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FW: NATAP Treating Acute HCV with PegIFN

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    Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: The HEP-NET acute-HCV-II study Hepatology Feb 2006 Johannes Wiegand 1,
    Message 1 of 1 , Feb 3, 2006
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      Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C
      infection: The HEP-NET acute-HCV-II study

      Hepatology Feb 2006

      Johannes Wiegand 1, Peter Buggisch 2, Wulf Boecher 3, Stefan Zeuzem 4,
      Cornelia M. Gelbmann 5, Thomas Berg 6, Wolfgang Kauffmann 7, Birgit
      Kallinowski 8', Markus Cornberg 1, Elmar Jaeckel 1, Heiner Wedemeyer 1,
      Michael P. Manns 1 *6, German HEP-NET Acute HCV Study Group
      1Department of Gastroenterology, Hepatology, and Endocrinology, Hannover
      Medical School, Hannover, Germany
      2Universitdtsklinikum Eppendorf, University of Hamburg, Hamburg, Germany
      3I. Medizinische Klinik, University of Mainz, Mainz, Germany
      4Medizinische Klinik II, Saarland University, Homburg, Germany
      5Innere Medizin I, University of Regensburg, Regensburg, Germany
      6Charite, Campus Virchow-Klinikum, Universitdtsmedizin Berlin, Berlin,
      Germany
      7Vivantes Klinikum Prenzlauer Berg, Berlin, Germany
      8Medizinische Klinik IV, University of Heidelberg, Heidelberg, Germany

      Potential conflict of interest: Dr. Zeuzem is a consultant for and has
      received unrestricted grants from Roche and Schering. Dr. Wiegand has
      received travel grants from Schering. Drs. Jaeckel and Comberg have received
      travel grants from Essex Pharma. Dr. Wedemeyer has received research and
      travel grants from Essex Pharma. Dr. Manns is a consultant for and has
      received research and travel grants from Schering. Dr. Buggisch is a
      consultant for, has received research and travel grants from, and has
      conducted clinical trials for Roche. He has also been a consultant and
      conducted clinical trials for Schering-Plough.

      ABSTRACT
      Early treatment of acute hepatitis C with interferon alpha-2b for 24 weeks
      prevents chronic infection in almost all patients. Because pegylated
      interferons have replaced conventional interferon in the therapy of chronic
      hepatitis C, the aim of this study was to analyze the efficacy of an early
      treatment of acute hepatitis C with peginterferon alfa- 2b. Between February
      2001 and February 2004, 89 individuals with acute HCV infection were
      recruited at 53 different centers in Germany. Patients received 1.5 g/kg
      peginterferon alfa-2b for 24 weeks; treatment was initiated after a median
      of 76 days after infection (range 14-150). End-of-treatment response and
      sustained virological response were defined as undetectable HCV RNA at the
      end of therapy and after 24 weeks of follow-up, respectively. In the total
      study population, virological response was 82% at the end of treatment and
      71% at the end of follow-up. Of 89 individuals, 65 (73%) were adherent to
      therapy, receiving 80% of the interferon dosage within 80% of the scheduled
      treatment duration. End-of-treatment and sustained virological response
      rates in this subpopulation were 94% and 89%, respectively. A maximum
      alanine aminotransferase level of more than 500 U/L prior to therapy was the
      only factor associated with successful treatment. In conclusion, in acute
      HCV infection, early treatment with peginterferon 2b leads to high
      virological response rates in individuals who are adherent to treatment. The
      high number of dropouts underlines the importance of thorough patient
      selection and close monitoring during therapy. Thus, future studies should
      identify factors predicting spontaneous viral clearance to avoid unnecessary
      therapy.

      Article Text

      Management of acute hepatitis C has become a controversial topic in recent
      years.[1][2] Acute infection with hepatitis C virus (HCV) leads to
      chronicity in 54% to 84% of patients.[3] Chronic hepatitis C can be cured
      with pegylated interferon alfa plus ribavirin in 54% to 63% of cases;
      however, this regimen is not successful in approximately half of patients
      infected with HCV genotype 1.[4-6] Prevention of a chronic course of
      hepatitis C seems to be a desirable therapeutic goal considering the high
      risk of chronicity, the substantial number of nonresponders in chronic HCV
      infection, and the potential risk to develop cirrhosis or hepatocellular
      carcinoma. In addition, in special patient groups such as health care
      personnel, the infection might have important legal and social consequences.

