Forecasting the effect of HIV-targeted interventions on the age distribution of people living with HIV: a case study from Kenya.

OBJECTIVES: Expansion of ART and increases to life expectancy have led to aging among people living with HIV (PWH). DESIGN: Kenyan decisionmakers need accurate forecasts of the age distribution of PWH to inform future policies. METHODS: We developed a model of HIV in Kenya, calibrated to historical estimates of HIV epidemiology. We forecasted changes in population size and age distribution of new HIV infections and PWH under the status quo and under scale-up of HIV services. RESULTS: Without scale-up, new HIV infections were forecasted to fall from 34,000 [28,000-41,000] in 2025 to 29,000 [15,000-57,000] in 2040; the percent of new infections occurring among persons over 30 increased from 33% [20-50%] to 40% [24-62%]. The median age of PWH increased from 39 years [38-40] in 2025 to 43 years [39-46] in 2040, and the percent of PWH over age 50 increased from 26% [23-29%] to 34% [26-43%]. Under the full intervention scenario, new infections were forecasted to fall to 6,000 [3,000-12,000] in 2040. The percent of new infections occurring in people over age 30 increased to 52% [34-71%] in 2040, and there was an additional shift in the age structure of PWH (forecasted median age of 46 [43-48] and 40% [33-47%] over age 50). CONCLUSIONS: PWH in Kenya are forecasted to age over the next 15 years; improvements to the HIV care continuum are expected to contribute to the growing proportion of older PWH.

A Generalizable Decision-Making Framework for Selecting Onsite versus Send-out Clinical Laboratory Testing.

BACKGROUND: Laboratory networks provide services through onsite testing or through specimen transport to higher-tier laboratories. This decision is based on the interplay of testing characteristics, treatment characteristics, and epidemiological characteristics. OBJECTIVES: Our objective was to develop a generalizable model using the threshold approach to medical decision making to inform test placement decisions. METHODS: We developed a decision model to compare the incremental utility of onsite versus send-out testing for clinical purposes. We then performed Monte Carlo simulations to identify the settings under which each strategy would be preferred. Tuberculosis was modeled as an exemplar. RESULTS: The most important determinants of the decision to test onsite versus send-out were the clinical utility lost due to send-out testing delays and the accuracy decrement with onsite testing. When the sensitivity decrements of onsite testing were minimal, onsite testing tended to be preferred when send-out delays reduced clinical utility by >20%. By contrast, when onsite testing incurred large reductions in sensitivity, onsite testing tended to be preferred when utility lost due to delays was >50%. The relative cost of onsite versus send-out testing affected these thresholds, particularly when testing costs were >10% of treatment costs. CONCLUSIONS: Decision makers can select onsite versus send-out testing in an evidence-based fashion using estimates of the percentage of clinical utility lost due to send-out delays and the relative accuracy of onsite versus send-out testing. This model is designed to be generalizable to a wide variety of use cases. HIGHLIGHTS: The design of laboratory networks, including the decision to place diagnostic instruments at the point-of-care or at higher tiers as accessed through specimen transport, can be informed using the threshold approach to medical decision making.The most important determinants of the decision to test onsite versus send-out were the clinical utility lost due to send-out testing delays and the accuracy decrement with onsite testing.The threshold approach to medical decision making can be used to compare point-of-care testing accuracy decrements with the lost utility of treatment due to send-out testing delays.The relative cost of onsite versus send-out testing affected these thresholds, particularly when testing costs were >10% of treatment costs.

Comparison of 3 optimized delivery strategies for completion of isoniazid-rifapentine (3HP) for tuberculosis prevention among people living with HIV in Uganda: A single-center randomized trial.

