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Background: Tuberculosis (TB) prevalence remains persistently high in many settings, with new or expanded interventions required to achieve substantial reductions. The HIV Prevention Trials Network (HPTN) 071 (PopART) community-randomised trial randomised 14 communities to receive the "PopART" intervention during 2014 to 2017 (7 arm A and 7 arm B communities) and 7 communities to receive standard-of-care (arm C). The intervention was delivered door-to-door by community HIV care providers (CHiPs) and included universal HIV testing, facilitated linkage to HIV care at government health clinics, and systematic TB symptom screening. The Tuberculosis Reduction through Expanded Anti-retroviral Treatment and Screening (TREATS) study aimed to measure the impact of delivering the PopART intervention on TB outcomes, in communities with high HIV and TB prevalence., Methods and Findings: The study population of the HPTN 071 (PopART) trial included individuals aged ≥15 years living in 21 urban and peri-urban communities in Zambia and South Africa, with a total population of approximately 1 million and an adult HIV prevalence of around 15% at the time of the trial. Two sputum samples for TB testing were provided to CHiPs by individuals who reported ≥1 TB suggestive symptom (a cough for ≥2 weeks, unintentional weight loss ≥1.5 kg in the last month, or current night sweats) or that a household member was currently on TB treatment. Antiretroviral therapy (ART) was offered universally at clinics in arm A and according to local guidelines in arms B and C. The TREATS study was conducted in the same 21 communities as the HPTN 071 (PopART) trial between 2017 and 2022, and TB prevalence was a co-primary endpoint of the TREATS study. The primary comparison was between the PopART intervention (arms A and B combined) and the standard-of-care (arm C). During 2019 to 2021, a TB prevalence survey was conducted among randomly selected individuals aged ≥15 years (approximately 1,750 per community in arms A and B, approximately 3,500 in arm C). Participants were screened on TB symptoms and chest X-ray, with diagnostic testing using Xpert-Ultra followed by culture for individuals who screened positive. Sputum eligibility was determined by the presence of a cough for ≥2 weeks, or ≥2 of 5 "TB suggestive" symptoms (cough, weight loss for ≥4 weeks, night sweats, chest pain, and fever for ≥2 weeks), or chest X-ray CAD4TBv5 score ≥50, or no available X-ray results. TB prevalence was compared between trial arms using standard methods for cluster-randomised trials, with adjustment for age, sex, and HIV status, and multiple imputation was used for missing data on prevalent TB. Among 83,092 individuals who were eligible for the survey, 49,556 (59.6%) participated, 8,083 (16.3%) screened positive, 90.8% (7,336/8,083) provided 2 sputum samples for Xpert-Ultra testing, and 308 (4.2%) required culture confirmation. Overall, estimated TB prevalence was 0.92% (457/49,556). The geometric means of 7 community-level prevalence estimates were 0.91%, 0.70%, and 0.69% in arms A, B, and C, respectively, with no evidence of a difference comparing arms A and B combined with arm C (adjusted prevalence ratio 1.14, 95% confidence interval, CI [0.67, 1.95], p = 0.60). TB prevalence was higher among people living with HIV than HIV-negative individuals, with an age-sex-community adjusted odds ratio of 2.29 [95% CI 1.54, 3.41] in Zambian communities and 1.61 [95% CI 1.13, 2.30] in South African communities. The primary limitations are that the study was powered to detect only large reductions in TB prevalence in the intervention arm compared with standard-of-care, and the between-community variation in TB prevalence was larger than anticipated., Conclusions: There was no evidence that the PopART intervention reduced TB prevalence. Systematic screening for TB that is based on symptom screening alone may not be sufficient to achieve a large reduction in TB prevalence over a period of several years. Including chest X-ray screening alongside TB symptom screening could substantially increase the sensitivity of systematic screening for TB., Trial Registration: The TREATS study was registered with ClinicalTrials.gov Identifier: NCT03739736 on November 14, 2018. The HPTN 071 (PopART) trial was registered at ClinicalTrials.gov under number NCT01900977 on July 17, 2013., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Klinkenberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Prevalence surveys remain the best way to assess the national tuberculosis (TB) burden in many countries. Challenges with using culture (the reference standard) for TB diagnosis in prevalence surveys have led to increasing use of molecular tests (Xpert assays), but discordance between these two tests has created problems for deciding which individuals have TB. We aimed to design an accurate diagnostic algorithm for TB prevalence surveys (TBPS) that limits the use of culture., Design: TBPS in four communities, conducted during 2019., Setting: Three Zambian communities and one South-African community included in the TBPS of the Tuberculosis Reduction through Expanded Anti-retroviral Treatment and Screening study., Participants: Randomly sampled individuals aged ≥15 years. Among those who screened positive on chest X-ray or symptoms, two sputum samples were collected for field Xpert-Ultra testing and a third for laboratory liquid-culture testing. Clinicians reviewed screening and test results; in Zambia, participants with Mycobacterium tuberculosis -positive results were followed up 6-13 months later. Among 10 984 participants, 2092 screened positive, 1852 provided two samples for Xpert-Ultra testing, and 1009 had valid culture results., Outcomes: Culture and Xpert-Ultra test results., Results: Among 946 culture-negative individuals, 917 were Xpert-negative, 12 Xpert-trace-positive and 17 Xpert-positive (grade very low, low, medium or high), with Xpert categorised as the highest grade of the two sample results. Among 63 culture-positive individuals, 8 were Xpert-negative, 9 Xpert-trace-positive and 46 Xpert-positive. Counting trace-positive results as positive, the sensitivity of Xpert-Ultra compared with culture was 87% (95% CI 76% to 94%) using two samples compared with 76% (95% CI 64% to 86%) using one. Specificity was 97% when trace-positive results were counted as positive and 98% when trace-positive results were counted as negative. Most Xpert-Ultra-positive/culture-negative discordance was among individuals whose Xpert-positive results were trace-positive or very low grade or they reported previous TB treatment. Among individuals with both Xpert-Ultra results grade low or above, the positive-predictive-value was 90% (27/30); 3/30 were plausibly false-negative culture results., Conclusion: Using Xpert-Ultra as the primary diagnostic test in TBPS, with culture only for confirmatory testing, would identify a high proportion of TB cases while massively reducing survey culture requirements., Trial Registration Number: NCT03739736., 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: Rwanda conducted a national tuberculosis (TB) prevalence survey to determine the magnitude of TB in the country and determine to what extent the national surveillance system captures all TB cases. In addition we measured the patient diagnostic rate, comparing the measured TB burden data with the routine surveillance data to gain insight into how well key population groups are being detected., Methods: A national representative nationwide cross-sectional survey was conducted in 73 clusters in 2012 whereby all enrolled participants (residents aged 15 years and above) were systematically screened for TB by symptoms and chest X-ray (CXR). Those with either clinical symptoms (cough of any duration) and/or CXR abnormalities suggestive of TB disease were requested to provide two sputum samples (one spot and one morning) for smear examination and solid culture., Results: Of the 45,058 eligible participants, 43,779 were enrolled in the survey. Participation rate was high at 95.7% with 99.8% of participants undergoing both screening procedures and 99.0% of those eligible for sputum examination submitting at least one sputum sample. Forty cases of prevalent mycobacterium tuberculosis (MTB) and 16 mycobacteria other than tuberculosis (MOTT) cases were detected during the survey. Chest x-ray as screening tool had 3 and 5 times greater predictive odds for smear positive and bacteriological confirmed TB than symptom screening alone respectively. A TB prevalence of 74.1 (95% CI 48.3-99.3) per 100,000 adult population for smear positive TB and 119.3 (95% CI 78.8-159.9) per 100,000 adult population for bacteriological confirmed MTB was estimated for Rwanda., Conclusions: The survey findings indicated a lower TB prevalence than previously estimated by WHO providing key lessons for national TB control, calling for more sensitive screening and diagnostic tools and a focus on key populations. Use of chest x-ray as screening tool was introduced to improve the diagnostic yield of TB., Competing Interests: We declare no competing interests.

