High Tuberculosis Burden Settings Research Articles

Use of integrase inhibitors in HIV-associated tuberculosis in high-burden settings: implementation challenges and research gaps.

People living with HIV have a higher risk of developing tuberculosis, and tuberculosis is one of the leading causes of death among people living with HIV globally. Treating HIV and tuberculosis concurrently has morbidity and mortality benefits. However, HIV and tuberculosis co-treatment is challenging due to drug-drug interactions, overlapping toxicities, tuberculosis-associated immune reconstitution syndrome, and concerns for treatment failure or drug resistance. Drug-drug interactions between antiretrovirals and tuberculosis drugs are driven mainly by the rifamycins (for example, the first-line tuberculosis drug rifampicin), and dose adjustments or drug switches during co-treatment are commonly required. Several implementation challenges and research gaps exist when combining the integrase strand transfer inhibitors (INSTIs), highly potent antiretroviral drugs recommended as first-line treatment of HIV, and drugs used for the treatment and prevention of tuberculosis. Ongoing and planned studies will address some critical questions on the use of INSTIs in settings with a high tuberculosis burden, including dosing of dolutegravir, bictegravir, and cabotegravir when used with the rifamycins for both tuberculosis treatment and prevention. Failure, in the past, to include people with tuberculosis in HIV clinical treatment trials has been responsible for some of the research gaps still evident for informing optimisation of HIV and tuberculosis co-treatment.

Spatially targeted digital chest radiography to reduce tuberculosis in high-burden settings: A study of adaptive decision making

BackgroundSpatially-targeted approaches to screen for tuberculosis (TB) could accelerate TB control in high-burden populations. We aimed to estimate gains in case-finding yield under an adaptive decision-making approach for spatially-targeted, mobile digital chest radiography (dCXR)-based screening in communities with varying levels of TB prevalence. MethodsWe used a Monte-Carlo simulation model to simulate a spatially-targeted screening intervention in 24 communities with TB prevalence estimates derived from a large community-randomized trial. We implemented a Thompson sampling algorithm to allocate screening units based on Bayesian probabilities of local TB prevalence that are continuously updated during weekly screening rounds. Four mobile units for dCXR-based screening and subsequent Xpert Ultra-based testing were allocated among the communities during a 52-week period. We estimated the yield of bacteriologically-confirmed TB per 1000 screenings comparing scenarios of spatially-targeted and untargeted resource allocation. ResultsWe estimated that under the untargeted scenario, an expected 666 (95% uncertainty interval 522–825) TB cases would be detected over one year, equivalent to 8.9 (7.5–10.3) per 1000 individuals screened. Allocating the screening units to the communities with the highest (prior-year) cases notification rates resulted in an expected 760 (617−926) TB cases detected, 10.1 (8.6–11.8) per 1000 screened. Adaptive, spatially-targeted screening resulted in an expected 1241 (995–1502) TB cases detected, 16.5 (14.5–18.7) per 1000 screened. Numbers of dCXR-based screenings needed to detect one additional TB case declined during the first 12–14 weeks as a result of Bayesian learning. ConclusionWe introduce a spatially-targeted screening strategy that could reduce the number of screenings necessary to detect additional TB in high-burden settings and thus improve the efficiency of screening interventions. Empirical trials are needed to determine whether this approach could be successfully implemented.

Detection of pulmonary tuberculosis in children using the Xpert MTB/RIF Ultra assay on sputum: a multicenter study.

