Cost-effectiveness of pretomanid-based regimen for highly drugresistant TB in a low-burden setting.

BACKGROUND: Recent clinical findings reported improvement in the treatment outcomes of highly resistant TB (HDR-TB) with the pretomanid (Pa) based regimen. This study aimed to evaluate the cost-effectiveness of the Pa-based regimen for HDR-TB treatment from the perspective of the healthcare sector in the United States.METHODS: A lifelong decision-analytic model was constructed to simulate potential treatment outcomes of 1) the bedaquiline-Pa-linezolid (BPaL) regimen, and 2) the bedaquiline-linezolid (B-L) based regimen in a hypothetical cohort of adult patients with HDR-TB. Primary model outputs were TB-related direct medical costs, qualityadjusted life-years (QALYs) and incremental cost per QALY gained (ICER).RESULTS: In the base-case analysis, the BPaL regimen gained 3.0054 QALYs and saved costs by USD60,433 when compared to the B-L-based regimen. In the probabilistic sensitivity analysis, the BPaL regimen gained higher QALYs at a lower cost in 80.3% of the time, and gained higher QALYs at a higher cost with ICER less than the willingness-to-pay (WTP) threshold (100,000 USD/QALY) in 19.0% of the simulations. The probability of the BPaL regimen being cost-effective was higher than the B-L-based regimen throughout the variation of WTP.CONCLUSION: BPaL therapy is likely the cost-effective option for HDR-TB treatment from the US healthcare sector perspective.

Pretomanida para o tratamento da tuberculose resistente a medicamentos / Pretomanid for the Treatment of Drug-Resistant Tuberculosis

