Naiker S., Connolly C., Wiesner L., Kellerman T., Reddy T., Harries A., McIlleron H., Lienhardt C., Pym A.
Medical Research Council, TB Research Unit, Durban, South Africa; Medical Research Council, Biostatistics Unit, Durban, South Africa; University of Cape Town, Division of Clinical Pharmacology, Department of Medicine, Cape Town, South Africa; International Union Against Tuberculosis and Lung Disease, Paris, France; WHO STOP Tuberculosis Programme, Geneva, Switzerland; University of KwaZulu-Natal, KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa
Naiker, S., Medical Research Council, TB Research Unit, Durban, South Africa; Connolly, C., Medical Research Council, Biostatistics Unit, Durban, South Africa; Wiesner, L., University of Cape Town, Division of Clinical Pharmacology, Department of Medicine, Cape Town, South Africa; Kellerman, T., University of Cape Town, Division of Clinical Pharmacology, Department of Medicine, Cape Town, South Africa; Reddy, T., Medical Research Council, Biostatistics Unit, Durban, South Africa; Harries, A., International Union Against Tuberculosis and Lung Disease, Paris, France; McIlleron, H., University of Cape Town, Division of Clinical Pharmacology, Department of Medicine, Cape Town, South Africa; Lienhardt, C., WHO STOP Tuberculosis Programme, Geneva, Switzerland; Pym, A., Medical Research Council, TB Research Unit, Durban, South Africa, University of KwaZulu-Natal, KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa
Background: Pharmacokinetic 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 results: Sixteen 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. Conclusions: A daily 150 mg dose of rifabutin in combination with LPV/r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR. © 2014 Naiker et al.
25 o desacetylrifabutin; aminotransferase; amylase; ethambutol; isoniazid; lamivudine; lopinavir; lopinavir plus ritonavir; pyrazinamide; rifabutin; rifampicin; rifaximin; stavudine; unclassified drug; anti human immunodeficiency virus agent; isoniazid; lamivudine; lopinavir; rifabutin; stavudine; tuberculostatic agent; adult; African; aminotransferase blood level; amylase blood level; antibiotic therapy; antiviral therapy; area under the curve; Article; CD4 lymphocyte count; clinical article; controlled study; crossover procedure; dosage schedule comparison; drug bioavailability; drug blood level; drug clearance; drug dose comparison; drug safety; drug tolerability; drug withdrawal; female; human; Human immunodeficiency virus infection; lung tuberculosis; male; maximum plasma concentration; minimum plasma concentration; mixed infection; neutropenia; open study; outcome assessment; plasma concentration-time curve; randomized controlled trial; side effect; steady state; time to maximum plasma concentration; treatment response; uveitis; virus load; Black person; blood; chemically induced; Coinfection; drug combination; HIV Infections; metabolism; neutropenia; South Africa; tuberculosis; uveitis; Adult; African Continental Ancestry Group; Anti-HIV Agents; Antibiotics, Antitubercular; Coinfection; Cross-Over Studies; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Lamivudine; Lopinavir; Male; Neutropenia; Rifabutin; South Africa; Stavudine; Tuberculosis; Uveitis