Boosted Reyataz: 48-Week Results

Atazanavir (ATV, Reyataz) is the first once-a-day (QD) protease inhibitor (PI) to be marketed in the United States. The drug was approved in mid-2003 at a dose of 400 mg QD, to be taken with food. The pivotal studies of atazanavir compared it to the two current standard-of-care drugs for first-line regimens, efavirenz (Sustiva) and ritonavir-boosted lopinavir (Kaletra). Although atazanavir suppressed HIV RNA as well as efavirenz in previously untreated patients in a 48-week trial, it did not perform as well as Kaletra in 24-week data from a comparison of unboosted atazanavir with ritonavir-boosted lopinavir (Kaletra) in treatment-experienced patients. At the time of its consideration by the FDA Antiviral Drugs Advisory Committee shortly before approval, there was concern expressed that low and widely varying trough blood levels of atazanavir may often fail to provide adequate viral suppression, especially in those with pre-existing PI resistance.

To address those worries, the sponsor showed the Committee some preliminary, 24-week data from a comparison of Kaletra with ritonavir-boosted atazanavir (ATV 300 mg/RTV 100 mg QD) in treatment-experienced individuals with multiple prior protease inhibitor resistance mutations. Although the FDA was not able to review this data for inclusion in the prescribing information, the early data suggested that when atazanavir blood levels were boosted by 100 mg of ritonavir, the viral load reductions seen at 24 weeks were equivalent to those produced by Kaletra in this highly treatment-experienced population.

At the 11th Annual Retrovirus Conference, Edwin DeJesus and colleagues have now reported on 48-week data from the comparison of ritonavir-boosted atazanavir with Kaletra (BMS AI424-045). Approximately 120 patients were randomized to each arm of the open-label trial. A third arm offering atazanavir plus saquinavir failed to perform as well as the ritonavir-boosted PIs. The nucleoside backbone was composed of tenofovir (300 mg) and one other drug.

The mean reduction in viral load at two weeks was -1.18 log copies/mL for boosted atazanavir and -1.31 log copies/mL for Kaletra. At 48 weeks, the mean viral load reduction was equivalent between the arms, at -1.93 log copies/mL for atazanavir/ritonavir and -1.87 for Kaletra. While the proportion of individuals responding with HIV RNA reductions below 400 log copies/mL was equivalent between the groups at about 57 percent, slightly more persons on Kaletra experienced reductions below 50 copies (46% vs. 38%).

Mean changes in CD4 cell counts were similar in the two groups although the Kaletra group showed a tendency to a greater rise during the first 16 weeks of the trial. At 48 weeks, the mean increase in CD4 cell count was 121 cells/mm³ in the Kaletra group and 110 cells/mm³ in the boosted atazanavir group.

Atazanavir is distinguished among protease inhibitors by having little impact on blood lipid levels such as cholesterol and triglycerides. Patients in this study who had developed high lipid levels after taking other protease inhibitors experienced normalization of lipids after switching to atazanavir. Lipid levels, especially triglycerides, increased or remained stable in those receiving Kaletra. A dose-limiting side effect of atazanavir may be the development of jaundice or yellowing of the eyes due to bilirubin increases that occur in a large proportion of treated patients. Bilirubin elevations were not associated with hepatotoxicity and did not result in any discontinuations in this trial.

Reference

1. DeJesus E, Grinsztejn B, Rodriguez C, et al. Efficacy and safety of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) vs lopinavir/ritonavir (LPV/RTV) in patients who have experienced virologic failure on multiple HAART regimens: 48-week results from BMS AI424-045. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Poster 547.