Household- Versus Incentive-Based Contact Investigation for Tuberculosis in Rural South Africa: A Cluster-Randomized Trial.

BACKGROUND: Household contact investigation for people newly diagnosed with tuberculosis (TB) is poorly implemented, particularly in low- and middle-income countries. Conditional cash incentives may improve uptake. METHODS: We conducted a pragmatic, cluster-randomized, crossover trial of 2 TB contact investigation approaches (household-based and incentive-based) in 28 public primary care clinics in South Africa. Each clinic used 1 approach for 18 months, followed by a 6-month washout period, after which the opposite approach was used. Fourteen clinics were randomized to each approach. In the household-based arm, we conducted TB screening and testing of contacts at the household. In the incentive-based arm, both index patients and ≤10 of their close contacts (either within or outside the household) were given small cash incentives for presenting to study clinics for TB screening. The primary outcome was the number of people with incident TB who were diagnosed and started on treatment at study clinics. RESULTS: From July 2016 to January 2020, we randomized 28 clinics to each study arm, and enrolled 782 index TB patients and 1882 contacts in the household-based arm and 780 index patients and 1940 contacts in the incentive-based arm. A total of 1413 individuals started on TB treatment in the household-based arm and 1510 in the incentive-based arm. The adjusted incidence rate ratio of TB treatment initiation in the incentive- versus household-based arms was 1.05 (95% confidence interval: .97-1.13). CONCLUSIONS: Incentive-based contact investigation for TB has similar effectiveness to traditional household-based approaches and may be a viable alternative or complementary approach to household-based investigation.

A user-centred implementation strategy for tuberculosis contact investigation in Uganda: protocol for a stepped-wedge, cluster-randomised trial.

BACKGROUND: Tuberculosis(TB) is among the leading causes of infectious death worldwide. Contact investigation is an evidence-based, World Health Organisation-endorsed intervention for timely TB diagnosis, treatment, and prevention but has not been widely and effectively implemented. METHODS: We are conducting a stepped-wedge, cluster-randomised, hybrid Type III implementation-effectiveness trial comparing a user-centred to a standard strategy for implementing TB contact investigation in 12 healthcare facilities in Uganda. The user-centred strategy consists of several client-focused components including (1) a TB-education booklet, (2) a contact-identification algorithm, (3) an instructional sputum-collection video, and (4) a community-health-rider service to transport clients, CHWs, and sputum samples, along with several healthcare-worker-focused components, including (1) collaborative improvement meetings, (2) regular audit-and-feedback reports, and (3) a digital group-chat application designed to develop a community of practice. Sites will cross-over from the standard to the user-centred strategy in six, eight-week transition steps following a randomly determined site-pairing scheme and timeline. The primary implementation outcome is the proportion of symptomatic close contacts completing TB evaluation within 60 days of TB treatment initiation by the index person with TB. The primary clinical effectiveness outcomes are the proportion of contacts diagnosed with and initiating active TB disease treatment and the proportion initiating TB preventative therapy within 60 days. We will assess outcomes from routine source documents using intention-to-treat analyses. We will also conduct nested mixed-methods studies of implementation fidelity and context and perform cost-effectiveness and impact modelling. The Makerere School of Public Health IRB(#554), the Uganda National Council for Science and Technology(#HS1720ES), and the Yale Institutional Review Board(#2000023199) approved the study and waived informed consent for the main trial implementation-effectiveness outcomes. We will submit results for publication in peer-reviewed journals and disseminate findings to local policymakers and representatives of affected communities. DISCUSSION: This pragmatic, quasi-experimental implementation trial will inform efforts to find and prevent undiagnosed persons with TB in high-burden settings using contact investigation. It will also help assess the suitability of human-centred design and communities of practice for tailoring implementation strategies and sustaining evidence-based interventions in low-and-middle-income countries. TRIAL REGISTRATION: The trial was registered(ClinicalTrials.gov Identifier NCT05640648) on 16 November 2022, after the trial launch on 7 March 2022.

