RESUMEN
Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles. We used a similar process as for the 2016 profiles, including a baseline treatment landscape analysis, an initial stakeholder survey, modelling studies estimating the impact and cost-effectiveness of novel tuberculosis treatment regimens, and an extensive stakeholder consultation. We developed target regimen profiles for the treatment of rifampicin-susceptible and rifampicin-resistant tuberculosis, as well as a pan-tuberculosis regimen that would be appropriate for patients with any type of tuberculosis. We describe the revised target regimen profile characteristics, with specific minimal and optimal targets to be met, rationale and justification, and aspects relevant to all target regimen profiles (drug susceptibility testing, adherence and forgiveness, treatment strategies, post-tuberculosis lung disease, and cost and access considerations). We discuss the trade-offs of proposed characteristics for decision-making at developmental or operational levels. We expect that, following these target regimen profile revisions, tuberculosis treatment developers will produce regimens that are quality-assured, affordable and widely available, and that meet the needs of affected populations.
Des traitements de la tuberculose plus simples, plus courts, plus sûrs et plus efficaces, facilement accessibles à toutes les personnes atteintes de tuberculose, font cruellement défaut. En 2016, l'Organisation mondiale de la santé (OMS) a élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose, afin de sensibiliser les concepteurs de médicaments aux caractéristiques importantes des schémas thérapeutiques et aux besoins des patients et des programmes au niveau national. Compte tenu des avancées récentes dans le traitement de la tuberculose, l'OMS a révisé et mis à jour ces profils de schéma thérapeutique. Nous avons appliqué un processus similaire à celui des profils de 2016, y compris une analyse de base des différentes possibilités thérapeutiques, une enquête initiale auprès des parties prenantes, des études de modélisation estimant l'impact et le rapport coût-efficacité des nouveaux schémas thérapeutiques pour la tuberculose, ainsi qu'une vaste consultation des parties prenantes. Nous avons élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose sensible à la rifampicine ou résistant à la rifampicine, ainsi qu'un schéma multiforme qui conviendrait aux patients atteints de n'importe quel type de tuberculose. Nous décrivons les caractéristiques du profil révisé de schéma thérapeutique cible, avec les objectifs minimaux et optimaux spécifiques à atteindre, le raisonnement et les aspects pertinents pour tous les profils de schéma thérapeutique cible (tests de sensibilité aux médicaments, observance thérapeutique et manque d'observance («forgiveness¼), stratégies de traitement, maladie pulmonaire post-tuberculeuse et considérations de coût et d'accès). Nous discutons des compromis des caractéristiques proposées pour la prise de décisions au niveau du développement ou au niveau opérationnel. Nous espérons qu'à la suite de ces révisions du profil de schéma thérapeutique cible, les concepteurs de traitements antituberculeux produiront des schémas dont la qualité est assurée, qui sont abordables et largement disponibles et qui répondent aux besoins des populations touchées.
Se necesitan con urgencia tratamientos más sencillos, breves, seguros y eficaces contra la tuberculosis que sean fácilmente accesibles para todas las personas con tuberculosis. En 2016, la Organización Mundial de la Salud (OMS) elaboró perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis con el fin de que los fabricantes de medicamentos conocieran tanto las características importantes de estos esquemas como las necesidades programáticas y de los pacientes en cada país. Teniendo en cuenta los recientes avances pioneros en el tratamiento de la tuberculosis, la OMS ha revisado y actualizado estos perfiles de esquemas terapéuticos. Se ha seguido un proceso similar al de los perfiles de 2016, que incluye un análisis de referencia del panorama terapéutico, una encuesta inicial a las partes interesadas, estudios de modelización para estimar el impacto y la rentabilidad de los nuevos esquemas terapéuticos para el tratamiento de la tuberculosis, y una amplia consulta a las partes interesadas. Se desarrollaron perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis sensibles a la rifampicina y resistente a la rifampicina, así como un esquema farmacológico capaz de tratar todas las formas de tuberculosis que sería apropiado para pacientes con cualquier tipo de tuberculosis. Se describieron las características revisadas de los perfiles objetivo de los esquemas terapéuticos, con los objetivos mínimos y óptimos específicos que deben alcanzarse, los fundamentos y la justificación, y los aspectos relevantes para todos los perfiles objetivo de los esquemas terapéuticos (pruebas de sensibilidad a los fármacos, adherencia y olvido, estrategias de tratamiento, enfermedad pulmonar postuberculosa, y consideraciones de coste y acceso). Se discutieron las ventajas y desventajas de las características propuestas para la toma de decisiones a nivel de desarrollo u operativo. Se espera que, tras estas revisiones de los perfiles objetivo de los esquemas terapéuticos, las personas encargadas del desarrollo de tratamientos para la tuberculosis elaboren esquemas terapéuticos de calidad garantizada, asequibles y ampliamente disponibles, y que respondan a las necesidades de las poblaciones afectadas.
