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Hepatitis C Virus Infection: An Update

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  • claudine intexas
    American Association for the Study of Liver Diseases 52nd Annual Meeting [Medscape, 2001. © 2001 Medscape, Inc.] Hepatitis C Virus Infection: An Update David
    Message 1 of 1 , Dec 8, 2001
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      American Association for the Study of Liver Diseases
      52nd Annual Meeting
      [Medscape, 2001. � 2001 Medscape, Inc.]

      Hepatitis C Virus Infection: An Update

      David Bernstein, MD
      Introduction
      Hepatitis C virus (HCV) infection continues to be a
      major focus of interest for researchers, as evidenced
      by sessions presented during the 52nd Annual Meeting
      of the American Association for the Study of Liver
      Diseases. Since the identification of the first
      antibody to HCV in 1989, significant progress has been
      made in our understanding of the natural history and
      treatment of this common infection.
      This review highlights some of the important new
      information regarding hepatitis C that was presented
      during this meeting, with a view toward implications
      for clinical practice.

      Interferon Therapy
      Acute Hepatitis C
      Although chronic hepatitis C is common, acute
      hepatitis C is uncommon in clinical practice. Due to
      the lack of large, well-controlled studies, the
      natural history and treatment of acute disease remains
      unclear.
      Gerlach and colleagues[1] reported on 56 patients with
      acute hepatitis C. The majority of these patients had
      some constitutional complaints, whereas 9 of 56 were
      completely asymptomatic. Twenty-four percent developed
      jaundice; 6 patients received immediate antiviral
      therapy and were not included in the analysis. Of the
      remaining 50 patients, 23 were HCV RNA-negative at the
      end of follow-up vs 27 who were HCV RNA-positive.
      Female sex, the development of jaundice, and
      constitutional symptoms were strong predictors of
      spontaneous viral clearance. The majority of patients
      (86%) who spontaneously cleared virus did so by week
      12 postexposure. Therefore, antiviral therapy was
      initiated at week 12. Twenty-four patients were
      started on therapy at week 12. As of the time of this
      presentation, there have been 15 sustained responders,
      1 relapser, and 3 nonresponders. Five patients remain
      in follow-up.

      This study is helpful in guiding development of a
      strategy for the treatment of acute hepatitis C.
      According to these findings, many symptomatic patients
      may spontaneously clear virus by week 12. Therefore,
      it seems reasonable to delay treatment in the
      symptomatic patient until the determination of a
      12-week serum HCV RNA. If this study is positive, an
      antiviral regimen should be initiated. In the case of
      asymptomatic acute hepatitis C, treatment should start
      as soon as the disease is identified.

      Durability of Response
      One of the most important questions asked by hepatitis
      C patients and treating physicians alike concerns the
      durability of the sustained viral response. By
      convention, the medical community has defined a
      sustained viral response to interferon or combination
      interferon plus ribavirin therapy as a negative serum
      HCV RNA 6 months after stopping antiviral therapy.
      What is the likelihood of the recurrence of viremia in
      patients who achieved a sustained viral response,
      according to the definition indicated above? John
      McHutchison, MD, from the Scripps Clinic in La Jolla,
      California, reported on the 4-year follow-up of
      patients treated in several crucial trials of both
      previously untreated hepatitis C patients or naive
      patients and patients who relapsed following cessation
      of interferon alfa-2b monotherapy.[2]

      In these trials, 455 patients treated with interferon
      alfa-2b plus ribavirin and 103 patients treated with
      interferon alfa-2b monotherapy were sustained
      responders. Three hundred twenty-two sustained viral
      responders to combination therapy and 73 sustained
      viral responders to interferon monotherapy
      participated in the follow-up. Of the group that
      responded to combination therapy, 112 were naive
      patients treated for 24 weeks, 151 were naive patients
      treated for 48 weeks, and 59 were relapse patients
      treated for 24 weeks. Of the group that responded to
      monotherapy, 4 were naive patients treated for 24
      weeks, 61 were naive patients treated for 48 weeks,
      and 8 were relapse patients treated for 24 weeks.