Conditional Cash Transfers to Incentivize Tuberculosis Screening: Description of a Novel Strategy for Contact Investigation in Rural South Africa.

BACKGROUND: Providing incentives to screen close contacts for tuberculosis (TB) is an alternative to household-based contact investigation. We aimed to characterize patients and contexts where this incentive-based strategy might be preferred. METHODS: This is a secondary analysis of a cluster randomized trial of TB contact investigation in Limpopo District, South Africa, conducted between 2016 and 2020. Twenty-eight clinics were randomly allocated to household-based vs incentive-based contact investigation. In the incentive-based arm, index participants and contacts received transport reimbursement and incentives for TB screening and microbiological diagnosis of contacts. We estimated differences in mean number of contacts per index participant with household-based vs incentive-based contact investigation overall and within subgroups of index participants. RESULTS: A total of 3776 contacts (1903 in the incentive-based and 1873 in the household-based arm) were referred by 2501 index participants. A higher proportion of contacts in the incentive-based than household-based arm were adults (72% vs 59%), reported chronic TB symptoms (25% vs 16%) or ever smoking (23% vs 11%). Index participants who walked or bicycled to a clinic referred 1.03 more contacts per index (95% confidence interval [CI], .48 to 1.57) through incentive-based than household-based investigation. Index participants living with >5 household members referred 0.48 more contacts per index (95% CI, .03 to .94) through household-based than incentive-based investigation. CONCLUSIONS: Relative to household-based investigation, incentive-based investigation identifies contacts likely at higher risk for active TB. Incentive-based investigation may be more appropriate for index participants who can easily access clinics, versus household-based investigation for patients with large households. Clinical Trials Registration. NCT02808507.

A clinical score for identifying active tuberculosis while awaiting microbiological results: Development and validation of a multivariable prediction model in sub-Saharan Africa.

BACKGROUND: In highly resource-limited settings, many clinics lack same-day microbiological testing for active tuberculosis (TB). In these contexts, risk of pretreatment loss to follow-up is high, and a simple, easy-to-use clinical risk score could be useful. METHODS AND FINDINGS: We analyzed data from adults tested for TB with Xpert MTB/RIF across 28 primary health clinics in rural South Africa (between July 2016 and January 2018). We used least absolute shrinkage and selection operator regression to identify characteristics associated with Xpert-confirmed TB and converted coefficients into a simple score. We assessed discrimination using receiver operating characteristic (ROC) curves, calibration using Cox linear logistic regression, and clinical utility using decision curves. We validated the score externally in a population of adults tested for TB across 4 primary health clinics in urban Uganda (between May 2018 and December 2019). Model development was repeated de novo with the Ugandan population to compare clinical scores. The South African and Ugandan cohorts included 701 and 106 individuals who tested positive for TB, respectively, and 686 and 281 randomly selected individuals who tested negative. Compared to the Ugandan cohort, the South African cohort was older (41% versus 19% aged 45 years or older), had similar breakdown of biological sex (48% versus 50% female), and had higher HIV prevalence (45% versus 34%). The final prediction model, scored from 0 to 10, included 6 characteristics: age, sex, HIV (2 points), diabetes, number of classical TB symptoms (cough, fever, weight loss, and night sweats; 1 point each), and >14-day symptom duration. Discrimination was moderate in the derivation (c-statistic = 0.82, 95% CI = 0.81 to 0.82) and validation (c-statistic = 0.75, 95% CI = 0.69 to 0.80) populations. A patient with 10% pretest probability of TB would have a posttest probability of 4% with a score of 3/10 versus 43% with a score of 7/10. The de novo Ugandan model contained similar characteristics and performed equally well. Our study may be subject to spectrum bias as we only included a random sample of people without TB from each cohort. This score is only meant to guide management while awaiting microbiological results, not intended as a community-based triage test (i.e., to identify individuals who should receive further testing). CONCLUSIONS: In this study, we observed that a simple clinical risk score reasonably distinguished individuals with and without TB among those submitting sputum for diagnosis. Subject to prospective validation, this score might be useful in settings with constrained diagnostic resources where concern for pretreatment loss to follow-up is high.

