Zidovudine (AZT): From First HIV Antiviral to Modern Therapy—Pharmacology, Uses, and Clinical Pearls

When the first case of acquired immunodeficiency syndrome appeared in the early 1980s, the world was unprepared for a disease that would silently undermine the immune system of millions. In 1987, the FDA approved zidovudine (AZT) as the first antiretroviral drug, offering a glimmer of hope for patients who previously had only palliative options. Today, zidovudine remains a cornerstone in certain HIV treatment regimens, a bridge therapy for pregnant women, and a valuable tool for preventing mother‑to‑child transmission. Understanding its pharmacology, clinical nuances, and safety profile is essential for pharmacists and clinicians navigating modern HIV care.

Introduction and Background

Zidovudine, also known by its generic name AZT (azidothymidine), is a nucleoside reverse transcriptase inhibitor (NRTI) that mimics thymidine. It was synthesized in 1964 by Dr. Yamanaka and colleagues at the University of Tokyo, initially for research into nucleoside analogues. Its antiviral activity was discovered serendipitously when it inhibited the replication of murine leukemia virus in vitro. By the mid‑1980s, the drug’s potential to block HIV reverse transcriptase led to clinical trials that culminated in its 1987 approval for AIDS treatment.

Since then, the epidemiology of HIV has evolved dramatically. According to the World Health Organization, 38 million people worldwide live with HIV, and antiretroviral therapy (ART) has reduced AIDS‑related mortality by more than 50% in the past decade. Zidovudine is now frequently used in combination with other ART agents, in pre‑exposure prophylaxis (PrEP) protocols, and as a single‑dose regimen for perinatal prevention. Its role exemplifies how a drug discovered over 50 years ago continues to adapt to contemporary therapeutic landscapes.

Mechanism of Action

At the molecular level, zidovudine interferes with HIV replication by targeting the viral enzyme reverse transcriptase (RT). Once inside the cell, zidovudine is phosphorylated by cellular kinases to its active triphosphate form, AZT‑TP. This active metabolite competes with natural deoxythymidine triphosphate (dTTP) for incorporation into the growing viral DNA chain during reverse transcription.

Competitive Inhibition of dNTP Pools

AZT‑TP is incorporated by RT into the nascent DNA strand. However, due to the presence of a nitrogen atom at the 3’ position of the sugar moiety, the DNA chain cannot be extended further, resulting in chain termination. This mechanism is similar to other NRTIs but unique in its structural mimicry of thymidine.

Effect on Viral Fitness and Resistance

Because AZT is a chain terminator, the virus must develop mutations in the RT enzyme to reduce drug binding. Common resistance mutations include M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E. These changes diminish the drug’s potency but also impose fitness costs on the virus, often leading to slower replication rates. Understanding resistance patterns is critical for selecting effective combination regimens.

Clinical Pharmacology

Pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of zidovudine influence dosing strategies, therapeutic outcomes, and safety profiles. The following table summarizes key PK/PD parameters compared to two other NRTIs: lamivudine (3TC) and tenofovir disoproxil fumarate (TDF).

Pharmacodynamically, zidovudine demonstrates a dose‑response relationship that plateaus at serum concentrations of 0.5–1.0 µg/mL. The drug’s efficacy is most pronounced when combined with other agents that target different stages of the viral life cycle, thereby reducing the likelihood of resistance.

Therapeutic Applications

• HIV‑1 Infection: Standard initial regimen in combination with other NRTIs and non‑nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs). Typical dose: 300 mg orally twice daily in adults.
• Pre‑Exposure Prophylaxis (PrEP): Single‑dose 200 mg oral as part of a tenofovir/emtricitabine backbone for high‑risk populations.
• Perinatal Prevention: Single 200 mg oral dose given to pregnant women at risk of transmitting HIV to the infant, reducing vertical transmission by ~80–90%.
• Off‑Label Use: Short‑term treatment for severe, life‑threatening opportunistic infections in patients with limited ART options.

Special populations:

1. Pediatrics: Weight‑based dosing (10 mg/kg twice daily) with caution due to higher incidence of myopathy.
2. Geriatric: Monitor for anemia and myopathy; dose adjustment often unnecessary but vigilance is key.
3. Renal Impairment: No dose adjustment required for mild to moderate CKD; avoid use in severe renal failure (eGFR <30 mL/min) due to renal excretion.
4. Hepatic Impairment: Use cautiously in moderate to severe hepatic disease; monitor liver enzymes.
5. Pregnancy: Category B; safe in pregnancy and breastfeeding; recommended for prevention of mother‑to‑child transmission.

