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Introduction: Tuberculosis (TB) is a leading cause of mortality among people living with HIV (PLHIV). An invigorated global END TB Strategy seeks to increase efforts in scaling up TB preventive therapy (TPT) as a central intervention for HIV programmes in an effort to contribute to a 90% reduction in TB incidence and 95% reduction in mortality by 2035. TPT in PLHIV should be part of a comprehensive approach to reduce TB transmission, illness and death that also includes TB active case-finding and prompt, effective and timely initiation of anti-TB therapy among PLHIV However, the use and implementation of preventive strategies has remained deplorably inadequate and today TB prevention among PLHIV has become an urgent priority globally. Discussion: We present a summary of the current and novel TPT regimens, including current evidence of use with antiretroviral regimens (ART). We review challenges and opportunities to scale-up TB prevention within HIV programmes, including the use of differentiated care approaches and demand creation for effective TB/HIV services delivery. TB preventive vaccines and diagnostics, including optimal algorithms, while important topics, are outside of the focus of this commentary. Conclusions: A number of new tools and strategies to make TPT a standard of care in HIV programmes have become available. The new TPT regimens are safe and effective and can be used with current ART, with attention being paid to potentia drug-drug interactions between rifamycins and some classes of antiretrovirals. More research and development is needed to optimize TPT for small children, pregnant women and drug-resistant TB (DR-TB). Effective programmatic scale-up can be supported through context-adapted demand creation strategies and the inclusion of TPT in client-centred services, such as differentiated service delivery (DSD) models. Robust collaboration between the HIV and TB programmes represents a unique opportunity to ensure that TB, a preventable and curable condition, is no longer the number one cause of death in PLHIV. Keywords: TB; HIV care continuum; differentiated care; public health; co-infection; treatment, 1 INTRODUCTION Tuberculosis (TB) is a leading cause of mortality among people living with HIV (PLHIV). This population contributes substantially to the global TB burden, with a higher risk of [...]

BackgroundTuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed.MethodsWe randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals.ResultsWe enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4).ConclusionsThe 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).

By comparing younger to older participants enrolled in a HIV vaccine efficacy trial, we aimed to gain insights into the inclusion of adolescents in future trials. This was a sub-analysis of a multisite HIV vaccine randomized clinical trial in South Africa, conducted January-September 2007. Motivations for trial enrolment, social harms, adverse events and loss to follow-up were compared between younger (18-20 years old) and older participants (21-35 years old). Both younger (n = 238) and older participants (n = 563) were equally likely to report enrolling for altruistic reasons. Younger females were less likely than older participants to join for trial reimbursement (p = 0.005), while younger males were more likely to enrol because the vaccine may provide protection from HIV-acquisition (p < 0.001). There were no significant differences in the number of social harms reported. Compared to males over 20 years old, 18-20-year-old females were less likely to experience adverse events (OR = 0.1, CI 0.01-0.80) and no more likely to be lost to follow-up (OR = 0.7, CI 0.39-1.25), while 18-20-year-old males were no more likely to experience adverse events (OR = 1.3, CI 0.58-2.83) or loss to follow-up (OR = 0.8, CI 0.51-1.41). Our data support the inclusion of younger participants who are at risk for HIV in future HIV vaccine efficacy trials.

Author(s): Gavin J. Churchyard 1,2,3,*, Sue Swindells 4 Latent TB infection: Global burden and risk factors for progressing to TB disease The World Health Organization (WHO) estimated that 10 million [...]

