Nucleoside Reverse Transcriptase Inhibitors

Nucleoside and nucleotide reverse transcriptase inhibitors are analogues of natural nucleosides that, once phosphorylated, are incorporated into viral DNA and stop chain elongation. They form the backbone of almost every HIV regimen, and several also act against hepatitis B virus. Tenofovir, lamivudine, emtricitabine and abacavir are current members.

Pharmacokinetics. All are cleared mainly by the kidney as unchanged drug or metabolites, and none depends on CYP enzymes, so interactions are few. Intracellular half-lives allow once-daily dosing.

Adult doses:

• Tenofovir disoproxil fumarate 300 mg daily. Tenofovir alafenamide 25 mg daily (10 mg with boosted protease inhibitors or cobicistat), with lower renal and bone toxicity.
• Lamivudine 300 mg daily (or 150 mg twice daily). Emtricitabine 200 mg daily.
• Abacavir 600 mg daily; test for HLA-B*5701 before starting where testing is available.
• Zidovudine 300 mg twice daily, now used mainly in some second-line regimens and infant prophylaxis.
• Stavudine and didanosine are obsolete because of neuropathy, lipoatrophy, pancreatitis and lactic acidosis.

Differences. Lamivudine and emtricitabine are interchangeable and the best tolerated; the M184V mutation causes resistance to both but slightly improves tenofovir activity. Tenofovir is active against hepatitis B. Abacavir is less reliable when the viral load is over 100,000 copies/mL in some combinations and is avoided with high cardiovascular risk.

Usual backbones. Tenofovir plus lamivudine or emtricitabine for first-line and hepatitis B coinfection. Abacavir plus lamivudine for patients who cannot take tenofovir (kidney disease, bone disease) and for children. Zidovudine plus lamivudine when tenofovir fails, depending on resistance.

Renal adjustment.

• Tenofovir disoproxil: creatinine clearance 30 to 49 mL/min, 300 mg every 48 hours; under 30 mL/min, avoid. Tenofovir alafenamide needs no adjustment down to 30 mL/min.
• Lamivudine: creatinine clearance 30 to 49 mL/min, 150 mg daily (adjust further below 30 mL/min). Emtricitabine 200 mg every 48 hours at 30 to 49 mL/min.

Hepatic. Abacavir 200 mg twice daily (oral solution) in mild impairment; avoid in moderate to severe disease. Zidovudine needs caution.

Children. Lamivudine 4 mg/kg twice daily (maximum 150 mg) or 8 mg/kg daily; abacavir 8 mg/kg twice daily or 16 mg/kg daily (maximum 600 mg daily); zidovudine in neonates by weight and gestation.

Region. In East Africa, abacavir hypersensitivity associated with HLA-B*5701 is less frequent in many African populations, but testing is not universal and clinical vigilance is required.

Contraindications. Abacavir: previous hypersensitivity or HLA-B*5701 positivity. Tenofovir disoproxil: creatinine clearance under 30 mL/min.

Serious adverse effects.

• Abacavir hypersensitivity (fever, rash, vomiting, cough, malaise, in the first 6 weeks): stop permanently and never rechallenge.
• Tenofovir disoproxil: proximal tubular injury with Fanconi syndrome, reduced bone density.
• Zidovudine: anaemia, neutropenia, myopathy, lactic acidosis.
• All class members: lactic acidosis and hepatic steatosis (rare, more with old agents).
• Withdrawal of tenofovir, lamivudine or emtricitabine in hepatitis B: severe flare.

Monitoring. Creatinine and urinalysis (phosphate if indicated) at baseline, 3 months, then yearly with tenofovir disoproxil; full blood count with zidovudine at baseline, 1, 3 months; hepatitis B status before any change.

Interactions. Tenofovir with other nephrotoxins (aminoglycosides, amphotericin B, NSAIDs). Zidovudine with ganciclovir, ribavirin and stavudine. Lamivudine with co-trimoxazole (minor rise in lamivudine levels).

Special groups.

• Pregnancy: tenofovir, lamivudine, emtricitabine and abacavir are used; zidovudine is used for infant prophylaxis.
• Breastfeeding: compatible.
• Older adults: monitor kidney and bone.