Randomised Pharmacokinetic Trial of Rifabutin with Lopinavir/Ritonavir-Antiretroviral Therapy in Patients with HIV-Associated Tuberculosis in Vietnam

Abstract

BackgroundRifampicin and protease inhibitors are difficult to use concomitantly in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there is concern that the current recommended dose is suboptimal. The principal aim of this study was to compare bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in patients with HIV-associated tuberculosis who initiated lopinavir/ritonavir-based antiretroviral therapy in Vietnam. Concentrations of lopinavir/ritonavir were also measured.MethodsThis was a randomized, open-label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis in Ho Chi Minh City (Clinical trial registry number NCT00651066). Rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir -based antiretroviral therapy using patient randomization lists. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after 2 weeks of rifabutin 300 mg daily, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir.ResultsSixteen and seventeen patients were respectively randomized to the two arms, and pharmacokinetic analysis carried out in 12 and 13 respectively. Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2 – 5 fold increases of the 25-O-desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations.ConclusionsBased on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis.Trial RegistrationClinicalTrials.gov NCT00651066

Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis

“…Unlike rifampin, rifabutin does not reduce concentrations of concomitantly administered protease inhibitors (PIs) significantly (1). The pharmacokinetics of rifabutin are highly varied (2)(3)(4). As a CYP3A4 substrate, rifabutin is subject to drug interaction with CYP3A4 inhibitors, such as PIs, and increases in exposure can result in an increased risk for adverse effects, particularly uveitis.…”

“…Following an overnight fast, blood samples were drawn immediately before dosing and at 2,3,4,5,6,8,12, and 24 h after dosing. A standard hospital breakfast (oats with 2 slices of toast and tea) was served Ͼ2 h after dosing.…”

Understanding the Tuberculosis Disease Progression and Future Directions of Research in Tuberculosis: A Mini Review

“…Rifabutin dose of 150 mg daily in adult HIV-infected TB patients receiving protease inhibitor based antiretroviral therapy was able to safely maintained rifabutin plasma concentrations and prevents the sub-optimal dosingrelated acquired rifamycin resistance (Lan et al 2014;Naiker et al 2014). …”

British HIV Association guidelines for the treatment of HIV‐1‐positive adults with antiretroviral therapy 2015

“…As darunavir/r also acts as an inducer, rifabutin 150 mg once daily can be given to reduce the theoretical risk of rifamycin resistance due to a risk of sub‐therapeutic rifabutin concentrations; this may, however, be associated with increased side effects . Recent data suggest rifabutin at 150 mg/day maintains adequate levels with lopinavir/r . Therapeutic drug monitoring may be useful in guiding doses.…”