Meta-analysis of 12 Randomized Controlled Trials Confirms Benefit of Extended Genotype 1 HCV Peginterferon alfa/ribavirin Treatment to 72 Weeks for Slow Responders

Posting Date: November 07, 2008

• Meta-analysis of 12 randomized controlled trials (RCTs)

Summary of Key Conclusions

• 72 weeks of peginterferon alfa/weight-based ribavirin more effective than 48 weeks for producing sustained virologic response (SVR) in patients with genotype 1 HCV who had a slow virologic response to treatment
• 16 weeks of peginterferon/weight-based ribavirin as effective for producing SVR as 24 weeks of treatment in patients with genotype 2/3 HCV who attained rapid virologic response to treatment

Background

• Extended treatment duration in genotype 1 HCV slow responders and shorter treatment duration in genotype 2/3 HCV rapid virologic responders controversial issues
  • Several studies report conflicting results
  • Meta-analysis of available RCTs would help determine utility of these approaches
• Current study analyzed available RCTs to assess efficacy of modified-duration treatment for HCV infection based on genotype and virologic response at Weeks 4 and 12
  • 72 vs 48 weeks of treatment for genotype 1 HCV slow responders
  • 24 weeks vs shorter treatment (12, 14, or 16 weeks) for genotype 2/3 HCV rapid virologic responders

Summary of Study Design

• All published RCTs from 2004-2008 comparing different durations of peginterferon/ribavirin compiled
  • Articles obtained by searching PubMed database, Cochrane library, ClinicalTrials.gov database, and abstracts of American Association for the Study of Liver Diseases and European Association for the Study of the Liver meetings
  • Authors contacted when available to obtain any relevant unreported data
    • Responses at Weeks 4 and 12 in studies designed before 2006
    • Details of RCTs not yet published as full papers
• Primary endpoint
  • SVR
• Random-effects modeling (DerSimonian-Laird analysis) used to determine pooled estimates of SVR
  • Heterogeneity tested with Cochrane Q test

Main Findings

• 12 RCTs identified for analysis (N = 2399): 10 full papers, 2 abstracts
  • 5 studies compared 48 vs 72 weeks of treatment for slow virologic responders with genotype 1 HCV (n = 345)
  • 7 studies compared 24 vs 12, 14, or 16 weeks of treatment for rapid virologic responders with genotype 2/3 HCV (n = 2054)
  • Studies grouped by fixed-dose ribavirin (ie, 800 mg/day) or weight-based ribavirin administered
  • Genotype 2/3 HCV patient analysis also categorized by suboptimal short therapy vs optimal short therapy
    • Suboptimal short therapy: 12 or 14 weeks of treatment or fixed-dose ribavirin administered (n = 1782)
    • Optimal short therapy: 16 weeks of treatment and weight-based ribavirin administered (n = 272)
• Slow virologic responders with genotype 1 HCV
  • Pooled estimate of SVR increase with 72 vs 48 weeks of treatment: 12% (95% confidence interval [CI]: 5% to 19%)
  • Benefit of extended treatment seen for regimens that used weight-based ribavirin but not fixed-dose ribavirin
  • No benefit of extended treatment observed for patients who had undetectable HCV RNA at Week 12

SVR Outcome in Genotype 1 HCV	Odds Ratio (95% CI)
72 vs 48 wks of treatment in slow virologic responders	1.62 (1.21-2.37)
Use of weight-based ribavirin	1.62 (1.10-2.39)
Use of fixed-dose ribavirin	1.70 (0.96-3.00)
72 vs 48 wks of treatment in patients with undetectable HCV RNA at Week 12	1.11 (0.92-1.33)
Use of weight-based ribavirin	1.24 (0.98-1.58)
Use of fixed-dose ribavirin	1.01 (0.83-1.22)

• Genotype 2/3 HCV with rapid virologic response and use of fixed-dose or weight-based ribavirin
  • 24 weeks of treatment significantly more effective than shorter treatment durations, particularly durations of 12 or 14 weeks

Pooled RCTs of Genotype 2/3 Rapid Virologic Responders, % (95% CI)	SVR Increase With 24 Weeks vs Shorter Treatment
16-wk treatment*	2 (-5 to 8)
12- or 14-wk treatment	11 (5 to 18)
Use of fixed-dose ribavirin†	13 (0 to 25)
Use of weight-based ribavirin	3 (-2 to 9)
Optimal short therapy	-2 (-6 to 3)
Suboptimal short therapy	10 (5 to14)

*Irrespective of ribavirin regimen.
^†Irrespective of duration of shorter treatment.

• No difference in virologic efficacy between 24-week vs 16-week treatment regimen with use of weight-based ribavirin in patients with genotype 2/3 HCV who attained a rapid virologic response

SVR Outcome in HCV Genotype 2/3	Odds Ratio (95% CI)
Treatment of patients with rapid virologic response	1.08 (1.01-1.16)
24- vs 12- or 14-wk treatment or use of fixed-dose ribavirin	1.12 (1.06-1.19)
24- vs 16-wk treatment and use of fixed-dose ribavirin	0.98 (0.94-1.03)

Reference