By Ronald Baker, PhD

Reyataz Capsule

Kaletra Tablet

Race-based differences in efficacy and safety have been reported among HIV positive individuals on HAART. However, data on this issue are limited. It is widely known that rates of obesity, diabetes, and the metabolic syndrome are increasing. In addition, studies suggest that certain racial/ethnic groups may be more susceptible to the risks associated with these conditions.

Ritonavir-boosted atazanavir (Reyataz) is a potent and generally well-tolerated once-daily HIV protease inhibitor (PI) that has been extensively studied in both treatment-naive and treatment-experienced individuals.

At the XVII International AIDS Conference last week in Mexico City (August 3-8, 2008), researchers presented results of the CASTLE trial, which assessed the potential differences in treatment effectiveness and safety in treatment-naive patients with a variety of racial/ethnic backgrounds.

The primary objective of this substudy was to analyze the 48-week CASTLE efficacy and safety data by racial/ethnic group and to assess the virologic, immunologic, and safety profiles of both an atazanavir/ritonavir-based regimen and a lopinavir/ritonavir (Kaletra)-based regimen.

CASTLE is a randomized, open label, prospective study comparing once-daily atazanavir/ritonavir vs twice-daily lopinavir/ritonavir, both in combination with fixed-dose tenofovir/emtricitabine (Truvada) in treatment-naive HIV patients.

The primary endpoint of the study was the proportion of patients with HIV RNA < 50 copies/mL at week 48. For this analysis, the proportion of patients with < 50 copies/mL (confirmed virological response, non-completer equals failure), CD4 cell count changes, adverse events (AEs), and fasting lipid changes were presented by race/ethnicity (classified as white, black, Asian, or other) through week 48.

Results

• Of 883 randomized patients, 48% were white, 18% were black, 9% were Asian, and 24% were "other" (Hispanic/Latino 6%, Mestizo 67%, mixed race 27%); racial/ethnic classification was similar between the 2 treatment arms.

• In the overall study population, 78% of those on atazanavir/ritonavir and 76% on lopinavir/ritonavir achieved HIV RNA < 50 copies/mL.

• Virological response to the 2 regimens was consistently high across all racial/ethnic subgroups.

• Overall, median CD4 cell count increases from baseline to week 48 were 191 cells/mm3 for the atazanavir/ritonavir group vs 200 cells mm3 for the atazanavir/ritonavir group.

• Among whites, the median increase was 226 cells/ mm3 for the atazanavir/ritonavir group vs 204 cells mm3 for the lopinavir/ritonavir group.

• Among blacks, the median increase was 142 cells mm3 for the atazanavir/ritonavir group vs 190 cells mm3 for the lopinavir/ritonavir group.

• Among Asians, the median increase was 198 cells mm3 for the atazanavir/ritonavir group vs 200 cells mm3 for the lopinavir/ritonavir group.

• Adverse events were not treatment limiting in most cases.

• The incidence of AE leading to discontinuation of study therapy was low overall population (2% with atazanavir/ritonavir, 3% with lopinavir/ritonavir).

• More patients receiving atazanavir/ritonavir discontinued due to jaundice or hyperbilirubinemia (<1% vs 0), while more people receiving lopinavir/ritonavir discontinued due to diarrhea (<1% vs 0).

• Overall, the incidences of jaundice and hyperbilirubinemia (all grades) in the atazanavir/ritonavir group were lowest in blacks (2% and 4%, respectively) and highest in Asians (26% and 40%, respectively).

• As expected, patients taking atazanavir/ritonavir had fewer gastrointestinal (GI) AEs, regardless of race/ethnicity.

• Among patients receiving lopinavir/ritonavir, diarrhea was most frequent among whites (14%) and lowest among blacks (5%).

• Patients receiving atazanavir/ritonavir had less elevation in total cholesterol, non-HDL ("bad") cholesterol and triglycerides regardless of ethnicity.

• The percent increase in total cholesterol from baseline to week 48 was 19% for blacks and Asians receiving lopinavir/ritonavir, compared with 3% and 6%, respectively, for those receiving atazanavir/ritonavir.

• In the lopinavir/ritonavir group, whites had a 27% increase in total cholesterol and patients in the other racial/ethnic groups had a 30% increase, compared with increases of 15% and 17%, respectively, for whites and other racial/ethnic groups receiving atazanavir/ritonavir.

• The most notable racial/ethnic trends in the data were an increase in triglycerides from baseline to week 48 in the lopinavir/ritonavir group, noted as a 100% increase in Asians and 60% increases in whites and other racial/ethnic groups.

• In contrast, triglyceride levels increased by 17% in whites, 0% in blacks, 21% in Asians, and 11% in the other racial/ethnic groups receiving atazanavir/ritonavir.

In conclusion, the study investigators noted:

• Both once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir regimens produced overall high levels of virological response and robust increases in CD4 cell count, but the regimens varied in efficacy and immunological response by race/ethnicity.

• In the primary analysis, once-daily boosted atazanavir was non-inferior to twice-daily lopinavir/ritonavir.

• As expected, direct hyperbilirubinemia occurred more frequently with atazanavir/ritonavir than with lopinavir/ritonavir, but was not treatment-limiting.

• The rates of direct hyperbilirubinemia (all grades and grade 3-4) were slightly higher among whites than other racial/ethnic groups, but were consistent with prior studies of atazanavir/ritonavir.

• While both atazanavir/ritonavir and lopinavir/ritonavir regimens show high levels of efficacy in all racial/ethnic groups at 48 weeks, variations in safety profiles -- particularly GI tolerability and increases in lipid parameters -- discriminated between the 2 boosted PIs.

• These differences provide important information for clinicians to consider when selecting regimens intended for long-term control of HIV infection.

8/12/08

Sources
D McGrath, J Uy, R Yang, and others. Efficacy and Safety by Racial Group in ARV-naïve Subjects Treated with Atazanavir/ritonavir or Lopinavir/ritonavir: 48-week Results of the CASTLE Study. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Poster TUPE0058.

Abbott Laboratories. Abbott's Kaletra Tablet Dosed Once-Daily or Twice-Daily Demonstrated Similar Clinical Results across Race and Gender Lines. Press Release. August 5, 2008.