Loading ...
Sorry, an error occurred while loading the content.


Expand Messages
  • 2byteme@bellsouth.net
    Fulminant Liver Failure From Acute HCV Superinfection in a Patient With HIV, HBV, and HDV Coinfections Kristin Lee, MD; Paul T. Smith, MD [The AIDS Reader
    Message 1 of 106 , Sep 2, 2000
    • 0 Attachment
      Fulminant Liver Failure From Acute
      HCV Superinfection in a Patient With
      HIV, HBV, and HDV Coinfections

      Kristin Lee, MD; Paul T. Smith, MD

      [The AIDS Reader 10(7):398-401, 2000. © 2000 Cliggott
      Publishing Co., Division of SCP/Cliggott Communications, Inc.]

      The primary causes of liver disease in injection drug users are
      acute and chronic viral infections. Because of shared routes of
      transmission, infections with HIV, hepatitis B virus (HBV),
      hepatitis C virus (HCV), and hepatitis delta virus (HDV) often
      coexist. Furthermore, evidence indicates that the courses of
      HBV, HCV, and HDV infections are modified by coinfection
      with HIV. Increased rates of HBV replication are seen in
      HIV-coinfected patients, while preliminary data suggest that
      HCV and HDV are characterized by prolonged viremia in
      HIV-infected patients.[1] However, to date, there is little
      information regarding the clinical implications of such "quadruple"
      infections in patients.

      One study from Barcelona, by Buti and Rosendo,[2] followed 86
      patients with chronic HBV and HDV coinfection during a period
      of 6.5 years in order to assess the natural course of HDV
      coinfection and to determine the impact of subsequent
      coinfection with HIV and/or HCV on disease progression. Of
      the 28 patients who died during follow-up, 18 were injection
      drug users infected with HBV, HCV, HDV, and HIV. The
      authors concluded that chronic HDV infection can be an
      especially severe form of hepatitis among injection drug users
      also coinfected with HCV and HIV. Several reports of acute
      HCV superinfection in HIV-negative, asymptomatic hepatitis B
      surface antigen (HbsAg)-positive carriers with HDV antibodies
      show much more severe liver decompensation than occurs in
      those without HDV markers.[3,4] It is not clear whether such
      observations can be extrapolated to HIV-infected individuals.
      We describe a case of acute HCV infection in an HIV-infected
      patient with a known history of chronic HBV infection.

      The patient, a 36-year-old, Hispanic, HIV-positive male,
      presented with a 1-month history of intermittent abdominal
      cramping, nausea, vomiting, and watery diarrhea. A recent
      workup for diarrhea, which included stool studies for bacteria,
      ova and parasites, Cryptosporidium, Microsporidia, and
      Cyclospora, was unrevealing. He was referred to his primary
      care doctor by his drug treatment program for evaluation of 1
      day of lethargy and jaundice. His primary care physician found
      him to be ill-appearing, orthostatic, and icteric. He was admitted
      for intravenous hydration and further evaluation.

      The patient's medical history was significant for HIV infection
      since 1987 and for HBV infection since 1990. His risk factors
      for both infections were unprotected intercourse with both men
      and women as well as a history of intravenous drug use. The
      patient had not received antiretroviral therapy during the previous
      10 months because of ongoing illicit drug use, but he had had an
      excellent earlier response to HAART. One month before
      admission, his CD4[+] cell count was 518/µL, and his HIV RNA
      was 49,657 copies/mL. He had previous exposure to hepatitis A
      virus (HAV), as evidenced by a positive IgG HAV antibody. His
      HBV infection had been stable during the previous 3 years, with
      chronic, mildly elevated liver transaminase levels (aspartate
      aminotransferase [AST], 64 U/L; alanine aminotransferase
      [ALT], 68 U/L) 3 weeks before admission. His baseline HBV
      serology revealed a positive HbsAg, a positive hepatitis B core
      IgG antibody (HbcAb), a positive hepatitis Be antigen (HbeAg),
      and a nonreactive hepatitis Be antibody (HbeAb) with a negative
      IgM HbcAb. A previous baseline HCV antibody test was

      Medications on admission included methadone, olanzapine,
      trazodone, paroxetine, and megestrol acetate. His social history
      was notable for long-standing intranasal cocaine/crack abuse
      despite involvement in both a day treatment and a methadone
      maintenance program. Of note is the fact that on admission, the
      patient did acknowledge intravenous drug use during the
      preceding few months, in which he shared "dirty" needles. He
      had previously remained "clean" with regard to intravenous drugs
      for several years.

