People living with HIV (PLHIV) have an increased risk of tuberculosis (TB) and severe COVID-19. TB and COVID-19 present with overlapping symptoms and co-infection can lead to poor outcomes. We assessed the frequency of SARS-CoV-2 positive serology and SARS-CoV-2 infection and the risk of mortality at 6 months in PLHIV with TB disease and SARS-CoV-2 infection. This multi-country, prospective, observational study, conducted between 7^th September 2020 and 7^th April 2022, included ambulatory adult PLHIV investigated for TB (with symptoms of TB or advanced HIV disease) in Kenya, Uganda, and South Africa. Testing included CD4 cell count, Xpert MTB/RIF Ultra assay (sputum), Determine TB LAM Ag assay (urine), chest X-ray, blood SARS-CoV-2 serology test and SARS-CoV-2 PCR (only if TB or COVID-19 symptoms). Individuals were followed for 6 months. Among 1254 participants, 1204 participants had SARS-CoV-2 serology (54% women, median CD4 344 cells/µL [IQR 132–673]), and 487 had SARS-CoV-2 PCR. SARS-CoV-2 serology positivity was 27.0% (325/1204), lower in PLHIV with CD4 counts <200 cells/µL (19.9%, 99/497) than in those with CD4 counts ≥200 cells/µL (31.6%, 222/703), p<0.001. SARS-CoV-2 PCR positivity was 8.6% (42/487) and 27.7% (135/487) had probable or confirmed SARS-CoV-2 infection. Among PLHIV with symptoms of TB or of COVID-19, 6.6% (32/487) had SARS-CoV-2 infection and TB disease. In multivariable analyses, the risk of death was higher in PLHIV with both SARS-CoV-2 infection and TB compared to those with only SARS-CoV-2 infection (adjusted hazard ratio [aHR] 8.90, 95%CI 1.47-53.96, p=0.017), with only TB (aHR 3.70, 95%CI 1.00-13.72, p=0.050) or with none of them (aHR 6.83, 95%CI 1.75-26.72, p=0.006). These findings support SARS-CoV-2 testing in PLHIV with symptoms of TB, and SARS-CoV-2 vaccination, especially for those with severe immunosuppression. PLHIV with COVID-19 and TB have an increased risk of mortality and would benefit from comprehensive management and close monitoring.

Tuberculosis (TB) among hospitalized patients is underdiagnosed. This study assessed systematic TB-screening, followed by an enhanced TB-diagnostic package for hospitalized patients implemented by trained lay health workers in KwaZulu-Natal, South Africa. In this before-and-after study we included patients ≥ 18 years. The intervention consisted of systematic clinical screening for TB, HIV and diabetes mellitus by lay health workers and provision of an enhanced TB-diagnostic package including sputum Xpert MTB/Rif Ultra, urine lateral-flow lipoarabinomannan assay (LF-LAM), chest x-ray, and sputum culture. We compared TB case findings with people hospitalized one year preceding the intervention. In the pre-intervention phase, 5217 people were hospitalized. Among 4913 (94.2%) people not on TB treatment, 367 (7.5%) were diagnosed with TB. In the intervention phase, 4015 eligible people were hospitalized. Among 3734 (93.0%) people not on TB treatment, 560 (15.0%) were diagnosed with TB. The proportion of patients diagnosed with TB was higher in the intervention phase (15.0% vs. 7.5%, p < 0.001). Overall in-hospital mortality was lower in the intervention phase [166/3734(4.5%) vs. 336/4913(6.8%), p < 0.001]. Lay health worker-led implementation of systematic TB-screening, coupled with provision of an enhanced TB-diagnostic package significantly improved TB case detection and mortality among hospitalized adults.

Clinical trials are considered to be the largest contributor to pharmaceutical development costs. However, public disclosure of the costs of individual clinical trials is rare. Médecins Sans Frontières (MSF) sponsored a phase 2b-3 randomised controlled trial (TB-PRACTECAL), which identified a new treatment regimen for drug-resistant TB. We aimed to analyse the costs of undertaking a pivotal clinical trial conducted in relatively low-resource health settings and to demonstrate the feasibility of reporting clinical trial costs. TB-PRACTECAL trial costs were analysed using MSF accounting documents. Costs were broken down by cost category, year, and trial site. Total costs for TB-PRACTECAL were €33.9 million and the average cost per patient was €61,460. Twenty-six percent of total costs represented central activities (e.g. trial planning, trial management) and 72% represented trial site activities, with 2% uncategorizable. Within trial site costs, personnel costs were the largest cost (43%) followed by external diagnostic services (11%), medicines (9%), and other medical consumables (7%). Cost variation across trial sites was driven by different varying levels of pre-existing trial infrastructure. A review of previous studies yielded a wide range of cost estimates for clinical trials (ranging US$7–221 million/trial for pharmaceutical phase 2 and 3 trials). Nearly all previous estimates derive from industry reporting that is neither standardized nor auditable; to our knowledge, this is the first published comprehensive analysis of direct expenditures of a specific clinical trial including detailed cost breakdowns. The €34 million cost of TB-PRACTECAL included investments in developing clinical trial infrastructure, the complexity of managing six sites across three health systems, and medical expenditures that are not typical of standard clinical trials. Greater transparency in drug development costs can inform medicine pricing negotiations and is a key element in the design and implementation of more equitable systems of biomedical research and development.

