Treatment outcomes among children, adolescents, and adults on treatment for tuberculosis in two metropolitan municipalities in Gauteng Province, South Africa

BACKGROUND : Gauteng Province has the second lowest tuberculosis (TB) incidence rate in South Africa but the greatest proportion of TB/HIV co-infection, with 68% of TB patients estimated to have HIV. TB treatment outcomes are well documented at the national and provincial level; however, knowledge gaps remain on how outcomes differ across detailed age groups. METHODS : Using data from South Africa’s National Electronic TB Register (ETR), we assessed all-cause mortality and loss to follow-up (LTFU) among patients initiating treatment for TB between 01/2010 and 12/2015 in the metropolitan municipalities of Ekurhuleni Metropolitan Municipality and the City of Johannesburg in Gauteng Province. We excluded patients who were missing age, had known drug-resistance, or transferred into TB care from sites outside the two metropolitan municipalities. Among patients assigned a treatment outcome, we investigated the association between age group at treatment initiation and mortality or LTFU (treatment interruption of ≥2 months) within 10 months after treatment initiation using Cox proportional hazard models and present hazard ratios and Kaplan-Meier survival curves. RESULTS : We identified 182,890 children (<10 years), young adolescent (10–14), older adolescent (15–19), young adult (20–24), adult (25–49), and older adult (≥50) TB cases without known drug-resistance. ART coverage among HIV co-infected patients was highest for young adolescents (64.3%) and lowest for young adults (54.0%) compared to other age groups (all over 60%). Treatment success exceeded 80% in all age groups (n = 170,017). All-cause mortality increased with age. Compared to adults, young adults had an increased hazard of LTFU (20–24 vs 25–49 years; aHR 1.43 95% CI: 1.33, 1.54) while children, young adolescents, and older adults had lower hazard of LTFU. Patients with HIV on ART had a lower risk of LTFU, but greater risk of death when compared to patients without HIV. CONCLUSIONS : Young adults in urban areas of Gauteng Province experience a disproportionate burden of LTFU and low coverage of ART among co-infected patients. This group should be targeted for interventions aimed at improving clinical outcomes and retention in both TB and HIV care.The American People and the President’s Emergency Plan for AIDS Relief (PEPFAR) through USAID under the terms of Cooperative Agreements AID- 674-A-12-00029 and 72067419CA00004 to HE2RO.https://bmcpublichealth.biomedcentral.comam2020Medical Microbiolog

Drug-Resistant Tuberculosis, KwaZulu-Natal, South Africa, 2001–2007

In Africa, incidence and prevalence of drug-resistant tuberculosis have been assumed to be low. However, investigation after a 2005 outbreak of extensively drug-resistant tuberculosis in KwaZulu-Natal Province, South Africa, found that the incidence rate for multidrug-resistant tuberculosis in KwaZulu-Natal was among the highest globally and would be higher if case-finding efforts were intensified

Application of provincial data in mathematical modelling to inform sub-national tuberculosis program decision-making in South Africa.

South Africa has the highest tuberculosis (TB) disease incidence rate in the world, and TB is the leading infectious cause of death. Decisions on, and funding for, TB prevention and care policies are decentralised to the provincial governments and therefore, tools to inform policy need to operate at this level. We describe the use of a mathematical model planning tool at provincial level in a high HIV and TB burden country, to estimate the impact on TB burden of achieving the 90-(90)-90 targets of the Stop TB Partnership Global Plan to End TB. "TIME Impact" is a freely available, user-friendly TB modelling tool. In collaboration with provincial TB programme staff, and the South African National TB Programme, models for three (of nine) provinces were calibrated to TB notifications, incidence, and screening data. Reported levels of TB programme activities were used as baseline inputs into the models, which were used to estimate the impact of scale-up of interventions focusing on screening, linkage to care and treatment success. All baseline models predicted a trend of decreasing TB incidence and mortality, consistent with recent data from South Africa. The projected impacts of the interventions differed by province and were greatly influenced by assumed current coverage levels. The absence of provincial TB burden estimates and uncertainty in current activity coverage levels were key data gaps. A user-friendly modelling tool allows TB burden and intervention impact projection at the sub-national level. Key sub-national data gaps should be addressed to improve the quality of sub-national model predictions

Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis: a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIF

Background In South Africa, sputum smear microscopy has been replaced with Xpert MTB/RIF as the initial diagnostic test for tuberculosis. In a pragmatic parallel cluster-randomised trial, we evaluated the eff ect on patient and programme outcomes. Methods We randomly allocated 20 laboratories (clusters) in medium-burden districts of South Africa to either an Xpert (immediate Xpert) or microscopy (Xpert deferred) group (1:1), stratifi ed by province. At two primary care clinics per laboratory, a systematic sample of adults giving sputum for tuberculosis investigation was assessed for eligibility. The primary outcome was mortality at 6 months from enrolment. Masking of participants’ group allocation was not possible because of the pragmatic trial design. The trial is registered with the ISRCTN registry (ISRCTN68905568) and the South African Clinical Trial Register (DOH-27-1011-3849). Findings Between June and November, 2012, 4972 people were screened, and 4656 (93·6%) enrolled (median age 36 years; 2891 [62%] female; 2212 [62%] reported being HIV-positive). There was no diff erence between the Xpert and microscopy groups with respect to mortality at 6 months (91/2324 [3·9%] vs 116/2332 [5·0%], respectively; adjusted risk ratio [aRR] 1·10, 95% CI 0·75–1·62]). Interpretation Xpert did not reduce mortality at 6 months compared with sputum microscopy. Improving outcomes in drug-sensitive tuberculosis programmes might require not only better diagnostic tests but also better linkage to care

Prevalence of drug-resistant tuberculosis and imputed burden in South Africa : a national and sub-national cross-sectional survey

BACKGROUND : Globally, per-capita, South Africa reports a disproportionately high number of cases of multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis. We sought to estimate the prevalence of resistance to tuberculosis drugs in newly diagnosed and retreated patients with tuberculosis provincially and nationally, and compared these with the 2001–02 estimates. METHODS : A cross-sectional survey was done between June 15, 2012–June 14, 2014, using population proportionate randomised cluster sampling in the nine provinces in South Africa. 343 clusters were included, ranging between 31 and 48 per province. A patient was eligible for inclusion in the survey if he or she presented as a presumptive case during the intake period at a drug resistance survey enrolling facility. Consenting participants (≥18 years old) completed a questionnaire and had a sputum sample tested for resistance to first-line and second-line drugs. Analysis was by logistic regression with robust SEs, inverse probability weighted against routine data, and estimates were derived using a random effects model. FINDINGS : 101 422 participants were tested in 2012–14. Nationally, the prevalence of MDR tuberculosis was 2·1% (95% CI 1·5–2·7) among new tuberculosis cases and 4·6% (3·2–6·0) among retreatment cases. The provincial point prevalence of MDR tuberculosis ranged between 1·6% (95% CI 0·9–2·9) and 5·1% (3·7–7·0). Overall, the prevalence of rifampicin-resistant tuberculosis (4·6%, 95% CI 3·5–5·7) was higher than the prevalence of MDR tuberculosis (2·8%, 2·0–3·6; p=0·01). Comparing the current survey with the previous (2001–02) survey, the overall MDR tuberculosis prevalence was 2·8% versus 2·9% and prevalance of rifampicin-resistant tuberculosis was 3·4% versus 1·8%, respectively. The prevalence of isoniazid mono-resistant tuberculosis was above 5% in all provinces. The prevalence of ethionamide and pyrazinamide resistance among MDR tuberculosis cases was 44·7% (95% CI 25·9–63·6) and 59·1% (49·0–69·1), respectively. The prevalence of XDR tuberculosis was 4·9% (95% CI 1·0–8·8). Nationally, the estimated numbers of cases of rifampicin-resistant tuberculosis, MDR tuberculosis, and isoniazid mono-resistant tuberculosis for 2014 were 13 551, 8249, and 17 970, respectively. INTERPRETATION : The overall prevalence of MDR tuberculosis in South Africa in 2012–14 was similar to that in 2001–02; however, prevalence of rifampicin-resistant tuberculosis almost doubled among new cases. Furthermore, the high prevalence of isoniazid mono-resistant tuberculosis, not routinely screened for, and resistance to second-line drugs has implications for empirical management.President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention under the terms of 1U19GH000571.http://www.thelancet.com/infection2019-07-01hj2018Medical Microbiolog

Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis: a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIF.

BACKGROUND: In South Africa, sputum smear microscopy has been replaced with Xpert MTB/RIF as the initial diagnostic test for tuberculosis. In a pragmatic parallel cluster-randomised trial, we evaluated the effect on patient and programme outcomes. METHODS: We randomly allocated 20 laboratories (clusters) in medium-burden districts of South Africa to either an Xpert (immediate Xpert) or microscopy (Xpert deferred) group (1:1), stratified by province. At two primary care clinics per laboratory, a systematic sample of adults giving sputum for tuberculosis investigation was assessed for eligibility. The primary outcome was mortality at 6 months from enrolment. Masking of participants' group allocation was not possible because of the pragmatic trial design. The trial is registered with the ISRCTN registry (ISRCTN68905568) and the South African Clinical Trial Register (DOH-27-1011-3849). FINDINGS: Between June and November, 2012, 4972 people were screened, and 4656 (93·6%) enrolled (median age 36 years; 2891 [62%] female; 2212 [62%] reported being HIV-positive). There was no difference between the Xpert and microscopy groups with respect to mortality at 6 months (91/2324 [3·9%] vs 116/2332 [5·0%], respectively; adjusted risk ratio [aRR] 1·10, 95% CI 0·75-1·62]). INTERPRETATION: Xpert did not reduce mortality at 6 months compared with sputum microscopy. Improving outcomes in drug-sensitive tuberculosis programmes might require not only better diagnostic tests but also better linkage to care. FUNDING: Bill & Melinda Gates Foundation