Perceptions of Community and Clinic-Based Adherence Clubs for Patients Stable on Antiretroviral Treatment: A Mixed Methods Study.

Adherence clubs for patients stable on antiretroviral treatment (ART) offer decongestion of clinics and task-shifting, improved adherence and retention in care. Findings on patient acceptability by club location (in the clinic vs. the community) are limited. This was a mixed-methods study set within a randomized controlled trial of community versus clinic-based adherence clubs for retention in care at Witkoppen Health and Welfare Centre in Johannesburg, South Africa. Participants were surveyed on preferences for adherence club-based care (e.g. location, convenience). We conducted in-depth interviews (IDIs) with 36 participants, and surveyed 568 participants: 49% in community-based clubs and 51% in clinic-based clubs. Participants in both arms favorably rated adherence clubs. Almost all (95%) in clinic-based clubs would recommend them to a friend, while fewer (88% in community-based club participants would do so (p = 0.004). Participants found clubs promoted social support, and were convenient and time-saving, though concerns around stigma and access to other health care were noted within community-based clubs. Adherence clubs are a highly acceptable form of differentiated care for stable ART patients. These data indicate that clinic-based clubs may be preferred above community-based clubs, potentially for reasons of stigma and access to additional health care services.

Promoting Tuberculosis Preventive Therapy for People Living with HIV in South Africa: Interventions Hindered by Complicated Clinical Guidelines and Imbalanced Patient-Provider Dynamics.

Isoniazid preventive therapy (IPT) reduces the risk of active tuberculosis among people living with HIV, but implementation of IPT in South Africa and elsewhere remains slow. The objective of this study was to examine both nurse perceptions of clinical mentorship and patient perceptions of in-queue health education for promoting IPT uptake in Potchefstroom, South Africa. We measured adoption, fidelity, acceptability, and sustainability of the interventions using both quantitative and qualitative methods. Adoption, fidelity, and acceptability of the interventions were moderately high. However, nurses believed they could not sustain their increased prescriptions of IPT, and though many patients intended to ask nurses about IPT, few did. Most patients attributed their behavior to an imbalance of patient-provider power. National IPT guidelines should be unambiguous and easily implemented after minimal training on patient eligibility and appropriate medication durations, nurse-patient dynamics should empower the patient, and district-level support and monitoring should be implemented.

The impact of community- versus clinic-based adherence clubs on loss from care and viral suppression for antiretroviral therapy patients: Findings from a pragmatic randomized controlled trial in South Africa.

