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Treatment of hepatitis C

      Abstract

      Hepatitis C virus is a leading cause of chronic liver disease, with over 170 million people infected worldwide. It is also the leading indication for liver transplantation. Complications from chronic hepatitis C infection include cirrhosis, hepatic decompensation, and hepatocellular carcinoma. As a result, treatment strategies to prevent such complications have been widely researched, although many questions remain unanswered. To date, the standard therapy for chronic hepatitis C infection is the combination of peginterferon and ribavirin. Treatment strategies differ based on factors such as genotype and liver biopsy results. Other strategies must be considered for special groups, such as patients with acute hepatitis C infection, hepatitis C/human immunodeficiency virus (HIV) coinfection, and prior nonresponse to interferon or relapse after its use. The goal of therapy is to achieve a sustained virologic response (ie, no detectable hepatitis C ribonucleic acid 6 months after completion of therapy). The substantial adverse effects associated with both interferon alfa and ribavirin often make it difficult for patients to continue with their therapies.

      Keywords

      Background

      Hepatitis C is a leading cause of chronic liver disease
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      Hepatitis C virus infection.
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      and is currently the most common indication for liver transplantation in the United States.
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      Liver transplantation in the United States from 1987–1998 updated results from the Pitt-UNOS Liver Transplant Registry.
      Over 4 million people have been exposed to hepatitis C in the United States and over 170 million people have been exposed worldwide.
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      The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.
      Hepatitis C is transmitted through contact with blood and blood products. The leading risk factor for hepatitis C infection today is injection drug use (Table 1).
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      Other potential modes of transmission, although less common, include occupational exposure, sexual transmission, intranasal cocaine use, tattooing, body piercing, and maternal-infant spread.
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      Recipients of therapeutic blood products before 1992, when screening became possible with the availability of serological markers, are also considered to be at risk of chronic hepatitis C infection.
      Centers for Disease Control and Prevention
      Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease.
      Patients with known risk factors should be screened for hepatitis C using an enzyme immunoassay (Figure 1).
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      • Rigsby M.O.
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      Testing for hepatitis C virus infection should be routine for persons at increased risk for infection.
      Positive enzyme immunoassay test results should be confirmed with either a recombinant immunoblot assay or hepatitis C ribonucleic acid (RNA) measurement.
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      Centers for Disease Control and Prevention
      Centers for Disease Control and Prevention. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus.
      Hepatitis C RNA measurement, which is considered the “gold standard” for the diagnosis of hepatitis C, has the advantage over the recombinant immunoblot assay of not only confirming an exposure to hepatitis C but also determining ongoing viral replication. Patients with a positive enzyme immunoassay but a negative hepatitis C RNA assay may have cleared the infection, may have hepatitis C RNA that is below the level of detection, or may never have been exposed to hepatitis C (false positive). A recombinant immunoblot assay would confirm that the enzyme immunoassay is a true positive. Referral to a hepatologist for counseling, education, and treatment consideration should be considered for any patient who is found to have hepatitis C.
      Table 1Risk factors for hepatitis C infection
      Injection drug use
      Recipient of clotting factor before 1987
      Intranasal cocaine use
      Sex with multiple partners
      Body piercing
      Long-term hemodialysis
      Occupational exposure (eg, needle stick)
      Perinatal transmission
      Blood transfusion or organ transplantation before 1992
      Adapted from Centers for Disease Control and Prevention.
      Centers for Disease Control and Prevention
      Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease.
      Figure thumbnail gr1
      Figure 1Diagnostic algorithm with chronic hepatitis C. *Liver biopsy is optional in patients with genotypes 2 and 3.
      The incubation period of hepatitis C is approximately 7 weeks.
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      Hepatitis C the clinical spectrum of disease.
      Hepatitis C is an uncommon cause of acute hepatitis in the United States. Hepatitis A is responsible for 40% to 55% of acute hepatitis, and hepatitis B is responsible for another 30% to 35%; hepatitis C accounts for only 12% to 16% of acute infections.
      • Alter M.J.
      Hepatitis C virus infection in the United States.
      Chronic hepatitis C is difficult to assess, because it is frequently subclinical, so many patients are not even aware that they are infected. Patients with chronic hepatitis C are at risk of cirrhosis and hepatocellular carcinoma.
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      • Tong M.J.
      The long-term outcomes of patients with compensated hepatitis C virus- related cirrhosis and history of parenteral exposure in the United States.
      There are 6 genotypes and numerous subtypes of hepatitis C based on RNA sequence diversity of the genome. Genotypes 1 and 2 are found worldwide, genotype 3 mostly in South and Southeast Asia, genotype 4 predominantly in Africa and the Middle East, genotype 5 mostly in South Africa, and genotype 6 mainly in Hong Kong and Vietnam. In the United States, genotype 1 accounts for more than 70% of all infections.
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      • Kruszon-Moran D.
      • Nainan O.V.
      • et al.
      The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.
      Genotype should be assessed in patients who are being considered for treatment. The genotype predicts the likelihood of achieving a sustained virologic response and determines how long treatment should be continued.
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      • Marcellin P.
      • Lee S.S.
      • et al.
      International Hepatitis Interventional Therapy Group (IHIT)
      Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.
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      • Gordon S.C.
      • Schiff E.R.
      • et al.
      Hepatitis Interventional Therapy Group
      Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C.
      • Poynard T.
      • McHutchison J.
      • Goodman Z.
      • et al.
      The ALGOVIRC Project Group
      Is an “a la carte” combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C?.
      • Lindsay K.L.
      • Trepo C.
      • Heintges T.
      • et al.
      Hepatitis Interventional Therapy Group
      A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C.
      • Zeuzem S.
      • Feinman S.V.
      • Rasenack J.
      • et al.
      Peginterferon alfa-2a in patients with chronic hepatitis C.
      • Heathcote E.J.
      • Shiffman M.L.
      • Cooksley W.G.
      • et al.
      Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis.
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.