      The remainder of the physical examination was significant for
      scleral icterus; a soft, nontender abdomen with mild
      hepatosplenomegaly; and mild asterixis. Although he was
      lethargic, he was fully oriented. Admission laboratory values
      revealed markedly elevated liver function tests (AST, 1992 U/L;
      ALT, 1841 U/L; total bilirubin, 5.5 mg/dL; direct bilirubin, 3.9
      mg/dL; alkaline phosphatase, 143 U/L; albumin, 2.2 g/dL),
      elevated coagulation parameters (prothrombin time, 19.1
      seconds; international normalized ratio, 2.6); normal electrolytes
      and renal function; a complete blood cell count notable for a
      platelet count of 86,000/µL; an elevated serum ammonia level of
      154 mg/dL; and undetectable serum acetaminophen and
      salicylate levels. At this time, the initial diagnosis was acute
      chronic hepatitis of unclear origin. Further evaluation included
      abdominal ultrasonography, which revealed a normal liver and a
      distended gallbladder, and an abdominal CT scan, which
      revealed moderate ascites and fatty infiltration of the liver but no
      focal hepatic lesions. Repeated hepatitis serology tests confirmed
      baseline patterns for HAV and HBV. A repeated HCV antibody
      test was negative.

      Despite aggressive supportive care, the patient's clinical status
      rapidly deteriorated, characterized by progressive hepatic
      encephalopathy. Liver enzyme levels peaked on hospital day 4
      (AST, 3728 U/L; ALT, 2773 U/L; total bilirubin, 13.7 mg/dL;
      direct bilirubin, 9.1 mg/dL; alkaline phosphatase, 145 U/L;
      albumin, 1.8 g/dL), as did the prothrombin time at 32.9 seconds.
      Cultures of blood, ascitic fluid, and urine remained negative. The
      patient became unresponsive and died 8 days following
      admission. Subsequent to his death as a result of fulminant
      hepatic failure, a serum HCV RNA polymerase chain reaction
      (PCR) on day 2 of hospitalization revealed more than 1,000,000
      copies/mL of virus, confirming the diagnosis of acute HCV
      infection on chronic HBV infection. A second HCV antibody
      test on hospital day 5 was reactive. In addition, a total antibody
      test for HDV on day 2 of hospitalization was reactive. Hence,
      this patient died of acute fulminant hepatic failure secondary to
      acute superinfection with HCV in the setting of coinfection with
      HBV and HDV. The family refused permission for autopsy.

      To our knowledge, this is the first reported case of acute HCV
      superinfection in a patient coinfected with HIV, HBV, and HDV
      resulting in fulminant liver failure and death. The documented
      seroconversion from negative to positive HCV antibody and the
      positive PCR (which illustrated HCV RNA viremia) established
      the diagnosis of acute HCV infection as a cause of his hepatic
      decompensation and death. Based on this patient's clinical
      course, an acute HDV superinfection is also plausible. Given the
      stability of his chronic HBV infection during the previous several
      years, coupled with only a recent relapse of intravenous drug use
      -- a known risk factor for HDV acquisition -- it is possible that
      his rapid decompensation resulted from acute infections with
      both HDV and HCV. In addition, the fact that the patient's IgM
      HbcAb remained negative is consistent with a possible acute
      HDV superinfection, reflecting suppression of HBV replication
      by HDV.[5]

      The diagnosis of acute HDV infection is generally problematic
      outside of a research laboratory. In fact, for several reasons, we
      were unable to determine serologically the timing of HDV
      infection in this patient. The large reference laboratory that
      performed the HDV total antibody test for this patient was
      unable to distinguish IgM from IgG HDV antibody. In addition,
      laboratory personnel were not able to quantitate the level of
      antibody, which, when elevated, may be suggestive of chronic,
      ongoing viral replication.