Microbiological confirmation is rare in children with active tuberculosis; therefore, a more accurate test is needed to detect pulmonary tuberculosis in children. In this multicenter study, we evaluated the utility of the Xpert MTB/RIF Ultra (Ultra) on sputum, an assay recommended by the World Health Organization to test for childhood tuberculosis in high-burden settings. Children with symptoms suggestive of tuberculosis were enrolled at three hospitals in China and categorized as having active tuberculosis or nontuberculosis. The sensitivity and specificity of Ultra were 42.1% (48/114) and 99.0% (208/210), respectively. Using three MTB culture results as the reference, the sensitivity of Ultra in the subset of 38 children with culture-positive and 76 children with culture-negative was 68.4% (26/38) and 28.9% (22/76), respectively(p < 0.001). A single MTB culture combined with a single Ultra could detect 54 (54/114,47.4%) cases with active TB, while repeated MTB culture combined with a single Ultra detected 60 (60/114, 52.6%) cases with active TB(p = 0.427). Among 155 children (58 with TB and 97 with RTIs) simultaneously tested with the Ultra and Xpert MTB/RIF (Xpert), the sensitivity of the Xpert (24.1%, 14/58) was lower than that of the Ultra (41.4%, 24/58; p = 0.048). Eight children were found to have rifampin-resistant MTB strains. The Xpert MTB/RIF Ultra assay should be implemented to test for pulmonary tuberculosis in children to achieve higher confirmation rates.

Barriers and strategies to successful tuberculosis treatment in a high-burden tuberculosis setting: a qualitative study from the patient\u2019s perspective

BackgroundPreviously treated tuberculosis (TB) patients are a widely reported risk factor for multidrug-resistant tuberculosis. Identifying patients’ problems during treatment is necessary to control TB, especially in a high-burden setting. We therefore explored barriers to successful TB treatment from the patients’ perspective, aiming to identify potential patient-centred care strategies to improve TB treatment outcome in Indonesia.MethodsA qualitative study was conducted in a province of Indonesia with high TB prevalence. Participants from various backgrounds (i.e., TB patients, physicians, nurses, pharmacists, TB activist, TB programmers at the district and primary care levels) were subject to in-depth interviews and focus group discussions (FGDs). All interviews and FGDs were transcribed verbatim from audio and visual recordings and the respective transcriptions were used for data analysis. Barriers were constructed by interpreting the codes’ pattern and co-occurrence. The information’s trustworthiness and credibility were established using information saturation, participant validation and triangulation approaches. Data were inductively analysed using the Atlas.ti 8.4 software and reported following the COREQ 32-items.ResultsWe interviewed 63 of the 66 pre-defined participants and identified 15 barriers. The barriers were classified into three themes, i.e., socio-demography and economy; knowledge and perception and TB treatment. Since the barriers can be interrelated, we determined five main barriers across all barrier themes, i.e., lack of TB knowledge, stigmatisation, long distance to the health facility, adverse drug reaction and loss of household income.ConclusionThe main treatment barriers can be considered to strengthen patient-centred care for TB patients in Indonesia. A multi-component approach including TB patients, healthcare providers, broad community and policy makers is required to improve TB treatment success.

Venous thromboembolic disease in adults admitted to hospital in a setting with a high burden of HIV and TB.

Background HIV and tuberculosis (TB) independently cause an increased risk for venous thromboembolic disease (VTE): deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Data from high HIV and TB burden settings describing VTE are scarce. The Wells’ DVT and PE scores are widely used but their utility in these settings has not been reported on extensively. Objectives To evaluate new onset VTE, compare clinical characteristics by HIV status, and the presence or absence of TB disease in our setting. We also calculate the Wells’ score for all patients. Methods A prospective cohort of adult in-patients with radiologically confirmed VTE were recruited into the study between September 2015 and May 2016. Demographics, presence of TB, HIV status, duration of treatment, CD4 count, viral load, VTE risk factors, and parameters to calculate the Wells’ score were collected. Results We recruited 100 patients. Most of the patients were HIV-infected (n=59), 39 had TB disease and 32 were HIV/TB co-infected. Most of the patients had DVT only (n=83); 11 had PE, and 6 had both DVT and PE. More than a third of patients on antiretroviral treatment (ART) (43%; n=18/42) were on treatment for <6 months. Half of the patients (51%; n=20/39) were on TB treatment for <1 month. The median (interquartile range (IQR)) DVT and PE Wells’ score in all sub-groups was 3.0 (1.0 - 4.0) and 3.0 (2.5 - 4.5), respectively. Conclusion HIV/TB co-infection appears to confer a risk for VTE, especially early after initiation of ART and/or TB treatment, and therefore requires careful monitoring for VTE and early initiation of thrombo-prophylaxis.