      Liver biopsy

      A liver biopsy is recommended to assess the severity of liver disease and the need for antiviral therapy. Liver biopsy is optional in patients with genotype 2 and 3 due to the high likelihood of viral response.
      National Institutes of Health Consensus Development Conference Statement
      Management of hepatitis C 2002.
      • Strader D.B.
      • Wright T.
      • Thomas D.L.
      • Seeff L.B.
      American Association for the Study of Liver Diseases
      Diagnosis, management, and treatment of hepatitis C.
      Repeat biopsies can also be useful to evaluate the progression of the disease in patients who have opted against treatment or in patients who did not respond to their initial therapy and are considering another course of therapy. Regardless of the alanine aminotransferase levels, liver biopsy should be performed when the results will influence whether treatment is recommended.
      • Strader D.B.
      • Wright T.
      • Thomas D.L.
      • Seeff L.B.
      American Association for the Study of Liver Diseases
      Diagnosis, management, and treatment of hepatitis C.
      Advanced fibrosis that requires antiviral therapy is seen in up to 40% of patients with persistently normal alanine aminotransferase levels.
      • Alberti A.
      • Noventa F.
      • Benvegnu L.
      • et al.
      Prevalence of liver disease in a population of asymptomatic persons with hepatitis C virus infection.
      The major limitations of liver biopsy are its sampling variability and the risk of adverse events.
      • Maharaj B.
      • Maharaj R.J.
      • Leary W.P.
      • et al.
      Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver.
      • Regev A.
      • Berho M.
      • Jeffers L.J.
      • et al.
      Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection.
      • Bedossa P.
      • Dargere D.
      • Paradis V.
      Sampling variability of liver fibrosis in chronic hepatitis C.
      In one study, the incidence of severe adverse events in 98 445 liver biopsies was 0.3 percent, with a mortality rate of 0.03 percent.
      • Poynard T.
      • Ratziu V.
      • Bedossa P.
      Appropriateness of liver biopsy.

