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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
Highlights
In 2011, there were an estimated 34 million adults and children living globally with HIV/AIDS and an estimated 8.7 million new cases of tuberculosis: 1.1 million persons had HIV-associated tuberculosis and 430,000 persons with HIV-associated tuberculosis died [1,2].Since 2003, there has been a remarkable scale up of antiretroviral therapy with 8 million people estimated to be on therapy by the end of 2011 [1]
With the development of point-of-care tests for viral load under the World Health Organization (WHO) new Treatment 2.0 initiative [4], and recommendations from the WHO that 12monthly viral load monitoring should become the norm for monitoring antiretroviral therapy [5], it is likely that increasing numbers of patients will be identified with treatment failure and will need switching to a second-line regimen with a protease inhibitor
Patient flow chart Thirty nine patients were assessed for eligibility for the trial, with Figure 2 showing the numbers randomized, allocated to interventions in Arm A and B, followed-up and subsequently having blood measurements for pharmacokinetic analysis
Summary
In 2011, there were an estimated 34 million adults and children living globally with HIV/AIDS and an estimated 8.7 million new cases of tuberculosis: 1.1 million persons had HIV-associated tuberculosis and 430,000 persons with HIV-associated tuberculosis died [1,2].Since 2003, there has been a remarkable scale up of antiretroviral therapy with 8 million people estimated to be on therapy by the end of 2011 [1]. With the development of point-of-care tests for viral load under the World Health Organization (WHO) new Treatment 2.0 initiative [4], and recommendations from the WHO that 12monthly viral load monitoring should become the norm for monitoring antiretroviral therapy [5], it is likely that increasing numbers of patients will be identified with treatment failure and will need switching to a second-line regimen with a protease inhibitor. While this is a welcome move, this change will have implications for the care and treatment of patients with HIVassociated tuberculosis.
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