3HP preventive treatment among children and adolescents with HIV and child household contacts of TB patients.

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.

INTRODUCTION: Le programme national indien d'élimination de la tuberculose prévoit de mettre en place un traitement préventif de courte durée contre la tuberculose (TPT) en utilisant trois mois de rifapentine et d'isoniazide (3HP). Il est essentiel de comprendre la faisabilité et la sécurité des enfants dans le cadre des programmes pour pouvoir les mettre en œuvre à grande échelle. Nous présentons les résultats d'une extension ciblée de la 3HP parmi les enfants et les adolescents vivant avec le VIH (CALHIV, pour l'anglais « children and adolescents living with HIV ¼) et les enfants contacts familiaux (>2 à <6 ans) de patients atteints de tuberculose pulmonaire (CHHC, pour l'anglais « child household contacts ¼). MÉTHODES: Des doses hebdomadaires de 3HP ont été administrées pendant 3 mois aux participants éligibles CALHIV et CHHC dans les cliniques de thérapie antirétrovirale (ART) et de tuberculose, respectivement, d'un hôpital public de Pune, en Inde, entre décembre 2021 et juillet 2023. RÉSULTATS: Sur 97 enfants dépistés, 91 ont initié 3HP (32 CALHIV et 59 CHHC). L'âge médian des CALHIV était de 14 ans ; 66% étaient de sexe masculin et sous ART à base de dolutegravir. L'âge médian des CHHC était de 4 ans ; 47% étaient des hommes. Trente et un (97%) CALHIV et 56 (95%) CHHC ont terminé l'étude 3HP sans ajustement de la dose de dolutégravir. Aucun des enfants participants n'a interrompu le traitement 3HP en raison d'effets indésirables. Aucun enfant participant n'a développé de tuberculose au cours de l'année de suivi post-3HP. CONCLUSION: Notre étude fournit des preuves de l'adoption et de la faisabilité de la mise en œuvre prévue de 3HP à l'échelle nationale.

Three months of weekly rifapentine plus isoniazid for TB prevention among people with HIV.

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.

CONTEXTE: Les données probantes sur la mise en œuvre de 3 mois de traitement hebdomadaire d'isoniazide (H, INH) et de rifapentine (P, RPT) (3HP) en tant que traitement préventif de la TB (TPT) pour les groupes à risque dans les conditions programmatiques indiennes sont limitées. MÉTHODES: Une étude de démonstration prospective évaluant la mise à l'échelle, l'innocuité et l'efficacité de la TPT 3HP chez les personnes vivant avec le VIH (PVVIH) dans des contextes programmatiques indiens a été menée. RÉSULTATS: Sur les 656 PVVIH dépistés, 502 (77%) ont reçu le traitement 3HP. Parmi eux, 20 (4%) ont interrompu le TPT en raison de toxicité, 17 (3,8%) ont été perdus de vue, un (0,2%) a développé une TB sensible à la rifampicine et 464 (92%) ont terminé le TPT 3HP. Parmi les 288 (57%) événements indésirables (AE, pour l'anglais, « adverse events ¼) en tout, 46 (9%) ont présenté des AE de Grade 2 ou supérieur. Le délai médian jusqu'à l'apparition d'un AE était de 14 jours (IQR 7­42). Des événements indésirables graves ont été rapportés chez 9 (2%) participants ; parmi eux, 7 (78%) n'étaient pas liés au traitement 3HP. Aucun épisode de TB n'a été observé pendant la période de suivi d'un an. CONCLUSION: Le taux d'achèvement du TPT 3HP est de 92%, avec peu d'événements indésirables conduisant à l'arrêt du TPT 3HP, fournissant des preuves de l'évolutivité et de l'innocuité du TPT 3HP chez les PVVIH dans le cadre de programmes de santé indiens.

Facilitators and barriers to adolescent participation in a TB clinical trial.

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..

Factors associated with non-completion of TB preventive treatment in Brazil.

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.

Clinical standards for the diagnosis, treatment and prevention of TB infection.

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.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

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 (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); 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 6Pa200MZ, 4Pa200MZ, 4Pa100MZ 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 6Pa200MZ 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.

Nevirapine pharmacokinetics in HIV-infected persons receiving rifapentine and isoniazid for TB prevention.

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.

Health-related quality of life of inpatients and outpatients with TB in rural Malawi.

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.

Subclinical tuberculosis and adverse infant outcomes in pregnant women with HIV.