INTRODUÇÃO: A tuberculose (TB) é uma das principais causas de morbidade e mortalidade relacionadas a um único agente infeccioso. Estima-se que um quarto da população mundial, o equivalente a cerca de 2 bilhões de pessoas, esteja infectada pelo bacilo Mycobacterium tuberculosis. No Brasil, é considerada como um grave problema de saúde pública, afetando anualmente cerca de 80 mil pessoas. No âmbito do Sistema Único de Saúde (SUS), estima-se que 770 novos casos de TB resistente a medicamentos de primeira linha foram diagnosticados em 2022. O tratamento para formas resistentes de TB mais longo é (18 a 20 meses), e requer medicamentos que são mais caros e que causam mais eventos adversos. Esquemas com pretomanida são recomendados como uma das opções terapêuticas pela Organização Mundial da Saúde (OMS) e pelo Centers for Disease Control and Prevention (CDC), sendo capaz de reduzir o tempo de tratamento para 6 a 9 meses e reduzir expressivamente os custos do tratamento. Salienta-se, entretanto, que a pretomanida não possui fabricação nacional e não tem registro sanitário no Brasil. Assim, a sua aquisição será realizada por intermédio da Organização Panamericana de Saúde (OPAS), em conformidade com a lei Nº 14.313, de 21 de março de 2022 que sanciona a aquisição medicamento e produto recomendados pela Conitec e adquiridos por intermédio de organismos multilaterais internacionais, para uso em programas de saúde pública do Ministério da Saúde e suas entidades vinculadas, nos termos do § 5º do art. 8º da Lei nº 9.782, de 26 de janeiro de 1999. PERGUNTA: Pretomanida é eficaz, segura e custo-efetiva como parte do regime de base otimizado, no tratamento de pacientes com tuberculose resistente a medicamentos, quando comparada ao regime de base otimizado sem pretomanida? EVIDÊNCIAS CLÍNICAS: Das 57 referências identificadas nas bases Medline (via PubMed), Embase, The Cochrane Library e LILACS, um único Ensaio Clínico Randomizado (ECR), aberto, fase 2-3, multicêntrico, contribuiu para a síntese de evidências deste relatório, que demonstrou não-inferioridade do tratamento proposto com pretomanida [Bedaquilina, pretomanida e linezolida (BPaL) e bedaquilina, pretomanida, linezolida e moxifloxacino (BPaLM)] em comparação ao esquema padrão utilizado pelo SUS (sem pretomanida), para desfechos desfavoráveis combinados (morte, falha no tratamento, descontinuação do tratamento, perda de acompanhamento ou recorrência de TB) e de segurança. A qualidade da evidência foi classificada como moderada a alta, segundo o GRADE. AVALIAÇÃO ECONÔMICA: A partir das evidências clínicas, considerou-se a não inferioridade do esquema terapêutico contendo pretomanida para realizar uma análise de custo-minimização, utilizando uma árvore de decisão simples. Dessa forma, comparou-se o regime de base otimizado com pretomanida com o regime sem pretomanida, para o tratamento completo de pacientes com TB RR, TB MDR ou TB Pré-XDR. Foi adotada a perspectiva do SUS e considerou-se apenas custos como desfecho. Ao final, a análise estimou que essa substituição resultaria em uma economia anual por paciente de R$ 17.463,00 em média. Especificamente para TB RR e TB MDR (BPaLM) seria uma economia de R$ 19.328,40 e de R$ 15.597,60 para TB pré-XDR (BPaL). ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Considerando-se a perspectiva do SUS e uma demanda aferida, foi adotado um marketshare de 85% no primeiro ano (2023) que chegou a 100% a partir do quarto ano (2026) para avaliar a incorporação da pretomanida no SUS. No cenário principal, no qual se considerou a média de pacientes com TB resistente a medicamentos, verificou-se uma economia estimada de R$ 13.631.563,50 no primeiro ano (2023), chegando a R$ 90.687.911,54 no acumulado de cinco anos (2023 a 2027), com a incorporação da pretomanida no SUS. Essa economia variou de R$ 13,6 milhões a R$ 16 milhões no primeiro ano (2023) e de R$ 89,4 milhões a R$ 95,8 milhões no acumulado de cinco anos (2023 a 2027), a depender do parâmetro explorado (estimativa da população ou market-share máximo) nos cenários alternativos. No entanto, estes resultados podem mudar de acordo com a variação cambial do dólar. RECOMENDAÇÕES INTERNACIONAIS: A pretomanida apresenta-se como opção recomendada pelo CDC e pela OMS como uma das opções terapêuticas para o tratamento de TB resistente a medicamentos, sendo capaz de reduzir o tempo de tratamento para 6 a 9 meses e desempenhar melhor custo-efetividade. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram detectadas quatro tecnologias potenciais para compor os esquemas de tratamento de pacientes com tuberculose multi-resistentes a medicamentos. São eles: canamicina e sutezolida, inibidores da síntese proteica ribossomal; cicloserina, um inibidor da GABA transaminase; protionamida, um inibidor da síntese de peptídeos. Nenhum deles possui aprovação no FDA, EMA e Anvisa. CONSIDERAÇÕES FINAIS: O uso da pretomanida, como parte de um regime de base otimizado, possui eficácia e segurança não-inferiores ao regime de base otimizado sem pretomanida. Além disso, o regime com pretomanida demonstrou potencial economia para o SUS na avaliação econômica e na análise de impacto orçamentário. Além disso, a OMS recomenda seu uso em pacientes com TB resistente, quando já não é possível compor um esquema terapêutico adequado com os medicamentos anteriormente disponíveis, como ocorre no Brasil. PERSPECTIVA DO PACIENTE: Foi aberta a Chamada Pública de número 24/2023, entre 13 e 23/07/2023, objetivando a inscrição de participantes para a Perspectiva do Paciente referente ao tema. Uma pessoa se inscreveu. No entanto, indicou não ter disponibilidade para participar da reunião da Conitec, na data prevista para a discussão do item. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O Comitê de Medicamentos da Conitec, em sua 121ª Reunião Ordinária, no dia 03 de agosto de 2023, deliberou que a matéria fosse disponibilizada em Consulta Pública com recomendação preliminar favorável à incorporação no SUS da pretomanida para o tratamento de pacientes com tuberculose resistente a medicamentos. Para essa recomendação, o Comitê considerou que os regimes terapêuticos com pretomanida estiveram relacionados a: I) evidências de não-inferioridade em relação aos regimes sem pretomanida; II) menor tempo de tratamento; III) potencialmente menos eventos adversos; IV) possibilidade de tratamentos totalmente orais, sem a necessidade de uso de injetáveis; V) maior adesão ao tratamento, evitando o abandono por parte do paciente; VI) potencial economia para o SUS na adoção de regimes terapêuticos com pretomanida. CONSULTA PÚBLICA: Foram recebidas 14 contribuições, sendo sete técnico-científicas e sete sobre experiência ou opinião. Todas as técnico-científicas concordaram com a recomendação inicial da Conitec. Os assuntos mais citados foram: importância de se incorporar mais uma opção terapêutica para tuberculose resistente a medicamentos, sua eficácia em associação a outros medicamentos, o fato de pretomanida ser oral contribuir para a adesão ao tratamento, redução do tempo de tratamento com pretomanida e a incorporação de pretomanida como parte de um esquema terapêutico otimizado. Todos os respondentes do formulário de experiência ou opinião apresentaram-se favoráveis à recomendação inicial da Conitec. Em geral, no que se às opiniões e à experiência com o pretomanida, os participantes mencionaram que o medicamento possibilita a diminuição do tempo de tratamento, que implica melhora da adesão e redução de custos ao SUS, bem como apresenta segurança e eficácia. Não mencionaram efeitos negativos ou dificuldades. Por fim, considerouse que as contribuições recebidas na Consulta Pública estiveram alinhadas com a recomendação preliminar da Conitec, não justificando mudança de entendimento sobre o tema. RECOMENDAÇÃO FINAL DA CONITEC: O Comitê de Medicamentos da Conitec, em sua 122ª Reunião Ordinária, no dia 13 de setembro de 2023, deliberou por unanimidade recomendar a incorporação da pretomanida para o tratamento da tuberculose resistente a medicamentos. Tendo em vista as contribuições da Consulta Pública, que reforçaram os benefícios esperados com o medicamento, os membros do Comitê mantiveram seu entendimento de que o regime com pretomanida se mostrou não-inferior em relação aos regimes sem pretomanida, representando menor tempo de tratamento, menos eventos adversos, maior adesão e potencial economia para o SUS. Assim, foi assinado o Registro de Deliberação nº 846/2023. DECISÃO: Incorporar, no âmbito do Sistema Único de Saúde - SUS, a pretomanida para o tratamento da tuberculose resistente a medicamentos, publicada no Diário Oficial da União nº 182, seção 1, página 270, em 22 de setembro de 2023

Assessment of a combined treatment with a therapeutic vaccine and benznidazole for the Trypanosoma cruzi chronic infection.