Asunto(s)
Antituberculosos , Tuberculosis , Organización Mundial de la Salud , Humanos , Antituberculosos/uso terapéutico , Tuberculosis/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Rifampin/uso terapéutico , Análisis Costo-Beneficio , Cumplimiento de la MedicaciónRESUMEN
The impact of HIV viral suppression on multidrug resistant tuberculosis (MDR-TB) treatment outcomes among people with HIV (PWH) has not been clearly established. Using secondary data from a cluster-randomized clinical trial among people with MDR-TB in South Africa, we examined the effects of HIV viral suppression at MDR-TB treatment initiation and throughout treatment on MDR-TB outcomes among PWH using multinomial regression. This analysis included 1479 PWH. Viral suppression (457, 30.9%), detectable viral load (524, 35.4%), or unknown viral load (498, 33.7%) at MDR-TB treatment initiation were almost evenly distributed. Having a detectable HIV viral load at MDR-TB treatment initiation significantly increased risk of death compared to those virally suppressed (relative risk ratio [RRR] 2.12, 95% CI 1.11-4.07). Among 673 (45.5%) PWH with a known viral load at MDR-TB outcome, 194 (28.8%) maintained suppression, 267 (39.7%) became suppressed, 94 (14.0%) became detectable, and 118 (17.5%) were never suppressed. Those who became detectable (RRR 11.50, 95% CI 1.98-66.65) or were never suppressed (RRR 9.28, 95% CI 1.53-56.61) were at significantly increased risk of death (RRR 6.37, 95% CI 1.58-25.70), treatment failure (RRR 4.54, 95% CI 1.35-15.24), and loss to follow-up (RRR 7.00, 95% CI 2.83-17.31; RRR 2.97, 95% CI 1.02-8.61) compared to those who maintained viral suppression. Lack of viral suppression at MDR-TB treatment initiation and failure to achieve or maintain viral suppression during MDR-TB treatment drives differences in MDR-TB outcomes. Early intervention to support access and adherence to antiretroviral therapy among PWH should be prioritized to improve MDR-TB treatment outcomes.
RESUMEN
Drug-resistant tuberculosis (DR-TB) threatens to derail tuberculosis control efforts, particularly in Africa where the disease remains out of control. The dogma that DR-TB epidemics are fueled by unchecked rates of acquired resistance in inadequately treated or non-adherent individuals is no longer valid in most high DR-TB burden settings, where community transmission is now widespread. A large burden of DR-TB in Africa remains undiagnosed due to inadequate access to diagnostic tools that simultaneously detect tuberculosis and screen for resistance. Furthermore, acquisition of drug resistance to new and repurposed drugs, for which diagnostic solutions are not yet available, presents a major challenge for the implementation of novel, all-oral, shortened (6-9 months) treatment. Structural challenges including poverty, stigma, and social distress disrupt engagement in care, promote poor treatment outcomes, and reduce the quality of life for people with DR-TB. We reflect on the lessons learnt from the South African experience in implementing state-of-the-art advances in diagnostic solutions, deploying recent innovations in pharmacotherapeutic approaches for rapid cure, understanding local transmission dynamics and implementing interventions to curtail DR-TB transmission, and in mitigating the catastrophic socioeconomic costs of DR-TB. We also highlight globally relevant and locally responsive research priorities for achieving DR-TB control in South Africa.