BACKGROUND: Tuberculosis (TB) in pregnant women with HIV is associated with adverse maternal and infant outcomes. Previous studies have described a substantial prevalence of subclinical TB in this group, but little is known about the impact of subclinical TB on maternal and pediatric outcomes.METHODS: The Tshepiso Study recruited 235 HIV-infected pregnant women with TB (and matched HIV-positive, TB-negative pregnant controls), in Soweto, South Africa, from 2011 to 2014. During enrolment screening, some women initially recruited as controls were subsequently diagnosed with prevalent TB. We therefore assessed the prevalence of subclinical TB, associated participant characteristics and outcomes.RESULTS: Of 162 women initially recruited as TB-negative controls, seven (4.3%) were found to have TB on sputum culture. All seven had negative WHO symptom screens, and six (86%) were smear-negative. Of their seven infants, one was diagnosed with TB, and three (43%) experienced complications compared to zero infants with TB and 11% experiencing complications in the control group of TB-negative mothers (P = 0.045).CONCLUSION: We discovered an appreciable prevalence of subclinical TB in HIV-infected pregnant women in Soweto, which had not been detected by screening algorithms based solely on symptoms. Infants of HIV-infected mothers with subclinical TB appear to have a higher risk of adverse outcomes than those of TB-negative mothers.

Detection and molecular characterization of urinary tract HIV-1 populations.

BACKGROUND: Identification of all possible HIV reservoirs is an important aspect in HIV eradication efforts. The urinary tract has however not been well studied as a potential HIV reservoir. In this pilot study we molecularly characterized HIV-1 viruses in urine and plasma samples to investigate HIV-1 replication, compartmentalization and persistence in the urinary tract. METHODS: Prospectively collected urine and blood samples collected over 12-36 months from 20 HIV-1 infected individuals were analysed including sampling points from prior to and after ART initiation. HIV-1 pol gene RNA and DNA from urine supernatant and urine pellets respectively were analysed and compared to plasma RNA viruses from the same individual. RESULTS: HIV-1 nucleic acid was detected in urine samples from at least one time point in 8/20 (40%) treatment-naïve subjects compared to 1/13 (7.7%) individuals on antiretroviral treatment (ART) during periods of plasma viral suppression and 1/7 (14.3%) individuals with virological failure. HIV-1 RNA was undetectable in urine samples after ART initiation but HIV-1 DNA was detectable in one patient more than 6 months after treatment initiation. There was co-clustering of urine-derived pol sequences but some urine-derived sequences were interspersed among the plasma-derived sequences. CONCLUSIONS: Suppressive ART reduces HIV-1 replication in the urinary tract but HIV-1 DNA may persist in these cells despite treatment. A larger number of sequences would be required to confirm HIV compartmentalization in the urinary tract.

Predictors of isoniazid preventive therapy completion among adults newly diagnosed with HIV in rural Malawi.

SETTING: To reduce the risk of tuberculosis (TB) among individuals with human immunodeficiency virus (HIV) infection, the World Health Organization recommends at least 6 months of isoniazid preventive therapy (IPT). Completion of IPT remains a major challenge in resource-limited settings. OBJECTIVE: To evaluate predictors of IPT completion in individuals newly diagnosed with HIV. DESIGN: Predictors of IPT completion among adults newly diagnosed with HIV in rural Malawi were evaluated using a multilevel logistic regression model. RESULTS: Of 974 participants who screened negative for active TB and were started on IPT, 732 (75%) completed treatment. Only one IPT-eligible individual refused treatment. Participants who were aged <25 years (compared with those aged 45 years, adjusted OR [aOR] 0.33, 95%CI 0.18-0.60) and male (compared to non-pregnant females, aOR 0.57, 95%CI 0.37-0.88) had lower odds of IPT completion. CONCLUSION: IPT provision at the time of initial HIV diagnosis was highly acceptable in rural Malawi; three quarters of those who initiated IPT successfully completed therapy. We observed lower odds of completion among males and among female participants aged <25 years. Additional efforts may be needed to ensure IPT completion among males and young females who have recently been diagnosed with HIV.

Delay in seeking care for tuberculosis symptoms among adults newly diagnosed with HIV in rural Malawi.

SETTING: Ten primary health clinics in rural Thyolo District, Malawi. OBJECTIVE: Tuberculosis (TB) is a common initial presentation of human immunodeficiency virus (HIV) infection. We investigated the time from TB symptom onset to HIV diagnosis to describe TB health-seeking behaviour in adults newly diagnosed with HIV. DESIGN: We asked adults (18 years) about the presence and duration of TB symptoms at the time of receiving a new HIV diagnosis. Associations with delayed health seeking (defined as >30 and >90 days from the onset of TB symptoms) were evaluated using multivariable logistic regression. RESULTS: TB symptoms were reported by 416 of 1265 participants (33%), of whom 36% (150/416) had been symptomatic for >30 days before HIV testing. Most participants (260/416, 63%) were below the poverty line (US$0.41 per household member per day). Patients who first sought care from informal providers had an increased odds of delay of >30 days (adjusted odds ratio [aOR] 1.6, 95%CI 0.9-2.8) or 90 days (aOR 2.0, 95%CI 1.1-3.8). CONCLUSIONS: Delayed health seeking for TB-related symptoms was common. Poverty was ubiquitous, but had no clear relationship to diagnostic delay. HIV-positive individuals who first sought care from informal providers were more likely to experience diagnostic delays for TB symptoms.