BACKGROUND: Expanding access to shorter regimens for tuberculosis (TB) prevention, such as once-weekly isoniazid and rifapentine taken for 3 months (3HP), is critical for reducing global TB burden among people living with HIV (PLHIV). Our coprimary hypotheses were that high levels of acceptance and completion of 3HP could be achieved with delivery strategies optimized to overcome well-contextualized barriers and that 3HP acceptance and completion would be highest when PLHIV were provided an informed choice between delivery strategies. METHODS AND FINDINGS: In a pragmatic, single-center, 3-arm, parallel-group randomized trial, PLHIV receiving care at a large urban HIV clinic in Kampala, Uganda, were randomly assigned (1:1:1) to receive 3HP by facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid. We assessed the primary outcome of acceptance and completion (≥11 of 12 doses of 3HP) within 16 weeks of treatment initiation using proportions with exact binomial confidence intervals (CIs). We compared proportions between arms using Fisher's exact test (two-sided α = 0.025). Trial investigators were blinded to primary and secondary outcomes by study arm. Between July 13, 2020, and July 8, 2022, 1,656 PLHIV underwent randomization, with equal numbers allocated to each study arm. One participant was erroneously enrolled a second time and was excluded in the primary intention-to-treat analysis. Among the remaining 1,655 participants, the proportion who accepted and completed 3HP exceeded the prespecified 80% target in the DOT (0.94; 97.5% CI [0.91, 0.96] p < 0.001), SAT (0.92; 97.5% CI [0.89, 0.94] p < 0.001), and Choice (0.93; 97.5% CI [0.91, 0.96] p < 0.001) arms. There was no difference in acceptance and completion between any 2 arms overall or in prespecified subgroup analyses based on sex, age, time on antiretroviral therapy, and history of prior treatment for TB or TB infection. Only 14 (0.8%) participants experienced an adverse event prompting discontinuation of 3HP. The main limitation of the study is that it was conducted in a single center. Multicenter studies are now needed to confirm the feasibility and generalizability of the facilitated 3HP delivery strategies in other settings. CONCLUSIONS: Short-course TB preventive treatment was widely accepted by PLHIV in Uganda, and very high levels of treatment completion were achieved in a programmatic setting with delivery strategies tailored to address known barriers. TRIAL REGISTRATION: ClinicalTrials.gov NCT03934931.

Active case-finding of tuberculosis compared with symptom-driven standard of care: a modelling analysis.

BACKGROUND: In settings with large case detection gaps, active case-finding (ACF) may play a critical role in the uberculosis (TB) response. However, ACF is resource intensive, and its effectiveness depends on whether people detected with TB through ACF might otherwise spontaneously resolve or be diagnosed through routine care. We analysed the potential effectiveness of ACF for TB relative to the counterfactual scenario of routine care alone. METHODS: We constructed a Markov simulation model of TB natural history, diagnosis, symptoms, ACF and treatment, using a hypothetical reference setting using data from South East Asian countries. We calibrated the model to empirical data using Bayesian methods, and simulated potential 5-year outcomes with an 'aspirational' ACF intervention (reflecting maximum possible effectiveness) compared with the standard-of-care outcomes. RESULTS: Under the standard of care, 51% (95% credible interval, CrI: 31%, 75%) of people with prevalent TB at baseline were estimated to be diagnosed and linked to care over 5 years. With aspirational ACF, this increased to 88% (95% CrI: 84%, 94%). Most of this difference represented people who were diagnosed and treated through ACF but experienced spontaneous resolution under standard-of-care. Aspirational ACF was projected to reduce the average duration of TB disease by 12 months (95% CrI: 6%, 18%) and TB-associated disability-adjusted life-years by 71% (95% CrI: 67%, 76%). CONCLUSION: These data illustrate the importance of considering outcomes in a counterfactual standard of care scenario, as well as trade-offs between overdiagnosis and averted morbidity through earlier diagnosis-not just for TB, but for any disease in which population-based screening is recommended.

Yellow fever in Ghana: Predicting emergence and ecology from historical outbreaks.

