A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis.

BACKGROUND: In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed. METHODS: We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points. RESULTS: Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%). CONCLUSIONS: In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).

Iron homeostasis governs erythroid phenotype in polycythemia vera.

Polycythemia vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentrations, placing them at risk of life-threatening thrombotic events. Our genome-wide association study of 440 PV cases and 403 351 controls using UK Biobank data showed that single nucleotide polymorphisms in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed overrepresentation of homozygous HFE variants in patients with PV. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of mouse models of PV, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Furthermore, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130-coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.

Enhanced tuberculosis diagnosis with computer-aided chest X-ray and urine LAM in adults with HIV admitted to hospital (CASTLE study): A cluster randomised trial.

BACKGROUND: People with HIV (PHIV) admitted to hospital have high mortality, with tuberculosis (TB) being the major cause of death. Systematic use of new TB diagnostics could improve TB diagnosis and might improve outcomes. METHODS: We conducted a cluster randomised trial among adult PHIV admitted to Zomba Central Hospital, Malawi. Admission-days were randomly assigned to: enhanced TB diagnostics using urine lipoarabinomannan (LAM) antigen tests (SILVAMP-LAM, Fujifilm, Japan and Determine-LAM, Alere/Abbot, USA), digital chest X-ray with computer aided diagnosis (dCXR-CAD, CAD4TBv6, Delft, Netherlands), plus usual care ("enhanced TB diagnostics"); or usual care alone ("usual care"). The primary outcome was TB treatment initiation during admission. Secondary outcomes were 56-day mortality, TB diagnosis within 24-hours, and undiagnosed TB at discharge, ascertained by culture of one admission sputum sample. FINDINGS: Between 2 September 2020 and 15 February 2022, we recruited 419 people. Four people were excluded post-recruitment, leaving 415 adults recruited during 207 randomly assigned admission-days in modified intention-to-treat analysis. At admission, 90.8% (377/415) were taking antiretroviral therapy (ART) with median (IQR) CD4 cell count 240 cells/mm3. In the enhanced diagnostic arm, median CAD4TBv6 score was 60 (IQR: 51-71), 4.4% (9/207) had SILVAMP-LAM-positive and 14.4% (29/201) had Determine-LAM positive urine with three samples positive by both urine tests. TB treatment was initiated in 46/208 (22%) in enhanced TB diagnostics arm and 24/207 (12%) in usual care arm (risk ratio [RR] 1.92, 95% CI 1.20-3.08). There was no difference in mortality by 56 days (enhanced TB diagnosis: 54/208, 26%; usual care: 52/207, 25%; hazard ratio 1.05, 95% CI 0.72-1.53); TB treatment initiation within 24 hours (enhanced TB diagnosis: 8/207, 3.9%; usual care: 5/208, 2.4%; RR 1.61, 95% CI 0.53-4.71); or undiagnosed microbiological-confirmed TB at discharge (enhanced TB diagnosis, 0/207 (0.0%), usual care arm 2/208 (1.0%) (p = 0.50). INTERPRETATION: Urine SILVAMP-LAM/Determine-LAM plus dCXR-CAD diagnostics identified more hospitalised PHIV with TB than usual care. The increase in TB treatment appeared mainly due to greater use of Determine-LAM, rather than SILVAMP-LAM or dCXR-CAD. Poor concordance between Determine-LAM and SILVAMP-LAM urine tests requires further investigation. Inpatient mortality for adults with HIV remains unacceptability high.

HIV, malnutrition, and noncommunicable disease epidemics among tuberculosis-affected households in east and southern Africa: A cross-sectional analysis of the ERASE-TB cohort.

BACKGROUND: As a result of shared social and structural risk factors, people in households affected by tuberculosis may have an increased risk of chronic conditions; at the same time, tuberculosis screening may be an opportunity for interventions. We sought to describe the prevalence of HIV, nutritional disorders, and noncommunicable diseases (NCDs) among members of tuberculosis-affected households in 3 African countries. METHODS AND FINDINGS: A part of a multicountry cohort study, we screened for tuberculosis, HIV, nutritional disorders (underweight, anaemia, overweight/obesity), and NCDs (diabetes, hypertension, and chronic lung disease) among members of tuberculosis-affected households aged ≥10 years in Mozambique, Tanzania, and Zimbabwe. We describe the prevalence of these conditions, their co-occurence within individuals (multimorbidity) and household-level clustering. Of 2,109 household contacts recruited, 93% (n = 1,958, from 786 households) had complete data and were included in the analysis. Sixty-two percent were female, median age was 27 years, and 0.7% (n = 14) were diagnosed with co-prevalent tuberculosis. Six percent of household members (n = 120) had previous tuberculosis, 15% (n = 294) were living with HIV, 10% (n = 194) had chronic lung disease, and 18% (n = 347) were anaemic. Nine percent of adults (n = 127) had diabetes by HbA1c criteria, 32% (n = 439) had hypertension. By body mass index criteria, 18% household members (n = 341) were underweight while 29% (n = 549) were overweight or obese. Almost half the household members (n = 658) had at least 1 modifiable tuberculosis risk factor. Sixty-one percent of adults (n = 822) had at least 1 chronic condition, 1 in 4 had multimorbidity. While most people with HIV knew their status and were on treatment, people with NCDs were usually undiagnosed and untreated. Limitations of this study include use of point-of-care HbA1c for definition of diabetes and definition of hypertension based on single-day measurements. CONCLUSIONS: Households affected by tuberculosis also face multiple other health challenges. Integrated approaches to tuberculosis screening may represent an opportunity for identification and treatment, including prioritisation of individuals at highest risk for tuberculosis to receive preventive therapy.

