Factors associated with tuberculosis treatment initiation among bacteriologically negative individuals evaluated for tuberculosis: an individual patient data meta-analysis.

Background: Globally, over one-third of pulmonary tuberculosis (TB) disease diagnoses are made based on clinical criteria after a negative diagnostic test result. Understanding factors associated with clinicians' decisions to initiate treatment for individuals with negative test results is critical for predicting the potential impact of new diagnostics. Methods: We performed a systematic review and individual patient data meta-analysis using studies conducted between January/2010 and December/2022 (PROSPERO: CRD42022287613). We included trials or cohort studies that enrolled individuals evaluated for TB in routine settings. In these studies participants were evaluated based on clinical examination and routinely-used diagnostics, and were followed for ≥1 week after the initial test result. We used hierarchical Bayesian logistic regression to identify factors associated with treatment initiation following a negative result on an initial bacteriological test (e.g., sputum smear microscopy, Xpert MTB/RIF). Findings: Multiple factors were positively associated with treatment initiation: male sex [adjusted Odds Ratio (aOR) 1.61 (1.31-1.95)], history of prior TB [aOR 1.36 (1.06-1.73)], reported cough [aOR 4.62 (3.42-6.27)], reported night sweats [aOR 1.50 (1.21-1.90)], and having HIV infection but not on ART [aOR 1.68 (1.23-2.32)]. Treatment initiation was substantially less likely for individuals testing negative with Xpert [aOR 0.77 (0.62-0.96)] compared to smear microscopy and declined in more recent years. Interpretation: Multiple factors influenced decisions to initiate TB treatment despite negative test results. Clinicians were substantially less likely to treat in the absence of a positive test result when using more sensitive, PCR-based diagnostics.

Transitional community adherence support for people leaving incarceration in South Africa: a pragmatic, open-label, randomised controlled trial.

BACKGROUND: People released from correctional facilities face multifactorial barriers to continuing HIV treatment. We hypothesised that barriers faced in the first 6 months of community re-entry would be decreased by a multilevel group-based and peer-led intervention, the Transitional Community Adherence Club (TCAC). METHODS: We did a pragmatic, open-label, individually randomised controlled trial in five correctional facilities in Gauteng, South Africa. Participants aged 18 years and older and receiving antiretroviral therapy (ART) in correctional facilities were enrolled before release and randomly assigned (1:2) to either passive referral (usual care) or TCACs. TCACs followed a 12-session curriculum over 6 months and were facilitated by trained peer and social workers. Participants were followed up by telephone and in person to assess the primary outcome: post-release enrolment in HIV treatment services at 6 months from the date of release. We did an intention-to-treat analysis to determine the effectiveness of TCACs compared with usual care. The trial was registered with the South African National Clinical Trials Register (DOH-27-0419-605) and ClinicalTrials.gov (NCT03340428). This study is completed and is listed as such on ClinicalTrials.gov. FINDINGS: From March 1, to Dec 13, 2019, we screened 222 individuals and enrolled 176 participants who were randomly assigned 1:2 to the usual care group (n=59) or TCACs (n=117). 175 participants were included in the final analysis. In the usual care group, 21 (36%) of 59 participants had enrolled in HIV treatment services at 6 months, compared with 71 (61%) of 116 in the TCAC group (risk ratio 1·7, 95% CI 1·2-2·5; p=0·0010). No adverse events were reported. INTERPRETATION: We found strong evidence that a differentiated service delivery model with curriculum and peer support designed specifically to address the needs of people with HIV returning from incarceration improved the primary outcome of enrolment in HIV treatment services. Our approach is a reasonable model to build further HIV treatment continuity interventions for individuals in the criminal justice system in South Africa and elsewhere. FUNDING: National Institute of Mental Health.

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.

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.

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.

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.

Preventive Treatment for Household Contacts of Drug-Susceptible Tuberculosis Patients.

