To investigate the pharmacokinetic and pharmacodynamic relationships of the human immunodeficiency virus (HIV)–protease inhibitor atazanavir (ATV) in the presence and absence of the pharmacokinetic booster ritonavir, utilizing ATV plasma trough concentrations (Ctrough) and clinical biomarkers of antiviral efficacy and safety over 48 weeks.
Randomized, open-label, multicenter, study designed to compare the efficacy and safety of ATV 300 mg plus ritonavir 100 mg (ATV300/r) with that of ATV 400 mg (ATV400).
Thirty clinic sites across 10 countries in Africa, Europe, North America, and South America.
Patients who were HIV-positive and treatment-naïve.
Randomized to once-daily ATV400 (105 patients) or ATV300/r (95 patients) plus lamivudine and extended-release stavudine.
Measurements and Main Results
The Ctrough approximately 24 hours after the prior unobserved dose was measured through week 48. Composite Ctrough (i.e., the geometric mean of all trough concentrations over the 48 weeks), population inhibitory quotient ([IQ], i.e., Ctrough divided population estimated protein binding adjusted effective concentration at 90% [EC90, 14 ng/ml]), composite population IQ (i.e., ATV composite trough divided by population estimated protein binding adjusted EC90), HIV RNA, CD4 cell counts, and metabolic and safety parameters were also assessed. For ATV400 and ATV300/r, respectively, geometric mean composite Ctrough (CV%) were 127 (106) ng/ml and 670 (63) ng/ml, geometric mean composite population IQ were 9 and 48, and composite Ctrough values of HIV EC90 or more were achieved in 98% and 100% of patients. High ATV Ctrough was associated with low HIV RNA at week 48; however, 88% of patients had HIV RNA less than 400 copies/ml in the lowest composite Ctrough quartile. There was no clear relationship between ATV Ctrough and changes in CD4 cell count. Increases in total bilirubin or jaundice were associated with higher Ctrough. Modest increases in triglycerides and cholesterol were associated with the addition of ritonavir.
ATV-containing regimens with or without ritonavir achieved ATV exposures that provide robust antiretroviral efficacy and acceptable tolerability in treatment-naïve patients.