      Treatment goals

      The objective of therapy is to eradicate the virus and prevent potential complications from chronic hepatitis C infection. The risk of chronic disease in infected patients is greater than 80%.
      • Farci P.
      • Alter H.J.
      • Wong D.
      • et al.
      A long-term study of hepatitis C virus replication in non-A, non-B hepatitis.
      • Barrera J.M.
      • Bruguera M.
      • Ercilla M.G.
      • et al.
      Persistent hepatitis C viremia after acute self-limiting posttransfusion hepatitis C.
      • Kenny-Walsh E.
      Irish Hepatology Research Group
      Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.
      • Missale G.
      • Bertoni R.
      • Lamonaca V.
      • et al.
      Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response.
      • Diepolder H.M.
      • Zachoval R.
      • Hoffmann R.M.
      • et al.
      Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection.
      Among patients who develop chronic infection, 5% to 20% might develop cirrhosis, generally over the course of 20 to 30 years
      • Strader D.B.
      • Seeff L.B.
      The natural history of chronic hepatitis C infection.
      • Poynard T.
      • Bedossa P.
      • Opolon P.
      The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups
      Natural history of liver fibrosis progression in patients with chronic hepatitis C.
      • Mathurin P.
      • Moussalli J.
      • Cadranel J.F.
      • et al.
      Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity.
      • Poynard T.
      • Ratziu V.
      • Benmanov Y.
      • et al.
      Fibrosis in patients with chronic hepatitis C detection and significance.
      ; among these cirrhotic patients, there is a 30% risk of developing decompensated liver disease after a decade, and a 1% to 2% yearly risk of developing hepatocellular carcinoma.
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C A retrospective follow-up study of 384 patients.
      Extrahepatic manifestations, such as cryoglobulinemia, that may lead to additional morbidity, and mortality must also be considered.
      • Pawlotsky J.M.
      • Roudot-Thoraval F.
      • Simmonds P.
      • et al.
      Extrahepatic immunologic manifestations in chronic hepatitis C and hepatitis C virus serotypes.
      Efficacy of the treatment is assessed by measurements of hepatitis C RNA viral load (Table 2). The goal is to achieve a sustained virologic response, defined by the continued absence of hepatitis C RNA 6 months after the completion of treatment. The likelihood of achieving a sustained virological response can be predicted at 3 months (Figure 2). If the hepatitis C RNA does not drop by at least 2 logs at 3 months after initiating therapy, treatment should be discontinued, because the likelihood of a sustained virologic response is only 0% to 3%
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      ; these patients are termed nonresponders, in whom treatment strategies may need to be reconsidered (see below). Ongoing studies are assessing whether the early virologic response could be less than 12 weeks. Relapsers are patients who had undetectable hepatitis C RNA levels during therapy but levels that became detectable when therapy was discontinued.
      Table 2Classifications of treatment responses to hepatitis C therapy
      Early virologic responseAbsence of hepatitis C ribonucleic acid or at least a 2-log decrease in ribonucleic acid within 12 weeks of initiating treatment for hepatitis C
      End of treatment responseAbsence of hepatitis C ribonucleic acid at the completion of treatment
      Sustained virologic responsePersistent absence of hepatitis C ribonucleic acid 6 months after the completion of therapy
      Figure thumbnail gr2
      Figure 2Use of early virologic response to predict sustained virological response. Data from Manns et al
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.
      and Fried et al.
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      *Probability of achieving a sustained virologic response.

