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Is HCV Curable?

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  • claudine intexas
    Wed. Jan 8, 2003 NATAP - www.natap.org Is HCV Curable? Reported by Jules Levin Over 90% of HCV mono-infected patients who have negative HCV viral load
    Message 1 of 1 , Feb 15, 2003
      Wed. Jan 8, 2003
      NATAP - www.natap.org

      Is HCV Curable?
      Reported by Jules Levin

      Over 90% of HCV mono-infected patients who have negative HCV viral
      load
      (undetectable) 6 months after stopping therapy remain undetectable.
      Small
      studies of perhaps 200 hundred patients in total have followed
      patients
      for
      3-11 years and find over 90% of these patients continue to have
      undetectable
      HCV in the blood. Small studies have shown that these patients do not

      have
      HCV in the liver either. The study discussed below found that 98% of

      patients achieving a sustained viral response (undetectable HCV viral

      load)
      did not have HCV in the liver. This of course is good news. Most
      doctors feel
      that a patient who achieves and sustains undetectable viral load is
      likely to
      remain healthy. Many patients who achieve a sustained viral response
      (SVR)
      are able to improve the condition of the liver (fibrosis and
      inflammation).
      Studies have also found that a percentage of patients who are not
      able
      to
      achieve an SVR are still able to slow disease progression
      (inflammation
      and
      fibrosis). However, we still need long-term studies which follow
      large
      numbers of patients for many years to evaluate long-term clinical
      outcomes:
      the development of cirrhosis and other severe complications of HCV,
      and
      longevity.

      This past year HCV researchers (Poynard, McHutchison, Lindsay et al)
      reported
      on the effect of HCV therapy on fibrosis and inflammation. They
      followed
      patients who received various regimens including interferon and
      Pegylated
      interferon, and they evaluated the outcomes in terms of improved
      fibrosis and
      inflammation. They found that inflammation and fibrosis improves in
      many
      patients whether or not they achieve an SVR, but of course achieving
      an
      SVR
      results in greater likelihood of improving the liver. They also found

      that
      49% of the 150 patients with cirrhosis in this study were able to
      "reverse"
      cirrhosis.
      Here is link to full article:
      http://www.natap.org/2002/may/050902_2.htm

      When doctors refer to HCV being "curable" it is often said that this
      is
      analagous the situation with cancer. In cancer if they can���t find
      cancer for
      a certain number of years after therapy has been finished they call
      the
      person cured. Does cancer ever re-emerge? We need long-term studies
      in
      HCV to
      evaluate the outcomes of patients who sustain undetectable HCV viral
      load in
      order to confirm this.

      In summary, if a patient can sustain an undetectable viral load for 6

      months
      to 1 year after stopping HCV therapy this gives them the best
      opportunity to
      remain healthy. It���s important to bear in mind that these study
      results apply
      to patients with HCV mono-infection. We are not certain if these
      findings
      apply precisely to HCV/HIV coinfected patients. Studies in coinfected

      patients are ongoing and soon we will have additional information on
      them.
      There is much research going on now into new drugs for treating HCV.
      For
      patients who do not achieve a sustained viral response with the
      current
      therapy, they may want to consider maintenance therapy if they have
      advanced
      liver disease. Maintenance therapy consists of continuing interferon
      at
      a
      half-dose. Studies have found that this slows disease progression.
      The
      first
      study data on a new HCV drug that appears promising was presented
      recently at
      the large annual liver conference (AASLD). They studied and reported
      for the
      first time results from patients with HCV who received an HCV
      protease
      inhibitor (BILN 1061). Patients received this new drug for 2 days and

      achieved potent reductions in viral of 2-3 logs. There were no
      apparent
      safety concerns. Phase II studies are expected to begin in early
      2003.

      Study title: Hepatic HCV RNA before and after treatment with
      interferon
      alone
      or combined with ribavirin

      "���..Of the 400 sustained responders, 393 (98%) had undetectable
      hepatic HCV
      RNA, whereas the other 7 (2%) had detectable viral RNA in the
      liver���.. Seven
      (2%) patients with a SVR had persistent hepatic HCV RNA; of these, 5
      were
      followed late after treatment, and 2 relapsed���.. Five of these 7
      patients
      have subsequently been followed annually. To date, 2 with high and
      low
      hepatic HCV-RNA levels, respectively, have relapsed (patients 2 and
      7),
      with
      serum HCV RNA reappearing 12 months after completion of therapy. Two
      others
      (patients 3 and 6) have a durable response at 3.5 years'
      posttreatment.
      Patient 5 was still virus-free at 12 months' posttreatment, but has
      not
      been
      followed further. Patients 1 and 4 achieved a sustained response at
      24
      weeks
      after treatment, but have not been followed subsequently���."

