BackgroundHIV co-infection affects host responses and pharmacokinetics (PK) of tuberculosis (TB) treatment. This study assessed the PK of first-line anti-TB drugs and clinical outcomes in patients with and without HIV co-infection.MethodsIn this prospective observational study, 61 adults with sputum-positive pulmonary TB, either confirmed by microscopy or GeneXpert, were enrolled, including 24 with HIV co-infection and 37 without. All HIV-positive participants were antiretroviral-naïve at enrolment. Standard anti-TB therapy was given, and PK assessments were conducted on Day 1 and Week 6. Efavirenz-based antiretroviral therapy (ART) began at a median of Day 21. Clinical outcomes, sputum conversion, and adverse events were monitored.ResultsAt baseline, patients with HIV co-infection had reduced clearance of isoniazid and ethambutol, reflected by slower elimination rates. These differences resolved by Week 6 and were not significantly impacted by ART initiation. Logistic regression showed that HIV-positive status (OR = 14.25, 95% CI: 1.22-166.37, p = 0.03), and higher baseline sputum bacillary load (OR = 3.92, 95% CI: 1.5-10.5, p = 0.006) were independently associated with delayed sputum conversion beyond 8 weeks. Baseline CRP showed an inverse association after adjustment, but this did not reach statistical significance (OR = 0.98, 95% CI: 0.96-1.00, p = 0.06).ConclusionHIV co-infection was associated with altered early PK of isoniazid and ethambutol although these differences were less apparent by Week 6. HIV-positive status and higher baseline sputum bacillary load were associated with delayed sputum conversion. Although some pharmacokinetic differences were statistically significant, their clinical relevance remains uncertain, and the current data do not support dose adjustment. These findings suggest early pharmacokinetic variability in TB-HIV co-infected patients and support further investigation in adequately powered exposure-response studies.Trial registrationClinicalTrials.gov: NCT02457208.