Union study provides findings on best rifabutin dosage for TB patients on antiretroviral therapy

The results of a phase II pharmacokinetics study conducted by The Union and its partners in Vietnam were published today in the scientific journal PlosOne. The study assessed different doses of rifabutin in combination with protease inhibitor-based antiretroviral therapy (ART) for HIV-infected patients who are also infected with TB. 

Rifampicin and protease inhibitors are difficult to use together in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there has been concern that the current recommended dose of 150 mg three times per week is suboptimal and may lead to the development of drug resistance.

The principal aim of this study was to compare the bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in Vietnamese adults with HIV-associated tuberculosis who initiated antiretroviral therapy with lopinavir/ritonavir. Concentrations of lopinavir/ritonavir were also measured. 

In this randomised, open-label, multi-dose, two-arm, cross-over trial, rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir-based antiretroviral therapy. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after two weeks of rifabutin 300 mg daily, after three weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after three weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir.

Sixteen and seventeen patients were randomised to the two arms, and pharmacokinetic analysis was carried out in 12 and 13 of them in the respective arms.

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, two- to five-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. Based on these findings, the researchers recommended that rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis.

The WHO Guidelines for the treatment of HIV-associated tuberculosis recommend that treatment be given daily throughout the intensive and continuation phases of anti-tuberculosis treatment. Giving rifabutin as a daily dose would be in line with these recommendations. This would facilitate the important programmatic issue of combining rifabutin with other anti-tuberculosis medications as a fixed-dose combination pill to be taken on a daily basis, a necessary measure if the results of this and other research are going to reach patients being managed routinely within general health service care. 

The Vietnam trial was funded by the Agence Nationale de Recherche sur le Sida et les hépatites virales (ANRS) and Fondation Total. 

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