      Detection of acute hepatitis C can be difficult, because infection is not
      often accompanied by relevant symptoms.[7] Furthermore, after the
      introduction of screening of blood products for HCV RNA, the main source of
      infection has shifted from transfusion to intravenous drug use.[8-10] For
      many reasons, drug addicts may not be eligible for clinical trials, which
      further limits the possibility to conduct prospective studies.

      It still remains controversial if therapy should be initiated as early as
      possible or if the start of therapy can be delayed, because no prospectively
      controlled trials have been reported.[11-19] Both approaches have yielded
      sustained response rates of 80% to 98%,[11][12] but final recommendations
      about the optimal interferon dosage and treatment duration cannot be made
      yet. However, it has been shown that use of ribavirin combination is not
      needed in the treatment of acute HCV infection.[14] In Germany, the
      awareness of acute hepatitis C infection increased substantially after a
      pilot trial with an interferon alfa-2b monotherapy for 24 weeks showed that
      HCV could be eradicated in 98% of patients independently of HCV
      genotype.[11] Because the standard therapy of chronic hepatitis C has moved
      from conventional interferon alfa to pegylated interferon alfa the aim of
      the present study was to evaluate the efficacy of early treatment with
      peginterferon alfa-2b in patients with acute HCV infection. The study was
      conducted with the support of the German Competence Network for Viral
      Hepatitis (HEP-NET), an organization of hepatology experts that was founded
      to establish nationwide standards for the treatment of viral hepatitis,
      transfer knowledge between different institutions of the health care system,
      and coordinate scientific studies.[20]

      Patients and Methods

      The study was designed as a nationwide open, uncontrolled multicenter trial.
      HEP-NET served as coordinator and central information unit and distributed
      information brochures to hospitals, outpatient clinics, private practices,
      and patient-advocacy groups. Patients (18-65 years of age) were eligible if
      they were HCV RNA-positive (as assessed via polymerase chain reaction) and
      had elevated serum alanine aminotransferase (ALT) levels. Acute HCV
      infection was considered to be present if at least 1 of the following
      criteria was fulfilled: (1) known or suspected exposure to HCV within the
      preceding 4 months, (2) documented seroconversion (anti-HCV-negative to
      anti-HCV-positive), or (3) ALT 20 times the upper limit of normal. If ALT
      was elevated below 20 times the upper limit of normal, patients were
      approved by the central study unit only after extensive discussion with the
      investigator if the additional criteria mentioned in the manuscript were
      fulfilled, including a very likely event of HCV transmission within the
      preceding 4 months in combination with HCV seroconversion. In addition, any
      history of previous liver disease and any previous ALT elevation were ruled
      out. These criteria were strictly used throughout the entire study period.
      Thus, to the best of our knowledge, cases with potential chronic HCV
      infection were ruled out.

      Exclusion criteria were: coinfection with hepatitis B virus or HIV;
      autoimmune diseases, especially autoimmune liver disease; leukocytopenia
      (<3,000 leukocytes/L); thrombocytopenia (<100,000 thombocytes/L),
      decompensated cirrhosis (Child-Pugh class B or C); decompensated renal
      (creatinin >2.0 mg/dL) or thyroid (TSH out of normal range) disease;
      psychiatric conditions such as severe depression; a history of seizures;
      poorly controlled diabetes mellitus or ophtalmological disease; pregnancy;
      or a history of organ transplantation or malignancy. Patients with ongoing
      abuse of alcohol or intravenous drugs were not eligible. In individual
      cases, if intravenous drug abuse was considered a single event or if the
      patient was participating in a withdrawal cure, inclusion in the study was
      possible.

      To ensure uniform standards throughout the different sites, enrollment and
      treatment criteria were strictly controlled by the HEP-NET Study House and
      the investigators of the Hannover Medical School. Prior to enrollment of a
      patient, each local investigator had to contact the central study unit in
      Hannover, where the HCV infection criteria and the inclusion/exclusion
      criteria were checked. Thus, each patient had to be approved by the central
      study unit before inclusion. During the study period, the peripheral centers
      were frequently contacted to collect the data of each visit into the central
      database as early as possible. If patients were lost to follow-up, the
      investigators tried repeatedly to recontact the individuals via telephone or
      mail.

