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Diagnosis and Management of Hepatitis C

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      Diagnosis and Management of Hepatitis C CME
      David Bernstein, MD
      Author affiliations and disclosures are at the end of
      this activity.

      Release Date: February 2, 2001

      Legal Disclaimer
      The material presented here does not reflect the views
      of Medical Education Collaborative, Medscape, or the
      companies providing unrestricted educational grants.
      These materials may discuss uses and dosages for
      therapeutic products that have not been approved by
      the United States Food and Drug Administration. All
      readers and continuing education participants should
      verify all information and consult a qualified health
      care professional before treating patients or
      utilizing any therapeutic product discussed in this
      continuing education activity.



      Table of Contents
      Introduction
      Risk Factors

      Natural History of Hepatitis C

      Clinical Presentation

      Extrahepatic Manifestations

      Diagnostic Testing

      Genotype

      Liver Biopsy

      Treatment

      The Role of Pegylated Interferon

      Cost-effectiveness

      Quality of Life

      Alternative Medicines

      Concluding Remarks

      References





      --------------------------------------------------------------------------------


      Introduction
      The elucidation of the hepatitis C genome in 1989 has
      led to the realization that this virus is a major
      health problem worldwide.[1a] Infection with the
      hepatitis C virus (HCV) is one of the most common
      causes of chronic liver disease in the United States
      and HCV-related disease is a leading indication for
      liver transplantation. An estimated 3.9 million
      Americans carry the antibody to HCV, while 2.7 million
      have detectable virus in the blood (ie, active
      infection). This means that about 1% of the United
      States population has hepatitis C.
      In the NHANES (National Health and Nutrition
      Examination Survey) study,[2] it was determined that
      1.5% of whites, 3.2% of blacks, and 2.1% of Hispanics
      are infected with HCV. The prevalence of hepatitis C
      in the Asian-American population is unknown. At the
      time of this study, the greatest prevalence was seen
      in patients aged 20-39 years. Because this study was
      performed about 10 years ago, however, the age of
      these patients has now shifted to the 30- to 49-year
      age range.

      The hepatitis C virus has very little in common with
      the better-known hepatitis viruses -- hepatitis A and
      B. It is a member of the Flaviviridae family, which
      includes such viruses as those that cause yellow fever
      and dengue. The viral particle consists of an envelope
      derived from host membranes, into which are inserted
      the virally encoded glycoproteins E1 and E2,
      surrounding a nucleocapsid and a positive-sense,
      single-stranded RNA genome of approximately 9500
      nucleotides.[3]

      The hepatitis C virus has been classified into 6 major
      genotypes based on phylogenetic analyses. The 6 major
      genotypes are named by number and are as follows:
      1,2,3,4,5, and 6.


      Risk Factors
      Background
      Hepatitis C is transmitted parenterally (see Table 1).
      The most common risk factor for hepatitis C is
      intravenous drug use.[1b] Prior to 1992 -- before the
      introduction of blood donor screening and surrogate
      hepatitis tests -- transfusion of blood or
      plasma-derived products was associated with
      significant risk of transmission of hepatitis C.[4]
      Other potential risk factors for hepatitis C include:
      intranasal cocaine use, tattooing, body piercing,
      accidental needle-stick injury,[5] and the sharing of
      household items, such as nail clippers, razor blades,
      and toothbrushes.

      Table 1. Potential Hepatitis C Risk Factors
      Common Uncommon
      Intravenous drug use Intranasal cocaine
      Blood transfusions prior to 1992 Body piercing
      Accidental needle-stick injury Tattoos
      Sexual transmission Sharing of household items
      Perinatal transmission Fistfights involving blood
      contact
      Kidney dialysis
      Transplant prior to 1992
      Hemophilia

      Case reports have also documented transmission of
      hepatitis C between patients who underwent colonoscopy
      with an inadequately disinfected colonoscope,[6]
      between 2 family members who had engaged in a
      fistfight during which there was blood exposure,[7]
      and during cardiothoracic surgery.[8]


      Needle-stick Injury
      Additionally, accidental needle-stick injury in
      healthcare workers may lead to the transmission of
      virus. The rate of transmission of hepatitis C as a
      result of needle-stick injury is less than that seen
      for hepatitis B, but greater than that which occurs
      with HIV. After a needle-stick injury, there is no
      prophylactic role for gammaglobulin or hepatitis B
      immune globulin in the prevention of HCV infection.
      Unfortunately, watchful waiting is an important
      strategy in determining whether disease will develop.
      If possible, it is appropriate to check the hepatitis
      viral load in the source patient to assess the risk of
      hepatitis C transmission. The risk of hepatitis C
      transmission from a patient without detectable
      hepatitis C RNA is negligible. If, however, the source
      patient is unavailable for testing or tests positive
      for HCV RNA, the needle-stick recipient should then be
      tested periodically for HCV and treated if indeed
      found to be HCV-RNA-positive.

      Sexual Transmission
      Sexual transmission of hepatitis C remains
      controversial and probably accounts for less than 5%
      of cases.[1b] Risk factors for sexual transmission
      include multiple sex partners, prostitute use, rectal
      intercourse, and traumatic sex. Sexual intercourse
      during menstruation or without adequate vaginal
      lubrication may increase the transmission rate.
      Studies in married couples have indicated a greater
      risk of spousal transmission with increasing duration
      of marriage.[9,10] Whether this risk is secondary to
      sexual transmission, the potential role of more
      frequent sharing of household (razors, toothbrushes,
      etc.) items or other factors remains to be determined.


