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Tuberculosis (TB) is the leading cause of death from a single infectious agent. The burden is highest in some low- and middle-income countries. One-quarter of the world's population is estimated to have been infected with TB, which is the seedbed for progressing from TB infection to the deadly and contagious disease itself. Although some individuals may clear their infections through innate and acquired immunity, many do not. People living with HIV, TB-exposed household contacts, other individuals recently infected, and immunosuppressed individuals are at especially high risk of progressing to TB disease. There have been major advances in recent years to support the programmatic management of TB infection. New tests of infection, including those that predict progression to TB disease, have become available. Numerous World Health Organization-recommended TB preventive treatment (TPT) regimens are available for all ages and for both drug-susceptible and drug-resistant TB infection. All regimens are generally safe, efficacious, and cost effective and have a low risk of generating resistance. TPT is recommended for pregnant women who are at risk for developing TB, but some regimens are associated with an increased likelihood of poor obstetric and fetal outcomes, and newer regimens have not yet been tested in pregnancy. New formulations of rifapentine-based TPT have been developed, and the cost has been radically reduced. Innovative models of delivery to support the scale up of TPT have been developed. Modeling suggests that scaling up TPT, especially regimens with optimal target product profile characteristics, can contribute substantially to ending the TB epidemic. The global uptake of TPT has increased substantially, especially for people living with HIV. Implementation gaps remain, particularly for children, pregnant women, and other household contacts. Further innovation is required to support the continued scale up of TPT and to contribute to ending the TB epidemic., Competing Interests: Declarations. Funding: GC and VC were supported by Unitaid through the IMPAACT4TB project (2017-20-IMPAACT4TB). GC is supported by an NIH grant UM1AI068636 for the PHOENIx MDR TB trial. REC was supported by Unitaid through the IMPAACT4TB project (2017-20-IMPAACT4TB) and NIH grant P30AI18436. KED is supported by NIH/NIAID K24AI150349. MG, AG, NSA, TR, CJH, SL, JSM, and VM have not received funding. Conflict of interest: VC, MG, AG, NSA, TR, CJM, JSM, VM, and KED have no relevant financial or non-financial interests to disclose. SML is funded by Merck through her institution for C19-related research and declares UpToDate—royalties for a chapter on TB infection in pregnancy. REC’s spouse owns stock in Merck. RC and GC have consulted for Johnson & Johnson. Availability of data and material: No data are available as this was a review. Ethics approval: Not applicable. The manuscript is a review and does not report results of a study that involved human participants, their data, or biological material. Consent for publication: Not applicable. The manuscript does not contain identifiable patient data. Consent for publication: Not applicable. The article does not contain clinical photos of patients or patient data that could be identifiable. Author contributions: VC and GC conceptualized and designed the outline of the paper. All authors (VC, MG, AG, NSA, TR, CJM, SL, JSM, VM, KED, REC, GC) contributed to specific sections of the manuscript and reviewed the paper. All authors read and approved the final version., (© 2024. The Author(s).)

Rationale: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/AIDS Clinical Trials Group A5349 represents the largest phase 3 randomized controlled therapeutic trial to date for such an investigation. Objectives: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure and efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits. Methods: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome. Measurements and Main Results: Among 2,255 participants with 6,978 plasma samples, pyrazinamide displayed sevenfold exposure variability (151-1,053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in therapeutic windows of 231-355 mg · h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1,000 mg would have permitted an additional 13.1% ( n  = 96) of participants allocated to the control and 9.2% ( n  = 70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared with the current weight-banded dosing. Conclusions: Flat dosing of pyrazinamide at 1,000 mg/d would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registered with www.clinicaltrials.gov (NCT02410772).

Objectives: Worldwide, adult men experience an excess burden of tuberculosis (TB) disease compared with women, but few studies have examined sex differences in TB among people with HIV. In this study, we aimed to investigate sex differences in TB infection and disease among people with HIV in Rio de Janeiro, Brazil., Design: Analysis of data from a randomized controlled trial and retrospective cohort study., Methods: We analyzed data from two studies conducted between 2005 and 2017. The THRio Study (2005-2012) evaluated increasing tuberculin skin testing (TST) and TB preventive therapy (TPT), and Universal ART in Rio study (UnivART; 2010-2017) was a virtual cohort study of people with HIV and TB with data from four national electronic registries., Results: Among 4606 people with HIV in THRio, 2992 (65.0%) had a TST placed and read, of whom 312 of 1865 (17%) males and 203 of 1127 (18%) females ( P  = 0.37) had prevalent TB infection. TB disease incidence was higher among males compared with females overall [IRR 1.33, 95% confidence interval (95% CI) 1.04-1.69], among males compared with females who did not receive TPT [incidence rate ratios (IRR) 1.30, 95% CI 1.01-1.67], and among males compared with females on ART (IRR 1.64, 95% CI 1.17-2.29). Among 54 957 people with HIV in UnivART, TB disease incidence rates were higher among males than females overall (IRR 1.28, 95% CI 1.18-1.39), among males compared with females on ART (IRR 1.58, 95% CI 1.40-1.77), and among males compared with females not on ART (IRR 1.11, 95% CI 0.99-1.25)., Conclusion: In this medium TB and HIV burden setting, TB disease incidence was higher among males than females with HIV, despite similar prevalence of TB infection., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54-0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07-1.91; extensive disease: HR 2.02, 95%CI 1.07-3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment., (© 2024. The Author(s).)

Background: Tuberculosis (TB) preventive therapy (TPT) reduces the risk of TB disease in people with human immunodeficiency virus (HIV), yet uptake has been suboptimal in many countries. We assessed whether QuantiFERON Gold In-Tube (QGIT) during routine HIV care increased TB infection (TBI) testing and TPT prescriptions., Methods: This parallel-arm, 1:1 cluster-randomized controlled trial compared the standard-of-care tuberculin skin test to QGIT in South Africa. We enrolled consenting, TPT-eligible adults diagnosed with HIV ≤30 days prior and used intention-to-treat analyses for the outcomes: proportion of patients with documented TBI results, proportion with documented TPT, and time from enrollment to outcomes., Findings: We enrolled 2232 patients across 14 clinics from November 2014 to May 2017 (58% in intervention clinics). At 24 months of follow-up, more participants in intervention clinics had TBI results (69% vs 2%, P < .001) and TPT prescriptions (45% vs 30%, P = .13) than control clinics. Controlling for baseline covariates, intervention clinics had 60% (95% confidence interval, 51-68; P < .001) more participants with TBI results and 12% (95% confidence interval, -6 to 31; P = .18) more with TPT prescriptions. Among participants with results, those in intervention clinics received results and TPT faster (intervention: median of 6 and 29 days after enrollment vs control: 21 and 54 days, respectively)., Interpretation: In this setting, QGIT in routine HIV care resulted in more patients with TBI results. Clinicians also initiated more people with HIV on TPT in QGIT intervention clinics, and did so more quickly, than the control arm., Clinical Trials Registration: NCT02119130., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Tuberculosis (TB) preventive treatment (TPT) is a long-standing recommendation for children exposed to TB but remains poorly implemented. Home-based contact management may increase access and coverage of TPT among children exposed to TB in their households., Methods: Sixty in-depth interviews were conducted with key informants including program managers, TB providers (known as TB focal persons), health extension workers and caregivers whose children had recently engaged with TB prevention services in Oromia, Ethiopia in 2021 to understand the barriers and facilitators to providing home-based TB prevention services for children aged < 15 years. Thematic content analysis was conducted including systematically coding each interview., Results: Home-based services were considered a family-centered intervention, addressing the time and financial constraints of clients. Stakeholders proposed a task-shared intervention between health extension workers and facility-based TB focal persons. They recommended that TB services be integrated into other home-based services, including HIV, nutrition, and vaccination services to reduce workload on the already overstretched health extension workers. Community awareness was considered essential to improve acceptability of home-based services and TPT in general among community members., Conclusions: Decentralization of TPT should be supported by task-sharing initiation and follow up between health extension workers and facility-based TB focal persons and integration of home-based services. Active community engagement through several existing mechanisms can help improve acceptability for both home-based interventions and TPT promotion overall for children., Trial Registration: The results presented here were from formative research related to the CHIP-TB Trial (Identifier NCT04369326) registered on April 30, 2020. This qualitative study was separately registered at NCT04494516 on 27 July 2020., (© 2024. The Author(s).)