Understanding the epidemiology and ecology of yellow fever in endemic regions is critical for preventing future outbreaks. Ghana is a high-risk country for yellow fever. In this study we estimate the epidemiology, ecological cycles, and areas at risk for yellow fever in Ghana based on historical outbreaks. We identify 2371 cases and 887 deaths (case fatality rate 37.4%) from yellow fever reported in Ghana from 1910 to 2022. Since implementation of routine childhood vaccination in 1992, the estimated mean annual number of cases decreased by 81% and the geographic distribution of yellow fever cases also changed. While there have been multiple large historical outbreaks of yellow fever in Ghana from the urban cycle, recent outbreaks have originated among unvaccinated nomadic groups in rural areas with the sylvatic/savanna cycles. Using machine learning and an ecological niche modeling framework, we predict areas in Ghana that are similar to where prior yellow fever outbreaks have originated based on temperature, precipitation, landcover, elevation, and human population density. We find differences in predictions depending on the ecological cycles of outbreaks. Ultimately, these findings and methods could be used to inform further subnational risk assessments for yellow fever in Ghana and other high-risk countries.

Accuracy of C-reactive Protein for Tuberculosis Detection in General-Population Screening and Ambulatory Care Triage in Uganda.

Rationale C-reactive protein (CRP) has demonstrated utility as a point-of-care triage test for tuberculosis (TB) in clinical settings, particularly among people with HIV, but its performance for general-population TB screening is not well characterized. Objective To assess the accuracy of CRP for detecting pulmonary TB disease among individuals undergoing community-based screening or presenting for evaluation of TB symptoms in Kampala, Uganda. Methods We pooled data from two case-control studies conducted between May 2018 and December 2022 among adolescents and adults (>15 years) in Kampala, Uganda. We conducted community-based screening for TB, regardless of symptoms. We enrolled people with Xpert MTB/RIF Ultra-positive (including trace) sputum results and a sample of people with Ultra-negative results. We also enrolled symptomatic patients diagnosed with TB and controls with negative TB evaluations from ambulatory care settings. Participants underwent further evaluation including sputum culture, CRP and HIV testing. We assessed accuracy of CRP alone or with symptom screening, against a bacteriologic reference standard. Our primary analysis evaluated the sensitivity and specificity of CRP at a cutoff of 5 mg/L. Diagnostic performance was summarized by calculating area under the receiver operating curve (AUC). Results In the community setting (N=544), CRP ≥5mg/L had a sensitivity of 55.3% (95% confidence interval: 47.0-63.4) and specificity of 84.7% (79.7-88.8) for confirmed TB; AUC was 0.75 (0.70-0.79). Screening for CRP >5 mg/L or positive symptoms increased sensitivity to 92.0% (86.4-95.8) at the expense of specificity (57.1% [50.8-63.2]). In the ambulatory care setting (N=944), sensitivity of CRP >5 mg/L was 86.7% (81.8-90.7), specificity was 68.6% (64.8-72.2), and AUC (0.84 [0.81-0.87]) did not differ significantly by HIV status. CRP >5 mg/L was >90% sensitive among individuals with a medium or high semiquantitative Xpert result in both settings. Conclusions While CRP did not meet WHO TB screening benchmarks in the community, it demonstrated high specificity, and sensitivity was high among individuals with high sputum bacillary burden who are likely to be most infectious. In ambulatory care, estimated sensitivity and specificity were each within four percentage points of WHO benchmarks with no meaningful difference in performance by HIV status. Primary Source of Funding NIH R01HL138728, R01HL153611.

Cost-effectiveness of Low-complexity Screening Tests in Community-based Case-finding for Tuberculosis.