Objective: To determine the prevalence of resistance to rifampicin alone; rifampicin and isoniazid, and second-line anti-TB drugs among sputum smear-positive tuberculosis patients in Zimbabwe., Design: A health facility-based cross-sectional survey., Results: In total, 1114 (87.6%) new and 158 (12.4%) retreatment TB patients were enrolled. MTB was confirmed by Xpert MTB/RIF among 1184 (93%) smear-positive sputum samples. There were 64 samples with Xpert MTB/RIF-determined rifampicin resistance. However, two were rifampicin susceptible on phenotypic drug susceptibility testing. The prevalence of RR-TB was [4.0% (95% CI, 2.9, 5.4%), n=42/1043) and 14.2% (95% CI, 8.9, 21.1%; n=20/141) among new and retreatment patients, respectively. The prevalence of MDR-TB was 2.0% (95% CI, 1.3, 3.1%) and 6.4% (95% CI, 2.4, 10.3%) among new and retreatment TB patients, respectively. Risk factors for RR-TB included prior TB treatment, self-reported HIV infection, travel outside Zimbabwe for ≥one month (univariate), and age <15 years. Having at least a secondary education was protective against RR-TB., Conclusion: The prevalence of MDR-TB in Zimbabwe has remained stable since the 1994 subnational survey. However, the prevalence of rifampicin mono-resistance was double that of MDR-TB., (Copyright © 2019. Published by Elsevier Ltd.)