The difficulties encountered in achieving treatments for chronic Chagas disease have promoted the investigation of new therapeutic strategies. In this study, we used two murine models of Trypanosoma cruzi chronic infection to determine the usefulness of applying a therapeutic vaccine alone or followed by benznidazole (Bz) chemotherapy. A vaccine formulation based on an N-terminal fragment of Trans-sialidase (TS) and Immunostimulant Particle Adjuvant (ISPA) - TSNt-ISPA was obtained. Firstly, the immunogenicity and protective capacity of TSNt-ISPA was demonstrated as a prophylactic formulation in an acute model of infection. Later, the formulation was assessed as a therapeutic vaccine alone or combined with (Bz) using two models of chronic infection. BALB/c mice chronically infected with Sylvio X10/4 or Tulahuen cl2 T. cruzi strains were not treated as control or treated only with the therapeutic vaccine TSNt-ISPA, with a combined treatment TSNt-ISPA+Bz (Bz applied after the vaccine), or only with Bz. The vaccination schedule consisted of TSNt-ISPA administration at days110, 120, and 130 post-infection (pi) and Bz administration was performed daily from day 140 to 170 pi. At day 273 pi, electrocardiographic (ECG) parameters, heart parasite load, myocarditis, and heart fibrosis were assessed. In both models, therapeutic administration of TSNt-ISPA reduced ECG alterations and the cardiac tissue damage observed in the chronic phase. Moreover, vaccine treatment significantly decreased heart parasite load in both Sylvio X10/4 and Tulahuen cl2 infected mice. The combined treatment, but not Bz or vaccine administration alone, allowed to restore ECG parameters in Tulahuen cl2 infected mice. The results indicate the usefulness of the therapeutic TSNt-ISPA formulation in BALB/c mice chronically infected with Sylvio X10/4 or Tulahuen cl2 strain. For the mice infected with T. cruzi Tulahuen cl2 strain, the combined treatment with the vaccine and Bz had a more positive effect on the course of heart disease than the individual treatments with the vaccine or Bz alone.

"We have already heard that the treatment doesn't do anything, so why should we take it?": A mixed method perspective on Chagas disease knowledge, attitudes, prevention, and treatment behaviour in the Bolivian Chaco.

BACKGROUND: Chagas disease (CD) is highly endemic in the Bolivian Chaco. The municipality of Monteagudo has been targeted by national interventions as well as by Médecins Sans Frontières to reduce infection rates, and to decentralize early diagnosis and treatment. This study seeks to determine the knowledge and attitudes of a population with increased awareness and to identify remaining factors and barriers for sustained vector control, health care seeking behaviour, and access, in order to improve future interventions. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional survey was conducted among approximately 10% (n = 669) of the municipality of Monteagudo's households that were randomly selected. Additionally, a total of 14 in-depth interviews and 2 focus group discussions were conducted with patients and key informants. Several attitudes and practices were identified that could undermine effective control against (re-)infection. Knowledge of clinical symptoms and secondary prevention was limited, and revealed specific misconceptions. Although 76% of the participants had been tested for CD, only 18% of those who tested positive concluded treatment with benznidazole (BNZ). Sustained positive serologies after treatment led to perceived ineffectiveness of BNZ. Moreover, access barriers such as direct as well as indirect costs, BNZ stock-outs and a fear of adverse reactions triggered by other community members made patients opt for alternative treatments against CD such as veterinary ivermectin, used by 28% of infected participants in our study. The lack of accessible care for chronic complications as well as socioeconomic consequences, such as the exclusion from both job opportunities and bank loans contributed to the ongoing burden of CD. CONCLUSIONS/SIGNIFICANCE: Large scale interventions should be accompanied by operational research in order to identify misconceptions and unintended consequences early on, to generate accessible data for future interventions, and for rigorous evaluation. An integrated, community-based approach tackling social determinants and including both traditional and animal health sectors might help to overcome current barriers and advocate for patients' rights.

Access to Chagas disease treatment in the United States after the regulatory approval of benznidazole.