Objective To assess the diagnostic value of provider-initiated symptom screening for tuberculosis (TB) and how HIV status affects it. Methods We performed a secondary analysis of randomly selected participants in a community-based TB-HIV prevalence survey in Harare, Zimbabwe. All completed a five-symptom questionnaire and underwent sputum TB culture and HIV testing. We calculated the sensitivity, specificity, and positive and negative predictive values of various symptoms and used regression analysis to investigate the relationship between symptoms and TB disease. Findings We found one or more symptoms of TB in 21.2% of 1858 HIV-positive (HIV+) and 9.9% of 7121 HIV-negative (HIV-) participants (P < 0 .001). TB was subsequently diagnosed in 48 HIV+ and 31 HIV-participants. TB was asymptomatic in 18 culture-positive individuals, 8 of whom (4 in each HIV status group) had positive sputum smears. Cough of any duration, weight loss and, for HIV+ participants only, drenching night sweats were independent predictors of TB. In HIV+ participants, cough of ≥ 2 weeks' duration, any symptom and a positive sputum culture had sensitivities of 48%, 81% and 65%, respectively; in HIV--participants, the sensitivities were 45%, 71% and 74%; respectively. Symptoms had a similar sensitivity and specificity in HIV+ and HIV- participants, but in HIV+ participants they had a higher positive and a lower negative predictive value. Conclusion Even smear-positive TB may be missed by provider-initiated symptom screening, especially in HIV+ individuals. Symptom screening is useful for ruling out TB, but better TB diagnostics are urgently needed for resource-poor settings. Objectif Evaluer la valeur diagnostique de la recherche des symptomes de la tuberculose (TB) a l'initiative du prestateur et comment le statut VIH influe sur cette valeur diagnostique. Methodes Nous avons realise une analyse secondaire sur des participants selectionnes au hasard parmi les sujets d'une enquete en communaute concernant la prevalence de la co-infection TB-VIH, menee a Harare, au Zimbabwe. Tous les participants ont repondu a un questionnaire portant sur cinq symptomes et ont fait l'objet d'une culture d'expectorations pour rechercher la tuberculose et d'un depistage du VIH. Nous avons calcule la sensibilite, la specificite et les valeurs predictives positive et negative des differents symptomes et etudie la relation entre ces symptomes et la tuberculose maladie en utilisant l'analyse par regression. Resultats Nous avons releve un ou plusieurs symptomes de la tuberculose chez 21,2 % des 1858 participants positifs pour le VIH (VIH+) et chez 9,9 % des 7121 participants negatifs pour ce virus (p < 0,001). La tuberculose a ensuite ete diagnostiquee chez 48 sujets VIH+ et chez 31 sujets VIH-. Cette maladie etait presente de maniere asymptomatique chez 18 individus positifs a la culture, dont 8 (4 pour chacun des statuts VIH) donnaient ales frottis d'expectorations positifs. La toux, quelle que soit sa duree, la perte de poids et pour les participants VIH+ uniquement, la sudation nocturne, constituaient des facteurs predictifs independants de la tuberculose. Chez les participants VIH+, la presence de toux pendant 2 semaines ou plus, chacun des symptomes et l'obtention d'une culture d'expectorations positive presentaient respectivement une sensibilite de 48, 81 et 65 %. Chez les participants VIH-, les sensibilites correspondantes valaient respectivement 45, 71 et 74 %. Les symptomes fournissaient donc une sensibilite et une specificite similaires chez les deux types de participants, mais chez les sujets VIH+, ils avaient une valeur predictive positive plus elevee et une valeur predictive negative plus faible. Conclusion La recherche des symptomes a l'initiative du prestateur peut laisser passer meme ales cas de tuberculose frottis positifs, en particulier chez les individus seropositifs pour le VIH. Le depistage sur la base des symptomes est utile pour exclure la tuberculose, mais les pays demunis ont besoin d'urgence d'un meilleur outil pour diagnostiquer cette maladie. Objetivo Determinar el valor diagnostico del cribado de sintomas de tuberculosis a instancias del profesional, asi como la influencia de la serologia VIH en dicho cribado. Metodos Realizamos un analisis secundario a partir de participantes seleccionados aleatoriamente en una encuesta comunitaria de prevalencia de la coinfeccion tuberculosis-VIH realizada en Harare, Zimbabwe. Todos ellos respondieron a un cuestionario sobre cinco sintomas y se sometieron a pruebas del VIH y de cultivo de esputo para la tuberculosis. Calculamos la sensibilidad, la especificidad y los valores predictivos positivo y negativo de Ios diversos sintomas y realizamos un analisis de regresion para investigar la relacion entre Ios sintomas y la tuberculosis. Resultados Detectamos uno o mas sintomas de tuberculosis en el 21,2% de 1858 pacientes VIH-positivos (VIH+) y el 9,9% de 7121 participantes VIH-negativos (VIH-) (p < 0,001). Posteriormente se diagnostico tuberculosis en 48 participantes VIH+ y 31 participantes VIH-. Sufrian tuberculosis asintomatica 18 personas con cultivo positivo, 8 de las cuales (4 en cada grupo serologico) presentaron esputo positivo. La tos de cualquier duracion, la perdida de peso y, solo en el caso de Ios participantes VIH+, la presencia de sudores nocturnos, fueron factores predictivos independientes de la tuberculosis. En las personas VIH+, la tos de mas de 2 semanas de duracion, la presencia de cualquiera de los sintomas y un cultivo de esputo positivo tuvieron una sensibilidad del 48%, 81% y 65%, respectivamente; entre los participantes VIH-, la sensibilidad fue del 45%, 71% y 74%, respectivamente. Los sintomas presentaron una sensibilidad y especificidad similares en Ios pacientes VIH+ y VIH-, pero en los primeros tenian un mayor valor predictivo positivo y un menor valor predictivo negativo. Conclusion Incluso la tuberculosis con baciloscopia positiva puede pasar desapercibida en el cribado de Ios sintomas realizado a instancias del profesional, especialmente en las personas VIH+. El cribado de los sintomas es util para descartar la tuberculosis, pero se necesitan urgentemente mejores medios de diagnostico de esta enfermedad para Ios entornos con recursos escasos., Introduction Symptom questionnaires provide a quick, cheap and convenient way to identify individuals at a high risk of tuberculosis (TB) disease, termed TB suspects, who then need investigation with more [...]