      Overall, 10 patients had a virologic relapse during
      the follow-up phase. Seven of these relapse patients
      had received combination therapy, whereas 3 had
      received interferon monotherapy. All patients relapsed
      within 2 years of stopping therapy. There has been no
      further recurrence of viremia in the last 2 years of
      follow-up. The overall likelihood of achieving a viral
      response 4 years after stopping therapy was reported
      by treatment group and is as follows: (1) previously
      untreated patients given interferon monotherapy for 24
      weeks, 75% � 22%; (2) previously untreated patients
      given combination therapy for 24 weeks, 97% � 1.6%;
      (3) previously untreated patients given combination
      therapy for 48 weeks, 99%� 1%; and (4) relapse
      patients given combination therapy for 24 weeks, 96% �
      2.9%.

      Based on these data, it appears that late relapse
      following a sustained viral response to either
      interferon alfa-2b monotherapy or in combination with
      ribavirin is uncommon, and the responses seen are
      highly durable over a 4-year period. However, the use
      of the term "cure" after a sustained viral response
      may be premature, as evidenced by the single sustained
      responder with cirrhosis who developed hepatocellular
      carcinoma in the follow-up period.

      Effects on Natural History
      Hepatitis C infection is known to progress to
      cirrhosis and its complications. The development of
      advanced disease is associated with an increased
      mortality rate when compared with the general
      population. Several studies have shown that interferon
      therapy may reduce the risk of developing
      hepatocellular carcinoma.
      Imai and colleagues[3] studied the effect of
      interferon therapy on the development of
      hepatocellular carcinoma and mortality in 3296
      patients with chronic hepatitis C. These investigators
      found that sustained and transient viral responders to
      interferon therapy had a significantly lower risk of
      developing hepatocellular carcinoma than did untreated
      patients. Nonresponders to interferon therapy
      developed hepatocellular carcinoma at a rate similar
      to untreated patients. Overall, survival rates were
      better in the interferon-treated group than in the
      untreated group, especially in those patients
      achieving either a sustained or transient viral
      response. Age at time of diagnosis, male sex, and
      higher histologic stage (P = .0001) were independent
      risk factors for cirrhosis and death.

      Pegylated interferon. Pegylated interferon in
      combination with ribavirin has become the new regimen
      of choice for treatment of hepatitis C. Studies with
      both pegylated interferon alfa-2a and pegylated
      interferon alfa-2b have shown improved efficacy over
      standard interferon alfa-2b plus ribavirin in
      eradicating virus.

      In a study reported by Poynard and colleagues,[4] the
      effect of pegylated interferon alfa-2b plus ribavirin
      on underlying hepatitis fibrosis was examined. This
      study involved 3010 patients with pre- and
      posttreatment liver biopsies who underwent antiviral
      therapy with interferon alfa-2b monotherapy,
      interferon alfa-2b plus ribavirin, or pegylated
      interferon alfa-2b plus ribavirin. Necrosis and
      inflammatory scores improved in 73% of patients
      receiving pegylated interferon plus ribavirin and in
      39% receiving standard interferon therapy. All
      regimens significantly reduced fibrosis progression
      rates in comparison to rates before treatment. This
      effect is likely related to the antifibrotic
      properties of interferon.

      Interesting to note is that these study authors
      reported on the reversal of cirrhosis in 75 of the 153
      patients with cirrhosis at baseline entry into the
      study. The well-known high rate of sampling error with
      percutaneous liver biopsy may play a role in these
      findings. The results of this study are very
      encouraging, and additional investigations need to
      corroborate these important histologic findings.

