Increasingly, Human immunodeficiency virus, HIV/ hepatitis C virus, HCV co-infected patients are being offered treatment for concomitant HCV infection. Combination therapy with pegylated interferon (pIFN) and ribavirin (RBV) delivers a sustained response to HCV infection if levels are sufficient to ensure adequate HCV clearance (Torrani et al., 2004). Intracellular phosphorylation of RBV and nucleoside analogues defines their efficacy and toxicity. Adverse effects such as anaemia are more severe in treated co-infected compared with mono-infected patients, forcing RBV dose reduction and compromising efficacy. As zidovudine (ZDV), stavudine (d4T) and RBV are substrates for the thymidine phosphorylation pathway, concerns remain that drug interactions may reduce antiretroviral (ARV) efficacy. We examined the relationships between haematological toxicity, RBV levels and intracellular triphosphate levels in peripheral blood mononuclear cells (PBMCs) of HIV/HCV co-infected patients treated with pIFN/RBV (without dose reduction).

Prospective, observational cohort study of HIV/HCV co-infected patients treated with pIFN (1.5mg kg ^-1) / RBV (1000/1200 mg) for 12 weeks. A pharmacokinetic investigation of the effect of this regimen on intracellular ZDV (n=6), d4T (n=5), and lamivudine (3TC; n=9) triphosphate levels was also undertaken. Blood was reserved at baseline and on days 3 and 14, and cell counts estimated. Intracellular triphosphate and endogenous nucleotide triphosphate levels in PBMCs were determined using a template primer extension assay. Plasma RBV levels were assayed by HPLC and cytotoxicity determined using a MTT assay. Data were analysed by repeated measures ANOVA with post hoc analysis.

The 12 wk response rate (non genotype 1) was 86%, with no loss of antiretroviral efficacy. RBV levels increased between day 3 and day 14 (5.6 ± 1.7 vs 11.4 ± 2.14 µ g.h.ml^-1). Haemoglobin decreased (13.9±0.7 vs 9.6±1.4g l^-1; P<0.001) and lactate dehydrogenase levels were increased (860±250 vs 420±100U; P<0.001) by day 14 in patients receiving ZDV compared with baseline. Cytotoxicity was observed in the PBMCs of RBV treated co-infected patients but not those of healthy controls. ZDV phosphorylation decreased by 44% (ZDVTP/dTTP ratio: 3.5±1.9 vs 2.18±0.5; P<0.02) from day 3 onwards. This represented a 1.8 fold increase in ZDVTP, but a 2.95 fold increase in dTTP (for ZDV) levels. The 3TCTP/dCTP ratio and the d4TTP/dTTP ratio and dTTP (for d4T) concentration were unchanged.

In conclusion, the RBV/ZDV combination caused significant haematological toxicity compared with other regimens. This was managed without RBV dose reduction and did not result in loss of ARV efficacy. Reports suggest RBV increases the endogenous dTTP pool providing negative feedback on thymidine kinase reducing ZDV phosphorylation. While we show a reduction in the ZDV phosphorylation ratio and an increase in dTTP (for ZDV), dTTP (for d4T) was unaltered, indicating that RBV does not cause a universal rise in dTTP levels. This may be explained by selective upregulation of thymidine kinase by the combined presence of RBV and ZDV, but not RBV/d4T.

Torrani, FJ et al., (2004) New Engl. J. Med, 351, 436-450.