People who live in the household of someone with infectious pulmonary tuberculosis are at a high risk of tuberculosis infection and subsequent progression to tuberculosis disease. These individuals are prioritized for contact investigation and tuberculosis preventive treatment (TPT). The treatment of TB infection is critical to prevent the progression of infection to disease and is prioritized in household contacts. Despite the availability of TPT, uptake in household contacts is poor. Multiple barriers prevent the optimal implementation of these policies. This manuscript lays out potential next steps for closing the policy-to-implementation gap in household contacts of all ages.

Neurodevelopmental outcomes of HIV/antiretroviral drug perinatally exposed uninfected children aged 3-6 years.

OBJECTIVE: Given the roll out of maternal antiretroviral therapy (ART) for prevention-of-perinatal-HIV-transmission, increasing numbers of children are perinatally HIV/antiretroviral exposed but uninfected (CAHEU). Some studies suggest CAHEU may be at increased risk for neurodevelopmental (ND) deficits. We aimed to assess ND performance among preschool CAHEU. DESIGN: This cross-sectional study assessed ND outcomes among 3-6-year-old CAHEU at entry into a multicountry cohort study. METHODS: We used the Mullen Scales of Early Learning (MSEL) and Kaufman Assessment Battery for Children (KABC-II) to assess ND status among 3-6-year-old CAHEU at entry into the PROMISE Ongoing Treatment Evaluation (PROMOTE) study conducted in Uganda, Malawi, Zimbabwe and South Africa. Statistical analyses (Stata 16.1) was used to generate group means for ND composite scores and subscale scores, compared to standardized test score means. We used multivariable analysis to adjust for known developmental risk factors including maternal clinical/socioeconomic variables, child sex, growth-for-age measurements, and country. RESULTS: 1647 children aged 3-6 years had baseline ND testing in PROMOTE; group-mean unadjusted Cognitive Composite scores on the MSEL were 85.8 (standard deviation [SD]: 18.2) and KABC-II were 79.5 (SD: 13.2). Composite score group-mean differences were noted by country, with South African and Zimbabwean children having higher scores. In KABC-II multivariable analyses, maternal age >40 years, lower education, male sex, and stunting were associated with lower composite scores. CONCLUSIONS: Among a large cohort of 3-6 year old CAHEU from eastern/southern Africa, group-mean composite ND scores averaged within the low-normal range; with differences noted by country, maternal clinical and socioeconomic factors.

Curating the Evidence About COVID-19 for Frontline Public Health and Clinical Care: The Novel Coronavirus Research Compendium.

The public health crisis created by the COVID-19 pandemic has spurred a deluge of scientific research aimed at informing the public health and medical response to the pandemic. However, early in the pandemic, those working in frontline public health and clinical care had insufficient time to parse the rapidly evolving evidence and use it for decision-making. Academics in public health and medicine were well-placed to translate the evidence for use by frontline clinicians and public health practitioners. The Novel Coronavirus Research Compendium (NCRC), a group of >60 faculty and trainees across the United States, formed in March 2020 with the goal to quickly triage and review the large volume of preprints and peer-reviewed publications on SARS-CoV-2 and COVID-19 and summarize the most important, novel evidence to inform pandemic response. From April 6 through December 31, 2020, NCRC teams screened 54 192 peer-reviewed articles and preprints, of which 527 were selected for review and uploaded to the NCRC website for public consumption. Most articles were peer-reviewed publications (n = 395, 75.0%), published in 102 journals; 25.1% (n = 132) of articles reviewed were preprints. The NCRC is a successful model of how academics translate scientific knowledge for practitioners and help build capacity for this work among students. This approach could be used for health problems beyond COVID-19, but the effort is resource intensive and may not be sustainable in the long term.

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.

Association between monocyte-to-lymphocyte ratio and tuberculin skin test positivity in HIV-positive adults.