      Antiviral treatment

      All patients with chronic hepatitis C infection should be considered potential candidates for therapy.
      • Poynard T.
      • Bedossa P.
      • Opolon P.
      The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups
      Natural history of liver fibrosis progression in patients with chronic hepatitis C.
      In the absence of contraindications (Table 3), treatment is recommended for patients who are at increased risk of developing cirrhosis, generally defined by a measurable hepatitis C RNA level and liver biopsy showing portal or bridging fibrosis along with at least moderate inflammation and necrosis.
      Table 3Absolute contraindications to hepatitis C therapy
      Active psychiatric illnesses, such as major depression, schizophrenia, or bipolar disorder that is not controlled
      Having undergone renal, heart, or lung transplant
      Comorbid conditions known to be exacerbated by interferon and ribavirin therapy, such as autoimmune hepatitis
      Untreated hyperthyroidism
      Severe concurrent disease such as severe hypertension, heart failure, considerable coronary artery disease, poorly controlled diabetes mellitus, severe chronic obstructive pulmonary disease
      Known hypersensitivity to drugs used to treat hepatitis C
      Pregnancy
      Breast feeding
      Inability to practice birth control
      Data adapted from National Institutes of Health
      National Institutes of Health Consensus Development Conference Statement
      Management of hepatitis C 2002.
      and Strader et al.
      • Strader D.B.
      • Wright T.
      • Thomas D.L.
      • Seeff L.B.
      American Association for the Study of Liver Diseases
      Diagnosis, management, and treatment of hepatitis C.
      The past decade has seen a steady improvement in therapies against hepatitis C. In the mid-1990s, monotherapy with interferon glycoproteins with antiviral and immunomodulatory activity,
      • Tilg H.
      New insights into the mechanisms of interferon alfa An immunoregulatory and anti-inflammatory cytokine.
      administered by an injection 3 times weekly for 6 to 12 months, was associated with an overall sustained virologic response of 6% to 10%.
      • Carithers Jr, R.L.
      • Emerson S.S.
      Therapy of hepatitis C meta-analysis of interferon alfa-2b trials.
      • Di Bisceglie A.M.
      • Martin P.
      • Kassianides C.
      • et al.
      Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial.
      • Davis G.L.
      • Balart L.A.
      • Schiff E.R.
      • et al.
      Hepatitis Interventional Therapy Group
      Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial.
      The addition of ribavirin (a guanosine nucleoside analog that is able to inhibit the replication of viruses) to interferon in the late 1990s was associated with an increase in sustained virologic response to approximately 30%.
      • Poynard T.
      • Marcellin P.
      • Lee S.S.
      • et al.
      International Hepatitis Interventional Therapy Group (IHIT)
      Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.
      • McHutchison J.G.
      • Gordon S.C.
      • Schiff E.R.
      • et al.
      Hepatitis Interventional Therapy Group
      Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C.
      • Reichard O.
      • Norkrans G.
      • Fryden A.
      • et al.
      The Swedish Study Group
      Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C.
      Of note, ribavirin monotherapy does not have any appreciable effect on hepatitis C RNA levels.
      • Bodenheimer Jr, H.C.
      • Lindsay K.L.
      • Davis G.L.
      • et al.
      Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C a multicenter trial.
      Realizing the importance of sustained interferon levels, the interferon product was pegylated, a process by which polyethylene glycol is covalently attached to a protein to increase its half-life, thereby resulting in better response rates (Table 4). Currently, the standard of care for the treatment of hepatitis C is the combination of peginterferon and ribavirin (Table 5), with a monthly cost of approximately $1200 for peginterferon and $1100 for ribavirin.
      Table 4Likelihood of sustained virologic response in different patient population settings
      ReferenceSustained virologic response (%)
      Treatment using peginterferon and ribavirin in all settings, except in acute hepatitis C, in which interferon was used with or without ribavirin.
      Acute hepatitis C
      • Jaeckel E.
      • Cornberg M.
      • Wedemeyer H.
      • et al.
      German Acute Hepatitis C Therapy Group
      Treatment of acute hepatitis C with interferon alfa-2b.
      ,
      • Gerlach J.T.
      • Diepolder H.M.
      • Zachoval R.
      • et al.
      Acute hepatitis C high rate of both spontaneous and treatment-induced viral clearance.
      ,
      • Nomura H.
      • Sou S.
      • Tanimoto H.
      • et al.
      Short-term interferon-alfa therapy for acute hepatitis C a randomized controlled trial.
      80–100 (overall with early intervention)
      Chronic hepatitis C
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.
      ,
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      ,
      • Hadziyannis S.J.
      • Sette Jr, H.
      • Morgan T.R.
      • et al.
      PEGASYS International Study Group
      Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C a randomized study of treatment duration and ribavirin dose.
      Genotype 142–65
      Genotypes 2 and 376–88
      Subsets of patients
       Nonresponders/relapsers
      Patients who did not respond to interferon or to interferon plus ribavirin or who relapsed after these treatments.
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial Group Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      18 (overall)
       HIV/hepatitis C coinfection
      In one study, the response rates in patients with genotype 1 and 4 were analyzed together, as were the response rates of genotype 2, 3 and 5.67
      • Chung R.
      • Andersen J.
      • Volberding P.
      • et al.
      Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.
      ,
      • Torriani F.J.
      • Rockstroh J.
      • Rodriguez-Torres M.
      • et al.
      Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.
      ,
      • Carrat F.
      • Bani-Sadr F.
      • Pol S.
      • et al.
      Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
      Genotype 117–29
      Genotypes 2 and 344–73
       Liver transplant recipients
      • Dumortier J.
      • Scoazec J.Y.
      • Chevallier P.
      • et al.
      Treatment of recurrent hepatitis C after liver transplantation a pilot study of peginterferon alfa-2b and ribavirin combination.
      ,
      • Mukherjee S.
      • Rogge J.
      • Weaver L.
      • et al.
      Pilot study of pegylated interferon alfa-2b and ribavirin for recurrent hepatitis C after liver transplantation.
      ,
      • Rodriguez-Luna H.
      • Khatib A.
      • Sharma P.
      • et al.
      Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon alpha2b and ribavirin an open-label series.
      26–45 (overall)
      low asterisk Treatment using peginterferon and ribavirin in all settings, except in acute hepatitis C, in which interferon was used with or without ribavirin.
      Patients who did not respond to interferon or to interferon plus ribavirin or who relapsed after these treatments.
      In one study, the response rates in patients with genotype 1 and 4 were analyzed together, as were the response rates of genotype 2, 3 and 5.
      • Carrat F.
      • Bani-Sadr F.
      • Pol S.
      • et al.
      Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
      Table 5Doses of peginterferon and ribavirin
      Food and Drug Administration approved doses. However, weight-based ribavirin is commonly used in clinical practice with peginterferon alfa-2b.
      Peginterferon is administered subcutaneously and ribavirin is administered orally in divided doses twice daily.
      Peginterferon type and doseRibavirin dose
      Peginterferon alfa-2a 180 mg/wk
       Genotype 11000 mg/d if weight ≤75 kg
      1200 mg/d if weight >75 kg
       Genotypes 2 and 3800 mg/d
      Peginterferon alfa-2b 1.5 mg/kg/wk800 mg/d
      low asterisk Food and Drug Administration approved doses. However, weight-based ribavirin is commonly used in clinical practice with peginterferon alfa-2b.
      Peginterferon is administered subcutaneously and ribavirin is administered orally in divided doses twice daily.
      The most common adverse effects associated with interferon include fatigue and flu-like symptoms (Table 6); interferon can also cause neutropenia and thrombocytopenia. With ribavirin, dose-dependent and reversible hemolytic anemia is the most prominent adverse effect,
      • Bodenheimer Jr, H.C.
      • Lindsay K.L.
      • Davis G.L.
      • et al.
      Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C a multicenter trial.
      whereas the most serious potential adverse effect is teratogenicity. Two forms of contraception must be used during therapy and for 6 months following treatment cessation.
      Table 6Selected common adverse effects reported with interferon and ribavirin*
      Clinical adverse effectFrequency of adverse effects (%)
      Interferon and ribavirinPeginterferon and ribavirin
      Fatigue55–6047–64
      Fever33–5639–46
      Headache52–5847–62
      Myalgia5042–56
      Arthralgia2824–34
      Nausea3329–43
      Cough1315–17
      Dyspnea2423–26
      Alopecia32–3421–36
      Injection site reaction3658–59
      Adapted from pivotal trials by Manns et al,
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.
      Fried et al,
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      and the National Institutes of Health.
      National Institutes of Health Consensus Development Conference Statement
      Management of hepatitis C 2002.
      The decision of whether to continue antiviral treatment depends on the severity of adverse effects, their effect on quality of life, and the degree of underlying histologic damage. Peginterferon and ribavirin should be discontinued if the hemoglobin level is less than 8.5 g/dL, the white blood cell count is less than 1 × 109/L, the absolute neutrophil count is less than 0.5 × 109/L, and/or platelet count is less than 50 × 109/L.

