Early ribavirin pharmacokinetics, HCV RNA and alanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with pegylated interferon and ribavirin

Abstract

Background/aims: We evaluated whether early ribavirin pharmacokinetics differ comparing hepatitis C/human immunodeficiency virus coinfected sustained virological responders and nonresponders.

Methods: Twenty-four treatment-naive coinfected patients received pegylated-interferon alfa-2b (12 kDa) (1.5 microg/kg) once weekly plus daily ribavirin (13.6 mg/kg/d) for up to 48 weeks. Serum HCV RNA, serum alanine aminotransferase, and plasma ribavirin levels were measured frequently during the first 16 days of therapy and monthly thereafter.

Results: Six patients were sustained responders. During the first 4 weeks of treatment, median plasma ribavirin levels and area under the ribavirin curve were significantly lower (p<0.0001 and p<0.01, respectively) in sustained responders compared with nonresponders. Compared to ribavirin levels at weeks 2 and 4, ribavirin levels in sustained responders continued to increase significantly until week 8 (p<0.02). At week 4, hemoglobin declines were significantly (p=0.002) greater in sustained responders than nonresponders. At week 1, serum HCV RNA levels and changes in alanine aminotransferase levels relative to baseline could identify likely responders better than plasma ribavirin levels.

Conclusions: We conjecture that intracellular ribavirin accumulation may be enhanced early in treatment in coinfected sustained responders, although this hypothesis should be investigated further. At week 1, serum HCV RNA and changes in alanine aminotransferase levels relative to baseline might identify likely responders.

Fig. 1

A) Plasma ribavirin levels during the first 28 days of treatment for individual patients stratified according to treatment outcome, sustained virological responders (SVRs) and nonresponders (NRs). B) Differences in median ribavirin (RBV) concentration in plasma during the first 18 weeks of treatment in SVRs and NRs. C) Cubic spline fit of median RBV levels during the first week for SVRs and NRs. An exact cubic spline was fit using the R spline function according to the Forsythe, Malcolm, and Moler method [35]. D) Differences in median RBV area under the curve during the first 8 days of treatment between SVRs and NRs. RBV area under the curve was significantly lower in SVRs compared with NRs for the first 28 days of treatment (p<0.01).

Fig. 2

A) Median alanine aminotransferase (ALT) decline from baseline in sustained virological responders (SVRs) and nonresponders (NRs) during the first four weeks of pegylated interferon and ribavirin treatment. B) Changes in log₁₀HCV RNA in SVRs, end of treatment responders (ETRs) and NRs during the first 28 days of pegylated interferon and ribavirin treatment. C) Median HCV RNA decline from baseline in SVRs and NRs during the first 28 days of pegylated interferon and ribavirin treatment. Dotted line indicates level of assay detection for HCV RNA (29 IU/ml).