      Perinatal Transmission
      Perinatal transmission of hepatitis C occurs in
      approximately 3% to 5% of infants born to women
      infected with HCV.[11] Perinatal transmission is
      associated with 2 independent risk factors: high viral
      load at time of delivery and having a mother who is
      HIV-positive.
      Italian investigators recently reported the decreased
      risk of perinatal transmission of hepatitis C with
      cesarean section when compared with vaginal
      delivery.[12] The risk of perinatal transmission of
      hepatitis C in a woman who is HIV-positive is
      estimated to be 15% to 35%. Infants born to hepatitis
      C-infected mothers may initially be hepatitis
      C-antibody-positive due to passive transfer of this
      antibody across the placenta. This antibody may be
      present throughout the first year of an uninfected
      newborn's life before disappearing. Therefore, the
      determination of hepatitis C infection in the newborn
      requires the demonstration of a positive HCV RNA in
      the serum. Breastfeeding by mothers with hepatitis C
      appears to be safe, with no reported cases of viral
      transmission to newborns.[13]


      Other Factors
      Other groups at high risk for hepatitis C infection
      include persons who received clotting factor
      concentrates prior to 1987, persons on hemodialysis,
      hemophiliacs, and individuals who received either a
      solid organ or bone marrow transplant prior to
      1992.[1b] Contamination of the ultrafiltrate dialysis
      membrane may help explain the high rate of hepatitis C
      infection seen in dialysis units.[14]

      Natural History of Hepatitis C
      Background
      The precise natural history of hepatitis C remains
      unknown because of the lack of prospective data, the
      inability to determine time of initial onset of
      disease, and the variable influences of multiple
      cofactors leading to disease progression. What has
      been determined, however, is that a subset of
      hepatitis C patients will progress to cirrhosis and
      its associated complications.
      Chronicity is the hallmark of hepatitis C infection.
      Approximately 15% to 30% of patients exposed to HCV
      recover spontaneously, while the remaining 70% to 85%
      develop chronic infection.[15] Most patients with
      chronic hepatitis C infection appear to have mild to
      moderate histologic disease.[16-20] Cirrhosis may
      develop in as many as 15% to 30% of infected patients
      (see Figure 1). Although fulminant disease is rare in
      hepatitis C, its occurrence has been reported.[21]



      Figure 1. Natural history of hepatitis C.

      Several studies have attempted to determine the rate
      of histologic disease progression in
      transfusion-acquired disease.[22-24] Tong and
      colleagues[22] found a mean interval of 20.6 years
      from time of infection to development of cirrhosis,
      and a mean interval of 28.3 years from time of
      diagnosis to development of hepatocellular carcinoma
      (HCC).

      The infusion of hepatitis C-contaminated anti-D immune
      globulin in 1977 and 1978 in Ireland has allowed the
      prospective evaluation of 376 women, 17 years after
      exposure.[25] Most of the hepatitis C-infected women
      had evidence of moderate hepatic inflammation on liver
      biopsy, while 51% had fibrosis, and only 2% had
      cirrhosis. The results of a similar German study of
      152 women infected with hepatitis C-contaminated Rh0
      immune globulin showed no evidence of cirrhosis 15
      years after exposure.[26]

      In a recent study published in the Annals of Internal
      Medicine, Seeff and coworkers[27] conducted a 45-year
      follow-up of hepatitis C infection in healthy young
      adults. In this retrospective study, stored sera from
      8568 US Air Force recruits in Wyoming dating from
      1948-1955 were evaluated for hepatitis C. Ten patients
      were found to be positive for HCV. Based on their
      findings, the study authors concluded that individuals
      with hepatitis C had low liver-related morbidity and
      mortality. However, because of the small sample size,
      these conclusions are suspect.


      Factors Influencing Disease Progression
      Several factors appear to influence the rate of
      progression of hepatitis C to cirrhosis.[28] These
      factors include alcohol use, age at time of exposure,
      sex, and coinfection with either hepatitis B or HIV
      (see Table 2).[29]

      Table 2. Factors Affecting Disease Progression
      Adverse No Effect
      Alcohol use Serum aminotransferase level
      Disease acquisition at age greater than 40 years Viral
      load
      Male sex Genotype
      HBV coinfection Mode of transmission
      HIV coinfection


      Alcohol. Alcohol ingestion and chronic hepatitis C
      infection appear to be synergistic in accelerating the
      progression of liver disease (see Table 3).[30,31] An
      increased risk of cirrhosis and decompensated liver
      disease is associated with sustained alcohol
      consumption of greater than 40 g/day.[28] Other
      effects of concomitant alcohol use in the setting of
      hepatitis C include increased transaminase levels,
      higher hepatitis C viral loads,[30] and increased
      number of hepatitis C quasispecies.[32] These
      elevations have been shown to be significantly reduced
      with a decrease in daily alcohol intake.[31]


      Table 3. Extrahepatic Manifestations of Hepatitis C
      Essential mixed cryoglobulinemia
      Lymphoma
      Glomerulonephritis
      Porphyria cutanea tarda
      Diabetes mellitus
      Corneal ulceration
      Autoimmune phenomena
      Uveitis
      Sialadenitis
      Peripheral neuropathy

      The mechanism by which alcohol effects a more rapid
      progression of disease is not known. The amplification
      of cytokine signals is believed to play a role in this
      process by stimulating stellate cells and increasing
      fibrosis.[33] Alcohol consumption also increases the
      risk of developing HCC.

      Age and gender. Acquisition of hepatitis C after age
      40 is associated with a more rapid disease
      progression. The reasons for this effect are uncertain
      but may be related to an aging immune system. Male sex
      is also associated with more rapid disease progression
      (see Table 2).[28]

      Coinfection. Hepatitis C and HIV coinfection appears
      to lead to rapid progression of liver disease.[29]
      Progression to cirrhosis or liver failure may occur
      within 10-15 years after infection with HCV, and this
      progression occurs at approximately twice the rate as
      what occurs with hepatitis C infection alone.[29]
      Hepatitis C and related liver disease are now the
      leading cause of non-AIDS-associated death in patients
      with HIV.[34]

      Role of other factors. Many factors initially
      considered to be important predictors of disease
      progression appear, in fact, not to have such a
      predictive role. These factors include mode of
      transmission, serum transaminase levels, hepatitis C
      viral loads, and hepatitis C genotype. The authors of
      one paper, however, concluded that
      transfusion-acquired disease was associated with more
      rapid disease progression than was disease acquisition
      due to other risk factors.[35]


      Clinical Presentation
      Most patients with hepatitis C are asymptomatic. But
      if symptoms do occur, the most common complaints are
      fatigue, abdominal pain, poor appetite, weight loss,
      and pruritus. The diagnosis of hepatitis C is made
      following the completion of specific tests requested
      by the clinician. The primary care physician generally
      performs this testing if risk factors are identified
      or abnormal liver chemistries noted. Blood banks and
      life insurance companies routinely test blood donors
      and applicants for hepatitis C. Hepatitis C testing,
      unlike testing for HIV, does not require that consent
      be obtained.
      Hepatitis C can lead to a broad spectrum of liver
      disease. Patients may develop mild disease as
      evidenced by mild inflammation and/or fibrosis. Others
      may develop increasing amounts of inflammation or
      fibrosis, which can lead to the development of
      significant fibrosis or cirrhosis.


