AIM:We report the longitudinal analysis of QuantiFERON-Gold Plus (QFT-plus) results from a clinical trial conducted in three high TB/HIV burden countries, comparing three different tuberculosis preventive treatment (TPT) regimens in people living with HIV (PLHIV). METHODS:PLHIV were enrolled in Ethiopia, Mozambique and South Africa, and randomised to: (i) one course of weekly rifapentine-isoniazid for 3 months (3HP); (ii) weekly rifapentine-isoniazid for 3 months given annually for 2 years (p3HP); (iii) daily isoniazid for 6 months (6H). QFT-plus testing was performed at baseline, M12 and M24. Quantitative and qualitative results, and serial changes (conversions and reversions) were assessed. RESULTS:From baseline to M12, 13.0% (196/1502) of participants converted, with no differences between 3HP (13.1%) and 6H (12.9%). From M12 to M24 conversion occurred in 4.0% of participants receiving p3HP and 9.4% of those receiving 3HP (p-value 0.110). Overall reversions occurred in 19.0% (178/935) of participants. Reversion rates were similar across study arms and timepoints. The risk of developing TB during the study period was higher among individuals QFT-plus positive at baseline (aHR, 1.66; 95% CI, 1.41-1.89, p-value = 0.034). CONCLUSION:QFT-Plus conversions and reversions occurred frequently in PLHIV and did not differ by TPT regimen, or between those who did and did not receive a second course of TPT. The high rate of QFT-positivity, along with the large proportion of conversions despite TPT highlights the complexity of interpreting serial IGRA results in PLHIV in high-transmission scenarios.

Multidrug-resistant tuberculosis (MDR-TB) remains a global health threat and accounts for a quarter of deaths due to antimicrobial resistance. Individuals infected with MDR-TB are at risk of progressing to TB disease. Treatment of drug-resistant TB infection to prevent progression to disease and avert the associated morbidity and mortality is a global priority. Randomized evidence to inform TB preventive treatment (TPT) guidelines has been lacking. Two recently completed trials provide the first randomized evidence that treatment of household contacts exposed to people with MDR-TB with daily levofloxacin for 6 months is safe and efficacious in preventing TB. Based on these results, the World Health Organization updated its TPT guidelines to make a strong recommendation for use of levofloxacin for 6 months in MDR-TB exposed contacts. Novel, shorter regimens in development will usher in a new era for the treatment of MDR-TB infection if shown to be safe and efficacious.

Over the past 80 years, tuberculosis treatment has evolved with the development of all-oral treatments, which are now given for 4-6 months for drug-sensitive tuberculosis and 6-9 months for drug-resistant tuberculosis. Treatment success is often reduced among people with HIV due to an interplay of factors, including immune dysregulation, lower drug concentrations, complexities of cotreatment (eg, high pill burden and overlapping toxicities), and social factors. Recent clinical trials have shown that among adults and adolescents, treatment duration can be decreased to 4 months with repurposed therapeutics for drug-sensitive tuberculosis, and a four-drug regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide has become part of WHO recommendations. Among children with drug-sensitive, non-severe tuberculosis disease, a 4-month regimen of standard tuberculosis drugs (eg, isoniazid, rifampicin, pyrazinamide, and ethambutol) is non-inferior to a 6-month regimen. Following recent research advances for drug-resistant tuberculosis, a 6-month regimen containing a potent combination of bedaquiline, pretomanid, linezolid, and moxifloxacin is a new standard for people with and without HIV. The tuberculosis drug development pipeline contains promising new therapeutics in various stages of development. To accelerate tuberculosis elimination, future research should focus on shortened treatment duration, and safer and effective therapeutics for tuberculosis-affected populations globally, including people with HIV, children, and pregnant people, and should assess newer modalities of treatment delivery.