Approximately 300,000 persons in the United States (US) are infected with Trypanosoma cruzi, the protozoan that causes Chagas disease, but less than 1% are estimated to have received antiparasitic treatment. Benznidazole was approved by the US Food and Drug Administration (FDA) for treatment of T. cruzi infection in 2017 and commercialized in May 2018. This paper analyzes factors that affect access to benznidazole following commercialization and suggests directions for future actions to expand access. We applied an access framework to identify barriers, facilitators, and key actors that influence the ability of people with Chagas disease to receive appropriate treatment with benznidazole. Data were collected from the published literature, key informants, and commercial databases. We found that the mean number of persons who obtained benznidazole increased from just under 5 when distributed by the CDC to 13 per month after the commercial launch (from May 2018 to February 2019). Nine key barriers to access were identified: lack of multi-sector coordination, failure of health care providers to use a specific order form, lack of an emergency delivery system, high medical costs for uninsured patients, narrow indications for use of benznidazole, lack of treatment guidelines, limited number of qualified treaters, difficulties for patients to make medical appointments, and inadequate evaluation by providers to determine eligibility for treatment. Our analysis shows that access to benznidazole is still limited after FDA approval. We suggest six areas for strategic action for the pharmaceutical company that markets benznidazole and its allied private foundation to expand access to benznidazole in the US. In addition, we recommend expanding the existing researcher-clinician network by including government agencies, companies and others. This paper's approach could be applied to access programs for benznidazole in other countries or for other health products that target neglected populations throughout the world.

New Scheme of Intermittent Benznidazole Administration in Patients Chronically Infected with Trypanosoma cruzi: Clinical, Parasitological, and Serological Assessment after Three Years of Follow-Up.

In a pilot study, we showed that the intermittent administration of benznidazole in chronic Chagas disease patients resulted in a low rate of treatment suspension and therapeutic failure, as assessed by quantitative PCR (qPCR) at the end of treatment. Here, a 3-year posttreatment follow-up study of the same cohort of patients is presented. The treatment scheme consisted of 12 doses of benznidazole at 5 mg/kg of body weight/day in two daily doses every 5 days. Parasite load, Trypanosoma cruzi-specific antibodies, and serum chemokine levels were measured prior to treatment and after a median follow-up of 36 months posttreatment by DNA minicircle kinetoplastid and nuclear DNA satellite sequence qPCR methods, conventional serological techniques, a Luminex-based assay with recombinant T. cruzi proteins, and a cytometric bead array. At the end of follow-up, 14 of 17 (82%) patients had negative qPCR findings, whereas three of 17 (18%) had detectable nonquantifiable findings by at least one of the qPCR techniques. A decline in parasite-specific antibodies at 12 months posttreatment was confirmed by conventional serological tests and the Luminex assays. Monocyte chemoattractant protein 1 levels increased after treatment, whereas monokine induced by gamma interferon levels decreased. New posttreatment electrocardiographic abnormalities were observed in only one patient who had cardiomyopathy prior to treatment. Together, these data strengthen our previous findings by showing that the intermittent administration of benznidazole results in a low rate of treatment suspension, with treatment efficacy comparable to that of a daily dose of 5 mg/kg for 60 days.

Efficacy and safety assessment of different dosage of benznidazol for the treatment of Chagas disease in chronic phase in adults (MULTIBENZ study): study protocol for a multicenter randomized Phase II non-inferiority clinical trial.

BACKGROUND: Chagas disease (CD) continues to be a neglected infectious disease with one of the largest burdens globally. Despite the modest cure rates in adult chronic patients and its safety profile, benznidazole (BNZ) is still the drug of choice. Its current recommended dose is based on nonrandomized studies, and efficacy and safety of the optimal dose of BNZ have been scarcely analyzed in clinical trials. METHODS/DESIGN: MULTIBENZ is a phase II, randomized, noninferiority, double-blind, multicenter international clinical trial. A total of 240 patients with Trypanosoma CD in the chronic phase will be recruited in four different countries (Argentina, Brazil, Colombia, and Spain). Patients will be randomized to receive BNZ 150 mg/day for 60 days, 400 mg/day for 15 days, or 300 mg/day for 60 days (comparator arm). The primary outcome is the efficacy of three different BNZ therapeutic schemes in terms of dose and duration. Efficacy will be assessed according to the proportion of patients with sustained parasitic load suppression in peripheral blood measured by polymerase chain reaction. The secondary outcomes are related to pharmacokinetics and drug tolerability. The follow-up will be 12 months from randomization to end of study participation. Recruitment was started in April 2018. CONCLUSION: This is a clinical trial conducted for the assessment of different dose schemes of BNZ compared with the standard treatment regimen for the treatment of CD in the chronic phase. MULTIBENZ may help to clarify which is the most adequate BNZ regimen in terms of efficacy and safety, predicated on sustained parasitic load suppression in peripheral blood. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03191162. Registered on 19 June 2017.

Congenital Chagas Disease in the United States: The Effect of Commercially Priced Benznidazole on Costs and Benefits of Maternal Screening.

Chagas disease, caused by Trypanosoma cruzi, is transmitted by insect vectors, and through transfusions, transplants, insect feces in food, and mother to child during gestation. An estimated 30% of infected persons will develop lifelong, potentially fatal cardiac or digestive complications. Treatment of infants with benznidazole is highly efficacious in eliminating infection. This work evaluates the costs of maternal screening and infant testing and treatment for Chagas disease in the United States, including the cost of commercially available benznidazole. We compare costs of testing and treatment for mothers and infants with the lifetime societal costs without testing and consequent morbidity and mortality due to lack of treatment or late treatment. We constructed a decision-analytic model, using one tree that shows the combined costs for every possible mother-child pairing. Savings per birth in a targeted screening program are $1,314, and with universal screening, $105 per birth. At current screening costs, universal screening results in $420 million in lifetime savings per birth-year cohort. We found that a congenital Chagas screening program in the United States is cost saving for all rates of congenital transmission greater than 0.001% and all levels of maternal prevalence greater than 0.06% compared with no screening program.