      Treatment

      Acute hepatitis C

      Most patients with acute hepatitis C are asymptomatic, thus making it difficult to identify those with de novo infection. Hepatitis C RNA is detectable as early as 1 to 2 weeks following exposure,
      • Hoofnagle J.H.
      Hepatitis C the clinical spectrum of disease.
      • Farci P.
      • Alter H.J.
      • Wong D.
      • et al.
      A long-term study of hepatitis C virus replication in non-A, non-B hepatitis.
      aminotransferase levels start to rise after 6 to 12 weeks,
      • Jaeckel E.
      • Cornberg M.
      • Wedemeyer H.
      • et al.
      German Acute Hepatitis C Therapy Group
      Treatment of acute hepatitis C with interferon alfa-2b.
      and hepatitis C antibodies are detected as early as 8 weeks after exposure.
      • Hoofnagle J.H.
      Hepatitis C the clinical spectrum of disease.
      Spontaneous viral clearance may occur during the first 12 weeks after infection.
      • Gerlach J.T.
      • Diepolder H.M.
      • Zachoval R.
      • et al.
      Acute hepatitis C high rate of both spontaneous and treatment-induced viral clearance.
      • Santantonio T.
      • Sinisi E.
      • Guastadisegni A.
      • et al.
      Natural course of acute hepatitis C a long-term prospective study.
      Due to the difficulty of identifying acute hepatitis C infection, only 1 randomized, prospective trial has assessed the treatment of acute disease. Various studies demonstrate excellent sustained virologic responses with earlier treatment.
      • Jaeckel E.
      • Cornberg M.
      • Wedemeyer H.
      • et al.
      German Acute Hepatitis C Therapy Group
      Treatment of acute hepatitis C with interferon alfa-2b.
      Interestingly, over 50% of patients who present with symptomatic acute hepatitis C clear the virus spontaneously.
      • Gerlach J.T.
      • Diepolder H.M.
      • Zachoval R.
      • et al.
      Acute hepatitis C high rate of both spontaneous and treatment-induced viral clearance.
      In the only controlled study of acute hepatitis C, patients were randomized to interferon monotherapy starting 8 weeks (early intervention) or 1 year (late intervention) after infection. The sustained virologic response was 100% with early intervention but only 53% with late intervention.
      • Nomura H.
      • Sou S.
      • Tanimoto H.
      • et al.
      Short-term interferon-alfa therapy for acute hepatitis C a randomized controlled trial.
      These aggregate data suggest that the sustained virologic response is higher when treatment is instituted no more than 3 months after infection, although it may be prudent to wait 12 weeks to allow for spontaneous resolution. Although the optimal dose and duration of treatment of acute hepatitis C is unclear, patients may benefit from 6 months of interferon therapy. Other options include peginterferon, with and without ribavirin.
      Currently, the best treatment for acute hepatitis C is a 6-month course of peginterferon and ribavirin (doses in Table 5). Although most studies used interferon in the treatment of acute hepatitis C, peginterferon is more convenient to use. Moreover, the addition of ribavirin to peginterferon is associated with a greater probability of a virologic response without a concomitant exacerbation of adverse effects.

