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Treatment considerations in patients with hepatitis C and cirrhosis

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    NATAP - www.natap.org Treatment considerations in patients with hepatitis C and cirrhosis All NATAP reports are posted & archived at NATAP website J Clin
    Message 1 of 1 , Jan 13, 2004
      NATAP - www.natap.org

      Treatment considerations in patients with hepatitis C and cirrhosis

      All NATAP reports are posted & archived at NATAP website

      J Clin Gastroenterol. 2003 Nov-Dec;37(5):395-8.
      E Jenny Heathcote
      University Health Network, Toronto Western Hospital, Toronto,
      Ontario, Canada.

      Patients with cirrhosis due to hepatitis C have a high chance of
      dying from progressive liver disease and thus have much to gain from
      successful antiviral therapy.

      The highest sustained virologic responses in patients with cirrhosis
      have been achieved using pegylated interferon alfa plus Ribavirin;
      43% or more remain with undetectable virus 6 months after the
      cessation of 48 weeks of treatment.

      In those who achieve a sustained virologic response, the degree of
      fibrosis is less as judged on post-treatment liver biopsy; cirrhosis
      may even regress. In those individuals with cirrhosis who achieve a
      sustained virologic response, the risk of developing hepatocellular
      carcinoma is significantly reduced and it is likely that their chance
      of developing liver failure is less.

      Patients who do not achieve sustained virologic response can still
      show histologic improvement as demonstrated on liver biopsy
      post-therapy as compared to baseline.

      Patients with compensated cirrhosis can benefit from therapy while
      those who are decompensated are prone to more safety issues. Thus,
      individuals with any evidence of hepatic decompensation should
      generally not be given interferon-based antiviral therapy, but
      treatment should be encouraged for those whose status is Child Class


      Successful antiviral therapy in patients with cirrhosis due to
      hepatitis C is potentially lifesaving, but those with cirrhosis are
      unfortunately a "difficult to treat" patient population. They are
      difficult to treat because not infrequently they have
      contraindications to current anti viral therapies, have a high side
      effect profile, and a lower rate of sustained virologic response to
      interferon (IFN)-based treatment compared with those without
      cirrhosis. Liver biopsy plays a vital role in the pre treatment
      assessment of liver disease severity. Without liver biopsy, the
      presence of underlying cirrhosis will often go unrecognized.


      Peripheral Blood Count

      Cirrhosis gives rise to portal hypertension that is frequently
      complicated by features of hypersplenism, specifically
      thrombocytopenia with or without leukopenia. Although
      thrombocytopenia may on occasion be immune-mediated in individuals
      with hepatitis C, it is most often a manifestation of hypersplenism.
      It is, however, extremely unusual for the platelet count to fall
      (with or without antiviral therapy) to such an extent that it
      promotes a bleeding disorder, although easy bruising and gum bleeding
      (often promoted by periodontal gum disease) complications may occur.
      Spontaneous episodes of septicemia are well-recognized in patients
      with cirrhosis. Such events are thought most often to be secondary to
      intra- and extrahepatic shunting of bacteria delivered to the liver
      via the portal vein. Although the precise role of leucopenia in
      promoting episodes of spontaneous sepsis in patients with cirrhosis
      remains undefined, IFN has a known bone marrow-suppressive effect and
      could produce a severe enough neutropenia to put the patient in
      danger. It is for these reasons that guidelines with regards to
      minimal acceptable numbers of circulating absolute neutrophils and
      platelets have been proposed. Most industry-initiated studies have
      prohibited the start of anti viral therapy in patients with cirrhosis
      with a platelet count of less than 70 x 106/mL or an absolute
      neutrophil count of less than 1.5 x 106/mL. In addition, guidelines
      recommending dose reduction and possible treatment discontinuation if
      the platelet count falls below 50 x 106/mL or the absolute neutrophil
      count falls to less than 0.5 x 106/mL. These guidelines have not been
      formally validated.

      Hepatic Decompensation

      Although the data are scant, there is good evidence that IFN-based
      therapy is inadvisable in individuals with decompensated cirrhosis
      due to hepatitis C.1 Early complications, mostly due to sepsis have
      been described and such individuals generally tolerate the treatment
      poorly. In addition, treatment may promote hepatic decompensation.

      Tolerance of Antiviral Therapy in Patients With Cirrhosis

      Intolerance, particularly due to neuropsychiatric side effect of IFN
      therapy, has been best described in individuals with cirrhosis due to
      hepatitis B.2 All forms of IFN therapy may be associated with a wide
      array of neuropsychiatric side effects. Although never formally
      examined, it is possible that anti viral therapy in cirrhotics could
      accentuate subclinical hepatic encephalopathy. The latter, depending
      on the method of assessment has been reported to be common in
      otherwise asymptomatic individuals with cirrhosis.3 Recent
      information suggests that individuals infected with hepatitis C virus
      (HCV), even in the absence of underlying cirrhosis, have significant
      neuropsychiatric deficiencies, particularly in the field of
      cognition.4, 5 It possible that this may in part explain the poor
      tolerance of IFN by individuals with hepatitis C.