      Given the common route of transmission of these viruses, the
      likelihood of multiple infections within a single host is not
      improbable. The current standard of care in persons infected
      with HIV includes screening for hepatitis B and C viruses,
      followed by vaccination against HBV in seronegative patients
      and counseling for risk reduction.[6] Given the few reports of
      more rapid liver decompensation and increased morbidity and
      mortality in patients "quadruply" infected with HIV, HBV, HCV,
      and HDV, perhaps screening for HDV should be adopted in this
      high-risk group. In addition, patients infected with multiple
      hepatotropic viruses likely warrant earlier, more aggressive
      diagnostic and treatment approaches. Finally, at this time,
      morbidity associated with acute HCV infection can only be
      ameliorated by preventive risk-reduction methods and by
      ongoing efforts at HCV vaccine development.


      1.Horvath J, Raffanti SP. Clinical aspects of the interactions
      between human immunodeficiency virus and the
      hepatotropic viruses. Clin Infect Dis. 1994;18:339-347.
      2.Buti M, Rosendo J. Chronic delta hepatitis: is the
      prognosis worse when associated with hepatitis C virus
      and human immunodeficiency virus infections? J Med
      Virol. 1996;49:66-69.
      3.Chu CM, Yeh CT, Liaw YF. Fulminant hepatic failure in
      acute hepatitis C: increased risk in chronic carriers of
      hepatitis B virus. Gut. 1999;45:613-617.
      4.Liaw YF. Role of hepatitis C in dual and triple hepatitis
      virus infection. Hepatology. 1997;22:1101-1108.
      5.Shaw-Stiffel T. Chronic hepatitis. In: Mandell GL, Bennett
      JE, Dolin R, eds. Principles and Practice of Infectious
      Diseases. 5th ed. Philadelphia: Churchill Livingstone;
      6.1999 USPHS/IDSA Guidelines for the prevention of
      opportunistic infections in persons infected with human
      immunodeficiency virus. MMWR. 1999;48:32-34.

      Dr Lee is an infectious diseases fellow, and Dr Smith is an
      instructor in medicine in the department of medicine, division of
      international medicine and infectious diseases, Weill Medical
      College of Cornell University, New York.
    • 2byteme@bellsouth.net
      Hepatology Focus Update on Hepatitis C Treatment Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA School of Medicine, Los Angeles,
      Message 106 of 106 , Feb 25, 2001
      • 0 Attachment
        Hepatology Focus
        Update on Hepatitis C Treatment

        Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA
        School of
        Medicine, Los Angeles, California

        Sammy Saab, MD, Clinical Instructor, UCLA School of Medicine, Los
        Angeles, California, and
        Paul Martin, MD, Medical Director, Liver Transplantation, Cedars-Sinai
        Medical Center,
        Associate Professor of Medicine, UCLA School of Medicine, Los Angeles,

        [Medscape Gastroenterology 3(1), 2001. © 2001 Medscape, Inc.]


        Although screening of blood products and other interventions such as
        clean-needle exchange
        programs have significantly reduced the incidence of acute hepatitis C
        in the United States and
        elsewhere, there remains a large reservoir of chronically infected
        individuals, many of whom are
        unaware of their infection. Current estimates suggest a seroprevalence
        of 1.8% among Americans,
        most of whom are viremic.[1] The clinical burden of chronic hepatitis C
        virus (HCV) infection is
        expected to increase over the next 2-3 decades as a large cohort of
        patients infected between the
        1960s and 1980s, primarily as a result of recreational drug use,
        develops progressive liver disease.
        Between 8000 and 10,000 deaths each year in the United States are
        believed to be caused by
        infection with HCV -- which is now the most frequent indication for
        liver transplantation.[2]

        Even before identification of HCV, interferon-alfa (IFN-alfa) had been
        evaluated as a potential
        therapy for what had been called chronic non-A, non-B hepatitis.[3]

        Further studies using normalization of serum alanine aminotransferase
        (ALT) levels and
        improvement in liver histology as endpoints demonstrated the efficacy of
        IFN-alfa as therapy for
        the causative agent of chronic non-A, non-B hepatitis (HCV).[4,5]
        Subsequent advances in
        molecular diagnosis have now increasingly allowed establishment of
        virologic criteria to evaluate
        efficacy of treatment in patients with chronic hepatitis C (see Table).