      Chronic hepatitis C

      Elevated aminotransferase levels

      Several studies have compared the safety and efficacy of peginterferon and ribavirin with standard interferon and ribavirin for the treatment of chronic hepatitis C in patients with elevated aminotransferase levels.
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      • Hadziyannis S.J.
      • Sette Jr, H.
      • Morgan T.R.
      • et al.
      PEGASYS International Study Group
      Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C a randomized study of treatment duration and ribavirin dose.
      In these studies, peginterferon and ribavirin were more efficacious without having more adverse effects.
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      With peginterferon and ribavirin, the overall sustained virologic response is between 54% and 63%,
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      • Hadziyannis S.J.
      • Sette Jr, H.
      • Morgan T.R.
      • et al.
      PEGASYS International Study Group
      Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C a randomized study of treatment duration and ribavirin dose.
      compared with a rate between 44% and 46% with interferon and ribavirin.
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      Predictors of poor sustained virologic response include genotype 1, high viral load, increased body weight, and substantial fibrosis (bridging fibrosis and cirrhosis).
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      For example, the sustained virologic response for patients with genotype 1 with peginterferon and ribavirin is between 42% and 56%. For patients with genotypes 2 and 3, the sustained virologic response is between 75% and 84%. In patients with genotype 1 and a high viral load, the sustained virologic response is between 26% and 42%. With low viral load, the sustained virologic response was between 52% and 56%. In patients with bridging fibrosis and cirrhosis, the sustained virologic response is between 29% and 43%.
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      Treatment of patients with compensated cirrhosis must be tempered by the fact that many patients are already thrombocytopenic before starting therapy, and many may be at risk of further decompensation when therapy is instituted. Patients with decompensated liver disease tolerate interferon poorly and have a higher incidence of adverse events
      • Crippin J.S.
      • McCashland T.
      • Terrault N.
      • et al.
      A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation.
      • Berenguer M.
      • Lopez-Labrador F.X.
      • Wright T.L.
      Hepatitis C and liver transplantation.
      • Forns X.
      • Garcia-Retortillo M.
      • Serrano T.
      • et al.
      Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation.
      ; they should not be given interferon.

