Weight-based Ribavirin Increases Sustained Response Rate among HIV-HCV Coinfected Genotype 1 Patients, but also Raises Risk of Anemia  

By Liz Highleyman

Numerous past studies of both hepatitis C virus (HCV) monoinfected and HIV-HCV coinfected patients have shown that an adequate dose of ribavirin helps prevent HCV relapse after completion of interferon-based therapy.

However, ribavirin can cause anemia as a side effect, which sometimes necessitates dose reduction or drug discontinuation. The risk increases among coinfected patients taking AZT (zidovudine; Retrovir), which can also cause anemia; current HIV-HCV coinfection treatment guidelines recommend that the 2 drugs not be used together.

It is now well established that HCV monoinfected genotype 1 patients have a likelihood of sustained response if they start ribavirin at a weight-based dose of 1000-1200 mg/day compared with the fixed 800 mg/day dose used in earlier trials. Recent data suggest this is also true for HIV-HCV coinfected patients.

In an analysis presented at the 58th Annual Meeting of the American Association for the Study of Liver Diseases in Boston (November 2-6, 2007), researchers used a mathematical model to estimate the trade-off between improved response rates and higher incidence of anemia in the APRICOT trial.

APRICOT included 868 HCV-HIV coinfected patients in 19 countries with compensated liver disease, stable HIV disease, and a CD4 count above 100 cells/mm³. Participants were randomly assigned to receive conventional interferon plus 800 mg/day ribavirin, pegylated interferon alfa-2a (Pegasys) plus placebo, or pegylated interferon plus ribavirin for 48 weeks. The 800 mg/day ribavirin dose was selected to minimize hematological toxicities and the potential for drug interactions with NRTIs. The SVR rate was highest in the pegylated interferon plus ribavirin arm: 40% overall, 29% for patients with HCV genotype 1, and 62% for those with genotypes 2/3.

In the present analysis, binary data from 176 genotype 1 patients in APRICOT were incorporated into an existing generalized additive model established with data from 817 HCV monoinfected genotype 1 patients enrolled in 2 Phase III clinical trials. The effect of prognostic factors on SVR and anemia (defined as hemoglobin < 10 g/dL) were analyzed, and simulations were run with the updated model to predict SVR rates and the incidence of anemia in coinfected genotype 1 patients treated if they had been treated with pegylated interferon plus 1000-1200 mg/day ribavirin.

Results

• After incorporating data from APRICOT, significant predictors of SVR retained in the model included:

• Patient age;
• HIV status (positive or negative);
• Baseline HCV viral load;
• Baseline ALT;
• Histological diagnosis (cirrhosis vs no cirrhosis);
• Ribavirin dose.

 

• Factors that significantly predicted anemia included:

• Patient age;
• Patient sex;
• HIV status;
• Baseline HCV viral load;
• Baseline ALT;
• Baseline hemoglobin level;
• Ribavirin dose.

 

• Use of 1000-1200 mg/day ribavirin in coinfected genotype 1 patients was predicted to increase the SVR rate by 8% (from 29% to 37%), and the incidence of anemia from 14% to 23%.

“Our simulations suggest that increasing ribavirin dose to 1000-1200 mg/day would improve SVR rates in patients coinfected with HIV and HCV genotype 1,” the researchers concluded.

“However, higher doses of ribavirin would also be associated with a higher incidence of anemia,” they added. “Therefore, hemoglobin levels should be monitored closely and the ribavirin doses should be decreased in small decrements to preserve chances for higher end of treatment responses and to prevent relapses.”

11/30/07

Reference
F Torriani, M. Rodriguez-Torres, J Rockstroh, and others. Outcomes in HIV-HCV Co-infected Genotype 1 Patients Treated with Peginterferon alfa-2a (40KD) plus Ribavirin (RBV) 1000/1200 mg/d: Predictions Based on a Generalized Additive Model (GAM). AASLD 2007. Abstract 1333.