Low SVR Rates for Treatment-Naive Genotype 1 HCV-Infected Patients With Advanced Fibrosis or Cirrhosis at Baseline: Results of Canadian POWeR Study

Posting Date: November 06, 2008

• Prospective Optimal Weight-Based Dosing Response (POWeR) study: prospective, open-label, noninterventional, phase IV study^[1]

Summary of Key Conclusions

• Lower rates of sustained virologic response (SVR) for genotype 1 HCV-infected patients with advanced fibrosis or cirrhosis compared with patients with mild to moderate fibrosis at baseline
• High baseline fibrosis scores associated with lower SVR and higher relapse rate compared with lower baseline fibrosis scores among genotype 1 patients
• Baseline HCV RNA had no effect on SVR among genotype 1 patients with advanced fibrosis or cirrhosis
  • Baseline HCV RNA predicts SVR only among patients with mild to moderate fibrosis

Background

• 54% to 63% of all patients with chronic HCV infection treated with peginterferon alfa-2b/ribavirin achieve SVR^[2-4]
  • SVR rates lower for genotype 1 patients ^[2-4]
• Baseline HCV RNA and fibrosis stage identified as predictors of treatment outcome in genotype 1 patients
  • SVR rates higher in patients with low HCV RNA^[4]
  • SVR rates lower in patients with bridging fibrosis or cirrhosis at baseline^[4]
• Above results attained in randomized clinical trials that strictly control enrollment and treatment regimens
  • Results may not apply in real-life clinical practice settings
• Current study assessed impact of advanced liver disease on SVR rates in previously untreated, genotype 1 HCV-infected patients treated with weight-based peginterferon alfa-2b/ribavirin in real clinical practice

Summary of Study Design

• Prospective, observational study
• Collected data only—no study-related intervention
• 138 community and academic centers in Canada 2002-2007
• Patients characterized at baseline for
  • Genotype
  • Liver histology by METAVIR score: F1 (= mild) to F4 (= cirrhosis)
  • HCV RNA (low: ≤ 600,000 IU/mL; high: > 600,000 IU/mL)
• Patients treated according to current treatment guidelines or standard of care at each site
  • Peginterferon alfa-2b 1.5 µg/kg/week plus ribavirin
  • Ribavirin dose weight based
    • < 64 kg: 800 mg/day
    • 64 - < 85 kg: 1000 mg/day
    • ≥ 85 kg: 1200 mg/day
  • Recommended treatment duration: 48 weeks
• Efficacy analyses
  • Primary endpoint: SVR (undetectable HCV RNA 24 weeks posttreatment)
  • Secondary endpoints
    • End-of-treatment (EOT) response: undetectable HCV RNA at completion of therapy
    • Relapse: undetectable HCV RNA at EOT but detectable during 24 weeks posttreatment
  • Intent-to-treat (ITT) analysis on all patients with liver biopsy and who received 1 treatment dose

Baseline Characteristics

• 718 genotype 1 HCV-infected patients with baseline METAVIR scores
  • Mild to moderate fibrosis (F1-F2): 432/718 (60%)
  • Bridging fibrosis-cirrhosis (F3-F4): 286/718 (40%)
• Baseline HCV RNA available for 651/718 (91%) patients
  • High HCV RNA(> 600,000 IU/mL): 356/651 (55%)
  • Low HCV RNA(≤ 600,000 IU/mL): 295/651 (45%)
• Combined baseline fibrosis and HCV RNA characteristics (n = 651)
  • Among 391 patients with mild to moderate fibrosis (F1-F2)
    • 56% had high HCV RNA
    • 44% had low HCV RNA
  • Among 260 patients with advanced fibrosis-cirrhosis (F3-F4):
    • 52.7% had high HCV RNA
    • 47.3% had low HCV RNA

Main Findings

• Overall SVR rate: 38% (ITT: n=718)
• SVR rate highest in patients with mild fibrosis (F1) at baseline, lowest in patients with baseline cirrhosis (F4)

Outcome, %	F1 (n = 180)	F2 (n = 252)	F3 (n = 152)	F4 (n = 134)	P Value (F1 vs F3 or F4)
SVR, %	52	46	26	18	<.0001

• SVR and EOT responses significantly higher in patients with baseline mild to moderate fibrosis (F1-F2) compared with those with baseline fibrosis or cirrhosis (F3-F4)

Outcome, %	Baseline Fibrosis F1-F2 (n = 432)	Baseline Fibrosis F3-F4 (n = 286)	P Value
SVR	48	22	<.0001
EOT	59	34	<.0001

• Relapse rates also higher in F3-F4 patients vs F1-F2: 35% vs 18%, respectively (P = .0009)
• Virologic response by baseline HCV RNA (n = 651)
  • Among patients with mild to moderate fibrosis (F1-F2) and baseline HCV RNA assessment (n= 391), SVR rates significantly higher for patients with low HCV RNA

Outcome, %	HCV RNA ≤ 600,000 IU/mL (n = 172)	HCV RNA > 600,000 IU/mL (n = 219)	P Value
SVR	58	41	.0008

• Among patients with bridging fibrosis or cirrhosis (F3-F4) and baseline HCV RNA assessment (n = 260), no significant difference in SVR rate by HCV RNA