-->

Darunavir/Ritonavir with Rifampicin may be hepatotoxic

Organisation: Position: Deadline Date: Location:

Darunavir/ritonavir administered with rifampicin causes hepatotoxicities in people living with HIV, according to results of a study led by researchers at the department of medicine, the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and the Desmond Tutu HIV Centre at the University of Cape Town. 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 co-administered 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-centre 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 enrol into 3 cohorts: cohort 1 (n=5), cohort 2 (n=12), and cohort 3 (n=11). Once enrolment was completed for cohort 1, enrolment 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.

Limitations of this study included that participants did not have TB, and therefore were not on anti-TB therapy (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.”

Abstract
Background: Darunavir/ritonavir is better tolerated than lopinavir/ritonavir and has a higher genetic barrier to resistance. Co-administration with rifampicin has been contraindicated as a significant reduction in darunavir exposure is expected. This is a barrier to darunavir/ritonavir use where TB is endemic.
Objectives: To evaluate the safety and pharmacokinetic profile of adjusted doses of darunavir/ritonavir with rifampicin.

Methods: Virally suppressed participants on second-line lopinavir/ritonavir-based ART were switched to darunavir/ritonavir 800/100 mg q24h. In sequence: rifampicin was added; the dose of ritonavir was escalated; and darunavir was increased (darunavir/ritonavir 1600/200 mg q24h and 800/100 mg q12h were given in randomized sequence with rifampicin). Darunavir plasma concentrations were measured on the seventh/last day of each treatment period. To prevent viral rebound, dolutegravir (50 mg q12h) was added during rifampicin administration and for 1 week thereafter. Clinical events, ALT and bilirubin were monitored every 2–3 days during rifampicin administration.
Results: A total of 17/28 participants started study treatment. Six (35.3%) were withdrawn for symptomatic hepatitis with severe ALT elevations, developing after 9–11 days of rifampicin and 2–4 days of ritonavir 200 mg. The study was stopped prematurely due to this high rate of hepatotoxicity. Only four participants completed the study. All hepatotoxicity resolved on withdrawal of study treatment. All participants were successfully re-established on their lopinavir/ritonavir-based regimen. After doubling the darunavir/ritonavir doses on rifampicin, darunavir pre-dose concentrations approached those on standard doses without rifampicin for q12h doses, but not for q24h doses.
Conclusions: Adjusted doses of darunavir/ritonavir with rifampicin had unacceptable risk of hepatotoxicity. Darunavir trough concentrations were markedly reduced with the daily adjusted dose.

Authors
Ebrahim I, Maartens G, Wiesner L, Orrell C, Smythe W, McIlleron H

Infectious Disease Advisor report

Journal of Antimicrobial Chemotherapy

Receive Medical Brief's free weekly e-newsletter



Related Posts

Thank you for subscribing to MedicalBrief


MedicalBrief is Africa’s premier medical news and research weekly newsletter. MedicalBrief is published every Thursday and delivered free of charge by email to over 33 000 health professionals.

Please consider completing the form below. The information you supply is optional and will only be used to compile a demographic profile of our subscribers. Your personal details will never be shared with a third party.


Thank you for taking the time to complete the form.