Rifabutin pharmacokinetics and safety among HIV/TB coinfected infants receiving lopinavir

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PROJECT SUMMARY ! Tuberculosis is the leading cause of death among children with HIV, yet optimal cotreatment regimens are lacking, particularly for the youngest and most vulnerable children. As a result, the World Health Organization (WHO) has designated evaluation of newer treatment options for HIV/TB coinfected children a research priority. To address this issue, we will carry out a prospective pharmacokinetic (PK) and safety study to evaluate a novel pediatric cotreatment strategy. For children <3 years of age, lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) is the current WHO-preferred first-line regimen to treat HIV infection. However, potent drug interactions prohibit use of LPV/r along with standard TB treatment in coinfected children, as rifampin lowers LPV concentrations by over 75%. For adults who require protease inhibitors such as LPV/r, the WHO recommends substituting rifabutin, which has minimal effect on LPV concentrations. This strategy has not been adequately studied in children, and so is generally unavailable as a pediatric treatment regimen. The Harvard/APIN pediatric ART program has supported rifabutin access for adults and children in Nigeria since 2008. Our group previously reported favorable programmatic experience with rifabutin in children, and are currently studying rifabutin PK and safety in older pediatric cohorts requiring LPV/r-based ART. At interim analysis, we found that most patients achieved rifabutin concentrations well above the target value, and severe neutropenia, the most concerning potential serious adverse event, was uncommon (5%). However, because the liver enzymes that metabolize rifabutin do not reach adult activity until at least 12 months of age, it is expected that higher rifabutin mg/kg dosing is necessary in infants. Thus, we will evaluate rifabutin concentrations among HIV/TB coinfected infants 2 weeks to <12 months of age. We hypothesize that rifabutin dosed 5 mg/kg daily in this cohort will achieve adequate rifabutin concentrations, equivalent to that observed with 2.5 mg/kg daily in the older cohort. Further, since variability in drug concentrations among children remains a barrier to achieving safe and effective dosing recommendations, we will utilize population PK modeling to quantify variability, evaluating patient factors such as malnutrition and advanced immunocompromise to predict optimal rifabutin dosing by weight. Finally, given the challenge of TB diagnosis among the youngest children, we will also evaluate newer urine-based TB diagnostics in this cohort. The goal of this study is to influence WHO treatment guidelines by providing essential knowledge of the efficacy and safety of this treatment strategy so that we may curb TB’s devastating toll among this highly vulnerable population.