Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis.

BACKGROUND: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes. METHODS: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression. RESULTS: Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events. CONCLUSIONS: Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation.

Annual Tuberculosis Preventive Therapy for Persons With HIV Infection : A Randomized Trial.

BACKGROUND: Tuberculosis preventive therapy for persons with HIV infection is effective, but its durability is uncertain. OBJECTIVE: To compare treatment completion rates of weekly isoniazid-rifapentine for 3 months versus daily isoniazid for 6 months as well as the effectiveness of the 3-month rifapentine-isoniazid regimen given annually for 2 years versus once. DESIGN: Randomized trial. (ClinicalTrials.gov: NCT02980016). SETTING: South Africa, Ethiopia, and Mozambique. PARTICIPANTS: Persons with HIV infection who were receiving antiretroviral therapy, were aged 2 years or older, and did not have active tuberculosis. INTERVENTION: Participants were randomly assigned to receive weekly rifapentine-isoniazid for 3 months, given either annually for 2 years or once, or daily isoniazid for 6 months. Participants were screened for tuberculosis symptoms at months 0 to 3 and 12 of each study year and at months 12 and 24 using chest radiography and sputum culture. MEASUREMENTS: Treatment completion was assessed using pill counts. Tuberculosis incidence was measured over 24 months. RESULTS: Between November 2016 and November 2017, 4027 participants were enrolled; 4014 were included in the analyses (median age, 41 years; 69.5% women; all using antiretroviral therapy). Treatment completion in the first year for the combined rifapentine-isoniazid groups (n = 3610) was 90.4% versus 50.5% for the isoniazid group (n = 404) (risk ratio, 1.78 [95% CI, 1.61 to 1.95]). Tuberculosis incidence among participants receiving the rifapentine-isoniazid regimen twice (n = 1808) or once (n = 1802) was similar (hazard ratio, 0.96 [CI, 0.61 to 1.50]). LIMITATION: If rifapentine-isoniazid is effective in curing subclinical tuberculosis, then the intensive tuberculosis screening at month 12 may have reduced its effectiveness. CONCLUSION: Treatment completion was higher with rifapentine-isoniazid for 3 months compared with isoniazid for 6 months. In settings with high tuberculosis transmission, a second round of preventive therapy did not provide additional benefit to persons receiving antiretroviral therapy. PRIMARY FUNDING SOURCE: The U.S. Agency for International Development through the CHALLENGE TB grant to the KNCV Tuberculosis Foundation.

Post-trial perceptions of a symptom-based TB screening intervention in South Africa: implementation insights and future directions for TB preventive healthcare services.

BACKGROUND: Tuberculosis is a top-10 cause of under-5 mortality, despite policies promoting tuberculosis preventive therapy (TPT). We previously conducted a cluster randomized trial to evaluate the effectiveness of symptom-based versus tuberculin skin-based screening on child TPT uptake. Symptom-based screening did not improve TPT uptake and nearly two-thirds of child contacts were not identified or not linked to care. Here we qualitatively explored healthcare provider perceptions of factors that impacted TPT uptake among child contacts. METHODS: Sixteen in-depth interviews were conducted with key informants including healthcare providers and administrators who participated in the trial in Matlosana, South Africa. The participants' experience with symptom-based screening, study implementation strategies, and ongoing challenges with child contact identification and linkage to care were explored. Interviews were systematically coded and thematic content analysis was conducted. RESULTS: Participants' had mixed opinions about symptom-based screening and high acceptability of the study implementation strategies. A key barrier to optimizing child contact screening and evaluation was the supervision and training of community health workers. CONCLUSIONS: Symptom screening is a simple and effective strategy to evaluate child contacts, but additional pediatric training is needed to provide comfort with decision making. New clinic-based child contact files were highly valued by providers who continued to use them after trial completion. Future interventions to improve child contact management will need to address how to best utilize community health workers in identifying and linking child contacts to care. TRIAL REGISTRATION: The results presented here were from research related to NCT03074799 , retrospectively registered on 9 March 2017.

Addressing critical needs in the fight to end tuberculosis with innovative tools and strategies.

This month in PLOS Medicine we launched a Special Issue on New Tools and Strategies for Tuberculosis Diagnosis, Care, and Elimination. In this issue's Editorial, the Guest Editors Claudia Denkinger, Richard Chaisson, and Mark Hatherill highlight some of the research that will publish and how these studies focusing on discovery, clinical trials and implementation research collectively add to the prospects for reaching the EndTB targets of the WHO by 2035.

Seventy Years of Tuberculosis Prevention: Efficacy, Effectiveness, Toxicity, Durability, and Duration.

