Stavudine:pharmacology,clinical use and future role

Stavudine is a nucleoside analogue reverse transcriptase inhibitor of HIV-1 and HIV-2 and demonstrates in vitro activity with an acceptable therapeutic index in a range of T-lymphocyte and haematopoietic precursor cell lines. It is additive or synergistic in vitro with a range of other antiretrovirals, including the proteinase inhibitor saquinavir, in two- and three-way combinations and is active against zidovudine (ZDV)-resistant virus. It exhibits excellent oral bioavailability, with cerebrospinal fluid (CSF)/plasma penetration. In clinical use, stavudine monotherapy exhibits similar antiretroviral activity to ZDV, and is of proven clinical benefit in ZDV-pre-treated patients. In combination with ddI and/or nelfinavir it results in more substantial and durable responses in immunological and virological markers than reported with either drug alone. Further data on stavudine in combination with other antiretrovirals are now awaited. Comparative trials in ZDV-experienced patients suggest a similar frequency of adverse events to that observed with ZDV. Peripheral neuropathy is the most common dose-limiting toxicity, with haematological and hepatic function disturbance being infrequent. Resistance to stavudine develops slowly in vitro and in vivo but may lead to co-resistance to ZDV or ddI. Stavudine will be used clinically as a combination agent both in initial therapy and in patients with prior ZDV experience.