Introduction: India's National TB Elimination Programme plans to roll out short-course TB preventive therapy (TPT) using 3 months of rifapentine and isoniazid (3HP). Understanding the feasibility and safety of children in programmatic settings is critical for widespread implementation. We present the findings of a targeted scale-up of 3HP among children and adolescents living with HIV (CALHIV) and child household contacts (>2 to <6 years) of pulmonary TB patients (CHHC)., Methods: Between December 2021 and July 2023, eligible CALHIV and CHHC participants were given weekly dosages of 3HP for 3 months at antiretroviral therapy (ART) and TB clinics, respectively, of a public hospital in Pune, India., Results: Of 97 children screened, 91 initiated 3HP (32 CALHIV and 59 CHHC). The median age of CALHIV was 14 years; 66% were male and on dolutegravir-based ART. The median age of CHHC was 4 years; 47% were males. Thirty-one (97%) CALHIV and 56 (95%) CHHC completed 3HP without dolutegravir dose adjustment. None of the child participants discontinued 3HP due to adverse events. No child participant developed TB during 1 year of follow-up post-3HP., Conclusion: Our study provides evidence of the uptake and feasibility of the planned nationwide rollout of 3HP., (© 2024 The Authors.)

Background: Evidence on implementation of three months of weekly isoniazid (H, INH) and rifapentine (P, RPT) (3HP) as a TB preventive therapy (TPT) for at-risk groups in Indian programmatic conditions is limited., Methods: A prospective demonstration study assessing scale-up, safety, and effectiveness of 3HP TPT among people living with HIV (PLHIV) in Indian programmatic settings was conducted., Results: Of 656 screened PLHIV, 502 (77%) received 3HP. Of these, 20 (4%) discontinued TPT due to toxicity,17 (3.8%) lost to follow-up, one (0.2%) had breakthrough rifampicin-sensitive TB, and 464 (92%) completed 3 HP TPT. Of 288 (57%) overall adverse events (AEs), 46 (9%) had Grade 2 or above AEs. The median time to AE was 14 days (IQR 7-42). Serious adverse events (SAEs) were reported in 9 (2%) participants; of these, 7 (78%) were not related to 3HP. No TB episodes occurred during the 1-year follow-up period., Conclusion: 3HP TPT completion rate of 92%, with few adverse events leading to 3HP discontinuation, providing evidence of the scalability and safety of 3HP TPT among PLHIV in Indian health program settings., (© 2024 The Authors.)

Background: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes., Methods: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression., Results: Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events., Conclusions: Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The association between covid-19 vaccine and menstrual disturbance is unclear., Methods: An in-person cross-sectional survey among female members ≥ 18 years enrolled in an ongoing Zero TB prospective cohort in Northern India who had received one or two doses of covid-19 vaccine was conducted to study the characteristics and association of menstrual disturbance within six months of receiving Covishield., Results: Between June 29 and September 5, 2021, 339 females ≥ 18 years of age were administered the survey. Median age was 30 (IQR: 22-39) years; 84 % were between 18 and 49 and 16 % were ≥ 50 years old. There were 152 college students, 27 healthcare workers, and 160 nuns. Forty-two women (12 %) had received one dose and 297 (88 %) had received two doses of Covishield. Overall, 66 (20 %) women reported experiencing menstrual disturbance after receiving Covishield vaccine. The problems included early menstruation: 6 % (n = 19/339); late menstruation: 4 % (n = 14/339); and heavier bleeding: 5 % (n = 17/339). Disturbances lasted for less than seven days and cycles normalized in 1-3 months. There was no post-menopausal bleeding. There was no significant difference in menstrual disturbance based on receiving one vs. two doses of Covishield (OR: 1.58; 95 % CI: 0.55-4.57; p = 0.381). History of SARS-CoV-2 infection was not associated with the development of menstrual disturbance among the vaccinees (OR: 0.63; 95 % CI: 0.24-1.73; p = 0.379). Presence of emotional disturbance at baseline (OR: 31; 95 % CI: 3.52-267; p = 0.002) or previous history of dysmenorrhea (OR: 41; 95 % CI: 8.7-196; p < 0.001) was associated with menstrual disturbance in the vaccinees, indicating their potential to confound or bias study results., Conclusion: Menstrual problems were reported by Covishield vaccinees, but they were minor and reversible within three months and do not constitute a ground for vaccine hesitancy. Studies designed to assess causal link taking care to avoid selection bias or confounding are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The inclusion of adolescents in TB drug trials is essential for the development of safe, child-friendly regimens for the prevention and treatment of TB. TB Trials Consortium Study 31/AIDS Clinical Trials Group A5349 (S31/A5349) enrolled adolescents as young as 12 years old. We assessed investigator and coordinator described facilitators and barriers to adolescent recruitment, enrollment, and retention.Interviews were conducted with six investigators from sites that enrolled adolescent participants and six investigators from non-enrolling sites. Additionally, two focus groups were conducted with study coordinators from enrolling sites and two focus groups with non-enrolling sites. Discussions were transcribed, analyzed, summarized, and summaries were reviewed by Community Research Advisors Group members and research group representatives for content validity.Investigators and coordinators attributed the successful enrollment of adolescents to the establishment and cultivation of external partnerships, flexibility to accommodate adolescents' schedules, staff engagement, recruitment from multiple locations, dedicated recruitment staff working onsite to access potential participants, creation of youth-friendly environments, and effective communications. Non-enrolling sites were mainly hindered by regulations. Suggestions for improvement in future trials focused on study planning and site preparations.Proactive partnerships and collaboration with institutions serving adolescents helped identify and reduce barriers to their inclusion in this trial..

