BACKGROUND
Studies have demonstrated an inverse log-linear relationship between body mass index (BMI) and tuberculosis incidence. However, a person’s BMI is dynamic and longitudinal changes may be more informative than cross-sectional assessments. We evaluate the association between cross-sectional and changing BMI and risk of tuberculosis and describe longitudinal trajectories in a high-risk cohort.
METHODS
ERASE-TB was a prospective longitudinal cohort study of household contacts ≥10 years in Southern Africa (Zimbabwe, Tanzania, and Mozambique), with 6-monthly follow-up up to 24 months. Associations between BMI and tuberculosis were investigated based on baseline (including haemoglobin) and changing BMI, using logistic, Poisson, and Cox models. Prevalent tuberculosis was defined as diagnosis during <30 days after recruitment. Growth mixture modelling (GMM) was used to model longitudinal latent trajectories.
RESULTS
Of 2,107 recruited household contacts (621 [29.5%] adolescents and 1,310 [62.2%] female), 520 (24.7%) were underweight. There were 21 and 41 people diagnosed with prevalent and incident tuberculosis, of whom 5/21 (23.8%) and 12/41 (29.3%) were underweight. Being underweight and anaemic (aHR: 3.77, 95% CI: 1.50-9.51) and >10% negative change in BMI during follow-up (aIRR: 2.27 (95% CI: 0.22-22.9) were associated with increased risk of incident tuberculosis. The association between continuous BMI-for-age Z-scores were non-linear, with increased risk of tuberculosis with lower BMI. Four latent groups were defined in the GMM: increasing, decreasing, and low/high stable BMI.
CONCLUSIONS
Declining BMI, regardless of absolute value, is a strong predictor of tuberculosis among household contacts. Longitudinal measurements should be considered in active case finding among tuberculosis-affected households.
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 < .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.
BACKGROUND
Only 63% of patients initiating multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment in 2020 were treated successfully. 24-Week all-oral bedaquiline, pretomanid, and linezolid (BPaL)–based regimens have demonstrated higher rates of treatment success and have been recommended by the World Health Organization. Operational research is urgently required to evaluate these regimens in non-trial settings.
METHODS
This was a prospective cohort study of patients with microbiologically confirmed MDR/RR-TB and pre–extensively drug-resistant TB (pre-XDR-TB) initiated on BPaL-based regimens in Belarus and Uzbekistan (February 2022–June 2023). All clinical care and research procedures were delivered by treating physicians. After treatment completion, patients were followed up at 6 and 12 months, including collecting sputum to ascertain recurrence. The primary objective was to estimate the effectiveness (cured or treatment completed) and safety (the occurrence of serious adverse events) of BPaL-based regimens.
RESULTS
A total of 677 patients initiated treatment with BPaL-based regimens during the study. We documented successful treatment outcomes in 95.3% (427/448) of patients with MDR/RR-TB treated with BPaL plus moxifloxacin and 90.4% (207/229) of patients with pre–XDR-TB treated with BPaL plus clofazimine. 10.2% (69/677) experienced serious adverse events including 24 deaths (3.5%), 11 of which occurred during treatment. 83.3% (20/24) of deaths were not related to TB or TB treatment. Of patients who were successfully treated and completed 12-month follow-up, 0.5% (2/383) had recurrence.
CONCLUSIONS
BPaL-based regimens for MDR/RR-TB and pre–XDR-TB are safe and highly effective in non-trial settings. These regimens should be considered for widespread implementation globally, and further research is needed to evaluate their performance in other key populations.
BACKGROUND
The 2022 WHO guidelines on multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) recommend six months of bedaquiline (Bdq) in the all-oral 9-month shorter regimen and six months or longer for Bdq and delamanid (Dlm) in the 18-20-month longer regimen. However, lack of evidence on extended treatment using Bdq or Dlm has limited their use to six months. We examine the frequency and incidence of QT prolongation based on duration of Bdq and/or Dlm use in longer regimens.
