Zalcitabine

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Abstract
Zalcitabine is a dideoxynucleoside antiretroviral agent that is phosphorylated to the active metabolite 2′,3′-dideoxycytidine 5′-triphosphate (ddCTP) within both uninfected and HIV-infected cells. At therapeutic concentrations, ddCTP inhibits HIV replication by inhibiting the enzynie reverse transcriptase and terminating elongation of the proviral DNA chain. The results of 3 large pivotal trials comparing zidovudine monotherapy with combination therapy have now clearly established that zalcitabine plus zidovudine combination therapy improves survival, delays disease progression and is associated with an improvement in viral load and CD4+ cell count compared with zidovudine monotherapy. More recently, clinical end-point and surrogate marker data have established the efficacy of zalcitabine in combination with the protease inhibitor saquinavir in zidovudine-experienced patients. Other studies have demonstrated the utility of zalcitabine in combination with ritonavir and the nucleoside analogue lamivudine. Importantly, early use of zalcitabine in the treatment sequence does not appear to limit the therapeutic efficacy of subsequent therapy with other nucleoside analogues such as lamivudine. Peripheral neuropathy is the most frequent dose-limiting adverse effect associated with zalcitabine therapy and is generally reversible on discontinuation of treatment. Stomatitis and mouth ulcers may occur frequently with zalcitabine therapy but tend to resolve with continuing treatment. Haematological toxicity, which is a common adverse effect associated with zidovudine, is reported infrequently with zalcitabine. Overall, combination therapy with zalcitabine plus zidovudine or saquinavir has been shown to have a tolerability profile comparable to that of either agent alone, although treatment with zidovudine plus zalcitabine was associated with a significant increase in the incidence of haematological toxicity compared with zidovudine monotherapy 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 combination therapy including zidovudine plus a protease inhibitor in the management of patients with HIV infection. Zalcitabine is phosphorylated to the active antiviral compound 2′,3′-dideoxy-cytidine 5′-triphosphate (ddCTP) within both uninfected and HIV-infected cells. ddCTP inhibits HIV replication by inhibition of the enzyme reverse transcriptase and termination of viral DNA chain elongation. In both these roles ddCTP competes with endogenous deoxycytidine triphosphate. Zalcitabine has demonstrated significant antiretroviral activity against HIV-1 in vitro. In addition, synergistic antiretroviral activity has been reported for zalcitabine in combination with several other antiretroviral agents including zidovudine, stavudine and saquinavir. Resistance to zalcitabine usually arises from a series of mutations within the HIV pol gene and develops less frequently than resistance to zidovudine. Cross-resistance between zidovudine and zalcitabine has been described. The activation state of the target cell, whether the cell under investigation is acutely or chronically infected with HIV, and/or the levels of intracellular phosphorylating enzymes may also contribute to variation in the antiviral activity of zalcitabine between cell lines. In vitro investigations suggest that zalcitabine-induced inhibition of an enzyme responsible for the synthesis of mitochondrial DNA (DNA polymerase γ) may be responsible for the development of peripheral neuropathy in clinical practice. Following oral administration, zalcitabine is rapidly absorbed, with peak plasma concentrations typically achieved in 1 to 2 hours. The oral bioavailability of zalcitabine exceeded 80% in some studies. Zalcitabine partially crosses the blood-brain barrier; drug concentrations in the CSF represented a mean of 14 to 20% of simultaneously measured plasma concentrations. Placental transfer of zalcitabine has been reported in vitro and in vivo. Zalcitabine has a short plasma elimination half-life of 1.1 to 1.8 hours and is predominantly excreted unchanged in the urine. Hepatic metabolism of the drug is minimal and only about 10% of an orally administered dose is excreted in the faeces. The results of 3 large pivotal studies, ACTG 175, CPCRA 007 and Delta, have clearly demonstrated that combination therapy with zidovudine plus zalcitabine or zidovudine plus didanosine improves survival and delays disease progression compared with zidovudine monotherapy. Although not exclusively limited to zidovudine-naive patients, the benefits of zalcitabine plus zidovudine therapy appear to be greater in this patient population than in zidovudine-experienced patients. Improvements in surrogate marker and clinical end-points have also been reported in zidovudine-experienced patient populations with advanced HIV infection (CD4+ cell count 50 to 300 cells/μl) treated with 2- or 3-drug combination regimens comprising zalcitabine plus the protease inhibitor saquinavir ± zidovudine. Zalcitabine has also demonstrated utility in combination with the protease inhibitor ritonavir as first-line treatment in a pilot study. Impressive surrogate marker data have also been reported in zidovudine-experienced patients receiving a 3-drug regimen comprising lamivudine, zalcitabine and zidovudine. Furthermore, the addition of lamivudine ± loviride to ongoing therapy with zidovudine plus zalcitabine in patients with advanced HIV infection was associated with a greater reduction in disease progression compared with the addition of lamivudine ± loviride to zidovudine alone. This therefore suggests that prior use of zalcitabine does not limit the subsequent utility of other nucleoside analogues such as lamivudine. Peripheral neuropathy is...