CCO Official Conference Coverage of the 2008 AASLD Meeting*

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Decreased Ribavirin Exposure an Independent Predictor of Relapse in HCV Patients Receiving Peginterferon alfa-2a/Ribavirin

Posting Date: November 04, 2008

• Retrospective analysis^[1] of 2 randomized, phase III studies^[2,3]

Summary of Key Conclusions

• Ribavirin dose exposure during treatment with peginterferon alfa-2a/ribavirin an independent, significant, potentially modifiable risk factor for relapse among patients infected with genotype 1 HCV
  • Identified by multiple logistic regression analysis
  • Reduced cumulative ribavirin exposure significantly increases the risk of relapse
  • Risk of relapse increases gradually with magnitude of ribavirin dose reduction
• Virologic response during first 12 weeks of treatment with peginterferon alfa-2a/ribavirin predicts relapse rates in HCV patients who achieve undetectable HCV RNA after 48 weeks of treatment
  • Lowest relapse rate when rapid virologic response (RVR) achieved
  • Highest relapse rate when partial early virologic response (pEVR), no RVR, or early virologic response (EVR) achieved
• Older age, higher body mass index, higher HCV RNA level, and lower ALT quotient also identified as significant baseline factors associated with increased risk of relapse

Background

• Relapses following peginterferon alfa-2a/ribavirin therapy for HCV associated with poor clinical outcome
  • In patients infected with genotype 1HCV, high relapse rates result in lower sustained virologic response (SVR) rates
• Identification of factors contributing to relapse might help select and optimize treatment
  • Maximizing cumulative exposure to ribavirin in combination with peginterferon alfa-2a shown to positively affect SVR rates
• Current study investigated role of baseline factors and ribavirin exposure on the probability of relapse for genotype 1 HCV patients receiving 48 weeks of peginterferon alfa-2a/ribavirin

Summary of Study Design

• Inclusion criteria
  • Genotype HCV 1 infection (N = 374)
  • End of treatment (EOT) response to 48 weeks of peginterferon alfa-2a 180 µg/week and ribavirin 1000/1200 mg/day
    • Ribavirin reduced to 600 mg/day to manage ribavirin-associated hemoglobin decreases
• Definitions of response
  • RVR: undetectable HCV RNA (< 50 IU/mL) at Week 4
  • Complete EVR (cEVR): undetectable HCV RNA at Week 12
  • pEVR: ≥ 2 log₁₀ decrease in HCV RNA at Week 12 but detectable
  • EOT: undetectable HCV RNA at Week 48
  • SVR: undetectable HCV RNA at 24 weeks after end of therapy
  • Relapse: detectable HCV RNA after EOT response or missing HCV RNA value 24 weeks after EOT response
• Assessments
  • Ribavirin exposure as percentage of target dose
  • Multiple logistic regression analysis to identify factors predictive of relapse in patients with undetectable HCV RNA at end of treatment (2 models)
    • Model 1: ribavirin reductions as continuous factor—10%, 20%, and 50% reduction of target dose
    • Model 2: ribavirin dose as categorized factor—< or ≥ 80% of target dose

Main Findings

• On-treatment virologic response during first 12 weeks of treatment with peginterferon alfa-2a/ribavirin influences relapse rate

On-Treatment Response, %	Relapse Rate (N = 374)
Overall	28
RVR	4
cEVR	24
pEVR	56
No RVR/EVR	62

• Reduced cumulative ribavirin exposure independently and significantly predicts relapse rates
  • Individuals receiving 50% of ribavirin target dose more than twice as likely to relapse vs individuals receiving target dose
• Risk of relapse increases gradually with amount of dose reduction

Cumulative Ribavirin Exposure	Odds Ratio for Relapse (95% Confidence Interval)	P Value
Model 1: decrease from target dose
10%	1.2 (1.0-1.3)	.0257
20%	1.4 (1.0-1.8)	.0257
50%	2.1 (1.1-4.2)	.0257
Model 2
< 80% vs ≥ 80% of target dose	1.7 (1.0-3.0)	.0444

Other Outcomes

• Other independent baseline factors significantly predicting increased risk of relapse
  • Older age
  • Higher body mass index
  • Higher HCV RNA
  • Lower ALT quotient

Factor	Odds Ratio (95% Confidence Interval)	P Value
Age, per 10-yr increment
Model 1	1.4 (1.1-1.8)	.0085
Model 2	1.4 (1.1-1.8)	.0066