Mortality in HIV and tuberculosis patients following implementation of integrated HIV-TB treatment: Results from an open-label cluster-randomized trial

BACKGROUND: HIV-TB treatment integration reduces mortality. Operational implementation of integrated services is challenging. This study assessed the impact of quality improvement (QI) for HIV-TB integration on mortality within primary healthcare (PHC) clinics in South Africa. METHODS: An open-label cluster randomized controlled study was conducted between 2016 and 2018 in 40 rural clinics in South Africa. The study statistician randomized PHC nurse-supervisors 1:1 into 16 clusters (eight nurse-supervisors supporting 20 clinics per arm) to receive QI, supported HIV-TB integration intervention or standard of care (control). Nurse supervisors and clinics under their supervision, based in the study health districts were eligible for inclusion in this study. Nurse supervisors were excluded if their clinics were managed by municipal health (different resource allocation), did not offer co-located antiretroviral therapy (ART) and TB services, services were performed by a single nurse, did not receive non-governmental organisation (NGO) support, patient data was not available for > 50% of attendees. The analysis population consists of all patients newly diagnosed with (i) both TB and HIV (ii) HIV only (among patients previously treated for TB or those who never had TB before) and (iii) TB only (among patients already diagnosed with HIV or those who were never diagnosed with HIV) after QI implementation in the intervention arm, or enrolment in the control arm. Mortality rates was assessed 12 months post enrolment, using unpaired t-tests and cox-proportional hazards model. (Clinicaltrials.gov, NCT02654613, registered 01 June 2015, trial closed). FINDINGS: Overall, 21 379 participants were enrolled between December 2016 and December 2018 in intervention and control arm clinics: 1329 and 841 HIV-TB co-infected (10·2%); 10 799 and 6 611 people living with Human Immunodeficiency Virus (HIV)/ acquired immunodeficiency syndrome (AIDS) (PLWHA) only (81·4%); 1 131 and 668 patients with TB only (8·4%), respectively. Average cluster sizes were 1657 (range 170–5782) and 1015 (range 33–2027) in intervention and control arms. By 12 months, 6529 (68·7%) and 4074 (70·4%) were alive and in care, 568 (6·0%) and 321 (5·6%) had completed TB treatment, 1078 (11·3%) and 694 (12·0%) were lost to follow-up, with 245 and 156 deaths occurring in intervention and control arms, respectively. Mortality rates overall [95% confidence interval (CI)] was 4·5 (3·4–5·9) in intervention arm, and 3·8 (2·6–5·4) per 100 person-years in control arm clusters [mortality rate ratio (MRR): 1·19 (95% CI 0·79–1·80)]. Mortality rates among HIV-TB co-infected patients was 10·1 (6·7–15·3) and 9·8 (5·0–18·9) per 100 person-years, [MRR: 1·04 (95% CI 0·51–2·10)], in intervention and control arm clusters, respectively. INTERPRETATION: HIV-TB integration supported by a QI intervention did not reduce mortality in HIV-TB co-infected patients. Demonstrating mortality benefit from health systems process improvements in real-world operational settings remains challenging. Despite the study being potentially underpowered to demonstrate the effect size, integration interventions were implemented using existing facility staff and infrastructure reflecting the real-world context where most patients in similar settings access care, thereby improving generalizability and scalability of study findings. FUNDING: Research reported in this publication was supported by South African Medical Research Council (SAMRC), and UK Government's Newton Fund through United Kingdom Medical Research Council (UKMRC).