Integrase Strand Transfer Inhibitors

Integrase strand transfer inhibitors block the integration of HIV DNA into the host genome. Dolutegravir, bictegravir, raltegravir, elvitegravir and cabotegravir are members. They give the fastest viral decline of any class, are well tolerated and are the preferred anchor of first-line therapy. Dolutegravir and bictegravir have high barriers to resistance.

Pharmacokinetics. Dolutegravir, bictegravir and cabotegravir are metabolised by UGT1A1 with a smaller CYP3A4 role, so they interact mainly with inducers. All chelate polyvalent cations. Dolutegravir inhibits the renal transporter OCT2, which raises creatinine by 0.1 to 0.15 mg/dL without a true fall in filtration.

• Dolutegravir: 50 mg once daily; 50 mg twice daily with rifampicin, carbamazepine, phenytoin, phenobarbital, or integrase resistance.
• Bictegravir: 50 mg once daily, available only combined with tenofovir alafenamide and emtricitabine.
• Raltegravir: 400 mg twice daily; 800 mg twice daily with rifampicin. Low genetic barrier.
• Elvitegravir: needs a booster (cobicistat) and is used less.
• Cabotegravir: oral 30 mg daily lead-in; injectable 600 mg intramuscularly monthly or every 2 months, paired with rilpivirine, for suppressed patients.

First-line. Tenofovir, lamivudine and dolutegravir once daily for adults and adolescents; abacavir, lamivudine and dolutegravir by weight band for children (dispersible tablets for young children).

Switch. Dolutegravir is used in second-line and third-line regimens with a boosted protease inhibitor when resistance testing supports it.

Cations. Give dolutegravir 2 hours before or 6 hours after antacids, calcium, iron, magnesium or zinc supplements, or take it together with a meal when the supplement is also taken with food.

Metformin. Dolutegravir 50 mg daily raises metformin exposure; limit metformin to 1 g daily and monitor glucose and renal function.

Pregnancy. Dolutegravir is preferred before conception and in all trimesters; the early concern about neural tube defects was not confirmed on larger follow-up.

Dose adjustment.

• Kidney: none for dolutegravir; bictegravir with tenofovir alafenamide is avoided when creatinine clearance is under 30 mL/min unless on dialysis.
• Liver: avoid in severe impairment.
• Children: weight-banded dosing.

Adverse effects. Headache, insomnia, nausea, weight gain (greater with tenofovir alafenamide), hyperglycaemia, mood change, and rarely hepatotoxicity or hypersensitivity. Injection site reactions with cabotegravir.

Contraindications. Dolutegravir with dofetilide.

Interactions. Inducers (rifampicin, carbamazepine, phenytoin, St John's wort) lower levels. Cations chelate. Dolutegravir raises metformin levels.

Monitoring. Viral load at 6 and 12 months then yearly, weight and glucose, liver enzymes if hepatitis coinfection or symptoms, mood review. Creatinine rise of up to 0.15 mg/dL after starting does not require stopping.

Common prescribing errors. Omitting the second dose with rifampicin or anticonvulsants; giving iron or calcium at the same time; using raltegravir at the low dose with rifampicin; assuming that a missed injection schedule is covered by oral doses.

Special groups.

• Breastfeeding: compatible.
• Older adults: monitor weight, glucose and cardiovascular risk.

Referral and escalation. Refer virological failure on dolutegravir for resistance testing; integrase mutations change the choice of next regimen.