Potential associations between atazanavir exposure and clinical outcome: a pharmacokinetic sub-study from the MODAt randomized trial

The 96-week results of the Monotherapy Once a Day with Atazanavir/r (MODAt) study [NCT01511809] showed an inferior virological efficacy of atazanavir (ATV)/ritonavir monotherapy versus triple therapy, which was promptly retrieved by the reintroduction of nucleoside/nucleotide inhibitors of reverse transcriptase [N(n)RTIs]. We aimed to identify potential relationships between ATV exposure and clinical outcome in HIV-1 subjects treated with ATV/ritonavir monotherapy [ATV/r 300/100mg] versus ATV/ritonavir triple therapy [ATV/r 300/100mg+2NRTIs]. A chromatographic method coupled with tandem mass spectrometry was applied to analyze ATV plasma concentrations in a pharmacokinetic sub-study from the MODAt trial. Mixed linear models were used to examine the ATV plasma concentration trend during follow-up and to assess the association between ATV plasma concentrations trajectories with the study arm or the occurrence of treatment failure or drug-related adverse events or the grading of baseline total bilirubin (<3 vs ≥3). The analyses were performed using SAS Software, release 9.4 (SAS Institute, Cary, NC, USA). Overall, ATV plasma Ctrough concentration did not vary during follow-up (slope: +0.75 ng/mL/week, 95%CI: -0.97 to 2.47, p=0.387); trajectories did not differ between study arms 2 (p=0.527). The unadjusted model-based means (95%CI) of ATV Ctrough during follow-up were 835 (95%CI: 657-1012) ng/ml in the ATV/r monotherapy arm as compared to 911 (95%CI: 740-1082) ng/mL in the ATV/r triple therapy arm (p=0.621). Mean ATV Ctrough was similar in subjects with or without adverse events (AEs). Subjects treated with ATV/r monotherapy showed significantly higher ATV concentrations as compared to subjects without adverse events or treated with ATV/r triple therapy. ATV concentrations were associated with the grading of baseline total bilirubin and the occurrence of drug-related AEs but not with HCV infection. Our findings showed a lack of association between ATV concentrations and treatment failure both in ATV/r monotherapy and triple therapy. Conversely, these data emphasized that ATV concentrations are associated with the development of side-effects in both subjects treated with ATV/r monotherapy and subjects treated with ATV/r triple therapy.