      Abstract summary: The clinical use of measuring hepatic hepatitis C
      virus
      (HCV) RNA before and after therapy in patients with chronic hepatitis
      C
      has
      been assessed in a number of small clinical trials. Viral clearance
      from the
      liver may be a better marker of long-term response than eradication
      of
      serum
      HCV RNA. The aim of this study was to evaluate quantitative hepatic
      HCV-RNA
      measurements before and after antiviral therapy. Two thousand
      eighty-nine
      chronic hepatitis C patients were enrolled in 3 published clinical
      trials
      evaluating interferon alfa-2b alone or with ribavirin either as
      initial
      therapy or for interferon relapse. Hepatic HCV-RNA quantitation was
      performed
      with a modified reverse-transcription polymerase chain reaction
      (RT-PCR)
      before and 24 weeks after therapy in 951 and 1,316 patients,
      respectively.
      Pretherapy hepatic HCV-RNA concentrations correlated best with serum
      HCV-RNA
      concentrations (R = .236, P = .0001) and negatively correlated with
      alanine
      transaminase (ALT) values (���0.178, P = .0001), duration of
      infection
      (���0.09,
      P = .02), parenchymal injury (���0.135, P = .0001), histologic
      activity
      index
      (HAI) inflammatory score (���0.085, P = .01), Knodell fibrosis score
      (���0.072, P
      = .03), and body weight (���0.078, P = .02). In paired liver biopsy
      specimens
      (n = 534), change in hepatic HCV RNA correlated with the change in
      the
      HAI (R
      = .346, P = .0001). Of 400 sustained virologic responders (SVR), 393
      (98%)
      had undetectable hepatic HCV RNA, whereas 7 (2%) had detectable
      hepatic
      HCV
      RNA; 5 have been followed and 2 have had reappearance of serum HCV
      RNA
      12
      months after therapy. In conclusion, measurement of hepatic HCV RNA
      before or
      after therapy reflects changes observed in serum HCV RNA, and
      correlates
      inversely with hepatic inflammation and fibrosis, but otherwise has
      minimal
      clinical use. (HEPATOLOGY 2002;35:688-693. Author: McHutichison et
      al)

      Hepatitis C is an important cause of chronic liver disease, with an
      estimated
      2.7 million persons infected in the United States and 150 million
      persons
      worldwide. Recent studies have shown that 35% to 40% of patients who
      receive
      the combination of interferon plus ribavirin achieve the long-term
      benefits
      of sustained viral eradication from serum. Therapy, however, is
      costly
      and
      associated with side effects that require discontinuation or dose
      reductions
      in up to 20% of patients. Thus, identification of factors that would
      allow
      selection of patients most likely to respond or maintain their
      response
      would
      be clinically valuable. Before treatment, young age, female gender,
      absence
      of cirrhosis, low levels of pretreatment serum hepatitis C virus
      (HCV)
      RNA,
      and infection with HCV genotypes 2 or 3 have been associated with
      response.
      Unfortunately, these variables cannot be used clinically to
      accurately
      predict response in any individual patient, rendering it difficult to

      use
      these prognostic indicators to deny therapy.

      The clinical use of quantifying hepatic HCV RNA before and after
      interferon
      therapy in patients with chronic hepatitis C infection has been
      assessed
      retrospectively in a number of small clinical studies. Viral
      clearance
      from
      the liver has been thought to be a better marker of long-term
      response
      than
      sustained eradication of serum HCV RNA, and most patients with a
      sustained
      virologic response (SVR) after therapy have also been shown to have
      undetectable liver HCV RNA.

      The aim of this study was to prospectively evaluate the clinical use
      of
      assessing liver HCV-RNA quantitation before therapy as a predictor of

      sustained response, and after therapy as an indicator of durable
      response, in
      patients with chronic hepatitis C infection.

      Two thousand eighty-nine patients with chronic hepatitis C infection
      were
      enrolled in 3 published clinical trials, comparing the safety and
      efficacy of
      interferon alfa-2b (INTRON A, Schering-Plough, Kenilworth, NJ) alone
      or
      combined with ribavirin (REBETOL, Schering-Plough) for 24 or 48 weeks

      for
      initial therapy or for relapse after interferon. At the time of liver

      biopsy
      (before and 24 weeks after therapy), a portion of liver tissue was
      immediately snap-frozen in liquid nitrogen and stored at ���70��C for

      HCV-RNA
      analysis.