      Extrahepatic Manifestations
      In addition to liver disease, hepatitis C is
      associated with a number of extrahepatic effects,
      including hematologic, renal, dermatologic, endocrine,
      and autoimmune disorders (see Table 3).[36-39]

      Hematologic Disorders
      Essential mixed cryoglobulinemia. Essential mixed
      cryoglobulinemia (EMC) is a condition that results in
      the deposition of circulating immune complexes in
      small- to medium-sized blood vessels. Patients with
      EMC usually present with rash, arthralgias, and
      weakness.
      A review of the literature reveals that hepatitis C
      can be found in 95% of all patients with EMC.[40-43]
      Several investigators have suggested that hepatitis C
      may have a causative role in EMC. Anti-HCV antibodies
      can be detected in the vessel walls of skin biopsies
      taken from patients with EMC and chronic vasculitis.
      Interferon therapy has been shown to reduce the
      cryocrit and allow symptomatic improvement of both
      rash and joint pains. The response is short-lived,
      however, because symptoms almost universally reappear
      upon cessation of therapy.[44-48]

      Lymphoma. Several reports have described an increased
      incidence of B-cell lymphoma in patients with
      hepatitis C. Rasul and colleagues[49] studied 16
      patients with chronic hepatitis C and cryoglobulinemia
      for the presence of lymphoma. Results of bone marrow
      biopsy were consistent with non-Hodgkin's lymphoma in
      2 patients and suspicious for lymphoma in 7. While
      this finding needs to be evaluated further in larger
      studies, the development of lymphadenopathy or
      unexplained chronic anemia in a patient with hepatitis
      C infection should raise concern about the possibility
      of underlying lymphoma.


      Renal Disorders
      Glomerulonephritis has been associated with hepatitis
      C.[50,51] These patients are found to have
      proteinuria, which can be significant and in the
      nephrotic range. Most cases of glomerulonephritis are
      associated with cryoglobulinemia. The most common
      histologic lesion seen is membranoproliferative
      glomerulonephritis. Interferon therapy may reduce
      proteinuria, but a sustained response is seldom
      achieved in these patients.[52,53] Ribavirin should be
      avoided in patients with significant renal impairment.
      Some may benefit from the use of plasmapheresis,
      although the relief tends to be short-lived.[54]

      Dermatologic Disorders
      Several dermatologic disorders have been described in
      association with hepatitis C. These include porphyria
      cutanea tarda, lichen planus, and cutaneous
      necrotizing vasculitis.[36]
      Porphyria cutanea tarda. Porphyria cutanea tarda (PCT)
      is the most common form of porphyria. PCT has been
      associated with hepatitis C infection, particularly in
      those patients with significant alcohol use.[38,55,56]
      Hepatitis C may occur in 58% to 71% of all PCT
      patients. This dermatologic disorder tends to present
      at an earlier age in patients with hepatitis C than in
      those PCT patients without hepatitis C. Despite this
      association, the clinical changes seen in the setting
      of PCT do not appear to be a direct consequence of the
      viral infection.

      Lichen planus. This condition has been associated with
      hepatitis C, although hepatitis C has not been shown
      to be the causative agent.[36]

      Cutaneous necrotizing vasculitis. This condition has
      been associated with hepatitis C as well, although
      hepatitis C has not been shown to be the causative
      agent.[36]


      Endocrine Disorders
      Hepatitis C has also been linked to both diabetes
      mellitus and an increased incidence of anti-thyroid
      antibodies.
      Diabetes mellitus. An association between hepatitis C
      and diabetes mellitus has recently been
      demonstrated.[57-59] Mason and colleagues[57]
      retrospectively evaluated 1117 patients with chronic
      hepatitis C and found this infection to be an
      independent predictor of diabetes.

      Additionally, Mehta and associates[58] found that
      among individuals older than 40 years of age, those
      with hepatitis C infection were more than 3 times as
      likely to have type 2 diabetes mellitus than those
      without hepatitis C infection. The prevalence of type
      1 diabetes was not increased. The link between these 2
      disorders must be further investigated in an effort to
      improve available therapies.


      Other Extrahepatic Manifestations
      Finally, hepatitis C has been associated with a number
      of other extrahepatic disorders as well, including
      sialadenitis, uveitis, corneal ulceration,
      polyarteritis nodosa, peripheral neuropathy, and the
      development of autoimmune phenomena.[37,38]

      Diagnostic Testing
      Hepatitis C Antibody Testing
      Two primary forms of testing are available for the
      detection of the anti-hepatitis C antibody (anti-HCV
      Ab): enzyme immunoassays (EIA) and recombinant
      immunoblot assays (RIBA).[60,61] These antibody tests
      are useful screening tools for hepatitis C, but they
      do have limitations.
      Both of these antibody tests will yield a positive
      result for current (active) and resolved disease.
      Antibody testing may not become positive for 3-6
      months after exposure, resulting in a delay in the
      diagnosis of acute disease. Immunosuppressed patients
      -- such as those with renal failure, those infected
      with HIV, or those post-organ transplantation -- may
      not express the hepatitis C antibody yet still may
      have hepatitis C infection. False-positive antibody
      testing may occur in low-risk blood donors.

      EIA. Three generations of EIA antibody testing have
      been developed since 1989. The EIA antibody is the
      main screening test for hepatitis C. The
      first-generation EIA antibody, which incorporated the
      c100-3 epitope from the nonstructural NS4 region, was
      used until 1992, at which time it was replaced by a
      second-generation EIA [EIA-2]. EIA-2 contains
      hepatitis C antigens from the viral core and from
      areas of the nonstructural NS3 and NS4 regions.[62] A
      third-generation EIA that contains reconfigured core
      and NS3 antigens and a newly incorporated antigen from
      the NS5 region was recently approved by the United
      States Food and Drug Administration (FDA) for
      screening blood products and is now in use at some
      institutions for diagnostic purposes (see Figure 2).
      EIA-3, with a sensitivity of 97%, offers slightly
      improved sensitivity over the 95% sensitivity seen
      with EIA-2.[62,63] Most centers in the United States
      use EIA-2 testing.



      Figure 2. Hepatitis C antibody tests categorized by
      antigens detected.

