Tuberculosis and HIV Coinfection: Current State of Knowledge and Research Priorities

Tuberculosis (TB) and human immunodeficiency virus (HIV) disease are the 2 leading causes of infectious disease–associated mortality worldwide. TB and HIV disease have been inextricably bound together from the early years of the HIV/AIDS epidemic. Their dangerous synergy affects all aspects of each disease, from pathogenesis and the epidemiologic profile; to clinical presentation, treatment, and prevention; to larger issues of social, economic, and political consequence. It is estimated that infection due to Mycobacterium tuberculosis, an ancient pathogen in humans, is present in one-third of the world's population, or ∼2 billion people. Eight million new cases of active TB have been estimated to occur worldwide annually, with more cases seen today than at any previous time in history [1]. It is estimated that 2–3 million people died of TB during the past year. In parallel, although HIV is only a recent pathogen of humans, it is estimated that 39 million people are currently living with HIV infection and AIDS. During the past year, 5 million adults and children were estimated to have been newly infected with HIV, and 3 million HIV-infected individuals died [2]. Both the TB and HIV/AIDS global pandemics are volatile and still evolving, particularly at the points of their intersection. The harmful interaction of TB and HIV/AIDS has added greatly to the suffering and loss of life caused by each pandemic. Together, the diseases expose underlying weaknesses in public health, medical, and social systems, as well as disparities in resources and human rights. Great accomplishments and the equally daunting challenges that remain illustrate how TB and HIV infection illuminate both the power and limitations of science. In industrialized countries, the rate of new M. tuberculosis and HIV infections has slowed, and the numbers of individuals living with HIV infection have increased. In contrast, in most resource-limited countries, particularly those where high rates of M. tuberculosis infection already exist, both the incidences and the prevalences of HIV/AIDS and TB have continued to dramatically increase.

The collision of the TB and HIV infection pandemics has resulted in ∼12–14 million people becoming infected with both M. tuberculosis and HIV. Between 1990 and 2005, the incidence of TB increased at an average rate of 7% per year in those countries where the prevalence of HIV infection among adults is high (⩾5%), but the average rate of increase was only 1.3% per year in countries where the prevalence of HIV infection is low (<5%) [1]. In many countries with limited resources, the TB case rate has increased 5- to 10-fold since the identification of HIV, and the prevalence of HIV infection among individuals with newly diagnosed TB exceeds 80% [3]. The greatest burden of the TB and HIV infection interface is seen in sub-Saharan Africa, where the enormous size of the problem is tragically, inversely proportionate to the paucity of resources available for its control. The growing recognition of multidrug-resistant TB (MDR-TB) and the recently described extensively drug-resistant TB (XDR-TB), associated with a very high mortality rate among HIV-infected individuals, may further undermine TB control efforts in resource-poor countries [4]. Although, to date, sub-Saharan Africa has borne the brunt of TB/HIV coinfection and its consequences, other, more populous parts of the world are increasingly struggling with increasing TB- and HIV-related morbidity and mortality.

The treatment of both TB and HIV infection has been enormously successful, but major diagnostic and therapeutic deficiencies remain. The coexistence of both diseases accentuates these deficiencies, with the decreased sensitivity of examination of sputum smears for TB, for example, resulting in new diagnostic, prevention, therapeutic, policy, and implementation challenges. As outlined in the World Health Organization (WHO) Global Plan to Stop TB, new scientific research, resources, and operational strategies that address TB and HIV infection together are essential to reduce the morbidity and mortality associated with both diseases [5].

On 30 June 2005, in Boston, Massachusetts, and on 25 July 2005, in Rio De Janeiro, Brazil, international experts met to present information and discuss current knowledge of issues related to TB and HIV coinfection. It was apparent that the data and expertise were extensive in some areas but were sparse or nonexistent in others. This supplement, the first of its kind, was conceived as an opportunity to assemble this information in a single volume, to provide current information and define deficiencies in a manner that could serve the needs of clinicians, scientific researchers, public health professionals, and interested community members. Authors were asked to provide up-to-date articles summarizing what is known and what needs to be known in several areas of particular relevance to TB and HIV coinfection, with emphasis given to therapeutics and resource-poor countries. The body of this supplement comprises these articles.

