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Darunavir Levels Not Tied to Detectable HIV RNA in MONET Monotherapy Trial
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11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento
Mark Mascolini
Plasma concentrations of darunavir and ritonavir correlated with time since last dose and adherence--but not with detectable viral load--in the 256 people enrolled in the MONET trial of darunavir/ritonavir monotherapy [1]. Four other trials--ARTEMIS, TITAN, POWER, and GRACE--also found no link between darunavir concentration and detectable viremia.
MONET randomized people with a viral load below 50 copies for at least 24 weeks to take once-daily darunavir/ritonavir with two nucleosides or once-daily darunavir/ritonavir alone [2]. Study participants had an average CD4 count of 571 in the monotherapy group and 579 in the triple therapy group. Duration of antiretroviral therapy averaged 9.1 years in the monotherapy group and 7.5 years in the triple-therapy group. At week 48 a per-protocol analysis found monotherapy noninferior to triple therapy in keeping viral loads below 50 copies.
Michael Kurowski and MONET colleagues regularly measured darunavir and ritonavir levels in all patients. Trial clinicians also estimated adherence at each visit with the Modified Medication Adherence Self-Report Inventory. The investigators used multiple linear regression analysis to correlate log-transformed darunavir and ritonavir levels at each visit with viral load at each visit, and with time since last dose, treatment group, and average adherence.
Neither darunavir nor ritonavir levels predicted a viral load breakthrough above 50 copies. Average darunavir trough concentrations were equivalent in people whose viral load always stayed below 50 copies (2951 ng/mL) and those with readings above 50 copies (3020 ng/mL).
Levels of each protease inhibitor did both correlate with two factors: time since last dose and adherence. In both cases, longer time since last dose meant a lower drug level (P < 0.001 for both drugs), and better adherence correlated with higher drug levels (P < 0.001 for both drugs).
Darunavir trough concentrations averaged 1528 ng/mL for people with 80% adherence and 3199 ng/mL for those with 100% adherence. Ritonavir troughs averaged 66 ng/mL with 80% adherence and 111 ng/mL with 100% adherence. Concentrations of ritonavir fell significantly during the trial, from an average peak of 135 ng/mL at week 12 to an average 65 ng/mL at week 48 (P < 0.001).
The findings suggest that missed darunavir/ritonavir doses are the prime drivers of detectable viremia in people taking these drugs as monotherapy or part of a triple regimen.
References
1. Kurowski M, Van Delft Y, Moecklinghoff C, Hill A. Plasma darunavir (DRV) and ritonavir (RTV) concentrations versus adherence in the MONET trial. 11th International Workshop on Clinical Pharmacology and HIV Therapy. April 7-9, 2010. Sorrento. Abstract 45.
2. Arribas J, Horban A, Gerstoft J, et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/mL. AIDS. 2010;24:223-230.
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