      EIA testing offers several distinct advantages in the
      diagnostic setting because these assays are easy to
      perform, are relatively inexpensive, and have high
      sensitivity. A positive EIA-antibody test requires a
      second confirmatory assay to make the diagnosis of
      hepatitis C. False-positive EIA testing may occur in
      low-risk patients and in patients with underlying
      autoimmune diseases. These patients may benefit from
      RIBA assay testing to differentiate a false-positive
      from a true-positive test.

      RIBA. These tests are supplemental assays to EIA
      testing. Both classes of antibody assays contain the
      same HCV antigens. RIBA testing is currently in its
      third generation of development. RIBA-2 uses the same
      recombinant antigens as EIA-2.

      Results from a RIBA-2 assay may be interpreted as
      positive if 2 or more antigens are positive,
      interpreted as indeterminate if 1 antigen is positive,
      or finally, interpreted as negative if all antigens
      are negative. RIBA testing is not more sensitive than
      EIA testing, but a RIBA-2 test can be used to
      distinguish between a false-positive EIA test and true
      previous exposure to hepatitis C. A third-generation
      RIBA test (RIBA-3) has recently been licensed in the
      United States. This assay incorporates the NS5 antigen
      with the standard antigens used in RIBA-2 (see Figure
      2). This third-generation test produces a reduced
      number of indeterminate results and is more specific
      than the RIBA-2 assay.[60,63]


      Molecular Assays
      The demonstration of hepatitis C viral particles in
      blood confirms the diagnosis of hepatitis C infection
      (see Figure 3). Two principal methods used to detect
      hepatitis C viral RNA are target amplification and
      signal amplification.


      Figure 3. Algorithm for hepatitis C diagnostic
      testing.

      Target amplification assays such as the polymerase
      chain reaction (PCR) rely on sequence-specific primers
      and a heat-stable DNA polymerase to generate a large
      number of copies of a portion of the viral genome.
      Signal amplification, as used in bDNA assays, uses a
      series of hybridization reactions between probes
      specific for several regions of the target molecule
      and subsequent hybridization to a DNA amplifier.[64]

      Viral load may be measured as either a qualitative or
      quantitative function. Qualitative testing is the most
      sensitive and specific and, therefore, the most
      accurate when used for initial diagnosis. Both
      qualitative and quantitative viral load testing have a
      role in the evaluation and treatment of patients with
      hepatitis C. Qualitative testing is important in
      confirming a positive anti-HCV test and in assessing
      sustained response to therapy. Quantitative testing is
      useful in determining diagnosis, predicting response
      to therapy, and monitoring response while on therapy.

      Many different "brands" of quantitative testing are
      available and until recently, results could not be
      compared across assays because of a lack of
      standardization. As of the year 2000, results of all
      quantitative assays are standardized as international
      units per milliliter. Viral load testing is useful in
      evaluating the patient with suspected acute hepatitis
      C infection because these assays should be positive
      within 1-2 weeks of initial exposure. These tests,
      however, do not correlate with disease severity or the
      rate of disease progression.

      Hepatitis C core antigen immunoassays, currently
      undergoing testing, may approach the clinical
      sensitivity of HCV-RNA testing.[65]


      Genotype
      Genetic analysis of HCV reveals the existence of
      numerous viral sequences, termed genotypes. These
      various genotypes differ in genetic composition by as
      much as 35%. Six major genotypes have been identified
      and these can be further subdivided into more than 100
      subtypes.[66,67]
      Genotype distribution is worldwide. However, 1a and 1b
      are the most common types in the United States,
      accounting for more than 75% of all infections.[68]
      Genotype 1b is the most prevalent viral species found
      in Japan. Genotype 3, which is uncommon in the United
      States except in younger intravenous drug users, is,
      however, highly prevalent on the Indian subcontinent.
      Genotype 4 accounts for the majority of HCV infection
      in Egypt and is also seen in other areas of Africa.
      Genotype 5 is common in South Africa and accounts for
      more than 50% of all cases of hepatitis C seen in that
      region. Finally, genotype 6 is found primarily in
      Southeast Asia.[67]

      Hepatitis C genotype does not appear to affect the
      rate of disease progression. Genotype is, however, a
      predictor of response to therapy.[69-71] Patients with
      genotype 2 or 3 are more likely to respond to therapy
      and, based on published data, may be treated with
      combination interferon and ribavirin for a 6-month
      course.[70] By contrast, patients infected with HCV
      genotypes 1 and 4 are less likely to respond to
      therapy and should be treated with combination
      interferon and ribavirin therapy for 1 year.
      Genotyping should be performed in all patients with
      hepatitis C for whom treatment is being considered.
      Obtaining the results of genotype testing can allow a
      more cost-effective approach to therapy.[72]


      Liver Biopsy
      The grading and staging of liver disease in patients
      with hepatitis C is crucial in helping guide
      treatment. Unfortunately, serum aminotransferase
      levels, HCV viral load, and hepatitis C genotype are
      all poor predictors of underlying histology.
      Therefore, despite the cost and discomfort associated
      with liver biopsy, it is recommended that it be
      performed in the initial evaluation of all hepatitis C
      patients, barring obvious contraindications.
      Information obtained from the biopsy can help exclude
      other causes of liver disease, help gauge the rate of
      progression of disease, and aid the treating physician
      in adjusting or terminating therapies if the patient
      is experiencing significant side effects.[20]

      Treatment
      The primary aim of therapy in the patient with
      hepatitis C is to achieve a sustained virologic
      response, which is defined as undetectable HCV RNA 6
      months after termination of antiviral therapy.
      Secondary goals of antiviral therapy include
      improvement in histology and quality of life, and the
      prevention of HCC (see Table 4). Patients with
      persistently abnormal liver enzymes, detectable HCV
      RNA, and an abnormal liver biopsy are candidates for
      antiviral therapy.

      Table 4. Goals of Therapy
      Primary
      Viral eradication
      Secondary
      Slow disease progression
      Improve underlying histology
      Prevent the development of hepatocellular carcinoma
      Improve quality of life after therapy

      Three discrete regimens are licensed in the United
      States for the treatment of chronic hepatitis C. These
      regimens include 3 approved interferons (IFN) --
      IFN-alfa-2a, IFN-alfa-2b, IFN-alfa con (consensus)-1
      -- and combination IFN-alfa-2b plus ribavirin.