Tuberculosis preventive treatment (TPT) is an essential intervention recommended for all child contacts in Ethiopia under 15 years who are at risk of tuberculosis (TB) infection. We conducted a cost and cost-effectiveness analysis of home-based versus facility-based TPT provision for child contacts in Ethiopia. As part of the CHIP TB trial, a pragmatic, cluster-randomized trial conducted at eighteen clinics in Ethiopia, clinics were randomized to either a home-based model (intervention arm), administered by community health workers, or a facility-based model (standard of care) for managing child contacts. Cost data were collected from both a health service perspective and a household perspective, capturing all costs relevant to TPT. Costs were evaluated on a per-household basis, with the primary outcome being the difference in median costs per household initiating TPT. A secondary outcome assessed the cost-effectiveness as the incremental cost per additional child contact starting TPT. Probabilistic sensitivity analyses (PSA) were conducted to examine the robustness of findings. At an average cost of US$18.92 per household managed, Home-based contact management, including TPT delivery was cost-saving compared to facility-based TPT delivery (US$27.24 per household managed) assessed based on the partial-societal perspectives, largely due to reductions in household out-of-pocket costs. The home-based strategy was both less costly and had increased TPT initiation in 61.5% of the scenarios assessed in the PSA. Home-based contact management is a cost-saving alternative for households and provides comparable initiation rates to facility-based care, making it a feasible approach to improve TB preventive treatment accessibility. Although it does not entirely replace facility-based care, a hybrid model that respects household preferences and allows flexibility in delivery could enhance TB care access for socio-economically disadvantaged households, potentially reducing health inequities. The trial was registered on clinicaltrials.gov NCT04369326 on April 30, 2020. https://clinicaltrials.gov/study/NCT04369326.

INTRODUCTION:Tuberculosis (TB) is the leading cause of death among people living with HIV. Global estimates among people living with HIV demonstrate that more incident cases and more deaths due to TB occur among women than men. Simultaneously, women experience higher levels of under and unpaid work compared to men. Given that poverty is an established determinant for TB, the aim of this study is to characterize the role of HIV-related employment discrimination and legal protections on TB outcomes for women living with HIV. METHODS:The People Living with HIV Stigma Index 2.0 study was implemented in 11 countries across sub-Saharan Africa, including Angola, Benin, Burkina Faso, Cote D'Ivoire, Ghana, Kenya, Mauritania, Nigeria, Lesotho, Togo and Zimbabwe. Study design and implementation were led by networks of people living with HIV in each country between 2020 and 2022. Interviewer-administered questionnaires were used to collect self-reported socio-behavioural measures among cisgender adult women living with HIV. Multilevel logistic regression models were used to estimate associations between economic instability and employment discrimination exposures and recent TB diagnoses in the context of varying discrimination protections for women living with HIV. RESULTS:Among 10,718 participants, 7.5% (n = 807) reported a recent TB diagnosis. Among women in countries without non-discrimination protections, recent TB diagnosis was negatively associated with current employment (aOR: 0.72; 95% CI: 0.62, 0.85) compared to no employment; and positively associated with being refused employment or income due to HIV status (aOR: 1.80; 95% CI: 1.36, 2.39) and ever being refused promotion (aOR: 2.00; 95% CI: 1.37, 2.91) compared to those who have not reported these experiences. Among women in countries with non-discrimination protections, recent TB diagnosis was associated with lower current employment (aOR: 0.72; 95% CI: 0.56, 0.92) but not associated with employment discrimination. CONCLUSIONS:The presence of social protections may modify the associations between employment discrimination and TB diagnosis. Employment discrimination was associated with TB diagnosis in settings without social protections but not in settings with those protections in place-highlighting a potential vulnerability among people living with HIV in settings without non-discrimination protections. Given the role of poverty in driving TB epidemics, social protections focused on employment, economic instability and opportunity may support TB prevention and control.