SETTING: Namibia ranks among the 30 high TB burden countries worldwide. Here, we report results of the second nationwide anti-TB drug resistance survey. OBJECTIVE: To assess the prevalence and trends of multidrug-resistant TB (MDR-TB) in Namibia. METHODS: From 2014 to 2015, patients with presumptive TB in all regions of Namibia had sputum subjected to mycobacterial culture and phenotypic drug susceptibility testing (DST) for rifampicin, isoniazid, ethambutol and streptomycin if positive on smear microscopy and/or Xpert MTB/RIF. RESULTS: Of the 4124 eligible for culture, 3279 (79.5%) had Mycobacterium tuberculosis isolated. 3126 (95%) had a first-line DST completed (2392 new patients, 699 previously treated patients, 35 with unknown treatment history). MDR-TB was detected in 4.5% (95%CI 3.7-5.4) of new patients, and 7.9% (95%CI 6.0-10.1) of individuals treated previously. MDR-TB was significantly associated with previous treatment (OR 1.8, 95%CI 1.3-2.5) but not with HIV infection, sex, age or other demographic factors. Prior treatment failure demonstrated the strongest association with MDR-TB (OR 17.6, 95%CI 5.3-58.7). CONCLUSION: The prevalence of MDR-TB among new TB patients in Namibia is high and, compared with the first drug resistance survey, has decreased significantly among those treated previously. Namibia should implement routine screening of drug resistance among all TB patients.

Background: Knowledge of the HIV status in patients with tuberculosis (TB) and vice versa is crucial for proper individual patient management, while knowledge of the prevalence of co-infection guides preventive and therapeutic strategies. The aim of the study was to assess if national disease databases on TB and HIV are adequate sources to provide this information., Methods: A two way capture-recapture analysis to assess the completeness of the registers, and to obtain the prevalence of TB-HIV co-infection in the Netherlands in the years 2002-2012., Results: HIV testing was performed in less than 50% of the patients with TB. Of the 932 TB-HIV infected patients, just 293 (31.4%) were registered in both registers. Under-reporting of TB-HIV co-infection ranged from 50% to 70% in the national TB register, and from 31% to 37% in the HIV database. Prevalence of TB-HIV co-infection in the Netherlands in 2012 was 7.1% (95% CI 6.0% to 8.3%), which was more than double of the prevalence estimated from the national TB database., Conclusions: TB-HIV co-infection is markedly under-reported in national disease databases. There is an urgent need for improved registration and preferably a routine data exchange between the two surveillance systems., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Tuberculosis in Zambia is a major public health problem, however the country does not have reliable baseline data on the TB prevalence for impact measurement; therefore it was among the priority countries identified by the World Health Organization to conduct a national TB prevalence survey., Objective: To estimate the prevalence of tuberculosis among the adult Zambian population aged 15 years and above, in 2013-2014., Methods: A cross-sectional population-based survey was conducted in 66 clusters across all the 10 provinces of Zambia. Eligible participants aged 15 years and above were screened for TB symptoms, had a chest x-ray (CXR) performed and were offered an HIV test. Participants with TB symptoms and/or CXR abnormality underwent an in-depth interview and submitted one spot- and one morning sputum sample for smear microscopy and liquid culture. Digital data collection methods were used throughout the process., Results: Of the 98,458 individuals who were enumerated, 54,830 (55.7%) were eligible to participate, and 46,099 (84.1%) participated. Of those who participated, 45,633/46,099 (99%) were screened by both symptom assessment and chest x-ray, while 466/46,099 (1.01%) were screened by interview only. 6,708 (14.6%) were eligible to submit sputum and 6,154/6,708 (91.7%) of them submitted at least one specimen for examination. MTB cases identified were 265/6,123 (4.3%). The estimated national adult prevalence of smear, culture and bacteriologically confirmed TB was 319/100,000 (232-406/100,000); 568/100,000 (440-697/100,000); and 638/100,000 (502-774/100,000) population, respectively. The risk of having TB was five times higher in the HIV positive than HIV negative individuals. The TB prevalence for all forms was estimated to be 455 /100,000 population for all age groups., Conclusion: The prevalence of tuberculosis in Zambia was higher than previously estimated. Innovative approaches are required to accelerate the control of TB.