      The Naive Patient
      Interferon monotherapy was the first antiviral regimen
      approved for chronic hepatitis C. Sustained response
      rates with IFN monotherapy were similar among the 3
      approved IFNs. Sustained response rates for
      IFN-alfa-2b administered at a dose of 3 million units
      3 times per week for 6 or 12 months were 8 % and 12%,
      respectively.[73] The sustained response rate
      associated with IFN-alfa con-1 given at a dose of 9
      mcg 3 times per week for 6 months was 12.1%.[74]
      Higher doses of IFN monotherapy were associated with
      increased end-of-treatment responses but without any
      improvement in sustained response. Induction trials
      using IFN monotherapy have not shown any increased
      efficacy over standard 3-times weekly dosing.
      Therefore, IFN monotherapy is currently recommended
      only for those patients who do not tolerate
      combination therapy with IFN and ribavirin.
      Patients should be followed on IFN monotherapy, with
      serial testing of alanine aminotransferase and HCV-RNA
      levels. Therapy should be discontinued in those
      patients who fail to demonstrate undetectable viral
      levels at week 12 of treatment.

      Several factors are associated with a favorable
      response to therapy with IFN monotherapy. The most
      important of these factors include the lack of
      cirrhosis on liver biopsy, the presence of either HCV
      genotype 2 or 3, and low HCV-RNA levels
      pretreatment.[73,74]

      Interferon is associated with numerous side effects.
      The most common of these is a flu-like illness that
      occurs in the first 4 weeks of therapy and which
      generally resolves on its own. After the first month
      of therapy, late side effects such as fatigue,
      headache, and neuropsychiatric changes may occur.
      Depression is also a common side effect of IFN, and
      patients with prior history of depression should be
      carefully monitored. Other less common adverse events
      may include hypothyroidism, hyperthyroidism,
      arthralgias, rash, and reversible alopecia.
      Neutropenia, and especially thrombocytopenia, may
      occur in patients on IFN therapy and can be managed
      with dose reduction.

      Combination therapy: the naive patient. Two large,
      randomized controlled trials compared combination
      IFN-alfa-2b plus ribavirin with IFN-alfa-2b
      monotherapy, given for 24 or 48 weeks to previously
      untreated hepatitis C patients (see Figure 4).[69,70]
      Individuals treated with the combination regimen had
      sustained virologic responses at 24 and 48 weeks of
      33% and 41%, respectively. This outcome compared
      favorably with the 6% and 16% sustained response rates
      achieved with 24 and 48 weeks, respectively, of IFN
      monotherapy.



      Figure 4. Sustained virologic response in US
      Combination Therapy Trial.[69]
      ETR = end-of-treatment response; SVR = sustained
      virologic response

      Careful analysis of these trials revealed the
      importance of genotype in both predicting response to
      therapy and determining duration of therapy. Genotype
      1 patients treated with combination therapy had
      sustained response rates at 24 and 48 weeks of 17% and
      29%, respectively. Genotype 2 and 3 patients had
      sustained response rates at 24 and 48 weeks of 66% and
      65%, respectively. Based on these data, it seems
      reasonable to treat genotype 2 and 3 patients for a
      total of 24 weeks. The presence of bridging fibrosis
      or cirrhosis resulted in reduced response rates in
      patients treated with combination therapy for 6
      months, but not in those treated with combination
      therapy for 12 months. Genotype 1 patients with high
      viral loads were the least likely to respond to
      combination therapy.

      The sustained response to 24 weeks of therapy with
      combination IFN and ribavirin vs IFN monotherapy was
      evaluated in 112 noncirrhotic hepatitis C patients
      infected with genotype 4. The sustained response rate
      in the combination-therapy group was 42% compared with
      only 8% in the monotherapy group.[75]

      Although the prevalence of the hepatitis C antibody is
      2-3 times greater among blacks than whites in the
      United States,[1b] blacks have been underrepresented
      in the many large published hepatitis C treatment
      trials.[76] In these trials, blacks are reported to
      have a lower response rate than whites to IFN
      monotherapy. Of the 1744 patients enrolled in the 2
      large, multicenter trials evaluating IFN plus
      ribavirin for the treatment of previously untreated
      hepatitis C patients, 53 were classified as
      black.[69,70]Among these 53 patients, 96% were
      genotype 1. The sustained response of these patients
      to 24 and 48 weeks of combination therapy were 20% and
      23%, respectively.[77] None of the black patients
      treated with IFN monotherapy had a sustained response.


      Five independent factors have been identified as
      predictors of sustained response in patients treated
      with combination therapy. These factors are genotype 2
      or 3, baseline viral load < 3.5 million copies/mL,
      minimal fibrosis, female sex, and age < 40 years.[78]
      Early loss of HCV RNA while on therapy may also be
      predictive of a sustained response.[79]

      Common side effects of ribavirin include anemia,
      depression, fatigue, irritability, rash, cough,
      shortness of breath, and insomnia. The anemia is the
      result of a dose-dependent hemolysis of red blood
      cells and occurs in nearly 100% of patients, with
      patients frequently showing a drop of 2-3 g from
      baseline hemoglobin. Therefore, ribavirin must be used
      with caution in patients with pre-existing anemia,
      diabetes, or coronary artery disease. Also important
      to note is that ribavirin is teratogenic, so patients
      and their sexual partners must be carefully counseled
      prior to initiation of therapy.


      Treatment of the Relapse Patient
      Relapse is defined as the reappearance of serum HCV
      RNA in a patient who had previously undetectable
      levels at the end of antiviral therapy. Occurrence of
      relapse following IFN monotherapy is more common than
      following combination IFN and ribavirin therapy.
      While re-treatment of IFN-monotherapy relapse patients
      with a repeat course of similar therapy is
      ineffective,[80] treatment with higher doses may
      improve sustained response rates.[81] A large,
      multicenter trial evaluated the use of high-dose
      consensus IFN (IFN-alfa con-1) in patients who had
      relapse following a 24-week course of standard dose
      IFN-alfa-2b or IFN-alfa con-1.[81] Subjects were
      randomized to receive 15 mcg of IFN-alfa con-1 for
      either 24 or 48 weeks. The sustained viral response
      was 28% at 24 weeks and 58% at 48 weeks. Re-treatment
      at this higher dose was not associated with more
      significant side effects than treatment with the
      standard IFN regimen. Factors predictive of a
      sustained virologic response in this trial included
      low initial viral load, HCV genotype 2 or 3, and the
      absence of cirrhosis.