RESUMEN
BACKGROUND: In 2019, the South African tuberculosis program replaced ethionamide with linezolid as part of an all-oral 9-month regimen. We evaluated treatment outcomes for patients assigned to regimens including linezolid in 2019 and ethionamide in 2017. METHODS: This retrospective cohort study included patients treated for multidrug-resistant/rifampicin-resistant tuberculosis throughout South Africa between 1 January and 31 December 2017 and 1 January to 31 December 2019. The cohort treated with a 9-month regimen containing ethionamide for four months, was compared with a cohort treated with a 9-month regimen containing linezolid for 2 months. The regimens were otherwise identical. Inverse probability weighting of propensity scores was used to adjust for potential confounding. A log-binomial regression model was used to estimate adjusted relative risk (aRR) comparing 24-month outcomes between cohorts including treatment success, death, loss to follow up, and treatment failure. Adverse event data were available for the linezolid cohort. FINDINGS: In total, 817 patients were included in the cohort receiving ethionamide and 4244 in the cohort receiving linezolid. No evidence for a difference was observed between linezolid and ethionamide regimens for treatment success (aRR = 0.96, 95% confidence interval [CI] .91-1.01), death (aRR = 1.01, 95% CI .87-1.17) or treatment failure (aRR = 0.87, 95% CI .44-1.75). Loss to follow-up was more common in the linezolid group, although estimates were imprecise (aRR = 1.22, 95% CI .99-1.50). CONCLUSIONS: No significant differences in treatment success and survival were observed with substitution of linezolid for ethionamide as a part of an all-oral 9-month regimen. Linezolid is an acceptable alternative to ethionamide in this shorter regimen for treatment of multidrug-resistant/rifampicin-resistant tuberculosis.
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Antituberculosos , Etionamida , Linezolid , Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Linezolid/administración & dosificación , Linezolid/uso terapéutico , Etionamida/uso terapéutico , Etionamida/administración & dosificación , Estudios Retrospectivos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Sudáfrica , Masculino , Femenino , Rifampin/uso terapéutico , Rifampin/administración & dosificación , Adulto , Antituberculosos/administración & dosificación , Antituberculosos/uso terapéutico , Resultado del Tratamiento , Persona de Mediana Edad , Administración Oral , Adulto Joven , Mycobacterium tuberculosis/efectos de los fármacosRESUMEN
BACKGROUND: The WHO has issued a call to action urging countries to accelerate the rollout of new WHO-recommended shorter all-oral treatment regimens for drug-resistant TB (DR-TB), which remains a public-health crisis. The all-oral, 6-month BPaL/M regimen comprises 3-4 drugs: pretomanid used in combination with bedaquiline and linezolid, with or without moxifloxacin. This regimen has been recommended by the WHO for use in DR-TB patients instead of ≥9-month (up to 24-month) regimens. This study aims to project this regimen's use, along with its components bedaquiline, pretomanid and linezolid, and other treatments for DR-TB globally through 2026. It is intended to guide global health stakeholders in planning and budgeting for DR-TB interventions. Projected usage could help estimate cost of the individual components of DR-TB regimens over time. METHODS: Semi-structured interviews were conducted with national TB programme participants in key countries to gather intelligence on established plans and targets for use of various DR-TB treatment regimens from 2023 to 2026. These data informed development of projections for the global use of regimens and drugs. RESULTS: Consistent global growth in the use of shorter regimens in DR-TB treatment was shown: BPaLM reaching 126,792 patients, BPaL reaching 43,716 patients, and the 9-11-month all-oral bedaquiline-based regimen reaching 13,119 patients by 2026. By 2026, the longer all-oral regimen is projected to be used by 19,262 patients, and individualised treatment regimens by 15,344 patients. CONCLUSION: The study shows BPaL/M will be used in majority of DR-TB patients by 2024, reaching 78% by 2026. However, national efforts to scale-up, case-finding, monitoring, drug-susceptibility testing, and implementation of new treatments will be essential for ensuring they are accessible to all eligible patients in the coming years and goals for ending TB are met. There is an urgent need to engage communities in capacity building and demand generation.
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Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Linezolid , Protocolos Clínicos , Transporte Biológico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
OBJECTIVES: Treatment for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) is increasingly transitioning from hospital-centred to community-based care. A national policy for decentralised programmatic MDR/RR-TB care was adopted in South Africa in 2011. We explored variations in the implementation of care models in response to this change in policy, and the implications of these variations for people affected by MDR/RR-TB. DESIGN: A mixed methods study was done of patient movements between healthcare facilities, reconstructed from laboratory records. Facility visits and staff interviews were used to determine reasons for movements. PARTICIPANTS AND SETTING: People identified with MDR/RR-TB from 13 high-burden districts within South Africa. OUTCOME MEASURES: Geospatial movement patterns were used to identify organisational models. Reasons for patient movement and implications of different organisational models for people affected by MDR/RR-TB and the health system were determined. RESULTS: Among 191 participants, six dominant geospatial movement patterns were identified, which varied in average hospital stay (0-281 days), average patient distance travelled (12-198 km) and number of health facilities involved in care (1-5 facilities). More centralised models were associated with longer delays to treatment initiation and lengthy hospitalisation. Decentralised models facilitated family-centred care and were associated with reduced time to treatment and hospitalisation duration. Responsiveness to the needs of people affected by MDR/RR-TB and health system constraints was achieved through implementation of flexible models, or the implementation of multiple models in a district. CONCLUSIONS: Understanding how models for organising care have evolved may assist policy implementers to tailor implementation to promote particular patterns of care organisation or encourage flexibility, based on patient needs and local health system resources. Our approach can contribute towards the development of a health systems typology for understanding how policy-driven models of service delivery are implemented in the context of variable resources.