BACKGROUND: Adherence clubs, where groups of 25-30 patients who are virally suppressed on antiretroviral therapy (ART) meet for counseling and medication pickup, represent an innovative model to retain patients in care and facilitate task-shifting. This intervention replaces traditional clinical care encounters with a 1-hour group session every 2-3 months, and can be organized at a clinic or a community venue. We performed a pragmatic randomized controlled trial to compare loss from club-based care between community- and clinic-based adherence clubs. METHODS AND FINDINGS: Patients on ART with undetectable viral load at Witkoppen Health and Welfare Centre in Johannesburg, South Africa, were randomized 1:1 to a clinic- or community-based adherence club. Clubs were held every other month. All participants received annual viral load monitoring and medical exam at the clinic. Participants were referred back to clinic-based standard care if they missed a club visit and did not pick up ART medications within 5 days, had 2 consecutive late ART medication pickups, developed a disqualifying (excluding) comorbidity, or had viral rebound. From February 12, 2014, to May 31, 2015, we randomized 775 eligible adults into 12 pairs of clubs-376 (49%) into clinic-based clubs and 399 (51%) into community-based clubs. Characteristics were similar by arm: 65% female, median age 38 years, and median CD4 count 506 cells/mm3. Overall, 47% (95% CI 44%-51%) experienced the primary outcome of loss from club-based care. Among community-based club participants, the cumulative proportion lost from club-based care was 52% (95% CI 47%-57%), compared to 43% (95% CI 38%-48%, p = 0.002) among clinic-based club participants. The risk of loss to club-based care was higher among participants assigned to community-based clubs than among those assigned to clinic-based clubs (adjusted hazard ratio 1.38, 95% CI 1.02-1.87, p = 0.032), after accounting for sex, age, nationality, time on ART, baseline CD4 count, and employment status. Among those who were lost from club-based care (n = 367), the most common reason was missing a club visit and the associated ART medication pickup entirely (54%, 95% CI 49%-59%), and was similar by arm (p = 0.086). Development of an excluding comorbidity occurred in 3% overall of those lost from club-based care, and was not different by arm (p = 0.816); no deaths occurred in either arm during club-based care. Viral rebound occurred in 13% of those lost from community club-based care and 21% of those lost from clinic-based care (p = 0.051). In post hoc secondary analysis, among those referred to standard care, 72% (95% CI 68%-77%) reengaged in clinic-based care within 90 days of their club-based care discontinuation date. The main limitations of the trial are the lack of a comparison group receiving routine clinic-based standard care and the potential limited generalizability due to the single-clinic setting. CONCLUSIONS: These findings demonstrate that overall loss from an adherence club intervention was high in this setting and that, importantly, it was worse in community-based adherence clubs compared to those based at the clinic. We urge caution in assuming that the effectiveness of clinic-based interventions will carry over to community settings, without a better understanding of patient-level factors associated with successful retention in care. TRIAL REGISTRATION: Pan African Clinical Trials Registry (PACTR201602001460157).

Contact tracing versus facility-based screening for active TB case finding in rural South Africa: A pragmatic cluster-randomized trial (Kharitode TB).

BACKGROUND: There is a dearth of comparative effectiveness research examining the implementation of different strategies for active tuberculosis (TB) case finding, particularly in rural settings, which represent 60% of the population of sub-Saharan Africa. METHODS AND FINDINGS: We conducted a pragmatic, cluster-randomized comparative effectiveness trial of two TB case finding strategies (facility-based screening and contact tracing) in 56 public primary care clinics in two largely rural districts of Limpopo Province, South Africa. In the facility-based screening arm, sputum Xpert MTB/RIF was performed on all patients presenting (for any reason) with TB symptoms to 28 study clinics, and no contact tracing was performed. In the contact-tracing arm, contacts of patients with active TB were identified (via household tracing in 14 clinics and using small monetary incentives in the other 14 clinics), screened for TB symptoms, and offered Xpert MTB/RIF testing. The primary outcome was the number of newly identified patients with TB started on treatment. The analysis used multivariable Poisson regression adjusted for historical clinic-level TB case volumes and district. The trial was registered with ClinicalTrials.gov (NCT02808507). From July 18, 2017, to January 17, 2019, a total of 3,755 individuals started TB treatment across 56 study clinics in the 18-month period. Clinic characteristics and clinic-level averages of patient characteristics were similar across the two arms: 40/56 (71%) clinics were in a rural location, 2,136/3,655 (58%) patients were male, and 2,243 (61%) were HIV positive. The treatment initiation ratio comparing the yield of TB patients started on treatment in the facility-based arm compared to that from the contact-tracing arm was 1.04 (95% confidence interval [CI] 0.83-1.30, p = 0. 73). In the contact-tracing arm, 1,677 contacts of 788 new TB index patients were screened, yielding 12 new patients with TB. Prespecified subgroup analyses resulted in similar results, with estimated treatment initiation ratios of 0.96 (95% CI 0.64-1.27; p = 0.78) and 1.23 (95% CI 0.87-1.59; p = 0.29) among historically smaller and historically larger clinics, respectively. This ratio was 1.02 (95% CI 0.66-1.37; p = 0.93) and 1.08 (95% CI 0.74-1.42; p = 0.68) in the Vhembe and Waterberg districts, respectively. The estimated treatment initiation ratio was unchanged in sensitivity analyses excluding 24 records whose TB registration numbers could not be verified (1.03, 95% CI 0.82-1.29; p = 0.78) and excluding transfers-in (1.02, 95% CI 0.80-1.29; p = 0.71). Study limitations include the possibility of imbalance on cluster size owing to changes in catchment population over time and the inability to distinguish the independent effects of the two contact investigation strategies. CONCLUSIONS: Contact tracing based on symptom screening and Xpert MTB/RIF testing did not increase the rate of treatment initiation for TB relative to the less resource-intensive approach of facility-based screening in this rural sub-Saharan setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02808507.