BACKGROUND: The tuberculin skin test (TST) identifies individuals at high risk of developing tuberculosis (TB) but poses many challenges. The blood monocyte-to-lymphocyte ratio (MLR) could be an alternative, as extremes in MLR have been associated with increased risk of TB disease. METHODS: At a primary care clinic in Johannesburg, a differential white blood cell count and TST was performed in adults starting antiretroviral treatment (ART) without symptoms suggestive of active TB. RESULTS: Of 259 participants, 171 had valid results of whom 30% (51/171) were TST positive and the median MLR was 0.18 (IQR 0.13-0.28). The MLR distribution differed between CD4 count categories (p < 0.01), with a broader range of values in TST negative participants with a low CD4 count (≤ 250 cells/mm3), likely reflecting HIV immunosuppression. MLR was associated with a positive TST (OR 0.78 per 0.1 increase, 95% CI 0.59, 0.97) in bivariate analysis but not in multivariate regression analysis (aOR 0.83 for every 0.1 increase, 95% CI 0.60, 1.08). CONCLUSION: In ART-naïve adults without symptoms suggestive of active TB, MLR was not independently associated with TST positivity and is thus unlikely to be a useful alternative to TST. Future research should focus on development of a cheap, simple and accurate biomarker to identify those people benefiting most from preventive TB therapy.

High conversion of tuberculin skin tests during the first year of antiretroviral treatment among South African adults in primary care.

OBJECTIVES: Anergy reduces the sensitivity of the tuberculin skin test (TST) to detect Mycobacterium tuberculosis infection in people living with HIV. Antiretroviral treatment (ART) can reverse TST anergy, but data is scarce. METHODS: To estimate TST conversion rates and factors associated with TST conversion, TST was placed at ART initiation, and 6 and 12 months thereafter (if TST negative at prior assessment). RESULTS: Of 328 ART-eligible participants, 70% (231/328) had a valid TST result of whom 78% (180/231) were TST negative. At 6-month follow-up, 22% (24/109, 95% confidence interval [CI] 15%, 31%) of participants on ART, without incident tuberculosis (TB), and with a valid TST result converted to a positive TST. Of these 109 individuals, those with baseline CD4+ cell count >250 cells/µl were more likely to TST convert compared to those with baseline CD4+ cell count ≤250 cells/µl (odds ratio [OR] 3.54, 95% CI 1.29, 11.47). At 12 months post-ART initiation, an additional 12% (9/78, 95% CI 6, 20) of participants on ART, without incident TB and with a valid TST result experienced TST conversion. After 1 year on ART, TST conversion rate was 38 per 100 person-years (95% CI 26, 52), and lower in individuals with baseline CD4+ cell count ≤250 cells/µl (23/100 person-years, 95% CI 11, 41) compared to those with baseline CD4+ cell count >250 cells/µl (50/100 person-years, 95% CI 32, 73). CONCLUSIONS: TST conversion rate in the first year of ART is high, especially among people with CD4+ cell count >250 cells/µl. A TST-based eligibility strategy at ART initiation may underestimate eligibility for preventive therapy for tuberculosis.

Curating and translating the evidence about SARS-CoV-2 and COVID-19 for frontline public health and clinical care: The Novel Coronavirus Research Compendium (NCRC).

The public health crisis created by the SARS-CoV-2 pandemic has spurred a deluge of scientific research aimed at informing public health and medical response to the COVID-19 pandemic. However, those working in frontline public health and clinical care had insufficient time to parse the rapidly evolving evidence and use it for decision making. Academics in public health and medicine were well-placed to translate the evidence for use by frontline clinicians and public health practitioners. The Novel Coronavirus Research Compendium (NCRC), a group of >50 faculty and trainees, began in March 2020 with the goal to quickly triage and review the large volume of preprints and peer-reviewed publications on SARS-CoV-2 and COVID-19, and to summarize the most important, novel evidence to inform pandemic response. From April 6, 2020 through January 1, 2021, 54,192 papers and preprints were screened by NCRC teams and 527 were selected for review and uploaded to the NCRC website for public consumption. The majority of papers reviewed were peer-reviewed publications (n=395, 75%), published in 102 journals; 25% (n=132) of papers reviewed were of preprints. The NCRC is a successful model of how academics can support practitioners by translating scientific knowledge into action and help to build capacity among students for this work. This approach could be used for health problems beyond COVID-19, but the effort is resource intensive and may not be sustainable over the long term.