      A second large study evaluated the use of combination
      IFN and ribavirin therapy in IFN monotherapy relapse
      patients.[82] Patients were treated for a total of 6
      months and randomized to receive standard-dose
      IFN-alfa-2b with or without ribavirin. A sustained
      virologic response was seen in 49% of patients treated
      with combination therapy and in only 8% of those
      treated with IFN monotherapy. Genotype other than type
      1 and low pretreatment HCV-RNA levels were positive
      predictive factors of a sustained response in this
      trial. Twelve percent of subjects treated with
      ribavirin required a dose reduction or interruption
      secondary to anemia, whereas only 3% of those
      receiving IFN monotherapy required dose reduction.

      As previously indicated, patients who relapse
      following IFN monotherapy may be effectively
      re-treated with either higher-dose IFN monotherapy or
      with combination IFN and ribavirin. But the increasing
      problem facing physicians today is how to approach the
      patient who relapses following combination therapy. At
      present, there are no large published studies to help
      answer this question. Several studies are ongoing with
      either pegylated interferon (peginterferon) alfa-2a or
      peginterferon alfa-2b in patients who relapsed
      following treatment with combination therapy of IFN
      plus ribavirin.


      Treatment of the Nonresponder
      Nonresponse to antiviral therapy is defined as the
      persistence of detectable HCV RNA throughout therapy,
      with detectable serum HCV RNA at the end of the
      therapeutic course. The sustained response to
      re-treatment of nonresponders to any form of antiviral
      therapy has been disappointing.
      Re-treatment of nonresponders to IFN monotherapy was
      evaluated in several small studies. In the consensus
      interferon trial, nonresponders to IFN monotherapy
      showed a 13% sustained virologic response rate at 48
      weeks of therapy with IFN-alfa con-1.[81] The use of
      combination IFN and ribavirin therapy in IFN
      nonresponders has resulted in sustained response rates
      ranging from 0% to 15%.[83-85] Of interest, a recent
      trial reported a 42% sustained response to intravenous
      recombinant IFN-beta in previous IFN
      nonresponders.[86]

      Approximately 60% of all patients treated with
      combination IFN and ribavirin are nonresponders. The
      approach to this group represents a growing challenge
      to the treating clinician. Although it seems
      reasonable that higher doses of IFN plus ribavirin or
      a weight-based system of ribavirin dosing should
      improve response to treatment in these patients,[87]
      there are little if any published data to support such
      an approach. The peginterferons may, however, prove
      useful in combination with IFN and ribavirin, and
      clinical trials designed to test this notion are
      currently ongoing.

      Virologic nonresponders to antiviral therapy may
      derive some benefit from re-treatment that is aimed at
      preventing histologic disease progression. Patients
      with underlying bridging fibrosis or cirrhosis are at
      a greater risk for developing complications of
      cirrhosis than are those without fibrosis. In addition
      to its antiviral effect, IFN was shown to have
      antiproliferative and antifibrotic activity through
      its downregulation of transforming growth factor
      b.[88,89] Recent studies showed improvement in
      underlying histology in nonresponders to antiviral
      therapy.[90,91] Several studies have also demonstrated
      a significant reduction in the relative risk of
      developing HCC among nonresponders to IFN
      monotherapy.[92-94]

      These studies have brought the issue of IFN
      maintenance therapy for prevention of fibrotic
      progression to the fore. Shiffman and colleagues[95]
      reported that a 2-year course of IFN monotherapy
      administered to nonresponders stabilized fibrosis and
      improved inflammation on serial biopsies. This concept
      has now led to the launch of a National Institutes of
      Health-sponsored trial -- the Hepatitis C Antiviral
      Long-term Treatment Against Cirrhosis or HALT-C trial
      -- to evaluate the effect of long-term
      peginterferon-alfa-2a therapy in patients with
      advanced fibrosis or cirrhosis who did not respond to
      combination pegylated IFN plus ribavirin.


      Treatment of the Post- Liver Transplant Patient
      Hepatitis C is the leading indication for liver
      transplantation in the United States. In patients who
      undergo liver transplantation secondary to hepatitis
      C, the reappearance of HCV RNA posttransplantation is
      an almost universal occurrence.[96]
      The natural history of posttransplantation hepatitis C
      appears to be rapid, with as many as 20% of recipients
      developing cirrhosis within 5 years of
      transplantation.[97] Studies with IFN monotherapy in
      this setting have reported biochemical responses in up
      to 25% of patients, but virologic response is
      rare.[98] One study reported a sustained response rate
      of 24% with a 6-month course of combination IFN and
      ribavirin.[99] After loss of HCV RNA with combination
      therapy, ribavirin monotherapy has been used as
      maintenance therapy.[100] Although combination therapy
      has not been associated with rejection, significant
      anemia secondary to hemolysis is common. Larger trials
      are needed to better address the issue of recurrence
      of hepatitis C after transplantation.


      The Role of Pegylated Interferon
      Rationale
      Pegylated IFNs are currently under investigation, and
      at this time are not approved for the treatment of
      hepatitis C in the United States. The concept behind
      the pegylation of IFN is to produce a molecule that
      can maintain longer-lasting therapeutic concentrations
      by optimizing both the absorption and distribution
      while decreasing the rate of clearance and reducing
      proteolysis at the same time. This is accomplished by
      the addition of a polyethylene glycol molecule (PEG)
      to standard IFN by means of a covalent bond. This PEG
      molecule is a nontoxic polymer that is readily
      excreted in the urine and this moiety may be either
      linear or branched. Larger PEG molecules lead to a
      greater reduction in renal clearance and provide
      greater subcutaneous absorption. Pegylated IFN is
      metabolized primarily in the liver,[101] and its
      excretion is not affected by renal abnormalities.[102]

