Darunavir (DRV)/ritonavir(r) is better tolerated than lopinavir (LPV)/r and has a higher genetic barrier to resistance. Co-administration of DRV/r with rifampin (RIF), the key component of first-line TB treatment, is currently contraindicated as significant reductions in DRV exposures are expected; this has been a barrier to the use of DRV/r in resource-limited settings where TB is endemic. We aimed to evaluate the safety and pharmacokinetics (PK) of adjusted doses of DRV/r in PLWH.
We enrolled virologically suppressed participants on a second-line DRV/r regimen without TB. Based on data from a Physiologically-Based PK model, we selected two adjusted doses of DRV/r (1600/200 mg daily and 800/100 mg 12 hourly) with RIF for comparison to plasma exposures with DRV/r 800/100 mg daily without RIF, in a cross-over design. Baseline DRV steady state PK was determined and RIF added for 7 days, then the dose of r was increased to 200 mg; 7 days later the dose of DRV was increased; after another 7 days participants were crossed over to the alternative adjusted DRV dose. DRV was measured in plasma samples after observed doses at baseline and after each dose adjustment. Non-compartmental analysis was used to estimate the PK measures. Clinical adverse events, ALT, and bilirubin were monitored every 2 to 3 days during treatment with RIF.
Seventeen of a planned 28 PLWH were enrolled and started on study treatment before the study was stopped due to high rates of hepatotoxicity. Only 4 participants completed the study. Six (35%) of the participants were withdrawn for DAIDS grade 3 (n=3) or 4 (n=3) ALT elevations developing after 9-12 days of RIF; 3 participants were symptomatic. Hepatotoxicity resolved in all cases after withdrawal of study treatment and participants were successfully re-established on their standard of care ART regimen. The PK parameters are shown in table 1. Trough concentrations were below the protein-adjusted EC50 of 200 ng/mL in 2 participants in the QD group adjusted dose group on RIF.
Adjusted doses of DRV/r with RIF were associated with unacceptable risk of hepatotoxicity and there was a marked reduction in DRV trough concentrations with the QD adjusted dose in our study.