Bedaquiline Resistance after Effective Treatment of Multidrug-Resistant Tuberculosis, Namibia.

Bedaquiline is currently a key drug for treating multidrug-resistant or rifampin-resistant tuberculosis. We report and discuss the unusual development of resistance to bedaquiline in a teenager in Namibia, despite an optimal background regimen and adherence. The report highlights the risk for bedaquiline resistance development and the need for rapid drug-resistance testing.

Defining Outcomes of Tuberculosis (Treatment): From the Past to the Future.

Untreated active tuberculosis (TB) has a very high long-term mortality. Treatment of TB reduces mortality dramatically and should maximize cure, preventing ongoing transmission and TB sequelae. However, predicting the risk of failure and relapse is crucial for the management of individual patients and for the evaluation of effectiveness of programs. Various outcome definitions for drug-sensitive and drug-resistant TB were developed, implemented, and endorsed since introduction of TB chemotherapy by the World Health Organization (WHO), mostly based on culture and smear results. They should be applicable for individual patient care, surveillance, and research. Definitions with focus on program evaluation differ from definitions to evaluate the efficacy and effectiveness of regimens. Lack of sputum production at the later stage of treatment reduces the easy applicability of current definitions. Definitions of failure and cure are sometimes difficult to apply. Alternative approaches suggest culture positivity at 6 months or more of treatment as an indicator for failure. New definitions for cure including a relapse-free period posttreatment and reduced number of culture and smear results are considered. Increasing variation and individualization of treatment and its duration urgently require new approaches using pathogen- or host-specific biomarkers, which indicate risk of failure and define cure. Such biomarkers are under evaluation but still far from translation in clinical routine practice.

Two Pandemics, One Challenge-Leveraging Molecular Test Capacity of Tuberculosis Laboratories for Rapid COVID-19 Case-Finding.

In many settings, the ongoing coronavirus disease (COVID-19) pandemic coincides with other major public health threats, in particular tuberculosis. Using tuberculosis (TB) molecular diagnostic infrastructure, which has substantially expanded worldwide in recent years, for COVID-19 case-finding might be warranted. We analyze the potential of using TB diagnostic and research infrastructures for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. We focused on quality control by adapting the 12 Quality System Essentials framework to the COVID-19 and TB context. We conclude that diagnostic infrastructures for TB can in principle be leveraged to scale-up SARS-CoV-2 testing, in particular in resource-poor settings. TB research infrastructures also can support sequencing of SARS-CoV-2 to study virus evolution and diversity globally. However, fundamental principles of quality management must be followed for both TB and SARS-CoV-2 testing to ensure valid results and to minimize biosafety hazards, and the continuity of TB diagnostic services must be guaranteed at all times.

Interpretation of serial interferon-gamma test results to measure new tuberculosis infection among household contacts in Zambia and South Africa.

BACKGROUND: A more stringent QuantiFERON-TB Gold In-Tube (QFT) conversion (from negative to positive) definition has been proposed to allow more definite detection of recent tuberculosis (TB) infection. We explored alternative conversion definitions to assist the interpretation of serial QFT results and estimate incidence of TB infection in a large cohort study. METHODS: We used QFT serial results from TB household contacts aged ≥15 years, collected at baseline and during two follow-up visits (2006-2011) as part of a cohort study in 24 communities in Zambia and South Africa (SA). Conversion rates using the manufacturers' definition (interferon-gamma (IFN-g) < 0.35 to ≥0.35, 'def1') were compared with stricter definitions (IFN-g < 0.2 to ≥0.7 IU/ml, 'def2'; IFN-g < 0.2 to ≥1.05 IU/ml, 'def3'; IFN-g < 0.2 to ≥1.4 IU/ml, 'def4'). Poisson regression was used for analysis. RESULTS: One thousand three hundred sixty-five individuals in Zambia and 822 in SA had QFT results available. Among HIV-negative individuals, the QFT conversion rate was 27.4 per 100 person-years (CI:22.9-32.6) using def1, 19.0 using def2 (CI:15.2-23.7), 14.7 using def3 (CI:11.5-18.8), and 12.0 using def4 (CI:9.2-15.7). Relative differences across def1-def4 were similar in Zambia and SA. Using def1, conversion was less likely if HIV positive not on antiretroviral treatment compared to HIV negative (aRR = 0.7, 95%CI = 0.4-0.9), in analysis including both countries. The same direction of associations were found using def 2-4. CONCLUSION: High conversion rates were found even with the strictest definition, indicating high incidence of TB infection among household contacts of TB patients in these communities. The trade-off between sensitivity and specificity using different thresholds of QFT conversion remains unknown due to the absence of a reference standard. However, we identified boundaries within which an appropriate definition might fall, and our strictest definition plausibly has high specificity.