INTRODUCTION: In high-burden settings, low-complexity screening tests for tuberculosis (TB) could expand the reach of community-based case-finding efforts. The potential costs and cost-effectiveness of approaches incorporating these tests are poorly understood. METHODS: We developed a microsimulation model assessing 3 approaches to community-based case-finding in hypothetical populations (India-, South Africa-, The Philippines-, Uganda-, and Vietnam-like settings) with TB prevalence 4 times that of national estimates: (1) screening with a point-of-care C-reactive protein (CRP) test, (2) screening with a more sensitive "Hypothetical Screening test" (95% sensitive for Xpert Ultra-positive TB, 70% specificity; equipment/labor costs similar to Xpert Ultra, but using a $2 cartridge) followed by sputum Xpert Ultra if positive, or (3) testing all individuals with sputum Xpert Ultra. Costs are expressed in 2023 US dollars and include treatment costs. RESULTS: Universal Xpert Ultra was estimated to cost a mean $4.0 million (95% uncertainty range: $3.5 to $4.6 million) and avert 3200 (2600 to 3900) TB-related disability-adjusted life years (DALYs) per 100 000 people screened ($670 [The Philippines] to $2000 [Vietnam] per DALY averted). CRP was projected to cost $550 (The Philippines) to $1500 (Vietnam) per DALY averted but with 44% fewer DALYs averted. The Hypothetical Screening test showed minimal benefit compared to universal Xpert Ultra, but if specificity were improved to 95% and per-test cost to $4.5 (all-inclusive), this strategy could cost $390 (The Philippines) to $940 (Vietnam) per DALY averted. CONCLUSIONS: Screening tests can meaningfully improve the cost-effectiveness of community-based case-finding for TB but only if they are sensitive, specific, and inexpensive.

Factors Associated With Non-vaccination for Influenza Among Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Vaccination for influenza is strongly recommended for people with chronic kidney disease (CKD) due to their immunocompromised state. Identifying risk factors for not receiving an influenza vaccine (non-vaccination) could inform strategies for improving vaccine uptake in this high-risk population. STUDY DESIGN: Longitudinal observational study. SETTING & PARTICIPANTS: 3,692 Chronic Renal Insufficiency Cohort Study (CRIC) participants. EXPOSURE: Demographic factors, social determinants of health, clinical conditions, and health behaviors. OUTCOME: Influenza non-vaccination, which was assessed based on a receipt of influenza vaccine ascertained during annual clinic visits in a subset of participants who were under nephrology care. ANALYTICAL APPROACH: Mixed-effects Poisson models to estimate adjusted prevalence ratios (APRs). RESULTS: Between 2009 and 2020, the pooled mean vaccine uptake was 72% (mean age, 66 years; 44% female; 44% Black race). In multivariable models, factors significantly associated with influenza non-vaccination were younger age (APR, 2.16 [95% CI, 1.85-2.52] for<50 vs≥75 years), Black race (APR, 1.58 [95% CI, 1.43-1.75] vs White race), lower education (APR, 1.20 [95% CI, 1.04-1.39 for less than high school vs college graduate]), lower annual household income (APR, 1.26 [95% CI, 1.06-1.49] for <$20,000 vs >$100,000), formerly married status (APR, 1.22 [95% CI, 1.09-1.35] vs currently married), and nonemployed status (APR, 1.13 [95% CI, 1.02-1.24] vs employed). In contrast, participants with diabetes (APR, 0.80 [95% CI, 0.73-0.87] vs no diabetes), chronic obstructive pulmonary disease (COPD) (APR, 0.80 [95% CI, 0.70-0.92] vs no COPD), end-stage kidney disease (APR, 0.64 [0.56 to 0.76] vs estimated glomerular filtration rate≥60mL/min/1.73m2), frailty (APR, 0.86 [95% CI, 0.74-0.99] vs no frailty), and ideal physical activity (APR, 0.90 [95% CI, 0.82-0.99] vs. physically inactive) were less likely to have non-vaccination status. LIMITATIONS: Possible residual confounding. CONCLUSIONS: Among adults with CKD receiving nephrology care, younger adults, Black individuals, and those with adverse social determinants of health were more likely to have the influenza non-vaccination status. Strategies are needed to address these disparities and reduce barriers to vaccination. PLAIN-LANGUAGE SUMMARY: Identifying risk factors for not receiving an influenza vaccine ("non-vaccination") in people living with kidney disease, who are at risk of influenza and its complications, could inform strategies for improving vaccine uptake. In this study, we examined whether demographic factors, social determinants of health, and clinical conditions were linked to the status of not receiving an influenza vaccine among people living with kidney disease and receiving nephrology care. We found that younger adults, Black individuals, and those with adverse social determinants of health were more likely to not receive the influenza vaccine. These findings suggest the need for strategies to address these disparities and reduce barriers to vaccination in people living with kidney disease.

