Stavudine: an update of its use in the treatment of HIV infection.
Stavudine is a thymidine nucleoside analogue which is phosphorylated intracellularly to an active metabolite, stavudine 5'-triphosphate. This metabolite inhibits HIV replication, either by competing with thymidine 5'-triphosphate for incorporation into viral DNA by reverse transcriptase or by causing 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 resistance is uncommon even after long periods of treatment. Initial treatment with stavudine-containing triple therapies reduced HIV RNA 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. Effects on clinical outcomes have not yet been established, although earlier trials 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 efficacy of stavudine-containing triple therapy was similar to that of zidovudine-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 antiretroviral-experienced patients receiving stavudine and 2 or 3 other antiretroviral agents. Stavudine-containing combination therapies have also been effective in reducing viral load and increasing CD4+ lymphocyte count in children, although data are limited. Like other nucleoside analogues, stavudine treatment can cause mitochondrial toxicity. The major adverse effect from this observed with stavudine therapy is peripheral neuropathy, which is both dosage- and treatment duration-dependent. Most cases respond to short term cessation of treatment and reintroduction of stavudine at half the previous dosage.


CONCLUSIONS
Stavudine-containing triple therapies are effective in the treatment of antiretroviral-naive adults with HIV infection as assessed by surrogate 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-experienced patients and children with HIV infection, although data are limited and more studies are needed. High-level resistance to stavudine is uncommon. The major adverse event associated with treatment is peripheral neuropathy, which may limit its use in some patients. Currently, stavudine has a valuable role as part of initial triple therapy in antiretroviral-naive adults with HIV/AIDS.
Hurst
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Adis International Limited, Mairangi Bay, Auckland, New Zealand. demail@adis.co.nz
Noble
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D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D018119:Stavudine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D018119:Stavudine