Stavudine

Abstract

Stavudine is a thymidine nucleoside analogue which is phosphorylated intracel-lularly 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 anti-retroviral-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. Conclusion: 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. Stavudine is a thymidine nucleoside analogue which enters cells by passive diffusion and subsequently undergoes intracellular phosphorylation to the active metabolite stavudine 5′-triphosphate. This metabolite competes with thymidine 5′-triphosphate for incorporation into viral DNA by reverse transcriptase and, if successfully incorporated, causes premature termination of the viral RNA chain. It is unclear which of these effects is primarily responsible for the inhibition of HIV replication observed. In vitro studies have found that stavudine can inhibit HIV in a variety of human T cell lines, with 50% viral inhibition generally occurring at concentrations of 0.05 to 0.5 µmol/L (IC50). Comparative studies indicate that, according to IC50 values, stavudine is 5- to 10-fold less potent than zidovudine. Additive and/or synergistic effects against HIV-1 in cell culture were seen when stavudine was combined with other antiretroviral agents. Stavudine-containing therapies (dual or triple) decreased CSF levels of HIV RNA to undetectable levels in clinical trials. In addition, 1 study in antiretroviral-naive patients with deteriorating mental function found that motor function improved and mental status stabilised after 1 year of treatment with stavudine. Both genotypic and phenotypic resistance to stavudine have been detected in in vitro and in vivo studies, with increases in IC50 of = 6- to 12-fold compared with either baseline values or a reference isolate. Mutations associated with resistance to stavudine alone are uncommon; however, mutations associated with resistance to multiple NRTIs (Q151M and associated secondary mutations, or amino acid insertions in codons 67 to 70) occur in 1 to 2% of isolates, with increases in stavudine IC50 of 4- to >70-fold. Resistance to stavudine was increased in isolates where resistance mutations to zidovudine were also present. In comparative in vitro studies, similar concentrations of stavudine caused greater reductions in mitochondrial DNA content than those of zidovudine. In contrast, zidovudine inhibited haemopoietic cell proliferation and differentiation in concentrations at which stavudine had no significant effects. Stavudine is well absorbed after oral administration, with a bioavailability of up to 100% for therapeutic doses. The peak plasma concentration (C_max) after a single oral dose of 40mg was 0.6 to 0.9 mg/L, with a time to reach C_max (t_max) of 0.75 hours. The area under the plasma concentration-time curve was 1.25 to 1.95 mg/L · h. Volume of distribution at steady state was 0.53 L/kg. Pharmacokinetic parameters after multiple doses of stavudine were similar to those seen after a single dose. Stavudine is capable of penetrating into the CSF. Stavudine undergoes intracellular phosphorylation to mono-, di- and triphosphate metabolites. The enzymes and rate-limiting steps involved in this process differ in some respects from those involved in the metabolism of zidovudine; however, in in vitro studies zidovudine significantly impaired the phosphorylation of stavudine at clinically significant concentrations. The plasma elimination half-life of stavudine was ≈1.6 to 2 hours after a single oral dose of 40mg. Approximately 40% of an oral dose of stavudine is excreted unchanged in the urine, and the remaining amount is thought to be metabolised. The clearance of stavudine decreases with increasing renal impairment, and dosages should therefore be adjusted for patients with renal failure. Co-administration of stavudine and zidovudine has resulted in lower levels of stavudine triphosphate in in vitro studies because of competition for intracellular triphosphorylation. Clinical studies involving these 2 drugs as dual therapy have also found reduced antiviral efficacy and/or adverse effects, and this combination is not recommended. Pharmacokinetic values for children were similar to those seen in adults, although children (under 30kg, per US recommendations) required twice the dose per unit bodyweight to achieve similar AUC and C_max values. Previous clinical trials established the efficacy of stavudine (alone or as part of dual therapy) with regard to clinical end-points. However, current therapeutic guidelines recommend commencing treatment with 3 antiretroviral agents (‘triple therapy’). In randomised nonblind clinical trials, stavudine-containing triple therapies reduced plasma HIV RNA levels to below the limit of detection (LOD; ≤500 copies/ml) in 68 to 100% of antiretroviral-naive patients after treatment for at