Background: There is limited information on the distribution of incubation periods of tuberculosis (TB)., Methods: In The Netherlands, patients whose Mycobacterium tuberculosis isolates have identical DNA fingerprints in the period 1993-2007 were interviewed to identify epidemiological links between cases. We determined the incubation period distribution in secondary cases. Survival analysis techniques were used to include secondary cases not yet symptomatic at diagnosis with weighting to adjust for lower capture probabilities of couples with longer time intervals between their diagnoses. In order to deal with missing data, we used multiple imputations., Results: We identified 1095 epidemiologically linked secondary cases, attributed to 688 source cases with pulmonary TB. Of those developing disease within 15 years, the Kaplan-Meier probability to fall ill within 1 year was 45%, within 2 years 62% and within 5 years 83%. The incubation time was shorter in secondary cases who were men, young, those with extra-pulmonary TB and those not reporting previous TB or previous preventive therapy., Conclusions: Molecular epidemiological analysis has allowed a more precise description of the incubation period of TB than was possible in previous studies, including the identification of risk factors for shorter incubation periods.

Molecular epidemiologic studies may use genotypic clustering of isolates as an indicator of recent transmission. It has been shown that missing cases lead to underestimating clustering, and modelling studies suggested that they may also lead to underestimating odds ratios for clustering. Using a national, comprehensive database from the Netherlands covering 15 years between 1993 and 2007 and including over 12,000 patients and their isolates, the authors determined the effects of sampling at random, in time, and by geographic area. As expected, sampling reduced the observed clustering percentages. However, sampling did not reduce the observed odds ratios for clustering. The main explanations for this discrepancy with model outcomes were that a substantial proportion of clustered cases were found in large clusters and that risk factors for clustering tended to be-among clustered cases-also risk factors for large clusters. The authors conclude that, in settings where risk factors for clustering may be interpreted as risk factors for recent transmission, these risk factors are also associated with larger cluster sizes. As a result, odds ratios would show limited sampling bias.

This study aimed to determine to what extent tuberculosis trends in the Netherlands depend on secular trend, immigration and recent transmission. Data on patients in the Netherlands Tuberculosis Register in the period 1993-2007 were matched with restriction fragment length polymorphism (RFLP) patterns of Mycobacterium tuberculosis isolates. Index patients were defined as patients with pulmonary tuberculosis whose isolates had RFLP patterns not observed in another patient in the previous 2 yrs. Among 8,330 patients with pulmonary tuberculosis the isolates of 56% of native and 50% of foreign-born patients were clustered. Of these, 5,185 were included in detailed analysis: 1,376 native index patients, 2,822 foreign-born index patients and 987 secondary cases within 2 yrs of diagnosis of the index case. The incidence of native and foreign-born index patients declined by 6% and 2% per year, respectively. The number of secondary cases per index case was 0.24. The decline of native cases contributed most to the overall decline of tuberculosis rates and was largely explained by a declining prevalence of latent infection. Tuberculosis among immigrants was associated with immigration figures. Progress towards elimination of tuberculosis would benefit from intensifying diagnosis and treatment of latent infection among immigrants and global tuberculosis control.

Setting: Kenya, a country with a high burden of tuberculosis (TB) and human immunodeficiency virus (HIV) infection., Objectives: To assess the prevalence of TB infection, bacille Calmette-Guérin (BCG) coverage and the annual risk of tuberculosis infection (ARTI), and to compare estimates with previous findings., Methods: A sample of primary school children aged 6-14 years from the same study districts sampled in previous surveys were tuberculin skin tested using the Mantoux method from September 2004 to July 2007. The prevalence of TB infection was estimated by the mirror method, with the mode at 17 mm., Results: Of the 94 771 registered children, 76 676 (80.9%) completed the survey investigations, 12 107 (15.8%) of whom had no BCG scar. The prevalence of TB infection was estimated at 10.2%, with a corresponding ARTI of 1.1%. The ARTI obtained from the current survey is comparable to that of the 1994-1996 survey and higher than that of the 1986-1990 survey. The BCG coverage was comparable with the 1994-1996 survey and higher than in the 1986-1990 survey., Conclusion: TB transmission in Kenya has remained the same over the last decade, which suggests that activities undertaken by the TB control programme have been sufficient to hold TB transmission steady, but insufficient to reduce it.

