Sustained high fatality during TB therapy amid rapid decline in TB mortality at population level: A retrospective cohort and ecological analysis from Shiselweni, Eswatini.

OBJECTIVES: Despite declining TB notifications in Southern Africa, TB-related deaths remain high. We describe patient- and population-level trends in TB-related deaths in Eswatini over a period of 11 years. METHODS: Patient-level (retrospective cohort, from 2009 to 2019) and population-level (ecological analysis, 2009-2017) predictors and rates of TB-related deaths were analysed in HIV-negative and HIV-coinfected first-line TB treatment cases and the population of the Shiselweni region. Patient-level TB treatment data, and population and HIV prevalence estimates were combined to obtain stratified annual mortality rates. Multivariable Poisson regressions models were fitted to identify patient-level and population-level predictors of deaths. RESULTS: Of 11,883 TB treatment cases, 1302 (11.0%) patients died during treatment: 210/2798 (7.5%) HIV-negative patients, 984/8443 (11.7%) people living with HIV (PLHIV), and 108/642 (16.8%) patients with unknown HIV-status. The treatment case fatality ratio remained above 10% in most years. At patient-level, fatality risk was higher in PLHIV (aRR 1.74, 1.51-2.02), and for older age and extra-pulmonary TB irrespective of HIV-status. For PLHIV, fatality risk was higher for TB retreatment cases (aRR 1.38, 1.18-1.61) and patients without antiretroviral therapy (aRR 1.70, 1.47-1.97). It decreases with increasing higher CD4 strata and the programmatic availability of TB-LAM testing (aRR 0.65, 0.35-0.90). At population-level, mortality rates decreased 6.4-fold (-147/100,000 population) between 2009 (174/100,000) and 2017 (27/100,000), coinciding with a decline in TB treatment cases (2785 in 2009 to 497 in 2017). Although the absolute decline in mortality rates was most pronounced in PLHIV (-826/100,000 vs. HIV-negative: -23/100,000), the relative population-level mortality risk remained higher in PLHIV (aRR 4.68, 3.25-6.72) compared to the HIV-negative population. CONCLUSIONS: TB-related mortality rapidly decreased at population-level and most pronounced in PLHIV. However, case fatality among TB treatment cases remained high. Further strategies to reduce active TB disease and introduce improved TB therapies are warranted.

The introduction of video-enabled directly observed therapy (video-DOT) for patients with drug-resistant TB disease in Eswatini amid the COVID-19 pandemic - a retrospective cohort study.

BACKGROUND: Video-enabled directly observed therapy (video-DOT) has been proposed as an additional option for treatment provision besides in-person DOT for patients with drug-resistant TB (DRTB) disease. However, evidence and implementation experience mainly originate from well-resourced contexts. This study describes the operationalization of video-DOT in a low-resourced setting in Eswatini facing a high burden of HIV and TB amid the emergence of the COVID-19 pandemic. METHODS: This is a retrospectively established cohort of patients receiving DRTB treatment during the implementation of video-DOT in Shiselweni from May 2020 to March 2022. We described intervention uptake (vs. in-person DOT) and assessed unfavorable DRTB treatment outcome (death, loss to care) using Kaplan-Meier statistics and multivariable Cox-regression models. Video-related statistics were described with frequencies and medians. We calculated the fraction of expected doses observed (FEDO) under video-DOT and assessed associations with missed video uploads using multivariable Poisson regression analysis. RESULTS: Of 71 DRTB patients eligible for video-DOT, the median age was 39 (IQR 30-54) years, 31.0% (n = 22) were women, 67.1% (n = 47/70) were HIV-positive, and 42.3% (n = 30) were already receiving DRTB treatment when video-DOT became available. About half of the patients (n = 37; 52.1%) chose video-DOT, mostly during the time when COVID-19 appeared in Eswatini. Video-DOT initiations were lower in new DRTB patients (aHR 0.24, 95% CI 0.12-0.48) and those aged ≥ 60 years (aHR 0.27, 95% CI 0.08-0.89). Overall, 20,634 videos were uploaded with a median number of 553 (IQR 309-748) videos per patient and a median FEDO of 92% (IQR 84-97%). Patients aged ≥ 60 years were less likely to miss video uploads (aIRR 0.07, 95% CI 0.01-0.51). The cumulative Kaplan-Meier estimate of an unfavorable treatment outcome among all patients was 0.08 (95% CI 0.03-0.19), with no differences detected by DOT approach and other baseline factors in multivariable analysis. CONCLUSIONS: Implementing video-DOT for monitoring of DRTB care provision amid the intersection of the HIV and COVID-19 pandemics seemed feasible. Digital health technologies provide additional options for patients to choose their preferred way to support treatment taking, thus possibly increasing patient-centered health care while sustaining favorable treatment outcomes.

