Procedures
tuberculosis, Tuberculosis
CNS TUBERCULOSIS, TUBERCULOSIS, TUBERCULOSIS
Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol [oral daily weight-based method] for the first 2 months followed by rifampicin and isoniazid [oral daily weight-based method] for the subsequent 4 months) provided by the local tuberculosis programme. The duration of maintenance therapy was extended if necessary (skeletal or CNS tuberculosis, poor resolution of tuberculosis symptoms, poor adherence, or delayed sputum smear conversion) by local tuberculosis clinics. ART was initiated 8–12 weeks after initiation of antituberculosis therapy, except for a 5-month period during the early COVID-19 pandemic, when national treatment guidelines recommended ART initiation within 2 weeks of starting antituberculosis therapy, regardless of CD4 count. Participants were instructed to take the single oral tenofovir disoproxil fumarate 300 mg daily, oral lamivudine 300 mg daily, and oral dolutegravir 50 mg daily tablets with food in the morning and the 50 mg dolutegravir or matching placebo orally with food 12 h later. The supplemental dolutegravir or placebo was continued for 2 weeks after antituberculosis therapy was stopped. Dolutegravir 50 mg (Myltega) and matching placebo were donated by Mylan Pharmaceuticals (Canonsburg, PA, USA). Participants were asked to return all unused study medication for collection and counting by study staff. Co-trimoxazole preventive therapy was supplied by the local tuberculosis programme (trimethoprim [160 mg] and sulfamethoxazole [800 mg] daily, taken orally).Tuberculosis diagnoses were made by local tuberculosis clinics and classified as microbiological or histological (acid-fast bacilli on sputum, Xpert MTB/RIF [Cepheid, Sunnyvale, CA, USA] or positive culture from any site, or histological diagnosis) or clinical or radiological (or both). Tuberculosis was classified as either pulmonary, extrapulmonary, or disseminated.Screening procedures were HIV-1 RNA testing, CD4 cell count (if no result <3 months old available), safety laboratory testing, and clinical assessment. Plasma HIV-1 RNA viral load was determined with the Abbott Alinity M HIV-1 test (Abbott, Abbott Park, Green Oaks, IL, USA; lower limit of detection 20 copies per mL). If the screening CD4 count was between 50 cells per μL and 99 cells per μL the test was repeated when ART was planned to start to reassess eligibility. Woman of childbearing potential had a urinary pregnancy test.Participants were enrolled within 8 weeks of the screening visit. Follow-up visits occurred at weeks 4, 8, 12, 16, 20, 24, and 48. Safety laboratory tests and plasma HIV-1 RNA were done at weeks 4, 8, 12, 24, and 48. CD4 counts were repeated at weeks 24 and 48. Plasma for dolutegravir trough concentrations and dried blood spots for tenofovir diphosphate were taken at weeks 4, 8, 12, 24, and 48. Pharmacokinetic samples were analysed by the Clinical Pharmacology Laboratory, University of Cape Town (Cape Town, South Africa) with accredited methods.Participants with unsuppressed HIV-1 RNA (≥50 copies per mL) received adherence counselling and repeat HIV-1 RNA sampling every 4 weeks until suppression or study-defined virological failure (defined as HIV-1 RNA >1000 copies per mL at week 24 or if HIV-1 RNA was <50 copies per mL and then rebounded to >1000 copies per mL at any timepoint). Genotypic antiretroviral resistance testing was done on participants with study-defined virological failure (Applied Biosystems HIV-1 Genotyping kit; ThermoFisher Scientific, Applied Biosystems; Waltham, MA, USA). Resistance was defined as potential low-level, intermediate-level, or high-level resistance according to the Stanford HIV Drug Resistance Database. We also did genotypic antiretroviral resistance testing on stored baseline samples if integrase strand transfer inhibitor resistance was detected.