Evaluating systematic targeted universal testing for tuberculosis in primary care clinics of South Africa: A cluster-randomized trial (The TUTT Trial).

BACKGROUND: The World Health Organization (WHO) recommends systematic symptom screening for tuberculosis (TB). However, TB prevalence surveys suggest that this strategy does not identify millions of TB patients, globally. Undiagnosed or delayed diagnosis of TB contribute to TB transmission and exacerbate morbidity and mortality. We conducted a cluster-randomized trial of large urban and rural primary healthcare clinics in 3 provinces of South Africa to evaluate whether a novel intervention of targeted universal testing for TB (TUTT) in high-risk groups diagnosed more patients with TB per month compared to current standard of care (SoC) symptom-directed TB testing. METHODS AND FINDINGS: Sixty-two clinics were randomized; with initiation of the intervention clinics over 6 months from March 2019. The study was prematurely stopped in March 2020 due to clinics restricting access to patients, and then a week later due to the Coronavirus Disease 2019 (COVID-19) national lockdown; by then, we had accrued a similar number of TB diagnoses to that of the power estimates and permanently stopped the trial. In intervention clinics, attendees living with HIV, those self-reporting a recent close contact with TB, or a prior episode of TB were all offered a sputum test for TB, irrespective of whether they reported symptoms of TB. We analyzed data abstracted from the national public sector laboratory database using Poisson regression models and compared the mean number of TB patients diagnosed per clinic per month between the study arms. Intervention clinics diagnosed 6,777 patients with TB, 20.7 patients with TB per clinic month (95% CI 16.7, 24.8) versus 6,750, 18.8 patients with TB per clinic month (95% CI 15.3, 22.2) in control clinics during study months. A direct comparison, adjusting for province and clinic TB case volume strata, did not show a significant difference in the number of TB cases between the 2 arms, incidence rate ratio (IRR) 1.14 (95% CI 0.94, 1.38, p = 0.46). However, prespecified difference-in-differences analyses showed that while the rate of TB diagnoses in control clinics decreased over time, intervention clinics had a 17% relative increase in TB patients diagnosed per month compared to the prior year, interaction IRR 1.17 (95% CI 1.14, 1.19, p < 0.001). Trial limitations were the premature stop due to COVID-19 lockdowns and the absence of between-arm comparisons of initiation and outcomes of TB treatment in those diagnosed with TB. CONCLUSIONS: Our trial suggests that the implementation of TUTT in these 3 groups at extreme risk of TB identified more TB patients than SoC and could assist in reducing undiagnosed TB patients in settings of high TB prevalence. TRIAL REGISTRATION: South African National Clinical Trials Registry DOH-27-092021-4901.

Pulmonary tuberculosis vs. Tindzhaka and Mafularha: A mixed methods inquiry of traditional healers' perceptions of tuberculosis in rural South Africa.

Although awareness of tuberculosis (TB) is high in South Africa, delays in TB testing or treatment persist. Even those with symptoms of TB often delay testing, with one study in Mpumalanga revealing a median allopathic care-seeking delay of four weeks. We sought to understand how traditional healers perceived TB symptoms among their patients, if they treated the disease, and what (if any) illnesses they defined as being traditional may have overlapping presentation with TB in South Africa. Nineteen traditional healers completed an in-depth interview (IDIs); 133 completed a quantitative survey about their treatment practices. IDIs focused on lung diseases treated, disease causation, treatment, and prognosis. Survey questions investigated diagnosis of lung ailments, including those treated by the allopathic health system and those by traditional healers. Traditional healers reported that they could differentiate between TB and traditional illnesses, like Tindzhaka and Mafularha, that presented with similar symptoms. Few (7.5%) believed they could treat TB, but the majority (72.9%) believed they could successfully treat Tindzhaka and Mafularha. Tindzhaka and Mafularha are interconnected illnesses that are reportedly caused by breaking social rules around death, sex and using the belongings of someone who recently passed away. Both, if not treated, are considered fatal. While we have no definitive data, traditional healers may be contributing to delays in the diagnosis and treatment for people with active TB by incorrectly diagnosing TB as Tindzhaka or Mafularha. Overcoming issues of trust and compensation, while respecting different forms of knowledge, are some of the challenges we face in successfully engaging with healers.

Yield of Facility-based Targeted Universal Testing for Tuberculosis With Xpert and Mycobacterial Culture in High-Risk Groups Attending Primary Care Facilities in South Africa.

BACKGROUND: We report the yield of targeted universal tuberculosis (TB) testing of clinic attendees in high-risk groups. METHODS: Clinic attendees in primary healthcare facilities in South Africa with one of the following risk factors underwent sputum testing for TB: human immunodeficiency virus (HIV), contact with a TB patient in the past year, and having had TB in the past 2 years. A single sample was collected for Xpert-Ultra (Xpert) and culture. We report the proportion positive for Mycobacterium tuberculosis. Data were analyzed descriptively. The unadjusted clinical and demographic factors' relative risk of TB detected by culture or Xpert were calculated and concordance between Xpert and culture is described. RESULTS: A total of 30 513 participants had a TB test result. Median age was 39 years, and 11 553 (38%) were men. The majority (n = 21734, 71%) had HIV, 12 492 (41%) reported close contact with a TB patient, and 1573 (5%) reported prior TB. Overall, 8.3% were positive for M. tuberculosis by culture and/or Xpert compared with 6.0% with trace-positive results excluded. In asymptomatic participants, the yield was 6.7% and 10.1% in symptomatic participants (with trace-positives excluded). Only 10% of trace-positive results were culture-positive. We found that 55% of clinic attendees with a sputum result positive for M. tuberculosis did not have a positive TB symptom screen. CONCLUSIONS: A high proportion of clinic attendees with specific risk factors (HIV, close TB contact, history of TB) test positive for M. tuberculosis when universal testing is implemented.