      Patients received 1.5 g/kg/wk peginterferon alfa-2b subcutaneously for 24
      weeks. Biochemical and hematological testings were performed locally. Viral
      genotypes were determined either locally or centrally in Hannover (INNO-LiPa
      HCV II Kit; Innogenetics, Heiden, Germany). HCV RNA was quantified before,
      during, and after treatment. The primary end point was defined as sustained
      virological response (HCV RNA-negative [as assessed via polymerase chain
      reaction] 24 weeks after the end of therapy) (Cobas Amplicor 3.0; Roche
      Diagnostics, Mannheim, Germany [detection limit 600 copies HCV RNA/mL]).
      Secondary end points were the absence of detectable levels of HCV RNA at the
      end of therapy and normalization of ALT levels.

      Safety of the study drug was assessed via analysis of documented adverse
      events and serious adverse events. Adverse events were classified as mild
      (no dose adjustment necessary), moderate (dose adjustment possible) or
      severe (dose adjustment mandatory).

      All patients provided written informed consent before enrolling in the
      study. The study was approved by the appropriate local ethics committees and
      the ethics committee of Hannover Medical School and was performed according
      to the Declaration of Helsinki of 1996.

      Results

      Baseline Characteristics of the Study Population.

      Between February 2001 and February 2004, 89 patients with acute HCV
      infection were recruited at 53 different centers (university hospitals [n =
      18], state hospitals [n = 26], private gastroenterologists and primary care
      physicians [n = 9]). Treatment was initiated in all 89 patients, and 70
      patients (79%) were adherent to therapy. Adherence to therapy was defined as
      application of at least 80% of the peginterferon alfa-2b dosage and therapy
      for 80% of the scheduled treatment period. Complete follow-up data were
      available for 65 of the adherent individuals (93%). In 19 patients (21%) the
      criteria of therapy adherence were not fulfilled, because the patients
      prematurely stopped therapy due to side effects, were lost to follow-up
      during treatment, or were not treated according to protocol (Fig. 1). The
      reasons for protocol violations were reduced interferon dosage (1.0 g/kg) in
      two cases, interferon injection every other week in one patient, and
      noncompliance in one patient.

      Suspected sources of infection were intravenous drug abuse and sexual
      transmission (each 22% of cases), medical procedures (19%; most common:
      surgery (11/17 individuals)), needle stick injuries (11%) and other
      potential transmission modes (acupuncture, blood brotherhood, bite injury,
      shared razor, tattooing, hair clippers; 8%). In 17% of patients no risk
      factor for infection could be determined.

      Jaundice was observed in 62% of cases, 40% of patients reported fatigue, and
      19% were asymptomatic. Additional demographic and clinical data of the study
      population are summarized in Table 1.

      Efficacy of Antiviral Therapy.



      Serum levels of ALT were within the normal limits in the total study
      population in 73% of patients at the end of therapy and in 86% after 24
      weeks of follow-up. In the subgroup of individuals adherent to therapy, ALT
      levels normalized in 75% and 91% of cases, respectively. Except for two
      patients with virological relapse, persistent elevations of ALT levels were
      only mild, not exceeding more than twice the upper limit of normal.

      At the end of treatment, HCV RNA was undetectable in 82% of patients of the
      total study cohort and in 94% of individuals adherent to therapy (Fig. 2).
      After 24 weeks of follow-up, a sustained virological response was observed
      in 71% and 89% of cases, respectively. In addition to the 58 successfully
      treated patients in the therapy adherent subgroup, five other individuals
      became sustained virological responders who were either treated with
      pegylated interferon only every other week (n = 1) or for a shorter period
      of 8-16 weeks due to side effects (n = 4).

      In the subgroup of patients adherent to therapy, we observed one patient
      with virological nonresponse, two patients with virological breakthrough,
      and 4 relapse cases (Table 2). These patients did not differ significantly
      from the sustained virological responders in age (>40 yr vs. <40 yr, P =
      1.0; >30 yr vs. <30 yr, P = .4), sex (P = .2), HCV genotype (HCV genotype 1
      and 4 vs. HCV genotype 2 and 3, P = 1.0), HCV RNA viral load (HCV RNA
      >850,000 IU/mL vs. HCV RNA <850,000 IU/mL, P = 1.0), or bilirubin levels at
      baseline (P = .2). Only maximum ALT levels of more than 500 U/L were
      significantly more frequent in patients with sustained treatment response (P
      = .025). Stepwise multivariate regression analysis confirmed the association
      of sustained virological response rates with ALT levels (P = .039). ALT
      levels in patients with HCV genotype 2 and 3 were not significantly higher
      than in patients with HCV genotype 1 and 4 (P = .15).

