BACKGROUND
New 6-month rifampicin-resistant tuberculosis treatment regimens containing bedaquiline, pretomanid, and linezolid (BPaL) with or without moxifloxacin or clofazimine, could improve treatment efficacy, safety, and tolerability, and free up resources within the health system. Following a change to WHO rifampicin-resistant tuberculosis treatment guidelines, countries are facing difficult decisions about when and how to incorporate new drug regimens into national guidelines. We aimed to assess the probability of BPaL-based regimens being cost-saving using data collected in the TB-PRACTECAL trial.
METHODS
This economic evaluation using a cost-utility analysis was embedded in five TB-PRACTECAL trial sites in Belarus, Uzbekistan, and South Africa. Between Nov 19, 2020, and Sept 27, 2022, we collected detailed primary unit cost data in six hospitals and four ambulatory health facilities and collected data on patient-incurred costs from 73 trial participants. The primary efficacy endpoint of the main trial, a composite of unfavourable outcomes (death, disease recurrence, treatment failure, early discontinuation of therapy, withdrawal, or loss to follow-up) and clinically important safety outcomes by 72 weeks of follow-up were incorporated into the analysis. Societal perspective cost data and effect outcome data were input into a Markov model to estimate the cost per disability-adjusted life-year (DALY) averted by BPaL-based regimens compared with the standard of care over a 20-year time horizon. We conducted a range of univariate and probabilistic sensitivity analyses to test our findings.
FINDINGS
BPaL-based regimens averted a mean of 1·28 DALYs and saved a mean of US$14 868 (SD 291) per person from the provider perspective compared with standard-of-care regimens over 20 years. Patient-incurred costs were reduced by a mean of $172 (SD 0·84) in BPaL-based regimen groups compared with standard of care. The main cost drivers for both providers and patients were inpatient bed-days; the duration of the inpatient period varied across countries. Varying a range of model parameters affected the degree of cost savings but did not change the finding that BPaL-based regimens are cost-saving compared with standard of care.
INTERPRETATION
This trial-based evidence adds to consistent indications from modelling studies that BPaL-based regimens are cost-saving for both the patient and health system. Urgent implementation of BPaL-based regimens in countries with a high burden of tuberculosis could improve treatment of rifampicin-resistant tuberculosis, reduce pill burden, and free up desperately needed resources within the health system.
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.).
INTRODUCTION
Migrant populations (asylum seekers, permit holders, refugees, and undocumented migrants) living in South Africa face various individual, social, and physical circumstances that underpin their decisions, motivation, and ability to receive the COVID-19 vaccine. We conducted a qualitative study to explore the experiences and perceptions of migrant populations in South Africa on COVID-19 vaccines to inform recommendations for improved COVID-19 immunization.
METHODS
We conducted an Interpretative Phenomenological Analysis (IPA) with 20 asylum seekers, permit holders, refugees, and undocumented migrants living in South Africa. We applied a maximum variation purposive sampling approach to capture all three categories of migrants in South Africa. Semi-structured interviews were conducted and recorded electronically with consent and permission from the study participants. The recordings were transcribed and analyzed thematically following the IPA using Atlas.ti version 9.
RESULTS
Four major reflective themes emanated from the data analysis. (1) While some migrants perceived being excluded from the South African national immunization program at the level of advertisement and felt discriminated against at the immunization centers, others felt included in the program at all levels. (2) Skepticism, myths, and conspiracy theories around the origin of SARS-CoV-2 and the COVID-19 vaccine are pervasive among migrant populations in South Africa. (3) There is a continuum of COVID-19 vaccine acceptance/hesitancy ranging from being vaccinated through waiting for the chance to be vaccinated to refusal. (4) Accepting the vaccine or being hesitant follows the beliefs of the participant, knowledge of the vaccine’s benefits, and lessons learned from others already vaccinated.
CONCLUSION
COVID-19 vaccine inclusiveness, awareness, and uptake should be enhanced through migrant-aware policies and actions such as community mobilization, healthcare professional training, and mass media campaigns.
The burden of advanced HIV disease remains a significant concern in sub-Saharan Africa. In 2015, the World Health Organization released recommendations to treat all people living with HIV (PLHIV) regardless of CD4 (“treat all”) and in 2017 guidelines for managing advanced HIV disease. We assessed changes over time in the proportion of PLHIV with advanced HIV and their care cascade in two community settings in sub-Saharan Africa.