How much should we still worry about QTc prolongation in rifampicin-resistant tuberculosis? ECG findings from TB-PRACTECAL clinical trial.

Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25-21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT02589782.

Multicomponent Strategy with Decentralized Molecular Testing for Tuberculosis.

BACKGROUND: Effective strategies are needed to facilitate the prompt diagnosis and treatment of tuberculosis in countries with a high burden of the disease. METHODS: We conducted a cluster-randomized trial in which Ugandan community health centers were assigned to a multicomponent diagnostic strategy (on-site molecular testing for tuberculosis, guided restructuring of clinic workflows, and monthly feedback of quality metrics) or routine care (on-site sputum-smear microscopy and referral-based molecular testing). The primary outcome was the number of adults treated for confirmed tuberculosis within 14 days after presenting to the health center for evaluation during the 16-month intervention period. Secondary outcomes included completion of tuberculosis testing, same-day diagnosis, and same-day treatment. Outcomes were also assessed on the basis of proportions. RESULTS: A total of 20 health centers underwent randomization, with 10 assigned to each group. Of 10,644 eligible adults (median age, 40 years) whose data were evaluated, 60.1% were women and 43.8% had human immunodeficiency virus infection. The intervention strategy led to a greater number of patients being treated for confirmed tuberculosis within 14 days after presentation (342 patients across 10 intervention health centers vs. 220 across 10 control health centers; adjusted rate ratio, 1.56; 95% confidence interval [CI], 1.21 to 2.01). More patients at intervention centers than at control centers completed tuberculosis testing (adjusted rate ratio, 1.85; 95% CI, 1.21 to 2.82), received a same-day diagnosis (adjusted rate ratio, 1.89; 95% CI, 1.39 to 2.56), and received same-day treatment for confirmed tuberculosis (adjusted rate ratio, 2.38; 95% CI, 1.57 to 3.61). Among 706 patients with confirmed tuberculosis, a higher proportion in the intervention group than in the control group were treated on the same day (adjusted rate ratio, 2.29; 95% CI, 1.23 to 4.25) or within 14 days after presentation (adjusted rate ratio, 1.22; 95% CI, 1.06 to 1.40). CONCLUSIONS: A multicomponent diagnostic strategy that included on-site molecular testing plus implementation supports to address barriers to delivery of high-quality tuberculosis evaluation services led to greater numbers of patients being tested, receiving a diagnosis, and being treated for confirmed tuberculosis. (Funded by the National Heart, Lung, and Blood Institute; XPEL-TB ClinicalTrials.gov number, NCT03044158.).

Assessing efficacy in non-inferiority trials with non-adherence to interventions: Are intention-to-treat and per-protocol analyses fit for purpose?

BACKGROUND: Non-inferiority trials comparing different active drugs are often subject to treatment non-adherence. Intention-to-treat (ITT) and per-protocol (PP) analyses have been advocated in such studies but are not guaranteed to be unbiased in the presence of differential non-adherence. METHODS: The REMoxTB trial evaluated two 4-month experimental regimens compared with a 6-month control regimen for newly diagnosed drug-susceptible TB. The primary endpoint was a composite unfavorable outcome of treatment failure or recurrence within 18 months post-randomization. We conducted a simulation study based on REMoxTB to assess the performance of statistical methods for handling non-adherence in non-inferiority trials, including: ITT and PP analyses, adjustment for observed adherence, multiple imputation (MI) of outcomes, inverse-probability-of-treatment weighting (IPTW), and a doubly-robust (DR) estimator. RESULTS: When non-adherence differed between trial arms, ITT, and PP analyses often resulted in non-trivial bias in the estimated treatment effect, which consequently under- or over-inflated the type I error rate. Adjustment for observed adherence led to similar issues, whereas the MI, IPTW and DR approaches were able to correct bias under most non-adherence scenarios; they could not always eliminate bias entirely in the presence of unobserved confounding. The IPTW and DR methods were generally unbiased and maintained desired type I error rates and statistical power. CONCLUSIONS: When non-adherence differs between trial arms, ITT and PP analyses can produce biased estimates of efficacy, potentially leading to the acceptance of inferior treatments or efficacious regimens being missed. IPTW and the DR estimator are relatively straightforward methods to supplement ITT and PP approaches.

