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Treatment of latent tuberculosis infection is an important control measure, especially in patients coinfected with HIV. In this international phase 3 trial, 1 month of isoniazid plus rifapentine was noninferior to the standard 9 months of isoniazid in HIV-infected patients.

IntroductionTreatment of latent tuberculosis infection (LTBI) plays a substantial role in the prevention of drug-susceptible tuberculosis (TB). However, clinical trials to evaluate the efficacy of preventive therapy for presumed multidrug-resistant (MDR) LTBI are lacking. This trial aims to evaluate the efficacy of the antibiotic levofloxacin in preventing the development of active TB among latently infected contacts of index patients with MDR-TB.Methods and analysisA double-blind placebo-controlled parallel group randomised controlled trial will be conducted in 10 provinces of Vietnam. Household contacts living with patients with bacteriologically confirmed rifampicin-resistant or MDR-TB will be eligible for recruitment if they have a positive tuberculin skin test or are known to be immunosuppressed, and do not have active TB. Participants will be randomised to receive either levofloxacin or placebo tablets once per day for 6 months. Screening for incident TB will be performed at 6 months intervals. The primary study outcome is the incidence of bacteriologically confirmed TB within 30 months after randomisation. Analysis will be by intention to treat, using Poisson regression.EthicsEthical approval from the University of Sydney Human Research Ethics Committee was obtained on 29 April 2015 (2014/929), and from the Vietnam Ministry of Health Institutional Review Board on 30 September 2015 (4040/QD-BYT).DisseminationFindings of the study will be published in peer-reviewed publications and conference presentations.Trial registration numberACTRN12616000215426.

Background. Randomized controlled trials have demonstrated that the newest latent tuberculosis (LTBI) regimen, 12 weekly doses of directly observed isoniazid and rifapentine (3HP), is as efficacious as 9 months of isoniazid, with a greater completion rate (82% vs 69%); however, 3HP has not been assessed in routine healthcare settings. Methods. Observational cohort of LTBI patients receiving 3HP through 16 US programs was used to assess treatment completion, adverse drug reactions, and factors associated with treatment discontinuation. Results. Of 3288 patients eligible to complete 3HP, 2867 (87.2%) completed treatment. Children aged 2–17 years had the highest completion rate (94.5% [155/164]). Patients reporting homelessness had a completion rate of 81.2% (147/181). In univariable analyses, discontinuation was lowest among children (relative risk [RR], 0.44 [95% confidence interval {CI}, .23–.85]; P = .014), and highest in persons aged ≥65 years (RR, 1.72 [95% CI, 1.25–2.35]; P < .001). In multivariable analyses, discontinuation was lowest among contacts of patients with tuberculosis (TB) disease (adjusted RR [ARR], 0.68 [95% CI, .52–.89]; P = .005) and students (ARR, 0.45 [95% CI, .21–.98]; P = .044), and highest with incarceration (ARR, 1.43 [95% CI, 1.08–1.89]; P = .013) and homelessness (ARR, 1.72 [95% CI, 1.25–2.39]; P = .001). Adverse drug reactions were reported by 1174 (35.7%) patients, of whom 891 (76.0%) completed treatment. Conclusions. Completion of 3HP in routine healthcare settings was greater overall than rates reported from clinical trials, and greater than historically observed using other regimens among reportedly nonadherent populations. Widespread use of 3HP for LTBI treatment could accelerate elimination of TB disease in the United States.