Background: Isoniazid preventive therapy (IPT) is recommended for tuberculosis prevention yet data on the safety of first-trimester pregnancy exposure are limited., Methods: Planned secondary analysis in a TB prevention trial of adverse pregnancy outcomes among participants assigned to 9-month IPT who became pregnant during (IPT-exposed) or after (unexposed) IPT. Regression models compared binary outcomes of a composite adverse outcome (any non-live birth, excluding induced abortion); preterm delivery <37 weeks; and low birth weight <2500 g) among exposure groups. Models were adjusted for latent TB infection, maternal age, CD4 count, and antiretroviral therapy (ART)., Results: In total, 128 participants had a known pregnancy outcome; 39 IPT-exposed and 89 unexposed. At pregnancy outcome, ART use was lower in IPT-exposed (79%) than unexposed women (98%). Overall, 29 pregnancies ended in a composite adverse outcome (25 spontaneous abortions, 2 stillbirths and 2 ectopic pregnancies), 15 preterm deliveries, and 10 infants with low birth weight. IPT was associated with the composite adverse outcome adjusting for covariates at enrollment (adjusted relative risk [aRR] 1.98; 95% confidence interval [CI] 1.15, 3.41), but the effect was attenuated when adjusted for covariates at pregnancy outcome (aRR 1.47; 95% CI .84, 2.55); IPT was not associated with preterm delivery (relative risk [RR] 0.87; 95% CI .32-2.42) or low birth weight (RR 1.01; 95% CI .29, 3.56)., Conclusions: First-trimester IPT exposure was associated with nearly two-fold increased risk of fetal demise, mostly spontaneous abortion, though the association was attenuated when adjusted for covariates proximal to pregnancy outcome including ART use. Further study is needed to inform TB prevention guidelines., Competing Interests: Potential conflicts of interest. A. G. reports Advisory Board roles from NIAID and Indo-US Science and Technology Forum (IUSSTF). M. H. reports institutional research and training grants related to infectious diseases from US NIH; board membership of Botswana-Harvard Partnership through employer; spouse's research grants from NIH related to infectious diseases research. C. A. B. reports institutional grant support for clinical trials from Gilead and DNAe; consulting fees (paid to author) from National Data and Analytics Platform (NDAP), Inc.; honoraria for medical education lectures and travel support (paid to author) from International Antiviral Society–United States (IAS-USA), a non-profit medical education entity; and unpaid positions as Present of the non-profit Conference on Retroviruses and Opportunistic Infections (CROI) Foundation Board, and Secretary/Treasurer of the IAS-USA Board of Directors. R. E. C. reports spouse's stock in Merck. S. S. reports institutional research support from ViiV Healthcare and participation on a Data Safety Monitoring or Advisory board for now completed NIH coronavirus disease (COVID)-related trials. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The provision of tuberculosis-preventive therapy (TPT) to vulnerable populations is critical for global control. Shorter-course TPT regimens are highly effective and improve completion rates. Despite incorporation of 1 month of rifapentine and isoniazid into global guidelines, current US TPT guidelines do not include this as a recommended regimen, but should., Competing Interests: Potential conflicts of interest. R. E. C. reports grants to his institution from the National Institutes of Health, USAID, Unitaid, and the Pittsfield Anti-Tuberculosis Association; his spouse is a stockholder for Merck. R. E. C. was the Co-Chair and corresponding author of BRIEF-TB. S. K. reports receipt of grants from US Civilian Research & Development Foundation (Innovative modelling for predicting TB treatment outcomes in global cohorts) and RePORT India phase II (DAA3-19-65671-1), payment or honoraria from Clinical Care Options, LLC (HIV-ASSIST for Primary Care Providers: Applying an HIV Care Decision-making Tool in Primary Care), and travel support from a Conference on Retroviruses and Opportunistic Infections (CROI) 2022 New Investigator Scholarship. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: 3 months of weekly rifapentine plus isoniazid (3HP) and 4 months of daily rifampicin (4R) are recommended for tuberculosis preventive treatment. As these regimens have not been compared directly, we used individual patient data and network meta-analysis methods to compare completion, safety, and efficacy between 3HP and 4R., Methods: We conducted a network meta-analysis of individual patient data by searching PubMed for randomised controlled trials (RCTs) published between Jan 1, 2000, and Mar 1, 2019. Eligible studies compared 3HP or 4R to 6 months or 9 months of isoniazid and reported treatment completion, adverse events, or incidence of tuberculosis disease. Deidentified individual patient data from eligible studies were provided by study investigators and outcomes were harmonised. Methods for network meta-analysis were used to generate indirect adjusted risk ratios (aRRs) and risk differences (aRDs) with their 95% CIs., Findings: We included 17 572 participants from 14 countries in six trials. In the network meta-analysis, treatment completion was higher for people on 3HP than for those on 4R (aRR 1·06 [95% CI 1·02-1·10]; aRD 0·05 [95% CI 0·02-0·07]). For treatment-related adverse events leading to drug discontinuation, risks were higher for 3HP than for 4R for adverse events of any severity (aRR 2·86 [2·12-4·21]; aRD 0·03 [0·02-0·05]) and for grade 3-4 adverse events (aRR 3·46 [2·09-6·17]; aRD 0·02 [0·01-0·03]). Similar increased risks with 3HP were observed with other definitions of adverse events and were consistent across age groups. No difference in the incidence of tuberculosis disease between 3HP and 4R was found., Interpretation: In the absence of RCTs, our individual patient data network meta-analysis indicates that 3HP provided an increase in treatment completion over 4R, but was associated with a higher risk of adverse events. Although findings should be confirmed, the trade-off between completion and safety must be considered when selecting a regimen for tuberculosis preventive treatment., Funding: None., Translations: For the French and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of interests REC reports funding from Unitaid through a grant subcontract to Johns Hopkins (2017-20-IMPAACT4TB). All other authors declare no competing interests., (Copyright © 2023 World Health Organization (acting as the host organization for Unitaid). Published by Elsevier Ltd. All rights reserved. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that Unitaid or WHO endorses any specific organisation, products or services. The use of the Unitaid or WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: Each year, 1 million children develop TB resulting in over 200,000 child deaths. TB preventive treatment (TPT) is highly effective in preventing TB but remains poorly implemented for household child contacts. Home-based child contact management and TPT services may improve access to care. In this study, we aim to evaluate the effectiveness and cost-effectiveness of home-based contact management with TPT initiation in two TB high-burden African countries, Ethiopia and South Africa., Methods: This pragmatic cluster randomized trial compares home-based versus facility-based care delivery models for contact management. Thirty-six clinics with decentralized TB services (18 in Ethiopia and 18 in South Africa) were randomized in a 1:1 ratio to conduct either home-based or facility-based contact management. The study will attempt to enroll all eligible close child contacts of infectious drug-sensitive TB index patients diagnosed and treated for TB by one of the study clinics. Child TB contact management, including contact tracing, child evaluation, and TPT initiation and follow-up, will take place in the child's home for the intervention arm and at the clinic for the control arm. The primary outcome is the cluster-level ratio of the number of household child contacts less than 15 years of age in Ethiopia and less than 5 years of age in South Africa initiated on TPT per index patient, comparing the intervention to the control arm. Secondary outcomes include child contact identification and the TB prevention continuum of care. Other implementation outcomes include acceptability, feasibility, fidelity, cost, and cost-effectiveness of the intervention., Discussion: This implementation research trial will determine whether home-based contact management identifies and initiates more household child contacts on TPT than facility-based contact management., Trial Registration: NCT04369326 . Registered on April 30, 2020., (© 2023. The Author(s).)