      Nonresponders

      By 2015, the number of nonresponders to either interferon/ribavirin or peginterferon/ribavirin seeking retreatment is expected to outgrow the number of patients who are seeking initial therapy. The primary goal of retreatment is to achieve a sustained virologic response. Secondary goals include the prevention of progressive histologic diseases, the regression of fibrosis, a decrease in the risk of hepatocellular carcinoma, and, potentially, a reduction of the risk of hepatic decompensation. The sustained virologic response in interferon/ribavirin nonresponders retreated with peginterferon/ribavirin is between 4% and 12%.
      • Krawitt E.L.
      • Lidofsky S.D.
      • Ferrentino N.
      • et al.
      Efficacy of peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C previously unresponsive to interferon-based therapy.
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial Group Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      • Jacobson I.M.
      • Ahmed F.
      • Russo M.W.
      • et al.
      Pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C: A trial of prior nonresponders to intereron monotherapy or combination therapy and in combination therapy relapsers: Final results.
      Unfortunately, retreatment options are limited, and their efficacy is low. Options in nonresponders may include peginterferon maintenance therapy or interferon alfacon-1 used in combination with ribavirin. When retreating nonresponders to interferon or interferon/ribavirin, early virologic response is often assessed at 20 to 24 weeks rather than at 12 weeks.
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial Group Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      In preliminary studies, the results from using interferon alfacon-1 and ribavirin appear promising in nonresponders to interferon/ribavirin and peginterferon/ribavirin.
      • Kaiser S.
      • Hass H.
      • Gregor M.
      Successful retreatment of peginterferon nonresponder patients with chronic hepatitis C with high dose consensus interferon induction therapy.
      • Leevy C.B.
      • Ramaraju G.
      • Chalmers C.P.
      • et al.
      End of treatment response for PEG-IFN + weight-based ribavirin nonresponders retreated with IFN alfacon-1 + weight-based ribavirin.
      However, larger trials are needed before this approach is used routinely in clinical practice.

      HIV/hepatitis C coinfection

      The human immunodeficiency virus and hepatitis C have similar modes of transmission, so rates of coinfection are higher. Several studies have shown that approximately 25% to 30% of all patients infected with HIV in the United States and Europe are also infected with hepatitis C,
      • Staples Jr, C.T.
      • Rimland D.
      • Dudas D.
      Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS) the effect of coinfection on survival.
      • Sherman K.E.
      • Rouster S.D.
      • Chung R.T.
      • Rajicic N.
      Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus a cross-sectional analysis of the US adult AIDS Clinical Trials Group.
      and up to 10% of patients infected with hepatitis C may have HIV coinfection.
      • Alter M.J.
      • Kruszon-Moran D.
      • Nainan O.V.
      • et al.
      The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.
      • Sherman K.E.
      • Rouster S.D.
      • Chung R.T.
      • Rajicic N.
      Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus a cross-sectional analysis of the US adult AIDS Clinical Trials Group.
      Response rates to interferon-based therapy appear to be slightly lower in patients with HIV/hepatitis C coinfection compared with patients infected with hepatitis C. As seen in hepatitis C alone, the combination of peginterferon and ribavirin is associated with a higher sustained virologic response than is standard interferon and ribavirin; the sustained virologic response ranged from 27% to 44% with the peginterferon/ribavirin group compared with 11% to 12% with the standard interferon/ribavirin groups.
      • Chung R.
      • Andersen J.
      • Volberding P.
      • et al.
      Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.
      • Torriani F.J.
      • Rockstroh J.
      • Rodriguez-Torres M.
      • et al.
      Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.
      • Carrat F.
      • Bani-Sadr F.
      • Pol S.
      • et al.
      Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
      For patients with genotype 1, the sustained virologic response ranges from 14% to 29% with peginterferon and ribavirin and from 44% to 73% for patients with genotypes 2 and 3.
      • Chung R.
      • Andersen J.
      • Volberding P.
      • et al.
      Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.
      • Torriani F.J.
      • Rockstroh J.
      • Rodriguez-Torres M.
      • et al.
      Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.
      • Carrat F.
      • Bani-Sadr F.
      • Pol S.
      • et al.
      Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
      In one study, the response rates of patients with genotype 4 were analyzed with those of genotype 1.
      • Carrat F.
      • Bani-Sadr F.
      • Pol S.
      • et al.
      Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
      Similarly, the response rates in patients with genotypes 2, 3 and 5 were also analyzed together. With treatment for hepatitis C, HIV RNA levels do not appreciable increase. CD4 counts decrease during treatment but return to baseline after completion of therapy. However, the adverse effects of treatment for hepatitis C treatment in HIV coinfected patients lead to high rates of discontinuing therapy.
      • Carrat F.
      • Bani-Sadr F.
      • Pol S.
      • et al.
      Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients a randomized controlled trial.
      • Brau N.
      • Rodriguez-Torres M.
      • Prokupek D.
      • et al.
      Treatment of chronic hepatitis C in HIV/HCV-coinfection with interferon alpha-2b+ full-course vs. 16-week delayed ribavirin.
      Patients on highly active antiretroviral therapy may be more susceptible to the hemolytic effects of ribavirin therapy,
      • Roberts R.B.
      • Jurica K.
      • Meyer W.A.
      • et al.
      A phase 1 study of ribavirin in human immunodeficiency virus-infected patients.
      resulting in reductions in its dose or the discontinuation of its use.
      • Brau N.
      • Rodriguez-Torres M.
      • Prokupek D.
      • et al.
      Treatment of chronic hepatitis C in HIV/HCV-coinfection with interferon alpha-2b+ full-course vs. 16-week delayed ribavirin.
      The decision to treat must be weighed against these additional safety concerns in HIV/hepatitis C coinfected patients.