Experience of social harms among female sex workers following HIV self-test distribution in Malawi: results of a cohort study.

BACKGROUND: In Malawi, female sex workers (FSW) have high HIV incidence and regular testing is suggested. HIV self-testing (HIVST) is a safe and acceptable alternative to standard testing services. This study assessed; whether social harms were more likely to be reported after HIVST distribution to FSW by peer distributors than after facility-based HIV testing and whether FSW regretted HIVST use or experienced associated relationship problems. METHODS: Peer HIVST distributors, who were FSW, were recruited in Blantyre district, Malawi between February and July 2017. Among HIVST recipients a prospective cohort was recruited. Interviews were conducted at baseline and at end-line, 3 months later. Participants completed daily sexual activity diaries. End-line data were analysed using logistic regression to assess whether regret or relationship problems were associated with HIVST use. Sexual activity data were analysed using Generalised Estimating Equations to assess whether HIVST use was temporally associated with an increase in social harms. RESULTS: Of 265 FSW recruited and offered HIVST, 131 completed both interviews. Of these, 31/131(23.7%) reported initial regret after HIVST use, this reduced to 23/131(17.6%) at the 3-month follow-up. Relationship problems were reported by 12/131(9.2%). Regret about HIVST use was less commonly reported in those aged 26-35 years compared to those aged 16-25 years (OR immediate regret-0.40 95% CI 0.16-1.01) (OR current regret-0.22 95% CI 0.07 - 0.71) and was not associated with the HIVST result. There was limited evidence that reports of verbal abuse perpetrated by clients in the week following HIVST use were greater than when there was no testing in the preceding week. There was no evidence for increases in any other social harms. There was some evidence of coercion to test, most commonly initiated by the peer distributor. CONCLUSIONS: Little evidence was found that the peer distribution model was associated with increased levels of social harms, however programmes aimed at reaching FSW need to carefully consider possible unintended consequences of their service delivery approaches, including the potential for peer distributors to coerce individuals to test or disclose their test results and alternative distribution models may need to be considered.

Forgiveness Is the Attribute of the Strong: Nonadherence and Regimen Shortening in Drug-sensitive Tuberculosis.

Rationale: "Forgiveness" charts the ability of a drug or regimen to withstand nonadherence without negative clinical consequences. Objectives: We aimed to determine the influence of regimen length, regimen drugs, and dosing, and when during treatment nonadherence occurs on the forgiveness of antituberculosis regimens. Methods: Using data from three randomized controlled trials comparing experimental 4-month regimens for drug-sensitive tuberculosis with the standard 6-month regimen, we used generalized linear models to examine how the risk of a negative composite outcome changed as dose-taking decreased. The percentage of doses taken and the absolute number of doses missed were calculated during the intensive and continuation phases of treatment, and overall. A mediation analysis was undertaken to determine how much the association between intensive phase dose-taking and the negative composite outcome was mediated through continuation phase dose-taking. Measurements and Main Results: Forgiveness of the 4- and 6-month regimens did not differ for any treatment period. Importantly, 4-month regimens were no less forgiving of small numbers of absolute missed doses than the 6-month regimen (e.g., for 3-7 missed doses vs. no missed doses [baseline], 6-month regimen adjusted risk ratio 1.65 [95% confidence interval, 0.80-3.41] and 4-month regimens 1.80 [1.33-2.45]). No 4-month regimen was conclusively more forgiving than another. We found evidence of mediation by continuation phase dose-taking on the intensive phase dose-taking and negative composite outcome relationship. Conclusions: With the current appetite for, and progress toward, shorter drug-sensitive tuberculosis regimens worldwide, we offer reassurance that shorter regimens are not necessarily less forgiving of nonadherence. Given the importance of continuation phase adherence, patient support during this period should not be neglected.

Impact of Community-Wide Tuberculosis Active Case Finding and Human Immunodeficiency Virus Testing on Tuberculosis Trends in Malawi.