Patient predictors of health-seeking behaviour for persons coughing for more than two weeks in high-burden tuberculosis communities: the case of the Western Cape, South Africa.

BACKGROUND: This study aimed to analyse the patient predictors of health-seeking behaviour for persons coughing for more than 2 weeks to better understand this vulnerable and important population. METHODS: The study analysed data from a cohort study (SOCS - Secondary Outcome Cohort Study) embedded in a community randomised trial ZAMSTAR (Zambia and South Africa TB and AIDS Reduction Study) in eight high-burden TB communities in the Western Cape, South Africa. These datasets are unique as they contain TB-related data as well as data on health, health-seeking behaviour, lifestyle choices, employment, socio-economic status, education and stigma. We use uni- and multivariate logistic regressions to estimate the odds ratios of consulting for a cough (of more than 2 weeks duration) for a range of relevant patient predictors. RESULTS: Three hundred and forty persons consulted someone about their cough and this represents 37% of the 922 participants who reported coughing for more than 2 weeks. In the multivariate analysis, respondents of black ethnic origin (OR 1.99, 95% CI 1.28-3.12, P < 0.01), those with higher levels of education (OR 1.05 per year of education, 95% CI 1.00-1.10, P = 0.05), and older respondents (OR 1.02 per year, 95% CI 1.01-1.04, P < 0.01) had a higher likelihood of consulting for their chronic cough. Individuals who smoked (OR 0.63, 95% CI 0.45-0.88, P < 0.01) and those with higher levels of socio-economic status (OR 0.81, 95% CI 0.71-0.92, P < 0.01) were less likely to consult. We find no evidence of stigma playing a role in health-seeking decisions, but caution that this may be due to the difficulty of accurately and reliably capturing stigma due to, amongst other factors, social desirability bias. CONCLUSIONS: The low levels of consultation for a cough of more than 2 weeks suggest that there are opportunities to improve case-finding. These findings on health-seeking behaviour can assist policymakers in designing TB screening and active case-finding interventions that are targeted to the characteristics of those with a chronic cough who do not seek care.

Patient Diagnostic Rate as Indicator of Tuberculosis Case Detection, South Africa.

To address the uncertainty of the indirectly measured tuberculosis case detection rate, we used survey data stratified by HIV status to calculate the patient diagnostic rate, a directly measurable indicator, in 8 communities in South Africa. Rates were lower among HIV-negative than HIV-positive persons. Tuberculosis programs should focus on HIV-negative persons.

It's complicated: why do tuberculosis patients not initiate or stay adherent to treatment? A qualitative study from South Africa.

BACKGROUND: Individuals who test positive for active tuberculosis (TB) but do not initiate treatment present a challenge to TB programmes because they contribute to ongoing transmission within communities. To better understand why individuals do not initiate treatment, or are adherent after initiating treatment, South African respondents were approached to obtain insights as to which factors enabled and inhibited the treatment process. METHODS: This qualitative work was nested in a larger study investigating initial loss to follow-up (LTFU) amongst new smear positive TB patients across five provinces of South Africa. In-depth interviews were done with 41 adherent and initial LTFU respondents. RESULTS: Key issues contributing to initial LTFU appeared to be a poor knowledge, or low awareness of TB treatment; stigma around TB including its connection to HIV; immediate problems in the respondents' lives particularly poverty, lack of access to transport and the need to continue working; and problems in the healthcare facilities including under resourced facilities, poor functioning health systems and negative staff attitudes. In contrast the reasons given for being adherent related to the level of illness, support received at home and healthcare facilities, a belief in the health system and positive experiences in the health service including positive attitudes from staff. CONCLUSIONS: Key changes need to be made to the healthcare system to enable patients to initiate treatment and remain adherent, but the six month regimen of daily observed treatment presents real practical and personal challenges to patients. Alternative strategies to DOTS at facility level should be investigated to bring services closer to communities to encourage patients to access care, initiate and adhere to treatment.