Rationale: We developed a standardized method, possible poor treatment response (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT02410772), an open-label trial comparing two 4-month rifapentine-based regimens with a standard 6-month regimen for the treatment of pulmonary tuberculosis (TB). Objectives: We describe the use of the PPTR process and evaluate whether the goals of minimizing bias in efficacy endpoint assessment and attainment of relevant data to determine outcomes for all participants were achieved. Methods: A PPTR event was defined as the occurrence of one or more prespecified triggers. Each PPTR required initiation of a standardized evaluation process that included obtaining multiple sputum samples for microbiology. Measurements and Main Results: Among 2,343 participants with culture-confirmed drug-susceptible TB, 454 individuals (19.4%) had a total of 534 individual PPTR events, of which 76.6% were microbiological (positive smear or culture at or after 17 wk). At least one PPTR event was experienced by 92.4% (133 of 144) of participants with TB-related unfavorable outcome and between 13.8% and 14.7% of participants with favorable and not-assessable outcomes. A total of 75% of participants with TB-related unfavorable outcomes had microbiological confirmation of failure to achieve a disease-free cure. Conclusions: Standardized methodologies, such as our PPTR approach, could facilitate unbiased efficacy outcome determinations, improve discrimination between outcomes that are related and unrelated to regimen efficacy, and enhance the ability to conduct pooled analyses of contemporary trials.

BACKGROUND: Among Brazilian initiatives to scale up TB preventive therapy (TPT) are the adoption of the 3HP regimen (12 weekly doses of rifapentine and isoniazid [INH]) in 2021 and the implementation in 2018 of the TPT surveillance information system. Since then, 63% of the 76,000 eligible individuals notified completed TPT. Recommended regimens in this period were 6H, 9H (6 or 9 months of INH) and 4R (4 months of rifampicin). OBJECTIVE: To analyse the factors associated with TPT non-completion. METHODS: We analysed the cohort of TPT notifications from 2018 to 2020. Robust variance Poisson regression model was used to verify the association of TPT non-completion with sociodemographic, clinical and epidemiological variables. RESULTS: Of the 39,973 TPT notified in the study period, 8,534 (21.5%) were non-completed, of which 7,858 (92.1%) were lost to follow-up. Age 15-60 years (relative risk [RR] 1.27, 95% confidence interval [95% CI] 1.20-1.35), TPT with isoniazid (RR 1.40, 95% CI 1.19-1.64) and Black/mixed race (RR 1.17, 95% CI 1.09-1.25) were associated with a higher risk of non-completion. CONCLUSION: Individuals in situations of social and financial vulnerability such as being Black/ pardo race, younger and on longer TPT regimens were more likely to be associated with TPT incompletion.

Isoniazid pharmacokinetics are not yet well-described during once weekly, high-dose administrations with rifapentine (3HP) for latent tuberculosis infection (LTBI). Fewer data describe 3HP with dolutegravir-based antiretroviral therapy for the treatment of human immunodeficiency virus (HIV). The only prior report of 3HP with dolutegravir reported elevated isoniazid exposures. We measured the plasma isoniazid levels in 30 adults receiving 3HP and dolutegravir for the treatment of LTBI and HIV. The patients were genotyped to determine NAT2 acetylator status, and a population PK model was estimated by nonlinear mixed-effects modeling. The results were compared to previously reported data describing 3HP with dolutegravir, 3HP alone, and isoniazid with neither dolutegravir nor rifapentine. The isoniazid concentrations were adequately described by a one compartment model with a transit compartment absorption process. The isoniazid clearance for slow (8.33 L/h) and intermediate (12 L/h) acetylators were similar to previously reported values. Rapid acetylators ( N = 4) had clearance similar to those of intermediate acetylators and much slower than typically reported, but the small sample size was limiting. The absorption rate was lower than usual, likely due to the coadministration with food, and it was faster among individuals with a low body weight. Low-body weight participants were also observed to have greater oral bioavailability. The isoniazid exposures were consistent with, or greater than, the previously reported "elevated" concentrations among individuals receiving 3HP and dolutegravir. The concentrations were substantially greater than those presented in previous reports among individuals receiving 3HP or isoniazid without rifapentine or dolutegravir. We discuss the implications of these findings and the possibility of a drug-drug interaction that is mediated by cellular transport. (This study has been registered at ClinicalTrials.gov under identifier NCT03435146 and has South African National Clinical Trial Registration no. DOH-27-1217-5770.).