      Naive Patients
      As a group, hemophilia patients are known to have one
      of the highest prevalence rates of chronic hepatitis C
      infection. Despite this fact, few studies have
      evaluated the treatment of patients with inherited
      coagulation disorders with antiviral therapy, and all
      of the major registration trials have excluded
      patients with hemophilia.
      Michael Fried, MD,[5] from the University of North
      Carolina, presented data on use of thrice-weekly
      interferon alfa-2b plus ribavirin in 113 patients with
      inherited coagulation defects and HCV infection.

      In this study, 93% of patients had either hemophilia A
      or B. The mean age was 28 years; 67% of subjects had
      genotype 1. Patients were randomized to receive either
      interferon alfa-2b (n = 57) or combination interferon
      alfa-2b plus ribavirin (n = 56). Subjects were treated
      for 1 year, with a 24-week follow-up period. Liver
      biopsies were not routinely performed. The sustained
      viral responses in the groups receiving combination
      therapy vs monotherapy were 29% and 7%, respectively.
      Among patients younger than 18 years of age treated
      with combination therapy, the sustained viral response
      was 59%. The sustained viral response of adult
      patients was 15%. Overall, 19% of patients in this
      study had to have treatment prematurely discontinued.
      Ten patients had therapy stopped secondary to adverse
      events.

      Although overall response rates to combination therapy
      were lower than those seen in the general hepatitis C
      population, the findings in this high-risk group are
      encouraging. The lack of baseline liver histology, the
      high degree of dose reduction, and the high rate of
      early treatment discontinuation may have contributed
      to the lower than expected sustained response rate in
      this intention-to-treat analysis.

      Relapsers and Nonresponders
      Relapsers and nonresponders to conventional antiviral
      therapy pose a difficult clinical challenge for
      practitioners and patients with hepatitis C infection.
      With the availability of pegylated interferon alone
      and in combination with other antiviral agents, many
      investigators have shown interest in the use of these
      drugs for this difficult-to-treat patient group.
      Afdhal and colleagues[6] reported on the use of
      once-weekly 40-kilodalton pegylated interferon alfa-2a
      in combination with ribavirin, mycophenolate mofetil,
      and amantadine, for the treatment of patients who
      either relapsed or did not respond to standard
      thrice-weekly combination interferon alfa-2b plus
      ribavirin therapy.

      One hundred twenty relapse and 120 nonresponder
      patients were included in the study. End-of-treatment
      (48 weeks) viral response data were reported for all
      groups. The 48-week viral response data in the relapse
      patient groups were as follows: (1) pegylated
      interferon alfa-2a plus ribavirin, 61%; (2) pegylated
      interferon alfa-2a plus mycophenolate mofetil, 72%;
      (3)pegylated interferon alfa-2a plus amantadine, 42%;
      and (4) pegylated interferon alfa-2a plus amantadine
      plus ribavirin, 71%. The 48-week viral response data
      in the nonresponder patient groups were as follows:
      (1) pegylated interferon alfa-2a plus ribavirin, 25%;
      (2) pegylated interferon alfa-2a plus mycophenolate
      mofetil, 28%; (3) pegylated interferon alfa-2a plus
      amantadine, 11%; and (4) pegylated interferon alfa-2a
      plus amantadine plus ribavirin, 40%. No significant
      adverse events have been noted.

      This preliminary report is encouraging but cannot be
      fully analyzed until all patients have completed a
      follow-up phase and until sustained viral response
      numbers are available.

      Pediatric Patients
      Despite numerous studies on interferon and ribavirin
      use in adults, few large investigations employing this
      combination are available in children.
      Kelly and colleagues[7] presented data on the
      treatment of 61 children with a mean age of 11 years.
      The sustained viral response with interferon alfa-2b
      thrice weekly plus ribavirin 8 mg/kg/day, 12
      mg/kg/day, and 15 mg/kg/day were 33%, 35%, and 45%,
      respectively. Children were able to tolerate the
      hemolytic and neutropenic effects of combination
      therapy better than described in adult populations.
      Efficacies of these regimens are similar to those seen
      in adults.

