Lopinavir/Ritonavir

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Abstract
Coformulated lopinavir/ritonavir (Kaletra®) is a boosted protease inhibitor (PI) containing lopinavir and low-dose ritonavir. It is approved for use in combination with other antiretroviral drugs for the treatment of HIV infection in adults, adolescents and children aged ≥6 months (in the US) or ≥2 years (in the EU). Lopinavir/ritonavir-based antiretroviral therapy (ART) is generally well tolerated and has shown durable virological efficacy in clinical trials in ART-naive and -experienced patients with virological failure. Lopinavir/ritonavir is one of the preferred PIs for first-line treatment of HIV infection in adults, adolescents and children, according to US and British guidelines, reflecting its comparatively better virological efficacy than nelfinavir and low incidence of de novo resistance during long-term treatment. Lopinavir/ritonavir-based treatment may produce a more effective virological response than other PI-based regimens in single PI-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive patients. In PI- and NNRTI-experienced patients, atazanavir/saquinavir was inferior to lopinavir/ritonavir; further well designed trials are required to determine the comparative efficacy of lopinavir/ritonavir versus other PIs such as ritonavir-boosted atazanavir, or fosamprenavir or tipranavir in these patients. Lopinavir/ritonavir is more likely than atazanavir (alone or boosted) or nelfinavir to cause hypertriglyceridaemia and is associated with a higher incidence of hypercholesterolaemia than atazanavir (alone or boosted). The new lopinavir/ritonavir tablet coformulation offers a reduced pill count and lack of food interaction, and ART-naive patients in the US and Canada, who are not receiving efavirenz, nelfinavir, nevirapine or amprenavir, may benefit from convenient once-daily administration of lopinavir/ritonavir. Thus, lopinavir/ritonavir is a convenient, effective option for use in the treatment of HIV infection in ART-naive and -experienced adults, adolescents and children. Lopinavir is a potent, HIV-specific protease inhibitor. The pattern of primary mutations associated with resistance to the lopinavir/ritonavir coformulation has not been determined in ART-naive patients with HIV infection and there was no evidence of clinical resistance to lopinavir in viral isolates from ART-naive adults who received lopinavir/ritonavir 400mg/100mg for up to 7 years in three clinical studies. The incidence of cross-resistance to other PIs due to lopinavir/ritonavir treatment appears to be low. The steady-state plasma lopinavir concentration at the end of the dose-administration period remained at least 51-fold above the lopinavir protein binding-adjusted 50% effective concentration after administration of lopinavir/ritonavir 800mg/200mg once daily and 400mg/100mg twice daily in ART-naive patients, and 400mg/100mg twice daily in ART-experienced patients with HIV infection. The rapid and extensive first-pass oxidative metabolism of lopinavir in the liver is mediated primarily by the cytochrome P450 (CYP)-3A4 and CYP3A5 isoenzymes; ritonavir inhibits the activity of CYP3A4 in a concentration-dependent manner in human liver microsomes resulting in increased plasma lopinavir concentrations after administration of coformulated lopinavir/ritonavir. The bioavailability of lopinavir is increased with concomitant administration of food with the capsule or liquid coformulations. The capsule, liquid and tablet lopinavir/ritonavir coformulations are bioequivalent at a dose of lopinavir/ritonavir 400mg/100mg. Concomitant administration of food with the tablet coformulation does not produce a clinically significant effect on the bioavailability of lopinavir; the tablet coformulation may be administered with or without food. Induction or inhibition of the CYP isoenzymes results in a variety of interactions between lopinavir/ritonavir and other drugs. The therapeutic efficacy of oral lopinavir/ritonavir in combination with other antiretroviral agents has been investigated in generally well designed trials in ART-naive and -experienced adults, adolescents and children with HIV infection. Combination antiretroviral therapy with lopinavir/ritonavir effectively reduced viral load in ART-naive patients at both the 400mg/100mg twice-daily and 800mg/200mg once-daily dosages; viral load decreased to <50 copies/mL in at least 50% of ART-naive patients receiving either lopinavir/ritonavir dosage. Lopinavir/ritonavir 400mg/100mg twice daily was more likely than nelfinavir 750mg three times daily to produce sustained virological suppression. The antiviral efficacy of lopinavir/ritonavir-based therapy was maintained for up to 7 years. In ART-naive or PI-experienced patients, a significantly better therapeutic response was achieved at week 48 with lopinavir/ritonavir- than saquinavir/ ritonavir-based therapy. In single PI-experienced, NNRTI-naive patients with virological failure, lopinavir/ritonavir-based therapy was significantly more effective than investigator-selected PI regimens containing saquinavir/ritonavir, indinavir/ritonavir, nelfinavir, indinavir, ritonavir, saquinavir and nelfinavir/saquinavir. In PI- and NNRTI-experienced patients, lopinavir/ritonavir produced a significantly better virological response than unboosted atazanavir and, in non-inferiority trials versus lopinavir/ritonavir, atazanavir plus ritonavir was non-inferior and atazanavir plus saquinavir was inferior; non-inferiority could not be established for fosamprenavir plus ritonavir. In HIV-infected children and adolescents, combination therapy with lopinavir/ritonavir produced a virological response at week 48 and this response was maintained for up to 72 weeks. Lopinavir/ritonavir-containing regimens were generally well tolerated in clinical trials; the most common adverse events were gastrointestinal, including diarrhoea, nausea and vomiting, and were usually of mild to moderate severity. The incidence of diarrhoea appears to be dose-related. Serious adverse events related to lopinavir/ritonavir are rare. Lopinavir/ritonavir was also generally well tolerated in paediatric patients. Except for a significantly higher incidence of diarrhoea with lopinavir/ ritonavir 400mg/100mg twice daily than with atazanavir plus ritonavir 300mg/ 100mg once-daily, lopinavir/ritonavir-based treatment was generally tolerated as well as or better than regimens containing atazanavir, atazanavir plus ritonavir or saquinavir, fosamprenavir plus ritonavir, nelfinavir or investigator-selected PIs. Lopinavir/ritonavir is more likely than atazanavir (alone or boosted) or nelfinavir to cause hypertriglyceridaemia and is associated with a higher incidence of hypercholesterolaemia than atazanavir (alone or boosted). Increased liver amino-transferase levels were observed in similar proportions of patients receiving antiretroviral therapy containing lopinavir/ritonavir and other PIs.