Tuberculosis (TB) is the leading infectious cause of death globally. India has the largest TB epidemic, accounting for one-quarter of cases and one-third of global TB deaths. Nonadherence to TB medications is associated with increased death, TB recurrence, and drug resistance. Specifically, missing >10% of doses is associated with six times greater risk of poor TB outcomes.2 The association between nonadherence to TB medications and emergence of drug resistance is one of the most concerning from a public health perspective. For example, one study found that nonadherence to TB therapy was associated with independent elevated risk of acquiring drug resistance (adjusted odds ratio 19.7, 95%CI 1.7-234). Another study found that, among people being treated for multidrug-resistant (MDR) TB, each additional month in which a patient failed to take 80% of their prescribed medication doses was associated with elevated risk of developing extensively drug-resistant (XDR) TB (adjusted hazard ratio 1.2, 95% CI 1.01-1.4).
Despite its importance, detecting nonadherence in routine care is challenging, especially as TB programs in low- and middle-income countries (LMICs) have moved away from directly observed therapy. Our research shows indirect measures-e.g., cellphone-based technology, pill counts, and patient-reported measures-miss detecting >30% of people with TB who are nonadherent by urine isoniazid testing.
Urine isoniazid testing is a low-cost, validated, direct point-of-care adherence measure that is predictive of TB outcomes. In a 650-participant cohort study in India, one unannounced home visit was conducted for each participant during TB therapy to conduct urine testing. That study found: (1) nonadherence was common by urine testing, with 18% of participants having missed more than 1 dose, and (2) negative urine test results were associated with 3.9 increased odds of death and 3.8 increased odds of loss to follow-up from treatment.
While urine testing has benefits, further research is needed to evaluate its uses under TB programs setting First, urine testing may perform differently in clinic as compared to unannounced home visits, as people with TB may modify adherence behavior in anticipation of scheduled clinic visits. Research is needed to understand how well testing at clinic visits represents adherence and predicts TB outcomes. Second, research is needed to understand reasons for nonadherence (i.e., negative urine test results) to inform personalized interventions for differentiated care. Third, implementation science research is needed to evaluate the use of urine testing in routine care in a manner that could lead to sustained use and impact.
The investigators propose conducting translational research involving clinical, behavioural, and implementation science to evaluate the use of urine isoniazid testing in the TB program. The investigators' central hypothesis is that urine testing could be useful within the routine care to facilitate early and accurate identification of people with TB who are likely to suffer poor outcomes, including death and TB recurrence. If this hypothesis is correct, the urine assay could serve as a triage test for developing differentiated care strategies, in which people at risk for poor outcomes are identified early and given intensified care
The investigators have the following specific aims:
Aim 1. To assess the agreement between urine test results collected at prescheduled clinic in comparison to unannounced home visits.
Summary of this aim: The investigators will enroll a cohort of 900 people starting 6-month drug-susceptible TB therapy. For each participant, to enable comparison of clinic and home samples, the investigators will conduct 1 urine test at a scheduled clinic visit and 1 urine test at an unannounced home visit during each of the intensive (first 2 months), early continuation (second 2 months), and late continuation (last 2 months) treatment phases.
Aim 2. To assess the relationship between nonadherence by urine testing and subsequent TB outcomes.
Summary of this aim: The investigators will follow the Aim 1 cohort participants through the completion of TB treatment (which usually takes 6 months) and then for 12 months after treatment and assess the following unfavorable outcomes: death, treatment failure, loss to follow-up, and TB recurrence. The investigators will assess the association between nonadherence by urine testing (separately for clinic and home samples) and the composite of these unfavorable outcomes (primary outcome) and with each unfavorable outcome individually (secondary outcomes).