Effect of household and community interventions on the burden of tuberculosis in southern Africa: the ZAMSTAR community-randomised trial.

BACKGROUND: Southern Africa has had an unprecedented increase in the burden of tuberculosis, driven by the HIV epidemic. The Zambia, South Africa Tuberculosis and AIDS Reduction (ZAMSTAR) trial examined two public health interventions that aimed to reduce the burden of tuberculosis by facilitating either rapid sputum diagnosis or integrating tuberculosis and HIV services within the community. METHODS: ZAMSTAR was a community-randomised trial done in Zambia and the Western Cape province of South Africa. Two interventions, community-level enhanced tuberculosis case-finding (ECF) and household level tuberculosis-HIV care, were implemented between Aug 1, 2006, and July 31, 2009, and assessed in a 2×2 factorial design between Jan 9, 2010, and Dec 6, 2010. All communities had a strengthened tuberculosis-HIV programme implemented in participating health-care centres. 24 communities, selected according to population size and tuberculosis notification rate, were randomly allocated to one of four study groups using a randomisation schedule stratified by country and baseline prevalence of tuberculous infection: group 1 strengthened tuberculosis-HIV programme at the clinic alone; group 2, clinic plus ECF; group 3, clinic plus household intervention; and group 4, clinic plus ECF and household interventions. The primary outcome was the prevalence of culture-confirmed pulmonary tuberculosis in adults (≥18 years), defined as Mycobacterium tuberculosis isolated from one respiratory sample, measured 4 years after the start of interventions in a survey of 4000 randomly selected adults in each community in 2010. The secondary outcome was the incidence of tuberculous infection, measured using tuberculin skin testing in a cohort of schoolchildren, a median of 4 years after a baseline survey done before the start of interventions. This trial is registered, number ISRCTN36729271. FINDINGS: Prevalence of tuberculosis was evaluated in 64,463 individuals randomly selected from the 24 communities; 894 individuals had active tuberculosis. Averaging over the 24 communities, the geometric mean of tuberculosis prevalence was 832 per 100,000 population. The adjusted prevalence ratio for the comparison of ECF versus non-ECF intervention groups was 1·09 (95% CI 0·86-1·40) and of household versus non-household intervention groups was 0·82 (0·64-1·04). The incidence of tuberculous infection was measured in a cohort of 8809 children, followed up for a median of 4 years; the adjusted rate ratio for ECF versus non-ECF groups was 1·36 (95% CI 0·59-3·14) and for household versus non-household groups was 0·45 (0·20-1·05). INTERPRETATION: Although neither intervention led to a statistically significant reduction in tuberculosis, two independent indicators of burden provide some evidence of a reduction in tuberculosis among communities receiving the household intervention. By contrast the ECF intervention had no effect on either outcome. FUNDING: Bill & Melinda Gates Foundation.

Characteristics of clients who access mobile compared to clinic HIV counselling and testing services: a matched study from Cape Town, South Africa.

