Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy

Abstract

BackgroundPharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin (150 mg daily) in combination with boosted lopinavir (LPV/r), than the previous dose of rifabutin (150 mg three times weekly {tiw}). But there are limited pharmacokinetic data evaluating the higher dose of rifabutin in combination with LPV/r. Sub-optimal dosing can lead to acquired rifamycin resistance (ARR). The plasma concentration of 25-O-desacetylrifabutin (d-RBT), the metabolite of rifabutin, increases in the presence of PIs and may lead to toxicity.Methods and resultsSixteen patients with TB-HIV co-infection received rifabutin 300 mg QD in combination with tuberculosis chemotherapy (initially pyrazinamide, isoniazid and ethambutol then only isoniazid), and were then randomized to receive isoniazid and LPV/r based ART with rifabutin 150 mg tiw or rifabutin 150 mg daily. The rifabutin dose with ART was switched after 1 month. Serial rifabutin and d-RBT concentrations were measured after 4 weeks of each treatment. The median AUC0–48 and Cmax of rifabutin in patients taking 150 mg rifabutin tiw was significantly reduced compared to the other treatment arms. Geometric mean ratio (90% CI) for AUC0–48 and Cmax was 0.6 (0.5-0.7) and 0.5 (0.4-0.6) for RBT 150 mg tiw compared with RBT 300 mg and 0.4 (0.4-0.4) and 0.5 (0.5-0.6) for RBT 150 mg tiw compared with 150 mg daily. 86% of patients on the tiw rifabutin arm had an AUC0-24 < 4.5 μg.h/mL, which has previously been associated with acquired rifamycin resistance (ARR). Plasma d-RBT concentrations increased 5-fold with tiw rifabutin dosing and 15-fold with daily doses of rifabutin. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities. One case of uveitis (grade 4), occurred in a patient taking rifabutin 300 mg daily prior to starting ART, and grade 3 neutropenia (asymptomatic) was reported in 4 patients. These events were not associated with increases in rifabutin or metabolite concentrations.ConclusionsA daily 150 mg dose of rifabutin in combination with LPV/r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR.Trial registrationClinicalTrials.gov Identifier: NCT00640887

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults

“…A boosted PI-based regimen should be used only if an InSTI-based regimen is not an option, and rifabutin, 150 mg daily, should be substituted for rifampin in the antituberculosis regimen (evidence rating AIa). 84–86 …”

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). …”

“…However, if rifampicin should be discontinued due to rifampicin-related adverse drug reactions or resistance to rifampicin, current recommendation suggest a higher doses and prolonged treatment for at least 12-18 months with isoniazid, ethambutol and fluoroquinolone (World Health Organization 2014). Rifampicin-related adverse drug reactions is accelerated when combining rifampicin with protease inhibitor based-antiretroviral therapy in HIV co-infected TB patients (Naiker et al 2014). The use of rifabutin, a rifamycin to replace rifampicin in the conditions where rifampicin is to be discontinued, was reported successful as it results in a comparable activity against Mycobacterium tuberculosis and lower incidence of adverse drug reactions (Tattevin et al 2003;Martinez et al 1999;Mancini et al 1992).…”