The Impact of Preventive Treatment for Multidrug- and Rifampin-Resistant Tuberculosis Exceeds Trial-Based Estimates.

BACKGROUND: Several clinical trials of tuberculosis preventive treatment (TPT) for household contacts of patients with multidrug- or rifampin-resistant tuberculosis (MDR/RR-TB) are nearing completion. The potential benefits of delivering TPT to MDR/RR-TB contacts extend beyond the outcomes that clinical trials can measure. METHODS: We developed an agent-based, household-structured TB and MDR/RR-TB transmission model, calibrated to an illustrative setting in India. We simulated contact investigation in households of patients with MDR/RR-TB, comparing an MDR/RR-TPT regimen (assuming 6-month duration, 70% efficacy) and associated active case finding against alternatives of contact investigation without TPT or no household intervention. We simulated the TB and MDR/RR-TB incidence averted relative to placebo over 2 years, as measurable by a typical trial, as well as the incidence averted over a longer time horizon, in the broader population, and relative to no contact investigation. RESULTS: Observing TPT and placebo recipients for 2 years as in a typical trial, MDR/RR-TPT was measured to prevent 72% (interquartile range, 45%-100%) of incident MDR/RR-TB among recipients; the median number needed to treat (NNT) to prevent 1 MDR/RR-TB case was 73, compared to placebo. This NNT decreased to 54 with 13-18 years of observation, to 27 when downstream transmission effects were also considered, and to 12 when the effects of active TB screening were included by comparing to a no-household-contact-intervention scenario. CONCLUSIONS: If forthcoming trial results demonstrate efficacy, the long-term population impact of TPT for MDR/RR-TB-including the large effect of increased active TB detection among MDR/RR-TB contacts-could be much greater than suggested by trial outcomes alone.

Efficacy of Two Evidence-Based Alcohol Consumption Interventions on Positive, Negative, and Neutral Days Among Hazardous Alcohol Users Living with HIV in Vietnam.

Social events and stressful settings can be catalysts for alcohol consumption. Motivational enhancement therapy (MET) and cognitive behavioral therapy (CBT) are widely used in alcohol interventions. We assessed how alcohol consumption varied across three types of days (positive/social, negative/stressful, and neutral) among hazardous alcohol users living with HIV in Vietnam. We further evaluated how those consumption patterns changed after two MET/CBT alcohol reduction interventions versus the standard of care (SOC). The 'combined' intervention offered 6 individual sessions and 3 group sessions; the 'brief' intervention offered 2 individual sessions and 2 phone calls. A 30-day timeline follow-back was administered at study visits, detailing daily drinks and events. Days were categorized as neutral, positive/social, or negative/stressful; negative binomial models and generalized estimating equations were used to estimate drinks consumed by type of day at baseline and 12 months. Prior to intervention, more drinks were consumed on positive/social days (5.2 drinks; 95% Confidence Interval [CI]:4.8, 5.7) than negative/stressful (1.5; 95% CI:1.3, 1.9) and neutral days (2.2; 95% CI: 1.9, 2.5). After the brief intervention, drinks consumed decreased on neutral days (ratio: 0.5: 95% CI: 0.4, 0.7). After the combined intervention, drinks consumed decreased on neutral days (ratio: 0.4; 95% CI: 0.3, 0.6), positive/social days (ratio: 0.6; 95% CI: 0.5, 0.7) and negative/stressful days (ratio: 0.3; 95% CI: 0.2, 0.6). No reductions in consumption were observed in the SOC group. Social/positive days had the highest alcohol consumption prior to intervention, and the combined intervention showed the greatest decrease in consumption on those days. CLINICAL TRIAL REGISTRATION: The study is registered at clinicaltrials.gov (NCT02720237).