BACKGROUND: Studies within sub-Saharan African countries have shown that mobile services increase uptake of HIV counselling and testing (HCT) services when compared to clinics and are able to access different populations, but these have included provider-initiated HCT in clinics. This study aimed to compare the characteristics of clients who self-initiated HCT at either a mobile or a clinic service in terms of demographic and socio-economic variables, also comparing reasons for accessing a particular health service provider. METHODS: This study took place in eight areas around Cape Town. A matched design was used with one mobile HCT service matched with one or more clinics (offering routine HCT services) within each of the eight areas. Adult clients who self-referred for an HIV test within a specified time period at either a mobile or clinic service were invited to participate in the study. Data were collected between February and April 2011 using a questionnaire. Summary statistics were calculated for each service type within a matched pair and differences of outcomes from pairs were used to calculate effect sizes and 95% confidence intervals. RESULTS: 1063 participants enrolled in the study with 511 from mobile and 552 from clinic HCT services. The proportion of males accessing mobile HCT significantly exceeded that of clinic HCT (p < 0.001). The mean age of participants attending mobile HCT was higher than clinic participants (p = 0.023). No significant difference was found for socio-economic variables between participants, with the exception of access to own piped water (p = 0.029). Participants who accessed mobile HCT were significantly more likely to report that they were just passing, deemed an "opportunistic" visit (p = 0.014). Participants who accessed clinics were significantly more likely to report the service being close to home or work (p = 0.035). CONCLUSIONS: An HCT strategy incorporating a mobile HCT service, has a definite role to play in reaching those population groups who do not typically access HCT services at a clinic, especially males and those who take advantage of the opportunity to test. Mobile HCT services can complement clinic services.

Enhanced active case finding of drug-resistant tuberculosis in Namibia: a protocol for the hotspots, hospitals, and households (H3TB) study.

INTRODUCTION: Namibia is a high tuberculosis (TB)-burden country with an estimated incidence of 460/100 000 (around 12 000 cases) per year. Approximately 4.5% of new cases and 7.9% of previously treated TB cases are multidrug resistant (MDR) and 47% of patients with MDR-TB are HIV coinfected. Published data suggest a clustering of MDR-TB transmission in specific areas. Identifying transmission clusters is key to implementing high-yield and cost-effective interventions. This includes knowing the yield of finding TB cases in high-transmission zones (eg, community hotspots, hospitals or households) to deliver community-based interventions. We aim to identify such transmission zones for enhanced case finding and evaluate the effectiveness of this approach. METHODS AND ANALYSIS: H3TB is an observational cross-sectional study evaluating MDR-TB active case finding strategies. Sputum samples from MDR-TB cases in three regions of Namibia will be evaluated by whole genome sequencing (WGS) in addition to routine sputum investigations (Xpert MTB/RIF, culture and drug susceptibility testing). We will collect information on household contacts, use of community spaces and geographical map intersections between participants, synthesising these data to identify transmission hotspots. We will look at the feasibility, acceptability, yield and cost of case finding strategies in these hotspots, and in households of patients with MDR-TB and visitors of hospitalised patients with MDR-TB. A compartmental transmission dynamic model will be constructed to evaluate the impact and cost-effectiveness of the strategies if scaled. ETHICS AND DISSEMINATION: Ethics approval was obtained. Participants will give informed consent. H3TB will capitalise on a partnership with the Ministry of Health and Social Services to follow up individuals diagnosed with MDR-TB and integrate WGS data with innovative contact network mapping, to allow enhanced case finding. Study data will contribute towards a systems approach to TB control. Equally important, it will serve as a role model for similar studies in other high-incidence settings.

Drug-Resistant Tuberculosis Case-Finding Strategies: Scoping Review.