Childhood Cancers Misdiagnosed as Tuberculosis in a High Tuberculosis Burden Setting

Tuberculosis (TB) and childhood cancers have overlapping presentations and malignancies may be misdiagnosed as TB in high TB-burden settings. This retrospective study investigated the diagnosis of TB in children with cancer registered in the Tygerberg Hospital Childhood Tumor Registry from 2008 to 2018. We studied children on anti-tuberculosis treatment (ATT) at cancer diagnosis or diagnosed with TB within 1 month of cancer diagnosis. We describe the circumstances and extent of this misdiagnosis, quantify the delay in therapy and document the outcomes of these children. Twenty-seven of 539 (5%) children in the registry started ATT before cancer diagnosis. Both pulmonary and extrapulmonary TB complicated the cancer diagnosis. Of the 27 patients on ATT at cancer diagnosis, 22 (81%) had contact with a TB case and in 6 of 12 children (50%) a tuberculin skin test was positive. At cancer diagnosis, 16/27 (59%) children had chest radiograph changes interpreted as TB with 11/27 (41%) regarded as suggestive of TB on expert review. The median diagnostic delay between TB and cancer diagnoses was 25 days (interquartile range 3.5-58). Of 539 children with cancer, 204 (38%) died of cancer, including 18/30 (60%) children on ATT at cancer diagnosis or diagnosed with TB within 1 month of cancer diagnosis (odds ratio 2.6; 95% confidence interval: 1.2-5.4; P = 0.012). The clinical and radiologic overlap of TB and cancer causes diagnostic confusion in a significant number of children with cancer and may contribute to increased mortality.

Tuberculosis detection from chest x-rays for triaging in a high tuberculosis-burden setting: an evaluation of five artificial intelligence algorithms

Artificial intelligence (AI) algorithms can be trained to recognise tuberculosis-related abnormalities on chest radiographs. Various AI algorithms are available commercially, yet there is little impartial evidence on how their performance compares with each other and with radiologists. We aimed to evaluate five commercial AI algorithms for triaging tuberculosis using a large dataset that had not previously been used to train any AI algorithms. Individuals aged 15 years or older presenting or referred to three tuberculosis screening centres in Dhaka, Bangladesh, between May 15, 2014, and Oct 4, 2016, were recruited consecutively. Every participant was verbally screened for symptoms and received a digital posterior-anterior chest x-ray and an Xpert MTB/RIF (Xpert) test. All chest x-rays were read independently by a group of three registered radiologists and five commercial AI algorithms: CAD4TB (version 7), InferRead DR (version 2), Lunit INSIGHT CXR (version 4.9.0), JF CXR-1 (version 2), and qXR (version 3). We compared the performance of the AI algorithms with each other, with the radiologists, and with the WHO's Target Product Profile (TPP) of triage tests (≥90% sensitivity and ≥70% specificity). We used a new evaluation framework that simultaneously evaluates sensitivity, proportion of Xpert tests avoided, and number needed to test to inform implementers' choice of software and selection of threshold abnormality scores. Chest x-rays from 23 954 individuals were included in the analysis. All five AI algorithms significantly outperformed the radiologists. The areas under the receiver operating characteristic curve were 90·81% (95% CI 90·33-91·29) for qXR, 90·34% (89·81-90·87) for CAD4TB, 88·61% (88·03-89·20) for Lunit INSIGHT CXR, 84·90% (84·27-85·54) for InferRead DR, and 84·89% (84·26-85·53) for JF CXR-1. Only qXR (74·3% specificity [95% CI 73·3-74·9]) and CAD4TB (72·9% specificity [72·3-73·5]) met the TPP at 90% sensitivity. All five AI algorithms reduced the number of Xpert tests required by 50% while maintaining a sensitivity above 90%. All AI algorithms performed worse among older age groups (>60 years) and people with a history of tuberculosis. AI algorithms can be highly accurate and useful triage tools for tuberculosis detection in high-burden regions, and outperform human readers. Government of Canada.

All-oral longer regimens are effective for the management of multidrug-resistant tuberculosis in high-burden settings.