Expanding access to shorter regimens for tuberculosis (TB) prevention, such as once-weekly isoniazid and rifapentine taken for 3 months (3HP), is critical for reducing global TB burden among people living with HIV (PLHIV). Our coprimary hypotheses were that high levels of acceptance and completion of 3HP could be achieved with delivery strategies optimized to overcome well-contextualized barriers and that 3HP acceptance and completion would be highest when PLHIV were provided an informed choice between delivery strategies. In a pragmatic, single-center, 3-arm, parallel-group randomized trial, PLHIV receiving care at a large urban HIV clinic in Kampala, Uganda, were randomly assigned (1:1:1) to receive 3HP by facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid. We assessed the primary outcome of acceptance and completion (≥11 of 12 doses of 3HP) within 16 weeks of treatment initiation using proportions with exact binomial confidence intervals (CIs). We compared proportions between arms using Fisher's exact test (two-sided α = 0.025). Trial investigators were blinded to primary and secondary outcomes by study arm. Between July 13, 2020, and July 8, 2022, 1,656 PLHIV underwent randomization, with equal numbers allocated to each study arm. One participant was erroneously enrolled a second time and was excluded in the primary intention-to-treat analysis. Among the remaining 1,655 participants, the proportion who accepted and completed 3HP exceeded the prespecified 80% target in the DOT (0.94; 97.5% CI [0.91, 0.96] p < 0.001), SAT (0.92; 97.5% CI [0.89, 0.94] p < 0.001), and Choice (0.93; 97.5% CI [0.91, 0.96] p < 0.001) arms. There was no difference in acceptance and completion between any 2 arms overall or in prespecified subgroup analyses based on sex, age, time on antiretroviral therapy, and history of prior treatment for TB or TB infection. Only 14 (0.8%) participants experienced an adverse event prompting discontinuation of 3HP. The main limitation of the study is that it was conducted in a single center. Multicenter studies are now needed to confirm the feasibility and generalizability of the facilitated 3HP delivery strategies in other settings. Short-course TB preventive treatment was widely accepted by PLHIV in Uganda, and very high levels of treatment completion were achieved in a programmatic setting with delivery strategies tailored to address known barriers. ClinicalTrials.gov NCT03934931.

In order to eliminate tuberculosis (TB) in the USA, primary care providers must take on an expanded role in the diagnosis and management of latent tuberculosis infection (LTBI). Clinical practice guidelines and recommendations exist for LTBI management, but there is a need for innovative tools to improve medical students' and residents' knowledge of evidence-based practices for LTBI testing and treatment. To assess the impact of LTBI-ASSIST, a free online decision support aid, as a novel educational tool and mechanism of delivering clinical practice guidelines for medical trainees. A single site, randomized controlled trial of trainees delivered by electronic survey. Medical students and Internal Medicine residents at the Johns Hopkins University School of Medicine. Participants were randomized in 1:1 ratio to receive the US clinical practice guidelines and recommendations for Latent TB management (control arm) or the guidelines plus an introduction to LTBI-ASSIST (LTBI-ASSIST arm) as they completed a case-based knowledge assessment and reported confidence with domains of LTBI care. (1) Proportion of questions answered correctly on a case-based knowledge assessment; (2) change in reported confidence with domains of LTBI care. One hundred and thirty participants completed the knowledge assessment. Those randomized to receive the LTBI-ASSIST Tool performed better on the case-based knowledge assessment with a mean score of 75.9% (95% CI: 70.6-81.1), compared to 57.4% (52.8-62.0) in the group that received the guidelines only (p <0.001). Similarly, the LTBI-ASSIST group reported a higher change in confidence (measured as post-assessment confidence minus pre-assessment confidence), compared to the control group, in six of the seven domains of LTBI care. LTBI-ASSIST can be an effective supplement to existing guidelines in educating medical trainees and helping providers find evidence-based, guideline-supported answers for questions encountered in clinical practice. NIH Clinical Trial Registry No. NCT05772065.

Epidemiological and interventional studies have been rarely conducted among those with positive interferon-γ release assay (IGRA) results and radiologically inactive tuberculosis (TB) lesions on chest radiograph. This study aimed to estimate the effectiveness and safety of a six-week twice-weekly regimen (rifapentine plus isoniazid) among this key population in rural China. First, chest digital radiography was conducted to screen individuals with inactive TB lesions. Then, the identified participants were further evaluated and eligible participants with IGRA-positive results were included in subsequent randomized controlled trial (RCT). Of 44,500 recruited residents, 2,988 presented with radiographically inactive TB among 43,670 with complete results of chest radiography and questionnaire, and 28.61% (855/2,988) tested IGRA positive. Subsequently, 677 eligible participants were included in this RCT (345 in the preventive treatment group and 332 in the untreated control group). The treatment completion rate was 80.00% (276/345), and 11.88% (41/345) participants reported side-effects including two cases of hepatotoxicity (0.58%, 2/345). In the intention-to-treat analysis, the cumulative incidence rate of microbiologically confirmed active TB during a two-year follow-up was 1.16 (95% confidence interval [CI]: 0.03-2.29) in the preventive treatment group and 1.51 (95% CI: 0.20-2.82) in the control group (p = .485). Subgroup analyses showed that the protective rates were 55.42% (95% CI: 10.33-93.07%) and 80.17% (95% CI: 25.36-97.96%) for participants with fibrosis and for those aged ≥60 years, respectively. The expected treatment effect was not observed for the six-week regimen in this study. Future studies with sufficient sample size are needed to verify our findings.