BACKGROUND: Finding individuals with drug-resistant tuberculosis (DR-TB) is important to control the pandemic and improve patient clinical outcomes. To our knowledge, systematic reviews assessing the effectiveness, cost-effectiveness, acceptability, and feasibility of different DR-TB case-finding strategies to inform research, policy, and practice, have not been conducted and the scope of primary research is unknown. OBJECTIVE: We therefore assessed the available literature on DR-TB case-finding strategies. METHODS: We looked at systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that sought to improve DR-TB case detection specifically. We excluded studies that included patients seeking care for tuberculosis (TB) symptoms, patients already diagnosed with TB, or were laboratory-based. We searched the academic databases of MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL (Cumulated Index to Nursing and Allied Health Literature), Epistemonikos, and PROSPERO (The International Prospective Register of Systematic Reviews) using no language or date restrictions. We screened titles, abstracts, and full-text articles in duplicate. Data extraction and analyses were carried out in Excel (Microsoft Corp). RESULTS: We screened 3646 titles and abstracts and 236 full-text articles. We identified 6 systematic reviews and 61 primary studies. Five reviews described the yield of contact investigation and focused on household contacts, airline contacts, comparison between drug-susceptible tuberculosis and DR-TB contacts, and concordance of DR-TB profiles between index cases and contacts. One review compared universal versus selective drug resistance testing. Primary studies described (1) 34 contact investigations, (2) 17 outbreak investigations, (3) 3 airline contact investigations, (4) 5 epidemiological analyses, (5) 1 public-private partnership program, and (6) an e-registry program. Primary studies were all descriptive and included cross-sectional and retrospective reviews of program data. No trials were identified. Data extraction from contact investigations was difficult due to incomplete reporting of relevant information. CONCLUSIONS: Existing descriptive reviews can be updated, but there is a dearth of knowledge on the effectiveness, cost-effectiveness, acceptability, and feasibility of DR-TB case-finding strategies to inform policy and practice. There is also a need for standardization of terminology, design, and reporting of DR-TB case-finding studies.

Implementation of targeted next-generation sequencing for the diagnosis of drug-resistant tuberculosis in low-resource settings: a programmatic model, challenges, and initial outcomes.

Targeted next-generation sequencing (tNGS) from clinical specimens has the potential to become a comprehensive tool for routine drug-resistance (DR) prediction of Mycobacterium tuberculosis complex strains (MTBC), the causative agent of tuberculosis (TB). However, TB mainly affects low- and middle-income countries, in which the implementation of new technologies have specific needs and challenges. We propose a model for programmatic implementation of tNGS in settings with no or low previous sequencing capacity/experience. We highlight the major challenges and considerations for a successful implementation. This model has been applied to build NGS capacity in Namibia, an upper middle-income country located in Southern Africa and suffering from a high-burden of TB and TB-HIV, and we describe herein the outcomes of this process.

A systematic review of risk factors for mortality among tuberculosis patients in South Africa.

BACKGROUND: Tuberculosis (TB)-associated mortality in South Africa remains high. This review aimed to systematically assess risk factors associated with death during TB treatment in South African patients. METHODS: We conducted a systematic review of TB research articles published between 2010 and 2018. We searched BioMed Central (BMC), PubMed®, EBSCOhost, Cochrane, and SCOPUS for publications between January 2010 and December 2018. Searches were conducted between August 2019 and October 2019. We included randomised control trials (RCTs), case control, cross sectional, retrospective, and prospective cohort studies where TB mortality was a primary endpoint and effect measure estimates were provided for risk factors for TB mortality during TB treatment. Due to heterogeneity in effect measures and risk factors evaluated, a formal meta-analysis of risk factors for TB mortality was not appropriate. A random effects meta-analysis was used to estimate case fatality ratios (CFRs) for all studies and for specific subgroups so that these could be compared. Quality assessments were performed using the Newcastle-Ottawa scale or the Cochrane Risk of Bias Tool. RESULTS: We identified 1995 titles for screening, 24 publications met our inclusion criteria (one cross-sectional study, 2 RCTs, and 21 cohort studies). Twenty-two studies reported on adults (n = 12561) and two were restricted to children < 15 years of age (n = 696). The CFR estimated for all studies was 26.4% (CI 18.1-34.7, n = 13257 ); 37.5% (CI 24.8-50.3, n = 5149) for drug-resistant (DR) TB; 12.5% (CI 1.1-23.9, n = 1935) for drug-susceptible (DS) TB; 15.6% (CI 8.1-23.2, n = 6173) for studies in which drug susceptibility was mixed or not specified; 21.3% (CI 15.3-27.3, n = 7375) for people living with HIV/AIDS (PLHIV); 19.2% (CI 7.7-30.7, n = 1691) in HIV-negative TB patients; and 6.8% (CI 4.9-8.7, n = 696) in paediatric studies. The main risk factors associated with TB mortality were HIV infection, prior TB treatment, DR-TB, and lower body weight at TB diagnosis. CONCLUSIONS: In South Africa, overall mortality during TB treatment remains high, people with DR-TB have an elevated risk of mortality during TB treatment and interventions to mitigate high mortality are needed. In addition, better prospective data on TB mortality are needed, especially amongst vulnerable sub-populations including young children, adolescents, pregnant women, and people with co-morbidities other than HIV. Limitations included a lack of prospective studies and RCTs and a high degree of heterogeneity in risk factors and comparator variables. SYSTEMATIC REVIEW REGISTRATION: The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42018108622. This study was funded by the Bill and Melinda Gates Foundation (Investment ID OPP1173131) via the South African TB Think Tank.