BACKGROUND: Tuberculosis case-finding interventions are critical to meeting World Health Organization End TB strategy goals. We investigated the impact of community-wide tuberculosis active case finding (ACF) alongside scale-up of human immunodeficiency virus (HIV) testing and care on trends in adult tuberculosis case notification rates (CNRs) in Blantyre, Malawi. METHODS: Five rounds of ACF for tuberculosis (1-2 weeks of leafleting, door-to-door enquiry for cough and sputum microscopy) were delivered to neighborhoods ("ACF areas") in North-West Blantyre between April 2011 and August 2014. Many of these neighborhoods also had concurrent HIV testing interventions. The remaining neighborhoods in Blantyre City ("non-ACF areas") provided a non-randomized comparator. We analyzed TB CNRs from January 2009 until December 2018. We used interrupted time series analysis to compare tuberculosis CNRs before ACF and after ACF, and between ACF and non-ACF areas. RESULTS: Tuberculosis CNRs increased in Blantyre concurrently with start of ACF for tuberculosis in both ACF and non-ACF areas, with a larger magnitude in ACF areas. Compared to a counterfactual where pre-ACF CNR trends continued during ACF period, we estimated there were an additional 101 (95% confidence interval [CI] 42 to 160) microbiologically confirmed (Bac+) tuberculosis diagnoses per 100 000 person-years in the ACF areas in 3 and a half years of ACF. Compared to a counterfactual where trends in ACF area were the same as trends in non-ACF areas, we estimated an additional 63 (95% CI 38 to 90) Bac + diagnoses per 100 000 person-years in the same period. CONCLUSIONS: Tuberculosis ACF was associated with a rapid increase in people diagnosed with tuberculosis in Blantyre.

Handling intercurrent events and missing data in non-inferiority trials using the estimand framework: A tuberculosis case study.

INTRODUCTION: The ICH E9 addendum outlining the estimand framework for clinical trials was published in 2019 but provides limited guidance around how to handle intercurrent events for non-inferiority studies. Once an estimand is defined, it is also unclear how to deal with missing values using principled analyses for non-inferiority studies. METHODS: Using a tuberculosis clinical trial as a case study, we propose a primary estimand, and an additional estimand suitable for non-inferiority studies. For estimation, multiple imputation methods that align with the estimands for both primary and sensitivity analysis are proposed. We demonstrate estimation methods using the twofold fully conditional specification multiple imputation algorithm and then extend and use reference-based multiple imputation for a binary outcome to target the relevant estimands, proposing sensitivity analyses under each. We compare the results from using these multiple imputation methods with those from the original study. RESULTS: Consistent with the ICH E9 addendum, estimands can be constructed for a non-inferiority trial which improves on the per-protocol/intention-to-treat-type analysis population previously advocated, involving respectively a hypothetical or treatment policy strategy to handle relevant intercurrent events. Results from using the 'twofold' multiple imputation approach to estimate the primary hypothetical estimand, and using reference-based methods for an additional treatment policy estimand, including sensitivity analyses to handle the missing data, were consistent with the original study's reported per-protocol and intention-to-treat analysis in failing to demonstrate non-inferiority. CONCLUSIONS: Using carefully constructed estimands and appropriate primary and sensitivity estimators, using all the information available, results in a more principled and statistically rigorous approach to analysis. Doing so provides an accurate interpretation of the estimand.

A qualitative exploration into the presence of TB stigmatization across three districts in South Africa.

BACKGROUND: Tuberculosis (TB) stigma is a barrier to active case finding and delivery of care in fighting the TB epidemic. As part of a project exploring different models for delivery of TB contact tracing, we conducted a qualitative analysis to explore the presence of TB stigma within communities across South Africa. METHODS: We conducted 43 in-depth interviews with 31 people with TB and 12 household contacts as well as five focus group discussions with 40 ward-based team members and 11 community stakeholders across three South African districts. RESULTS: TB stigma is driven and facilitated by fear of disease coupled with an understanding of TB/HIV duality and manifests as anticipated and internalized stigma. Individuals are marked with TB stigma verbally through gossip and visually through symptomatic identification or when accessing care in either TB-specific areas in health clinics or though ward-based outreach teams. Individuals' unique understanding of stigma influences how they seek care. CONCLUSION: TB stigma contributes to suboptimal case finding and care at the community level in South Africa. Interventions to combat stigma, such as community and individual education campaigns on TB treatment and transmission as well as the training of health care workers on stigma and stigmatization are needed to prevent discrimination and protect patient confidentiality.

Risk factors for poor engagement with a smart pillbox adherence intervention among persons on tuberculosis treatment in Ethiopia.