BACKGROUND:Tuberculosis preventive treatment with 3 months of once-weekly isoniazid (900 mg) and rifapentine (900 mg; 3HP) is a recommended option for people with HIV; among adults with virological suppression, the 3HP regimen given with dolutegravir-based antiretroviral therapy (ART) is safe and maintained virological suppression. The DOLPHIN-TOO study assessed safety, dolutegravir pharmacokinetics, and virological efficacy of concurrent initiation of dolutegravir-based ART and 3HP among antiretroviral-naive adults with HIV. METHODS:DOLPHIN-TOO was a non-randomised, open-label, pragmatic phase 1/2 trial done at The Aurum Institute Tembisa Clinical Research Site (Tembisa, South Africa). Antiretroviral-naive adults (aged ≥18 years) with HIV and no symptoms of tuberculosis disease or microbiologically confirmed absence of tuberculosis disease were sequentially enrolled and assigned to 6 months of once-daily isoniazid 300 mg (6H; n=25) or to 3HP (n=50). Once-daily dolutegravir 50 mg with tenofovir disoproxil fumarate 300 mg and lamivudine 300 mg was initiated on day 0 and tuberculosis preventive treatments were initiated on day 1; sparse pharmacokinetic sampling for dolutegravir was done on day 1 (before starting 3HP or 6H), and in week 3 (day 17) and week 8 (day 52) of treatment. HIV-1 RNA viral loads were measured serially by PCR. The primary endpoints were adverse events (grade 3 or worse per the Division of AIDS Adverse Event Grading Table version 2.1) and population pharmacokinetics of dolutegravir with and without 3HP, using 6H as a pharmacokinetic control. Non-linear mixed-effects modelling was used for pharmacokinetic analysis. The analysis population for both safety and pharmacokinetics was the intention-to-treat population. The trial is registered with the South African National Clinical Trials Register, DOH-27-1217-5770, and ClinicalTrials.gov, NCT03435146, and is completed. FINDINGS:75 participants were sequentially enrolled from Aug 31, 2021, to June 28, 2022, and assigned to 6H (n=25) or 3HP (n=50). Overall median age of participants was 35 years (IQR 27-41), all participants were Black African, and 37 (49%) were female and 38 (51%) were male. At baseline, overall median HIV viral load was 27 056 copies per mL (IQR 7088-111 620), and 20 (27%) participants had HIV viral loads higher than 100 000 copies per mL; median baseline CD4 count was 283 cells per μL. One grade 3 or worse adverse event was reported: a grade 3 cutaneous abscess requiring hospitalisation (unrelated to treatment) in a participant in the 6H group. No treatment-related grade 3 adverse events occurred. Coadministered 3HP increased dolutegravir clearance by 72% (relative standard error 12%), from 0·95 L/h before 3HP treatment to 1·64 L/h during 3HP treatment. Median dolutegravir trough concentrations were significantly lower in the 3HP group than in the 6H group at week 3 (720 ng/mL [range 92-4250] vs 1310 ng/mL [431-2980]; Wilcoxon rank-sum p=0·0006) and week 8 (669 ng/mL [184-4440] vs 1285 ng/mL [475-2890]; p=0·0066). All dolutegravir trough values were higher than the in-vitro protein-adjusted 90% maximal inhibitory concentration for dolutegravir of 64 ng/mL. INTERPRETATION:Our results indicate that simultaneous initiation of 3HP tuberculosis preventive treatment and dolutegravir-based ART was safe and achieved therapeutic concentrations among antiretroviral-naive individuals with HIV, and dolutegravir dose adjustments are not needed. FUNDING:Unitaid, ViiV Healthcare. TRANSLATIONS:For the Afrikaans, Xhosa and Zulu translations of the abstract see Supplementary Materials section.

A previous study demonstrated noninferior efficacy of 4-month rifapentine/moxifloxacin regimen for tuberculosis (TB) treatment compared with the standard regimen. We explored results among study participants with diabetes. Among 2,516 randomized participants, 181 (7.2%) had diabetes. Of 166 participants with diabetes in the microbiologically eligible analysis group, 26.3% (15/57) had unfavorable outcomes in the control regimen, 13.8% (8/58) in the rifapentine/moxifloxacin regimen, and 29.4% (15/51) in the rifapentine regimen. The difference in proportion of unfavorable outcomes between the control and rifapentine/moxifloxacin arms in the microbiologically eligible analysis group was -12.5% (95% CI -27.0% to 1.9%); the difference between the control and rifapentine arms was 3.1% (95% CI -13.8% to 20.0%). Safety outcomes were similar in the rifapentine/moxifloxacin regimen and control arms. Among participants with TB and diabetes, the rifapentine/moxifloxacin arm had fewest unfavorable outcomes and was safe. Our findings indicate that the rifapentine/moxifloxacin regimen can be used in persons with TB and diabetes.