        Definition of Virologic Response in Patients Receiving Therapy for
        Chronic Hepatitis C

        End-of-treatment response (ETR) refers to absence of viremia (ie, serum
        HCV RNA below level
        of detection) at completion of therapy. Sustained response (SR)
        indicates persistent absence of
        serum HCV RNA 6 months or more after cessation of therapy. A study by
        Marcellin and
        coworkers[6] on the long-term clinical outcome in 80 patients with
        chronic HCV followed for a
        mean of 4 years following therapy highlighted the clinical implications
        of a virologic SR. Persistent
        absence of HCV RNA from serum was observed in 96% of patients with a
        lack of histologic
        progression on serial liver biopsy. In addition, ALT levels were
        persistently normal in over 90%.
        The most recent follow-up biopsy showed normal or near normal histologic
        findings in 62% of
        these patients. Thus, virologic SR was shown to be associated with both
        an absence of detectable
        serum HCV RNA and marked histologic improvement.

        Relapsers are defined as patients who have undetectable serum HCV RNA at
        completion of
        therapy but who subsequently redevelop viremia. Nonresponders (NRs) are
        patients who fail to
        clear HCV RNA from serum during therapy.

        A recent paper by Everson and associates[7] underscores the importance
        of HCV RNA testing in
        defining treatment response. In patients with marked fibrosis and
        cirrhosis, they found a major
        discrepancy between biochemical (ALT) and virologic (HCV RNA) responses
        to therapy. Two of
        7 (29%) patients with marked fibrosis and 2 of 6 (33%) patients with
        cirrhosis cleared HCV RNA
        without normalizing ALT. In contrast, only 3 patients (10%) without
        significant fibrosis had an
        HCV RNA response without normalization of ALT. Thus, clinical trials for
        chronic HCV are now
        typically reported using virologic response rates.

        What then are the current goals of antiviral therapy in patients with
        chronic hepatitis C? Immediate
        goals are eradication of viral replication and improvement in hepatic
        inflammation and fibrosis.
        Long-term potential goals include prevention of cirrhosis,
        hepatocellular carcinoma, and liver

        Interferon Monotherapy

        IFN-alfa 2 was the first agent approved for the treatment of chronic
        HCV. Since the initial trials
        establishing its efficacy, data regarding treatment duration and dose
        have evolved. Currently, 2
        forms of IFN-alfa that differ by a single amino acid residue are
        approved for treatment of chronic
        HCV infection: IFN-alfa 2b (Schering-Plough, Kenilworth, New Jersey) and
        IFN-alfa 2a
        (Hoffmann-La Roche, Basel, Switzerland). The recommended dose is 3
        million units 3 times each
        week for up to 12 months.

        When used alone in monotherapy, the alfa interferons have similar
        efficacies, with SRs of only 10%
        to 20%, with the modestly higher response rates associated with more
        prolonged therapy.
        Higher-dose IFN-alfa (ie, > 9 million units per week) results in SRs
        between 8% and 20% in
        treatment-naive patients. High-dose IFN-alfa has also been studied in
        NRs and relapsers, but with
        mixed results. With prior NR, SRs achieved with higher doses are only
        between 0% and 4%. In
        relapsers, SRs range from 20% to 40%. However, side effects are more
        troublesome with higher

        Because of the low overall response rate to standard IFN-alfa, more
        recent studies have focused
        on newer regimens, including synthetic IFN (IFN alfacon-1),
        "combination" therapy (IFN-alfa 2b
        + ribavirin), and longer-acting IFNs (pegylated IFNs). A number of major
        pretherapy predictors
        of NR have been identified, notably HCV genotype 1, the presence of
        cirrhosis, and higher viral
        load.[9] In addition, patient's race appears to affect response to IFN,
        with African Americans
        having an overall low SR to therapy.[10]

        Combination Therapy

        A significant improvement in SR resulted from the addition of ribavirin
        to standard IFN-alfa.
        Ribavirin, a guanosine analogue, was initially evaluated as monotherapy
        for chronic HCV because
        of its antiviral activity against other RNA viruses.[11-13] Although as
        monotherapy it reduces ALT
        levels, it does not appear to have a direct antiviral effect and fails
        to lower serum HCV RNA
        levels. Moreover, results of most studies with ribavirin have found no
        improvement in hepatic
        histology, although a longer 2-year treatment regimen was shown to
        reduce necroinflammatory