      African Americans
      The sustained viral response of African Americans to
      standard interferon plus ribavirin combination therapy
      has been disappointing and poorly characterized.
      Jeffers and associates[8] reported on the use of
      pegylated interferon alfa-2a plus ribavirin in
      previously untreated African Americans with chronic
      hepatitis C and HCV genotype 1 infection. All patients
      participating in this study are scheduled to be
      treated with pegylated interferon alfa-2a plus
      ribavirin for 48 weeks. The study authors reported on
      preliminary 24-week data.

      African American and white patients underwent a
      virologic assessment of response at week 24.
      Seventy-three percent of whites and 56.9% of African
      Americans had a 2-log drop in HCV RNA level. Loss of
      viremia at week 24 was seen in 65.2% of whites and 49%
      of African Americans. Late virologic clearance was
      more common in African Americans.

      These preliminary findings support the continued study
      of pegylated interferon alfa-2a plus ribavirin in
      African American patients infected with HCV genotype
      1.

      Maintenance Therapy
      The hepatitis C antiviral long-term treatment against
      cirrhosis (HALT-C) trial was designed and sponsored by
      the National Institutes of Health to determine if
      long-term interferon therapy could prevent the
      progression of baseline histology, reduce the
      development of hepatocellular carcinoma, and prevent
      the need for liver transplantation in patients with
      chronic hepatitis C and cirrhosis.[9]
      Patients enrolled in this trial had to have a positive
      serum HCV RNA, baseline liver biopsy showing advanced
      fibrosis or cirrhosis, and previous nonresponse to
      interferon monotherapy or combination
      interferon-plus-ribavirin therapy. All patients
      enrolled in the study were treated with 24 weeks of
      pegylated interferon alfa-2a 180 mcg/week plus
      ribavirin 1000 or 1200 mg per day, depending on body
      weight. Patients found to have a negative HCV RNA at
      20 weeks continued therapy for a total of 48 weeks.
      Patients found to be serum HCV RNA-positive at 20
      weeks were eligible to enter the HALT-C trial.

      Upon entering the HALT-C trial, patients were
      randomized to either pegylated interferon alfa-2a or
      placebo for a 4-year treatment course. Liver biopsies
      are scheduled to be performed every 2 years during
      this ongoing trial. Adrian Di Bisceglie, MD, presented
      preliminary data from this study. To date, 268
      patients have completed 20 weeks of therapy -- 88% of
      these are white, 84% are HCV genotype 1, and 41% had
      underlying cirrhosis at baseline. At week 20, 15
      patients had therapy discontinued due to adverse
      events. Of the remaining 253 patients, 107 (42%) had
      undetectable virus. Fifty-three percent of patients
      who received prior interferon monotherapy and 31% of
      those who previously received combination interferon
      and ribavirin therapy were HCV-negative at week 20.
      Ten percent of blacks were virus-negative at week 20.

      Virologic response was influenced by genotype, with
      HCV genotypes 2 and 3 patients having a significantly
      greater viral response rate. Body mass index did not
      appear to influence response. The sustained viral
      response rates and the results of the remainder of the
      HALT-C trial remain to be determined.

      Quality of Life
      Quality-of-life analysis has emerged as an important
      component in our evaluation of hepatitis C infection
      and its treatments. The overall quality of life of
      hepatitis C patients has been reported to be lower
      than that of the general population. Hepatitis C
      therapy has also been shown to lower the quality of
      life while the patient is on therapy and, therefore,
      limits patient adherence to these therapies. Sustained
      viral response to antiviral therapy improves quality
      of life following therapy. Thus, the evaluation of
      quality of life on antiviral therapy has assumed a
      more important role because adherence to therapy has
      been positively correlated with sustained viral
      response.
      Hassanein and colleagues[10] reported on the quality
      of life in patients treated with combination pegylated
      interferon alfa-2a plus ribavirin, pegylated
      interferon alfa-2a monotherapy, and standard
      interferon alfa-2b plus ribavirin. The instruments
      used to assess quality of life were the Short Form-36
      and the fatigue severity scale. During the 48 weeks of
      therapy, patients receiving pegylated interferon
      alfa-2a plus ribavirin reported better quality of life
      and less fatigue than those receiving interferon
      alfa-2b plus ribavirin. The most significant
      differences seen were better vitality scores, less
      body pain, improved social functioning, and less
      fatigue with pegylated interferon alfa-2a plus
      ribavirin. At the end of follow-up, those patients who
      achieved a sustained viral response reported
      significant improvements in quality of life and
      fatigue scores, regardless of the therapy received.
      The greatest improvements in quality of life were
      reported in the role-physical, role-emotional, general
      health, and vitality scores.