METHODS
We analyzed a prospective cohort of MDR/RR-TB patients from 16 countries who initiated treatment with Bdq and/or Dlm containing regimens from 1 April 2015-30 September 2018. Data were systematically collected using a shared protocol. The outcome of interest was the first clinically relevant prolonged QT interval (grade 3 or above) or a Serious Adverse Event (SAE) involving prolonged QT of any grade.
RESULTS
Among 2,553 patients, 59% received >6 months of Bdq and/or Dlm. Of these, 579 (20.9%) patients experienced a prolonged QT event, the majority (95.5%) being grade 1 or 2. Sixty-four(2.5%) patients experienced the outcome of interest with only 12 (0.5%) having ≥ 1 QT prolonging drugs permanently suspended. The incidence rate of the first prolonged QT event was highest in the first six months of treatment and lower in subsequent six-month periods.
CONCLUSION
We demonstrate that Bdq and/or Dlm use beyond six months is safe in longer MDR/RR-TB regimens with most clinically relevant QT prolongation events occurring in the first six months. ECG monitoring for early identification of QT prolongating events is possible in programmatic conditions.
Background
People with human immunodeficiency virus (PWH) with recurrent visceral leishmaniasis (VL) could potentially drive Leishmania transmission in areas with anthroponotic transmission such as East Africa, but studies are lacking. Leishmania parasitemia has been used as proxy for infectiousness.
Methods
This study is nested within the Predicting Visceral Leishmaniasis in HIV-InfectedPatients (PreLeisH) prospective cohort study, following 490 PWH free of VL at enrollment for up to 24–37 months in northwest Ethiopia. Blood Leishmania polymerase chain reaction (PCR) was done systematically. This case series reports on 10 PWH with chronic VL (≥3 VL episodes during follow-up) for up to 37 months, and 3 individuals with asymptomatic Leishmania infection for up to 24 months.
Results
All 10 chronic VL cases were male, on antiretroviral treatment, with 0–11 relapses before enrollment. Median baseline CD4 count was 82 cells/µL. They displayed 3–6 VL treatment episodes over a period up to 37 months. Leishmania blood PCR levels were strongly positive for almost the entire follow-up (median cycle threshold value, 26 [interquartile range, 23–30]), including during periods between VL treatment. Additionally, we describe 3 PWH with asymptomatic Leishmania infection and without VL history, with equally strong Leishmania parasitemia over a period of up to 24 months without developing VL. All were on antiretroviral treatment at enrollment, with baseline CD4 counts ranging from 78 to 350 cells/µL.
Conclusions
These are the first data on chronic parasitemia in PWH from Leishmania donovani–endemic areas. PWH with asymptomatic and symptomatic Leishmania infection could potentially be highly infectious and constitute Leishmania superspreaders. Xenodiagnosis studies are required to confirm infectiousness.
Effectiveness, safety, tolerability, and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel 6-month oral regimens that include bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently completed clinical trials.
METHODS
A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment-related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid.
RESULTS
Data from 3 clinical trials investigating 8 unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200 mg linezolid, 68 of 195 (35%) experienced a grade 3–4 adverse event versus 89 of 396 (22%) patients receiving BPaL-containing regimens containing 600 mg linezolid.
CONCLUSIONS
Regimens containing BPaL were relatively well tolerated when they included a daily linezolid dose of 600 mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB.
Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment-follow-up.
METHODS
We analyzed data on 1,991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using five approaches for handling post-treatment deaths, we estimated the six-month post-treatment TB recurrence risk overall, and by HIV status. We used inverse-probability-weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights.
RESULTS
The estimated TB recurrence risk was 7.4 per 1000 (95% confidence interval (CI): 3.5,12.9) when deaths were handled as non-recurrences, and 7.6 per 1000 (95% CI: 3.6,13.1) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risk of composite recurrence outcomes were 25.5 (95% CI: 15.4,38.1), 11.7 (95% CI: 6.5,18.3), and 8.6 (95% CI: 4.2,14.6) per 1000 for recurrence or 1) any death, 2) death with unknown or TB-related cause, 3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability-weighting had a small impact on estimates.
CONCLUSIONS
The estimated six-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.