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Antituberculosos , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Antituberculosos/uso terapéutico , Sudáfrica , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Rifampin , HospitalizaciónRESUMEN
The National Health Laboratory Service (NHLS) collects all public health laboratory test results in South Africa, providing a cohort from which to identify groups, by age, sex, HIV, and viral suppression status, that would benefit from increased tuberculosis (TB) testing. Using NHLS data (2012-2016), we assessed levels and trends over time in TB diagnostic tests performed (count and per capita) and TB test positivity. Estimates were stratified by HIV status, viral suppression, age, sex, and province. We used logistic regression to estimate the odds of testing positive for TB by viral suppression status. Nineteen million TB diagnostic tests were conducted during period 2012-2016. Testing per capita was lower among PLHIV with viral suppression than those with unsuppressed HIV (0.08 vs 0.32) but lowest among people without HIV (0.03). Test positivity was highest among young adults (aged 15-35 years), males of all age groups, and people with unsuppressed HIV. Test positivity was higher for males without laboratory evidence of HIV than those with HIV viral suppression, despite similar individual odds of TB. Our results are an important national baseline characterizing who received TB testing in South Africa. People without evidence of HIV, young adults, and males would benefit from increased TB screening given their lower testing rates and higher test positivity. These high-test positivity groups can be used to guide future expansions of TB screening.
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Infecciones por VIH , Tuberculosis , Masculino , Adulto Joven , Humanos , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Sudáfrica/epidemiología , Tuberculosis/diagnóstico , Tuberculosis/epidemiología , Tamizaje Masivo , Modelos LogísticosRESUMEN
BACKGROUND: Coinfection with multidrug-resistant tuberculosis (MDR-TB) and HIV is common, but few published studies examine how undergoing MDR-TB treatment affects HIV disease indicators. METHODS: Using data from a nested, retrospective cohort of people with HIV (PWH) and successful MDR-TB treatment outcomes, we built multivariable regression models to explore correlates of HIV viral suppression at MDR-TB treatment completion. RESULTS: Among 531 PWH successfully treated for MDR-TB, mean age was 37.4 years (SD 10.2, interquartile range 30-43), 270 (50.8%) were male, 395 (74.4%) were virally suppressed at MDR-TB outcome, and 259 (48.8%) took bedaquiline. Older age (adjusted odds ratio [aOR] 1.04, 95% confidence interval [CI]: 1.01 to 1.06) increased odds of viral suppression, while having a prior TB episode (aOR 0.45, 95% CI: 0.31 to 0.64), having a detectable viral load at MDR-TB treatment initiation (aOR 0.17, 95% CI: 0.09 to 0.30), living in a township (aOR 0.49, 95% CI: 0.28 to 0.87), and being changed from efavirenz-based antiretroviral therapy (ART) to a protease inhibitor due to bedaquiline usage (aOR 0.19, 95% CI: 0.04 to 0.82) or not having an ART change while on bedaquiline (aOR 0.29, 95% CI: 0.11 to 0.75) lowered odds of viral suppression. Changing from efavirenz to nevirapine due to bedaquiline usage did not significantly affect odds of viral suppression (aOR 0.41, 95% CI: 0.16 to 1.04). CONCLUSIONS: Increased pill burden and adverse treatment effects did not significantly affect HIV viral suppression while switching ART to a protease inhibitor to accommodate bedaquiline or not changing ART while taking bedaquiline did, suggesting that PWH and MDR-TB may benefit from additional support if they must switch ART.