Recent World Health Organization guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline and/or delamanid as part of their multidrug regimen. Patients with a positive baseline culture were included. 6-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods. Culture conversion was observed in 83.8% (526 out of 628) of patients receiving an all-oral regimen and 85.5% (425 out of 497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95% CI 0.88-1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients. Among individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.

Mortality from drug-resistant tuberculosis in high-burden countries comparing routine drug susceptibility testing with whole-genome sequencing: a multicentre cohort study

SummaryBackgroundDrug resistance threatens global tuberculosis control. We aimed to examine mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and whole-genome sequencing (WGS).MethodsIn this multicentre cohort study, we collected pulmonary Mycobacterium tuberculosis isolates and clinical data from individuals with tuberculosis from antiretroviral therapy programmes and tuberculosis clinics in Côte d’Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, Peru, South Africa, and Thailand, stratified by HIV status and drug resistance. Sites tested drug susceptibility using routinely available methods. WGS was done on Illumina HiSeq 2500 in the USA and Switzerland, and TBprofiler was used to analyse the genomes. We included individuals aged 16 years or older with pulmonary tuberculosis (bacteriologically confirmed or clinically diagnosed). We analysed mortality in multivariable logistic regression models adjusted for sex, age, HIV status, history of tuberculosis, and sputum positivity.FindingsBetween Sept 1, 2014, and July 4, 2016, of 634 patients included in our previous analysis, we included 582 patients with tuberculosis (median age 33 years [IQR 27–43], 225 [39%] women, and 247 [42%] HIV-positive). Based on WGS, 339 (58%) isolates were pan-susceptible, 35 (6%) monoresistant, 146 (25%) multidrug-resistant, and 24 (4%) pre-extensively drug-resistant (pre-XDR) or XDR. The analysis of mortality was based on 530 patients; 63 (12%) died and 77 (15%) patients received inappropriate treatment. Mortality ranged from 6% (18 of 310) in patients with pan-susceptible tuberculosis to 39% (nine of 23) in patients with pre-XDR or XDR tuberculosis. The adjusted odds ratio for mortality was 4·92 (95% CI 2·47–9·78) among undertreated patients, compared with appropriately treated patients.InterpretationIn seven countries with a high burden of tuberculosis, we observed discrepancies between drug resistance patterns obtained locally and WGS. The underdiagnosis of drug resistance resulted in inappropriate treatment and higher mortality. WGS can provide accurate and detailed drug resistance information required to improve the outcomes of drug-resistant tuberculosis in high-burden settings. Our results support WHO’s call for point-of-care tests based on WGS.FundingNational Institutes of Allergy and Infectious Diseases, Swiss National Science Foundation, and Swiss National Center for Mycobacteria.

Evaluation of a new interferon gamma release assay, in comparison to tuberculin skin tests and quantiferon tuberculosis goldplus for the detection of latent tuberculosis infection in children from a high tuberculosis burden setting.

: Detection of latent tuberculosis infection (LTBI) in children, exposed to tuberculosis (TB) infections, followed by appropriate treatment, could be instrumental in reducing TB burden. Interferon Gamma release assays (IGRA) have higher specificity than tuberculin skin tests (TST), hence are more effective option for diagnosis. Hence, the present study was aimed to diagnose the presence of latent TB in children with the help of a new Standard E TB-Feron Enzyme-Linked Immunosorbent Assay (TBF) and evaluating its efficiency as compared to TST and Quantiferon TB Gold plus (QFT Plus). Diagnosis of LTBI in participants, <18 years old, who were the close household contacts of patients with active TB was carried out employing techniques such as TST, QFT Plus, and TBF. Higher positive results were obtained with IGRA assays QFT Plus and TBF than TST. The perfect agreement was observed between QFT Plus and TBF assays with a Kappa value of 0.9176 whereas TST and TBF assay showed moderate agreement with a Kappa value of 0.42365. The level of cytokines secreted as a result of stimulation by the antigens from QFT Plus tubes was lower in comparison to antigens from TBF tubes. Hence, TBF, which showed similar efficiency as the widely used QFT Plus, can be a useful detection technique for LTBI in children. Moreover, it could prove to be an efficient alternative to expensive IGRAs like QFT Plus.