Case-Finding Strategies for Drug-Resistant Tuberculosis: Protocol for a Scoping Review.

BACKGROUND: Transmission of drug-resistant tuberculosis (DR-TB) is ongoing. Finding individuals with DR-TB and initiating treatment as early as possible is important to improve patient clinical outcomes and to break the chain of transmission to control the pandemic. To our knowledge systematic reviews assessing effectiveness, cost-effectiveness, acceptability, and feasibility of different case-finding strategies for DR-TB to inform research, policy, and practice have not been conducted, and it is unknown whether enough research exists to conduct such reviews. It is unknown whether case-finding strategies are similar for DR-TB and drug-susceptible TB and whether we can draw on findings from drug-susceptible reviews to inform decisions on case-finding strategies for DR-TB. OBJECTIVE: This protocol aims to describe the available literature on case-finding for DR-TB and to describe case-finding strategies. METHODS: We will screen systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that specifically sought to improve DR-TB case detection. We will exclude studies that invited individuals seeking care for TB symptoms, those including individuals already diagnosed with TB, or laboratory-based studies. We will search the academic databases including MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL, Epistemonikos, and PROSPERO with no language or date restrictions. We will screen titles, abstracts, and full-text articles in duplicate. Data extraction and analyses will be performed using Excel (Microsoft Corp). RESULTS: We will provide a narrative report with supporting figures or tables to summarize the data. A systems-based logic model, developed from a synthesis of case-finding strategies for drug-susceptible TB, will be used as a framework to describe different strategies, resulting pathways, and enhancements of pathways. The search will be conducted at the end of 2021. Title and abstract screening, full text screening, and data extraction will be undertaken from January to June 2022. Thereafter, analysis will be conducted, and results compiled. CONCLUSIONS: This scoping review will chart existing literature on case-finding for DR-TB-this will help determine whether primary studies on effectiveness, cost-effectiveness, acceptability, and feasibility of different case-finding strategies for DR-TB exist and will help formulate potential questions for a systematic review. We will also describe case-finding strategies for DR-TB and how they fit into a model of case-finding pathways for drug-susceptible TB. This review has some limitations. One limitation is the diverse, inconsistent use of intervention terminology within the literature, which may result in missing relevant studies. Poor reporting of intervention strategies may also cause misunderstanding and misclassification of interventions. Lastly, case-finding strategies for DR-TB may not fit into a model developed from strategies for drug-susceptible TB. Nevertheless, such a situation will provide an opportunity to refine the model for future research. The review will guide further research to inform decisions on case-finding policies and practices for DR-TB. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40009.

Health trends, inequalities and opportunities in South Africa's provinces, 1990-2019: findings from the Global Burden of Disease 2019 Study.