Tuberculosis (TB) has been a leading infectious cause of death worldwide for much of human history, with 1.6 million deaths estimated in 2017. The Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health has played an important role in understanding and responding to TB, and it has made particularly substantial contributions to prevention of TB with chemoprophylaxis. TB preventive therapy is highly efficacious in the prevention of TB disease, yet it remains underutilized by TB programs worldwide despite strong evidence to support its use in high-risk groups, such as people living with HIV and household contacts, including those under 5 years of age. We review the evidence for TB preventive therapy and discuss the future of TB prevention.

Controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection.

The billions of people with latent tuberculosis infection serve as the seedbeds for future cases of active tuberculosis. Virtually all episodes of tuberculosis disease are preceded by a period of asymptomatic Mycobacterium tuberculosis infection; therefore, identifying infected individuals most likely to progress to disease and treating such subclinical infections to prevent future disease provides a crucial opportunity to interrupt tuberculosis transmission and reduce the global burden of tuberculosis disease. Programmes focusing on single strategies rather than comprehensive programmes that deliver an integrated arsenal for tuberculosis control might continue to struggle. Tuberculosis preventive therapy is a poorly used method that is essential for controlling the reservoirs of disease that drive the epidemic. Comprehensive control strategies that combine preventive therapy for the most high-risk populations and communities with improved case-finding and treatment, control of transmission, and health systems strengthening could ultimately lead to worldwide tuberculosis elimination. In this Series paper we outline challenges to implementation of preventive therapy and provide pragmatic suggestions for overcoming them. We further advocate for tuberculosis preventive therapy as the core of a renewed worldwide focus to implement a comprehensive epidemic control strategy that would reduce new tuberculosis cases to elimination targets. This strategy would be underpinned by accelerated research to further understand the biology of subclinical tuberculosis infections, develop novel diagnostics and drug regimens specifically for subclinical tuberculosis infection, strengthen health systems and community engagement, and enhance sustainable large scale implementation of preventive therapy programmes.

Pregnancy in Women With HIV in a Tuberculosis Preventive Therapy Trial.

BACKGROUND: Tuberculosis preventive therapy (TPT) is recommended for people with HIV infection, including during pregnancy. The effect of TPT exposure at conception and during pregnancy is poorly documented. METHODS: We report pregnancy outcomes among South African women with HIV enrolled in a randomized trial of 4 TPT regimens (two 3-month regimens, rifapentine/isoniazid [3HP] or rifampin/isoniazid [3HR], isoniazid for 6 months, or isoniazid continuously). Descriptive statistics and risk ratios were assessed to examine relationships between study regimens and outcomes. RESULTS: 216/896 women (24%) conceived during the study. Women who conceived were younger (27.9 vs 31.3 years) and had higher mean CD4 counts (589.1 vs 536.7). The odds of pregnancy were higher in women in the rifamycin-isoniazid arms than those in the isoniazid arms (3HP: relative risk [RR] 1.73, P = 0.001; 3HR:RR 1.55, P = 0.017) despite increased contraceptive use compared with the standard 6H therapy. Thirty-four women became pregnant while taking preventive treatment (8 rifamycin and 26 isoniazid monotherapy). Pregnancy outcomes in these women were as follows: 17 (50%) mother/baby healthy, 3 (9%) spontaneous abortions, 6 (18%) elective abortions, 1 (3%) premature delivery, 2 (6%) neonatal deaths [1 rifamycin-isoniazid and 1 isoniazid], and 5 (15%) unknown. CONCLUSIONS: Pregnancy was common in women who had received TPT and more frequent in women who had received rifamycin-isoniazid-based regimens.

The Mid-Atlantic Centers for AIDS Research Consortium: Promoting HIV Science Through Regional Collaboration.

The Centers for AIDS Research (CFAR) program was established by the National Institutes of Health in 1988 to catalyze and support high-impact HIV research and to develop the next generation of HIV investigators at academic institutions throughout the United States. In 2014, the Penn CFAR, the Johns Hopkins University CFAR and the District of Columbia CFAR developed a partnership-the Mid-Atlantic CFAR Consortium (MACC)-to promote cross-CFAR scientific collaboration, mentoring, and communication and to address the regional HIV epidemic. Over the past 6 years, the creation of the MACC has resulted in a rich web of interconnectivity, which has fostered scientific collaboration through working groups on the black men who have sex with men (MSM) and Latinx regional HIV epidemics, joint peer-reviewed publications, and successful collaborative grant applications on topics ranging from HIV prevention in young MSM, transgender women, implementation science, and clinical epidemiology; supported developmental activities through the MACC Scholars program, cross-CFAR mentoring, joint symposia, cross-CFAR seminar participation, and keynote speakers; and promoted strategic communication through advisory committees, best practices consultations, and the social and behavioral science research network. The MACC has been highly impactful by promoting HIV science through regional collaboration, supporting a diverse network of scholars across three cities and focusing on the epidemic in underrepresented and marginalized communities. Lessons learned from this consortium may have implications for scientific research centers beyond the field of HIV.

