Dolutegravir

Dolutegravir is an oral integrase strand transfer inhibitor with a high barrier to resistance, rapid viral suppression and few side effects. It is the preferred third drug in first-line and second-line HIV treatment worldwide, usually with tenofovir and lamivudine or emtricitabine, or with abacavir and lamivudine in children. It raises serum creatinine without a true fall in kidney function, and it can cause weight gain and insomnia.

Class. Integrase strand transfer inhibitor.

Mechanism. Binds the integrase active site and blocks strand transfer, preventing integration of viral DNA into the host genome. Resistance needs several mutations (for example G118R with R263K).

Pharmacokinetics. Oral bioavailability increased by food. Half life about 14 hours. Metabolised mainly by UGT1A1 with a minor CYP3A4 route. It inhibits OCT2 and MATE1 transporters, which raises metformin and creatinine levels.

HIV-1 infection (adults and children 20 kg or more). 50 mg orally once daily, with two nucleosides. Duration: lifelong.

Twice daily dosing (50 mg twice daily, 12 hours apart). - With rifampicin, and for 2 weeks after rifampicin ends. - With efavirenz, nevirapine, carbamazepine, phenytoin, phenobarbital, and etravirine without a boosted protease inhibitor. - Integrase inhibitor resistance (selected mutations).

Children (dispersible tablets, 3 months and over). Weight-banded: 3 to under 6 kg 5 mg; 6 to under 10 kg 15 mg; 10 to under 14 kg 20 mg; 14 to under 20 kg 25 mg; once daily.

Pre-exposure prophylaxis and post-exposure prophylaxis. 50 mg once daily with tenofovir and emtricitabine for 28 days after exposure.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 100 mg daily.

Main alternatives. Raltegravir, darunavir with ritonavir, efavirenz.

Contraindications. Hypersensitivity; co-administration with dofetilide or pilsicainide.

Serious adverse effects. Hypersensitivity reaction with rash and liver injury (rare), hepatotoxicity (more in hepatitis B or C co-infection), depression and suicidal thoughts (uncommon), and immune reconstitution syndrome.

Common adverse effects. Headache, insomnia, nausea, weight gain, and rise in serum creatinine of about 10 to 15 micromol/L without change in true glomerular filtration.

Interactions. - Metformin: limit the metformin dose to 1000 mg daily and monitor. - Polyvalent cations: take dolutegravir 2 hours before or 6 hours after antacids, calcium, iron, magnesium or zinc; with food, calcium and iron can be taken together. - Rifampicin, efavirenz, nevirapine and anticonvulsant inducers need 50 mg twice daily. - Dofetilide: contraindicated.

Common prescribing errors. Using 50 mg once daily with rifampicin, giving together with iron or antacids on an empty stomach, and mistaking the creatinine rise for kidney injury.

Special groups. - Pregnancy: preferred at all stages; the early neural tube defect signal has not been confirmed. - Breastfeeding: compatible. - Children: weight-banded dosing; dispersible tablets are not interchangeable with film-coated tablets. - Older adults: usual dose. - Kidney impairment: no adjustment; monitor true function by another marker if needed. - Liver impairment: no adjustment in mild to moderate disease; not studied in severe.

Regional points. In East Africa the fixed-dose combination of tenofovir, lamivudine and dolutegravir is the first-line regimen for adults, adolescents and women of childbearing potential, and tuberculosis co-treatment requires the twice daily dose during rifampicin therapy and for 2 weeks after.

Formulations. Tablets 50 mg; dispersible tablets 10 mg and 5 mg (where available); fixed-dose combinations with tenofovir and lamivudine or emtricitabine, with abacavir and lamivudine, and with lamivudine alone.

Administration. With or without food; with food when taken with iron or calcium supplements.

Baseline. HIV test, viral load, hepatitis B and C status, creatinine, liver tests, pregnancy test, weight.

Monitoring. Viral load at 6 months and then yearly; liver tests if hepatitis co-infection; weight, glucose and blood pressure yearly; mood and sleep.

Stopping thresholds. Stop for hypersensitivity with liver injury, or for ALT over 3 times the upper limit of normal with symptoms, or over 5 times without.

Referral and escalation. Specialist review for confirmed viral load over 1000 copies/mL after 3 months of adherence support, and for suspected drug resistance.