Novel developments in the epidemic of human immunodeficiency virus and tuberculosis coinfection

Abstract

Tuberculosis (TB) disease remains one of the highest causes of mortality in HIV-infected individuals, and HIV-TB coinfection continues to grow at alarming rates, especially in sub-Saharan Africa. Surprisingly, a number of important areas regarding coinfection remain unclear. For example, increased risk of TB disease begins early in the course of HIV infection; however, the mechanism by which HIV increases this risk is not well understood. In addition, there is lack of consensus on the optimal way to diagnose latent TB infection and to manage active disease in those who are HIV infected. Furthermore, effective point-of-care testing for TB disease remains elusive. This review discusses key areas in the epidemiology, pathogenesis, diagnosis, and management of active and latent TB in those infected with HIV, focusing attention on issues related to high- and low-burden areas. Particular emphasis is placed on controversial areas where there are gaps in knowledge and on future directions of study.

Figure 1.

Increased incidence of tuberculosis (TB) early in HIV and incomplete protection from TB after HAART. (A) Incidence of TB in South African gold miners who are HIV negative or who have seroconverted to HIV-infected as a function of years since negative HIV test or date of seroconversion. Data show early doubling in incidence of TB among HIV seroconverters after first year and continued rise thereafter. Adapted from Reference 9. (B) Incidence of TB among South African cohorts divided who are HIV-infected and taking or not taking highly active antiretroviral therapy (HAART) therapy, as a function of initial CD4⁺ T-cell count at commencement of study. Data show that although HAART significantly reduced TB incidence especially among those with low CD4⁺ T-cells counts, protection is incomplete, and among those with relatively high CD4⁺ T-cell count, protection is minimal during study period (approximate follow-up, 16 mo). Adapted from Reference 20.

Figure 2.

Immunity against Mycobacterium tuberculosis (MTb) and the effects of HIV. (A) Alveolar macrophages (AMs) are the first cells to encounter and engulf MTb bacteria when they are inhaled deeply into the lungs. MTb bacteria have evolved to escape intracellular killing by AMs by arresting phagosomal maturation and possibly escaping the phagosome to allow for persistence and growth within AMs. The defense mechanisms against this include chemokines/cytokine secretion which activate antimycobacterial defenses and adaptive immunity (56, 142, 143), autophagy (59), and apoptosis (51) among others. (B) HIV is known to affect a number of these steps, including increased phagocytosis of MTb to allow access to intracellular environment (54, 55), decreased AM apoptosis (55) in response to MTb, decreased autophagy (58), and decreased chemokine/cytokine production (56). HIV also affects function and numbers of CD4⁺ T cells, leading to increased bacillary loads, inadequate granuloma formation, and dissemination (144). DC = dendritic cell; TNF = tumor necrosis factor.

Figure 3.

The microscopic-observation drug susceptibility (MODS) assay. (A) Typical cording formation characterized by M. tuberculosis growth in liquid medium visualized by an inverted light microscope at an original magnification of ×400. (B) Magnification of typical cords of MTb. (C) Picture of MODS culture plate. Cultures are prepared in a 24-well tissue culture plate in six columns of four wells each. Each column of four wells is used for a single sample–two wells are drug free and one each contains rifampicin and isoniazid. Six columns allow for five samples per plate and one negative control column. Plates are permanently sealed inside Ziploc bags after inoculation to avoid cross-contamination and for safety and are examined within bags daily for 15 days and then on alternate days until Day 21. Nontuberculous mycobacteria do not form cords, except for M. chelonae, which can be identified by rapid growth.