Factors associated with non-completion of follow-up: 33-month latent tuberculous infection treatment trial.

SETTING: A post-hoc exploratory analysis of a randomized, open-label clinical trial that enrolled 8053 participants from the United States, Canada, Brazil, and Spain. OBJECTIVE: To assess factors associated with non-completion of study follow-up (NCF) in a 33-month latent tuberculous infection treatment trial, PREVENT TB. DESIGN: Participants were randomized to receive 3 months of weekly directly observed therapy vs. 9 months of daily self-administered therapy. NCF was defined as failing to be followed for at least 993 days (33 months) from enrollment. Possible factors associated with NCF were analyzed using univariate and multivariate regression via Cox proportional hazard model. RESULTS: Of 7061 adults selected for analysis, 841 (11.9%) did not complete study follow-up. Homelessness, young age, low education, history of incarceration, smoking, missing an early clinic visit, receiving isoniazid only, and male sex were significantly associated with NCF. Similar results were found in the North American region (United States and Canada) only. In Brazil and Spain, the only significant factor was missing an early clinic visit. CONCLUSIONS: Study subjects at higher risk for NCF were identified by characteristics known at enrollment or in early follow-up. Evaluation of follow-up in other trials might help determine whether the identified factors consistently correlate with retention.

Treatment of non-cavitary pulmonary tuberculosis with shortened fluoroquinolone-based regimens: a meta-analysis.

SETTING: Several recent trials evaluating 4-month fluoroquinolone (FQ) containing regimens found that none of the experimental regimens were non-inferior to standard 6-month therapy in treating patients with drug-susceptible pulmonary tuberculosis (PTB). OBJECTIVE: To answer whether FQ-containing duration-shortened regimens are non-inferior to standard therapy in the treatment of patients with non-cavitary PTB. DESIGN: Systematic review of all randomized and quasi-randomized trials that substituted an FQ into standard therapy for less than 6 months' duration to treat drug-susceptible, non-cavitary PTB. Non-inferiority was based on a 6% margin of difference. RESULTS: Of 4594 total participants in the three trials that met the inclusion criteria, 1066 patients had non-cavitary disease. The pooled difference in unfavorable outcomes was 5% (95%CI -3 to 13) in patients with non-cavitary disease treated with FQ-containing regimens vs. standard therapy. In subgroup analyses, the pooled difference in unfavorable outcomes was 1% (95%CI -3 to 5) when comparing the daily form of intervention regimen with standard therapy, and -1% (95%CI -5 to 4) between regimens replacing ethambutol (EMB) with an FQ and standard therapy. No difference in risk of adverse events was noted. CONCLUSION: Daily administered 4-month regimens with substitution of EMB by an FQ may be non-inferior to standard therapy in patients with culture-confirmed, non-cavitary, drug-susceptible PTB.

Latent tuberculous infection in schoolchildren and contact tracing in Matlosana, North West Province, South Africa.

This is a cross-sectional study to estimate the prevalence of latent tuberculous infection (LTBI) and the annual risk of tuberculous infection (ARTI) among a sample of children aged 5 and 7 years in Matlosana, South Africa. LTBI prevalence was significantly higher in children aged 7 years (n = 704) (19.7%, 95%CI 16.75-22.65) than in those aged 5 years (212/1401, 15.1%, 95%CI 13.23-16.97) (P = 0.0075). The ARI was 2.9% (95%CI 2.2-3.6).

Undiagnosed TB in adults dying at home from natural causes in a high TB burden setting: a post-mortem study.

BACKGROUND: A high proportion of deaths in Africa occur at home, where cause of death (CoD) is often unknown. We ascertained undiagnosed pulmonary tuberculosis (TB) by performing limited autopsies in adults dying at home in whom there was no apparent CoD. METHODS: Mortuaries in Matlosana, South Africa, identified potentially eligible adults with no ante-mortem diagnosis and/or no recent hospital admission. A questionnaire was administered to family members. Bilateral lung core biopsies and modified bronchoalveolar lavage (BAL) were performed. The biopsies were examined histologically and submitted with BAL aspirates for mycobacterial culture (MGIT(TM)) and Xpert(®) MTB/RIF testing. Human immunodeficiency virus (HIV) testing was not performed. RESULTS: Of 162 families approached, 28 refused and 29 of the deceased were on or had recently stopped anti-tuberculosis treatment; 85 were included. All were Black and 53% were men. The median age was 57 years (interquartile range [IQR] 44-66) and median symptom duration (mainly cough) was 63 days (IQR 14-112). Laboratory evidence of TB was found in 27 (31.8%); 21 were Xpert-positive, 23 were MGIT-positive and 14 had histological evidence consistent with active TB. CONCLUSION: In this high HIV prevalence setting, a quarter of the home deaths had evidence of undiagnosed, likely infectious TB, suggesting that TB-related mortality is under-ascertained and under-reported, with serious implications for TB control in high TB burden settings.