From Epidemiologic Knowledge to Improved Health: A Vision for Translational Epidemiology.

Epidemiology should aim to improve population health; however, no consensus exists regarding the activities and skills that should be prioritized to achieve this goal. We performed a scoping review of articles addressing the translation of epidemiologic knowledge into improved population health outcomes. We identified 5 themes in the translational epidemiology literature: foundations of epidemiologic thinking, evidence-based public health or medicine, epidemiologic education, implementation science, and community-engaged research (including literature on community-based participatory research). We then identified 5 priority areas for advancing translational epidemiology: 1) scientific engagement with public health; 2) public health communication; 3) epidemiologic education; 4) epidemiology and implementation; and 5) community involvement. Using these priority areas as a starting point, we developed a conceptual framework of translational epidemiology that emphasizes interconnectedness and feedback among epidemiology, foundational science, and public health stakeholders. We also identified 2-5 representative principles in each priority area that could serve as the basis for advancing a vision of translational epidemiology. We believe an emphasis on translational epidemiology can help the broader field to increase the efficiency of translating epidemiologic knowledge into improved health outcomes and to achieve its goal of improving population health.

Maternal Motivation to Take Preventive Therapy in Antepartum and Postpartum Among HIV-Positive Pregnant Women in South Africa: A Choice Experiment.

HIV-positive pregnant women who are initiated on lifelong antiretroviral therapy (ART) and isoniazid preventive therapy (IPT) have lower adherence rates after delivery. We quantified maternal motivation to take preventive therapy before and after delivery among pregnant women newly diagnosed with HIV. We enrolled pregnant women (≥ 18 years) with a recent HIV diagnosis (< 6 months) at 14 public primary health clinics in Matlosana, South Africa and followed them in the postpartum period. Participants received eight choice tasks comparing two mutually exclusive sub-sets of seven possible benefits related to preventive therapy identified through literature reviews and key informant interviews. Data was analyzed using conditional logit regression in the antepartum versus postpartum periods. Coefficients are reported with 95% confidence intervals (CI). Sixty-five women completed surveys both at enrollment and in the postpartum period. All women were already on ART, while 21 (32%) were receiving IPT at enrollment. The mean CD4 count was 436 (± 246) cells/mm3. In the antepartum period, preventing HIV transmission to partners was the most important benefit (coefficients (ß) = 0.87, 95% CI 0.64, 1.11), followed by keeping healthy for family (ß = 0.75, 95% CI 0.52, 0.97). Such prioritization significantly decreased in the postpartum period (p < 0.001). Compared to other motivators, keeping a high CD4 count was least prioritized in the antepartum period (ß = 0.19, 95% CI - 0.04, 0.43) but was most prioritized in the postpartum period (ß = 0.39, 95% CI 0.21, 0.57). These results highlight that messages on family might be particularly salient in the antepartum period, and keeping CD4 count high in the postpartum period. Understanding maternal motivation may help to design targeted health promotion messages to HIV-positive women around the time of delivery.