This case report presents a rare instance of concomitant splenic tuberculosis (TB), Epstein–Barr virus (EBV)-related T-cell leukemia/lymphoma, and malaria in a 28-year-old pregnant woman at a Médecins Sans Frontières-supported hospital in South Sudan. The patient was admitted with splenomegaly, anorexia, weakness, and transfusion-refractory anemia. She tested positive for malaria and was treated appropriately. Because of ongoing consumptive anemia, cachexia, and weakness severely impacting her quality of life, the patient underwent splenectomy. A diagnosis of TB was ultimately confirmed post-splenectomy through histopathological analysis and molecular testing. Gross findings from the pathologic analysis of a splenic sample revealed miliary deposits, necrotizing granulomas, and atypical lymphocytic infiltrates consistent with TB and EBV-associated leukemia/lymphoma. Despite temporary improvement post-operatively and the initiation of TB therapy, the patient discontinued treatment and was lost to follow-up, likely resulting in mortality. This report presents an unusual combination of concomitant pathologies that underscore the diagnostic challenges and complexity of managing overlapping infectious and hematological disorders in resource-limited settings.

Risk factors for baseline bedaquiline (BDQ) resistance, amplification during treatment, and correlations with treatment outcomes are not fully understood. This cohort included Armenian patients with multidrug-resistant TB predominantly fluoroquinolone-resistant enrolled between 2013 and 2015 in a BDQ compassionate use program. BDQ resistance at baseline and during treatment was assessed using MGIT (pDSTMGIT), minimal inhibitory concentration in 7H11 (MIC7H11), and whole-genome sequencing. Risk factors, such as treatment effectiveness or stage of the disease, were analyzed for association with baseline BDQ resistance, acquired BDQ resistance, and treatment outcome. Among 39 patients, baseline BDQ resistance was 6% (2/33) by pDSTMGIT and 7% (2/29) by MIC7H11. All four baseline isolates with an Rv0678 mutation were phenotypically resistant. During treatment, 48% of the patients acquired BDQ resistance by pDSTMGIT, and 52% acquired mutations at various frequencies (97% in Rv0678). None of the factors significantly contributed to baseline or acquired BDQ resistance. Unfavorable treatment outcome (41%) was more frequent in the presence of acquired Rv0678 mutations [odds ratio (OR) 132, 95% confidence interval (CI) 7.43, 2375], phenotypic BDQ resistance (OR 176, 95% CI 6.48, 2423), or MIC increase above or below the critical concentration (both OR 84.3, 95% CI 2.93, 2423) during treatment. For these highly treatment-experienced patients, low baseline prevalence but high incidence of acquired BDQ resistance was observed. Acquisition of mutations in BDQ candidate resistance genes, regardless of their frequency, or increased MICs during treatment, even below the critical concentration, should be seen as a warning sign of resistance amplification and increased risk of unfavorable treatment outcome.

Each day more than 500 children younger than 15 years die from tuberculosis. Considerable progress has been made to control tuberculosis, but the impact on reducing the burden of childhood tuberculosis lags behind that in adults. A key barrier to decreasing morbidity and mortality associated with childhood tuberculosis is the paucity of accurate and feasible diagnostic tools for this population. WHO estimates that 58% of children younger than 5 years with tuberculosis are never diagnosed or reported.

BACKGROUND

Bedaquiline (BDQ) resistance presents a critical challenge in the fight against tuberculosis (TB), particularly multidrug-resistant (MDR) strains. The emergence of resistance to BDQ, a key drug in treating MDR-TB, poses significant threats to TB treatment effectiveness.

METHODS

The National Institute of Tuberculosis and Respiratory Diseases in Delhi and the Médecins Sans Frontières clinic in Mumbai provide BDQ, delamanid, and carbapenem-based regimens for patients with suspected or confirmed treatment failure. BDQ phenotypic drug-susceptibility testing (DST) was performed for all BDQ-exposed patients. Treatment regimens were individualized based on exposure history, comorbidities, drug interactions, prior adverse drug reactions, and DST results.

RESULTS

Of 117 BDQ-exposed patients from December 2020–December 2022, 42 (36%) exhibited a BDQ-resistant strain. Median (IQR) age was 24 (22–32) years, with 63 (54%) females and 94% with pulmonary TB. Patients with a BDQ-resistant strain were older (median age: 27 vs 23 years; P = .04), more likely to have lung cavities (risk ratio [RR]: 1.8; 95%-CI: 1.1–3.1; P = .02), and be resistant to clofazimine (RR: 2.3; 95%-CI: 1.5–3.6; P = .001). Overall, 102 patients initiated treatment. Patients with BDQ-resistance had higher risk of unfavorable outcomes compared with BDQ-susceptible patients (RR:2.1; 95%-CI: 1.5–2.8; P &lt; .001). Overall, 87% (33/38) of patients with BDQ-resistance experienced unfavorable treatment outcomes: 15 (40%) died, 15 (40%) had treatment failure, and 3 (8%) were lost-to-follow-up.

CONCLUSIONS

The study highlights a concerning rate of BDQ-resistance among previously treated patients, resulting in poor treatment outcomes. To prevent treatment failure, we recommend implementing BDQ-DST, developing affordable and accurate rapid tests for BDQ-resistance, and intensifying research and development efforts for newer TB drugs.