Fabio Scano

Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings

The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of antiretroviral therapy (ART) in resource-limited settings, especially in patients with tuberculosis. However, there are no consensus case definitions for IRIS or tuberculosis-associated IRIS. Moreover, previously proposed case definitions are not readily applicable in settings where laboratory resources are limited. As a result, existing studies on tuberculosis-associated IRIS have used a variety of non-standardised general case definitions. To rectify this problem, around 100 researchers, including microbiologists, immunologists, clinicians, epidemiologists, clinical trialists, and public-health specialists from 16 countries met in Kampala, Uganda, in November, 2006. At this meeting, consensus case definitions for paradoxical tuberculosis-associated IRIS, ART-associated tuberculosis, and unmasking tuberculosis-associated IRIS were derived, which can be used in high-income and resource-limited settings. It is envisaged that these definitions could be used by clinicians and researchers in a variety of settings to promote standardisation and comparability of data.

Tuberculosis incidence in prisons: a systematic review.

A systematic review by Iacopo Baussano and colleagues synthesizes published research to show that improved tuberculosis (TB) control in prisons could significantly reduce the burden of TB both inside and outside prisons.

T-cell assays for the diagnosis of latent tuberculosis infection: moving the research agenda forward.

For nearly a century, the tuberculin skin test was the only tool available for the detection of latent tuberculosis infection. A recent breakthrough has been the development of T-cell-based interferon-gamma release assays. Current evidence suggests interferon-gamma release assays have higher specificity than the tuberculin skin test, better correlation with surrogate markers of exposure to Mycobacterium tuberculosis in low-incidence settings, and less cross-reactivity as a result of BCG vaccination compared with the tuberculin skin test. The body of literature supporting the use of interferon-gamma release assays has rapidly expanded. However, several unresolved and unexplained issues remain. To address these issues, a group of experts met in Geneva, Switzerland, in March, 2006, to discuss the research evidence on T-cell-based assays, their clinical usefulness, limitations, and directions for future research, with a specific focus on resource-limited and high HIV prevalence settings. On the basis of 2 days of discussions, a comprehensive research agenda was generated, which will propel the field forward by stimulating focused high-impact research and encourage the investment of resources needed to tackle priority research questions, especially in resource-limited settings. Ultimately, if adequately financed, the research findings will inform appropriate use of novel latent tuberculosis infection diagnostics in global tuberculosis control.

Tuberculosis among Health Care Workers

To assess the annual risk for latent tuberculosis infection (LTBI) among health care workers (HCWs), the incidence rate ratio for tuberculosis (TB) among HCWs worldwide, and the population-attributable fraction of TB to exposure of HCWs in their work settings, we reviewed the literature. Stratified pooled estimates for the LTBI rate for countries with low (<50 cases/100,000 population), intermediate (50-100/100,000 population), and high (>100/100,000 population) TB incidence were 3.8% (95% confidence interval [CI] 3.0%-4.6%), 6.9% (95% CI 3.4%-10.3%), and 8.4% (95% CI 2.7%-14.0%), respectively. For TB, estimated incident rate ratios were 2.4 (95% CI 1.2-3.6), 2.4 (95% CI 1.0-3.8), and 3.7 (95% CI 2.9-4.5), respectively. Median estimated population-attributable fraction for TB was as high as 0.4%. HCWs are at higher than average risk for TB. Sound TB infection control measures should be implemented in all health care facilities with patients suspected of having infectious TB.

Towards universal access to HIV prevention, treatment, care, and support: the role of tuberculosis/HIV collaboration

Tuberculosis is the oldest of the worlds current pandemics and causes 8.9 million new cases and 1.7 million deaths annually. The disease is among the most common causes of morbidity and mortality in people living with HIV. However, tuberculosis is more than just part of the global HIV problem; well-resourced tuberculosis programmes are an important part of the solution to scaling-up towards universal access to comprehensive HIV prevention, diagnosis, care, and support. This article reviews the impact of the interactions between tuberculosis and HIV in resource-limited settings; outlines the recommended programmatic and clinical responses to the dual epidemics, highlighting the role of tuberculosis/HIV collaboration in increasing access to prevention, diagnostic, and treatment services; and reviews progress in the global response to the epidemic of HIV-related tuberculosis.

Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: An analytical review

We reviewed 47 prospective studies of recurrence of pulmonary tuberculosis (TB) after cure to assess the influence of human immunodeficiency virus (HIV) infection and rifampin treatment. Multivariate regression revealed that the recurrence rate for HIV-uninfected persons increased with decreasing duration of therapy: it was 1.4 cases per 100 person-years for recipients of >or=7 months of rifampin therapy and 2.0 and 4.0 cases per 100 person-years for recipients of 5-6 and 2-3 months of rifampin therapy, respectively (trend P=.00014), over a mean follow-up duration of 34 months, at a TB incidence of 250 cases per 100,000 person-years. Relative risks of recurrence associated with HIV infection at these 3 treatment durations were 2.2, 2.1, and 3.4, respectively, with a significant interaction between HIV infection status and treatment duration (P=.025). The recurrence rate increased with the background TB incidence (P=.048), and it decreased over time since completion of treatment in HIV-uninfected but not in HIV-infected patients (overall trend, P=.00008; difference by HIV infection status, P=.025). In countries where HIV infection is endemic, TB recurrence may be reduced by administration of rifampin-based treatment for at least 6 months, in accordance with World Health Organization recommendations.

Drug-Resistant Tuberculosis, KwaZulu-Natal, South Africa, 2001–2007

In Africa, incidence and prevalence of drug-resistant tuberculosis have been assumed to be low. However, investigation after a 2005 outbreak of extensively drug-resistant tuberculosis in KwaZulu-Natal Province, South Africa, found that the incidence rate for multidrug-resistant tuberculosis in KwaZulu-Natal was among the highest globally and would be higher if case-finding efforts were intensified.

