Darunavir/ritonavir administered with rifampicin causes hepatotoxicities in people living with HIV, according to results of a study published in the Journal of Antimicrobial Chemotherapy.

Darunavir/ritonavir-based antiretroviral therapy (ART) is better tolerated and has a higher genetic barrier to resistance compared with second-line lopinavir/ritonavir-based ART for treatment of HIV. Darunavir, the preferred boosted protease inhibitor in high-income countries, is contraindicated when darunavir/ritonavir is coadministered with rifampicin (a key first-line tuberculosis [TB] treatment), due to its induction of cytochrome P450 (CYP) 3A4, because it causes significant reductions in darunavir metabolism. As a result, rifabutin replaces rifampicin in high-income countries because it is a weaker CYP3A4 inducer that does not reduce PI concentrations; however, rifabutin is not available in most low- to middle-income countries where TB is endemic.

Previous data has demonstrated that when lopinavir/ritonavir dose is doubled or when additional ritonavir is administered with rifampicin, therapeutic concentrations of lopinavir can be achieved, but high rates of symptomatic hepatitis were reported. A physiologically based pharmacokinetic model predicted that increasing the dose of dose of darunavir/ritonavir to 800 mg/100 mg twice daily or 1600 mg/200 mg once daily could overcome the inducing effects of rifampicin. Therefore, this open-label, single-center study evaluated the safety and pharmacokinetic profile of adjusted doses of darunavir/ritonavir with rifampicin (ClinicalTrials.gov identifier: NCT03892161).

The study planned for 28 participants to enroll into 3 cohorts: cohort 1 (n=5), cohort 2 (n=12), and cohort 3 (n=11). Once enrollment was completed for cohort 1, enrollment for cohort 2 depended on the clinical safety review of cohort 1. From day 1 to day 42, participants were to be switched to darunavir/ritonavir (800 mg/100 mg) for 6 weeks; baseline darunavir steady-state pharmacokinetics were to be determined after day 7. Rifampicin was then to be added for 7 days (660 mg for participants weighing <70 kg and 750 mg for participants ³70 kg). After another 7 days, participants were randomly assigned to double doses of darunavir/ritonavir (1600 mg/200 mg daily or 800 mg/100 mg twice daily). Participants were then crossed over to the alternative doubled darunavir/ritonavir dose and 7 days after this crossover, pharmacokinetics were to be evaluated.

In total, 17 black participants who demonstrated virologic suppression and on second-line lopinavir/ritonavir-based ART were included. Participants were divided into 1 of 2 cohorts: cohort 1 (n=5) and cohort 2 (n=12). However, the study was prematurely stopped due to the development of symptomatic grade ³3 ALT elevations without jaundice in 6 (35.3%) participants. These hepatotoxicities developed after 9 to 11 days of receiving rifampicin and 2 to 4 days of receiving 200 mg ritonavir. Only 4 participants completed the study. Once study treatment was discontinued, the hepatotoxicity resolved.

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Limitations of this study included that participants did not have TB, and therefore were not on anti-TB therapy (eg, isoniazid), which could affect the pharmacokinetics and hepatotoxicity of rifampicin and darunavir/ritonavir since isoniazid is a potent inhibitor of CYP3A4. In addition, 16 of the 17 participants included were women who had body mass indexes that were higher than most patient populations with TB, could have hindered the pharmacokinetic and safety results.

Results led to the conclusion that doubling the administered darunavir/ritonavir twice daily dose may counteract the inducing effect of rifampicin, but daily administration does not achieve adequate darunavir exposures; however, this conclusion lacks power due to the premature stop in the study. Overall, the study authors conclude that, “In vitro and animal studies to investigate the underlying mechanism of darunavir/ritonavir-induced hepatotoxicity could inform safer future strategies.”

Reference

Ebrahim I, Maartens G, Wiesner L, Orrell C, Smythe W, McIlleron H. Pharmacokinetic profile and safety of adjusted doses of darunavir/ritonavir with rifampicin in people living with HIV. J Antimicrob Chemother. 2020;75:1019-1025.