Background: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH)., Methods: PWH and CD4+ counts ≥100 cells/μL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz., Results: A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/μL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes -7.4%; 95% confidence interval [CI] -20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%)., Conclusions: In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/μL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe., Clinical Trials Registration: NCT02410772., Competing Interests: Potential conflicts of interest. The authorship team members have declared any potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Sanofi's commercial interests did not influence the study design; the collection, analysis, or interpretation of data; the preparation of this manuscript; or the decision to submit this manuscript for publication. A Sanofi technical expert served on the protocol team. A. V. reports unpaid participation on 2 advisory boards for a TB trial of high-dose rifampin (InterTB; St George's Hospital, London), and for a trial of shortened treatment for latent TB (McGill University, Montreal) and other financial or nonfinancial interests as part of this trial, Sanofi (Paris, France, and Bridgewater, NJ, USA) donated rifapentine and all other study drugs, supported shipping of study drugs to all sites, and provided funding support for pharmacokinetic testing. From 2007 until 2016, Sanofi donated a total of $2.9 million to the CDC Foundation to supplement CDC funding for rifapentine research; these funds supported prior TBTC studies of rifapentine but were not part of the support for this trial. This information was included in the main study publication (New England Journal of Medicine, 2021). L. M. reports grants or contracts from Merck Sharpe & Dohme Corp (institution received clinical trial fees), Viiv Healthcare (institution received clinical trial fees), Kowa Pharmaceuticals America (pharmaceutical support on protocol), Sanofi-Aventis (pharmaceutical support on protocol), and Adagio Therapeutics, Inc (institution received clinical trial fees). R. M. S. reports grants or contracts from TB Alliance: Drug regimen optimization for new and existing TB drugs, NIH/NIAID: Novel Biomarkers to Shorten TB Treatment, BMGF: TB Drug Lesion Penetration and Translational Modeling, NIH/NIAID/Rutgers: Impact of Pregnancy on Tuberculosis, BMGF/C-Path: In silico assessment of Adaptive Trial Designs, BMGF/DRI: Accelerating evaluation and development of new combination TB drug treatments, UNITAID/SU: Better Evidence and Formulations for Improved MDR-TB Treatment for Children (BENEFIT Kids), NIH/NIAID: Identifying Optimal Treatment Strategies for Tuberculosis, NIH/NIAID/SU: Optimizing and operationalizing pediatric drug-resistant tuberculosis treatment, and BMGF/C-Path: Model-based meta-analysis of endpoints analyzed in Phase III Quinolones clinical trials; including leadership or fiduciary role in other board, society, committee or advocacy group for Leadership and Operations Center (LOC), AIDS Clinical Trials Group (ACTG), WHO working group: Reaching UNGA HLM on TB targets for ending TB in children and adolescents, and Working Group on New TB Drugs (WGND), Core Member. S. S. reports Research contracts with ViiV Healthcare (paid to institution) and participates for NIH DMSB (unpaid participation). R. E. C. reports contract to institution from Unitaid, grant to institution from National Institutes of Health and Novartis, consultant from Johnson & Johnson and spouse is stockholder for Merck. S. E. D. reports support for attending meetings and/or travel from US CDC contract (provided reimbursement of travel expenses to attend the twice-yearly scientific meetings of the CDC TB Trials Consortium.). I. M. S. is the Vice-Chair for ACTG International. P. N. reports a contract from the CDC TB Trials Consortium. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We conducted a systematic review examining the cost effectiveness of a 3-month course of isoniazid and rifapentine, known as 3HP, given by directly observed treatment, compared to 9 months of isoniazid that is directly observed or self-administered, for latent tuberculosis infection. 3HP has shown to be effective in reducing progression to active tuberculosis and like other short-course regimens, has higher treatment completion rates compared to standard regimens such as 9 months of isoniazid. Decision makers would benefit from knowing if the higher up-front costs of rifapentine and of the human resources needed for directly observed treatment are worth the investment for improved outcomes., Methods: We searched PubMed, Embase, CINAHL, LILACS, and Web of Science up to February 2022 with search concepts combining latent tuberculosis infection, directly observed treatment, and cost or cost-effectiveness. Studies included were in English or French, on human subjects, with latent tuberculosis infection, provided information on specified anti-tubercular therapy regimens, had a directly observed treatment arm, and described outcomes with some cost or economic data. We excluded posters and abstracts, treatment for multiple drug resistant tuberculosis, and combined testing and treatment strategies. We then restricted our findings to studies examining directly-observed 3HP for comparison. The primary outcome was the cost and cost-effectiveness of directly-observed 3HP., Results: We identified 3 costing studies and 7 cost-effectiveness studies. The 3 costing studies compared directly-observed 3HP to directly-observed 9 months of isoniazid. Of the 7 cost-effectiveness studies, 4 were modelling studies based in high-income countries; one study was modelled on a high tuberculosis incidence population in the Canadian Arctic, using empiric costing data from that setting; and 2 studies were conducted in a low-income, high HIV-coinfection rate population. In five studies, directly-observed 3HP compared to self-administered isoniazid for 9 months in high-income countries, has incremental cost-effectiveness ratios that range from cost-saving to $5418 USD/QALY gained. While limited, existing evidence suggests 3HP may not be cost-effective in low-income, high HIV-coinfection settings., Conclusion: Cost-effectiveness should continue to be assessed for programmatic planning and scale-up, and may vary depending on existing systems and local context, including prevalence rates and patient expectations and preferences., (© 2022. The Author(s).)

Background: Tuberculosis preventive therapy (TPT) is recommended for people with HIV infection, including during pregnancy. The effect of TPT exposure at conception and during pregnancy is poorly documented., Methods: We report pregnancy outcomes among South African women with HIV enrolled in a randomized trial of 4 TPT regimens (two 3-month regimens, rifapentine/isoniazid [3HP] or rifampin/isoniazid [3HR], isoniazid for 6 months, or isoniazid continuously). Descriptive statistics and risk ratios were assessed to examine relationships between study regimens and outcomes., Results: 216/896 women (24%) conceived during the study. Women who conceived were younger (27.9 vs 31.3 years) and had higher mean CD4 counts (589.1 vs 536.7). The odds of pregnancy were higher in women in the rifamycin-isoniazid arms than those in the isoniazid arms (3HP: relative risk [RR] 1.73, P = 0.001; 3HR:RR 1.55, P = 0.017) despite increased contraceptive use compared with the standard 6H therapy. Thirty-four women became pregnant while taking preventive treatment (8 rifamycin and 26 isoniazid monotherapy). Pregnancy outcomes in these women were as follows: 17 (50%) mother/baby healthy, 3 (9%) spontaneous abortions, 6 (18%) elective abortions, 1 (3%) premature delivery, 2 (6%) neonatal deaths [1 rifamycin-isoniazid and 1 isoniazid], and 5 (15%) unknown., Conclusions: Pregnancy was common in women who had received TPT and more frequent in women who had received rifamycin-isoniazid-based regimens., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The Brief Rifapentine-Isoniazid Efficacy for TB Prevention/A5279 trial demonstrated a 1-month daily regimen of rifapentine and isoniazid was noninferior to 9 months of isoniazid alone for preventing TB in persons living with HIV (PLWH). Our objective was to evaluate rifapentine pharmacokinetics in trial participants receiving antiretroviral therapy (ART) and perform simulations to compare weight-based rifapentine dosing with a standard, fixed dose. Nonlinear mixed effect modeling was used to estimate rifapentine and 25-desacetyl rifapentine population pharmacokinetic characteristics. The pharmacokinetic model was validated using a nonparametric bootstrap and visual predictive checks. Monte Carlo simulations were performed to compare weight-based and fixed dose regimens. Rifapentine and 25-desacetyl rifapentine concentrations (347 of each; 185 participants) were each described with a one-compartment model with one-way conversion between rifapentine and 25-desacetyl rifapentine. The absorption rate was nearly doubled in fed versus fasting states. Rifapentine clearance was increased 31% in those receiving efavirenz (EFV)-based versus nevirapine-based ART. Metabolite clearance was allometrically scaled with fat-free mass. Simulations showed lower rifapentine exposures with weight-based compared with fixed dosing. With 10 mg/kg weight-based regimens, 26% and 62% of simulated exposures in <35 kg and 35-45 kg weight classes were above target (AUC 0 to 24 h of 257 mg*hr/L); 85% of simulated exposures across all weight classes with fixed dosing were above target. These data support fixed dosing with rifapentine 600 mg daily for TB prevention regardless of weight for PLWH 13 years or older receiving the 4-week regimen and no need for dose adjustment when given with EFV-based ART. Clinical Trials Registration. NCT01404312.