      Clinical Trials
      Two pegylated formulations of IFN are currently under
      investigation in the United States: a linear 12-kD
      peginterferon-alfa-2b (PegIntron) and a branched chain
      40-kD peginterferon-alfa-2a (Pegasys).
      A double-blind, randomized, controlled trial was
      presented at the 2000 meeting of the European
      Association for the Study of the Liver that compared 3
      regimens of peginterferon-alfa-2b (0.5, 1.0, and 1.5
      mcg/kg per week) with standard IFN-alfa-2b 3 MU given
      3 times weekly in previously untreated patients with
      hepatitis C. The sustained response rates for patients
      who received 0.5, 1.0, and 1.5 mcg/kg of the pegylated
      IFN were 18%, 25%, and 23%, respectively, compared
      with a 12% sustained response rate found in patients
      who received the conventional IFN. The overall
      genotype 1 response rate was 14% in both the 1.0- and
      1.5-mcg/kg groups (see Figure 5).[103]



      Figure 5. End-of-treatment viral response, sustained
      viral response, and genotype response with
      PegIntron.[103]

      EOT = end-of-treatment response; SVR = sustained
      virologic response

      Zeuzem and colleagues[104] reported the results of a
      trial comparing once-weekly peginterferon-alfa-2a at a
      dose of 180 mcg with standard-dose interferon-alfa-2a
      3 times weekly for 48 weeks in previously untreated
      patients with hepatitis C. All patients were assessed
      at week 72 for a sustained virologic response. These
      investigators obtained a sustained response rate of
      39% for the pegylated-IFN group compared with a 19%
      response rate for the standard-IFN group. A sustained
      response rate of 28% was seen in patients infected
      with HCV genotype 1 who received peginterferon-alfa-2a
      (see Figure 6). The frequency and severity of adverse
      events were similar in both treatment groups.
      Pretreatment factors associated with a sustained
      response, in order of significance, included genotype
      other than type 1, alanine aminotransferase quotient >
      3, HCV RNA level < 2 million copies by the Cobas
      Amplicor HCV PCR (version 2.0 ; Hoffmann-LaRoche,
      Basel, Switzerland), body surface area < 2 M2, lack of
      bridging fibrosis or cirrhosis, and age < 40 years.



      Figure 6. End-of-treatment viral response, sustained
      viral response, and genotype response with
      Pegasys.[104]
      EOT = end-of-treatment response; SVR = sustained
      virologic response

      In the largest trial of cirrhotic hepatitis C patients
      receiving IFN therapy performed to date, Heathcote and
      colleagues[105] reported on the use of pegylated
      IFN-alfa-2a in the treatment of patients with bridging
      fibrosis or cirrhosis (see Figure 7). Patients were
      randomized to receive IFN-alfa-2a 3 MU 3 times per
      week, 90 mcg of peginterferon-alfa-2a weekly, or 180
      mcg of peginterferon-alfa-2a weekly, for a total of 48
      weeks, and were followed up for 24 weeks. In an
      intention-to-treat analysis, a sustained response
      (response at week 72) was seen in 8%, 15%, and 30% of
      patients treated with standard IFN-alfa-2a, 90 mcg of
      peginterferon-alfa-2a, and 180 mcg of
      peginterferon-alfa-2a, respectively. The difference in
      rate of response between the standard-IFN and
      180-mcg-peginterferon groups was statistically
      significant. The sustained response of patients
      infected with genotype 1 and non-1 who were treated
      with the higher dose of peginterferon was 13% and 51%,
      respectively.



      Figure 7. End-of-treatment virologic response and
      sustained viral response in pegylated IFN alfa-2a
      Cirrhotic Trial.[105 ]

      A previous small dose-finding study by Glue and
      coworkers[106] showed that peginterferon-alfa-2b and
      ribavirin were safe when used in combination. The
      results of a larger trial using combination
      peginterferon-alfa-2b plus ribavirin in previously
      untreated patients with hepatitis C were reported in
      October 2000 at the annual meeting of the American
      Association for the Study of Liver Diseases (AASLD) in
      Dallas, Texas. Results showed that the overall
      sustained response of patients to
      peginterferon-alfa-2b given at 1.5 mcg/kg per week,
      plus ribavirin 1000-1200 mg/day, was 54%. The response
      rates of patients with genotype 1 and non-1 to this
      regimen were 42% and 82%, respectively.[87]

      The FDA approved pegylated IFN-alfa 2b monotherapy in
      January 2001. The use of combination pegylated IFN
      plus ribavirin is still under investigation, with
      several large trials currently underway to determine
      the effectiveness of this new regimen.


      Cost-effectiveness
      Screening
      Mass screening for hepatitis C by means of hepatitis C
      antibody testing does not appear to be a
      cost-effective strategy. However, an abstract
      presented at the AASLD meeting in October reported
      that alanine aminotransferase screening for chronic
      hepatitis C is cost-effective in individuals between
      15 and 58 years of age (ie, across broad age groups).
      Improvements in cost efficiency may be obtained
      through identification of risk factors for HCV prior
      to screening.[107]

      Treatment
      Several models have been developed in an effort to
      estimate the cost-effectiveness of both IFN
      monotherapy and combination IFN/ribavirin therapy for
      the treatment of patients with hepatitis
      C.[72,108,109] Bennett and associates[108] reported
      that when using a 5% discount rate, the marginal
      cost-effectiveness ratio of 6 months of IFN
      monotherapy in previously untreated patients with mild
      histologic disease was well within the range of other
      well-accepted medical interventions. Kim and
      colleagues,[109] using a 3% discount rate, estimated
      the marginal cost-effectiveness ratio for 6 months of
      IFN monotherapy to be $4000 per quality-adjusted life
      year gained, and $5000 per quality-adjusted life year
      gained for 12 months of IFN monotherapy. Both of these
      figures are within the range of acceptability to our
      society, and therefore, therapy is considered
      cost-effective. This study also found that IFN
      monotherapy was not cost-effective in patients older
      than age 60.
      Combination therapy with IFN and ribavirin is
      significantly more expensive than IFN monotherapy.
      Wong and colleagues[72] evaluated the
      cost-effectiveness of combination therapy vs IFN
      monotherapy for a treatment duration of 24 and 48
      weeks. Both the 24- and 48-week IFN-plus-ribavirin
      regimens were more cost-effective than 48 weeks of IFN
      monotherapy. Combination therapy for a duration of 24
      weeks was found to be more cost-effective in patients
      with genotype 2 and 3 disease. In all other evaluated
      parameters, including viral load and underlying
      histology, combination therapy for a 48-week duration
      was more cost-effective than the 24-week regimen.[72]