Delamanid para el tratamiento de pacientes con tuberculosis resistente / Delamanid for the treatment of patients with tuberculosis resistant

INTRODUCCIÓN: La incidencia de TB en Perú se estima en 123 por 100,000 habitantes para la TB farmacosensible (comparado a 132 por 100,000 habitantes global y 29 por 100,000 habitantes regional), y de 10 por 100,000 habitantes para la TB multi drogo resistente (TB-MDR) (comparado a 6.4 por 100 000 global y 1 por 100,000 habitantes regional). La relativa alta prevalencia de TB MDR en Perú (6% entre los nuevos casos y 21% en los casos que regresan a tratamiento) aumenta la carga en el sistema de salud. A. Cuadro clínico: El manejo y tratamiento de TB MDR es complejo, incluye un elevado costo, el uso de drogas anti-tuberculosas altamente toxicas con potenciales efectos adversos, mayor tiempo de tratamiento, com una carga incrementada de fallo al tratamiento y de mortalidad. El tratamiento requiere de un curso de fármacos de segunda línea por al menos 9 a 20 meses, con continuo acompañamiento y monitório de efectos adversos. B. Tecnología sanitária: El delamanid es un derivado nitro-dihidro-imidazooxazol, considerado como una nueva droga antituberculosa que inhibe la síntesis del ácido micólico y ha demostrado una actividad potente in vitro e in vivo contra las cepas drogo-resistentes del M. tuberculosis. También se cree que los nitroimidazoles parecen matar la bacteria tuberculosa debido a la liberación de óxido nítrico cuando la droga es metabolizada. Se han encontrado estúdios satisfactorios a los dos meses de tratamento con conversión de cultivos en pacientes con TB MDR. OBJETIVO: Evaluar la eficacia y seguridad, así como documentos relacionados a la decisión de cobertura del delamanid para tuberculosis resistente. METODOLOGÍA: Se realizó una búsqueda en las principales bases de datos bibliográficas: MEDLINE, LILACS, COCHRANE, así como en buscadores genéricos de Internet incluyendo Google Scholar y TRIPDATABASE. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales de neumología e infectología y agencias de tecnologias sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Se identificaron dos ECAs, tres GPC y 1 TS. No se encontraron evaluaciones económicas de la región. CONCLUSIONES: La evidencia comparativa de delamanid es escasa y se basa en dos ensayos clínico aleatorizados. Mientras que un ECA muestra una diferencia significativa con respecto a la conversión del cultivo (desenlace principal para tuberculosis) a los dos meses de esquemas para TB-MDR con delamamid comparado con el mismo esquema con placebo, el otro ECA no muestra diferencia en el tiempo médio para la conversión del cultivo de esputo entre estos grupos. Sin embargo, se demostró que delamanid es seguro no demostrando diferencias en eventos adversos comparado con placebo y sin muertes asociadas al tratamiento. Las GPC y ETS recabadas consideran a delamanid dentro de sus recomendaciones fundamentando esta decisión a partir de estudios no comparativos que demuestran eficacia y un alto perfil de seguridad.

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.

Estimating the impact of a novel drug regimen for treatment of tuberculosis: a modeling analysis of projected patient outcomes and epidemiological considerations.

BACKGROUND: Regimens that could treat both rifampin-resistant (RR) and rifampin-susceptible tuberculosis (TB) while shortening the treatment duration have reached late-stage clinical trials. Decisions about whether and how to implement such regimens will require an understanding of their likely clinical impact and how this impact depends on local epidemiology and implementation strategy. METHODS: A Markov state-transition model of 100,000 representative South African adults with TB was used to simulate implementation of the regimen BPaMZ (bedaquiline, pretomanid, moxifloxacin, and pyrazinamide), either for RR-TB only or universally for all patients. Patient outcomes, including cure rates, time with active TB, and time on treatment, were compared to outcomes under current care. Sensitivity analyses varied the drug-resistance epidemiology, rifampin susceptibility testing practices, and regimen efficacy. RESULTS: Using BPaMZ exclusively for RR-TB increased the proportion of all RR-TB that was cured by initial treatment from 60 ± 1% to 67 ± 1%. Expanding use of BPaMZ to all patients increased cure of RR-TB to 89 ± 1% and cure of all TB from 87.3 ± 0.1% to 89.5 ± 0.1%, while shortening treatment by 1.9 months/person. In sensitivity analyses, reducing the coverage of rifampin susceptibility testing resulted in lower projected proportions of patients cured under all regimen scenarios (current care, RR-only BPaMZ, and universal BPaMZ), compared to the proportions projected using South Africa's high coverage; however, this reduced coverage resulted in greater expected incremental benefits of universal BPaMZ implementation, both when compared to RR-only BPaMZ implementation and when compared to to current care under the same low rifampin susceptibility testing coverage. In settings with higher RR-TB prevalence, the benefits of BPaMZ were magnified both for RR-specific and universal BPaMZ implementation. CONCLUSIONS: Novel regimens such as BPaMZ could improve RR-TB outcomes and shorten treatment for all patients, particularly with universal use. Decision-makers weighing early options for implementing such regimens at scale will want to consider the expected impact on patient outcomes and on the burden of treatment in their local context.

