title: Extended peginterferon plus ribavirin treatment for 72 weeks versus standard peginterferon plus ribavirin treatment for 48 weeks in chronic hepatitis C genotype 1 infected slow-responder adult patients.
abstract: BACKGROUND
  The standard length of peginterferon plus ribavirin treatment for chronic hepatitis C virus (HCV) genotype 1 infected patients is 48 weeks. However, the number of patients demonstrating a sustained virological response is not high. In order to improve sustained virological response, extending the length of the treatment period has been suggested.
  
  
  OBJECTIVE
  To study the benefits and harms of extended 72-week treatment in comparison with 48-week treatment with peginterferon plus ribavirin in patients with chronic HCV genotype 1 infection who have shown a slow antiviral response.
  
  
  METHODS
  We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and LILACS until November 2011. We identified further trials by reviewing reference lists and contacting principal authors.
  
  
  METHODS
  Trials were eligible for this review if they included patients infected with hepatitis C virus genotype 1 who had a slow antiviral response, and if those patients were randomised to completing 72 weeks versus 48 weeks of treatment with pegylated interferon and ribavirin.
  
  
  METHODS
  Two authors independently assessed the trials for risk of bias, and extracted the data. The primary outcomes were overall mortality, liver-related mortality, and liver-related morbidity. We extracted data separately according to two definitions of slow responders: 1) patients with ≥ 2 log viral reduction but still detectable HCV RNA after 12 weeks of treatment and undetectable HCV RNA after 24 weeks of treatment; 2) patients with detectable HCV RNA after four weeks of treatment. We calculated risk ratios from individual trials as well as in the meta-analyses of trials.
  
  
  RESULTS
  We included seven trials with 1369 participants. All trials had high risk of bias. Five trials used our first definition of slow responders, and three other trials (including one that used both definitions) used the second definition. None of the included trials mentioned our primary outcomes. However, regarding the secondary outcomes, extension of the treatment period to 72 weeks increased the sustained virological response according to both definitions (71/217 (32.7%) versus 52/194 (26.8%); risk ratio (RR) 1.43, 95% confidence interval (CI) 1.07 to 1.92, P = 0.02, I(2) = 8%; and 265/499 (53.1%) versus 207/496 (41.7%); RR 1.27, 95% CI 1.07 to 1.50, P = 0.006, I(2) = 38%), with a risk difference of 0.11 and calculated number needed to treat of nine. The end of treatment response was not significantly different between the two treatment groups. The number of participants who relapsed virologically was found to be lower in the groups that had been treated for 72 weeks using both definitions (27/84 (32.1%) versus 46/91 (50.5%); RR 0.59, 95% CI 0.40 to 0.86, P = 0.007, I(2) = 18%, 3 trials; and 85/350 (24.3%) versus 146/353 (41.4%); RR 0.59, 95% CI 0.47, 0.73, P < 0.000001, I(2) = 0%, 3 trials). The length of treatment did not significantly affect the adherence (247/279 (88.5%) versus 252/274 (92.0%); RR 0.95, 95% CI 0.84 to 1.07, P = 0.42, I(2) = 69%, 3 trials). In the single trial that reported adverse events, no significant difference was seen between the two treatment groups.
  
  
  CONCLUSIONS
  This review demonstrates higher a proportion of sustained virological response after extension of treatment from 48 weeks to 72 weeks in HCV genotype 1 infected patients in whom HCV RNA was still detectable but decreased by ≥ 2 log after 12 weeks and became negative after 24 weeks of treatment, and in patients with detectable HCV RNA after four weeks of treatment with peginterferon plus ribavirin. The observed intervention effects can be caused by both systematic error (bias) and random errors (play of chance). There was no reporting on mortality and the reporting of clinical outcomes and adverse events was insufficient. More data are needed in order to recommend or reject the policy of extending the treatment period for slow responders.
authors.affiliation: Hepatology and Nutrition Department,MD Anderdson Cancer Center, Houston, Texas, USA. liorshlomit@yahoo.com.
authors.forename: Lior H
authors.initials: LH
authors.lastname: Katz
authors.forename: Hadar
authors.initials: H
authors.lastname: Goldvaser
authors.forename: Anat
authors.initials: A
authors.lastname: Gafter-Gvili
authors.forename: Ran
authors.initials: R
authors.lastname: Tur-Kaspa
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000379:methods; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000008:administration & dosage; D012254:Ribavirin / Q000008:administration & dosage*; D013997:Time Factors; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a