Adverse Effects and Safety

Common side effects include nausea (≈25%), vomiting (≈15%), and headache (≈10%). Hematologic toxicity—particularly anemia and neutropenia—occurs in 5–10% of patients and warrants routine CBC monitoring. Myopathy, manifested by proximal muscle weakness and elevated creatine kinase, is reported in 1–2% of users.

Black box warnings: Severe bone marrow suppression, peripheral neuropathy, and lactic acidosis. The drug is contraindicated in patients with severe anemia (Hb <10 g/dL) or pre‑existing peripheral neuropathy.

Monitoring parameters: CBC with differential, liver function tests, serum creatine kinase, and renal function every 4–6 weeks during the first year of therapy. Discontinue if Hb <8 g/dL or if CK >10× upper limit of normal.

Clinical Pearls for Practice

• Always co‑prescribe folic acid (1 mg daily) to mitigate hematologic toxicity.
• Use a “split‑dose” schedule (morning and evening) to improve absorption and reduce GI upset.
• For perinatal prevention, administer the 200 mg dose within 2–4 hours of delivery, regardless of gestational age.
• Monitor for myopathy early—ask patients about muscle pain or weakness and check CK if symptomatic.
• In patients requiring rifampin, consider alternative ART agents or dose adjustment of zidovudine; therapeutic drug monitoring is advised.
• Use the mnemonic “AZT‑AN” (Anemia, Neutropenia, Myopathy, Anorexia, Nausea) to remember the most common adverse effects.
• For pediatric dosing, calculate weight‑based dose and double‑check for dosing errors; use a syringe or oral solution for accuracy.

Comparison Table

Exam‑Focused Review

Common exam question stems:

• “A 28‑year‑old woman with HIV presents with fatigue and pallor. Which antiretroviral is most likely responsible for her anemia?”
• “Which drug is contraindicated in patients with severe anemia and a history of peripheral neuropathy?”
• “A patient on zidovudine develops proximal muscle weakness. What is the most appropriate next step?”

Key differentiators students often confuse:

• AZT vs. 3TC: Both are NRTIs, but AZT has a higher risk of myopathy and anemia.
• AZT vs. TDF: TDF has a longer half‑life and is primarily renally cleared, whereas AZT is metabolized by glucuronidation.
• AZT vs. Efavirenz: Efavirenz is an NNRTI with neuropsychiatric side effects, not a chain terminator.

Must‑know facts for NAPLEX/USMLE/clinical rotations:

• AZT is a first‑line agent in pregnant women to reduce vertical transmission.
• Folate supplementation is mandatory to prevent macrocytic anemia.
• Monitor CBC and CK every 4–6 weeks during the first year.
• Avoid concomitant use of rifampin without dose adjustment.
• AZT is contraindicated in patients with severe anemia (Hb <10 g/dL).

Key Takeaways

1. Zidovudine is the first FDA‑approved antiretroviral and remains vital for perinatal and certain adult HIV regimens.
2. Its mechanism involves chain termination via incorporation of AZT‑TP into viral DNA.
3. Pharmacokinetics: oral bioavailability ~80%, half‑life 1.5–2.5 h, glucuronidation via UGT2B7.
4. Therapeutic dose in adults: 300 mg BID; pediatric dosing is weight‑based (10 mg/kg BID).
5. Common adverse effects: anemia, neutropenia, myopathy, nausea.
6. Black box warnings for severe bone marrow suppression and peripheral neuropathy.
7. Key drug interactions include grapefruit juice (increases levels) and rifampin (decreases levels).
8. Folate supplementation and regular CBC/CK monitoring mitigate hematologic and myopathic toxicity.
9. Use in pregnancy reduces mother‑to‑child transmission by up to 90% when administered appropriately.
10. Always consider resistance patterns; AZT resistance mutations compromise efficacy in monotherapy.

Always counsel patients on the importance of adherence, routine monitoring, and reporting new symptoms promptly to prevent serious complications associated with zidovudine therapy.