Intersecting Epidemics: HIV/AIDS and Tuberculosis

Hi, I’m Justin Eusebio.

While tuberculosis is one of the world’s oldest surviving plagues
and HIV-1 infection is one of medicine’s newest challenges, there
is an undeniable relationship between HIV/AIDS and tuberculosis.
Independently, Mycobacteria tuberculosis and HIV are formidable
pathogens but in concert, the prospects for controlling either
epidemic are jeopardized. TB-HIV coinfection and interaction
complicate all aspects of each disease: pathogenesis, epidemiology,
clinical presentation, diagnosis, treatment, prevention, and even
social and economic issues.

Not only are individuals more likely to undergo tuberculosis
infection if living with HIV, depending on their geographic
location, people living with HIV infection are 6-50 times more
likely to develop active TB than people living without HIV. Thus,
with one-third of the world’s population at least latently infected
with Mycobacteria tuberculosis, the current pace of new HIV-1
infections threatens public health on a wide scale.

Tuberculosis infection is believed to have the greatest potential
among other common opportunistic infections to increase viral load
and to accelerate HIV-1 disease progression. This is in part due to
the chronic nature of active TB disease, the marked increase in
tumor necrosis factor-alpha (TNF-α) expression for macrophage
activation, and intensified antigen presentation causing the
recruitment of CD4 T lymphocytes to the site of TB infection.

Manoff and others demonstrated that active tuberculosis is
associated with increased viral load in HIV-1 infected patients.
Also, TB-HIV coinfected persons have a significantly higher HIV RNA
load than persons without opportunistic infections and similar CD4
cell counts.


Figure 1. Schematic hypothetical individual’s of risk of TB
infection compared to CD4 cell count.
From: Havlir, Diane V., Haileyesus Getahun, and Ian Sanne.
“Opportunities and Challenges for HIV Care in Overlapping HIV and
TB Epidemics.” Journal of the American Medical Association 300.4
(2008): 423-430.

Researchers from Case Western Reserve University demonstrated that
not only do TB-HIV co-infected patients have significantly higher
viral loads than those without TB, the timing of infection by M.
tuberculosis affects HIV-1 disease progression. In fact, these
researchers showed that TB had its strongest impact on HIV-1 viral
load when patients are least immunodeficient. Furthermore, from the
same study, more than 25% of TB-HIV coinfected patients developed
TB when their CD4 cell counts were at least 500 cells/µl. Thus TB
infection is unique because it can occur at any CD4 cell count
level.
Perhaps the most problematic tuberculosis-induced effect
contributing to HIV-1 disease progression is its apparent impact on
HIV-1 evolution. While reverse transcriptase, a polymerase without
proofreading capabilities, provides an effective mechanism for
genetic diversity, M. tuberculosis infection increases HIV-1
heterogeneity through compartmentalization.

In a cohort of patients matched by their CD4 cell counts, dually
infected TB-HIV patients were found to have greater systemic, or
more general, HIV-1 heterogeneity and more frequent occurrences of
distinct HIV-1 quasispecies than HIV-1 patients without TB
infection. A population of diverse quasispecies increases the viral
capacity to evolve and adapt to the host immunological response.
Furthermore, upon examination of the lung sites of M. tuberculosis
infection of TB-HIV coinfected patients, Collins and others found
greater genetic HIV-1 heterogeneity and distinct quasispecies in
the pleural space compared to blood samples. While phylogenetically
distinct HIV-1 subpopulations have been shown to develop in other
organs or tracts in humans (i.e. kidneys, brain, urogenital tract
and blood), compartmentalization of HIV-1 occurs most significantly
and is more defined in the lungs of co-infected TB-HIV patients.
Therefore, the lungs, induced by active tuberculosis disease,
function as a reservoir for genetically diverse HIV-1.