BACKGROUND:Based on results from preclinical and clinical studies, a five-drug combination of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine was identified with treatment shortening potential for drug-susceptible tuberculosis; the Clo-Fast trial aimed to determine the efficacy and safety of this regimen. We compared 3 months of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine, administered with a clofazimine loading dose, to the standard 6 month regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol in drug-susceptible tuberculosis. METHODS:Clo-Fast was a phase 2c open-label trial recruiting participants at six sites in five countries. Participants aged 18 years or older with pulmonary tuberculosis who were sputum smear positive for acid-fast bacilli or molecular tuberculosis assay positive (with Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid) were eligible for enrolment. Individuals with HIV infection with a CD4+ cell count ≥100 cells per mm3 could participate. Participants were randomly assigned in a 2:1 ratio (group 1: group 2) or a 2:1:1 ratio (group 1: group 2: group 3), depending on consent to participate in the intensive pharmacokinetic visits required in group 3, using a central web-based system with permuted blocks. The group 1 regimen included 8 weeks of rifapentine-isoniazid-pyrazinamide-ethambutol-clofazimine, with a 2-week 300 mg clofazimine loading dose, followed by 5 weeks of rifapentine-isoniazid-pyrazinamide-clofazimine (13 weeks total). The group 2 control regimen included 8 weeks of isoniazid-rifampicin-pyrazinamide-ethambutol followed by 18 weeks of rifampicin-isoniazid. Group 3 was identical to group 1 over the first 4 weeks of treatment, except that the regimen was administered without a clofazimine loading dose (100 mg daily); after 4 weeks of group 3 treatment, participants transitioned to local standard of care to complete treatment. Group 3 was designed to assess the effect of a 2-week loading dose on clofazimine pharmacokinetics. Randomisation was stratified by HIV status and advanced disease on chest radiograph. The primary efficacy endpoint was time to sputum culture-negative status by 12 weeks. The primary safety endpoint was the proportion of participants experiencing any grade 3 or worse adverse event over 65 weeks. The key secondary endpoint was unfavourable clinical or bacteriological outcomes by week 65. The efficacy analysis population contained participants assigned to groups 1 and 2 who were not late exclusions (no positive culture at screening, entry, or week 1, or if rifampicin resistance or isoniazid resistance was detected at screening or entry); the safety analysis population contained all randomly assigned participants who took at least one dose of treatment. The trial was registered with ClinicalTrials.gov ID: NCT04311502. FINDINGS:104 participants were randomly assigned to group 1 (n=58), group 2 (n=31), and group 3 (n=15). 82 (79%) were male and 74 (71%) had radiographically advanced disease; 30 (29%) were people with HIV. The trial was stopped early for lack of clinical efficacy. For the primary efficacy outcome, 49 (89%) of 55 group 1 participants and 28 (90%) of 31 group 2 participants had stable sputum culture conversion by week 12 (adjusted hazard ratio 1·21 [90% CI 0·82-1·79]; p=0·2089). Adverse events grade 3 or worse occurred in 26 (45%) of 58 group 1 participants and five (16%) of 31 group 2 participants (difference 30%, 90% CI 14-45; p=0·002). The cumulative probability of a week 65 unfavourable outcome was 52% (95% CI 37-69) in group 1 versus 27% (14-50) in group 2 (p=0·049). INTERPRETATION:Although the trial was stopped early, we found that a 3-month regimen containing clofazimine and rifapentine had 12-week culture conversion rates that did not differ statistically from the standard of care. The regimen was associated with an unacceptably high proportion of participants with unfavourable composite clinical outcomes and grade 3 or worse adverse events. FUNDING:US National Institutes of Health Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) and the National Institute of Allergy and Infectious Diseases.

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.

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.

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).

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.

AbstractThe 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.

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.

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.

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.

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..

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.