BACKGROUND: Non-adherence to tuberculosis treatment increases the risk of poor treatment outcomes. Digital adherence technologies (DATs), including the smart pillbox (EvriMED), aim to improve treatment adherence and are being widely evaluated. As part of the Adherence Support Coalition to End TB (ASCENT) project we analysed data from a cluster-randomised trial of DATs and differentiated care in Ethiopia to examine individual-factors for poor engagement with the smart pillbox. METHODS: Data were obtained from a cohort of trial participants with drug-sensitive tuberculosis (DS-TB) whose treatment started between 1 December 2020 and 1 May 2022, and who were using the smart pillbox. Poor engagement with the pillbox was defined as (i) > 20% days with no digital confirmation and (ii) the count of days with no digital confirmation, and calculated over a two evaluation periods (56-days and 168-days). Logistic random effects regression was used to model > 20% days with no digital confirmation and negative binomial random effects regression to model counts of days with no digital confirmation, both accounting for clustering of individuals at the facility-level. RESULTS: Among 1262 participants, 10.8% (133/1262) over 56-days and 15.8% (200/1262) over 168-days had > 20% days with no digital confirmation. The odds of poor engagement was less among participants in the higher stratum of socio-economic position (SEP) over 56-days. Overall, 4,689/67,315 expected doses over 56-days and 18,042/199,133 expected doses over 168-days were not digitally confirmed. Compared to participants in the poorest SEP stratum, participants in the wealthiest stratum had lower rates of days not digitally confirmed over 168-days (adjusted rate ratio [RRa]:0.79; 95% confidence interval [CI]: 0.65, 0.96). In both evaluation periods (56-days and 168-days), HIV-positive status (RRa:1.29; 95%CI: 1.02, 1.63 and RRa:1.28; 95%CI: 1.07, 1.53), single/living independent (RRa:1.31; 95%CI: 1.03, 1.67 and RRa:1.38; 95%CI: 1.16, 1.64) and separated/widowed (RRa:1.40; 95%CI: 1.04, 1.90 and RRa:1.26; 95%CI: 1.00, 1.58) had higher rates of counts of days with no digital confirmation. CONCLUSION: Poorest SEP stratum, HIV-positive status, single/living independent and separated/ widowed were associated with poor engagement with smart pillbox among people with DS-TB in Ethiopia. Differentiated care for these sub-groups may reduce risk of non-adherence to TB treatment.

Cluster randomised trials with a binary outcome and a small number of clusters: comparison of individual and cluster level analysis method.

BACKGROUND: Cluster randomised trials (CRTs) are often designed with a small number of clusters, but it is not clear which analysis methods are optimal when the outcome is binary. This simulation study aimed to determine (i) whether cluster-level analysis (CL), generalised linear mixed models (GLMM), and generalised estimating equations with sandwich variance (GEE) approaches maintain acceptable type-one error including the impact of non-normality of cluster effects and low prevalence, and if so (ii) which methods have the greatest power. We simulated CRTs with 8-30 clusters, altering the cluster-size, outcome prevalence, intracluster correlation coefficient, and cluster effect distribution. We analysed each dataset with weighted and unweighted CL; GLMM with adaptive quadrature and restricted pseudolikelihood; GEE with Kauermann-and-Carroll and Fay-and-Graubard sandwich variance using independent and exchangeable working correlation matrices. P-values were from a t-distribution with degrees of freedom (DoF) as clusters minus cluster-level parameters; GLMM pseudolikelihood also used Satterthwaite and Kenward-Roger DoF. RESULTS: Unweighted CL, GLMM pseudolikelihood, and Fay-and-Graubard GEE with independent or exchangeable working correlation matrix controlled type-one error in > 97% scenarios with clusters minus parameters DoF. Cluster-effect distribution and prevalence of outcome did not usually affect analysis method performance. GEE had the least power. With 20-30 clusters, GLMM had greater power than CL with varying cluster-size but similar power otherwise; with fewer clusters, GLMM had lower power with common cluster-size, similar power with medium variation, and greater power with large variation in cluster-size. CONCLUSION: We recommend that CRTs with ≤ 30 clusters and a binary outcome use an unweighted CL or restricted pseudolikelihood GLMM both with DoF clusters minus cluster-level parameters.

Annual Tuberculosis Preventive Therapy for Persons With HIV Infection : A Randomized Trial.

BACKGROUND: Tuberculosis preventive therapy for persons with HIV infection is effective, but its durability is uncertain. OBJECTIVE: To compare treatment completion rates of weekly isoniazid-rifapentine for 3 months versus daily isoniazid for 6 months as well as the effectiveness of the 3-month rifapentine-isoniazid regimen given annually for 2 years versus once. DESIGN: Randomized trial. (ClinicalTrials.gov: NCT02980016). SETTING: South Africa, Ethiopia, and Mozambique. PARTICIPANTS: Persons with HIV infection who were receiving antiretroviral therapy, were aged 2 years or older, and did not have active tuberculosis. INTERVENTION: Participants were randomly assigned to receive weekly rifapentine-isoniazid for 3 months, given either annually for 2 years or once, or daily isoniazid for 6 months. Participants were screened for tuberculosis symptoms at months 0 to 3 and 12 of each study year and at months 12 and 24 using chest radiography and sputum culture. MEASUREMENTS: Treatment completion was assessed using pill counts. Tuberculosis incidence was measured over 24 months. RESULTS: Between November 2016 and November 2017, 4027 participants were enrolled; 4014 were included in the analyses (median age, 41 years; 69.5% women; all using antiretroviral therapy). Treatment completion in the first year for the combined rifapentine-isoniazid groups (n = 3610) was 90.4% versus 50.5% for the isoniazid group (n = 404) (risk ratio, 1.78 [95% CI, 1.61 to 1.95]). Tuberculosis incidence among participants receiving the rifapentine-isoniazid regimen twice (n = 1808) or once (n = 1802) was similar (hazard ratio, 0.96 [CI, 0.61 to 1.50]). LIMITATION: If rifapentine-isoniazid is effective in curing subclinical tuberculosis, then the intensive tuberculosis screening at month 12 may have reduced its effectiveness. CONCLUSION: Treatment completion was higher with rifapentine-isoniazid for 3 months compared with isoniazid for 6 months. In settings with high tuberculosis transmission, a second round of preventive therapy did not provide additional benefit to persons receiving antiretroviral therapy. PRIMARY FUNDING SOURCE: The U.S. Agency for International Development through the CHALLENGE TB grant to the KNCV Tuberculosis Foundation.