      Liver transplant recipients

      Hepatitis C is currently the most common indication for orthotopic liver transplantation.
      • Feray C.
      • Gigou M.
      • Samuel D.
      • et al.
      The course of hepatitis C virus infection after liver transplantation.
      • Bizollon T.
      • Ducerf C.
      • Trepo C.
      Hepatitis C virus recurrence after liver transplantation.
      • Gane E.
      Hepatitis C virus infection following liver transplantation.
      However, recurrence after transplantation is universal.
      • Saab S.
      • Wang V.
      Recurrent hepatitis C following liver transplant diagnosis, natural history, and therapeutic options.
      Although the 5-year survival rate for transplant recipients with hepatitis C is similar to other patients, more recent data suggest decreased long-term survival.
      • Forman L.M.
      • Lewis J.D.
      • Berlin J.A.
      • Feldman H.I.
      • Lucey M.R.
      The association between hepatitis C infection and survival after orthotopic liver transplantation.
      • Berenguer M.
      • Prieto M.
      • Juan S.J.
      • et al.
      Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients.
      Moreover, accelerated recurrent hepatitis C infection after transplantation can rapidly result in development of cirrhosis and decompensated disease. Efforts to treat recurrent disease have been hampered by the limited efficacy and adverse effects of current therapies. The combination of interferon and ribavirin has been associated with a sustained virologic response rate of approximately 20%
      • Samuel D.
      • Bizollon T.
      • Feray C.
      • et al.
      Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation a randomized study.
      • Bizollon T.
      • Ahmed S.N.
      • Radenne S.
      Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence.
      • Shakil A.O.
      • McGuire B.
      • Crippin J.
      • et al.
      A pilot study of interferon alfa and ribavirin combination in liver transplant recipients with recurrent hepatitis C.
      and perhaps increasing to approximately 30% with the combination of peginterferon and ribavirin.
      • Dumortier J.
      • Scoazec J.Y.
      • Chevallier P.
      • et al.
      Treatment of recurrent hepatitis C after liver transplantation a pilot study of peginterferon alfa-2b and ribavirin combination.
      • Mukherjee S.
      • Rogge J.
      • Weaver L.
      • et al.
      Pilot study of pegylated interferon alfa-2b and ribavirin for recurrent hepatitis C after liver transplantation.
      • Rodriguez-Luna H.
      • Khatib A.
      • Sharma P.
      • et al.
      Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon alpha2b and ribavirin an open-label series.
      However, adverse effects, including rejection of the transplant, are a major concern.
      • Bizollon T.
      • Ducerf C.
      • Trepo C.
      Hepatitis C virus recurrence after liver transplantation.
      • Wright T.L.
      • Combs C.
      • Kim M.
      • et al.
      Interferon-alpha therapy for hepatitis C virus infection after liver transplantation.
      • Saab S.
      • Kalmaz D.
      • Gajjar N.A.
      • et al.
      Outcomes of acute rejection after interferon therapy in liver transplant recipients.

      Future treatments

      A number of therapies for hepatitis C are being studied in early clinical trials
      • Pawlotsky J.M.
      • McHutchison J.G.
      Hepatitis C: development of new drugs and clinical trials: promises and pitfalls: summary of an AASLD hepatitis single topic conference, Chicago, IL, February 27-March 1, 2003.
      : therapies directed against specific hepatitis C targets (polymerase and protease inhibitors, antisense nucleotides), immunomodulators (histamine, chloride matrix and thymosin alfa), vaccines, alternative interferons (oral interferon alfa, purified multisubtype human interferon alfa, interferon omega and interferon gamma), alternative interferon delivery systems (fusion protein interferon alfa-albumin and transfersome containing interferon alfa), and ribavirin prodrugs and L isomers. However, no new drugs are expected on the market for several years, and interferon is likely to remain the core of any regimen that becomes available.

      Acknowledgments

      We thank Joshua Marehbian, Ian Cown, and Lisette Peralta for editorial assistance.

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