STAVUDINE - A REVIEW OF ITS PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES AND CLINICAL POTENTIAL IN HIV-INFECTION

Stavudine is a nucleoside analogue which undergoes intracellular phosp horylation to its active metabolite, stavudine-5'-triphosphate. At cli nically relevant concentrations, the active metabolite restricts HIV r eplication by inhibiting the inclusion of thymidine-5'-triphosphate in to proviral DNA by HIV reverse transcriptase, and/or by causing DNA ch ain termination. Viral resistance to stavudine does not commonly devel op during treatment. Where it has developed, up to a 12-fold increase in resistance has been observed in clinical isolates from patients tre ated with stavudine for long periods. Stavudine 40mg twice daily and z idovudine 200mg 3 times daily were compared in 822 patients at various stages of HIV infection who had previously received long term zidovud ine therapy. Stavudine was superior for both primary and surrogate end -points including clinical progression, treatment failure, increase in CD4+ cell counts and bodyweight gain. In a larger study, stavudine 40 mg twice daily provided greater benefit than stavudine 20mg twice dail y in terms of weight gain, haematological findings and the number of h ospitalisations in 11 784 patients intolerant of, resistant to, zidovu dine and didanosine. Peripheral neuropathy is the major dose-limiting adverse event associated with stavudine therapy and occurred more freq uently with stavudine than zidovudine. However, haematological adverse events were observed less frequently with stavudine than with zidovud ine. Thus, stavudine is effective in alleviating signs and symptoms of HIV infection in patients intolerant of, or no longer responding to, zidovudine or didanosine. It is also more effective than zidovudine in slowing disease progression in patients previously treated with zidov udine for long periods. The results of studies which will reveal the r ole of stavudine therapy in untreated patients and in combination with other anti-HIV agents are awaited with interest.