Tobacco smoking clusters in households affected by tuberculosis in an individual participant data meta-analysis of national tuberculosis prevalence surveys: Time for household-wide interventions?

Tuberculosis (TB) and non-communicable diseases (NCD) share predisposing risk factors. TB-associated NCD might cluster within households affected with TB requiring shared prevention and care strategies. We conducted an individual participant data meta-analysis of national TB prevalence surveys to determine whether NCD cluster in members of households with TB. We identified eligible surveys that reported at least one NCD or NCD risk factor through the archive maintained by the World Health Organization and searching in Medline and Embase from 1 January 2000 to 10 August 2021, which was updated on 23 March 2023. We compared the prevalence of NCD and their risk factors between people who do not have TB living in households with at least one person with TB (members of households with TB), and members of households without TB. We included 16 surveys (n = 740,815) from Asia and Africa. In a multivariable model adjusted for age and gender, the odds of smoking was higher among members of households with TB (adjusted odds ratio (aOR) 1.23; 95% CI: 1.11-1.38), compared with members of households without TB. The analysis did not find a significant difference in the prevalence of alcohol drinking, diabetes, hypertension, or BMI between members of households with and without TB. Studies evaluating household-wide interventions for smoking to reduce its dual impact on TB and NCD may be warranted. Systematically screening for NCD using objective diagnostic methods is needed to understand the actual burden of NCD and inform comprehensive interventions.

Association of diabetes, smoking, and alcohol use with subclinical-to-symptomatic spectrum of tuberculosis in 16 countries: an individual participant data meta-analysis of national tuberculosis prevalence surveys.

Background: Non-communicable diseases (NCDs) and NCD risk factors, such as smoking, increase the risk for tuberculosis (TB). Data are scarce on the risk of prevalent TB associated with these factors in the context of population-wide systematic screening and on the association between NCDs and NCD risk factors with different manifestations of TB, where ∼50% being asymptomatic but bacteriologically positive (subclinical). We did an individual participant data (IPD) meta-analysis of national and sub-national TB prevalence surveys to synthesise the evidence on the risk of symptomatic and subclinical TB in people with NCDs or risk factors, which could help countries to plan screening activities. Methods: In this systematic review and IPD meta-analysis, we identified eligible prevalence surveys in low-income and middle-income countries that reported at least one NCD (e.g., diabetes) or NCD risk factor (e.g., smoking, alcohol use) through the archive maintained by the World Health Organization and by searching in Medline and Embase from January 1, 2000 to August 10, 2021. The search was updated on March 23, 2023. We performed a one-stage meta-analysis using multivariable multinomial models. We estimated the proportion of and the odds ratio for subclinical and symptomatic TB compared to people without TB for current smoking, alcohol use, and self-reported diabetes, adjusted for age and gender. Subclinical TB was defined as microbiologically confirmed TB without symptoms of current cough, fever, night sweats, or weight loss and symptomatic TB with at least one of these symptoms. We assessed heterogeneity using forest plots and I2 statistic. Missing variables were imputed through multi-level multiple imputation. This study is registered with PROSPERO (CRD42021272679). Findings: We obtained IPD from 16 national surveys out of 21 national and five sub-national surveys identified (five in Asia and 11 in Africa, N = 740,815). Across surveys, 15.1%-56.7% of TB were subclinical (median: 38.1%). In the multivariable model, current smoking was associated with both subclinical (OR 1.67, 95% CI 1.27-2.40) and symptomatic TB (OR 1.49, 95% CI 1.34-1.66). Self-reported diabetes was associated with symptomatic TB (OR 1.67, 95% CI 1.17-2.40) but not with subclinical TB (OR 0.92, 95% CI 0.55-1.55). For alcohol drinking ≥ twice per week vs no alcohol drinking, the estimates were imprecise (OR 1.59, 95% CI 0.70-3.62) for subclinical TB and OR 1.43, 95% CI 0.59-3.46 for symptomatic TB). For the association between current smoking and symptomatic TB, I2 was high (76.5% (95% CI 62.0-85.4), while the direction of the point estimates was consistent except for three surveys with wide CIs. Interpretation: Our findings suggest that current smokers are more likely to have both symptomatic and subclinical TB. These individuals can, therefore, be prioritised for intensified screening, such as the use of chest X-ray in the context of community-based screening. People with self-reported diabetes are also more likely to have symptomatic TB, but the association is unclear for subclinical TB. Funding: None.