Evidence for the Use of Triage, Respiratory Isolation, and Effective Treatment to Reduce the Transmission of Mycobacterium Tuberculosis in Healthcare Settings: A Systematic Review.

Evidence is limited for infection prevention and control (IPC) measures reducing Mycobacterium tuberculosis (MTB) transmission in health facilities. This systematic review, 1 of 7 commissioned by the World Health Organization to inform the 2019 update of global tuberculosis (TB) IPC guidelines, asked: do triage and/or isolation and/or effective treatment of TB disease reduce MTB transmission in healthcare settings? Of 25 included articles, 19 reported latent TB infection (LTBI) incidence in healthcare workers (HCWs; absolute risk reductions 1%-21%); 5 reported TB disease incidence in HCWs (no/slight [high TB burden] or moderate [low burden] reduction) and 2 in human immunodeficiency virus-positive in-patients (6%-29% reduction). In total, 23/25 studies implemented multiple IPC measures; effects of individual measures could not be disaggregated. Packages of IPC measures appeared to reduce MTB transmission, but evidence for effectiveness of triage, isolation, or effective treatment, alone or in combination, was indirect and low quality. Harmonizing study designs and reporting frameworks will permit formal data syntheses and facilitate policy making.

Cost-effectiveness of a Novel Lipoarabinomannan Test for Tuberculosis in Patients With Human Immunodeficiency Virus.

BACKGROUND: A novel urine lipoarabinomannan assay (FujiLAM) has higher sensitivity and higher cost than the first-generation AlereLAM assay. We evaluated the cost-effectiveness of FujiLAM for tuberculosis testing among hospitalized people with human immunodeficiency virus (HIV), irrespective of symptoms. METHODS: We used a microsimulation model to project clinical and economic outcomes of 3 testing strategies: (1) sputum Xpert MTB/RIF (Xpert), (2) sputum Xpert plus urine AlereLAM (Xpert+AlereLAM), (3) sputum Xpert plus urine FujiLAM (Xpert+FujiLAM). The modeled cohort matched that of a 2-country clinical trial. We applied diagnostic yields from a retrospective study (yields for Xpert/Xpert+AlereLAM/Xpert+FujiLAM among those with CD4 <200 cells/µL: 33%/62%/70%; among those with CD4 ≥200 cells/µL: 33%/35%/47%). Costs of Xpert/AlereLAM/FujiLAM were US$15/3/6 (South Africa) and $25/3/6 (Malawi). Xpert+FujiLAM was considered cost-effective if its incremental cost-effectiveness ratio (US$/year-of-life saved) was <$940 (South Africa) and <$750 (Malawi). We varied key parameters in sensitivity analysis and performed a budget impact analysis of implementing FujiLAM countrywide. RESULTS: Compared with Xpert+AlereLAM, Xpert+FujiLAM increased life expectancy by 0.2 years for those tested in South Africa and Malawi. Xpert+FujiLAM was cost-effective in both countries. Xpert+FujiLAM for all patients remained cost-effective compared with sequential testing and CD4-stratified testing strategies. FujiLAM use added 3.5% (South Africa) and 4.7% (Malawi) to 5-year healthcare costs of tested patients, primarily reflecting ongoing HIV treatment costs among survivors. CONCLUSIONS: FujiLAM with Xpert for tuberculosis testing in hospitalized people with HIV is likely to increase life expectancy and be cost-effective at the currently anticipated price in South Africa and Malawi. Additional studies should evaluate FujiLAM in clinical practice settings.

Effect of community-led delivery of HIV self-testing on HIV testing and antiretroviral therapy initiation in Malawi: A cluster-randomised trial.

