Zidovudine

Zidovudine is an oral and intravenous thymidine analogue and nucleoside reverse transcriptase inhibitor, the first antiretroviral licensed. It is now used mainly in fixed combinations in selected programmes, for infant prophylaxis, and as intravenous cover during delivery when the mother’s viral load is high. Bone marrow suppression, myopathy and lactic acidosis are the main toxicities and carry boxed warnings.

Class. Nucleoside reverse transcriptase inhibitor.

Mechanism. Phosphorylated to zidovudine triphosphate, which competes with thymidine triphosphate and terminates viral DNA synthesis. Thymidine analogue mutations cause resistance and cross-resistance with stavudine.

Pharmacokinetics. Oral bioavailability about 64%. Plasma half life about 1 hour and intracellular half life about 7 hours. Hepatic glucuronidation, with renal excretion of the glucuronide.

HIV-1 infection (adults and adolescents 30 kg or more). 300 mg orally twice daily with lamivudine and a third drug.

Children. Weight-banded: 4 to under 9 kg 12 mg/kg twice daily; 9 to under 30 kg 9 mg/kg twice daily; 30 kg or more 300 mg twice daily.

Prevention of mother-to-child transmission.

• Infant, birth weight 2 kg or more: 4 mg/kg orally twice daily from birth for 4 to 6 weeks with nevirapine in high-risk infants.
• Mother with high viral load near delivery: 2 mg/kg intravenously over 1 hour, then 1 mg/kg/hour until the cord is clamped.

Dose adjustment for kidney function. CrCl under 15 mL/min: 100 mg every 6 to 8 hours (or 300 mg once daily); haemodialysis 100 mg every 6 to 8 hours.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 600 mg daily orally.

Main alternative. Tenofovir disoproxil fumarate or abacavir.

Contraindications. Hypersensitivity; neutrophils under 0.75 x 10^9/L or haemoglobin under 75 g/L.

Serious adverse effects. Severe anaemia and neutropenia, myopathy, lactic acidosis with hepatic steatosis, and lipoatrophy.

Common adverse effects. Nausea, headache, fatigue, macrocytosis and nail pigmentation.

Interactions.

• Stavudine: antagonistic; never combine.
• Ganciclovir, valganciclovir, flucytosine, co-trimoxazole, dapsone and ribavirin add marrow toxicity.
• Probenecid raises zidovudine levels.
• Fluconazole raises levels; rifampicin lowers them slightly.

Common prescribing errors. Starting with low haemoglobin and not monitoring the blood count, combining with stavudine, and unrecognised myopathy.

Special groups.

• Pregnancy: safe; it reduces transmission.
• Breastfeeding: compatible, though not preferred.
• Children: weight-banded dosing; check haemoglobin.
• Older adults: usual dose with careful blood monitoring.
• Kidney impairment: 100 mg every 6 to 8 hours when CrCl is under 15 mL/min.
• Liver impairment: accumulation; reduce the dose or lengthen the interval in cirrhosis.

Regional points. Zidovudine with lamivudine is still used in some second-line regimens after tenofovir failure and for infant prophylaxis, where anaemia from malaria and malnutrition makes blood monitoring particularly important.

Formulations. Tablets 300 mg; capsules 100 mg; oral solution 10 mg/mL; intravenous solution 10 mg/mL; fixed-dose combinations with lamivudine, and with lamivudine and nevirapine.

Administration. With or without food; take with food if nausea. Intravenous: dilute in 5% glucose to 4 mg/mL and infuse over 1 hour.

Baseline. Full blood count, creatinine, liver tests, creatine kinase if muscle symptoms, pregnancy test.

Monitoring. Full blood count at 4, 8 and 12 weeks and then every 3 to 6 months; creatine kinase if myopathy is suspected.

Stopping thresholds. Stop or switch for haemoglobin under 75 g/L or a fall of more than 25%, neutrophils under 0.75 x 10^9/L, myopathy, or lactic acidosis.

Referral and escalation. Specialist review for severe anaemia, treatment failure and lactic acidosis.