Setting: Six provinces in Vietnam where the DOTS strategy was introduced in 1989., Objective: To assess the impact of improved tuberculosis (TB) control on TB epidemiology in Vietnam., Methods: Data from the surveillance system in the period 1990-2003 were analysed to assess trends of notification rates and the mean ages of notified cases. Data from repeated tuberculin surveys in the period 1986-2002 were estimated to assess the prevalence of TB infection, the annual risk of infection and its trend using various cut-off points in those with and without bacille Calmette-Guérin (BCG) scar., Results: Age-standardised notification rates in the period 1996-2003 declined significantly, by 2.6% to 5.9% per year, in five provinces. However, in four provinces notification rates in the age group 15-24 years increased significantly, by 4.5% to 13.6% per year, during this period. The mean age of newly diagnosed patients with smear-positive TB increased up to 1995 but decreased thereafter. The annual risk of TB infection showed a significant annual decrease (4.9% per year) in one province in surveys performed between 1986 and 1997, and in two provinces (6.6% and 4.7%) in surveys conducted between 1993 and 2002., Conclusion: These data suggest limited impact to date of the DOTS strategy in Vietnam.

Objective: To assess the impact of the HIV epidemic on tuberculosis transmission in Tanzania by estimating the trend in annual risk of tuberculosis infection (ARTI) over the period 1983-2003., Design: Tuberculin survey among school children aged 6-14 years, randomly selected by cluster sampling., Methods: Primary outcome was the ARTI among children without a BCG vaccination scar. To obtain time trends, data were reanalysed from three previous surveys carried out at intervals of 5 years since 1983, using identical methods and definitions., Results: Of 96,226 children included in the analysis (74% of those enrolled), 10,239 (11%) had no BCG scar. The ARTI was 0.68% (95% confidence interval 0.55-0.81). Despite a doubling of notification rates of smear-positive tuberculosis since 1983, this represents an average annual decline since the first survey of 2.7% (P < 0.001). The declining trend in ARTI was observed in 17 of 20 regions, with no association between this trend and region-specific prevalence of HIV infection among patients with tuberculosis (P = 0.575). A similar decline in ARTI was observed among children with a BCG scar and for various ways of estimating the prevalence of tuberculosis infection from the distribution of skin test reactions., Conclusion: Despite substantial increases in tuberculosis incidence, the overall population-level effect of the HIV epidemic on tuberculosis transmission in Tanzania has been limited. This suggests that in the presence of a strong control programme, the HIV epidemic has limited impact on tuberculosis transmission.

Background: Severe liver injury has been attributed to preventive treatment of latent tuberculosis infection with a 2-month course of rifampin-pyrazinamide., Methods: A retrospective cohort study in The Netherlands compared the hepatotoxicity of preventive treatment with rifampin-pyrazinamide with that of preventive treatment with isoniazid, and also with that of treatment for active tuberculosis containing at least isoniazid, rifampin, and pyrazinamide., Results: Preventive treatment with rifampin-pyrazinamide caused severe hepatotoxicity more often than did preventive treatment with isoniazid (odds ratio [OR], 2.61; 95% confidence interval [CI], 1.26-5.39; P=.012), especially in patients <25 years old. It also caused severe hepatotoxicity more often than triple- or quadruple-drug tuberculosis treatment (OR, 2.61; 95% CI, 1.21-5.59; P=.016), especially if the pyrazinamide dose was > or =30 mg/kg. Preventive treatment with rifampin-pyrazinamide was more hepatotoxic even when the advised pyrazinamide dose of up to 20 mg/kg for preventive treatment was compared with the pyrazinamide dose of 30 mg/kg for tuberculosis treatment., Conclusions: Preventive treatment with rifampin-pyrazinamide causes severe hepatotoxicity more often than does preventive treatment with isoniazid or curative treatment for tuberculosis.