Benznidazol en adultos con infección crónica por trypanosoma cruzy, con/sin patología demostrada / Benznidazole in adults with chronic infection by Trypanosoma cruzy, with / without proven pathology

CONTEXTO: La enfermedad de Chagas o tripanosomiasis americana es una parasitosis sistémica crónica, de transmisión vectorial y endémica. La infección por T. cruzi evoluciona en dos fases: aguda y crónica. El objetivo del tratamiento en la fase aguda es reducir la parasitemia. Durante la fase crónica, la infección es detectable por métodos serológicos y moleculares. El 30% de las fases crónicas evolucionan a patología demostrable. La eficacia de los tripanocidas para la fase crónica en relación a la patología cardíaca que se desarrolla es controversial, y constituye un punto de incertidumbre en la decisión clínica. El tratamiento tripanocida está constituido por dos drogas: Benznidazol y Nifurtimox. El tratamiento debe prolongarse por 60 días y los efectos adversos son frecuentes, sobre todo con la mayor edad de los pacientes. OBJETIVO: Evaluar eficacia y seguridad de benznidazol en el tratamiento de la miocardiopatía chagásica en pacientes con chagas crónico. METODOLOGÍA: Se formuló una pregunta P.I.C.O. con la siguiente población como foco: pacientes 19- 55 años con chagas crónico (serología positiva) con o sin patología cardíaca demostrada, dado que en la provincia de Mendoza, por su situación epidemiológica respecto a Chagas, se plantea por parte los equipos de salud la necesidad de incorporar el tratamiento médico ya que los pacientes además sufren estigmatización entre otras cosas, por la presencia de la enfermedad. Se realizó una búsqueda electrónica de publicaciones en idiomas inglés y español. Se priorizó en ensayos clínicos randomizados, revisiones sistemáticas, metanálisis y Evaluaciones económicas, Guías de práctica clínica e Informes breves o completos de T.S. El Comité Provincial de Tecnologías Sanitarias (CoPTeS) en reunión plenaria convocó a infectólogos de los hospitales de Mendoza, a fin de presentar los hallazgos y conocer su perspectiva. EL CoPTeS ha considerado que en lo relativo a impacto en la Salud Pública, dado que el perfil epidemiológico de la enfermedad de Chagas a cambiado en Argentina y en Mendoza, con la transmisión congénita como la principal vía de incidencia, sobre la transfusional y la vectorial, la atención de pacientes serológicos positivos en el rango de 19- 50 años, permitiría disminuir la incidencia. CONCLUSIONES: EL CoPTeS sugiere la indicación e incorporación de Benznidazol en el tratamiento de los pacientes con Chagas crónico en la provincia de Mendoza bajo todos los criterios del presente informe: pacientes de 19-55 años de edad con Chagas crónico sin daño cardíaco específico determinado por prueba de laboratorio (ELISA ó IFI ) y que hayan recibido de su médico tratante adecuada información sobre los efectos y riesgos del tratamiento, mediante: establecimiento de un proceso de decisiones compartidas acerca del tratamiento y sus efectos (documentando en historia clínica), acuerden un seguimiento estricto del paciente durante el tratamiento (semanal), suscriban y reciban una Hoja de información al paciente y Formulario de Consentimiento Informado; pacientes mujeres en edad fértil no embarazadas, que se encuentren en fase crónica de la infección, conformar además un Registro Provincial de los pacientes en sistema adecuado a tal fin (electrónico), especificando respuesta al tratamiento y variables de seguridad y eficacia.(AU)

Longitudinal follow up of serological response in children treated for Chagas disease.

BACKGROUND: Evaluation of therapeutic response in chronic Chagas disease is a major challenge, due to prolonged persistence of Trypanosoma cruzi-specific antibodies, lack of sensitivity of parasitological tests, and need for long-term follow-up to observe negative seroconversion of conventional serological tests (CS). The objective of this study was to evaluate F2/3-ELISA serology, a promising early biomarker of therapeutic response, and T.cruzi Polymerase chain reaction (PCR) for T. cruzi Deoxyribonucleic acid (DNA), for neonatal diagnosis and evaluation of parasitemia after treatment. METHODS: Prospective cohort study, with three-year clinical, serological and parasitological follow-up of pediatric Chagas disease patients treated with benznidazole. Serology was evaluated by Enzyme-Linked ImmunoSorbent Assay (ELISA), Indirect hemagglutination (IHA) and F2/3-ELISA; Parasitemia by microhematocrit (MH) and PCR. RESULTS: A cohort of 107 pediatric patients treated with benznidazole was enrolled in the study. ELISA and IHA were initially reactive in 100% of patients, F2/3-ELISA serology was reactive in 80% (86/107) and 91% (97/107) had detectable parasitemia. Seventy-six (71%) patients completed at least 36 months of serological follow up after treatment. Although a similar decreasing linear trend was observed for all serological tests, F2/3-ELISA presented earlier, age dependent, negative seroconversion compared to CS. All patients reaching undetectable CS titers had previously seroreverted by F2/3-ELISA. All patients with persistently decreasing antibody titers had negative PCRs throughout the follow up period. No new cardiological lesions were observed during the 3 years follow-up period. CONCLUSIONS: The data reported here, using CS, F2/3 ELISA and PCR provide support for the efficacy of benznidazole in congenital Chagas diseases. These results provide support for scaling up of screening, diagnosis and access to benznidazole treatment. TRIAL REGISTRATION: ClinicalTrials.gov 0028/04 in the Research Council, Secretary of Health Buenos Aires city Goberment.

