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.
The incidence and mortality of kala-azar (KA, visceral leishmaniasis) in India have fallen drastically in the past few years, and in 2023 the reported KA incidence reached the threshold for elimination as a public health problem (<1 case/10 000 of population at subdistrict level). One of the strategies adopted by India's kala-azar elimination program (KAEP) was the regular independent assessment of the program implementation by teams of experts. We present the findings of assessments undertaken in 2019, 2021 and 2023, when the KAEP was in the last mile of elimination. Factors that contributed to its success were political commitment, intensified implementation, a strong network of KA partners and committed donors. Bottlenecks were observed in disease surveillance, data utilization, vector-control operations and program management at implementation. To sustain the gains and achieve validation of elimination, the KAEP should continue the following minimal essential services: optimized active and passive case detection and management of KA, post-KA dermal leishmaniasis, KA-HIV coinfection and relapse supported by vector-control interventions. Long-term measures that will sustain elimination are overall socioeconomic development, including improved living conditions, parallel with efficient surveillance and operational research that is aligned with the changing epidemiology of the disease.
BACKGROUND
Visceral leishmaniasis (VL) is a vector-borne disease caused by Leishmania parasites and transmitted by sand fly bites, targeted for elimination in India. VL primarily affects rural, low-income populations with limited health care access. In South Asia, few studies have explored patients’ perspectives, diagnoses, and treatment experiences; particularly lacking an understanding about the patients’ life experiences outside of clinical research settings.
METHODOLOGY/PRINCIPAL FINDINGS
A qualitative study was conducted in Bihar, India, using moderator-facilitated, protocol-defined discussion. Eighteen adult patients and 12 caregivers of children diagnosed with and treated for VL within the last 12 months were identified by self-report. Mean time from symptom onset to diagnosis was 13.8 days. Challenges of the early patient life experience included lack of urgency by health care professionals, delayed diagnosis, and no guarantee of treatment at the location of their VL diagnosis (63% had to switch to a different center for treatment, at times delaying treatment). Key barriers identified in previous studies that were re-confirmed in this study include out-of-pocket financial burden, absence from work/home duties, and long-distance travel to hospitals. Patients and caregivers (n = 29/30) expressed a preference for a potential oral treatment that could be taken close to home.
CONCLUSIONS/SIGNIFICANCE
This study reveals new insights about the patient life experience and reconfirms previous research indicating that access to care for patients with VL in the Bihar area remains a challenge. Although most patients with VL seek care early, diagnosis often requires multiple visits to a health care facility. Despite access to therapy in public hospitals, some patients reported a preference for private care. Even if diagnosis takes place in a government-funded public setting, some patients reported needing to move from the location of diagnosis to another center to receive therapy, creating an additional burden for patients. As a potential alternative to current parenteral treatment, adult patients and caregivers of pediatric patients expressed interest in a potential oral therapy because it may reduce barriers to access care.
BACKGROUND
For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant tuberculosis.
METHODS
We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z). Participants were randomly assigned (with the use of Bayesian response-adaptive randomization) to receive one of five combinations or standard therapy. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was -12 percentage points.
RESULTS
Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat analysis, and 562 in the per-protocol analysis. In the modified intention-to-treat analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes. The risk difference between standard therapy and each of the four new regimens that were found to be noninferior in the modified intention-to-treat population was as follows: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, -0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, -4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, -7.5 to 12.5). Differences were similar in the per-protocol population, with the exception of DCMZ, which was not noninferior in that population. The proportion of participants with grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxic events occurred in 11.7% of participants overall and in 7.1% of those receiving standard therapy.
CONCLUSIONS
Consistent results across all the analyses support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis. (Funded by Unitaid and others; endTB ClinicalTrials.gov number, NCT02754765.).
BACKGROUND
Nipah virus (NiV), a highly lethal virus in humans, circulates in Pteropus bats throughout South and Southeast Asia. Difficulty in obtaining viral genomes from bats means we have a poor understanding of NiV diversity.
METHODS
We develop phylogenetic approaches applied to the most comprehensive collection of genomes to date (N = 257, 175 from bats, 73 from humans) from 6 countries over 22 years (1999–2020). We divide the 4 major NiV sublineages into 15 genetic clusters. Using Approximate Bayesian Computation fit to a spatial signature of viral diversity, we estimate the presence and the average size of genetic clusters per area.
RESULTS
We find that, within any bat roost, there are an average of 2.4 co-circulating genetic clusters, rising to 5.5 clusters at areas of 1500–2000 km2. We estimate that each genetic cluster occupies an average area of 1.3 million km2 (95% confidence interval [CI], .6–2.3 million km2), with 14 clusters in an area of 100 000 km2 (95% CI, 6–24 km2). In the few sites in Bangladesh and Cambodia where genomic surveillance has been concentrated, we estimate that most clusters have been identified, but only approximately 15% of overall NiV diversity has been uncovered.
CONCLUSIONS
Our findings are consistent with entrenched co-circulation of distinct lineages, even within roosts, coupled with slow migration over larger spatial scales.