      A SVR was defined as loss of serum HCV RNA by reverse-transcription
      polymerase chain reaction (RT-PCR) 24 weeks after completion of
      therapy. Pre-
      and posttherapy liver tissue was available for analysis from 951 and
      1,316
      patients, respectively.

      RESULTS

      Of the 2,089 patients evaluated, pre- and posttherapy liver tissue
      was
      available for analysis from 951 and 1,316 patients, respectively. The

      discrepancy in the lower number of patients with pretreatment
      biopsies
      available for this study resulted from the fact that this protocol
      was
      introduced after some patients had already undergone their
      pretreatment
      liver
      biopsy. Thus, patients with a biopsy obtained within a few months of
      these
      clinical trials did not undergo a repeat pretreatment liver biopsy
      before
      study entry. Most pretreatment liver-biopsy specimens (903 of 951
      [95%])
      contained detectable HCV RNA.. Of the remaining 48 (5%) that were
      negative,
      37 (77%) were associated with reduced amplification of the internal
      assay
      controls, indicating that there was insufficient remaining viable
      tissue to
      perform RT-PCR.

      Of the 1,316 liver biopsies tested for HCV RNA 24 weeks after
      therapy,
      400
      were from sustained responders and 916 from nonresponders (those who
      did not
      achieve a sustained response). Of the 400 sustained responders, 393
      (98%) had
      undetectable hepatic HCV RNA, whereas the other 7 (2%) had detectable

      viral
      RNA in the liver. The remaining 916 liver biopsies tested were from
      nonresponders, of which 850 (93%) had detectable HCV RNA, but in 66
      (7%)
      biopsies, HCV RNA was undetectable. However, 34 (52%) of these
      specimens from
      nonresponders, and 17 of 393 (4%) from sustained responders, had
      reduced
      amplification of internal controls, consistent with viable tissue
      inadequate
      to assess whether HCV RNA was present or absent.

      Pretreatment hepatic HCV-RNA values correlated closely with baseline
      serum
      HCV-RNA levels (r = 0.236, P = .0001).

      A significant negative correlation was observed with the baseline ALT

      ratio
      (ALT value at baseline expressed as a ratio to the upper limit of
      normal) (r
      = ���0.178, P = .0001), body weight (r = ���0.078, P = .019), and
      duration of
      infection (r = ���0.088, P = .017). However, the date of acquisition
      of
      infection was based on the patient's reporting; therefore, the
      duration
      of
      infection represents an estimated value in the majority of cases.
      Analysis of
      subgroup means by ANOVA also showed a statistical association between

      hepatic
      HCV-RNA levels and the reported mode of acquisition (P = .0001), as
      well as a
      higher hepatic HCV-RNA level in patients with genotype 1 compared
      with
      non-1 (
      P = .0007).

      When we evaluated the relationship between hepatic HCV-RNA
      concentrations and
      histologic changes before treatment, we found a negative correlation
      between
      pretreatment hepatic HCV-RNA values and parenchymal injury (r =
      ���0.135, P =
      .0001), HAI inflammatory score (r = ���0.085, P = .012), and Knodell
      fibrosis
      score (r = ���0.072, P = .034); however, we found no association with

      other
      components of the HAI.

      Although pretreatment hepatic HCV-RNA values were predictive of
      response to
      antiviral therapy when analyzed alone or after controlling for
      treatment,
      when other prognostic factors such as genotype and serum HCV RNA were

      included in the logistic regression, the effect of the hepatic HCV
      RNA
      in
      predicting response became nonsignificant.

      There were 534 patients with paired liver biopsies available before
      and
      after
      therapy. Of these, 364 (68%) were nonresponders and 170 (32%)
      sustained
      responders. Overall, the observed change in liver HCV RNA correlated
      significantly with the change in the HAI (r = .346, P = .0001).
      However, this
      correlation was not observed when either nonresponders (r = .026, P =

      .62) or
      sustained responders (r = ���.062, P = .42) were analyzed separately.

      Seven
      patients achieved a SVR to therapy but had detectable hepatic HCV RNA

      at the
      24-week posttreatment biopsy. One of these (patient 3) was from the
      interferon-relapse retreatment trial, and most had low levels of
      detectable
      hepatic HCV RNA at follow-up.