        However, in combination with IFN-alfa 2b, ribavirin leads to a
        significant increase in SR in
        treatment-naive patients.[14] SRs of 31% with 24 weeks and 38% with 48
        weeks of combination
        therapy were achieved vs 6% with 24 weeks and 13% with 48 weeks of IFN
        monotherapy.[14] In
        relapsers, enhanced SR rates also occur on retreatment using combination
        therapy, from 30% to
        49%; in prior NRs, SR of 14% has been reported with 6 months of
        combination therapy.[15,16]

        Histologic improvement was more common among treatment-naive patients
        treated with
        combination therapy.[14] Similar improvement was found in a randomized
        controlled trial of
        treatment-relapse patients.[15]

        However, the improved SR rates observed with combination therapy are
        also associated with
        more expense and an increased frequency of adverse effects compared with
        monotherapy.[14] Dose-related hemolytic anemia is a particular concern
        with ribavirin[11,13] as is
        teratogenicity, based on animal studies.[16] The mean drop in hemoglobin
        in patients treated with
        combination therapy is between 2 and 3 g/dL, although a fall of more
        than 4 g/dL has been
        observed in about 10% of patients. The anemia may be poorly tolerated in
        patients with ischemic
        heart disease in particular as treatment is extended to older
        patients.[17] Accumulation of ribavirin
        metabolites that are not cleared by dialysis occurs in end-stage renal

        Consensus Interferon

        Consensus IFN (CIFN; IFN alfacon-1, Amgen, Thousand Oaks, California) is
        a genetically
        engineered compound synthesized by combining the most common amino acid
        sequences from
        naturally occurring IFNs.[19,20] CIFN shares 88% homology with IFN-alfa
        and 30% with
        IFN-beta. Although it has greater cytokine induction, antiviral,
        antiproliferative, natural killer cell,
        and gene-induction activities than both IFN-alfa 2a and IFN-alfa 2b on
        an equal mass basis, initial
        studies with the recommended CIFN dose of 9 mcg in IFN-naive patients
        with chronic hepatitis C
        resulted in viral response rates similar to those achieved with standard
        IFN-alfa monotherapy.[19,20]

        More recently, higher-dosage CIFN regimens of 15 mcg thrice weekly were
        reported to result in
        virologic SRs of 13% in prior NRs and 58% in relapsers treated for 48

        Pegylated Interferon

        Pharmacokinetic studies have provided a rationale for enhanced IFN
        dosing. The initial decline in
        serum HCV RNA levels seen after a single dose of IFN therapy is believed
        to reflect a direct
        antiviral effect, whereas the subsequent and more delayed decline in HCV
        RNA levels is due to
        destruction of infected hepatocytes.[22] An important limitation of the
        antiviral effect of standard
        IFN dosing is the rapid decline in circulating drug level with
        thrice-weekly administration. The short
        half-life of the drug and the rapid production of HCV virions diminish
        the efficacy of standard IFN
        therapy. In an effort to achieve more stable and efficacious IFN
        activity, pegylated formulations
        have been developed.

        The production of a pegylated IFN involves the addition of a nontoxic
        long-acting formulation of
        interferon using the drug delivery system of pegylation. Polyethylene
        glycol molecules are added to
        IFN-alfa 2a (Pegasys, Hoffmann-La Roche) and IFN-alfa 2b (PEG-Intron,
        Pegylation is already used in the delivery of other drugs. Its
        attachment to IFN-alfa permits
        once-weekly dosing.

        In a recent report, Zeuzem and colleagues[23] indicate that at week 72,
        the SR was 39% after 48
        weeks of therapy at a dose of 180 mcg with pegylated IFN alfa-2a
        compared with a 19% SR in
        control patients. Drug discontinuation in these treatment-naive patients
        and frequency of dose
        reduction were similar in the 2 treatment arms. Heathcote and
        colleagues[24] have also reported on
        the use of pegylated IFN alfa-2a in a controlled trial in cirrhotic
        patients. SR was 30% following 48
        weeks of therapy with 180 mcg, compared with 8% for patients treated
        with standard alfa IFN,
        again without a significant increase in side effects with the pegylated

        Trepo and colleagues[25] have also reported, in abstract form, initial
        studies with pegylated IFN-alfa
        2b. Virologic SR for the unmodified IFN-alfa 2b (3 million units, thrice
        weekly for 48 weeks) was
        12%, whereas the SR for the pegylated IFN-alfa 2b was 18%, 25%, and 23%
        with 0.5 mcg/kg,
        1.0 mcg/kg, and 1.5 mcg/kg, respectively, administered weekly in
        treatment-naive patients.