BACKGROUND: Over the last 30 years, South Africa has experienced four 'colliding epidemics' of HIV and tuberculosis, chronic illness and mental health, injury and violence, and maternal, neonatal, and child mortality, which have had substantial effects on health and well-being. Using data from the 2019 Global Burden of Diseases, Injuries and Risk Factors Study (GBD 2019), we evaluated national and provincial health trends and progress towards important Sustainable Development Goal targets from 1990 to 2019. METHODS: We analysed GBD 2019 estimates of mortality, non-fatal health loss, summary health measures and risk factor burden, comparing trends over 1990-2007 and 2007-2019. Additionally, we decomposed changes in life expectancy by cause of death and assessed healthcare system performance. RESULTS: Across the nine provinces, inequalities in mortality and life expectancy increased over 1990-2007, largely due to differences in HIV/AIDS, then decreased over 2007-2019. Demographic change and increases in non-communicable diseases nearly doubled the number of years lived with disability between 1990 and 2019. From 1990 to 2019, risk factor burdens generally shifted from communicable and nutritional disease risks to non-communicable disease and injury risks; unsafe sex remained the top risk factor. Despite widespread improvements in healthcare system performance, the greatest gains were generally in economically advantaged provinces. CONCLUSIONS: Reductions in HIV/AIDS and related conditions have led to improved health since 2007, though most provinces still lag in key areas. To achieve health targets, provincial governments should enhance health investments and exchange of knowledge, resources and best practices alongside populations that have been left behind, especially following the COVID-19 pandemic.

Who is more likely to return for TB test results? A survey at three high-burden primary healthcare facilities in Cape Town, South Africa.

BACKGROUND: In low- and middle-income countries with a high burden of tuberculosis (TB), a large proportion of people who are tested for TB do not return to the health facility to collect their test results and initiate treatment, thus putting themselves at increased risk of adverse outcomes. METHODS: This prospective study aimed to identify predictors of returning to the primary health care (PHC) facility to collect TB test results. From 15 August to 15 December 2017, 1105 people who tested for pulmonary TB at three Cape Town PHC facilities were surveyed. Using multi-variate logistic regressions on an analysis sample of 1097 people, three groups of predictors were considered: (i) demographics, health and socio-economic status; (ii) costs and benefits; and (iii) behavioural factors. RESULTS: Forty-four percent of people tested returned to the PHC facility to collect their test results within the stipulated 2 days, and 68% returned before the end of the study period. Return was strongly and positively correlated with expecting a TB-positive result, cognitive avoidance and postponement behaviour. CONCLUSION: Interventions to improve pre-treatment loss to follow-up should target patients who think they do not have TB, and those with a history of postponement behaviour and cognitive avoidance.

Mortality in South African Children and Adolescents Routinely Treated for Tuberculosis.

BACKGROUND: In South Africa, tuberculosis (TB) is a leading cause of death among those <20 years of age. We describe changes in TB mortality among children and adolescents in South Africa over a 13-year period, identify risk factors for mortality, and estimate excess TB-related mortality. METHODS: Retrospective analysis of all patients <20 years of age routinely recorded in the national electronic drug-susceptible TB treatment register (2004-2016). We developed a multivariable Cox regression model for predictors of mortality and used estimates of mortality among the general population to calculate standardized mortality ratios (SMRs). RESULTS: Between 2004 and 2016, 729 463 children and adolescents were recorded on TB treatment; 84.0% had treatment outcomes and 2.5% (18 539) died during TB treatment. The case fatality ratio decreased from 3.3% in 2007 to 1.9% in 2016. In the multivariable Cox regression model, ages 0 to 4, 10 to 14, and 15 to 19 years (compared with ages 5 to 9 years) were associated with increased risk of mortality, as was HIV infection, previous TB treatment, and extrapulmonary involvement. The SMR of 15 to 19-year-old female patients was more than double that of male patients the same age (55.3 vs 26.2). Among 10 to 14-year-olds and those who were HIV-positive, SMRs increased over time. CONCLUSIONS: Mortality in South African children and adolescents treated for TB is declining but remains considerable, with 2% dying during 2016. Adolescents (10 to 19 years) and those people living with HIV have the highest risk of mortality and the greatest SMRs. Interventions to reduce mortality during TB treatment, specifically targeting those at highest risk, are urgently needed.

Mortality during tuberculosis treatment in South Africa using an 8-year analysis of the national tuberculosis treatment register.