Nifurtimox versus benznidazole or placebo for asymptomatic Trypanosoma cruzi infection (Equivalence of Usual Interventions for Trypanosomiasis - EQUITY): study protocol for a randomised controlled trial.

BACKGROUND: Either benznidazole (BZN) or nifurtimox (NFX) is recommended as equivalent to treat Trypanosoma cruzi infection. Nonetheless, supportive data from randomised trials is limited to individuals treated with BZN in southern cone countries of Latin America. METHODS: The goal of this randomised, concealed, blind, parallel-group trial is to inform the trypanocidal efficacy and safety of NFX and its equivalence to BZN among individuals with T. cruzi positive serology (TC+). Eligible individuals are TC+, 20-65 years old, with no apparent symptoms/signs or uncontrolled risk factors for cardiomyopathy and at negligible risk of re-infection. Consenting individuals (adherent to a 10-day placebo run-in phase) receive a 120-day BID blinded treatment with NFX, BZN or matching placebo (2:2:1 ratio). The four active medication arms include (1) a randomly allocated sequence of 60-day, conventional-dose (60CD) regimes (BZN 300 mg/day or NFX 480 mg/day, ratio 1:1), followed or preceded by a 60-day placebo treatment, or (2) 120-day half-dose (120HD) regimes (BZN 150 mg/day or NFX 240 mg/day, ratio 1:1). The primary efficacy outcome is the proportion of participants testing positive at least once for up to three polymerase chain reaction (PCR) assays (1 + PCR) 12-18 months after randomisation. A composite safety outcome includes moderate to severe adverse reactions, consistent blood marker abnormalities or treatment abandons. The trial outside Colombia (expected to recruit at least 60% of participants) is pragmatic; it may be open-label and not include all treatment groups, but it must adhere to the randomisation and data administration system and guarantee a blinded efficacy outcome evaluation. Our main comparisons include NFX groups with placebo (for superiority), NFX versus BZN groups and 60CD versus 120HD groups (for non-inferiority) and testing for the agent-dose and group-region interactions. Assuming a 1 + PCR ≥ 75% in the placebo group, up to 25% among BZN-treated and an absolute difference of up to ≥ 25% with NFX to claim its trypanocidal effect, 60-80 participants per group (at least 300 from Colombia) are needed to test our hypotheses (80-90% power; one-sided alpha level 1%). DISCUSSION: The EQUITY trial will inform the trypanocidal effect and equivalence of nitroderivative agents NFX and BZN, particularly outside southern cone countries. Its results may challenge current recommendations and inform choices for these agents. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02369978 . Registered on 24 February 2015.

Economic value of a therapeutic Chagas vaccine for indeterminate and Chagasic cardiomyopathy patients.

BACKGROUND: Therapeutic vaccines to prevent Chagas disease progression to cardiomyopathy are under development because the only available medications (benznidazole and nifurtimox) are limited by their efficacy, long treatment course, and side effects. Better understanding the potential clinical and economic value of such vaccines can help guide development and implementation. METHODS: We developed a computational Chagas Markov model to evaluate the clinical and economic value of a therapeutic vaccine given in conjunction with benznidazole in indeterminate and chronic Chagas patients. Scenarios explored the vaccine's impact on reducing drug treatment dosage, duration, and adverse events, and risk of disease progression. RESULTS: When administering standard-of-care benznidazole to 1000 indeterminate patients, 148 discontinued treatment and 219 progressed to chronic disease, resulting in 119 Chagas-related deaths and 2293 DALYs, costing $18.9 million in lifetime societal costs. Compared to benznidazole-only, therapeutic vaccination administered with benznidazole (25-75% reduction in standard dose and duration), resulted in 37-111 more patients (of 1000) completing treatment, preventing 11-219 patients from progressing, 6-120 deaths, and 108-2229 DALYs (5-100% progression risk reduction), saving ≤$16,171 per patient. When vaccinating determinate Kuschnir class 1 Chagas patients, 10-197 fewer patients further progressed compared to benznidazole-only, averting 11-228 deaths and 144-3037 DALYs (5-100% progression risk reduction), saving ≤$34,059 per person. When vaccinating Kuschnir class 2 patients, 13-279 fewer progressed (279 with benznidazole-only), averting 13-692 deaths and 283-10,785 DALYs (5-100% progression risk reduction), saving ≤$89,759. Therapeutic vaccination was dominant (saved costs and provided health benefits) with ≥ 5% progression risk reduction, except when only reducing drug treatment regimen and adverse events, but remained cost-effective when costing <$200. CONCLUSIONS: Our study helps outline the thresholds at which a therapeutic Chagas vaccine may be cost-effective (e.g., <5% reduction in preventing cardiac progression, 25% reduction in benznidazole treatment doses and duration) and cost-saving (e.g., ≥5% and 25%, respectively).