        As with standard IFN-alfa monotherapy, ribavirin may augment response
        rates when combined
        with the pegylated IFNs.[26,27] Recent trials will help evaluate further
        the role of ribavirin in
        augmenting the efficacy of pegylated IFN (see Figure).

        Figure. Initial antiviral therapy against hepatitis C virus.*
        * Abbreviations: IFN = interferon; CSN = consensus interferon;
        IFN/RIB =
        interferon + ribavirin; PEG = pegylated interferon; PEG/RIB =
        pegylated interferon +

        Future Trends

        There has been continued interest in developing non-IFN-based therapies
        for HCV despite the
        promise of the pegylated IFNs. A recent study examined the role of human
        interleukin-10 in
        treating prior NRs with chronic HCV.[28] Although, HCV RNA remained
        detectable in all patients
        at the end of treatment,[25] 5 (23%) of the 22 treated patients had
        persistent ALT normalization at
        the end of follow-up. Future studies should determine whether combining
        interleukin-10 with other
        antiviral agents will increase efficacy in this setting. Interleukin-12
        has also been evaluated as
        monotherapy, again without clear antiviral benefit.[29]

        There is also increasing enthusiasm for targeting HCV molecular
        products. For example, ribozyme
        gene therapy has the potential to accurately degrade HCV RNA.[30] Human
        studies are anticipated.


        Treatment options for HCV infection continue to expand. Whereas SRs of
        10% were achieved
        with IFN monotherapy only several years ago, it may soon be possible to
        achieve SR rates greater
        than 50% with combination pegylated IFN and ribavirin. Molecular-based,
        specific therapeutic
        strategies are also likely to become a reality in the future, although
        therapy will remain
        interferon-based the next several years.

        Table. Response (HCV RNA/ALT*) to Antiviral Therapy

        Type of Response†
        End of
        6 Months After


        * HCV RNA measured by polymerase chain reaction; ALT = alanine
        aminotransferase; HCV = hepatitis C virus.
        † Positive denotes HCV RNA present in the serum by polymerase chain
        reaction and
        abnormal alanine aminotransferase values. Negative denotes no serum
        HCV RNA by
        polymerase chain reaction and normal alanine aminotransferase


