ZALCITABINE - AN UPDATE OF ITS PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES AND CLINICAL EFFICACY IN THE MANAGEMENT OF HIV-INFECTION

Zalcitabine is a dideoxynucleoside antiretroviral agent that is phosph orylated to the active metabolite 2',3'-dideoxycytidine 5'-triphosphat e (ddCTP) within both uninfected and HIV-infected cells. At therapeuti c concentrations, ddCTP inhibits HIV replication by inhibiting the enz yme reverse transcriptase and terminating elongation of the proviral D NA chain. The results of 3 large pivotal trials comparing zidovudine m onotherapy with combination therapy have now clearly established that zalcitabine plus zidovudine combination therapy improves survival, del ays disease progression and is associated with art improvement in vira l load and CD4+ cell count compared with zidovudine monotherapy. More recently, clinical end-point and surrogate marker data have establishe d the efficacy of zalcitabine in combination with the protease inhibit or saquinavir in zidovudine-experienced patients. Other studies have d emonstrated the utility of zalcitabine in combination with ritonavir a nd the nucleoside analogue lamivudine. Importantly early use of zalcit abine in the treatment sequence does not appear to limit the therapeut ic efficacy of subsequent therapy with other nucleoside analogues such as lamivudine. Peripheral neuropathy is the most frequent dose-limiti ng adverse effect associated with zalcitabine therapy and is generally reversible on discontinuation of treatment. Stomatitis and mouth ulce rs may occur frequently with zalcitabine therapy bur tend to resolve w ith continuing treatment. Haematological toxicity, which is a common a dverse effect associated with zidovudine, is reported infrequently wit h zalcitabine. Overall, combination therapy with zalcitabine plus zido vudine or saquinavir has been shown to have a tolerability profile com parable to that of either agent alone, although treatment with zidovud ine plus zalcitabine was associated with a significant increase in the incidence of haematological toxicity compared with zidovudine monothe rapy in one study. Therefore, current data suggest that zalcitabine is a useful antiretroviral agent for inclusion as a component of initial double combination therapy with zidovudine or as part of triple combi nation therapy including zidovudine plus a protease inhibitor in the m anagement of patients with HIV infection.