Impact of isoniazid preventive therapy for HIV-infected adults in Rio de Janeiro, Brazil: an epidemiological model.

BACKGROUND: The potential epidemiological impact of isoniazid preventive therapy (IPT), delivered at levels that could be feasibly scaled up among people living with HIV (PLHIV) in modern, moderate-burden settings, remains uncertain. METHODS: We used routine surveillance and implementation data from a cluster-randomized trial of IPT among HIV-infected clinic patients with good access to antiretroviral therapy in Rio de Janeiro, Brazil, to populate a parsimonious transmission model of tuberculosis (TB)/HIV. We modeled IPT delivery as a constant process capturing a proportion of the eligible population every year. We projected feasible reductions in TB incidence and mortality in the general population and among PLHIV specifically at the end of 5 years after implementing an IPT program. RESULTS: Data on time to IPT fit an exponential curve well, suggesting that IPT was delivered at a rate covering 20% (95% confidence interval: 16% to 24%) of the 2500 eligible individuals each year. By the end of year 5 after modeled program rollout, IPT had reduced TB incidence by 3.0% [95% uncertainty range (UR): 1.6% to 7.2%] in the general population and by 15.6% (95% UR: 15.5% to 36.5%) among PLHIV. Corresponding reductions in TB mortality were 4.0% (95% UR: 2.2% to 10.3%) and 14.3% (14.6% to 33.7%). Results were robust to wide variations in parameter values on sensitivity analysis. CONCLUSIONS: TB screening and IPT delivery can substantially reduce TB incidence and mortality among PLHIV in urban, moderate-burden settings. In such settings, IPT can be an important component of a multi-faceted strategy to feasibly reduce the burden of TB in PLHIV.

Human immunodeficiency virus-associated tuberculosis: update on prevention and treatment.

Tuberculosis (TB) is the leading cause of opportunistic infection and mortality among HIV-infected persons. Screening for symptoms of TB in people with HIV infection, use of isoniazid preventive therapy for those with latent TB infection, earlier diagnosis and treatment of active TB disease, and early initiation of antiretroviral therapy are essential for controlling the spread of TB. Treatment of HIV-related TB is complicated by overlapping drug toxicities and drug-drug interactions between antiretroviral therapy and anti-TB therapy and risk for development of immune reconstitution inflammatory disease. This review provides an overview of the prevention and treatment of TB in HIV-infected persons.

A cluster-randomized trial of provider-initiated (opt-out) HIV counseling and testing of tuberculosis patients in South Africa.

OBJECTIVE: To determine whether implementation of provider-initiated human immunodeficiency virus (HIV) counseling would increase the proportion of tuberculosis (TB) patients who received HIV counseling and testing. DESIGN: Cluster-randomized trial with clinic as the unit of randomization. SETTING: Twenty, medium-sized primary care TB clinics in the Nelson Mandela Metropolitan Municipality, Port Elizabeth, Eastern Cape Province, South Africa. SUBJECTS: A total of 754 adults (18 years and older) newly registered as TB patients in the 20 study clinics. INTERVENTION: Implementation of provider-initiated HIV counseling and testing. MAIN OUTCOME MEASURES: Percentage of TB patients HIV counseled and tested. SECONDARY: Percentage of patients with HIV test positive, and percentage of those who received cotrimoxazole and who were referred for HIV care. RESULTS: : A total of 754 adults newly registered as TB patients were enrolled. In clinics randomly assigned to implement provider-initiated HIV counseling and testing, 20.7% (73/352) patients were counseled versus 7.7% (31/402) in the control clinics (P = 0.011), and 20.2% (n = 71) versus 6.5% (n = 26) underwent HIV testing (P = 0.009). Of those patients counseled, 97% in the intervention clinics accepted testing versus 79% in control clinics (P = 0.12). The proportion of patients identified as HIV infected in intervention clinics was 8.5% versus 2.5% in control clinics (P = 0.044). Fewer than 40% of patients with a positive HIV test were prescribed cotrimoxazole or referred for HIV care in either study arm. CONCLUSIONS: Provider-initiated HIV counseling significantly increased the proportion of adult TB patients who received HIV counseling and testing, but the magnitude of the effect was small. Additional interventions to optimize HIV testing for TB patients urgently need to be evaluated.