least 20 weeks. Mean (or median) reductions from baseline in plasma viral RNA levels ranged from 1.88 to 3.3 log 10 copies/ml and CD4+ lymphocyte counts increased from baseline by a mean (or median) 66 to 274 cells/µL during the same period. Randomised nonblind comparative trials allowing the assessment of the efficacy of stavudine- and zidovudine-containing triple therapies (both drugs used in combination with lamivudine and indinavir) in antiretroviral-naive patients found similar results with both treatments. In 1 study, 72% of stavudine recipients had a viral load below the LOD (50 copies/ml) after 1 year of treatment, compared with 79% of zidovudine recipients; preliminary analysis after 24 weeks of treatment in the other trial found that 87% of stavudine recipients and 80% of zidovudine recipients had a viral load below the LOD (500 copies/ml). However, there were no statistical comparisons, and neither trial has been published in full. Other comparative trials that did not allow for direct comparison between stavudine and zidovudine (because of differences in background drugs) did not, overall, find any statistically significant differences between treatment groups. Protease-sparing regimens that included stavudine reduced viral load below the LOD (500 or 200 copies/ml) in 84 to 88% of patients after ≈6 months; stavudine in combination with at least one PI reduced viral load below the LOD (500 or 400 copies/ml) in 68 to 87% of patients after 20 to 24 weeks. Stavudine has also been used successfully as part of quadruple therapy in the treatment of antiretroviral-naive patients. In patients previously treated with antiretrovirais, stavudine-containing triple therapy combinations reduced plasma viral load from baseline by a mean (or median) 1.46 to 2.2 logio copies/ml after at least 3 months of treatment, with an increase in CD4+ lymphocyte count of 55 to 230 cells/μL. Starting stavudine-containing triple therapy in asymptomatic patients who had previously received zidovudine and either didanosine or zalcitabine resulted in significant improvements in the percentage of patients with viral load below the LOD (200 copies/ml) after 24 weeks compared with those continuing with their previous treatment (48 vs 0%, p < 0.05), and significantly greater reductions in plasma HIV RNA (1.46 vs 0.12 log ₁₀ copies/ml, p < 0.05). Results from small studies indicate that ≥70% of all antiretro viral-experienced patients who received stavudine in combination with 3 other antiretroviral drugs had viral loads below the LOD (400 or 500 copies/ml) after treatment periods of 8 to 48 weeks. Stavudine-containing triple therapies were effective in the treatment of anti-retro viral-naive and experienced children, although available data are limited and there have been no comparative trials in this area. Adverse events associated with stavudine therapy are thought to be mostly due to mitochondrial toxicity resulting from the inhibition of human DNA polymerase γ. The major adverse effect is peripheral neuropathy (PN), the incidence of which is dependent on the dosage and duration of treatment. It is also more likely to develop in patients with underlying PN or an AIDS diagnosis at baseline, or those who have a history of PN. In clinical trials, between 12 and 21% of patients who received stavudine in dosages of up to 40mg twice daily developed PN. In 1 study, 63% of cases responded to short periods of treatment cessation followed by reintroduction of stavudine in half dosages. A comparative monotherapy trial established that PN was significantly more common with stavudine than with zidovudine, whereas the reverse was true for haematological abnormalities. The rare but potentially fatal syndrome of hepatic steatosis and lactic acidosis (also thought to result from mitochondrial toxicity) has been reported in patients receiving stavudine. Lipodystrophy has also been observed, with 1 study suggesting that it may be more common with stavudine than with zidovudine. Other adverse events that have been reported during treatment with stavudine-containing triple therapies include diarrhoea, elevation of liver transaminases and/or bilirubin, skin rashes, neurological disorders, nausea and abdominal pain. Recommended dosages for stavudine require adjustment according to bodyweight and renal function. Adults with normal renal function who weigh ≥60kg should receive 40mg twice daily; the recommended dosage for those weighing <60kg with normal renal function is 30mg twice daily. Stavudine may be taken with or without food. During treatment with stavudine, patients should be monitored for the development of PN and/or hepatic abnormalities. If either of these develop, stavudine is to be discontinued until the condition resolves; treatment may then be recommenced at half the previous dosage.