      Efficacy of Anti Viral Efficacy in Cirrhosis caused by Hepatitis C

      Sustained Virologic Response

      The early studies using standard IFN monotherapy showed disappointing
      results in patients with cirrhosis.6 When the data from 6 European
      trials were pooled, the likelihood of a sustained virologic response
      (undetectable HCV RNA 6 months after completing therapy) was
      negligible in treatment-naive individuals with cirrhosis infected
      with HCV genotype 1. The response rates were somewhat improved once
      the combination of IFN alfa 2b plus ribavirin was introduced.
      Sustained virologic responses were reported in as many as 20% of
      patients with cirrhosis infected with HCV genotype 2 or 3.7

      Early studies with peginterferon alfa-2a (40KD) (PEGASYS) indicated
      that this long-acting form of IFN, even when given as monotherapy,
      markedly enhanced the sustained virologic response in individuals
      with cirrhosis or bridging fibrosis. In one study that recruited only
      patients with cirrhosis or bridging fibrosis, the overall sustained
      virologic response was 30% when peginterferon alfa-2a 180 [million
      units]g was given once weekly for 48 weeks. This represented a marked
      improvement over the 8% rate achieved with unpegylated IFN alfa-2a.8
      Efficacy was poorest in those infected with HCV genotype 1 (sustained
      virologic response of 12%), whereas in those with HCV genotype non-1
      infections, the sustained virologic response was 51%.

      In a large, randomized study, Pegylated IFN alfa-2b 1.5 [million
      units]/kg weekly (PEGINTRON) plus Ribavirin 800 mg per day for 48
      weeks produced a sustained virologic response of 44% in the subset of
      individuals with bridging fibrosis or cirrhosis: a similar rate of
      41% was seen in those treated with IFN alfa-2b plus Ribavirin.9

      Treatment with peginterferon alfa-2a (40 KD) (PEGASYS) in combination
      with Ribavirin improves sustained virologic response, relative to
      standard IFN plus Ribavirin, in patients with cirrhosis. In a recent
      study, once-once weekly peginterferon alfa-2a 180 [mu]g plus
      Ribavirin 1000 to 1200 mg per day, administered for 48 weeks,
      produced a sustained virologic response of 43%; inanother study using
      the IFN alfa-2b plus Ribavirin the SVR was 33% (Fig. 1).10 Another
      study using the same peginterferon alfa-2a plus Ribavirin regimen
      showed a sustained virologic response in 50% of patients with
      bridging fibrosis or cirrhosis (See Fig. 1).11

      figure 1.

      [Unable to display image]

      Histologic Response

      Comparison of posttreatment with pretreatment liver biopsies in
      individuals who have undergone a course of IFN-based therapy shows
      animprovement in total histologic activity index (HAI) scores, both
      in patients with a sustained virologic response and in some who do
      not clear virus but who experience a fall in viral titer and
      improvement in liver biochemistry during treatment. Improvements in
      the necroinflammatory component of this score have generally been
      greater than the degree of improvement in fibrosis.

      In a trial in patients with advanced fibrosis or cirrhosis, 54% of
      those treated with peginterferon alfa-2a (40KD) (PEGASYS) monotherapy
      (180 [mu]g once weekly) had an improvement of 2 points or more in
      their total HAI scores, which was a significant improvement over the
      31% histologic response rate seen in patients treated with standard
      IFN alfa-2a (P = 0.02).8 In addition, the degree of improvement in
      HAI score was significantly greater (P = 0.02) with peginterferon
      alfa-2a (40KD) (-2.6 points) than with standard IFN alfa-2a (-0.8).12

      A recent study specifically assessed changes in liver fibrosis
      observed in 153 patients with cirrhosis at baseline who were
      subsequently treated with either standard IFN alfa-2b plus ribavirin
      or pegylated IFN alfa-2b plus Ribavirin.13 Regression of fibrosis,
      assessed by the 5-point METAVIR scoring system, where 0 = no fibrosis
      and 4 = cirrhosis, was observed in 75 patients. In 23 patients, the
      METAVIR stage fell by 1 point; in 26 patients, by 2 points; in 23
      patients by 3 points; and in 3 patients, no fibrosis was seen on the
      posttreatment biopsy. Whereas one may question the reliability of a
      change from 4 to 3, there is little difficulty distinguishing stage 2
      from stage 4 using the METAVIR scale. In only 1/3 of patients was
      this improvement associated with a sustained virologic response.
      These changes were noted shortly after the cessation of therapy and
      it is reasonable to assume that further improvement in the degree of
      fibrosis is likely over longer follow-up periods in patients with a
      sustained virologic response, as was reported by Shiratori et al.14