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Infecciones por VIH , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Masculino , Adulto , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Antituberculosos/uso terapéutico , Estudios Retrospectivos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Resultado del Tratamiento , Antivirales/uso terapéutico , Inhibidores de Proteasas/uso terapéuticoRESUMEN
OBJECTIVES: The study aimed to describe the prevalence of and risk factors for post-COVID-19 condition (PCC). METHODS: This was a prospective, longitudinal observational cohort study. Hospitalized and nonhospitalized adults were randomly selected to undergo telephone assessment at 1, 3, and 6 months. Participants were assessed using a standardized questionnaire for the evaluation of symptoms and health-related quality of life. We used negative binomial regression models to determine factors associated with the presence of ≥1 symptoms at 6 months. RESULTS: A total of 46.7% of hospitalized and 18.5% of nonhospitalized participants experienced ≥1 symptoms at 6 months (P ≤0.001). Among hospitalized people living with HIV, 40.4% had persistent symptoms compared with 47.1% among participants without HIV (P = 0.108). The risk factors for PCC included older age, female sex, non-Black race, presence of a comorbidity, greater number of acute COVID-19 symptoms, hospitalization/COVID-19 severity, and wave period (lower risk of persistent symptoms for the Omicron compared with the Beta wave). There were no associations between self-reported vaccination status with persistent symptoms. CONCLUSION: The study revealed a high prevalence of persistent symptoms among South African participants at 6 months but decreased risk for PCC among participants infected during the Omicron BA.1 wave. These findings have serious implications for countries with resource-constrained health care systems.
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COVID-19 , Infecciones por VIH , Adulto , Humanos , Femenino , Estudios de Cohortes , Sudáfrica , Estudios Prospectivos , Estudios de Seguimiento , Calidad de VidaRESUMEN
BACKGROUND: This retrospective cohort study assessed benefits and risks of bedaquiline treatment in multidrug-resistant-tuberculosis (MDR-TB) combination therapy by evaluating safety, effectiveness, drug utilization and emergence of resistance to bedaquiline. METHODS: Data were extracted from a register of South African drug-resistant-tuberculosis (DR-TB) patients (Electronic DR-TB Register [EDRWeb]) for newly diagnosed patients with MDR-TB (including pre-extensively drug-resistant [XDR]-TB and XDR-TB and excluding rifampicin-mono-resistant [RR]-TB, as these patients are by definition not multidrug-resistant), receiving either a bedaquiline-containing or non-bedaquiline-containing regimen, at 14 sites in South Africa. Total duration of treatment and follow-up was up to 30 months, including 6 months' bedaquiline treatment. WHO treatment outcomes within 6 months after end-of-treatment were assessed in both patient groups. Longer term mortality (up to 30 months from treatment start) was evaluated through matching to the South African National Vital Statistics Register. Multivariable Cox proportional hazards analyses were used to predict association between receiving a bedaquiline-containing regimen and treatment outcome. RESULTS: Data were extracted from EDRWeb for 5981 MDR-TB patients (N = 3747 bedaquiline-treated; N = 2234 non-bedaquiline-treated) who initiated treatment between 2015 and 2017, of whom 40.7% versus 80.6% had MDR-TB. More bedaquiline-treated than non-bedaquiline-treated patients had pre-XDR-TB (27.7% versus 9.5%) and XDR-TB (31.5% versus 9.9%) per pre-2021 WHO definitions. Most patients with treatment duration data (94.3%) received bedaquiline for 6 months. Treatment success (per pre-2021 WHO definitions) was achieved in 66.9% of bedaquiline-treated and 49.4% of non-bedaquiline-treated patients. Death was reported in fewer bedaquiline-treated (15.4%) than non-bedaquiline-treated (25.6%) patients. Bedaquiline-treated patients had increased likelihood of treatment success and decreased risk of mortality versus non-bedaquiline-treated patients. In patients with evaluable drug susceptibility testing data, 3.5% of bedaquiline-susceptible isolates at baseline acquired phenotypic resistance. Few patients reported bedaquiline-related treatment-emergent adverse events (TEAEs) (1.8%), TEAE-related bedaquiline discontinuations (1.4%) and QTcF values > 500 ms (2.5%) during treatment. CONCLUSION: Data from this large cohort of South African patients with MDR-TB showed treatment with bedaquiline-containing regimens was associated with survival and effectiveness benefit compared with non-bedaquiline-containing regimens. No new safety signals were detected. These data are consistent with the positive risk-benefit profile of bedaquiline and warrant continued implementation in combination therapy for MDR-TB treatment.