BACKGROUND: Undiagnosed HIV infection remains substantial in key population subgroups including adolescents, older adults, and men, driving ongoing transmission in sub-Saharan Africa. We evaluated the impact, safety, and costs of community-led delivery of HIV self-testing (HIVST), aiming to increase HIV testing in underserved subgroups and stimulate demand for antiretroviral therapy (ART). METHODS AND FINDINGS: This cluster-randomised trial, conducted between October 2018 and July 2019, used restricted randomisation (1:1) to allocate 30 group village head clusters in Mangochi district, Malawi to the community-led HIVST intervention in addition to the standard of care (SOC) or the SOC alone. The intervention involved mobilising community health groups to lead the design and implementation of 7-day HIVST campaigns, with cluster residents (≥15 years) eligible for HIVST. The primary outcome compared lifetime HIV testing among adolescents (15 to 19 years) between arms. Secondary outcomes compared: recent HIV testing (in the last 3 months) among older adults (≥40 years) and men; cumulative 6-month incidence of ART initiation per 100,000 population; knowledge of the preventive benefits of HIV treatment; and HIV testing stigma. Outcomes were measured through a post-intervention survey and at neighboring health facilities. Analysis used intention-to-treat for cluster-level outcomes. Community health groups delivered 24,316 oral fluid-based HIVST kits. The survey included 90.2% (3,960/4,388) of listed participants in the 15 community-led HIVST clusters and 89.2% (3,920/4,394) of listed participants in the 15 SOC clusters. Overall, the proportion of men was 39.0% (3,072/7,880). Most participants obtained primary-level education or below, were married, and reported a sexual partner. Lifetime HIV testing among adolescents was higher in the community-led HIVST arm (84.6%, 770/910) than the SOC arm (67.1%, 582/867; adjusted risk difference [RD] 15.2%, 95% CI 7.5% to 22.9%; p < 0.001), especially among 15 to 17 year olds and boys. Recent testing among older adults was also higher in the community-led HIVST arm (74.5%, 869/1,166) than the SOC arm (31.5%, 350/1,111; adjusted RD 42.1%, 95% CI 34.9% to 49.4%; p < 0.001). Similarly, the proportions of recently tested men were 74.6% (1,177/1,577) and 33.9% (507/1,495) in the community-led HIVST and SOC arms, respectively (adjusted RD 40.2%, 95% CI 32.9% to 47.4%; p < 0.001). Knowledge of HIV treatment benefits and HIV testing stigma showed no differences between arms. Cumulative incidence of ART initiation was respectively 305.3 and 226.1 per 100,000 population in the community-led HIVST and SOC arms (RD 72.3, 95% CI -36.2 to 180.8; p = 0.18). In post hoc analysis, ART initiations in the 3-month post-intervention period were higher in the community-led HIVST arm than the SOC arm (RD 97.7, 95% CI 33.4 to 162.1; p = 0.004). HIVST uptake was 74.7% (2,956/3,960), with few adverse events (0.6%, 18/2,955) and at US$5.70 per HIVST kit distributed. The main limitations include the use of self-reported HIV testing outcomes and lack of baseline measurement for the primary outcome. CONCLUSIONS: In this study, we found that community-led HIVST was effective, safe, and affordable, with population impact and coverage rapidly realised at low cost. This approach could enable community HIV testing in high HIV prevalence settings and demonstrates potential for economies of scale and scope. TRIAL REGISTRATION: Clinicaltrials.gov NCT03541382.

Dynamics of sputum conversion during effective tuberculosis treatment: A systematic review and meta-analysis.

BACKGROUND: Two weeks' isolation is widely recommended for people commencing treatment for pulmonary tuberculosis (TB). The evidence that this corresponds to clearance of potentially infectious tuberculous mycobacteria in sputum is not well established. This World Health Organization-commissioned review investigated sputum sterilisation dynamics during TB treatment. METHODS AND FINDINGS: For the main analysis, 2 systematic literature searches of OvidSP MEDLINE, Embase, and Global Health, and EBSCO CINAHL Plus were conducted to identify studies with data on TB infectiousness (all studies to search date, 1 December 2017) and all randomised controlled trials (RCTs) for drug-susceptible TB (from 1 January 1990 to search date, 20 February 2018). Included articles reported on patients receiving effective treatment for culture-confirmed drug-susceptible pulmonary TB. The outcome of interest was sputum bacteriological conversion: the proportion of patients having converted by a defined time point or a summary measure of time to conversion, assessed by smear or culture. Any study design with 10 or more particpants was considered. Record sifting and data extraction were performed in duplicate. Random effects meta-analyses were performed. A narrative summary additionally describes the results of a systematic search for data evaluating infectiousness from humans to experimental animals (PubMed, all studies to 27 March 2018). Other evidence on duration of infectiousness-including studies reporting on cough dynamics, human tuberculin skin test conversion, or early bactericidal activity of TB treatments-was outside the scope of this review. The literature search was repeated on 22 November 2020, at the request of the editors, to identify studies published after the previous censor date. Four small studies reporting 3 different outcome measures were identified, which included no data that would alter the findings of the review; they are not included in the meta-analyses. Of 5,290 identified records, 44 were included. Twenty-seven (61%) were RCTs and 17 (39%) were cohort studies. Thirteen studies (30%) reported data from Africa, 12 (27%) from Asia, 6 (14%) from South America, 5 (11%) from North America, and 4 (9%) from Europe. Four studies reported data from multiple continents. Summary estimates suggested smear conversion in 9% of patients at 2 weeks (95% CI 3%-24%, 1 single study [N = 1]), and 82% of patients at 2 months of treatment (95% CI 78%-86%, N = 10). Among baseline smear-positive patients, solid culture conversion occurred by 2 weeks in 5% (95% CI 0%-14%, N = 2), increasing to 88% at 2 months (95% CI 84%-92%, N = 20). At equivalent time points, liquid culture conversion was achieved in 3% (95% CI 1%-16%, N = 1) and 59% (95% CI 47%-70%, N = 8). Significant heterogeneity was observed. Further interrogation of the data to explain this heterogeneity was limited by the lack of disaggregation of results, including by factors such as HIV status, baseline smear status, and the presence or absence of lung cavitation. CONCLUSIONS: This systematic review found that most patients remained culture positive at 2 weeks of TB treatment, challenging the view that individuals are not infectious after this interval. Culture positivity is, however, only 1 component of infectiousness, with reduced cough frequency and aerosol generation after TB treatment initiation likely to also be important. Studies that integrate our findings with data on cough dynamics could provide a more complete perspective on potential transmission of Mycobacterium tuberculosis by individuals on treatment. TRIAL REGISTRATION: Systematic review registration: PROSPERO 85226.