Evidence for tuberculosis in individuals with Xpert Ultra "trace" sputum during screening of high-burden communities.

BACKGROUND: "Trace" results on Xpert MTB/RIF Ultra ("Ultra") - a molecular diagnostic test for tuberculosis (TB) - are often interpreted as an indication for TB treatment, but may also represent detection of nonviable bacilli or analytical error. In community screening settings where individual TB risk is low, there is limited guidance on how to interpret Ultra-trace results. METHODS: We conducted systematic Ultra TB screening of adults and adolescents (≥15 years) in Kampala, Uganda through door-to-door and event-based sputum collection. We enrolled individuals with trace-positive sputum for detailed clinical, radiographic, and microbiological (including two sputum cultures, repeat Ultra, and for people with HIV, urine lipoarabinomannan) evaluation, and compared those findings to similar evaluations in controls with Ultra-negative and Ultra-positive (non-trace) sputum. RESULTS: Of 21,957 people screened with Ultra, 211 (1.0%) tested positive, including 96 (46% of positives) with trace results. Of 92 people enrolled with trace-positive sputum; 12% (11/92) were HIV-positive and 14% (13/92) had prior TB. The prevalence of TB among participants with trace-positive sputum results was 14% (13/92) by culture, 24% (22/92) using broader microbiological criteria, and 26% (24/92) after accounting for clinical diagnosis. The prevalence of cough and of abnormal chest CT findings were 32% and 26%, respectively, if Ultra-negative; 34% and 54% if trace-positive/non-microbiologically confirmed; 71% and 95% if trace-positive/microbiologically confirmed; and 72% and 92% if Ultra-positive (more than trace). CONCLUSION: Most individuals with trace-positive sputum in Ugandan communities did not have microbiologically confirmed TB but had more symptoms and chest CT abnormalities than people with Ultra-negative sputum.

Methods for measuring short-term geographical mobility used in infectious disease research: a scoping review protocol.

INTRODUCTION: Geographical mobility, the movement of individuals or populations, may increase an individual's risk of acquiring or transmitting infectious diseases, including HIV, tuberculosis, malaria and COVID-19. Many studies have collected information on short-term mobility through self-reported travel histories or using GPS trackers, but there has been no consistent conceptualisation and operationalisation of such geographical mobility in global health research. This protocol aims to describe and synthesise different approaches to measuring short-term mobility. METHODS AND ANALYSIS: We will search three databases (PubMed, Embase and Global Health) for peer-reviewed articles. After removing duplicates, two reviewers will first screen the titles and abstracts and then proceed to full-text screening. We will include studies that measure mobility at the individual level in the context of infectious diseases, including clinical trials, epidemiological studies and analyses of register data. Additional articles for inclusion may be identified through review of references in selected papers. We will summarise the method of data collection (GPS trackers, cellphones, retrospective self-report, travel journal, etc) and the specific measures used (overnight travel, having a secondary residence, travel outside of district, etc). ETHICS AND DISSEMINATION: This study consists of reviewing and abstracting existing data from publicly available materials, and therefore does not require ethical approval. The results of this study will be submitted for peer reviewed publication and may be presented at a relevant global health conference.

Preventing tuberculosis with community-based care in an HIV-endemic setting: a modeling analysis.

