High initiation but sub-optimal completion of tuberculosis preventive treatment among people living with HIV on ART, persistent tuberculosis incidence and programmatic implications: Findings from a two-year multi-country cohort study

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Abstract Background TB preventive treatment (TPT) is recommended for those at risk of TB, but despite encouraging trial data, evidence of its effectiveness from routine settings with diverse TPT regimens is limited. We describe routine TPT implementation outcomes in people living with HIV (PLWH) to identify bottlenecks and opportunities for improvement along the cascade of care. Methods From 2021-2023, we conducted a 24-month prospective cohort study of PLWH in nine health facilities in Ethiopia, South Africa and Zimbabwe. Socio-demographic and clinical data were collected at enrolment. During follow-up, we collected information on TPT initiation, TPT-related side effects and completion. A sub-group of PLWH were allocated digital boxes (evriMED1000) as a proxy measure for assessing treatment completion. TB case ascertainment was based on confirmed diagnoses abstracted from clinic records and symptom agnostic sputum testing initially using Xpert MTB/RIF assay and subsequently MGIT culture at 12- and 24-months post-enrolment. Results We enrolled 2,095 participants, mostly female (n=1,489; 71.1%), of median age 42 years [interquartile range: 35-50]. Approximately 60% were considered eligible for TPT (n=1,312) and 1,110 (84.6%) were initiated on TPT within 60 days of ART initiation or at a refill visit during the observation period (n=625 on 3HP and n=487 on 6H/12H). TPT completion via digital pillbox assessment was 55.4% (n=406/733). Symptoms compatible with TPT side effects were commonly reported in 3HP vs.6H/12H [190(31.0%) vs. 51(11.0%)]. TB incidence rate was 1.27 (95%CI: 0.95-1.69)/100 person-years during study follow-up in a mostly long-term ART population and was lower for PLWH who completed TPT (aIRR: 0.39; 95% CI: 0.20-0.78, p-value: 0.01). Conclusions There were losses along the cascade, particularly at completion. In programmatic settings, we observed more potential side effects in 3HP compared to 6H/12H. Interventions to support TPT completion are needed. Author Summary What is already known on this topic Clinical trials have shown that 3HP is well tolerated and has higher completion rates than 6H/12H. Identifying bottlenecks to and determinants of successful TPT implementation in programmatic settings is necessary. What this study adds In a multi-site and country cohort of 2,095 PLWH attending routine HIV care, we observed that most individuals could be initiated on TPT and that side effects were generally mild but correlated with not completing TPT There are gaps in adhering to guidelines especially on the prescription of TPT to PLWH with prior TB. Clinical reporting (defined as date of TPT completion from clinic records) of TPT completion is an overestimation: only slightly more than half of participants initiated on TPT completed it as assessed by the digital pillbox (Medication Event Reminder Monitor-MERM). Incident TB disease (often asymptomatic) occurred among 2.5% of participants over the two years of follow-up. TPT, even at the relatively low rates of completion reported by the digital pillbox, appeared to reduce the rate of incident TB disease by 61%. How this study might affect research, practice or policy These findings should reassure clinical providers that most patients can be safely initiated on any TPT regimen, that side effects are generally self-limiting and do not require clinical intervention, and that TPT is effective in protecting against incident TB disease. These results emphasize the need for additional approaches to support TPT prescribing and patient-level adherence and regimen completion. Tools to accurately measure TPT completion are required. These findings show that providers should be encouraged to initiate TPT to all eligible PLWH to close the existing gaps. While improved adherence might lead to a reduced TB incidence rate, the impact with the current programmatic implementation still has public health importance. This is an important point as countries navigate a resource-constrained future.

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