Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis.

BACKGROUND: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). METHODS AND FINDINGS: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. CONCLUSIONS: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

Quality of drug-resistant tuberculosis care: Gaps and solutions.

Drug-resistant forms of tuberculosis (DR-TB) are a significant cause of global morbidity and mortality and the treatment of DR-TB is characterized by long and toxic regimens that result in low rates of cure. There are few formal studies documenting the quality of DR-TB treatment services provided globally, but the limited data that do exist show there is a quality crisis in the field. This paper reviews current issues impacting quality of care in DR-TB, including within the areas of patient-centeredness, safety, effectiveness and equity. Specific issues affecting DR-TB quality of care include: 1) the use of regimens with limited efficacy, significant toxicity, and high pill burden; 2) standardized treatment without drug susceptibility testing; 3) non-quality assured medications and drug stock outs; 4) lack of access to newer and repurposed drugs; 5) high rates of adverse events coupled with minimal monitoring and management; 6) care provided by multiple providers in the private sector; 7) depression, anxiety, and stress; and 8) stigma and discrimination. The paper discusses potential ways to improve quality in each of these areas and concludes that many of these issues arise from the traditional "public health approach" to TB and will only transformed when a human-rights based approach is put into practice.

The Lancet Respiratory Medicine Commission: 2019 update: epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant and incurable tuberculosis.

The Lancet Respiratory Medicine Commission on drug-resistant tuberculosis was published in 2017, which comprehensively reviewed and provided recommendations on various aspects of the disease. Several key new developments regarding drug-resistant tuberculosis are outlined in this Commission Update. The WHO guidelines on treating drug-resistant tuberculosis were updated in 2019 with a reclassification of second line anti-tuberculosis drugs. An injection-free MDR tuberculosis treatment regimen is now recommended. Over the past 3 years, advances in treatment include the recognition of the safety and mortality benefit of bedaquiline, the finding that the 9-11 month injectable-based 'Bangladesh' regimen was non-inferior to longer regimens, and promising interim results of a novel 6 month 3-drug regimen (bedaquiline, pretomanid, and linezolid). Studies of explanted lungs from patients with drug-resistant tuberculosis have shown substantial drug-specific gradients across pulmonary cavities, suggesting that alternative dosing and drug delivery strategies are needed to reduce functional monotherapy at the site of disease. Several controversies are discussed including the optimal route of drug administration, optimal number of drugs constituting a regimen, selection of individual drugs for a regimen, duration of the regimen, and minimal desirable standards of antibiotic stewardship. Newer rapid nucleic acid amplification test platforms, including point-of-care systems that facilitate active case-finding, are discussed. The rapid diagnosis of resistance to other drugs, (notably fluoroquinolones), and detection of resistance by targeted or whole genome sequencing will probably change the diagnostic landscape in the near future.

A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment.

Multigram drug depot systems for extended drug release could transform our capacity to effectively treat patients across a myriad of diseases. For example, tuberculosis (TB) requires multimonth courses of daily multigram doses for treatment. To address the challenge of prolonged dosing for regimens requiring multigram drug dosing, we developed a gastric resident system delivered through the nasogastric route that was capable of safely encapsulating and releasing grams of antibiotics over a period of weeks. Initial preclinical safety and drug release were demonstrated in a swine model with a panel of TB antibiotics. We anticipate multiple applications in the field of infectious diseases, as well as for other indications where multigram depots could impart meaningful benefits to patients, helping maximize adherence to their medication.

Tuberculosis.

Tuberculosis remains the leading cause of death from an infectious disease among adults worldwide, with more than 10 million people becoming newly sick from tuberculosis each year. Advances in diagnosis, including the use of rapid molecular testing and whole-genome sequencing in both sputum and non-sputum samples, could change this situation. Although little has changed in the treatment of drug-susceptible tuberculosis, data on increased efficacy with new and repurposed drugs have led WHO to recommend all-oral therapy for drug-resistant tuberculosis for the first time ever in 2018. Studies have shown that shorter latent tuberculosis prevention regimens containing rifampicin or rifapentine are as effective as longer, isoniazid-based regimens, and there is a promising vaccine candidate to prevent the progression of infection to the disease. But new tools alone are not sufficient. Advances must be made in providing high-quality, people-centred care for tuberculosis. Renewed political will, coupled with improved access to quality care, could relegate the morbidity, mortality, and stigma long associated with tuberculosis, to the past.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis.

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

The need to accelerate access to new drugs for multidrug-resistant tuberculosis.

Approximately half a million people are thought to develop multidrug-resistant tuberculosis annually. Barely 20% of these people currently receive recommended treatment and only about 10% are successfully treated. Poor access to treatment is probably driving the current epidemic, via ongoing transmission. Treatment scale-up is hampered by current treatment regimens, which are lengthy, expensive, poorly tolerated and difficult to administer in the settings where most patients reside. Although new drugs provide an opportunity to improve treatment regimens, current and planned clinical trials hold little promise for developing regimens that will facilitate prompt treatment scale-up. In this article we argue that clinical trials, while necessary, should be complemented by timely, large-scale, operational research that will provide programmatic data on the use of new drugs and regimens while simultaneously improving access to life-saving treatment. Perceived risks - such as the rapid development of resistance to new drugs - need to be balanced against the high levels of mortality and transmission that will otherwise persist. Doubling access to treatment and increasing treatment success could save approximately a million lives over the next decade.

