Lack of interference between ribavirin and nucleosidic analogues in HIV/HCV co-infected individuals undergoing concomitant antiretroviral and anti-HCV combination therapy.

Abstract

HIV and hepatitis C virus (HCV) share parenteral routes of transmission through exposure to contaminated blood. The prevalence of HCV seropositivity among HIV-infected homosexual/bisexual men and intravenous drug users has been reported to be 10 and 80%, respectively [1]. Co-infection with HIV alters the clinical course of hepatitis C by inducing a more rapid progression to fibrosis and cirrhosis [2]. The morbidity and mortality rate from liver disease is thus higher in co-infected patients than in immunocompetent patients infected with HCV alone [3], emphasizing the need for active therapeutic intervention to treat HCV infection in co-infected patients [4]. On the basis of the promising results of combination therapy with IFN-α and ribavirin for chronic hepatitis C in immunocompetent individuals [5], we have recently engaged in an open prospective trial of this combination therapy in patients co-infected with HCV and HIV [6]. As ribavirin, zidovudine (ZDV) and stavudine (D4T) are metabolized to their triphosphate active forms by thymidine kinase, ribavirin has been suggested to reduce the intracellular phosphorylation of nucleosidic reverse transcriptase inhibitors [7]. No data are, however, available at this time on the clinical relevance of this putative antagonistic interaction. We have investigated the changes in plasma HIV-RNA levels during and after combination therapy with IFN and ribavirin in the first 38 HIV/HCV co-infected patients of our cohort undergoing stable antiretroviral therapy to reach 6 months of follow-up after discontinuation of a 6 or 12 month course of IFN and ribavirin. Nineteen of the 38 patients had been treated with a combination of two nucleosidic analogues, D4T and lamivudine (3TC) (n = 15) or ZDV and 3TC (n = 4) for a mean duration of 20 ± 10 months before the initiation of IFN and ribavirin. The remaining 19 patients had been treated with a triple combination antiretroviral regimen including a protease inhibitor with D4T and 3TC (n = 13) or ZDV and 3TC (n = 6) for a mean duration of 24 ± 8 months. The patients did not change their antiretroviral regimen throughout the period of the study. Seven patients received IFN (3 MU three times a week) and ribavirin (1000 mg per day) combination therapy for 6 months and 31 patients were treated for 12 months, depending on the severity of histological lesions in the pretreatment liver biopsy. The mean duration of HIV and HCV-targeted therapies was similar in the group of patients treated with double combination nucleosidic antiretroviral therapy and in the group receiving triple combination antiretroviral therapy. The plasma levels of HIV RNA were measured using the Quantiplex HIV-RNA 2.0 assay (Chiron, Emeryville, CA, USA.) with a threshold of detection of 500 copies/ml. The number of CD4 T cells was assessed by conventional cytofluorometric methods. Statistical evaluation was performed using the Wilcoxon signed-rank test. As shown in Table 1, the mean plasma HIV-RNA levels did not differ between baseline (before initiation of IFN and ribavirin), the time at which IFN and ribavirin were discontinued and at 6 monrths after discontinuation of IFN and ribavirin. As described previously by others in patients receiving IFN alone, the absolute number of CD4 cells decreased significantly during IFN treatment and returned to baseline values thereafter, suggesting that CD4 cells are trapped in extravascular sites during therapy with IFN [8]. Our observations strongly argue against the in-vivo relevance of the in-vitro competition between ribavirin, D4T and ZDV for intracellular phosphorylation. Ribavirin may thus be initiated in HIV/HCV co-infected patients receiving ZDV or D4T without switching reverse transcriptase inhibitors.Table 1: Changes in CD4 cell counts and plasma HIV viral load in HIV/hepatitis C virus co-infected patients treated with antiretroviral drugs and IFN in combination with ribavirina. Alain Landaua Dominique Batisse Christophe Piketty Raymond Jiana Michel D. Kazatchkine