Stavudine (d4T) is a synthetic nucleoside analog and reverse transcriptase inhibitor (NRTI) used primarily in the treatment of HIV-1 infection. It was initially synthesized in the 1960s during research on antiviral nucleoside analogs, but its potent anti-HIV activity was discovered in the late 1980s, during the global search for effective therapies against HIV/AIDS. Stavudine was subsequently approved for clinical use in the early 1990s and became a key component of combination antiretroviral therapy (cART), helping to suppress viral replication, preserve immune function, and delay progression to AIDS. Its development represented a significant advance in HIV treatment, particularly in resource-limited settings, though its use has declined in recent years due to toxicity concerns and the availability of safer and more effective alternatives.
BRAND NAMES
Stavudine (d4T) has been marketed under several brand names, including:
Zerit® – the most widely recognized brand.
Stavir®
Stavadine®
Stavex®
Zerit® is the primary brand used globally, especially in combination antiretroviral therapy (cART) regimens for HIV treatment.
MECHANISM OF ACTION
Stavudine is a nucleoside reverse transcriptase inhibitor (NRTI). Once inside the cell, it is phosphorylated to its active triphosphate form (stavudine triphosphate). This active metabolite competitively inhibits HIV-1 reverse transcriptase, the viral enzyme responsible for converting viral RNA into DNA. By incorporating into the growing viral DNA chain, stavudine causes chain termination, preventing further viral DNA synthesis and thereby blocking HIV replication. This selective inhibition targets viral replication without directly affecting host DNA synthesis, though mitochondrial toxicity can occur due to partial inhibition of mitochondrial DNA polymerase-γ.
PHARMACOKINETICS
Absorption
Stavudine is quickly absorbed when taken orally, reaching peak plasma levels within 1–2 hours. It has a high absolute oral bioavailability of nearly 100%, and while food may slightly slow absorption, it does not affect the overall extent. The drug distributes into total body water and enters cells via passive diffusion.
Distribution
The mean volume of distribution for stavudine in HIV-infected adults is approximately 46 liters. This corresponds to roughly 0.73 L/kg.
Metabolism
Stavudine is converted by cellular kinases into its active triphosphate form and also undergoes limited hepatic metabolism, producing minor metabolites through oxidation and glucuronidation. A large portion of the drug is excreted unchanged by the kidneys via glomerular filtration and active tubular secretion. Although the complete metabolic pathway in humans is not fully defined, metabolism accounts for a smaller fraction of elimination compared to renal excretion.
Excretion
Stavudine is primarily eliminated unchanged via the kidneys. Renal excretion occurs through a combination of glomerular filtration and active tubular secretion. Only a small portion of the drug is metabolized in the liver to minor metabolites, so renal clearance is the main route of elimination. Impaired kidney function can significantly affect stavudine clearance and may require dose adjustments.
PHARMACODYNAMICS
Stavudine is a nucleoside reverse transcriptase inhibitor (NRTI) that exerts its antiviral effect by targeting HIV-1 reverse transcriptase. After entering host cells, it is phosphorylated to its active triphosphate form, which competitively inhibits reverse transcriptase and incorporates into viral DNA. This incorporation leads to chain termination, preventing the synthesis of viral DNA and thereby suppressing HIV replication.
The drug selectively affects viral replication over host DNA, but prolonged use can cause mitochondrial toxicity, which may contribute to adverse effects such as peripheral neuropathy, lactic acidosis, and hepatic steatosis. Overall, stavudine reduces viral load and helps maintain or improve CD4+ T-cell counts, contributing to immune system preservation in HIV-infected patients.
ADMINISTRATION
Stavudine is an oral medication (capsules or solution) used in combination with other antiretroviral agents to treat HIV infection. It is generally taken twice daily, every 12 hours, and can be administered with or without food.
DOSAGE AND STRENGTH
Adults:
Standard oral dose: 30–40 mg twice daily, depending on body weight.
<60 kg: 30 mg twice daily
≥60 kg: 40 mg twice daily
Pediatric (children ≥3 months):
Dose: 1 mg/kg per dose, given twice daily (maximum 40 mg per dose).
Strengths Available:
Available in capsule strengths of 15 mg, 20 mg, 30 mg, and 40 mg.
Oral solution: 1 mg/mL
DRUG INTERACTIONS
Stavudine (d4T) interacts with several drugs mainly through toxicity or antagonism. It should not be combined with zidovudine, as both reduce each other’s effect, or with didanosine or hydroxyurea, which increase the risk of pancreatitis, neuropathy, and lactic acidosis. Ribavirin decreases stavudine’s activation and raises toxicity. Alcohol, neurotoxic (e.g., isoniazid) and hepatotoxic drugs (e.g., ketoconazole) can worsen side effects. Stavudine is renally excreted with minimal metabolic interactions, but renal impairment or nephrotoxic drugs may affect its clearance.
FOOD INTERACTIONS
Stavudine absorption is not affected by food, so it can be taken with or without meals. However, it is best to take it consistently the same way each time to maintain stable drug levels. There are no significant food interactions, but alcohol should be avoided as it increases the risk of pancreatitis and liver toxicity. Maintaining a balanced diet may help reduce side effects such as neuropathy and lactic acidosis.
CONTRAINDICATIONS
Stavudine is contraindicated in patients with hypersensitivity to the drug, a history of pancreatitis or severe peripheral neuropathy, and in those with severe liver disease or prior lactic acidosis/hepatic steatosis from NRTI therapy. It should not be used together with zidovudine (AZT) due to antagonistic effects. Caution is advised in patients with renal impairment, obesity, alcoholism, or prolonged NRTI use, as these increase the risk of mitochondrial toxicity.
SIDE EFFECTS
Peripheral neuropathy.
Lactic acidosis and hepatotoxicity.
Unusual tiredness or weakness.
Nausea, vomiting, and stomach pain.
Trouble breathing.
Yellowing of the skin or eyes (jaundice).
Dark urine.
Pancreatitis.
Lipodystrophy.
Immune reconstitution inflammatory syndrome (IRIS).
OVERDOSE
Nausea and vomiting.
Headache.
Fatigue or excessive tiredness and weakness.
Numbness, tingling, burning, or pain in the hands or feet (peripheral neuropathy).
Unusual or severe stomach pain.
Shortness of breath.
TOXICITY
Stavudine toxicity is primarily due to mitochondrial dysfunction. The most common and serious effects include peripheral neuropathy, which may be irreversible, pancreatitis, and lactic acidosis with hepatic steatosis, especially with prolonged use or in patients with obesity or concurrent NRTI therapy. Other toxicities include hepatotoxicity, gastrointestinal upset, myopathy, and lipodystrophy with fat redistribution and metabolic changes. Early recognition and discontinuation of stavudine at the onset of symptoms are crucial to prevent permanent damage.