High prevalence of multidrug-resistant tuberculosis, Swaziland, 2009-2010.

In Africa, although emergence of multidrug-resistant (MDR) tuberculosis (TB) represents a serious threat in countries severely affected by the HIV epidemic, most countries lack drug-resistant TB data. This finding was particularly true in the Kingdom of Swaziland, which has the world's highest HIV and TB prevalences. Therefore, we conducted a national survey in 2009-2010 to measure prevalence of drug-resistant TB. Of 988 patients screened, 420 new case-patients and 420 previously treated case-patients met the study criteria. Among culture-positive patients, 15.3% new case-patients and 49.5% previously treated case-patients harbored drug-resistant strains. MDR TB prevalence was 7.7% and 33.8% among new case-patients and previously treated case-patients, respectively. HIV infection and past TB treatment were independently associated with MDR TB. The findings assert the need for wide-scale intervention in resource-limited contexts such as Swaziland, where diagnostic and treatment facilities and health personnel are lacking.

Outcomes of HIV-infected versus HIV-non-infected patients treated for drug-resistance tuberculosis: Multicenter cohort study.

BACKGROUND: The emergence of resistance to anti-tuberculosis (DR-TB) drugs and the HIV epidemic represent a serious threat for reducing the global burden of TB. Although data on HIV-negative DR-TB treatment outcomes are well published, few data on DR-TB outcomes among HIV co-infected people is available despite the great public health importance. METHODS: We retrospectively reported and compared the DR-TB treatment outcomes of HIV-positive and HIV-negative patients treated with an individualized regimen based on WHO guidelines in seven countries: Abkhazia, Armenia, Colombia, Kenya, Kyrgyzstan, Swaziland and Uzbekistan. RESULTS: Of the 1,369 patients started DRTB treatment, 809 (59.1%) were multi-drug resistant (MDR-TB) and 418 (30.5%) were HIV-positive. HIV-positive patients were mainly from African countries (90.1%) while HIV-negative originated from Former Soviet Union (FSU) countries. Despite a higher case fatality rate (19.0% vs 9.4%), HIV-positive MDR-TB patients had a 10% higher success rate than HIV-negative patients (64.0% vs 53.2%, p = 0.007). No difference in treatment success was found among polydrug-resistant (PDR-TB) patients. Overall, lost to follow-up rate was much higher among HIV-negative (22.0% vs. 8.4%). Older age and not receiving ART were the only factors associated with unfavorable treatment outcome among HIV-positive patients. CONCLUSIONS: As already known for HIV-negative patients, success rate of DR-TB HIV-positive patients remains low and requires more effective DR-TB regimen using new drugs also suitable to HIV-infected patients on ART. The study also confirms the need of ART introduction in HIV co-infected patients.