      Compliance.

      The difference of virological response rates between the total study
      population and the individuals adherent to therapy was mainly due to 13
      cases who were lost to follow-up. The lost to follow-up rates did not differ
      between the different institutions (university hospitals, general hospitals,
      and private practices) that guided the patients during therapy (P = 0.3).
      Six of the 13 patients had previously used intravenous drugs. However,
      previous intravenous drug abuse was not associated with being lost to
      follow-up (P = 1.0). Patient sex did not correlate with therapy adherence (P
      = 0.8) or lost to follow-up rates (P = 1.0).

      Safety.

      The overall tolerance of therapy was comparable to previous studies with
      peginterferon alfa-2b.[4][21] The spectrum of side effects and their
      reported intensity is shown in Fig. 3. Psychiatric symptoms were the most
      frequent side effects after flu-like symptoms and were responsible for
      discontinuing interferon treatment in 6 of 11 patients with premature
      stoppage of therapy. Patients who experienced psychiatric side effects
      tended to stop therapy prematurely more often than those who did not
      experience these effects (P = .06).


      The most relevant serious adverse event was the suicide of one patient. This
      patient received psychiatric evaluation before therapy because of a suicide
      attempt 2 years earlier, after his wife had died. No obvious
      contraindications against interferon treatment were noticed. During therapy,
      the patient was seen weekly by the same physician without any signs of
      psychiatric alteration. However, the patient committed suicide during week
      22 of therapy.

      Two other serious adverse events occurred: 1 patient was in a deadly car
      accident, and another had a severe increase in ALT levels (2,369 U/L) during
      week 4 of therapy, requiring hospitalization and premature termination of
      therapy. The ALT increase was most likely due to patient noncompliance,
      because the patient interrupted therapy after week 2 or 3.

      A notable side effect was the relapse of intravenous drug use at week 22 of
      therapy in one individual. Fortunately, drug consumption was successfully
      stopped after supportive psychological therapy. Reinfection with HCV did not
      occur.

      Discussion

      The aim of the present study was to evaluate the efficacy of an early
      therapy with peginterferon alfa-2b in patients with acute HCV infection.
      Compared with our previous nationwide German trial,[11] the number of
      patients and the number of recruiting centers was doubled within a similar
      study period. To our knowledge, this study cohort represents the largest
      ever described for a treatment trial of acute hepatitis C. The high
      recruitment rate is a result of the Jaeckel study and the support of the
      German Competence Network for Viral Hepatitis (HEP-NET), which markedly
      increased awareness of the disease. The more effective coordination reduced
      the median time from infection to the start of therapy from 89 to 76 days.
      However, the increase of the study population was associated with more
      frequent treatment failures, protocol violations, and patients lost to
      follow-up. Thus, the overall sustained virological response rates were lower
      than expected after the Jaeckel trial. Only in the patients adherent to
      therapy were the results almost in the same range as in the previous trial
      using conventional interferon alfa-2b. The only factor correlating with
      successful therapy was a high maximum ALT level before treatment. Whether
      the slightly higher sustained response rates in the Jaeckel trial using
      conventional interferon (98% vs. 89%) can be explained by the 4 weeks of
      daily induction dosing treatment applied in the first trial[11] remains to
      be investigated.

      The high number of patients lost to follow-up highlights again that
      individuals with acute hepatitis C are difficult to treat. A recent report
      from Switzerland on intravenous drug users with acute hepatitis C
      demonstrated low adherence to therapy, especially in females and individuals
      with ongoing drug abuse.[18] Previous drug abuse and female sex did not
      significantly affect adherence in the present study. However, this study
      demonstrates that close monitoring both during therapy and follow-up is
      required - particularly for patients with acute hepatitis C - because our
      patients' selection criteria did not reliably prevent weak adherence, even
      though individuals with ongoing intravenous drug abuse were excluded.

