This proposal presents a five year research career development program focused on clinical pharmacology that includes training and mentorship and research activities aimed at supporting the transition from an early stage to lead investigator. The research focus is in HIV-associated tuberculosis (TB) in South Africa. The World Health Organization recommends dolutegravir-based first-line antiretroviral (ART) regimens for the treatment of HIV. A drug-interaction with rifampicin reduces the plasma concentrations of dolutegravir, however, increasing dolutegravir to 50mg twice daily was shown to be effective at 24 weeks in HIV treatment- nave TB patients in a small international study (INSPIRING). More data, in sufficient numbers of black, African HIV-TB co-infected patients in high-burden settings and the effect of twice daily dosing on adherence and treatment outcomes in programmatic settings, is needed. There is limited data on the use of dolutegravir in patients taking second-line drugs (SLD) for multidrug-resistant (MDR) TB such as bedaquiline. The goal of this study is therefore to determine the impact on HIV treatment outcomes, when co-treating HIV-TB co-infected patients, on anti-TB drugs, with dolutegravir-based ART regimens. Since the efficacy of antiretroviral treatment, including dolutegravir-based regimens is best assessed when information about both pharmacokinetics (PK) and drug adherence are taken into account, the specific aims of this proposal are: 1. To characterize the PK and PK-PD relationships of dolutegravir (DTG) 50mg twice daily when combined with standard anti-TB therapy in HIV and drug-sensitive TB co-infected African patients by comparing DTG PK during vs. after TB treatment to determine relationships between DTG PK and virologic and immunologic responses. 2. To determine associations between DTG drug levels in hair (as a biomarker of adherence) and HIV treatment outcomes. 3. To assess the effects of SLD on the pharmacokinetics of once-daily DTG and describe HIV and TB treatment outcomes in patients with MDR-TB and HIV. This study is timely and relevant since it seeks to fill key knowledge gaps on the roll-out of dolutegravir in South Africa, and other similar high-burden settings globally, in the context of HIV-TB co-infection, and will likely impact HIV-TB policy and practice guidelines. The outlined proposal builds on the candidate?s previous research in clinical pharmacology and integrates the expertise represented by her primary mentor team of Drs Kogieleum Naidoo, Nesri Padayatchi, Prof. Kelly Dooley; at the Centre for the AIDS Programme of Research in South Africa, and John Hopkins University, USA: in HIV and TB clinical trials and clinical pharmacology of infectious diseases. The proposed research, training, mentorship and hands on experience, will position the candidate with a unique set of clinical research and pharmacology skills that will enable her transition to independence as lead investigator and global leader in studies focused on the clinical pharmacology of HIV-TB therapeutics, as well as build expertise in LMIC and specifically high-burden settings to conduct locally relevant but globally responsive research in HIV and TB.
The World Health Organization recommends the antiretroviral drug dolutegravir as first-line treatment of HIV, however, there is some uncertainty regarding its optimal use in in patients with HIV-TB co-infection taking tuberculosis drugs due to some drug-drug interactions that may reduce dolutegravir efficacy. This study aims to fill this knowledge gap by understanding the impact of drug interactions with tuberculosis drugs on dolutegravir drug concentrations, adherence and treatment outcomes. The study will be conducted in a high HIV-TB burden setting in KwaZulu-Natal South Africa.