Atazanavir

Atazanavir (Reyataz®) is a novel protease inhibitor (PI) approved for use in combination with other antiretroviral drugs for the treatment of HIV infection. In antiretroviral therapy (ART)-experienced patients the drug is administered with low-dose ritonavir (i.e. boosted). In the US, unboosted atazanavir is also approved for use in ART-naive patients.

In adult patients with HIV infection, atazanavir-containing highly active antiretroviral therapy (HAART) regimens provided marked improvements in virological and immunological markers and was generally well tolerated. Furthermore, recommended atazanavir regimens were no less effective than, and generally as well tolerated as, other HAART regimens in these patients, including regimens containing co-formulated lopinavir/ritonavir. Atazanavir may have an advantage over other PIs because of its favourable effect on lipid profiles, once-daily dosing, low capsule burden and, in patients with low prior PI exposure, a favourable resistance profile. Given these advantages and taking into consideration between-country differences in the approved indications, atazanavir is a valuable option as the PI component of HAART for the management of HIV infection in adult ART-naive patients, particularly where metabolic complications are a concern, and as a first-or second-line PI in combination with low-dose ritonavir in adult ART-experienced patients.

Atazanavir prevents the formation of mature virions by inhibiting the processing of viral gag and gag-pol polyproteins in HIV-infected cells. The unique, signature mutation for atazanavir resistance in isolates from ART-naive patients was an isoleucine to leucine substitution at amino acid residue 50 of the HIV-1 protease gene. This mutation was atazanavir-specific and conferred increased susceptibility to other PIs. However, in ART-experienced patients who had never previously received atazanavir, atazanavir susceptibility was reduced in the presence of multiple mutations associated with resistance to other PIs. There was high cross-resistance to atazanavir in patients with prior exposure to at least three other PIs.

Limited data suggest that atazanavir-containing regimens were not associated with insulin resistance, and evidence from clinical trials showed that atazanavir had a lower propensity to cause dyslipidaemia than nelfinavir or efavirenz in ART-naive patients or lopinavir/ritonavir in ART-experienced patients. Moreover, ART-experienced patients with hyperlipidaemia receiving atazanavir-containing therapy experienced reductions from baseline in total cholesterol, non-high-density lipoprotein cholesterol and trigylceride levels.

The pharmacokinetics of oral atazanavir administered once daily are nonlinear. Greater atazanavir exposure was observed in healthy volunteers than in patients with HIV infection. Boosting with low-dose ritonavir increases atazanavir plasma trough concentrations (the pharmacodynamically linked variable) because of the pharmacokinetic interaction between these drugs. The terminal elimination half-life of unboosted atazanavir was approximately 7 hours in patients with HIV infection or healthy volunteers.

The hepatic cytochrome P450 3A isoenzyme metabolises atazanavir to pharmacologically inactive metabolites that are, along with the unchanged drug, eliminated primarily via the biliary pathway. Pharmacokinetic drug interactions between atazanavir and numerous coadministered drugs, including certain antiretroviral drugs, antimycobacterials, calcium channel antagonists, oral contraceptives and proton pump inhibitors, have been demonstrated.

In phase II or III trials in ART-naive patients receiving a dual-nucleoside reverse transcriptase inhibitor (NRTI)-containing regimen, the efficacy of atazanavir 400mg once daily was similar to that of nelfinavir 750mg three times daily, nelfinavir 1250mg twice daily or efavirenz 600mg once daily after 48 weeks’ treatment. Viral suppression was maintained for an additional 24 weeks in an open-label extension study.

In a randomised 48-week phase III trial in patients also receiving two NRTIs, who had previously failed two HAART regimens, the efficacy of atazanavir 300mg once daily boosted with ritonavir 100mg once daily was noninferior to that of co-formulated lopinavir/ritonavir 400mg/100mg twice daily. However, the efficacy of saquinavir soft gelatin capsules 1200mg once daily plus atazanavir 400mg once daily was inferior to that of lopinavir/ritonavir. The favourable effect of atazanavir plus ritonavir on viral suppression and immunological outcomes was maintained for up to 96 weeks.

Atazanavir in combination with other antiretroviral drugs was generally well tolerated (treatment duration up to 120 weeks). The type of most treatment-related adverse effects was broadly similar between atazanavir recipients and recipients of nelfinavir, efavirenz or co-formulated lopinavir/ritonavir, with the exception of jaundice and scleral icterus, which occurred only in patients receiving atazanavir. Atazanavir-containing regimens were associated with less diarrhoea than nelfinavir- and lopinavir/ritonavir-containing regimens.

The most frequent laboratory abnormality associated with the use of atazanavir-containing regimens was elevated total bilirubin, predominantly of the unconjugated type, which was generally reversible and not associated with elevated aminotransferase levels. Hyperbilirubinaemia infrequently lead to discontinuation. In addition, the incidence of grade 3 or 4 hyperbilirubinaemia in atazanavir recipients was similar between HIV-infected patients positive for hepatitis B and/or C virus and those negative for hepatitis.