Background Novel drug regimens are needed for tuberculosis (TB) treatment. New regimens aim to improve on characteristics such as duration, efficacy, and safety profile, but no single regimen is likely to be ideal in all respects. By linking these regimen characteristics to a novel regimen's ability to reduce TB incidence and mortality, we sought to prioritize regimen characteristics from a population-level perspective. Methods and Findings We developed a dynamic transmission model of multi-strain TB epidemics in hypothetical populations reflective of the epidemiological situations in India (primary analysis), South Africa, the Philippines, and Brazil. We modeled the introduction of various novel rifampicin-susceptible (RS) or rifampicin-resistant (RR) TB regimens that differed on six characteristics, identified in consultation with a team of global experts: (1) efficacy, (2) duration, (3) ease of adherence, (4) medical contraindications, (5) barrier to resistance, and (6) baseline prevalence of resistance to the novel regimen. We compared scale-up of these regimens to a baseline reflective of continued standard of care. For our primary analysis situated in India, our model generated baseline TB incidence and mortality of 157 (95% uncertainty range [UR]: 113-187) and 16 (95% UR: 9-23) per 100,000 per year at the time of novel regimen introduction and RR TB incidence and mortality of 6 (95% UR: 4-10) and 0.6 (95% UR: 0.3-1.1) per 100,000 per year. An optimal RS TB regimen was projected to reduce 10-y TB incidence and mortality in the India-like scenario by 12% (95% UR: 6%-20%) and 11% (95% UR: 6%-20%), respectively, compared to current-care projections. An optimal RR TB regimen reduced RR TB incidence by an estimated 32% (95% UR: 18%-46%) and RR TB mortality by 30% (95% UR: 18%-44%). Efficacy was the greatest determinant of impact; compared to a novel regimen meeting all minimal targets only, increasing RS TB treatment efficacy from 94% to 99% reduced TB mortality by 6% (95% UR: 1%-13%, half the impact of a fully optimized regimen), and increasing the efficacy against RR TB from 76% to 94% lowered RR TB mortality by 13% (95% UR: 6%-23%). Reducing treatment duration or improving ease of adherence had smaller but still substantial impact: shortening RS TB treatment duration from 6 to 2 mo lowered TB mortality by 3% (95% UR: 1%-6%), and shortening RR TB treatment from 20 to 6 mo reduced RR TB mortality by 8% (95% UR: 4%-13%), while reducing nonadherence to the corresponding regimens by 50% reduced TB and RR TB mortality by 2% (95% UR: 1%-4%) and 6% (95% UR: 3%-10%), respectively. Limitations include sparse data on key model parameters and necessary simplifications to model structure and outcomes. Conclusions In designing clinical trials of novel TB regimens, investigators should consider that even small changes in treatment efficacy may have considerable impact on TB-related incidence and mortality. Other regimen improvements may still have important benefits for resource allocation and outcomes such as patient quality of life., Author(s): Emily A. Kendall 1,*, Sourya Shrestha 2, Ted Cohen 3, Eric Nuermberger 1, Kelly E. Dooley 1,4, Lice Gonzalez-Angulo 5, Gavin J. Churchyard 6, Payam Nahid 7, Michael L. [...]