A implantação da estratégia DOTS na cidade do Rio de Janeiro / Implementation of the DOTS strategy in the city of Rio de Janeiro

Introdução: o objetivo deste estudo foi descrever a implementação da estratégia DOTS (Estratégia de Tratamento Diretamente Observado de Curta duração) nos centros de saúde na cidade do Rio de Janeiro, apresentando os resultados obtidos após dois anos de desenvolvimento de projetos-piloto. Métodos: análise dos dados contidos nos "Livros de Registro e Controle do Tratamento", regularmente notificados à Secretaria Municipal de Saúde do Rio de Janeiro, visando avaliar o impacto do tratamento diretamente observado (DOT) nos índices de cura e o efeito da implementação da estratégia DOTS na qualidade do programa de controle da tuberculose (PCT). Resultados: De Janeiro de 1999 a Dezembro de 2001, 3657 casos de TB foram registrados nas áreas onde a estratégia DOTS foi implantada. Destes, 1730 receberam DOT e 1927 receberam tratamento auto-administrado (TAA). Entre os caos novos, 81% dos que receberam DOT e 71% dos que receberam TAA foram tratados com sucesso (OR 1,66, IC 95%: 1,3 -1,8), p<0,01. As taxas de negativação da baciloscopia do escarro após 2 e 3 meses de tratamento foram de 84% e 91% respectivamente para aqueles que receberam DOT e 75% e 83% para o grupo em TAA. Nos centros de saúde onde a estratégia DOTS foi implantada houve, em 3 anos, melhora geral dos índices de cura e de abandono, assim como dos percentuais de baciloscopias realizadas para acompanhamento do tratamento. Conclusão: Pacientes que receberam DOTS tiveram maior chance de cura do que aqueles que receberam TAA. A implantação da estratégia DOTS melhorou a qualidade do PCT.

Introduction: The objective of this study is to describe the implementation of DOTS (Directly Observed Treatment, Short course) strategy in health centers in the city of the Rio de Janeiro presenting the results 2 years after teh development of pilot projects. Methods: analysis of data recorded on the "TB treatment and outcome registration books", regularly reported to the City Health Secretariat, to evaluate the results of the directly observed therapy (DOT) on the treatment success rates and the effect of DOTS implementation on the equality of the TB control program. Results: From January 1999 to December 2001, 3,657 TB cases were registered in the areas where the DOTS strategy was implemented. Of these, 1,730 received directly observed treatment (DOT) and 1,927 received self-administered treatment (SAT). In the DOT group 81% of the new cases were treated successfully, whereas in the SAT 71% of the new cases were treated successfully (OR1,66, 95% CI:1,3 -1,8, p <0,01). The sputum smear conversion rates for the new cases after 2 and 3 months' treatment were respectively 84% and 91% for the group on DOT and 75% and 83% for those on SAT. In the health centers where the DOTS strategy was implemented there was a general improvement on the cure and default rates, and also on the proportion of patients monitored bacteriologically during treatment. Conclusion: patients receiving DOT were much more likely to complete treatment than those receiving SAT. The implementation of the DOTS strategy improved the quality of the TB control program.

Servicio de orientación y detección de HIV vinculado a un programa comunitário antituberculoso en una población de alto riesgo / Wide-spread HIV counseling and testing linked to a community-based tuberculosis control program in a high-risk population

La finalidad del trabajo que aquí se describe fue evaluar el tamizaje comunitario para la detección de casos de infección por VIH vinculado a un programa de lucha antituberculosa en una población en alto riesgo de ambas infecciones. De mayo de 1990 a agosto de 1992, trabajadores de salud comunitarios se comunicaron con adultos en domicilios y dispensarios de Cité Soleil, Haití, para ofrecerles servicios institucionales de asesoramiento individual y de detección de VIH y de tuberculosis. A todas las personas que aceptaron la prueba se les dio asesoramiento posterior sobre VIH. Las que tenían tuberculosis activa recibieron tratamiento y a las que tenían enfermedad latente más infección por VHI se les dio la oportunidad de participar en un ensayo clínico sobre quimioprofilaxis antituberculosa. Las personas sometidas al tamizaje para la deteccíon de VIH, que fueron 10 611, constituyeron 10,0(por cento) de la poblacíon adulta de Cité Soleil. Se encontró infección por VIH en 1629 (15,4 por cento) de ellas y tuberculosis activa en 242 (2,3 por cento). Infección latente por Mycobacterium tuberculosis fue detectada en 4800 (65,7 por cento) de los 7309 habitantes de la comunidad que fueron sometidos al tamizaje completo para la detección de tuberculosis, y de esos 4800,781 (16,3 por cento) también estaban infectados por VIH. La elevada prevalencia de infección por VIH en la población examinada, al comparársela con la de otros grupos sometidos a tamizaje en la misma comunidad, indica que las personas en alto riego de infección por VIH buscaron selectivamente o aceptaron someterse a las pruebas de tamizaje ofrecidas en los dispensarios de tuberculosis. Asimismo, a muchas personas se les diagnosticó tuberculosis activa en una fase más temprana de la enfermidad de lo que hubiera sido posible sin un programa de tamizaje. En general, los resultados indican que cuando el tamizaje comunitario para la detección de VIH es parte de un programa de lucha antituberculosa, el resultado puede ser una mejor focalización de destinatarios para las pruebas de detección de ambas infecciones