In addition to accelerating the disease progression of one another,
their collision has highlighted underlying public health and human
rights failures. Africa, although only home to 10% of the world’s
population, is the major site of intersection between the two
epidemics with an astounding 75% of the world’s TB-HIV
coinfections.


Figure 2. The disproportionate incidence of HIV and HIV-TB
coinfection in Africa in 2000. Each person indicates 5% of the
global population. The African population is shaded red while blue
represents the rest of the world.
From: Corbett, Elizabeth L, Barbara Marston, Gavin J. Churchyard,
and Keven M. De Cock. “Tuberculosis in Sub-Saharan Africa:
Opportunities, Challenges, and Change in the Era of Antiretroviral
Treatment.” Lancet 367 (2006): 926-937.

Thus, novel TB diagnostic tests are needed in HIV-endemic regions
because HIV infection reduces the sensitivity of current diagnostic
methods such as direct smear sputum microscopy. In terms of
treatment, high pill burden and toxicity often discourage adherence
among many coinfected patients. Furthermore, rifampicin, a common
antibiotic component of tuberculosis chemotherapy disrupts
antiretroviral treatment by accelerating the metabolism of both
protease inhibitors and nonnucleoside reverse transcriptase
inhibitors (NNRTs). Finally, if antiretroviral treatment of
coinfected patients is started too soon after treatment for TB, a
rapid recovery of CD4 T cell levels may induce an overwhelming
inflammatory response against previously hidden opportunistic
infections resulting immune reconstitution inflammatory syndrome
(IRIS).

The connection between the biology of the two diseases is clear and
complications are numerous. Thus, experts in HIV and experts in TB
should respond accordingly and move towards greater collaboration
and shared research.

Until next, this is Justin Eusebio.


For more information:

Bartlett, John G. “Tuberculosis and HIV Infection: Partners in
Human Tragedy.” Journal of Infectious Diseases 196 (2007):
S124-5.

Collins, Kalonji R., Miguel E. Quioñones-Mateu, Mianda Wu, Henry
Luzze, John L. Johnson, Christina Hirsch, Zahra Toossi, and Eric J.
Arts. “Human Immunodeficiency Virus Type 1 (HIV-1) Quasispecies at
the Sites of Mycobacterium tuberculosis Infection Contribute to
Systemic HIV-1 Heterogeneity.” Journal of Virology 76.4 (2002):
1697-1706.

Collins, Kalonji R., Miguel E. Quioñones-Mateu, Zhara Toossi, and
Eric J. Arts. “Impact of Tuberculosis on HIV-1 Replication,
Diversity and Disease Progression.” AIDS Review 4 (2002):
165-176.

Kalonji Collins et. al, “Greater diversity of HIV-1 quasispecies in
HIV-infected individuals with active tuberculosis.” Journal of
Acquired Immune Deficiency Syndrome 24, 408-417.

Friedland, Gerald, Gavin J. Churchyard, and Edward Nardell.
“Tuberculosis and HIV Coinfection: Current State of Knowledge and
Research Priorities.” Journal of Infectious Diseases 196 (2007):
S1-3.

Manoff, SB, H Farzadegan, A Muñoz, JA Astemborski, D Vlahov, RT
Rizzo, L Solomon, and NM Graham. “The Effect of Latent
Mycobacterium tuberculosis infection on Human Immunodeficiency
Virus (HIV) Disease Progression and HIV RNA Load Among Injecting
Drug Users.” The Journal of Infectious Diseases 174.2 (1996):
299-308.

Nunn, Paul, Alasdair Reid, Kevin De Cock. “Tuberculosis and HIV
Infection: The Global Setting.” The Journal of Infectious Diseases
196 (2007): S5-14.

Vignuzzi, Marco, Jeffrey K. Stone, Jamie J. Arnold, Craig E.
Cameron, and Raul Andino. “Quasispecies Diversity Determines
Pathogenesis through Cooperative Interactions within a Viral
Population.” Nature 439.7074 (2006): 344-348.