      The advent of pegylated IFN has raised questions about
      its relative cost-effectiveness. This concept is
      difficult to analyze at present, because pegylated IFN
      has only just been approved for use in the United
      States, and therefore, its pricing is unknown.
      However, assuming that pegylated IFNs significantly
      improve sustained response rates, cost-effectiveness
      can be estimated in the absence of pricing. Based on
      this assumption, Wong estimated that if
      peginterferon-alfa-2b increases the sustained response
      rate by 10% to 30% and increases relative costs by 10%
      to 30%, a 48-week course should both prolong life and
      be cost-effective.[110]


      Liver Biopsy
      One of the dilemmas facing clinicians is whether to
      treat a patient who has hepatitis C and mild disease
      on liver biopsy. Wong and colleagues[111] evaluated
      this scenario from the perspective of
      cost-effectiveness. In a mathematical model, they
      compared the cost of immediate combination IFN and
      ribavirin therapy vs watchful waiting for patients
      with histologically mild disease. While this model
      suggested that periodic biopsies would avoid
      institution of therapy in many patients, immediate
      treatment of these patients was found to be
      cost-effective by eradicating virus and thereby
      potentially preventing disease progression.

      Quality of Life
      The affect of hepatitis C on the quality of life is
      beginning to emerge as an important parameter in the
      evaluation of infected patients. Physicians have the
      perception that patients with hepatitis C are largely
      asymptomatic, and that having the disease seldom has
      an impact on patients' lives. However, studies with
      large numbers of patients are showing that hepatitis C
      does indeed negatively affect quality of
      life.[112-114]
      Until recently, quality-of-life instruments were not
      validated for use in patients with chronic hepatitis
      C. Several instruments -- such as the hepatitis
      quality-of-life questionnaire (HQLQ) and the
      short-form 36 (SF-36) -- have now been validated for
      use in this setting (see Figure 8). The SF-36 is a
      simple questionnaire that includes 36 questions that
      evaluate 8 domains of general well-being. Higher SF-36
      scores represent better quality of life.



      Figure 8. Domains represented by Short Form-36.[113]

      Foster and colleagues[113] evaluated quality of life
      in noncirrhotic patients prior to initiation of
      treatment. In all 8 domains of the SF-36, hepatitis C
      patients reported a significantly lower quality of
      life than did controls. The subgroup of patients with
      hepatitis C who had used intravenous drugs in the past
      showed the greatest impairment in quality-of-life
      scores. The amount of inflammation on liver biopsy was
      not associated with the degree of impairment of
      quality of life.

      Bonkovsky and coworkers[114] confirmed in a study of
      642 patients that individuals with hepatitis C report
      lower quality-of-life scores than do healthy controls.
      Additionally, findings showed that patients who had a
      sustained response to IFN monotherapy experienced
      significant improvements in perceived wellness and
      functional status, which then translated into
      significant improvements in quality of life. Ware and
      colleagues[115] used the HQLQ to evaluate changes in
      quality of life in IFN monotherapy relapse patients
      treated with combination IFN and ribavirin therapy. A
      sustained virologic response was associated with
      improvements in vitality, social functioning, and
      health distress.

      Antiviral therapies are associated with a decline in
      quality of life during therapy.[116] This decline
      returns to baseline with cessation of therapy.[115]
      This trend was recently demonstrated to be similar for
      newer agents as well, such as
      peginterferon-alfa-2a.[117]

      Hepatitis C patients have lower quality-of-life scores
      than the general population, and the evaluation of
      quality of life thus takes on greater importance in
      the care of hepatitis C patients. Abnormalities in
      quality of life are not entirely attributable to
      histologic disease severity. Newer therapies, such as
      the pegylated IFNs, may help improve quality of life
      both during and after therapy.


      Alternative Medicines
      The rate of complementary medicine use by hepatitis C
      patients dissatisfied with conventional medications is
      estimated to be as high as 60%.[118] Various types of
      agents and approaches are used in this setting,
      including milk thistle, vitamin therapies, Chinese
      herbal therapies, acupuncture, and
      lifestyle-modification techniques. Despite the
      widespread use of these modalities, few -- if any --
      well-designed clinical trials evaluating the efficacy
      of these therapies in hepatitis C have been published.

      Silymarin or milk thistle is the most common
      alternative medication used by patients with
      hepatitis. Silymarin, which exhibits certain
      antioxidant properties and may function as a
      free-radical scavenger, has been used to treat all
      forms of liver disease for more than 2000 years. It
      appears to be safe for use in this setting.[119] The
      effects of this agent on HCV, however, have never been
      formally evaluated in controlled trials. Recently,
      results of a controlled trial showed no benefit of
      silymarin use in patients with primary biliary
      cirrhosis.[120]

      The widespread use of these products does present some
      serious health risks. Many patients who take
      alternative therapies either do not seek, or delay the
      use of, conventional therapies, which may have been
      effective. In addition, many alternative therapies are
      associated with significant liver toxicity. Common
      examples of hepatotoxic agents include chaparral leaf,
      valerian, skullcap, mistletoe, germander, Jin Bu Huan,
      and pyrrolizidine alkaloids.[121] These products are
      available over the counter. Therefore, alternative
      medicines should be used with caution.

      The increasing use of alternative medicines in
      hepatology has been fueled by patient dissatisfaction
      with conventional therapies. Physicians must keep an
      open mind and familiarize themselves with the
      purported efficacy and potential toxicities of
      alternative medications in order to provide effective
      counsel to their patients. Patients must inform their
      physicians of all their medications, alternative or
      conventional. Together, patients, pharmacists, and
      physicians must ensure that hepatotoxic agents are not
      ingested.


      Concluding Remarks
      Progress in the knowledge of the natural history and
      treatment of hepatitis C has expanded tremendously
      since the discovery of the hepatitis C antibody in
      1989. This viral disease is transmitted primarily in a
      parenteral manner, with previous recreational drug use
      and previous blood or blood product transfusion being
      the greatest risk factors. Diagnosis of hepatitis C is
      made by the detection of viral particles in the blood,
      and liver biopsy is essential to determine the extent
      of damage caused by this virus. Current therapies are
      based upon dual treatment with IFN and ribavirin.
      Recently, a new long-acting pegylated IFN has been
      approved for use as monotherapy in the United States,
      and any new agents are under development for the
      treatment of hepatitis C. The next decade hopefully
      will bring even greater advances in our knowledge of
      this common liver disease.

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