METHODS
Cross-sectional population-based surveys were conducted in Ndhiwa (Kenya) in 2012 and 2018 and in Eshowe (South Africa) in 2013 and 2018. We recruited individuals aged 15-59 years. Consenting participants were interviewed and tested for HIV at home. All participants with HIV had CD4 count measured. Advanced HIV was defined as CD4 < 200 cells/µL.
RESULTS
Overall, 6076 and 6001 individuals were included in 2012 and 2018 (Ndhiwa) and 5646 and 3270 individuals in 2013 and 2018 (Eshowe), respectively. In Ndhiwa, the proportion of PLHIV with advanced HIV decreased from 2012 (159/1376 (11.8%; 95% CI: 9.8-14.2)) to 2018 (53/1000 (5.0%; 3.8-6.6)). The proportion of individuals with advanced HIV on antiretroviral therapy (ART) was 9.1% (6.9-11.8) in 2012 and 4.2% (3.0-5.8) in 2018. In Eshowe, the proportion with advanced HIV was 130/1400 (9.8%; 8.0-11.9) in 2013 and 38/834 (4.5%; 3.3-6.1) in 2018. The proportion with advanced HIV among those on ART was 6.9% (5.5-8.8) in 2013 and 2.8% (1.8-4.3) in 2018. There was a significant increase in coverage for all steps of the care cascade among people with advanced HIV between the two Ndhiwa surveys, with all the changes occurring among men and not women. No significant changes were observed in Eshowe between the surveys overall and by sex.
CONCLUSION
The proportion with advanced HIV disease decreased between the first and second surveys where all guidelines have been implemented between the two HIV surveys.
Tuberculosis (TB) is a major public health challenge encountered across many Médecins Sans Frontières (MSF) fields. Management of drug-resistant TB is an operational priority for MSF. endTB is an MSF-sponsored randomised trial funded by Unitaid as part of the larger endTB project. The trial objective was to examine five new all-oral, shortened regimens for patients with fluoroquinolone-susceptible, rifampicin-resistant/multidrug- resistant TB (RR/MDR-TB).
METHODS
endTB was a phase 3, randomised, controlled, non-inferiority trial performed in seven countries (Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa) in five WHO regions. Participants with RR/MDR-TB (aged ≥15 years old) were randomly assigned to six regimen groups (1:1:1:1:1:1; 9BLMZ, 9BCLLfxZ, 9BDLLfxZ, 9DCLLfxZ, 9DCMZ, or control) using Bayesian response-adapted randomisation. Experimental regimens were 9 months long; all contained 4–5 drugs, including pyrazinamide, a fluoroquinolone, either bedaquiline and/or delamanid, and linezolid and/or clofazimine. The internal, concurrent control regimen was the evolving WHO- recommended standard. Primary outcome was the proportion of favourable outcome at week 73, defined by two negative sputum culture results. The non-inferiority margin was 12%. We performed efficacy comparisons in the modified intention-to-treat population (mITT), which included all randomised participants who took at least one dose of study treatment (safety population) and who had a positive pre-randomisation TB culture, and in the per-protocol population (PP), defined as mITT excluding participants who did not receive the protocol-defined treatment. We performed safety comparisons on the safety population. This study is registered on ClinicalTrials.gov (NCT02754765).
RESULTS
Of 754 participants enrolled between 2017 and 2021, 696 and 559 were included in the mITT and PP analyses, respectively. Median age was 32.0 years (IQR 23.0–44.0), and 264 (38%) of 696 participants were female. Overall, regimens 9BLLfxCZ, 9BLMZ, and 9BDLLfxZ achieved non-inferiority in mITT and PP analyses. 9BLLfxCZ also achieved superiority. 9DCMZ regimen achieved non-inferiority in mITT, but not in PP. 9DCLLfxZ did not achieve non-inferiority. The proportion of participants experiencing grade 3 or higher adverse events or serious adverse events was similar between the regimens. Grade 3 or higher hepatotoxicity occurred in 12.6% (78/619) of participants in the experimental regimens overall and in 7.1% (9/126) of participants in the control group.
CONCLUSION
The endTB trial results increase patient-centred treatment options for RR/MDR-TB with three shortened, all-oral, non- inferior regimens to a current well-performing standard of care. A fourth regimen could be considered for patients for whom bedaquiline and/or linezolid is not available. These results could be extrapolated to children and pregnant women. The implications on the MSF TB field activities are important and could lead to improved access to care and better treatment outcome.