Xpert MTB/RIF and Xpert Ultra assays for screening for pulmonary tuberculosis and rifampicin resistance in adults, irrespective of signs or symptoms.

Xpert MTB/RIF and Xpert Ultra assays for screening for pulmonary tuberculosis and rifampicin resistance in adults, irrespective of signs or symptoms.

Blood-based host biomarker diagnostics in active case finding for pulmonary tuberculosis: A diagnostic case-control study.

BackgroundThere is a need to identify scalable tuberculosis screening strategies among high burden populations. The WHO has identified a non-sputum-based triage test as a development priority.MethodsWe performed a diagnostic case-control study of point-of-care C-reactive protein (CRP) and Prototype-Xpert-MTB-Host-Response (Xpert-MTB-HR) assays in the context of a mass screening program for tuberculosis in two prisons in Brazil. All incarcerated individuals irrespective of symptoms were screened by sputum Xpert MTB/RIF and sputum culture. Among consecutive, Xpert MTB/RIF or culture-confirmed cases and Xpert MTB/RIF and culture-negative controls, CRP was quantified in serum by a point-of-care assay (iChroma-II) and a 3-gene expression score was quantified from whole blood using the Xpert-MTB-HR cartridge. We evaluated receiver operating characteristic area under the curve (AUC) and assessed specificity at 90% sensitivity and sensitivity at 70% specificity, consistent with WHO target product profile (TPP) benchmarks.FindingsTwo hundred controls (no TB) and 100 culture- or Xpert MTB/RIF-positive tuberculosis cases were included. Half of tuberculosis cases and 11% of controls reported any tuberculosis symptoms. AUC for CRP was 0·79 (95% CI: 0·73–0·84) and for Xpert-MTB-HR was 0·84 (95% CI: 0·79–0·89). At 90% sensitivity, Xpert-MTB-HR had significantly higher specificity (53·0%, 95% CI: 45·0–69·0%) than CRP (28·1%, 95% CI: 20·2–41·8%) (p = 0·003), both well below the TPP benchmark of 70%. Among individuals with medium or high sputum Xpert MTB/RIF semi-quantitative load, sensitivity (at 70% specificity) of CRP (90·3%, 95% CI: 74·2–98·0) and Xpert-MTB-HR (96·8%, 95% CI: 83·3–99·9%) was higher.InterpretationFor active case finding in this high tuberculosis-burden setting, CRP and Xpert-MTB-HR did not meet TPP benchmarks for a triage test. However, Xpert-MTB-HR was highly sensitive in detecting individuals with medium or high sputum bacillary burden.FundingNational Institutes of Health (R01 AI130058 and R01 AI149620) and Brazilian National Council for Scientific and Technological Development (CNPq-404182/2019-4).

Novel health system strategies for tuberculin skin testing at primary care clinics: Performance assessment and health economic evaluation

BackgroundTuberculin skin test (TST) for guiding initiation of tuberculosis preventive therapy poses major challenges in high tuberculosis burden settings.MethodsAt a primary care clinic in Johannesburg, South Africa, 278 HIV-positive adults self-read their TST by reporting if they felt a bump (any induration) at the TST placement site. TST reading (in mm) was fast-tracked to reduce patient wait time and task-shifted to delegate tasks to lower cadre healthcare workers, and result was compared to TST reading by high cadre research staff. TST reading and placement cost to the health system and patients were estimated. Simulations of health system costs were performed for 5 countries (USA, Germany, Brazil, India, Russia) to evaluate generalizability.ResultsAlmost all participants (269 of 278, 97%) correctly self-identified the presence or absence of any induration [sensitivity 89% (95% CI 80,95) and specificity 99.5% (95% CI 97,100)]. For detection of a positive TST (induration ≥ 5mm), sensitivity was 90% (95% CI 81,96) and specificity 99% (95% CI 97,100). TST reading agreement between low and high cadre staff was high (kappa 0.97, 95% CI 0.94, 1.00). Total TST cost was 2066 I$ (95% UI 594, 5243) per 100 patients, 87% (95% UI 53, 95) of which were patient costs. Combining fast-track and task-shifting, reduced total costs to 1736 I$ (95% UI 497, 4300) per 100 patients, with 31% (95% UI 15, 42) saving in health system costs. Combining fast-tracking, task-shifting and self-reading, lowered the TST health system costs from 16% (95% UI 8, 26) in Russia to 40% (95% UI 18, 54) in the USA.ConclusionA TST strategy where only patients with any self-read induration are asked to return for fast-tracked TST reading by lower cadre healthcare workers is a promising strategy that could be effective and cost-saving, but real-life cost-effectiveness should be further examined.