Introduction: Antiretroviral therapy (ART) and TB preventive treatment (TPT) both prevent tuberculosis (TB) disease and deaths among people living with HIV. Differentiated care models, including community-based care, can increase uptake of ART and TPT to prevent TB in settings with a high burden of HIV-associated TB, particularly among men. Methods: We developed a gender-stratified dynamic model of TB and HIV transmission and disease progression among 100,000 adults ages 15-59 in KwaZulu-Natal, South Africa. We drew model parameters from a community-based ART initiation and resupply trial in sub-Saharan Africa (Delivery Optimization for Antiretroviral Therapy, DO ART) and other scientific literature. We simulated the impacts of community-based ART and TPT care programs during 2018-2027, assuming that community-based ART and TPT care were scaled up to similar levels as in the DO ART trial (i.e., ART coverage increasing from 49% to 82% among men and from 69% to 83% among women) and sustained for ten years. We projected the number of TB cases, deaths, and disability-adjusted life years (DALYs) averted relative to standard, clinic-based care. We calculated program costs and incremental cost-effectiveness ratios from the provider perspective. Results: If community-based ART care could be implemented with similar effectiveness to the DO ART trial, increased ART coverage could reduce TB incidence by 27.0% (range 21.3% - 34.1%) and TB mortality by 36.0% (range 26.9% - 43.8%) after ten years. Increasing both ART and TPT uptake through community-based ART with TPT care could reduce TB incidence by 29.7% (range 23.9% - 36.0%) and TB mortality by 36.0% (range 26.9% - 43.8%). Community-based ART with TPT care reduced gender disparities in TB mortality rates by reducing TB mortality among men by a projected 39.8% (range 32.2% - 46.3%) and by 30.9% (range 25.3% - 36.5%) among women. Over ten years, the mean cost per DALY averted by community-based ART with TPT care was $846 USD (range $709 - $1,012). Conclusions: By substantially increasing coverage of ART and TPT, community-based care for people living with HIV could reduce TB incidence and mortality in settings with high burdens of HIV-associated TB and reduce TB gender disparities.

Preferences of people living with HIV for features of tuberculosis preventive treatment regimens - a discrete choice experiment.

Background: Tuberculosis (TB) preventive treatment (TPT) is recommended for people living with HIV (PLHIV) in high TB burden settings. While 6 months of daily isoniazid remains widely used, shorter regimens are now available. However, little is known about preferences of PLHIV for key features of TPT regimens. Methods: We conducted a discrete choice experiment among adult PLHIV engaged in care at an urban HIV clinic in Kampala, Uganda. In nine random choice tasks, participants chose between two hypothetical TPT regimens with different features (pills per dose, frequency, duration, need for adjusted antiretroviral therapy [ART] dosage and side effects). We analyzed preferences using hierarchical Bayesian estimation, latent class analysis, and willingness-to-trade simulations. Results: Of 400 PLHIV, 392 (median age 44, 72% female, 91% TPT-experienced) had high quality choice task responses. Pills per dose was the most important attribute (relative importance 32.4%, 95% confidence interval [CI] 31.6 - 33.2), followed by frequency (20.5% [95% CI 19.7 - 21.3]), duration (19.5% [95% CI 18.6 - 20.5]), and need for ART dosage adjustment (18.2% [95% CI 17.2 - 19.2]). Latent class analysis identified three preference groups: one prioritized less frequent, weekly dosing (N=222; 57%); another was averse to ART dosage adjustment (N=107; 27%); and the last prioritized short and tolerable regimens (N=63; 16%). All groups highly valued fewer pills per dose. Participants were willing to accept a regimen of 2.8 months' additional duration [95% CI: 2.4 - 3.2] to reduce pills per dose from five to one, 3.6 [95% CI 2.4 - 4.8] months for weekly rather than daily dosing, and 2.2 [95% CI 1.3 - 3.0] months to avoid ART dosage adjustment. Conclusions: To align with preferences of PLHIV, decision-makers should prioritize the development and implementation of TPT regimens with fewer pills, less frequent dosing, and no need for ART dosage adjustment, rather than focus primarily on duration of treatment.

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.

Investigating linkage to care between hospitals and primary care clinics for people with TB in rural South Africa.