In 2011, the South African HIV treatment eligibility criteria were expanded to allow all tuberculosis (TB) patients lifelong ART. The impact of this change on TB mortality in South Africa is not known. We evaluated mortality in all adults (≥ 15 years old) treated for drug-susceptible TB in South Africa between 2009 and 2016. Using a Cox regression model, we quantified risk factors for mortality during TB treatment and present standardised mortality ratios (SMR) stratified by year, age, sex, and HIV status. During the study period, 8.6% (219,618/2,551,058) of adults on TB treatment died. Older age, male sex, previous TB treatment and HIV infection (with or without the use of ART) were associated with increased hazard of mortality. There was a 19% reduction in hazard of mortality amongst all TB patients between 2009 and 2016 (adjusted hazard ratio: 0.81 95%CI 0.80-0.83). The highest SMR was in 15-24-year-old women, more than double that of men (42.3 in 2016). Between 2009 and 2016, the SMR for HIV-positive TB patients increased, from 9.0 to 19.6 in women, and 7.0 to 10.6 in men. In South Africa, case fatality during TB treatment is decreasing and further interventions to address specific risk factors for TB mortality are required. Young women (15-24-year-olds) with TB experience a disproportionate burden of mortality and interventions targeting this age-group are needed.

Development and validation of a prediction model for active tuberculosis case finding among HIV-negative/unknown populations.

A prediction model of prevalent pulmonary tuberculosis (TB) in HIV negative/unknown individuals was developed to assist systematic screening. Data from a large TB screening trial were used. A multivariable logistic regression model was developed in the South African (SA) training dataset, using TB symptoms and risk factors as predictors. The model was converted into a scoring system for risk stratification and was evaluated in separate SA and Zambian validation datasets. The number of TB cases were 355, 176, and 107 in the SA training, SA validation, and Zambian validation datasets respectively. The area under curve (AUC) of the scoring system was 0·68 (95% CI 0·64-0·72) in the SA validation set, compared to prolonged cough (0·58, 95% CI 0·54-0·62) and any TB symptoms (0·6, 95% CI 0·56-0·64). In the Zambian dataset the AUC of the scoring system was 0·66 (95% CI 0·60-0·72). In the cost-effectiveness analysis, the scoring system dominated the conventional strategies. The cost per TB case detected ranged from 429 to 1,848 USD in the SA validation set and from 171 to 10,518 USD in the Zambian dataset. The scoring system may help targeted TB case finding under budget constraints.

The impact of isoniazid resistance on the treatment outcomes of smear positive re-treatment tuberculosis patients in the state of Andhra Pradesh, India.

BACKGROUND: Multi drug resistant and rifampicin resistant TB patients in India are treated with the World Health Organization (WHO) recommended standardized treatment regimens but no guidelines are available for the management of isoniazid (INH) resistant TB patients. There have been concerns that the standard eight-month retreatment regimen being used in India (2H3R3Z3E3S3/1H3R3Z3E3/5H3R3E3; H-Isoniazid; R-Rifampicin; Z-Pyrazinamide; E-Ethambutol; S-Streptomycin) may be inadequate to treat INH resistant TB cases and leads to poor treatment outcomes. We aimed to assess if INH resistance is associated with unfavorable treatment outcomes (death, default, failure and transferred out) among a cohort of smear positive retreatment TB patients registered in three districts of Andhra Pradesh, India. METHODS: We conducted a retrospective record review of all smear positive retreatment TB patients without rifampicin resistance registered during April-December 2011. RESULTS: Of 1,947 TB patients, 1,127 (58%) were tested with LPA-50 (4%) were rifampicin resistant, 933 (84%) were sensitive to INH and rifampicin and 144 (12%) were INH resistant. Of 144 INH resistant cases, 64 (44%) had poor treatment outcomes (25 (17%) default, 22 (15%) death, 12 (8%) failure and 5 (3%) transfer out) as compared to 287 (31%) among INH sensitive cases [aRR 1.46; 95%CI (1.19-1.78)]. CONCLUSION: Our study confirms that INH resistance is independently associated with unfavorable treatment outcomes among smear positive retreatment TB patients, indicating that the current treatment regimen may be inadequate. These findings call for an urgent need for randomized controlled trials to discover the most effective treatment regimen for managing INH resistant TB.