      This study emphasizes the importance of quality of
      life on therapy as it relates to adherence and
      improved sustained viral response. Because adherence
      is associated with an improved viral response, the
      quality of life on therapy has assumed greater
      importance in the physician's choice of therapies.
      Those therapies with less of a side-effect profile may
      aid in achieving a better compliance rate and
      therefore improve sustained viral response rates by
      allowing patients to take the prescribed dosages of
      antiviral therapy for the prescribed period of time.

      Alternative Agents
      The results of trials using several new agents for the
      treatment of chronic hepatitis C infection were
      presented during this meeting as well.

      ISIS 14803
      ISIS 14803 is an antisense oligodeoxynucleotide that
      inhibits HCV RNA and protein expression in cell
      culture and mouse models.
      McHutchison and coworkers[11] reported on the use of
      this agent in a small number of patients who were
      nonresponsive to combination interferon and ribavirin
      therapy. This pilot trial of 11 patients found that
      use of this novel compound at a dose of 2 mg/kg
      resulted in less than a 2-log drop in viral levels in
      2 patients. The antiviral activity was dose-dependent
      and did not result in loss of viremia in any patient.
      Additional studies are planned with this compound.

      Histamine Dihydrochloride
      Lurie and colleagues[12] reported on the utility of
      combination histamine dihydrochloride and interferon
      alfa-2b in previously untreated patients with chronic
      hepatitis C infection.
      One hundred twenty-nine patients were entered into the
      study and 108 were available at the end of follow-up
      for evaluation. The overall sustained response rate
      for the combination of these 2 agents was 40%. The HCV
      genotype 1 response was 38% and the nongenotype 1
      response was 45%. Patients with a high viral load had
      a sustained viral response of 29%, whereas those with
      low viral load had responses of 54%.

      The addition of histamine dihydrochloride to standard
      interferon therapy appears to improve the sustained
      viral response of standard interferon alfa-2b
      monotherapy. These sustained viral response rates,
      however, are all lower than that seen with combination
      pegylated interferon plus ribavirin.

      Interleukin-12
      Pockros and colleagues[13] reported on the use of
      recombinant human interleukin-12 in a population of
      patients previously unresponsive to antiviral therapy.
      Approximately 1% of patients showed a sustained
      virologic response, whereas 3% developed severe
      adverse events, resulting in early termination of the
      trial.

      Conclusion
      Discussion of hepatitis C and its treatment comprised
      a significant portion of these meeting proceedings.
      Important data were addressed regarding the treatment
      of special patient groups, such as children, blacks,
      and hemophiliacs. Many of the papers presented
      concerned the use of pegylated interferon plus
      ribavirin for the treatment of previously untreated
      hepatitis C patients as well as patients unresponsive
      to previous antiviral regimens. Several new agents for
      the treatment of hepatitis C were also discussed,
      although based on reported data, none appears to
      suggest immediately that it would have greater
      efficacy than current therapies.
      Perhaps the most important points made during this
      meeting concerned the high durability of a sustained
      viral response given its current definition, as well
      as the increased importance that quality-of-life
      assessments play in the ongoing evaluation of
      patients. As we move into the 21st century, we are
      realizing yet again that patient concerns and
      well-being are first and foremost on the agenda of
      physicians treating for hepatitis C.