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Tuberculosis Extensivamente Resistente a Drogas , Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Estudios Retrospectivos , Sudáfrica , Pruebas de Sensibilidad Microbiana , Antituberculosos/efectos adversos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Estudios de CohortesRESUMEN
BACKGROUND: There are limited data on the experiences of children being treated for drug-resistant tuberculosis (DR-TB), and most work in the area has been done with older children and adolescents. Comprehensive explorations of the caregiver experiences in this area are also lacking. OBJECTIVE: To describe the experiences of being treated for drug-resistant tuberculosis of children and their caregivers. METHODS: This was a qualitative study done using focus group discussions (FGDs) among three different groups of participants: 1) health care providers involved in the care of children being treated for DR-TB (including physicians, nurses, and pharmacists)-herein referred to as providers; 2) household caregivers of children being treated for DR-TB-herein referred to as caregivers; and 3) children who were being treated for DR-TB-herein referred to as children. The population was a convenience sample and included children hospitalized between January 1, 2018, and June 30, 2020, ages 0-14 years old, as well as their caregivers and providers. Focus group transcripts and notes were analysed using a thematic network analysis based in grounded theory The analysis was iterative and the coding system developed focused on "stressful experiences" as well as ways to address them along the diagnostic and treatment journey. This paper follows the COREQ guidelines. RESULTS: 16 children between the ages 7 and 14 years participated in 5 FGDs, 30 caregivers participated in 7 FGDs, and 12 providers participated in 3 FDGs. Data from the children and the caregivers were the focus of this analysis, although some themes were informed by the discussions with the providers as well. In general, it was reported that for a child diagnosed with DR-TB, there is a lived experience of stress that impacts their physical, mental, and social well-being. These pediatric patients and their families therefore develop strategies for coping with these disruptions to their lives. In general, there were major disruptive experiences that resulted from the process around receiving a diagnosis of DR-TB and second distinct set of stressful experiences that occurred during the treatment of DR-TB once the diagnosis had been made. These stresses occur in the physical, mental, and social realms, and families develop multiple strategies to cope with them, demonstrating resilience in the face of this disease. CONCLUSION: Addressing the stresses experienced by children and their caregivers through child-friendly DR-TB testing, treatment, and counseling is not only essential for ending TB but also for enacting a human-rights based approach to child health in general. Children with DR-TB are a vulnerable population, and they have often been the last to benefit from advances in general pediatric care and in DR-TB care more specifically.
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Tuberculosis Resistente a Múltiples Medicamentos , Adolescente , Cuidadores/psicología , Niño , Femenino , Personal de Salud , Humanos , Investigación Cualitativa , Sudáfrica/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/epidemiologíaRESUMEN
BACKGROUND: Post COVID-19 condition (PCC), as defined by WHO, refers to a wide range of new, returning, or ongoing health problems in people who have had COVID-19, and it represents a rapidly emerging public health priority. We aimed to establish how this developing condition has affected patients in South Africa and which population groups are at risk. METHODS: In this prospective cohort study, we used the DATCOV national hospital surveillance system to identify participants aged 18 years or older who had been hospitalised with laboratory-confirmed SARS-CoV-2 infection in South Africa. Participants underwent telephone follow-up assessment at 1 month and 3 months after hospital discharge. Participants were assessed using a standardised questionnaire for the evaluation of symptoms, functional status, health-related quality of life, and occupational status. We used negative binomial regression models to determine factors associated with PCC. FINDINGS: Of 241â159 COVID-19 admissions reported to DATCOV between Dec 1, 2020, and Aug 23, 2021, 8309 were randomly selected for enrolment. Of the 3094 patients that we were able to contact, 2410 (77·9%) consented to participate in the study at 1 month after discharge. Of these, 1873 (77·7%) were followed up at 3 months after hospital discharge. Participants had a median age of 52 years (IQR 41-62) and 960 (51·3%) were women. At 3 months of follow-up, 1249 (66·7%) of 1873 participants reported new or persistent COVID-19-related symptoms, compared with 1978 (82·1%) of 2410 at 1 month after hospital discharge. The most common symptoms reported at 3 months were fatigue (50·3%), shortness of breath (23·4%), confusion or lack of concentration (17·5%), headaches (13·8%), and problems seeing or blurred vision (10·1%). On multivariable analysis, the factors associated with persistent symptoms after acute COVID-19 were being female (adjusted incident rate ratio 1·20, 95% CI 1·04-1·38) and admission to an intensive care unit (1·17, 1·01-1·37). INTERPRETATION: Most participants in this cohort of individuals previously hospitalised with COVID-19 reported persistent symptoms 3 months after hospital discharge and a significant impact of PCC on their functional and occupational status. The large burden of PCC symptoms identified in this study emphasises the need for a national health strategy. This should include the development of clinical guidelines and training of health-care workers for identifying, assessing, and caring for patients affected by PCC; establishment of multidisciplinary health services; and provision of information and support to people who have PCC. FUNDING: Bill & Melinda Gates Foundation, UK Foreign, Commonwealth & Development Office, and Wellcome.
