Bristol-Myers Squibb

FDA approval of stavudine was granted in 1994 for adults and in 1996 for pediatric use. Initial approval (for patients with advanced HIV disease intolerant to, or experiencing progression of disease on, previously approved drugs) was based on increases in CD4 T-lymphocyte counts with stavudine in zidovudine-experienced patients. As further evidence of efficacy (sustained increases in CD4 cell counts and reductions in HIV viral load) became available, approval of stavudine was generalized to include use in combination therapy for HIV infection.

The FDA has granted generic formulations of stavudine "tentative approval" status for purchase and use only as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-poor countries. For a table of FDA-approved drugs for use under PEPFAR, see HIV InSite's PEPFAR overview.

Stavudine is available in capsule or solution formulations; these are approved for twice-daily dosing.

Dosing of Stavudine Adult Wt >=60 kg 40 mg BID Wt <60 kg 30 mg BID Pediatric* Birth-13 days 0.5 mg/kg Q 12 hrs Age >14 days, and wt <30 kg 1 mg/kg Q 12 hrs Wt >=30 kg Adult dose

Key to abbreviations: wt, weight; Q, every; QD, once daily; BID, twice daily. * Stavudine is not FDA approved for use in children <6 months of age. However, it has been studied in younger children; usual doses are indicated.

		There are no food restrictions.

		Dosage adjustment is recommended in renal insufficiency.

		Please consult product labeling for detailed dosing information.

		FDA Pregnancy Category C.

Many antiretroviral combinations containing stavudine have been found to be effective at suppressing HIV viral load and increasing CD4 cell counts. In general, 3-drug combinations have been found to have a more sustained effect than 2-drug combinations. Stavudine should not be administered concurrently with certain medications because of additive or overlapping potential adverse effects. For example, the combination of stavudine and didanosine should be avoided because of increased risk of peripheral neuropathy and hyperlactatemia, and should not be used in pregnant women because of reports of lactic acidosis with pancreatitis or hepatic steatosis.

Patients receiving stavudine together with other potentially neurotoxic drugs (such as ribavirin, isoniazid, or vincristine) should be monitored closely for the development of neuropathic symptoms.

Stavudine and zidovudine should not be used in combination because they compete with each other for activation by intracellular phosphorylation, resulting in diminished antiviral activity.(1)

Treatment guidelines of the U.S. Department of Health and Human Services state that stavudine is "not recommended" for initial treatment of HIV infection because of a high rate of toxicity, including peripheral neuropathy, lipoatrophy, and lactic acidosis.

A direct comparison of stavudine with zidovudine, each in combination with lamivudine and indinavir as initial therapy, found no difference in the two regimens in maintaining viral load suppression at 48 weeks.(2) While serious adverse events were not significantly different between treatment arms, there was increased nausea and vomiting in the zidovudine-containing arm, and increased diarrhea and rash in the stavudine-containing arm.

A comparison of stavudine with tenofovir, each combined with lamivudine and efavirenz in initial therapy, showed similar rates of viral suppression at 48 and 96 weeks (HIV RNA <50 copies/mL in 74% of stavudine recipients vs 78% of tenofovir recipients at 96 weeks), but higher rates of adverse effects in the stavudine group.(3)

A comparison of stavudine with emtricitabine, each combined with didanosine and efavirenz in antiretroviral-naive patients, showed significantly lower rates of virologic suppression at 48 weeks in the stavudine arm (HIV RNA <50 copies/mL in 59% of stavudine recipients vs 78% of emtricitabine recipients; p < .001). The mean CD4 increase was lower in stavudine recipients, but this difference was not statistically significant (120 cells/µL in the stavudine group vs 153 cells/µL in the emtricitabine group; p = .15).(4)

Symptomatic side effects of stavudine include peripheral neuropathy, which may range in severity from mild to disabling, and pancreatitis. Nucleoside analogues are associated with mitochondrial toxicity leading to potentially serious long-term side effects such as lactic acidosis, lipodystrophy, and disorders of lipid metabolism.(5) Stavudine appears to contribute to these disorders more often than other nucleoside analogues.(3,6,7) The combination of stavudine + didanosine has additive toxicity and should be avoided, when possible; in particular, this combination should not be used in pregnant women if other options are available.(4,7,8,9) It is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with stavudine is initiated.

Resistance to stavudine is associated with the selection of 1 or more of several resistance mutations.

Implications of stavudine resistance for treatment with other antiretrovirals

Mutations at sites associated with zidovudine resistance (eg, codons 41 and 215) frequently occur on stavudine treatment. The codon 151 mutation, associated with resistance to multiple nucleoside analogues, occurs infrequently but is most commonly observed in patients treated with zidovudine + didanosine or stavudine + didanosine.

Implications of resistance to other antiretrovirals for treatment with stavudine

Viral isolates with zidovudine resistance are likely to show resistance to stavudine, as are strains carrying multinucleoside-resistance mutations (including insertions following codon 69, or mutation at codon 151). Resistance testing may be helpful in assessing the utility of stavudine in the individual situation, although the genotypic correlates of stavudine resistance are not clearly defined. For example, resistance to stavudine has been associated with a mutation at codon 75 in laboratory strains and some clinical isolates, but decreased virologic responses to stavudine frequently occur in the absence of this mutation.