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.

Performance of Xpert MTB/RIF, Xpert Ultra, and Abbott RealTime MTB for Diagnosis of Pulmonary Tuberculosis in a High-HIV-Burden Setting.

More sensitive tests are needed for the diagnosis of smear-negative and HIV-associated tuberculosis. This study compares the sensitivities and specificities of three molecular tests, namely, the Xpert MTB/RIF test, the Xpert Ultra (Ultra), and RealTime MTB (RT-MTB), in a high HIV prevalence setting. Symptomatic adults were recruited from three outpatient sites, and each provided 4 sputum specimens. The diagnostic performance of Xpert MTB/RIF, Ultra, and RT-MTB was evaluated, with culture as a reference standard. HIV infection occurred in 62% of patients, with a median CD4 count of 220 cells/µl. The Ultra test had the highest sensitivity of 89.3% (95% confidence interval [CI], 78.1 to 96) compared to those of the Xpert MTB/RIF at 82.1% (95% CI, 69.6 to 91.1; P = 0.12) and RT-MTB at 78.6% (95% CI, 65.6 to 88.4; P = 0.68). The specificity was highest with the Xpert MTB/RIF at 100% (95% CI, 98 to 100), followed by RealTime MTB at 96.7% (95% CI, 92.9 to 98.8; P = 0.03) and the Ultra at 95.6% (95% CI, 91.5 to 98.1; P = 0.08). In patients with smear-negative disease, the Ultra was more sensitive than the Xpert MTB/RIF (64.7% [95% CI, 38.3 to 85.8] versus 41.2% [95% CI, 18.4 to 67.1], respectively; P = 0.12), and RT-MTB performed equally to Xpert MTB/RIF. In a comparison of the Ultra and RT-MTB on the same sputum specimen pellets, the Ultra was more sensitive than RT-MTB in the overall cohort (88.9% [95% CI, 77.4 to 95.8] versus 77.8% [95% CI, 64.4 to 88], respectively; P = 0.03) and among people with HIV (87.5% [95% CI, 71 to 96.5] versus 68.6% [95% CI, 50 to 83.9], respectively; P = 0.03). Although these results did not reach statistical significance, they suggest that the Ultra is more sensitive than the Xpert MTB/RIF and RT-MTB, most prominently in smear-negative disease. This was accompanied by a loss of specificity.

Severe adverse events during second-line tuberculosis treatment in the context of high HIV Co-infection in South Africa: a retrospective cohort study.

BACKGROUND: According to the World Health Organization, South Africa ranks as one of the highest burden of TB, TB/HIV co-infection, and drug-resistant TB (DR-TB) countries. DR-TB treatment is complicated to administer and relies on the use of multiple toxic drugs, with potential for severe adverse drug reactions. We report the occurrence of adverse events (AEs) during a standardised DR-TB treatment regimen at two outpatient, decentralized, public-sector sites in Johannesburg, South Africa. METHODS: We reviewed medical records of the six-month intensive treatment phase for rifampicin-resistant (RR) TB patients registered May 2012 - December 2014. Patients contributed follow-up time until death, loss from treatment, censoring (6 months) or data extraction. A standardized regimen of kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide was used according to national guidelines. AEs were graded using the AIDS Clinical Trial Group scale. We present subhazard ratios from competing risk analysis for time to severe AE, accounting for mortality and loss from treatment. RESULTS: Across the two sites, 578 eligible patient files were reviewed. 36.7 % were categorized as low weight (≤50 kg) at DR-TB initiation. 76.0 % had no history of TB treatment prior to the current episode of RR TB. 26.8 % were diagnosed with RR TB while hospitalized, indicating poor clinical condition. 82.5 % of patients were also HIV positive, of whom 43.8 % were on ART prior to RR TB treatment and 32.1 % initiated ART with or after RR TB treatment. Median CD4 count was 114.5 (IQR: 45-246.5). Overall, 578 reports of AEs were captured for 204 patients (35.3 %) and 110 patients (19.0 %) had at least one severe AE reported. Patients with at least one AE experienced a median of 3 (IQR: 2-4) AEs per patient. HIV-positive patients with CD4 counts ≤100 cells/mm3 and those newly initiating ART were more likely to experience a severe AE (sHR: 2.76, 95 % CI: 1.30-5.84 and sHR: 3.07, 95 % CI: 1.46-6.46, respectively). CONCLUSION: Severe AE are common during the first 6 months of RR TB treatment and HIV-positive patients newly initiating ART have the highest subdistribution hazard ratio for severe AE, accounting for the competing risks of death and loss from treatment.