecdotal studies
suggest graft survival not improved by clearing virus)
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| Treatment: 4 studies looking at SVR rates found cure rates 15% to 30%; target antiviral therapy—interferon can
cause rejection; disease progresses rapidly; strategies include 1) protocol liver biopsies on all patients; determine
amount of inflammation or fibrosis, predict cirrhosis risk, and target therapy accordingly; 2) use early markers predictive
of future recurrence of severe fibrosis; 3) look at hepatic vein pressure gradients
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| Predicting risk: speaker’s center looked at ability of biopsy at 4 mo or 1 yr to predict future risk of developing cirrhosis;
low amount of inflammation associated with low risk over 5 yr; by 1 yr, can select patients who will develop more
progressive disease; in hepatitis C, inflammation leads to fibrosis, so inflammation surrogate marker; potential for using
histological activity index (HAI) score early on to target group for early treatment
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| Fibrosis scores: best predictor of worse fibrosis is early fibrosis; many programs do protocol biopsies, targeting HAI
scores >4 or fibrosis scores of 2; when that end point met, antiviral treatment initiated
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Suggested Reading
Armstrong GL et al: The prevalence of hepatitis C infection in the US, 1999-2002. Ann Int Med 144:705, 2006;
Blasco A et al: Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver
transplant. Hepatology 43:492, 2006; Bonkovsky HL et al: Health-related quality of life in patients with chronic
hepatitis C and advanced fibrosis. J Hepatol 46:420, 2007; Cornberg M et al: Treatment with daily interferon
(CIFN) plus ribavirin in nonresponder patients with chronic hepatitis C: a randomized open-label pilot study. J Hepatol
44:291, 2006; Davis GL et al: Response to higher doses of interferon alpha2b in patients with chronic hepatitis C: a
randomized multicenter trial. Hepatology 24:1034, 1996; Fattovich G et al: Morbidity and mortality in compensated
cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 12:463, 1997; Firpi RJ et al: Cyclosporine
suppresses hepatitis C virus in vitro and increases the chance of a sustained virological reponse after liver
transplantation. Liver Transpl 12:51, 2006; Firpi RJ et al: One year protocol liver biopsy can stratify fibrosis progression
in liver transplant recipients with recurrent hepatitis C infection. Liver Transpl 10:1240, 2004; Hadziyannis SJ
et al: Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment
duration and ribavirin dose. Ann Int Med 140:346, 2004; Ikeda K et al: A multivariate analysis of risk factors for
hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology
18:47, 1993; Morelli G et al: Late presentation of a biliary tract complication after right hepatic donation resulting in
secondary biliary cirrhosis. Liver Transpl 12:306, 2006; Pockros PJ: Noninvasive markers of fibrosis in chronic hepatitis
patients. J Clin Gastroenterol 40:461, 2006; Seef LB et al: 45 year follow-up with hepatitis C virus infection in
healthy young adults. Ann Int Med 132:105, 2000.
Educational Objectives
| The goal of this program is to improve the management of hepatitis C, including liver transplantation and posttransplant
measures. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Describe the life cycle of the hepatitis C virus and steps in the cycle that provide good targets for therapeutic intervention.
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| 2. Assess new drugs in development for treatment of hepatitis C.
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| 3. Summarize the natural history of hepatitis C and factors associated with disease progression, morbidity, and mortality.
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| 4. Identify patients with hepatitis C who are at high risk for liver cancer.
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| 5. Discuss factors associated with recurrence of hepatitis C after liver transplantation.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the following has been disclosed: Dr. Pockros has been involved in research,
consulting, and speaking for Roche, Valgant, Denix, Wyeth, Vertex, Schering-Plough, HGS, and Novartis. Dr.
Fontana is affiliated with the Cleveland Clinic. Dr. Nelson receives research support from Schering-Plough, Roche, and
Novartis and is on the Speakers’ Bureaus of Schering-Plough and Roche.
Acknowledgements
Dr. Pockros spoke in San Diego, CA, at New Treatments in Chronic Liver Disease, presented March 31 to April 1,
2007, by the Scripps Clinic. Drs. Fontana and Nelson spoke in Cleveland, OH, at Viral Hepatitis Summit, presented August
24-26, 2006, by the Cleveland Clinic. The Audio-Digest Foundation thanks the speakers and the sponsors for their
cooperation in the production of this program.
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