Background: A 4-month regimen containing rifapentine and moxifloxacin has noninferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB)., Methods: In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing antiretroviral therapy (ART) (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200 mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin. Mid-interval efavirenz concentrations were measured (a) during ART and TB cotreatment (Weeks 4, 8, 12, and 17, different by EFV group) and (b) when ART was taken alone (pre- or post-TB treatment, Weeks 0 and 22). Apparent oral clearance (CL/F) was estimated and compared. Target mid-interval efavirenz concentrations were > 1 mg/L. Co-treatment was considered acceptable if > 80% of participants had mid-interval efavirenz concentrations meeting this target., Results: EFV1 and EFV2 included 70 and 41 evaluable participants, respectively. The geometric mean ratio comparing efavirenz CL/F with vs without TB drugs was 0.79 (90% confidence interval [CI] .72-.85) in EFV1 and 0.84 [90% CI .69-.97] in EFV2. The percent of participants with mid-interval efavirenz concentrations > 1mg/L in EFV1 at Weeks 0, 4, 8, and 17 was 96%, 96%, 88%, and 89%, respectively. In EFV2, at approximately 4 and 8 weeks post efavirenz initiation, the value was 98%., Conclusions: TB treatment containing high-dose daily rifapentine modestly decreased (rather than increased) efavirenz clearance and therapeutic targets were met supporting the use of efavirenz with these regimens, without dose adjustment., Clinical Trials Registration: NCT02410772., Competing Interests: Potential conflicts of interest. The authorship team members have declared (below or attached) any potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Sanofi commercial interests did not influence the study design; the collection, analysis, or interpretation of data; the preparation of this manuscript; or the decision to submit this manuscript for publication. A Sanofi technical expert served on the protocol team. N. M. reports a grant to the institution for pneumonia research from Pfizer and a subaward to collect specimens to validate a TB diagnostic from Roche. L. M. reports grants or contracts from Merck Sharpe & Dohme (institution received clinical trial fees), ViiV Healthcare (institution received clinical trial fees), Kowa Pharmaceuticals America (pharmaceutical support on protocol), and Sanofi-Aventis (pharmaceutical support on protocol) outside of the submitted work. S. S. reports research grant support to the institution from ViiV Healthcare outside of the submitted work and support for attending meetings and/or travel from the National Institutes of Health (NIH). C. V. F. reports being a member of the Safety Monitoring Committee for Division of Microbiology and Infectious Diseases (DMID), NIAID, NIH, for 2 protocols on (1) an influenza virus challenge study and (2) a safety and pharmacokinetics of single doses of an antifungal, VT-1598 (no payments are made to institution or personally for service on this SMC). R. E. C. reports consulting fees from Sanofi. U. L. reports funding support for travel to ACTG Annual Network Meeting from AIDS Clinical Trials Group. A. A. V. reports working with a group at CDC that perform TB trials. The group has collaborated with pharmaceutical partners. Sanofi collaborated in Study 31/A5349 and provided support for testing PK of TB drugs, and provided drugs for the trial. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: This study aimed to determine the effectiveness of Covishield vaccine among residents of congregate residential facilities., Design: A prospective cohort study in congregate residential facilities., Setting: Dharamshala, Himachal Pradesh, India, from December 2020 to July 2021., Participants: Residents of all ages in seven facilities-three monasteries, two old age homes and two learning centres-were enrolled., Exposures: First and second doses of Covishield vaccine against SARS-CoV-2 infection., Main Outcomes Measures: Primary outcome was development of COVID-19. Secondary outcome was unfavourable outcomes, defined as a composite of shortness of breath, hospitalisation or death. Vaccine effectiveness (%) was calculated as (1-HR)×100., Results: There were 1114 residents (median age 31 years) participating in the study, 82% males. Twenty-eight per cent (n=308/1114) were unvaccinated, 50% (n=554/1114) had received one dose and 23% (n=252/1114) had received two doses of Covishield. The point prevalence of COVID-19 for the facilities ranged from 11% to 57%. Incidence rates (95% CI) of COVID-19 were 76 (63 to 90)/1000 person-months in the unvaccinated, 25 (18 to 35)/1000 person-months in recipients of one dose and 9 (4 to 19)/1000 person-months in recipients of two doses. The effectiveness of first and second doses of Covishield were 71% (adjusted HR (aHR) 0.29; 95% CI 0.18 to 0.46; p<0.001) and 80% (aHR 0.20; 95% CI 0.09 to 0.44; p<0.001), respectively, against SARS-CoV-2 infection and 86% (aHR 0.24; 95% CI 0.07 to 0.82; p=0.023) and 99% (aHR 0.01; 95% CI 0.002 to 0.10; p<0.001), respectively, against unfavourable outcome. The effectiveness was higher after 14 days of receiving the first and second doses, 93% and 98%, respectively. Risk of infection was higher in persons with chronic hepatitis B (aHR 1.78; p=0.034) and previous history of tuberculosis (aHR 1.62; p=0.047)., Conclusion: Covishield was effective in preventing SARS-CoV-2 infection and reducing disease severity in highly transmissible settings during the second wave of the pandemic driven by the Delta variant., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population., Methods: In this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895., Findings: We identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (<10 g/dL), body-mass index (<18·5 kg/m 2 ), and lymphadenopathy had high specificities (80-90%) but low sensitivities (29-43%). The WHO-recommended algorithm had a sensitivity of 58% (50-66) and a specificity of 99% (98-100); Xpert for all had a sensitivity of 68% (57-76) and a specificity of 99% (98-99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62-81] vs 57% [47-67]) and specificities were similar (98% [96-98] vs 99% [98-100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35-71) and specificity was 71% (51-85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70-97]) and lower specificity (33% [17-54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76-91) and specificity was 37% (25-51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79-86]), but higher specificity (67% [60-73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75-90]), but higher specificity than (64% [57-71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively., Interpretation: C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications., Funding: World Health Organization., Competing Interests: Declaration of interests AC reports grants from National Institutes of Health (NIH), Global Health Labs, and Stop TB Partnership, and consulting fees from the US Centers for Disease Control and Prevention (CDC). AK reports grants from Sanofi. FAK reports grants from WHO, Canadian Institutes of Health Research, Fonds de Recherche Quebec, and McGill Interdisciplinary Initiative on Infection and Immunity. GT reports receipt of consumables and equipment from Boditech and Cepheid. NM reports grants from Pfizer and Roche. REC reports grants from NIH, CDC, and Unitaid, and consulting fees from Sanofi. SML reports grants from NIH and CDC. SSk reports grants from Swedish Heart-Lung Foundation. TKr reports consulting fees from WHO. All other authors declare no competing interests., (© 2022 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3·0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT. METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement. RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care. CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

The Centers for AIDS Research (CFAR) program was established by the National Institutes of Health in 1988 to catalyze and support high-impact HIV research and to develop the next generation of HIV investigators at academic institutions throughout the United States. In 2014, the Penn CFAR, the Johns Hopkins University CFAR and the District of Columbia CFAR developed a partnership-the Mid-Atlantic CFAR Consortium (MACC)-to promote cross-CFAR scientific collaboration, mentoring, and communication and to address the regional HIV epidemic. Over the past 6 years, the creation of the MACC has resulted in a rich web of interconnectivity, which has fostered scientific collaboration through working groups on the black men who have sex with men (MSM) and Latinx regional HIV epidemics, joint peer-reviewed publications, and successful collaborative grant applications on topics ranging from HIV prevention in young MSM, transgender women, implementation science, and clinical epidemiology; supported developmental activities through the MACC Scholars program, cross-CFAR mentoring, joint symposia, cross-CFAR seminar participation, and keynote speakers; and promoted strategic communication through advisory committees, best practices consultations, and the social and behavioral science research network. The MACC has been highly impactful by promoting HIV science through regional collaboration, supporting a diverse network of scholars across three cities and focusing on the epidemic in underrepresented and marginalized communities. Lessons learned from this consortium may have implications for scientific research centers beyond the field of HIV.

