Stavudine - An update of its use in the treatment of HIV infection

Stavudine is a thymidine nucleoside analogue which is phosphorylated intrac ellularly to an active metabolite, stavudine 5'-triphosphate. This metaboli te inhibits HIV replication, either by competing with thymidine 5'-triphosp hate for incorporation into viral DNA by reverse transcriptase or by causin g premature termination of the viral chain after incorporation. Resistance to stavudine, either alone or as part of resistance to multiple nucleoside reverse transcriptase inhibitors, has been reported; however, high-level re sistance is uncommon even after long periods of treatment. Initial treatment with stavudine-containing triple therapies reduced HIV RN A levels to below the limit of detection (LOD; 500 copies/ml) in 68 to 100% of antiretroviral-naive patients after at least 20 weeks of treatment. Eff ects on clinical outcomes have not yet been established, although earlier t rials showed significant improvements with stavudine (alone or with 1 other drug) in patients who had previously received zidovudine. Results from 2 randomised nonblind clinical trials indicated that the effic acy of stavudine-containing triple therapy was similar to that of zidovudin e-containing triple therapy (when used in combination with the same drugs), although there were no statistical comparisons. Improvements in surrogate end-points have also been seen in trials in antir etroviral-experienced patients receiving stavudine and 2 or 3 other antiret roviral agents. Stavudine-containing combination therapies have also been e ffective in reducing viral load and increasing CD4+ lymphocyte count in chi ldren, although data are limited. Like other nucleoside analogues, stavudine treatment can cause mitochondria l toxicity. The major adverse effect from this observed with stavudine ther apy is peripheral neuropathy, which is both dosage- and treatment duration- dependent. Most cases respond to short term cessation of treatment and rein troduction of stavudine at half the previous dosage. Conclusion: Stavudine-containing triple therapies are effective in the trea tment of antiretroviral-naive adults with HIV infection as assessed by surr ogate end-points; earlier trials involving 1 or 2-drug therapy showed that stavudine can significantly improve clinical end-points. Stavudine has also been beneficial as part of combination regimens in antiretroviral-experien ced patients and children with HIV infection, although data are limited and more studies are needed. High-level resistance to stavudine is uncommon. T he major adverse event associated with treatment is peripheral neuropathy, which may limit its use in some patients. Currently, stavudine has a valuab le role as part of initial triple therapy in antiretroviral-naive adults wi th HIV/AIDS.