Lopinavir Ritonavir

Lopinavir with ritonavir is an oral fixed combination: lopinavir is the protease inhibitor, and low-dose ritonavir boosts its levels. It has been the main second-line drug and the first choice for infants with HIV, with a heat-stable tablet and a pellet formulation. Diarrhoea, nausea and lipid rise are common, and the oral solution contains alcohol and propylene glycol.

Class. HIV protease inhibitor with pharmacokinetic booster.

Mechanism. Lopinavir inhibits HIV protease, preventing cleavage of viral polyproteins. Ritonavir inhibits CYP3A4 and raises lopinavir levels.

Pharmacokinetics. Tablets are absorbed with or without food; the oral solution needs food. Half life of lopinavir about 5 to 6 hours. Metabolised by CYP3A4; ritonavir also induces some enzymes.

HIV-1 infection (adults). Lopinavir 400 mg with ritonavir 100 mg (two tablets of 200/50 mg) orally twice daily; or 800/200 mg once daily in naive patients who are not pregnant and not on enzyme inducers.

With efavirenz or nevirapine (adults, treatment-experienced). 600/150 mg twice daily (three tablets of 200/50 mg); the same higher dose is considered in the third trimester of pregnancy.

With rifampicin. Lopinavir 400 mg with ritonavir 400 mg twice daily (extra ritonavir added) in adults; or double-dose lopinavir with ritonavir 800/200 mg twice daily, with close monitoring of liver tests.

Children (14 days and over). Weight-banded; pellets (40/10 mg) from 3 kg; tablets from 14 kg; 35 kg or more: adult doses. With rifampicin, extra ritonavir is added to give a lopinavir to ritonavir ratio of 1 to 1.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 800 mg of lopinavir daily (1000 mg with certain inducers).

Main alternatives. Atazanavir or darunavir with ritonavir.

Contraindications. Hypersensitivity; co-administration with the following drugs: amiodarone, dronedarone, flecainide, propafenone, quinidine, ranolazine, lovastatin, simvastatin, lurasidone, pimozide, ergot alkaloids, oral midazolam, triazolam, sildenafil for pulmonary hypertension, colchicine in kidney or liver impairment, and strong inducers (carbamazepine, phenytoin, phenobarbital, St John’s wort); oral solution in preterm neonates.

Serious adverse effects. Pancreatitis, hepatotoxicity, PR and QT prolongation, hyperglycaemia and diabetes, severe skin reactions, and, in neonates, toxicity from propylene glycol and alcohol in the solution.

Common adverse effects. Diarrhoea, nausea, vomiting, raised triglycerides and cholesterol, and fatigue.

Interactions. Boosting causes the same interactions as ritonavir; efavirenz and nevirapine lower levels; rifampicin lowers levels strongly, so extra ritonavir is added; hormonal contraceptives are less effective; methadone is lowered.

Common prescribing errors. Using once daily dosing with enzyme inducers or in pregnancy, not adjusting with rifampicin, and using the oral solution in preterm infants.

Special groups. - Pregnancy: safe and widely used; higher dose in the third trimester for treatment-experienced patients. - Breastfeeding: compatible. - Children: first choice in infants; pellets from 3 kg; avoid the solution in preterm neonates. - Older adults: usual dose. - Kidney impairment: no adjustment. - Liver impairment: caution; avoid in severe disease.

Regional points. Heat-stable tablets and pellets suit settings without refrigeration, and the pellets are in common use in East African paediatric programmes; bitter taste and large tablets reduce adherence.

Formulations. Film-coated tablets 100/25 mg and 200/50 mg; pellets 40/10 mg in capsules; oral solution 80/20 mg/mL.

Administration. Tablets with or without food, swallowed whole; solution with food.

Baseline. Liver tests, lipids, glucose, drug history and interaction check, ECG if on QT drugs.

Monitoring. Liver tests at 4 and 12 weeks and then every 6 months; lipids and glucose yearly; viral load at 3 and 6 months; weight in children.

Stopping thresholds. Stop for pancreatitis, severe skin reaction, or ALT over 3 times the upper limit of normal with symptoms, or over 5 times without.

Referral and escalation. Specialist review for treatment failure, tuberculosis co-treatment and neonates.