      References
      1. Gerlach TJ, Zachoval R, Gruener N, et al. Acute
      hepatitis C: natural course and response to anti-viral
      treatment. Hepatology. 2001;341A. [Abstract 676]
      2. McHutchison J, Davis G, Esteban-Mur R, et al.
      Durability of sustained virological responses in
      patients with chronic hepatitis C after treatment with
      interferon alfa-2b alone or on combination with
      ribavirin. Hepatology. 2001;34:244A. [Abstract 281]
      3. Imai Y, Kasahara A, Okanoue T, et al. Effect of
      interferon therapy on the risk of hepatocellular
      carcinoma and mortality in patients with chronic
      hepatitis C: a large retrospective cohort study of
      3296 patients. Hepatology. 2001;34:216A. [Abstract
      171]
      4. Poynard T, McHutchison J, Manns M, et al. Impact of
      pegylated interferon alfa-2b and ribavirin on the
      progression of liver fibrosis in patients with chronic
      hepatitis C. Hepatology. 2001;34:244A. [Abstract 282]
      5. Fried M, Peter J, Hoots K, et al. Hepatitis C in
      adults and adolescents with inherited coagulation
      disorders in the United States: results of a
      randomized, multi-center trial of combination therapy.
      Hepatology. 2001;34:243A. [Abstract 278]
      6. Afdhal N, Flamm S, Imperial J, et al. Analysis of
      40 KDA peginterferon alfa-2a (Pegasys[R]) in
      combination with ribavirin, mycophenolate mofetil,
      amantadine or amantadine plus ribavirin in patients
      that did not respond to Rebetron[tm] therapy: a report
      of two randomized, multicenter, efficacy and safety
      trials. Hepatology. 2001;34:243A. [Abstract 277]
      7. Kelly DA, Bunn SK, Apelian D, et al. Safety,
      efficacy and pharmacokinetics of interferon alfa-2b
      plus ribavirin in children with chronic hepatitis C.
      Hepatology. 2001; 342A. [Abstract 680]
      8. Jeffers LJ, Cassidy W, Howell C, et al. 40 KDA
      Peginterferon alfa-2a in combination with ribavirin in
      African American and Caucasian patients with HCV
      genotype 1: a preliminary report of a comparative,
      multicenter, efficacy and safety study. Hepatology.
      2001;326A. [Abstract 617]
      9. Shiffman ML, HALT-C Trial Investigators.
      Retreatment of interferon and interferon-ribavirin
      non-responders with peginterferon-alfa 2a and
      ribavirin: initial results from the lead in phase of
      the HALT-C trial. Hepatology. 2001;34:243A. [Abstract
      279]
      10. Hassanein TI, Cooksley G, Sulkowski M, et al.
      Treatment with 40 KDA Peg-interferon (Pegasys[R]) in
      combination with ribavirin significantly enhances
      quality of life compared with interferon alfa-2b plus
      ribavirin. Hepatology. 2001;34: 243A.[Abstract 280]
      11. McHutchison JG, Pockros P, Nyberg L, et al. A dose
      escalation study of ISIS 14803, an anti-sense
      inhibitor of HCV, in chronic hepatitis C patients.
      Hepatology. 2001;350A. [Abstract 712]
      12. Lurie Y, Pakula R, Malnick S, et al. Efficacy and
      safety of the combination of histamine dihydrochloride
      and interferon alfa-2b in a phase 2 trial in naive
      patients with chronic hepatitis C. Hepatology.
      2001;350A. [Abstract 713]
      13. Pockros PJ, McHutchison JG, O'Brien C, et al. A
      phase 2 randomize, double blind, placebo controlled,
      multicenter trial of recombinant human interleukin-12
      for the treatment of chronic hepatitis C virus
      infection in patients non-responsive to previous
      treatment with or without ribavirin. Hepatology.
      2001;350A. [Abstract 714]


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