Objectives: In Brazil, annual tuberculin skin tests (TSTs) are recommended for people living with HIV (PLWH) with CD4 >350, with tuberculosis preventive therapy provided on test conversion. We aimed to determine the yield of repeat TSTs for PLWH., Design: Secondary analysis of the stepped-wedge, cluster-randomized THRio trial for isoniazid preventive therapy (IPT) to prevent tuberculosis (TB)., Methods: We analyzed data from newly registered PLWH with negative baseline TST results. We calculated the number of TST conversions after 1 and/or 2 years among patients eligible for follow-up TSTs, the proportion of converters initiating IPT, and incidence of TB/death., Results: Among 1770 PLWH with a negative baseline TST, 679 (38%) were female and median age was 36 years (IQR 29-43). Eighty-six (5%) developed TB or died within 1 year. Among 1684 eligible for a follow-up 1-year TST, 582 (35%) were tested and 53 (9%) were positive. Forty-nine converters (92%) started IPT. Of 529 patients with a negative 1-year TST, 7 (1%) developed TB or died over the following year. Of 522 patients eligible for a 2-year TST, 158 (30%) were tested and 13 (8%) were positive. Ten converters (77%) started IPT. Of 1102 patients who did not receive a 1-year TST, 33 (3%) developed TB or died. Of the 1069 patients eligible for a 2-year TST, 259 (24%) were tested and 34 (13%) were positive. Thirty converters (88%) started IPT., Conclusions: In this cohort of PLWH in Brazil, TST conversion was high among those retested, but only 48% received a follow-up TST within 2 years., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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.

The current intersection of the COVID-19 and HIV-1 pandemics, has raised concerns about the risk for poor COVID-19 outcomes particularly in regions like sub-Saharan Africa, disproportionally affected by HIV. DPP4/CD26 has been suggested to be a potential therapeutic target and a biomarker for risk in COVID-19 patients with high risk co-morbidities. We therefore evaluated soluble DPP4 (sDPP4) levels and activity in plasma of 131 HIV-infected and 20 HIV-uninfected South African individuals. Flow cytometry was performed to compare cell surface expression of DPP4/CD26 and activation markers on peripheral blood mononuclear cells of extreme clinical phenotypes. Progressors had lower specific DPP4 activity and lower frequency of CD3 + T-cells expressing CD26 than HIV-1 controllers, but more activated CD3 + CD26 + T-cells. The frequency of CD26-expressing T-cells negatively correlated with HLA-DR + and CD38 + T-cells. Divergent DPP4/CD26 expression between HIV-1 controllers and progressors may have implications for risk and treatment of COVID-19 in people living with HIV., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis., Methods: In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months., Results: Among 2516 participants who had undergone randomization, 2343 had a culture positive for Mycobacterium tuberculosis that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group., Conclusions: The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.)., (Copyright © 2021 Massachusetts Medical Society.)

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed. METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa 200 MZ) or 4 months (4Pa 200 MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa 100 MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed. RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa 200 MZ, 4Pa 200 MZ, 4Pa 100 MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa 200 MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died. CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Background: The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug-drug interactions with concomitantly used ART., Objectives: To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and isoniazid for TB prevention in people living with HIV., Methods: Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/isoniazid was calculated., Results: Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13-66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266-9302) ng/mL; week 2, 5537 (3552-8462) ng/mL; and week 4, 5388 (3516-8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/isoniazid, 2.03 (1.58-2.58) L/h; and during rifapentine/isoniazid, 2.62 (1.81-3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26-1.33)., Conclusions: The CL/F of nevirapine significantly increased with concomitant rifapentine/isoniazid. The decrease in nevirapine trough concentrations during rifapentine/isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug-drug interaction suggests daily rifapentine/isoniazid for TB prevention should not be co-administered with nevirapine-containing ART., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Tuberculosis is a top-10 cause of under-5 mortality, despite policies promoting tuberculosis preventive therapy (TPT). We previously conducted a cluster randomized trial to evaluate the effectiveness of symptom-based versus tuberculin skin-based screening on child TPT uptake. Symptom-based screening did not improve TPT uptake and nearly two-thirds of child contacts were not identified or not linked to care. Here we qualitatively explored healthcare provider perceptions of factors that impacted TPT uptake among child contacts., Methods: Sixteen in-depth interviews were conducted with key informants including healthcare providers and administrators who participated in the trial in Matlosana, South Africa. The participants' experience with symptom-based screening, study implementation strategies, and ongoing challenges with child contact identification and linkage to care were explored. Interviews were systematically coded and thematic content analysis was conducted., Results: Participants' had mixed opinions about symptom-based screening and high acceptability of the study implementation strategies. A key barrier to optimizing child contact screening and evaluation was the supervision and training of community health workers., Conclusions: Symptom screening is a simple and effective strategy to evaluate child contacts, but additional pediatric training is needed to provide comfort with decision making. New clinic-based child contact files were highly valued by providers who continued to use them after trial completion. Future interventions to improve child contact management will need to address how to best utilize community health workers in identifying and linking child contacts to care., Trial Registration: The results presented here were from research related to NCT03074799 , retrospectively registered on 9 March 2017.

Background: Tuberculosis (TB) rates among Tibetan refugee children and adolescents attending boarding schools in India are extremely high. We undertook a comprehensive case finding and TB preventive treatment (TPT) program in 7 schools in the Zero TB Kids project. We aimed to measure the TB infection and disease burden and investigate the risk of TB disease in children and adults who did and did not receive TPT in the schools., Methods and Findings: A mobile team annually screened children and staff for TB at the 7 boarding schools in Himachal Pradesh, India, using symptom criteria, radiography, molecular diagnostics, and tuberculin skin tests. TB infection (TBI) was treated with short-course regimens of isoniazid and rifampin or rifampin. TB disease was treated according to Tibetan and Indian guidelines. Between April 2017 and December 2019, 6,582 schoolchildren (median age 14 [IQR 11-16] years) and 807 staff (median age 40 [IQR 33-48] years) were enrolled. Fifty-one percent of the students and 58% of the staff were females. Over 13,161 person-years of follow-up in schoolchildren (median follow-up 2.3 years) and 1,800 person-years of follow-up in staff (median follow-up 2.5 years), 69 TB episodes occurred in schoolchildren and 4 TB episodes occurred in staff, yielding annual incidence rates of 524/100,000 (95% CI 414-663/100,000) person-years and 256/100,000 (95% CI 96-683/100,000) person-years, respectively. Of 1,412 schoolchildren diagnosed with TBI, 1,192 received TPT. Schoolchildren who received TPT had 79% lower risk of TB disease (adjusted hazard ratio [aHR] 0.21; 95% CI 0.07-0.69; p = 0.010) compared to non-recipients, the primary study outcome. Protection was greater in recent contacts (aHR 0.07; 95% CI 0.01-0.42; p = 0.004), the secondary study outcome. The prevalence of recent contacts was 28% (1,843/6,582). Two different TPT regimens were used (3HR and 4R), and both were apparently effective. No staff receiving TPT developed TB. Overall, between 2017 and 2019, TB disease incidence decreased by 87%, from 837/100,000 (95% CI 604-1,129/100,000) person-years to 110/100,000 (95% CI 36-255/100,000) person-years (p < 0.001), and TBI prevalence decreased by 42% from 19% (95% CI 18%-20%) to 11% (95% CI 10%-12%) (p < 0.001). A limitation of our study is that TB incidence could be influenced by secular trends during the study period., Conclusions: In this study, following implementation of a school-wide TB screening and preventive treatment program, we observed a significant reduction in the burden of TB disease and TBI in children and adolescents. The benefit of TPT was particularly marked for recent TB contacts. This initiative may serve as a model for TB detection and prevention in children and adolescents in other communities affected by TB., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Spouse of RC owns stock in Merck. RC has received consulting fees from Sanofi. Other authors have declared that no competing interests exist.