Towards TB elimination: how are macro-level factors perceived and addressed in policy initiatives in a high burden country?

BackgroundNotwithstanding extensive general discussion of the effects of upstream forces on health, there has been limited empirical examination, let alone systematic evidence documenting policy responses to such pathways in the area of tuberculosis (TB) management and control. Our study aimed to gain insight into how macro level drivers of TB are perceived by key stakeholders involved in TB management and control in a high-endemic country, and to assess how such concerns are being addressed in policy initiatives in this setting. South Africa was chosen for this case study due to our team’s long-standing collaborations there, its very high burden of TB, and its introduction of a strategic plan to combat this disease.MethodSemi-structured interviews were conducted with 20 key informants who were purposively selected for their knowledge and expertise of TB in South Africa. South Africa’s National Strategic Plan for HIV, TB and STIs 2017–2022 was then reviewed to examine how identified themes from the interviews were reflected in this policy document.ResultsA history of colonization, the migrant labour system, economic inequality, poor shelter, health system challenges including TB governance, the HIV epidemic, and pertinent socio-cultural factors were all perceived to be major drivers of the epidemic. Although South Africa’s current National Strategic Plan makes a firm discursive commitment to addressing the structural or macro-level drivers of TB, our analysis revealed that this commitment was not clearly reflected in projected budgetary allocations.ConclusionAs in many other high burden settings, macro-level drivers of TB are widely recognized. Nonetheless, while micro-level (biomedical and clinical) measures, such as improving diagnostic procedures and investment in more efficacious drugs, are being (and well should be) implemented, our findings showed that macro-level drivers of TB are underrepresented in budgeting allocations for initiatives to combat this disease. Although it could be argued that structural drivers that undermine health-promoting actions are beyond the purview of the health sector itself, we argue that strategic plans to combat TB in high burden settings need more attention to directly considering such drivers to prompt the necessary changes and reduce the burden of this and other such diseases.

Childhood tuberculosis in high burden settings.

An estimated one million cases of tuberculosis (TB) occur globally each year in children younger than 15 years, approximately a quarter of whom will die from TB [1]. The majority of the childhood TB cases and deaths occur in low- and middle-income countries (LMIC), where difficulties and delays, principally in TB case detection, contribute to poor outcomes in children [2]. Childhood TB is paucibacillary and obtaining good quality sputum specimen is a challenge, particularly in the very young. In addition, the clinical presentation of TB in children mimics other common childhood diseases such as HIV, pneumonia, viral and bacterial blood infection and malnutrition.

Molecular bacterial load assay versus culture for monitoring treatment response in adults with tuberculosis.

