Use of Growth Factors to Prevent Peginterferon alfa-2b/Ribavirin Dose Reductions Does Not Improve SVR Rates in Small Genotype 1 HCV Study

Posting Date: November 05, 2008

• Randomized trial

Summary of Key Conclusions

• Preemptive use of adjuvant growth factors to prevent dose reduction due to peginterferon alfa-2b/ribavirin-associated cytopenias did not produce higher sustained virologic response (SVR) rates compared with standard therapy in treatment-naive patients with genotype 1 HCV
• Numerically more patients who received standard peginterferon alfa-2b/ribavirin vs peginterferon alfa-2b/ribavirin plus adjuvant therapy had dose reductions, yet numerically more of these patients attained SVR (P = NS for both)

Background

• Peginterferon alfa-2b/ribavirin for 48 weeks of standard therapy for genotype 1 HCV
• Hematologic toxicity associated with peginterferon alfa-2b/ribavirin a common reason for dose reduction/discontinuation in treated patients
  • Dose reduction/discontinuation can compromise virologic response
  • Growth factors sometimes used to prevent dose reductions due to cytopenias
    • No evidence that this approach improves virologic response
• Current study compared virologic efficacy of standard therapy with peginterferon alfa-2b/ribavirin vs peginterferon alfa-2b/ribavirin plus adjuvant therapy with growth factors preemptively targeting hematologic toxicity in treatment-naive patients chronically infected with genotype 1 HCV

Schematic of Study Design

• Criteria for drug dose adjustments

Laboratory Parameter (Drug Reduced)	Standard Therapy		Adjuvant Therapy
	Dose Reduction	Drug Discontinuation	Start Adjuvant Therapy	Dose Reduction	Drug Discontinuation
Hemoglobin	< 10.0 g/dL (ribavirin)	< 8.5 g/dL(ribavirin)	< 12.0 g/dL or < 75% of baseline(ribavirin)	< 10.0 g/dL (ribavirin)	< 8.5 g/dL(ribavirin)
Granulocyte count, cells/mm3	< 750 (peginterferon)	< 500(peginterferon)	< 900 (peginterferon)	< 750 (peginterferon)	< 500(peginterferon)
Platelet count, cells/mm3	< 80,000(peginterferon)	< 50,000(peginterferon)		< 55,000(peginterferon)	< 30,000(peginterferon)
Indirect bilirubin, mg/dL	> 5 (ribavirin)	> 4 for 4 weeks		> 5 (ribavirin)	> 4 for 4 weeks
Creatinine, mg/dL		> 2			> 2
AST or ALT, U/L		> 1000			> 1000

Eligibility

• Standard inclusion/exclusion criteria used

Baseline Characteristics

• Baseline characteristics generally well balanced between treatment arms, except that adjuvant-therapy arm had slightly higher proportion of males and blacks

Characteristic	Standard Therapy (n = 78)	Adjuvant Therapy (n = 74)
Mean age, yrs ± SD	46 ± 8	46 ± 9
Male, n (%)	47 (60)	51 (69)
Race, n (%)
White	61 (78)	53 (72)
Black	11 (14)	17 (23)
Hispanic	6 (8)	4 (5)
Mean HCV RNA, IU/mL	4.4 x 106	4.4 x 106
High HCV RNA, %	78	70
Mean fibrosis stage (± SD)	1.48 ± 1	1.82 ± 1
METAVIR stage F3/F4, n (%)	14 (18)	19 (25)

Description of Current Analysis

• Primary endpoints
  • End-of-treatment response
  • SVR
• Secondary endpoint
  • Safety

Main Findings

• No difference in virologic response rate observed between standard-therapy and adjuvant-therapy arms