Background: While household contact investigation is widely recommended as a means to reduce the burden of tuberculosis (TB) among children, only 27% of eligible pediatric household contacts globally received preventive treatment in 2018. We assessed the cost-effectiveness of household contact investigation for TB treatment and short-course preventive therapy provision for children under 15 years old across 12 high TB burden countries., Methods: We used decision analysis to compare the costs and estimated effectiveness of three intervention scenarios: (a) status quo (existing levels of coverage with isoniazid preventive therapy), (b) contact investigation with treatment of active TB but no additional preventive therapy, and (c) contact investigation with TB treatment and provision of short-course preventive therapy. Using country-specific demographic, epidemiological and cost data from the literature, we estimated annual costs (in 2018 USD) and the number of TB cases and deaths averted across 12 countries. Incremental cost effectiveness ratios were assessed as cost per death and per disability-adjusted life year [DALY] averted., Findings: Our model estimates that contact investigation with treatment of active TB and provision of preventive therapy could be highly cost-effective compared to the status quo (ranging from $100 per DALY averted in Malawi to $1,600 in Brazil; weighted average $383 per DALY averted [uncertainty range: $248 - $1,130]) and preferred to contact investigation without preventive therapy (weighted average $751 per DALY averted [uncertainty range: $250 - $1,306]). Key drivers of cost-effectiveness were TB prevalence, sensitivity of TB diagnosis, case fatality for untreated TB, and cost of household screening., Interpretation: Based on this modeling analysis of available published data, household contact investigation with provision of short-course preventive therapy for TB has a value-for-money profile that compares favorably with other interventions., Funding: Unitaid (2017-20-IMPAACT4TB)., Competing Interests: Dr. Chaisson reports personal fees from Sanofi, outside the submitted work, and grants from Unitaid. All the other authors declare no conflict of interest., (© 2020 The Authors.)

Objectives: The effect of rifapentine plus isoniazid on efavirenz pharmacokinetics was characterized in AIDS Clinical Trials Group protocol A5279 (NCT01404312). The present analyses characterize pharmacogenetic interactions between these drugs, and with nevirapine., Methods: A subset of HIV-positive individuals receiving efavirenz- or nevirapine-containing antiretroviral therapy in A5279 underwent pharmacokinetic evaluations at baseline, and again weeks 2 and 4 after initiating daily rifapentine plus isoniazid. Associations with polymorphisms relevant to efavirenz, nevirapine, isoniazid, and rifapentine pharmacokinetics were assessed., Results: Of 128 participants, 101 were evaluable for associations with rifapentine and its active 25-desacetyl metabolite, 87 with efavirenz, and 38 with nevirapine. In multivariable analyses, NAT2 slow acetylators had greater week 4 plasma concentrations of rifapentine (P = 2.6 × 10) and 25-desacetyl rifapentine (P = 7.0 × 10) among all participants, and in efavirenz and nevirapine subgroups. NAT2 slow acetylators also had greater plasma efavirenz and nevirapine concentration increases from baseline to week 4, and greater decreases from baseline in clearance. CYP2B6 poor metabolizers had greater efavirenz concentrations at all weeks and greater nevirapine concentrations at baseline. None of 47 additional polymorphisms in 11 genes were significantly associated with pharmacokinetics., Conclusions: Among HIV-positive individuals receiving efavirenz or nevirapine, and who then initiated rifapentine plus isoniazid in A5279, NAT2 slow acetylators had greater rifapentine and 25-desacetyl rifapentine concentrations, and greater increases from baseline in plasma efavirenz and nevirapine concentrations. These associations are likely mediated by greater isoniazid exposure in NAT2 slow acetylators.

Background: To determine the association of human leukocyte antigen (HLA) alleles as correlates of risk for and protection against tuberculin skin test (TST) positivity and active TB disease amongst HIV-infected adults., Methods: Genomic DNA was extracted from 754 HIV-infected adults whole-blood. HLA-A, -B, -C and -DRB1 loci were genotyped by next generation sequencing methods. HLA alleles were analysed by the presence/absence of TST immune conversion and active TB disease and further stratified by exposure to a household TB contact, CD4 + T-cell count and, for active TB disease, TST-positivity., Results: HLA-A*29:11 and - B*45:01/07 were associated with TST-positivity, while HLA-A*24:02, -A*29:02 and -B*15:16 with TST-negativity. In participants with a household TB contact, HLA-A*66:01, -A*68:02 and -B*49:01 were associated with TST-negativity. For TB disease, HLA-B*41:01, -C*06:02, -DRB1*04:01 and -DRB1*15:01 were associated with susceptibility, while HLA-B*07:02 and -DRB1*11:01 were protective, even for CD4 + T-cell count <350 cells/mm 3 . For initial TST-positivity and subsequent TB disease, HLA-A*01:01 and -DRB1*11:01 conveyed protection including for those with CD4 + T-cell count <350 cells/mm 3 ., Conclusion: Several HLA alleles are noted as correlates of TB infection, risk and natural protection in HIV-infected individuals. HLA associations may enable risk stratification of those with HIV infection. Protective alleles may assist in future TB vaccine development., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

INTRODUCTION: Patients being treated for TB may suffer reductions in health-related quality of life (HRQoL). This study aims to assess the extent of such reductions and the trajectory of HRQoL over the course of treatment in rural Malawi. METHODS: We collected patient demographic and socioeconomic status, TB-related characteristics, and HRQoL data (i.e., EQ-5D and a visual analogue scale VAS) from adults (age ≥18 years) being treated for TB in 12 primary health centers and one hospital in rural Thyolo District, Malawi, from 2014 to 2016. Associations between HRQoL and patient characteristics were estimated using multivariable linear regression. RESULTS: Inpatients ( n = 197) consistently showed lower median HRQoL scores and suffered more severe health impairments during hospitalization than outpatients ( n = 156) (EQ5D and VAS: 0.79, 55 vs. 0.84, 70). Longer treatment duration was associated with higher HRQoL among outpatients (EQ5D: 0.034 increase per 2 months, 95%CI 0.012-0.057). We found no substantial associations between patients´ demographic and socioeconomic characteristics and HRQoL in this setting. CONCLUSION: HRQoL scores among patients receiving treatment for TB in rural Malawi differ by clinical setting and duration of treatment, with greater impairment among inpatients and those early in their treatment course.