Atazanavir/ritonavir: a review of its use in HIV therapy.

Recommendations for a highly active antiretroviral therapy (HAART) in either pretreated patients or symptomatic patients with an AIDS-defining event are based on a combination of three or more agents from different antiretroviral classes including two nucleoside reverse transcriptase inhibitors with at least one protease inhibitor. The majority of currently available protease inhibitors are coadministered with low-dose ritonavir as a pharmacoenhancer that significantly increases protease inhibitor plasma concentrations. Atazanavir is a highly active azapeptide inhibitor of the HIV protease. It was the first, and to date the only, protease inhibitor designed to be applied once daily (q.d.) and is expected to overcome the problems of earlier agents of this class of drugs, such as unfavorable adverse events like hyperlipidemia, diarrhea and lipodystrophy. Atazanavir, formerly known as BMS-232632, can be dosed either at 400 mg q.d. without a pharmacoenhancer as first-line HIV therapy or combined with ritonavir as atazanavir/ritonavir 300/100 mg q.d. for therapy-experienced patients. The pharmacoenhancing effect of ritonavir on atazanavir resulted in a potent, clinically effective and well-tolerated antiretroviral drug with high plasma concentrations and a sufficient genetic barrier to viral resistance. Nevertheless, noninferiority to lopinavir/ritonavir-containing HAART could not be shown when atazanavir was given unboosted in pretreated patients in the AI424-043 study. When atazanavir was boosted with low-dose ritonavir its efficacy was comparable to that of lopinavir/ritonavir in non-naive patients (AI424-045 study). Additionally, specific side effects were identified during clinical practice, such as an increased rate of patients with jaundice, and, more recently, genetic risk factors causing hyperbilirubinemia. Atazanavir inhibits glucuronyltransferase, an enzyme responsible for the metabolism of bilirubin in liver, thus increasing unconjugated bilirubin levels in blood. However, atazanavir itself also enhances plasma concentrations of other coadministered HIV-1 protease inhibitors, so that its use as a combination partner in boosted double protease inhibitor combinations, with or without the addition of nucleoside reverse transcriptase inhibitors, is being evaluated. Unboosted atazanavir is approved for first-line HIV therapy in adults in the United States, and atazanavir/ritonavir is recommended for the second-line therapy of HIV-1 infection in adult HIV-1-infected patients in the United States and the European Union. More recently, data from the CASTLE study (AI424-138) have been reported at the 15th Conference on Retroviruses and Opportunistic Infections by Molina et al., where boosted atazanavir-containing HAART was compared to a regimen with lopinavir/ritonavir in therapy-naive patients.