Derivation and external validation of a risk score for predicting HIV-associated tuberculosis to support case finding and preventive therapy scale-up: A cohort study.

BACKGROUND: Among people living with HIV (PLHIV), more flexible and sensitive tuberculosis (TB) screening tools capable of detecting both symptomatic and subclinical active TB are needed to (1) reduce morbidity and mortality from undiagnosed TB; (2) facilitate scale-up of tuberculosis preventive therapy (TPT) while reducing inappropriate prescription of TPT to PLHIV with subclinical active TB; and (3) allow for differentiated HIV-TB care. METHODS AND FINDINGS: We used Botswana XPRES trial data for adult HIV clinic enrollees collected during 2012 to 2015 to develop a parsimonious multivariable prognostic model for active prevalent TB using both logistic regression and random forest machine learning approaches. A clinical score was derived by rescaling final model coefficients. The clinical score was developed using southern Botswana XPRES data and its accuracy validated internally, using northern Botswana data, and externally using 3 diverse cohorts of antiretroviral therapy (ART)-naive and ART-experienced PLHIV enrolled in XPHACTOR, TB Fast Track (TBFT), and Gugulethu studies from South Africa (SA). Predictive accuracy of the clinical score was compared with the World Health Organization (WHO) 4-symptom TB screen. Among 5,418 XPRES enrollees, 2,771 were included in the derivation dataset; 67% were female, median age was 34 years, median CD4 was 240 cells/µL, 189 (7%) had undiagnosed prevalent TB, and characteristics were similar between internal derivation and validation datasets. Among XPHACTOR, TBFT, and Gugulethu cohorts, median CD4 was 400, 73, and 167 cells/µL, and prevalence of TB was 5%, 10%, and 18%, respectively. Factors predictive of TB in the derivation dataset and selected for the clinical score included male sex (1 point), ≥1 WHO TB symptom (7 points), smoking history (1 point), temperature >37.5°C (6 points), body mass index (BMI) <18.5kg/m2 (2 points), and severe anemia (hemoglobin <8g/dL) (3 points). Sensitivity using WHO 4-symptom TB screen was 73%, 80%, 94%, and 94% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, but increased to 88%, 87%, 97%, and 97%, when a clinical score of ≥2 was used. Negative predictive value (NPV) also increased 1%, 0.3%, 1.6%, and 1.7% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, when the clinical score of ≥2 replaced WHO 4-symptom TB screen. Categorizing risk scores into low (<2), moderate (2 to 10), and high-risk categories (>10) yielded TB prevalence of 1%, 1%, 2%, and 6% in the lowest risk group and 33%, 22%, 26%, and 32% in the highest risk group for XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively. At clinical score ≥2, the number needed to screen (NNS) ranged from 5.0 in Gugulethu to 11.0 in XPHACTOR. Limitations include that the risk score has not been validated in resource-rich settings and needs further evaluation and validation in contemporary cohorts in Africa and other resource-constrained settings. CONCLUSIONS: The simple and feasible clinical score allowed for prioritization of sensitivity and NPV, which could facilitate reductions in mortality from undiagnosed TB and safer administration of TPT during proposed global scale-up efforts. Differentiation of risk by clinical score cutoff allows flexibility in designing differentiated HIV-TB care to maximize impact of available resources.