The lack of rapid, sensitive, and deployable tuberculosis diagnostic tools is hampering the early diagnosis of tuberculosis and early detection of treatment failures. The conventional sputum smear microscopy or Xpert MTB/RIF assay cannot distinguish between alive and dead bacilli and the culture method delays providing results. Tuberculosis molecular bacterial load assay is a reverse transcriptase real-time quantitative polymerase chain reaction that quantifies viable tuberculosis bacillary load as a marker of treatment response for patients on anti-tuberculosis therapy. However, results are not synthesized enough to inform its comparative advantage to tuberculosis culture technique which is yet the gold standard of care. With this review, we searched electronic databases, including PubMed, Embase, and Web of Science, from March 2011 up to February 2021 for clinical trials or prospective cohort studies that compared tuberculosis molecular bacterial load assay with tuberculosis culture in adults. We included eight studies that meet the inclusion criteria. Tuberculosis molecular bacterial load assay surpasses culture in monitoring patients with tuberculosis during the first few weeks of anti-tuberculosis treatment. It is more desirable over culture for its shorter time to results, almost zero rates of contamination, need for less expertise on the method, early rate of decline, lower running cost, and reproducibility. Its rapid and specific tuberculosis treatment monitoring competency benefits patients and healthcare providers to monitor changes of bacillary load among isolates with drug-susceptible or resistance to anti-tuberculosis regimens. Despite of the high installing cost of the tuberculosis molecular bacterial load assay method, molecular expertise, and a well-equipped laboratory, tuberculosis molecular bacterial load assay is a cost-effective method with comparison to culture in operational running. To achieve maximum utility in high tuberculosis burden settings, an intensive initial investment in nucleic acid extraction and polymerase chain reaction equipment, training in procedures, and streamlining laboratory supply procurement systems are crucial. More evidence is needed to demonstrate the potential large-scale and sustainable use of tuberculosis molecular bacterial load assay over culture in resource-constrained settings.

Validation of PHASE for deriving N-acetyltransferase 2 haplotypes in the Western Cape mixed ancestry population.

BackgroundThere is a shortage of data on the accuracy of statistical methods for the prediction of N-acetyltransferase 2 (NAT2) haplotypes in the mixed ancestry population of the Western Cape.ObjectiveThis study aimed to identify the NAT2 haplotypes and assess the accuracy of PHASE version 2.1.1 in assigning NAT2 haplotypes to a mixed ancestry population from the Western Cape.MethodsThis study was conducted between 2013 and 2016. The NAT2 gene was amplified and sequenced from the DNA of 100 self-identified mixed ancestry participants. Haplotyping was performed by molecular and computational techniques. Agreement was assessed between the two techniques.ResultsHaplotypes were assigned to 93 samples, of which 67 (72%) were ambiguous. Haplotype prediction by PHASE demonstrated 94.6% agreement (kappa 0.94, p < 0.001) with those assigned using molecular techniques. Five haplotype combinations (from 10 chromosomes) were incorrectly predicted, four of which were flagged as uncertain by the PHASE software. Only one resulted in the assignment of an incorrect acetylation phenotype (intermediate to slow), although the software flagged this for further analysis. The most common haplotypes were NAT2*4 (28%) followed by NAT2*5B (27.4%), NAT2*6A (21.5%) and NAT2*12A (7.5%). Four rare single nucleotide variants (c.589C>T, c.622T>C, c.809T>C and c.387C>T) were detected.ConclusionPHASE accurately predicted the phenotype in 92 of 93 samples (99%) from genotypic data in our mixed ancestry sample population, and is therefore a suitable alternative to molecular methods to individualise isoniazid therapy in this high burden tuberculosis setting.

Evaluating the yield of systematic screening for tuberculosis among three priority groups in Ho Chi Minh City, Viet Nam

BackgroundIn order to end tuberculosis (TB), it is necessary to expand coverage of TB care services, including systematic screening initiatives. However, more evidence is needed for groups among whom systematic screening is only conditionally recommended by the World Health Organization. This study evaluated concurrent screening in multiple target groups using community health workers (CHW).MethodsIn our two-year intervention study lasting from October 2017 to September 2019, CHWs in six districts of Ho Chi Minh City, Viet Nam verbally screened three urban priority groups: (1) household TB contacts; (2) close TB contacts; and (3) residents of urban priority areas without clear documented exposure to TB including hotspots, boarding homes and urban slums. Eligible persons were referred for further screening with chest radiography and follow-on testing with the Xpert MTB/RIF assay. Symptomatic individuals with normal or without radiography results were tested on smear microscopy. We described the TB care cascade and characteristics for each priority group, and calculated yield and number needed to screen. Subsequently, we fitted a mixed-effect logistic regression to identify the association of these target groups and secondary patient covariates with TB treatment initiation.ResultsWe verbally screened 321 020 people including 24 232 household contacts, 3182 social and close contacts and 293 606 residents of urban priority areas. This resulted in 1138 persons treated for TB, of whom 85 were household contacts, 39 were close contacts and 1014 belonged to urban priority area residents. The yield of active TB in these groups was 351, 1226 and 345 per 100 000, respectively, corresponding to numbers needed to screen of 285, 82 and 290. The fitted model showed that close contacts [adjusted odds ratio (aOR) = 2.07; 95% CI: 1.38–3.11; P < 0.001] and urban priority area residents (aOR = 2.18; 95% CI: 1.69–2.79; P < 0.001) had a greater risk of active TB than household contacts.ConclusionsThe study detected a large number of unreached persons with TB, but most of them were not among persons in contact with an index patient. Therefore, while programs should continue to optimize screening in contacts, to close the detection gap in high TB burden settings such as Viet Nam, coverage must be expanded to persons without documented exposure such as residents in hotspots, boarding homes and urban slums.