      Five of these 7 patients have subsequently been followed annually. To

      date, 2
      with high and low hepatic HCV-RNA levels, respectively, have relapsed

      (patients 2 and 7), with serum HCV RNA reappearing 12 months after
      completion
      of therapy. Two others (patients 3 and 6) have a durable response at
      3.5
      years' posttreatment. Patient 5 was still virus-free at 12 months'
      posttreatment, but has not been followed further. Patients 1 and 4
      achieved a
      sustained response at 24 weeks after treatment, but have not been
      followed
      subsequently.

      Discussion By Authors

      When this study was initiated, the clinical value of measuring
      hepatic
      HCV
      RNA as a predictor of response, relapse, or disease severity was
      unclear.
      Smaller studies have demonstrated that changes in hepatic HCV RNA
      with
      therapy reflect changes in serum HCV RNA, and that the persistence of

      hepatic
      HCV RNA at the end of therapy may predict relapse. Other studies
      using
      non���PCR-based techniques for the detection of intrahepatic HCV RNA,

      such as
      branched-chain DNA target amplification or in situ hybridization,
      have
      also
      demonstrated a correlation between hepatic HCV-RNA levels and serum
      HCV
      RNA.
      This large trial allowed a careful prospective evaluation of these
      issues.

      Our results indicate that measurement of hepatic HCV RNA before or
      after
      therapy reflects levels of serum HCV RNA.

      Seven (2%) patients with a SVR had persistent hepatic HCV RNA; of
      these, 5
      were followed late after treatment, and 2 relapsed. Combination
      therapy
      for
      previously untreated patients with chronic hepatitis C results in
      posttreatment virologic relapse rates of 20% to 40% depending on the
      duration
      of therapy. Accurate, early identification of these relapsing
      patients
      is not
      possible and cannot be predicted at this time. Most relapses occur
      during the
      first 3 months following treatment. After this period, the late
      relapse
      rate
      over several years in patients with a SVR is approximately 5% to 10%.

      Small
      studies of hepatic HCV RNA have documented that hepatic viral
      clearance
      correlates with long-term SVR. In our study, only 2 of 7 patients
      with
      a SVR,
      but detectable posttreatment hepatic HCV RNA, have relapsed within 12

      months.

      In this study, the posttreatment liver biopsies were obtained 24
      weeks
      after
      the end of therapy. Whether earlier relapse, within the first 6
      months
      after
      therapy, could be predicted by assessing hepatic HCV RNA at the end
      of
      treatment was not evaluated in this study. Presumably, residual virus

      within
      the liver (or other extrahepatic reservoirs) is responsible for most
      early
      relapses, and this might have been detectable if hepatic HCV-RNA
      estimation
      had been performed at the end of treatment, as indicated in a
      previous
      small
      trial. Larger prospective trials would be required to further
      evaluate
      this
      concept, but end-of-therapy biopsies are rarely obtained either in
      clinical
      trials or in routine clinical practice.

      Hepatic HCV-RNA concentrations before treatment correlated with both
      serum
      HCV-RNA concentrations and HCV genotype, and were higher in genotype
      1���infected patients, as previously noted. In addition, hepatic
      HCV-RNA
      concentrations were associated with certain demographic variables. A
      strong
      inverse correlation existed between pretreatment hepatic HCV-RNA
      concentrations and the degree of liver parenchymal injury, and with
      baseline
      ALT values; a weaker correlation was found with the estimated
      duration
      of
      infection, body weight, HAI inflammatory, and Knodell fibrosis
      scores.
      Reasons for these negative correlations are speculative. The precise
      mechanisms of hepatocyte injury in chronic hepatitis C are unknown
      but
      presumably immune-mediated. This study did not indicate an
      association
      between hepatic HCV-RNA levels and the degree of histologic activity
      as
      would
      be expected if a direct viral cytopathic mechanism were the
      predominant
      factor in hepatic injury.

      In this study, 5% of pretreatment and 7% of posttreatment liver
      specimens
      were falsely negative (HCV RNA detected in the serum but not in the
      liver),
      and most of these could be explained by reduced amplification within
      the
      assay. Whereas sampling could be a potential explanation, other
      studies
      suggest that HCV is distributed evenly throughout the liver, but may
      only
      infect 5% to 25% of hepatocytes. Technical factors could explain
      these
      occasional negative samples, but in most instances, the accompanying
      internal
      controls were also negative, suggesting that the liver tissue was
      insufficient or improperly stored to maintain nucleic-acid viability.


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