People with tuberculosis (TB) are often lost to follow-up during treatment transition to another facility. These losses may result in substantial morbidity and mortality but are rarely recorded. We conducted a record review on adults diagnosed with TB at 11 hospitals in Limpopo, South Africa, who were subsequently transferred to a local clinic to initiate or continue treatment. We then performed in-depth record reviews at the primary care clinic to which they were referred and called participants who could not be identified as starting treatment. Between August 2017 and April 2018, we reviewed records of 778 individuals diagnosed with TB in-hospital and later referred to local clinics for treatment. Of the 778, 88 (11%) did not link to care, and an additional 43 (5.5%) died. Compared to people without cough, those with cough had higher odds of linking to care (aOR = 2.01, 95% CI: 1.26-3.25, p = 0.005) and were also linked more quickly [adjusted Time Ratio (aTR) = 0.53, 95% CI:0.36-0.79, p<0.001], as were those diagnosed microbiologically (aOR = 1.86, 95% CI: 1.16-3.06, p = 0.012; aTR = 0.58, 95% CI: 0.34-0.98, p = 0.04). People diagnosed with TB in hospitals often disengage following referral to local clinics. Interventions to identify and re-engage people who do not present to local clinics within days of referral might close an important gap in the TB treatment cascade.

Impact and cost-effectiveness of short-course tuberculosis preventive treatment for household contacts and people with HIV in 29 high-incidence countries: a modelling analysis.

BACKGROUND: Guidelines and implementation of tuberculosis preventive treatment (TPT) vary by age and HIV status. Specifically, TPT is strongly recommended for people living with HIV/AIDS (PLWHA) and household contacts younger than 5 years but only conditionally recommended for older contacts. Cost remains a major barrier to implementation. The aim of this study was to evaluate the cost-effectiveness of TPT for household contacts and PLWHA. METHODS: We developed a state-transition model to simulate short-course TPT for household contacts and PLWHA in 29 high-incidence countries based on data from previous studies and public databases. Our primary outcome was the incremental cost-effectiveness ratio, expressed as incremental discounted costs (2020 US$, including contact investigation costs) per incremental discounted disability-adjusted life year (DALY) averted, compared with a scenario without any TPT or contact investigation. We propagated uncertainty in all model parameters using probabilistic sensitivity analysis and also evaluated the sensitivity of results to the screening algorithm used to rule out active disease, the choice of TPT regimen, the modelling time horizon, assumptions about TPT coverage, antiretroviral therapy discontinuation, and secondary transmission. FINDINGS: Between 2023 and 2035, scaling up TPT prevented 0·9 (95% uncertainty interval 0·4-1·6) people from developing tuberculosis and 0·13 (0·05-0·27) tuberculosis deaths per 100 PLWHA, at an incremental cost of $15 (9-21) per PLWHA. For household contacts, TPT (with contact investigation) averted 1·1 (0·5-2·0) cases and 0·7 (0·4-1·0) deaths per 100 contacts, at a cost of $21 (17-25) per contact. Cost-effectiveness was most favourable for household contacts younger than 5 years ($22 per DALY averted) and contacts aged 5-14 years ($104 per DALY averted) but also fell within conservative cost-effectiveness thresholds in many countries for PLWHA ($722 per DALY averted) and adult contacts ($309 per DALY averted). Costs per DALY averted tended to be lower when compared with a scenario with contact investigation but no TPT. The cost-effectiveness of TPT was not substantially altered in sensitivity analyses, except that TPT was more favourable in analysis that considered a longer time horizon or included secondary transmission benefits. INTERPRETATION: In many high-incidence countries, short-course TPT is likely to be cost-effective for PLWHA and household contacts of all ages, regardless of whether contact investigation is already in place. Failing to implement tuberculosis contact investigation and TPT will incur a large burden of avertable illness and mortality in the next decade. FUNDING: Unitaid.

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 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 with a waiver of informed consent for the main trial implementation-effectiveness outcomes. We will submit trial results for publication in a peer-reviewed journal and disseminate findings to local shareholders, including 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 setting using contact investigation. It will help assess the suitability of human-centred design and communities of practice for tailoring implementation strategies and sustain evidence-based interventions in low-and-middle-income countries. Trial registration number ClinicalTrials.gov Identifier: NCT05640648.