Background. Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid for 9 months (9H) for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome. Methods. We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT Tuberculosis study. Results. Among 7552 persons who received ≥1 dose of study drug, 153 had a SDR: 138/3893 (3.5%) with 3HP vs 15/3659 (0.4%) with 9H (P < .001). In the 3HP arm, 87 (63%) had flu-like syndrome and 23 (17%) had cutaneous reactions; 13/3893 (0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (adjusted odds ratio [aOR] 9.4; 95% confidence interval [CI], 5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3; 95% CI, 2.3, 4.7), female sex (aOR 2.0; 95% CI, 1.4, 2.9), age ≥35 years (aOR 2.0; 95% CI, 1.4, 2.9), and lower body mass index (body mass index [BMI]; P = .009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4; 95% CI, 1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9; 95% CI, 1.3, 27.1). Conclusions. SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear. Clinical Trials Registration. NCT00023452.

Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy. To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (H, 300 mg) (9H). Data from reproductive-age (15-51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date. Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13% - 14% = -1%; 95% confidence interval = -17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% - 5% = -5%; 95% confidence interval = -18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively. Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33).

Trials of isoniazid preventive therapy (IPT) for people living with HIV in southern Africa have shown high rates of tuberculosis disease immediately after cessation of therapy. This could be due to the lack of cure following preventive therapy or reinfection with rapid progression to disease. Using a model fitted to trial data, we estimate the degree to which preventive therapies cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-tuberculosis-burden settings. We identified randomized controlled trials that compared IPT to placebo or alternative regimen in HIV-positive, tuberculin skin test positive individuals. A mathematical model describing tuberculosis transmission in a closed cohort of HIV-positive, M. tuberculosis infected, antiretroviral therapy naive individuals following completion of preventive therapy (or placebo) was fitted to posttherapy tuberculosis rates to estimate the annual risk of M. tuberculosis reinfection and the proportion of individuals whose latent infection was cured after therapy. Three trials met our inclusion criteria. Estimated annual risks of reinfection ranged between 3.7 and 4.9%. Our results suggest 6 mo of isoniazid cured in a small proportion [estimated proportion cured = 0% (interquartile range 0–30.9%)]. The proportion cured for 3-mo regimens containing rifampicin or rifapentine was 19–100%. IPT alone does not cure existing infections in the majority of HIV-infected individuals. In high-incidence settings, continuous IPT should be integrated with HIV care. Where the risk of reinfection is lower, preventive therapy with more curative drugs should be preferred for HIV-positive individuals to achieve durable patient benefit.

Background. Overall rates of noncompletion of treatment (NCT) for latent tuberculosis infection (LTBI) in the PREVENT TB trial were 18% for 3 months of directly observed once-weekly rifapentine (maximum dose, 900 mg) plus isoniazid (maximum dose, 900 mg) (3HP-DOT) and 31% for 9 months of daily self-administered isoniazid (maximum dose, 300 mg; 9H-SAT). NCT for LTBI reduces its effectiveness. The study objective was to assess factors associated with NCT for LTBI among adult participants enrolled at US and Canadian sites of the PREVENT TB trial. Methods. This was a post hoc exploratory analysis of the randomized, open-label PREVENT TB trial. Factors were analyzed by univariate and multivariate logistic regression (with enrollment site as a random effect). Results. From 6232 participants analyzed, 1406 (22.6%) did not complete LTBI treatment (317 NCT attributed to an adverse event [NCT-AE] and 1089 NCT attributed to reasons other than an adverse event [NCT-O]). The proportion of NCT-AE was similar with both regimens (3HP-DOT = 6.4% vs 9H-SAT = 5.9%; P = .23); NCT-O was higher among participants enrolled in 9H-SAT (9H-SAT = 24.5% vs 3HP-DOT = 12.7%; P = .02). Among those in the NCT-AE group, being non-Hispanic and receiving 3HP-DOT, having cirrhosis and receiving 9H-SAT, alcohol consumption among men, and use of concomitant medication were associated with NCT-AE. Among those in the NCT-O group, receiving 9H-SAT, missing ≥1 early visit, men receiving 9H-SAT, men with a history of incarceration, alcohol abuse, use ever of intravenous drugs, younger age receiving 9H-SAT, and smoking were associated with NCT-O. Conclusions. Factors associated with NCT, such as missing a clinic visit early during treatment, might help identify persons for whom tailored interventions could improve completion of LTBI treatment. Clinical Trials Registration. NCT00023452.