Rilpivirine

Rilpivirine is an oral second-generation non-nucleoside reverse transcriptase inhibitor used with two nucleosides for treatment-naive adults and adolescents with low viral load, for switching in suppressed patients, and, with cabotegravir, as a long-acting injection. It needs gastric acid and a meal for absorption, so acid suppressants and fasting cause failure. It has fewer central nervous system effects and lipid changes than efavirenz, but a lower barrier to resistance.

Class. Non-nucleoside reverse transcriptase inhibitor.

Mechanism. Binds to HIV-1 reverse transcriptase in a flexible conformation that tolerates some resistance mutations. E138K with M184I is the usual failure pattern.

Pharmacokinetics. Oral absorption falls by about 40% when fasting or taking only a protein drink. Highly protein bound; half life about 50 hours orally and 13 to 28 weeks after an injection. Metabolised by CYP3A4, so inducers lower and inhibitors raise levels.

HIV-1 infection (adults and adolescents 12 years and over, 35 kg or more). 25 mg orally once daily with a meal of at least 390 kcal, combined with two nucleosides. For naive patients, use only when viral load is under 100,000 copies/mL and CD4 count is over 200 cells/microlitre.

Long-acting injection (virologically suppressed adults, with cabotegravir). Rilpivirine 900 mg with cabotegravir 600 mg intramuscularly, a second injection 1 month later, then every 2 months; or 600 mg with 400 mg monthly. An oral lead-in of 25 mg with cabotegravir 30 mg for about 4 weeks is optional.

Loading dose, maintenance dose and titration. Not applicable orally. Maximum: 25 mg daily.

Main alternatives. Dolutegravir-based regimens, efavirenz, doravirine.

Contraindications. Hypersensitivity; co-prescription with rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, dexamethasone (more than a single dose), St John’s wort, and proton pump inhibitors.

Serious adverse effects. Depression and suicidal thoughts, hepatotoxicity, severe rash and hypersensitivity, QT prolongation at supratherapeutic doses, and, with injection, injection-site reactions and rare post-injection reactions.

Common adverse effects. Headache, insomnia, rash, dizziness, nausea and mild lipid or creatinine change.

Interactions. - Acid suppression: avoid proton pump inhibitors; give H2 blockers 12 hours before or 4 hours after; antacids 2 hours before or 4 hours after. - Efavirenz, nevirapine and etravirine lower levels: avoid. - Macrolides and azole antifungals raise levels (monitor the QT interval). - Rifabutin: increase rilpivirine to 50 mg once daily.

Common prescribing errors. Giving fasting, giving with a proton pump inhibitor or rifampicin, and starting naive patients with a high viral load or low CD4 count.

Special groups. - Pregnancy: exposure falls in the third trimester; avoid unless suppressed and monitored. - Breastfeeding: limited data; avoid. - Children: 12 years and over, 35 kg or more. - Older adults: usual dose. - Kidney impairment: no adjustment; caution in severe impairment. - Liver impairment: no adjustment in mild to moderate disease; not studied in severe.

Regional points. Tuberculosis co-treatment with rifampicin is common and rules out rilpivirine; in East Africa it is used mainly in selected suppressed patients and where long-acting injection programmes exist.

Formulations. Tablets 25 mg; fixed-dose tablets with tenofovir and emtricitabine, and with dolutegravir; long-acting injection 600 mg/2 mL.

Administration. Once daily with a meal, at the same time each day. Injection: gluteal intramuscular route, given by a health professional.

Baseline. Viral load, CD4 count, resistance result where available, drug history, mental health review, liver tests, hepatitis B status.

Monitoring. Viral load at 3 and 6 months and then every 6 to 12 months; mood; liver tests; ECG if on QT-prolonging drugs.

Stopping thresholds. Stop for severe rash, hypersensitivity, severe depression, or ALT over 3 times the upper limit of normal with symptoms, or over 5 times without. Confirmed virological failure: stop and test for resistance.

Referral and escalation. Specialist review for virological failure, psychiatric symptoms and complex interactions.