Novel health system strategies for tuberculin skin testing at primary care clinics: Performance assessment and health economic evaluation.

BACKGROUND: Tuberculin skin test (TST) for guiding initiation of tuberculosis preventive therapy poses major challenges in high tuberculosis burden settings. METHODS: At a primary care clinic in Johannesburg, South Africa, 278 HIV-positive adults self-read their TST by reporting if they felt a bump (any induration) at the TST placement site. TST reading (in mm) was fast-tracked to reduce patient wait time and task-shifted to delegate tasks to lower cadre healthcare workers, and result was compared to TST reading by high cadre research staff. TST reading and placement cost to the health system and patients were estimated. Simulations of health system costs were performed for 5 countries (USA, Germany, Brazil, India, Russia) to evaluate generalizability. RESULTS: Almost all participants (269 of 278, 97%) correctly self-identified the presence or absence of any induration [sensitivity 89% (95% CI 80,95) and specificity 99.5% (95% CI 97,100)]. For detection of a positive TST (induration ≥ 5mm), sensitivity was 90% (95% CI 81,96) and specificity 99% (95% CI 97,100). TST reading agreement between low and high cadre staff was high (kappa 0.97, 95% CI 0.94, 1.00). Total TST cost was 2066 I$ (95% UI 594, 5243) per 100 patients, 87% (95% UI 53, 95) of which were patient costs. Combining fast-track and task-shifting, reduced total costs to 1736 I$ (95% UI 497, 4300) per 100 patients, with 31% (95% UI 15, 42) saving in health system costs. Combining fast-tracking, task-shifting and self-reading, lowered the TST health system costs from 16% (95% UI 8, 26) in Russia to 40% (95% UI 18, 54) in the USA. CONCLUSION: A TST strategy where only patients with any self-read induration are asked to return for fast-tracked TST reading by lower cadre healthcare workers is a promising strategy that could be effective and cost-saving, but real-life cost-effectiveness should be further examined.

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.

Brief Report: Proportion and Predictors of Adult TB Contacts Accepting HIV Testing During an Active TB Case Finding Intervention in South Africa.

BACKGROUND: Many individuals at risk for HIV may be reached through active TB case finding interventions in areas with highly prevalent co-epidemics of TB/HIV. METHODS: We analyzed data from a cluster-randomized trial of 2 TB case finding strategies: facility-based screening and contact investigation of newly identified TB cases. In both arms, on-site rapid HIV testing was offered to all contacts older than 18 months who did not self-report HIV-positive status. Those who were HIV infected were referred appropriately. All contacts 15 years and older were included in this analysis. RESULTS: Among 2179 contacts identified, 50% (1092) accepted HIV testing and counselling, of whom 6.3% (68) tested HIV-positive. Contacts who were unemployed [adjusted prevalence ratio (aPR) 1.14, 95% confidence interval (CI): 1.04 to 1.25], had not been to a clinic (aPR 1.09, 95% CI: 1.02 to 1.18) or HIV tested (aPR 1.25, 95% CI: 1.14 to 1.39) 6 months before, and those reporting gastrointestinal symptoms (aPR 1.22, 95% CI: 0.98 to 1.52) and genitourinary symptoms (aPR 1.30, 95% CI: 1.17 to 1.45) were significantly associated with accepting HIV testing. Women [adjusted odds ratio (aOR) 2.19, 95% CI: 1.26 to 3.81], individuals with a past history of tuberculosis (aOR 1.96, 95% CI: 0.93 to 4.14), and those not HIV tested 6 months before (aOR 2.20, 95% CI: 1.28 to 3.79) were significantly associated with testing HIV-positive. CONCLUSION: Offering HIV testing in the context of active tuberculosis case finding represents an opportunity to identify a large proportion of previously undiagnosed individuals with HIV in a population that might otherwise not seek testing.

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.

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.

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.

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).