Nonnucleoside Reverse Transcriptase Inhibitors

Nonnucleoside reverse transcriptase inhibitors bind a hydrophobic pocket on HIV-1 reverse transcriptase, distorting the active site. They are inactive against HIV-2 and group O HIV-1. A single mutation (K103N for efavirenz and nevirapine) is enough to cause high-level resistance, so adherence matters.

Pharmacokinetics. All are metabolised by CYP enzymes, so they interact widely. Efavirenz and nevirapine are inducers; efavirenz is metabolised mainly by CYP2B6, and slow-metaboliser alleles that raise levels are common in people of African ancestry.

• Efavirenz: 600 mg once daily at bedtime on an empty stomach; 400 mg is an alternative with similar efficacy. Long half-life makes missed doses forgiving.
• Nevirapine: 200 mg daily for 14 days, then 200 mg twice daily (or 400 mg extended-release daily). No longer first-line because of hepatotoxicity and rash.
• Rilpivirine: 25 mg daily with a meal of at least 390 kcal; needs gastric acid. Poor responses with viral load over 100,000 copies/mL.
• Doravirine: 100 mg daily; fewer lipid and CNS effects.
• Etravirine: 200 mg twice daily after food; used in treatment-experienced patients.

Role. Alternative to dolutegravir, used when integrase inhibitors cannot be given or when drug interactions favour efavirenz. Nevirapine is used mainly in infant prophylaxis for 6 weeks (weight-based daily dose) and in some existing regimens.

Rifampicin.

• Efavirenz 600 mg is used unchanged.
• Nevirapine is avoided because levels fall.
• Rilpivirine is contraindicated.
• Doravirine is not used with rifampicin; with rifabutin the dose is 100 mg twice daily.

Efavirenz effects on other drugs. Lowers dolutegravir (50 mg twice daily needed), bedaquiline (avoid), methadone, voriconazole, and levonorgestrel implants and some oral contraceptives, so an additional or alternative method is advised.

Dose adjustment.

• Kidney: no adjustment.
• Liver: avoid nevirapine in moderate to severe impairment; efavirenz needs monitoring.
• Children: efavirenz from 3 months and 3.5 kg by weight band; nevirapine by body surface area.

Contraindications. Nevirapine: previous severe hepatitis or rash with it; women with CD4 over 250 cells/mm3 and men over 400 cells/mm3 starting treatment (higher hepatotoxicity risk). Rilpivirine with proton pump inhibitors.

Serious adverse effects.

• Efavirenz: dizziness, vivid dreams, insomnia, depression, suicidal ideation, psychosis, rash, hepatitis, gynaecomastia, QT prolongation at high exposure.
• Nevirapine: hepatotoxicity and Stevens-Johnson syndrome, mostly in the first 18 weeks.
• Rilpivirine: depression, QT prolongation at supratherapeutic dose.
• Class: hypersensitivity rash, usually in the first 6 weeks.

Monitoring. Liver enzymes at baseline and at weeks 2, 4, 8 and 12, then every 3 months for nevirapine; mood and sleep review for efavirenz. Stop nevirapine for rash with mucosal involvement or systemic symptoms, or ALT more than 5 times the upper limit.

Common prescribing errors. Starting nevirapine at full dose without the 14-day lead-in; giving efavirenz with food (raises levels and toxicity); co-prescribing rilpivirine with rifampicin or antacids.

Special groups.

• Pregnancy: efavirenz is acceptable if needed; avoid nevirapine in women with CD4 in the higher-risk range.
• Breastfeeding: compatible.
• Older adults: neuropsychiatric review.

Referral and escalation. Refer rash with systemic features, jaundice, persistent neuropsychiatric symptoms, or virological failure.