On estime à un demi-million le nombre de personnes qui contractent chaque année la tuberculose multirésistante. De nos jours, à peine 20% d'entre elles reçoivent le traitement recommandé, et seulement 10% environ sont traitées avec succès. L'accès limité au traitement est probablement responsable de l'épidémie actuelle qui se propage par une transmission continue. L'amélioration de l'accès au traitement est freinée par les schémas thérapeutiques actuels, lesquels sont très longs, chers, mal tolérés et difficiles à gérer dans les régions où résident la plupart des patients. Bien que de nouveaux médicaments permettent d'améliorer les schémas thérapeutiques, les essais cliniques actuels et prévus ne laissent que peu d'espoir quant au développement de schémas qui favoriseraient l'amélioration rapide de l'accès au traitement. Dans cet article, nous soutenons que les essais cliniques sont certes nécessaires, mais qu'ils doivent être accompagnés d'une recherche opérationnelle de grande ampleur effectuée en temps voulu. Cette recherche permettrait d'obtenir des données programmatiques sur l'utilisation des nouveaux médicaments et schémas tout en améliorant l'accès à un traitement pouvant sauver des vies. Les risques perçus ­ tels que le développement rapide d'une résistance aux nouveaux médicaments ­ doivent être mis en balance avec les taux élevés de mortalité et de transmission qui se maintiendraient sans cela. Doubler l'accès au traitement et accroître son efficacité permettrait de sauver environ un million de vies au cours de la décennie à venir.

Se estima que alrededor de 500.000 personas al año desarrollan tuberculosis multirresistente. Apenas el 20% de estas personas recibe un tratamiento recomendado y solo el 10% se somete a un tratamiento eficaz. Probablemente la epidemia actual, a través de la transmisión continua, se deba al escaso acceso al tratamiento. La ampliación del tratamiento se ve obstaculizada por los regímenes terapéuticos actuales, que son prolongados, caros, producen intolerancia y son complicados de administrar en los lugares donde residen los pacientes. A pesar de que los nuevos fármacos son una oportunidad de mejorar los regímenes terapéuticos, los ensayos clínicos actuales y planificados no ofrecen demasiadas esperanzas para desarrollar regímenes que faciliten una ampliación del tratamiento a corto plazo. En este artículo sostenemos que los ensayos clínicos, mientras sea necesario, deberían ir acompañados de una investigación operativa oportuna a gran escala que proporcione información programática sobre el uso de los nuevos fármacos y regímenes, mientras mejora el acceso a un tratamiento que salvará vidas. Los riesgos, como el rápido desarrollo de la resistencia a nuevos fármacos, deberían equilibrarse frente a los altos niveles de mortalidad y transmisión que, de otro modo, continuarán existiendo. Duplicar el acceso al tratamiento y aumentar su éxito podría salvar alrededor de un millón de vidas en la próxima década.

Access to new medications for the treatment of drug-resistant tuberculosis: patient, provider and community perspectives.

Multidrug-resistant tuberculosis (MDR-TB) is on the rise, and is difficult to treat. The approval of two new drugs, bedaquiline and delamanid, and growing evidence for the use of linezolid, offer renewed hope for addressing MDR-TB. However, access to these medicines remains a significant challenge. These drugs have not been registered for TB in most settings; barriers to preapproval access persist; and high pricing and intellectual property restrictions limit access. Many unanswered research questions about optimal use of these drugs also limit access, particularly for vulnerable populations. This review outlines challenges in accessing drugs encountered from the perspective of clinicians, patients and affected communities, and offers potential solutions.

Lay health workers and HIV care in rural Lesotho: a report from the field.

Lay health workers (LHWs) are individuals who participate in a variety of health services, even though they have no formal professional training. They have been used in a variety of settings, especially where health care needs outstrip available human resources. Lesotho faces a severe human resource shortage as it attempts to manage its HIV pandemic, with more than 25% of the population infected with HIV. This article reports on a program that provided HIV services in seven rural clinics in Lesotho. LHWs played an important role in the provision of HIV services that ranged from translation, adherence counseling, voluntary counseling and testing (VCT) for HIV and patient triage, to medication distribution and laboratory specimen processing. Training the LHWs was part of the clinic physicians' responsibilities and thus required no additional funding beyond regular clinic operations. This lent sustainability to the training of the LHWs. This paper describes the recruitment, training, activities, and perceptions of the LHW work between June 2006 and December 2008. LHWs participated successfully in the care of thousands of people with HIV in Lesotho and their experience can serve as a model for other countries facing the disease.

A novel training model to address health problems in poor and underserved populations.

Health disparities are increasingly common and many U.S. practitioners have informal experience working in resource-poor settings. There are, however, few graduate medical education programs that focus on health equity. A graduate medical education program in health equity was developed at Brigham and Women's Hospital based on a review of existing literature and on a survey of junior faculty who have had informal health disparities experience. The Howard Hiatt Residency in Global Health Equity and Internal Medicine was developed as a four-year program to provide intensive training in internal medicine and health disparities. Participating residents are matched with a mentor who has clinical and research experience in the field of global health. In addition to a series of didactic teaching sessions and longitudinal seminars that focus on issues of global health equity, residents take graduate level courses in epidemiology, health policy, ethics, and medical anthropology. Residents also carry out an independent research project in a geographic area that suffers from health disparities. Two residents are selected for training per year. Participating faculty are multidisciplinary and come from diverse Harvard-affiliated institutions. Graduate medical education in the United States with a focus on health equity is lacking. It is hoped that the novel training program in health equity for internal medical residents developed at Brigham and Women's Hospital can serve as a model for other teaching hospitals based in the United States.