Prevalence of bacteriologically confirmed pulmonary tuberculosis in South Africa, 2017-19 : a multistage, cluster-based, cross-sectional survey

DATA SHARING : Individual, deidentified participant data, including data dictionaries, may be shared. Templates of the informed consent forms may be shared upon request. The data will be available following publication, with no end date, and will be shared with anyone who wishes to access them with a clear data sharing agreement, for any purpose of analyses. For data access, please contact the corresponding author and the tuberculosis programme at the National Department of Health in South Africa.BACKGROUND : Tuberculosis remains an important clinical and public health issue in South Africa, which has one of the highest tuberculosis burdens in the world. We aimed to estimate the burden of bacteriologically confirmed pulmonary tuberculosis among people aged 15 years or older in South Africa. METHODS : This multistage, cluster-based, cross-sectional survey included eligible residents (age ≥15 years, who had slept in a house for ≥10 nights in the preceding 2 weeks) in 110 clusters nationally (cluster size of 500 people; selected by probability proportional-to-population size sampling). Participants completed face-to-face symptom questionnaires (for cough, weight loss, fever, and night sweats) and manually read digital chest X-ray screening. Screening was recorded as positive if participants had at least one symptom or an abnormal chest X-ray suggestive of tuberculosis, or a combination thereof. Sputum samples from participants who were screen-positive were tested by the Xpert MTB/RIF Ultra assay (first sample) and Mycobacteria Growth Indicator Tube culture (second sample), with optional HIV testing. Participants with a positive Mycobacterium tuberculosis complex culture were considered positive for bacteriologically confirmed pulmonary tuberculosis; when culture was not positive, participants with a positive Xpert MTB/RIF Ultra result with an abnormal chest X-ray suggestive of active tuberculosis and without current or previous tuberculosis were considered positive for bacteriologically confirmed pulmonary tuberculosis. FINDINGS : Between Aug 15, 2017, and July 28, 2019, 68 771 people were enumerated from 110 clusters, with 53 250 eligible to participate in the survey, of whom 35 191 (66·1%) participated. 9066 (25·8%) of 35 191 participants were screen-positive and 234 (0·7%) were identified as having bacteriologically confirmed pulmonary tuberculosis. Overall, the estimated prevalence of bacteriologically confirmed pulmonary tuberculosis was 852 cases (95% CI 679–1026) per 100 000 population; the prevalence was highest in people aged 35–44 years (1107 cases [95% CI 703–1511] per 100 000 population) and those aged 65 years or older (1104 cases [680–1528] per 100 000 population). The estimated prevalence was approximately 1·6 times higher in men than in women (1094 cases [95% CI 835–1352] per 100 000 population vs 675 cases [494–855] per 100 000 population). 135 (57·7%) of 234 participants with tuberculosis screened positive by chest X-ray only, 16 (6·8%) by symptoms only, and 82 (35·9%) by both. 55 (28·8%) of 191 participants with tuberculosis with known HIV status were HIV-positive. INTERPRETATION : Pulmonary tuberculosis prevalence in this survey was high, especially in men. Despite the ongoing burden of HIV, many participants with tuberculosis in this survey did not have HIV. As more than half of the participants with tuberculosis had an abnormal chest X-ray without symptoms, prioritising chest X-ray screening could substantially increase case finding.Global Fund, Bill & Melinda Gates Foundation, USAID.http://www.thelancet.com/infectionhj2023Medical Microbiolog

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

Summary 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

Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study

BACKGROUND : In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis. METHODS : Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing. FINDINGS : Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic sequencing were 91% (95% CI 87–94) for rpoB (rifampicin resistance), 86% (74–93) for katG, inhA, and fabG promoter combined (isoniazid resistance), 54% (39–68) for pncA (pyrazinamide resistance), 85% (77–91) for gyrA and gyrB combined (ofloxacin resistance), and 88% (81–92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic sequencing and the estimated prevalence by phenotypic testing. INTERPRETATION : Genetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation.The Bill & Melinda Gates Foundation, the United States Agency for International Development, and the TB Alliance.www.thelancet.com/infectionhttp://www.thelancet.com/infectionam2018Medical Microbiolog