This is an observational study to assess treatment efficacy and emergence of HIV drug resistance following initiation of TLD and rifampicin‐containing tuberculosis treatment. To the greatest extent possible, participants will be managed according to local standards of care provided at the local health facilities. Participants will be divided into four study groups for enrollment:

Group 1: Participants switching to TLD from a first‐line ARV regimen.

Group 2: Participants switching to TLD from a second‐line ARV regimen.

Group 3: Participants initiating concomitant TLD and RIF‐containing TB treatment.

Group 4: ART‐naïve participants initiating therapy with TLD. Each participant will be followed for 36 months, with study specific evaluations at 3, 6, 12, 18, 24 30 and 36 months. The study targets 1350 participants across all participating sites, with an estimated 100 participants from the Kisumu site.

Rationale: Integrase strand transfer inhibitor (INSTI)-based ARV regimens, especially those including DTG, have emerged as highly attractive regimens for ART-naïve and ART-experienced patients. There is limited data on the performance and emergence of resistance to TLD in diverse settings. Understanding the risks and benefits of TLD rollout is critical to monitor programmatic and clinical outcomes for patients initiating or transitioning to TLD.

Objectives: The primary objective of the study is to estimate the proportion of participants achieving virologic success (HIV-1 RNA ≤1000 copies/mL) and the proportion with new DTG resistance mutations at 6 months of TLD therapy with or without Rifampicin-contianing tuberculosis (TB) treatment. The secondary objectives include: To describe treatment outcomes at 6, 12, 24, and 36 months after starting TLD according to the US Food and Drug Administration (FDA) Snapshot algorithm. To assess the long-term durability of TLD (up to 36 months) in suppressing viremia. To assess drug resistance and accumulation of drug resistance mutations over time. To describe the frequency of toxicities leading to discontinuation of the TLD regimen. To assess change in quality of life after starting TLD. To describe the frequency of clinical events relevant for TLD.

Overall Design: This is an observational, longitudinal prospective cohort study to assess therapeutic efficacy and emergence of HIV drug resistance following switching to TLD from first-line (Group 1) or second-line (Group 2) antiretroviral therapy (ART), or start of concomitant TLD and rifampicin (RIF)-containing tuberculosis (TB) treatment (group 3), or upon ART initiation (group 4). Each participant will be followed for 36 months.

Target Population: HIV-infected adults and adolescents (>30 kg, ≥10 years of age) initiating or switching to TLD and receiving care through a President’s Emergency Plan for AIDS Relief (PEPFAR)-supported treatment program. Across all sites, approximately 1350 participants: 540 in Group 1 with the goal of at least 180 in Group 1a, 540 in Group 2 with the goal of at least 180 in Group 2a, 90 in Group 3, and 180 in Group 4. The Kisumu site will contribute approximately 100 participants across all recruitment groups.

Intervention: This being an observational study, no treatments are provided through the study/trial site. Qualifying treatment (initiated within 7 days after study entry): For Groups 1, 2, and 4 - Co-formulated tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg/dolutegravir 50 mg (TLD) taken once daily. For Group 3 - During TB treatment and for 2 weeks following completion of rifampicin-containing TB treatment, TLD taken once daily with an additional daily dose of DTG 50 mg such that DTG is taken twice daily. TB treatment will follow WHO Guidelines.

Analysis: The primary objective regarding virologic success rates will be addressed by computing the proportion of participants in each study group/subgroup for whom virologic success has been achieved (based on the primary outcome measure) together with the associated two-sided 95% Wald CI. The primary objective regarding drug resistance will be addressed by computing the cumulative proportion of participants in each study group with virologic failure and new DTG drug resistance mutations together with the associated two-sided 95% CI.