      The overall safety and tolerance of the medication did not differ from
      previous studies with peginterferon alfa-2b.[4][21] We observed a trend for
      psychiatric symptoms to be associated with premature termination of therapy.
      In addition, three serious adverse events occurred, including one suicide
      and one patient with a relapse of intravenous drug abuse. These observations
      clearly highlight the need of thorough patient selection and extensive
      information about potential side effects and about treatment alternatives,
      especially because other long-term side effects after interferon therapy
      seem to be possible in single cases.[22] Thus, therapy of acute HCV should
      be performed only by physicians experienced in handling the patients and the
      medication with its potential complications.

      It should be noted that 10% to50% of patients with acute hepatitis C may
      clear the infection spontaneously.[2][7][23] Treating these individuals as
      early as possible may unneccessarily place them at risk for adverse events
      and may cause substantial therapeutic costs. Thus, overtreatment must be
      balanced against the risk of chronification. Unfortunately, there are no
      markers that reliably predict the natural course of the disease. ALT levels
      failed to predict the spontaneous outcome of acute HCV infection[24];
      however, low ALT levels were associated with treatment failure in the
      present study and may therefore be considered before the initiation of
      therapy. An alternative to early treatment of acute HCV infection may be a
      delayed therapy to treat only those patients who do not clear the virus
      spontaneously. Gerlach et al.[12] treated only individuals who were still
      viremic 12 weeks after the onset of symptoms corresponding to 4-5 months of
      infection. The response rate in symptomatic patients was 91% in this study
      cohort. In other smaller patient cohorts, a delayed monotherapy either with
      conventional interferon or with pegylated interferon alfa lead to sustained
      virological response rates of 80% to 100%.[14][16][19][25] However, therapy
      should not be delayed for too long,[25] because response rates dropped to
      40% in a Japanese study if treatment was initiated after 1 year.[13] In
      European patients, the risk for treatment failure may also be dependent on
      the time between initial presentation and treatment initiation.[15] Thus,
      there is increasing evidence that delayed therapy may be effective for many
      patients; however, randomized trials comparing immediate versus delayed
      therapy have not been published yet.

      Future trials on acute HCV should also try to identify predictive factors
      for the natural course of the infection. The relevance of clinical symptoms
      and racial differences is unknown.[12-14][19][24] HCV genotyping should be
      performed in every patient to further individualize the indication before
      therapy. HCV genotype 1 and 4 are difficult to treat in chronic HCV but can
      be effectively cured in acute infection.[11][14][16] On the other hand,
      there are data indicating a higher rate of spontaneous viral clearance in
      acute HCV genotype 3 infection.[26] Considering the likelihood of successful
      therapy with pegylated interferon alfa plus ribavirin in individuals with
      genotype 3, a more reserved therapeutical approach may be reasonable in
      these patients. In certain settings, repeated HCV RNA testing might help to
      identify individuals who are able to clear the virus spontaneously,[24]
      although frequent HCV RNA testing may be difficult to apply in a routine
      clinical setting. Another criterion for the initiation of therapy is the
      social background of the patient. For social and legal purposes, it may be
      dangerous to delay therapy in infected health care workers - especially if
      there is no evidence of a late relapse after early interferon therapy, even
      years later.[22]

      There is no evidence to combine ribavirin with interferon alfa in acute
      hepatitis C. The present study, in addition to several previous trials,
      report high rates of viral clearance using conventional interferon treatment
      or pegylated interferon alfa without ribavirin.[11][13][17] Moreover, the
      only randomized trial thus far comparing monotherapy and combination therapy
      in acute hepatitis C did not yield any significant difference in response
      rates between both approaches.[14] These data are supported by the recent
      study of Santantonio et al.,[19] who also used peginterferon alfa-2b,
      although the number of patients was limited and consisted mainly of
      individuals infected with HCV genotype 2 and 3.

      In conclusion, the present study shows high rates of viral clearance in
      early therapy with peginterferon alfa-2b in patients with acute hepatitis C
      who are adherent to therapy. However, it also highlights limitations and
      risks of this therapeutical concept in routine clinical practice. Thus,
      future studies should aim to identify factors predicting spontaneous viral
      clearance to avoid unnecessary therapy.




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