Global Tuberculosis Control: Toward the 2015 Targets and Beyond

Tuberculosis (TB) remains a major health threat around the world. In 2013, an estimated 11 million prevalent cases (that is, the number of cases in a population at any given time) and 9.0 million incident cases (that is, the number of new cases that occur in a population in 1 year) occurred globally (1). Of the estimated cases, 3.3 million were missed by health systems, either by remaining undiagnosed or by being diagnosed but not reported (1). In the same year, an estimated 480000 new cases of multidrug-resistant (MDR) TB, defined as resistance to both isoniazid and rifampicin, emerged, but only 136000 were diagnosed and notified (1). An estimated 1.1 million incident cases occurred among people living with HIV, 550000 occurred among children, and 3.3 million occurred among women (1). Approximately 1.5 million deaths were caused by TB worldwide, of which 210000 were due to MDR TB and 360000 were among people living with HIV (1). Despite the continued severity of the epidemic, progress has been made in global TB control since 1990: The absolute number of cases globally declined at an average rate of 1.5% per year from 2000 to 2013 and 0.6% between 2012 and 2013 (1, 2). Countries have prioritized TB control by implementing internationally recommended strategies, increasing domestic funding, and incorporating TB into development agendas. Community-based organizations and other local groups have played an increasingly important role in TB care and prevention, aiding in providing comprehensive patient services. In this article, we review the progress toward the 2015 TB global targets since 1990 (Appendix). We detail current challenges to control efforts, including MDR TB and co-infection with HIV and TB, as well as broader socioeconomic issues. Beyond 2015, control strategies should quickly implement technical and operational innovations, as well as promote universal health care to improve access to services and avoid catastrophic expenditures. After 1990: The Road to the 2015 Policies and Targets Since 1990, several key events have shifted global strategies to control TB, and global epidemiology has also changed (Figure 1). In 1991, the World Health Assembly set global targets for 2000 (3), with a model-based goal of reducing prevalence and incidence by 5% to 10% annually (4, 5). Targets were based on the assumption that achieving a 85% cure rate and 70% case detection rate would reduce prevalence of active TB cases, thus leading to reduced transmission and the overall burden of illness and death (6, 7). To further increase international attention and political commitment, the World Health Organization (WHO) declared a global tuberculosis emergency in 1993 (8). The next year, WHO announced a new strategy focused on bacteriologic detection among persons spontaneously presenting with symptoms to health service points and the provision of standardized short-course chemotherapy. In 1995, this strategy was branded as DOTS (directly observed treatment, short-course) (9, 10). After initial positive results from China and elsewhere (11), the strategy was promoted aggressively worldwide, although a lack of funding and political commitment were major barriers for its adoption at the country level. Figure 1. Timeline of key events and epidemiologic shifts (left) and the evolving global strategies to control TB (right). BDQ = bedaquiline; DLM = delamanid; DOTS = directly observed treatment, short-course; EMA = European Medicines Agency; FDA = U.S. Food and Drug Administration; FIND = Foundation for Innovative New Diagnostics; Global Fund = Global Fund to Fight AIDS, Tuberculosis and Malaria; MDG = Millennium Development Goal; MDR = multidrug-resistant; TB = tuberculosis; TB Alliance = Global Alliance for TB Drug Development; UN = United Nations; WHA = World Health Assembly; WHO = World Health Organization. Recognizing the growing number of TB organizations at all levels, as well as its own financial constraints (12), WHO convened an ad hoc committee in London in 1998 (13). The event was a watershed moment toward more collaborative partnerships and coordinated global action. Since then, established health organizations (such as WHO, the International Union Against Tuberculosis and Lung Disease, the U.S. Centers for Disease Control and Prevention, and the KNCV [Koninklijke Nederlandse Chemische Vereniging] Tuberculosis Foundation) were joined by many bilateral organizations, private companies, nongovernment organizations, and newly formed research and funding institutions (including the Bill & Melinda Gates Foundation and the Global Fund to Fight AIDS, Tuberculosis and Malaria [Global Fund]). Formally founded in 2001, the Stop TB Partnership has served as a platform to facilitate collaboration among these organizations. Two important milestones occurred in 2000. In March, a ministerial conference held in Amsterdam sought to expand the global implementation of the DOTS strategy (14), and by year end, 148 countries had committed to scaling up the strategy (9, 15). In September, the United Nations Millennium Summit incorporated TB targets into the Millennium Development Goals, with 2015 set as the target year (16). After waning international interest in the 1970s and 1980s (10), TB moved back onto the global agenda during the 1990s. By the early 2000s, the Millennium Development Goal to halt and reverse the global incidence of TB was achieved. In 2006, the Stop TB Strategy was launched as an enhancement of DOTS, in line with a broader push toward the Millennium Development Goals (17, 18). The strategy explicitly addressed MDR TB and co-infection with HIV and TB while also promoting publicprivate mixed approaches and community engagement. After a 2009 ministerial meeting of the 27 countries with a high burden of MDR and extensively drug-resistant TB, drug resistance became a global priority, as galvanized by a World Health Assembly resolution (19, 20). Substantial gains have been made in TB research and development (21). New molecular diagnostics, such as the Xpert MTB/RIF (Cepheid) or GenoType MTBDRplus assay (Hain Lifescience), have been introduced, and existing funding mechanisms, such as the Global Fund and UNITAID, have allowed for the deployment of new diagnostics in complex, low-resource settings (22). Two new medicines, bedaquiline and delamanid, have gained conditional approval for use in MDR TB cases, and 16 new vaccine candidates are at various stages of clinical trials (2327). Global TB prevalence, incidence, and mortality rates have been declining since the early 2000s (Figure 2). New treatment options have been explored, with varying success (28, 29). Moving forward, control strategies must address social and economic determinants of disease, be integrated into development agendas, and promote universal health coverage as a means to mitigate barriers to accessing services (30). In 2014, the 67th World Health Assembly approved the WHO End TB Strategy, 20162035, which encapsulates broader approaches toward ending the TB epidemic as a major challenge to public health (31). Although the assessment of the epidemiologic effect of policy shifts is not an easy task, given that economic improvements contribute to reducing the burden of TB, robust control measures since 1990 have been concomitant to progress in epidemiologic indicators toward the 2015 targets. Figure 2. Global tuberculosis trends in prevalence, incidence, and mortality per 100000 population, 1990 to 2013. Shading indicates the lower and upper bounds of the 95% uncertainty interval. Data from reference 1. * Deaths due to tuberculosis among people living without HIV. Reaching the 2015 Targets Recent retrospective analysis estimates that overall TB mortality rates (not including people living with HIV) decreased from 30 cases per 100000 persons in 1990 to 20 cases per 100000 persons in 2009 (4). From 2000 to 2013, approximately 37 million lives were saved by TB prevention, diagnostic, and treatment interventions (1). Increased funding has been pivotal. Total domestic and international donor TB funding in 104 low- and middle-income countries increased from

Electronic recording and reporting system for tuberculosis in China: experience and opportunities

1.7 billion in 2002 to

The affordability for patients of a new universal MDR-TB coverage model in China.

4.4 billion in 2011, and domestic funding alone increased from