The global status of the TB and HIV infection pandemics and the policy and public health response during the past years are detailed and summarized by Paul Nunn, Alasdair Reid, and Kevin De Cock [6] of the Stop TB Department and HIV/AIDS Department of the WHO, respectively. The great need for new, rapid diagnostic methods and potent therapeutic agents for TB, accentuated by the HIV infection epidemic, as well as the present and future status of these methods and agents are discussed by Mark Perkins of the Foundation for Innovative Diagnostics and Jane Cunningham of the United Nations Development Programme/UNICEF/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases [7] and Melvin Spigelman from The Global Alliance for TB Drug Development [8]. Philip Onyebujoh, Isabela Ribeiro, and Christopher Whalen [9] provide a review and discussion of treatment strategies for dual TB and HIV infection, including when to start antiretroviral therapy for coinfected patients, what to start with, and other critical strategic research questions. Underlining the lack of and need for scientific evidence to support practice and policy, Blanc and colleagues [10] from France, the United States, Switzerland, and Cambodia provide information on existing and planned clinical trials to address issues regarding when to initiate antiretroviral therapy for coinfected patients. Helen McIlleron and colleagues [11] provide an extensive and thoughtful review of the literature on drug-drug interactions, additive toxicities, and immune reconstitution inflammatory syndrome, each of which may complicate the concomitant treatment of both diseases. Taking one important step back, Gavin Churchyard and colleagues [12] from South Africa, the WHO, the United Kingdom, and the United States explore the issue of TB preventive therapy, giving particular emphasis to the issues raised in the presence of HIV infection. Marais and colleagues [13] from South Africa and Malawi provide insights into the special challenges associated with TB and HIV infection in children. The previously neglected but critical issues of infection control in the era of HIV and of MDR-TB and XDR-TB are comprehensively reviewed, and recommendations are provided by Naomi Bock, Paul Jensen, and Bess Miller from the Centers for Disease Control and Prevention and Edward Nardell from Harvard Medical School [14]. The ominous increase in drug-resistant TB, fueled and accentuated by HIV coinfection, is defined and documented by Charles Wells and colleagues [15]. Finally, to illustrate, on the ground, the practical issues associated with TB and HIV infection program collaboration and integration, 3 separate models of HIV infection collaboration and integrated care and treatment are described by Friedland, Harries, and Coetzee [16] in national and local urban and rural settings in Malawi and South Africa. Finally, thoughtful and insightful comments on the issue of TB and HIV coinfection are provided by John Bartlett [17].

We have attempted to address the issue of TB and HIV coinfection comprehensively, but we appreciate that important issues and areas have not received the attention that they deserve. The focus of this supplement has been diagnostic and therapeutic issues; the critical areas of pathogenesis and prevention, including TB vaccine development, have been, of necessity, omitted. Furthermore, the geographic orientation of the supplement has been toward sub-Saharan Africa, where the intersection of the TB and HIV epidemics has had its greatest impact. We recognize that other areas of the world are undergoing similar challenges and are faced with special issues that are distinct from those in sub-Saharan Africa. In many areas of the world where HIV infection and TB coexist, illicit injection drug abuse adds additional complex challenges to the diagnosis, therapeutics, and organization and implementation of prevention, care, and treatment. The absence of these issues from this supplement is in no way intended to diminish their importance but, rather, is a reflection of the wide array of issues raised by TB and HIV coinfection and the constraints of space for their accommodation. In the rapidly evolving era of TB and HIV coinfection, there will be a need for future supplements with both similar and differing geographic and thematic foci. These supplements will be expected to provide timely updates on newly acquired knowledge as well as changing research priorities, particularly with respect to new TB diagnostics, therapeutics, and vaccines, as well as the policies and practices that result in universal access to their benefits.

We thank the many authors of this supplement for their contributions, and we gratefully acknowledge the support of the Division of AIDS of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the Forum for Collaborative HIV Research (including special contributions from the WHO Stop TB Department, the International AIDS Society, and GlaxoSmithKline), the World Bank, the Agence Nationale de Recherches sur le Sida et les HÉpatites Virales (France), and the Centers for Disease Control and Prevention. We also received excellent editorial and clerical support from Susan Hender at Yale School of Medicine and Emily Walton at The Journal of Infectious Diseases. We also thank Martin Hirsch, Editor of The Journal of Infectious Diseases, for initially suggesting this supplement and for his encouragement and support from its conception to completion.

• © 2007 by the Infectious Diseases Society of America.