      Long Term Survival

      Early reports suggested that IFN-based antiviral therapy, when given
      to individuals with cirrhosis, did not result in any long-term
      benefit, as the rate of hepatic decompensation and the incidence of
      hepatocellular carcinoma were not affected. However, sustained
      virologic response was rarely achieved in these early studies.6
      Subsequently, long-term follow-up of large numbers of treated
      patients indicated that a significant reduction in the rate of
      hepatocellular carcinoma was achieved in those individuals with
      cirrhosis who achieved a sustained virologic response (Table 1).15
      Benefit in terms of a reduction in rates of hepatocellular carcinoma
      may also be seen in patients who have a sustained biochemical
      response to therapy even though viremia may persist. Unfortunately,
      these data were not obtained from long-term follow-up of randomized
      controlled trials. Data in support of reduced rates of hepatic
      decompensation in patients with cirrhosis patients treated with
      IFN-based therapy is hard to interpret for the same reason, (ie,lack
      of randomization). As IFN therapy for chronic hepatitis C has now
      been licensed for a decade, randomization of patients to an untreated
      control arm in a prospective trial would be considered unethical.
      Thus, in many long-term follow-up studies, which suggest that death
      from liver failure is reduced in patients with hepatitis C treated
      with IFN-based therapy, the comparison group has always been those,
      who, for whatever reason, did not receive treatment as the result of
      some circumstance other than randomization. Such patients may have
      had contraindications to therapy due to the severity of their liver
      disease or were denied treatment because of serious comorbidities,
      (eg, psychiatric conditions). In the study by Fattovich et al,16
      individuals treated with IFN had an apparent survival benefit, but
      when the untreated patients were matched for baseline signs of liver
      function (eg, bilirubin) no apparent difference in survival was
      observed between treated and untreated individuals. In another study
      by Serfaty et al,17 668 patients with compensated cirrhosis due to
      hepatitis C were followed for a mean of 40 months. Using multivariate
      analysis, nontreatment with IFN was the only independent risk factor
      for both hepatocellular carcinoma and hepatic decompensation.

      Table 1. Annual Incidence of Hepatocellular Carcinoma (liver cancer)

      [Unable to display image]

      In terms of progression to hepatocellular carcinoma and survival, no
      long-term data are available following treatment with IFN plus
      ribavirin. As this therapy results in a markedly enhanced rate of
      sustained virologic response compared with standard IFN monotherapy,
      and as follow-up studies beyond 2 years suggest that the relapse of
      viral infection does not occur, it is highly likely that the
      combination therapy will demonstrate a long-term survival benefit,
      particularly in individuals who already had developed cirrhosis prior
      to the onset of antiviral therapy. Therapy based on Pegylated IFNs
      could be expected to further improve the outcome; however,
      information is needed regarding the long-term benefits of treatment
      with Pegylated IFNs on liver disease progression and survival. The
      hepatitis C antiviral long-term treatment against cirrhosis trial
      (HALT-C), an ongoing NIH-sponsored study, is assessing the effect of
      long-term treatment with peginterferon alfa-2a (40KD) on progression
      to cirrhosis, hepatocellular carcinoma, and liver transplantation in
      patients with fibrosis at the start of treatment.18 In the trial,
      patients with significant hepatic fibrosis who did not respond to
      previous therapy (IFN with or without ribavirin) are administered
      peginterferon alfa-2a (40KD) plus ribavirin for 20 weeks. Those with
      persistent HCV viremia are subsequently randomized to continue
      therapy with peginterferon alfa-2a (40KD) alone for an additional 42
      months, or to stop treatment. Preliminary data from this trial show
      that 59 of 138 patients (43%) treated for up to 20 weeks with
      peginterferon alfa-2a (40KD)plus ribavirin achieved a virologic
      response, and there was no significant difference between responders
      and nonresponders in terms of cirrhosis on liver biopsy (32% and 43%,
      respectively) but we have yet to know whether there will be a
      difference in the sustained virologic response rates.19


      Despite the fact that individuals with cirrhosis may be more at risk
      for developing troublesome neuropsychiatric complications and
      laboratory events such as leukopenia or thrombocytopenia, these
      patients have the most to gain from successful antiviral therapy.
      There are good recent data to suggest that the rate of hepatocellular
      carcinoma is reduced by effective antiviral therapy. It remains
      unproven but likely that survival free of liver failure is improved
      in this particular patient population treated successfully for
      hepatitis C. Even though antiviral therapy in individuals with
      cirrhosis due to hepatitis C seems to have a marked benefit, regular
      surveillance for liver cancer, portal hypertension and liver failure
      should probably be maintained lifelong


      1.Crippin JS, McCashland T, Terrault N, et al. A pilot study of the
      tolerability and efficacy of antiviral therapy in hepatitis C
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      2.Renault PF, Hofnagle JH, Park Y, et al. Psychiatric Complications
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