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COVID-19 , SARS-CoV-2 , Adulto , COVID-19/epidemiología , Estudios de Cohortes , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Sudáfrica/epidemiologíaRESUMEN
BACKGROUND: There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group). METHODS: Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes. FINDINGS: Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4-11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment. INTERPRETATION: Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients. FUNDING: WHO Global TB Programme. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
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Infecciones por VIH , Tuberculosis Resistente a Múltiples Medicamentos , Antituberculosos/uso terapéutico , Diarilquinolinas , Infecciones por VIH/tratamiento farmacológico , Humanos , Estudios Retrospectivos , Rifampin/uso terapéutico , Sudáfrica , Resultado del Tratamiento , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
Rationale: Improving treatment outcomes while reducing drug toxicity and shortening the treatment duration to â¼6 months remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Objectives: To conduct a multicenter randomized controlled trial in adults with MDR/RR-TB (i.e., without resistance to fluoroquinolones or aminoglycosides). Methods: Participants were randomly assigned (1:1 ratio) to a â¼6-month all-oral regimen that included levofloxacin, bedaquiline, and linezolid, or the standard-of-care (SOC) ⩾9-month World Health Organization (WHO)-approved injectable-based regimen. The primary endpoint was a favorable WHO-defined treatment outcome (which mandates that prespecified drug substitution is counted as an unfavorable outcome) 24 months after treatment initiation. The trial was stopped prematurely when bedaquiline-based therapy became the standard of care in South Africa. Measurements and Main Results: In total, 93 of 111 randomized participants (44 in the comparator arm and 49 in the interventional arm) were included in the modified intention-to-treat analysis; 51 (55%) were HIV coinfected (median CD4 count, 158 cells/ml). Participants in the intervention arm were 2.2 times more likely to experience a favorable 24-month outcome than participants in the SOC arm (51% [25 of 49] vs. 22.7% [10 of 44]; risk ratio, 2.2 [1.2-4.1]; P = 0.006). Toxicity-related drug substitution occurred more frequently in the SOC arm (65.9% [29 of 44] vs. 34.7% [17 of 49]; P = 0.001)], 82.8% (24 of 29) owing to kanamycin (mainly hearing loss; replaced by bedaquiline) in the SOC arm, and 64.7% (11 of 17) owing to linezolid (mainly anemia) in the interventional arm. Adverse event-related treatment discontinuation in the safety population was more common in the SOC arm (56.4% [31 of 55] vs. 32.1% [17 of 56]; P = 0.007). However, grade 3 adverse events were more common in the interventional arm (55.4% [31 of 56] vs. 32.7 [18 of 55]; P = 0.022). Culture conversion was significantly better in the intervention arm (hazard ratio, 2.6 [1.4-4.9]; P = 0.003) after censoring those with bedaquiline replacement in the SOC arm (and this pattern remained consistent after censoring for drug replacement in both arms; P = 0.01). Conclusions: Compared with traditional injectable-containing regimens, an all-oral 6-month levofloxacin, bedaquiline, and linezolid-containing MDR/RR-TB regimen was associated with a significantly improved 24-month WHO-defined treatment outcome (predominantly owing to toxicity-related drug substitution). However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB.Clinical trial registered with www.clinicaltrials.gov (NCT02454205).
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Tuberculosis Resistente a Múltiples Medicamentos , Adulto , Antituberculosos/efectos adversos , Diarilquinolinas/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Humanos , Levofloxacino/uso terapéutico , Linezolid/uso terapéutico , Rifampin/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
BACKGROUND: Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015-19). METHODS: Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes. FINDINGS: Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR. INTERPRETATION: Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential. FUNDING: National Institute for Communicable Diseases of South Africa.