Tuberculosis prevention in children: a prospective community-based study in South Africa.

Tuberculosis (TB) preventive therapy reduces TB risk in children. However, the effectiveness of TB preventive therapy in children living in high TB burden settings is unclear.In a prospective observational community-based cohort study in Cape Town, South Africa, we assessed the effectiveness of routine TB preventive therapy in children ≤15 years of age in a high TB and HIV prevalence setting.Among 966 children (median (interquartile range) age 5.07 (2.52–8.72) years), 676 (70%) reported exposure to an adult with TB in the past 3 months and 240 out of 326 (74%) eligible children initiated isoniazid preventive therapy under programmatic guidelines. Prevalent (n=73) and incident (n=27) TB were diagnosed among 100 out of 966 (10%) children. Children who initiated isoniazid preventive therapy were 82% less likely to develop incident TB than children who did not (adjusted OR 0.18, 95% CI 0.06–0.52; p=0.0014). Risk of incident TB increased if children were <5 years of age, living with HIV, had a positive Mycobacterium tuberculosis-specific immune response or recent TB exposure. The risk of incident TB was not associated with sex or Mycobacterium bovis bacille Calmette–Guérin vaccination status. Number needed to treat (NNT) was lowest in children living with HIV (NNT=15) and children <5 years of age (NNT=19) compared with children of all ages (NNT=82).In communities with high TB prevalence, TB preventive therapy substantially reduces the risk of TB among children who are <5 years of age or living with HIV, especially those with recent TB exposure or a positive M. tuberculosis-specific immune response in the absence of disease.

Evaluation of genotype MTBDRplus V2 and genotype MTBDRsl V2 for the diagnosis of extrapulmonary tuberculosis in India

Microbiological diagnosis of extra-pulmonary tuberculosis (EPTB) has been one of the most difficult aspects of tuberculosis (TB) management. Availability of better imaging and diagnostic modalities has led to an increase in the number of diagnosed cases. The current upsurge in multidrug-resistant tuberculosis warrants routine testing of EPTB samples for resistance at baseline with shorter turn-around time.A total of 369 EPTB specimens were subjected to Ziehl-Neelsen (ZN) stain, liquid culture (LC) with phenotypic drug susceptibility testing, MTBDRplus V.2 and MTBDRsl V.2. The molecular categorisation of resistant specimens was further reconfirmed with sequencing.The sensitivity and specificity of MTBDRplus V.2 to detect Mycobacterium tuberculosis (MTB) when compared to ZN stain was 97.9% and 89.2%, respectively while it was 73.4% and 83.8%, respectively when compared to LC. Similarly, for MTBDRsl V.2, the sensitivity and specificity for detection of MTB when compared with ZN was 95.6% and 91.9%, respectively and 75% and 89.2%, respectively when compared to LC. In smear-positive specimens, 94% (141/150) and 86% (129/150) valid results were observed in MTBDRplus V.2 and MTBDRsl V.2, respectively.The utilisation of both MTBDRplus V.2 and MTBDRsl V.2 for the diagnosis of smear-positive EPTB specimens would be useful in programmatic management of TB in high-burden settings.