Randomised pharmacokinetic trial of rifabutin with lopinavir/ritonavir-antiretroviral therapy in patients with HIV-associated tuberculosis in Vietnam.

BACKGROUND: Rifampicin 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. METHODS: This 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. RESULTS: Sixteen 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. CONCLUSIONS: Based on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00651066

Immunovirological response to combined antiretroviral therapy and drug resistance patterns in children: 1- and 2-year outcomes in rural Uganda

Children living with HIV continue to be in urgent need of combined antiretroviral therapy (ART). Strategies to scale up and improve pediatric HIV care in resource-poor regions, especially in sub-Saharan Africa, require further research from these settings. We describe treatment outcomes in children treated in rural Uganda after 1 and 2 years of ART start

Risk factors for virological failure and subtherapeutic antiretroviral drug concentrations in HIV-positive adults treated in rural northwestern Uganda

ABSTRACT: BACKGROUND: Little is known about immunovirological treatment outcomes and adherence in HIV/AIDS patients on antiretroviral therapy (ART) treated using a simplified management approach in rural areas of developing countries, or about the main factors influencing those outcomes in clinical practice. METHODS: Cross-sectional immunovirological, pharmacological, and adherence outcomes were evaluated in all patients alive and on fixed-dose ART combinations for 24 months, and in a random sample of those treated for 12 months. Risk factors for virological failure (>1,000 copies/mL) and subtherapeutic antiretroviral (ARV) concentrations were investigated with multiple logistic regression. RESULTS: At 12 and 24 months of ART, 72% (n=701) and 70% (n=369) of patients, respectively, were alive and in care. About 8% and 38% of patients, respectively, were diagnosed with immunological failure; and 75% and 72% of patients, respectively, had undetectable HIV RNA (<400 copies/mL). Risk factors for virological failure (>1,000 copies/mL) were poor adherence, tuberculosis diagnosed after ART initiation, subtherapeutic NNRTI concentrations, general clinical symptoms, and lower weight than at baseline. About 14% of patients had low ARV plasma concentrations. Digestive symptoms and poor adherence to ART were risk factors for low ARV plasma concentrations. CONCLUSIONS: Efforts to improve both access to care and patient management to achieve better immunological and virological outcomes on ART are necessary to maximize the duration of first-line therapy