Cost-effectiveness of bedaquiline or delamanid plus background regimen for multidrug-resistant tuberculosis in a high-income intermediate burden city of China.

OBJECTIVE: Hong Kong is a high-income city of China with an intermediate tuberculosis (TB) burden, and 1% of TB cases are multidrug-resistant (MDR-TB). The aim of this study was to examine the potential cost-effectiveness of adding bedaquiline or delamanid to the background regimen (BR) for the treatment of MDR-TB in Hong Kong. METHODS: A decision-analytic model was designed to simulate outcomes over a 10-year time horizon for MDR-TB patients treated with bedaquiline plus BR (B-BR), delamanid plus BR (D-BR), or BR alone. Outcome measures included direct medical costs and quality-adjusted life-years (QALYs) gained. RESULTS: In the base-case analysis, BR was the least costly regimen (USD 47396) with the lowest QALYs gained (6.347). Compared to BR, B-BR gained an additional 0.731 QALYs with incremental cost of USD 9. The incremental cost-effectiveness ratio (ICER) of B-BR was USD 12/QALY. D-BR was more costly than BR by USD 20 164 and gained an additional 0.012 QALYs. The ICER of D-BR was USD 1 680333/QALY. In the probabilistic sensitivity analysis with 10000 Monte Carlo simulations, B-BR and D-BR were cost-effective 99.98% and 5.13% of the time, respectively, using 1× gross domestic product per capita (USD 46 182) as the willingness-to-pay threshold. CONCLUSIONS: Bedaquiline is more likely than delamanid to be cost-effective when added to BR for the treatment of MDR-TB in Hong Kong.

Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients.

Pretomanid is a nitroimidazole antibiotic in late-phase clinical testing as a component of several novel antituberculosis (anti-TB) regimens. A population pharmacokinetic model for pretomanid was constructed using a Bayesian analysis of data from two phase 2 studies, PA-824-CL-007 and PA-824-CL-010, conducted with adult (median age, 27 years) patients in Cape Town, South Africa, with newly diagnosed pulmonary TB. Combined, these studies included 63 males and 59 females administered once-daily oral pretomanid doses of 50, 100, 150, 200, 600, 1,000, or 1,200 mg for 14 days. The observed pretomanid plasma concentration-time profiles for all tested doses were described by a one-compartment model with first-order absorption and elimination and a sigmoidal bioavailability dependent on dose, time, and the predose fed state. Allometric scaling with body weight (normalized to 70 kg) was used for volume of distribution and clearance, with the scaling exponents equal to 1 and 3/4, respectively. The posterior population geometric means for the clearance and volume of distribution allometric constants were 4.8 ± 0.2 liters/h and 130 ± 5 liters, respectively, and the posterior population geometric mean for the half-maximum-effect dose for the reduction of bioavailability was 450 ± 50 mg. Interindividual variability, described by the percent coefficient of variation, was 32% ± 3% for clearance, 17% ± 4% for the volume of distribution, and 74% ± 9% for the half-maximum-effect dose. This model provides a dose-exposure relationship for pretomanid in adult TB patients with potential applications to dose selection in individuals and to further clinical testing of novel pretomanid-containing anti-TB regimens.

Therapeutic drug monitoring of benznidazole and nifurtimox: a systematic review and quality assessment of published clinical practice guidelines

Abstract The pharmacological management of adults with chronic-phase Chagas disease is challenging despite it being the recent focus of extensive research. One of the challenges in the current clinical practice guidelines (CPGs) landscape is the existence of non-evidence-based recommendations for the use of laboratory tests in treatment monitoring. This study aimed to systematically assess the quality and consistency of recommendations of CPGs on the pharmacological management of adults with chronic-phase Chagas disease. Systematic literature searches were conducted in MEDLINE, EMBASE, SciELO and Google to identify all published CPGs relevant to the pharmacological management of Chagas disease, between January 2010 and March 2016. Three independent reviewers assessed the quality of each CPG using the Appraisal of Guidelines Research and Evaluation (AGREE) II instrument. A total of five CPGs were included and the overall quality of the guidelines for therapeutic drug monitoring of Chagas disease was moderate-to-low. There was considerable variation in the quality of the CPGs across the AGREE II domains. The domains of scope/purpose, stakeholder involvement, and clarity of presentation were rated well, and the domains of applicability and editorial independence received poor ratings. This review showed that the methodological quality of CPGs for Chagas disease was generally inappropriate, and there was no explicit link between the best available evidence and current recommendations.