        1.Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of
        hepatitis C virus
        infection in the United States, 1988 through 1994. N Engl J Med.
        2.Centers for Disease Control and Prevention Web site. Available at
        Accessed February 1, 2000.
        3.Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic
        non-A, non-B hepatitis
        with recombinant human alpha interferon. A preliminary report. N
        Engl J Med.
        4.Di Bisceglie AM, Martin P, Kassianides C, et al. Recombinant
        interferon alfa therapy for
        chronic hepatitis C. A randomized, double-blind, placebo-controlled
        trial. N Engl J Med.
        5.Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic
        hepatitis C with recombinant
        interferon alfa. A multicenter randomized, controlled trial.
        Hepatitis Interventional Therapy
        Group. N Engl J Med. 1989;321:1501-1506.
        6.Marcellin P, Boyer N, Gervais A, et al. Long-term histologic
        improvement and loss of
        detectable intrahepatic HCV RNA in patients with chronic hepatitis
        C and sustained
        response to interferon-alpha therapy. Ann Intern Med.
        7.Everson GT, Jensen DM, Craig JR, et al. Efficacy of interferon
        treatment for patients with
        chronic hepatitis C: comparison of response in cirrhotics,
        fibrotics, or nonfibrotics.
        Hepatology. 1999;30:271-276.
        8.Iino S. High dose interferon treatment in chronic hepatitis C. Gut.
        9.Davis GL, Lau JY. Factors predictive of a beneficial response to
        therapy of hepatitis C.
        Hepatology. 1997;26:122S-127S.
        10.Reddy KR, Hoofnagle JH, Tong MJ, et al. Racial differences in
        responses to therapy with
        interferon in chronic hepatitis C. Consensus Interferon Study
        Group. Hepatology.
        11.Dusheiko G, Main J, Thomas H, et al. Ribavirin treatment for
        patients with chronic hepatitis
        C: results of a placebo-controlled study. J Hepatol.
        12.Bodenheimer HC Jr, Lindsay KL, Davis GL, et al. Tolerance and
        efficacy of oral ribavirin
        treatment of chronic hepatitis C: a multicenter trial. Hepatology.
        13.Di Bisceglie AM, Conjeevaram HS, Fried MW, et al. Ribavirin as
        therapy for chronic
        hepatitis C. A randomized, double-blind, placebo-controlled trial.
        Ann Intern Med.
        14.McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b
        alone or in combination
        with ribavirin as initial treatment for chronic hepatitis C.
        Hepatitis Interventional Therapy
        Group. N Engl J Med. 1998;339:1485-1492.
        15.Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone
        or in combination with
        ribavirin for the treatment of relapse of chronic hepatitis C.
        International Hepatitis
        Interventional Therapy Group. N Engl J Med. 1998;339:1493-1499.
        16.Barbaro G, Di Lorenzo G, Belloni G, et al. Interferon alpha-2B and
        ribavirin in combination
        for patients with chronic hepatitis C who failed to respond to, or
        relapsed after, interferon
        alpha therapy: a randomized trial. Am J Med. 1999;107:112-118.
        17.Lyons M, Coddou A, Varon C, et al. Side effect profile of
        combination with interferon
        alpha-2b and ribavirin in a community-based clinical trial.
        Gastroenterology. 1999;116:A77.
        18.Glue P, Tan Y, Sacks M, et al. Use of ribavirin in patients with
        renal and hepatic dysfunction
        -- pharmacokinetic data and recommendations. Hepatology.
        19.Ozes ON, Reiter Z, Klein S, et al. A comparison of interferon-Con1
        with natural
        recombinant interferons-alpha: antiviral, antiproliferative, and
        natural killer-inducing activities.
        J Interferon Res. 1992;12:55-59.
        20.Klein SB, Blatt LM, Taylor MW. Consensus interferon induces peak
        mRNA accumulation
        at lower concentrations than interferon-alpha 2a. J Interferon Res.
        21.Heathcote EJ, Keeffe EB, Lee SS, et al. Re-treatment of chronic
        hepatitis C with consensus
        interferon. Hepatology. 1998;27:1136-1143.
        22.Zeuzem S. Clinical implications of hepatitis C viral kinetics. J
        Hepatol. 1999;31:61S-64S.
        23.Zeuzem S, Feinman SV, Raseneck J, et al. Peginterferon alfa-2a in
        patients with chronic
        hepatitis C. N Engl J Med. 2000;343:1666-1672.
        24.Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon
        alfa-2a in patients with
        chronic hepatitis C and cirrhosis. N Engl J Med.
        25.Trepo C, Lindsay K, Niederau C, et al. Pegylated interferon alfa-2B
        monotherapy is superior to interferon alfa-2B (Intron A) for the
        treatment of chronic
        hepatitis C. J Hepatol. 2000;32:29.
        26.Sulkowski MS, Reindollar R, Yu J. Pegylated interferon alfa-2A
        (PEGASYS) and ribavirin
        combination therapy for chronic hepatitis C: a phase II open-label
        study. Gastroenterology.
        27.Manns MP, McHutchinson JG, Gordan S, et al. Peginterferon alfa-2b
        plus ribavirin
        compared to interferon alfa-2b plus ribavirin for the treatment of
        chronic hepatitis C: 24
        week treatment analysis of a multicenter, multinational phase III
        randomized controlled trial.
        Hepatology. 2000;32:297A.
        28.Nelson DR, Lauwers GY, Lau JY, et al. Interleukin 10 treatment
        reduces fibrosis in patients
        with chronic hepatitis C: a pilot trial of interferon
        nonresponders. Gastroenterology.
        29.Zeuzem S, Hopf U, Carreno V, et al. A phase I/II study of
        recombinant human
        interleukin-12 in patients with chronic hepatitis C. Hepatology.
        30.Welch PJ, Yei S, Barber JR. Ribozyme gene therapy for hepatitis C
        virus infection. Clin
        Diagn Virol. 1998;10:163-171.
      Your message has been successfully submitted and would be delivered to recipients shortly.