Saturday, October 17, 2009

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.

Friday, October 02, 2009

Preventing Mother to Child Transmission of HIV in Mwandi, Zambia- A Success

Welcome to this installment of the AIDS Pandemic, a podcast hosted by Dave Wessner of the Department of Biology at Davidson College. I am Sarah Bertram.

This past summer, I traveled to Mwandi, Zambia through a Davidson biology and pre-medical program. Mwandi is a predominantly Lozi village of about 7,000 people and the catchment area totals about 25,000 people. We spent 5 weeks in Africa, 3 of which were spent working in the Mwandi Mission Hospital, the Mwandi AIDS clinic, the Orphans and Vulnerable Children’s center, and the Mother and Child Health Center. We all went with a research topic to study that was based on some aspect of Mwandian life. I looked at Mwandi’s Prevention of Mother to Child Transmission of HIV, otherwise known as the PMTCT program, and its effectiveness over the past three years. Here, I will talk about my findings.

About out of every five pregnant women in Zambia is infected with HIV and without any prevention or treatment interventions, more than 300,000 babies would contract HIV from their mothers each year. Starting in 1999, many Zambian mission and government hospitals started PMTCT programs. The Mwandi PMTCT program was launched in 2005 by an American Pediatrician in conjunction with the Mwandi missionary who was going to serve as the leader of the program. The procedure for PMTCT at the Mwandi Mission Hospital is as follows: 1) discuss the PMTCT program and HIV/AIDS information during group antenatal care visits, 2) offer private pre-test counseling, 3) test the mother for HIV and CD4 counts and give her the results, and 4) offer post-test counseling and discuss further treatment and a re-test in three months. According to the hospital staff in Mwandi, HIV testing of any pregnant mother is required by law in Zambia.

If a woman tests positive, she is evaluated at the Pastoral Care Center for AIDS treatment. If she is considered a WHO stage IV or has multiple symptoms for WHO stage III, HAART treatment is usually started unless the woman chooses to undergo short-course treatment instead. Many of the HIV positive mothers choose to undergo HAART treatment because of its documented increased ability to treat HIV/AIDS symptoms and to lower the viral load by decreasing viral replication. The Mwandi hospital staff is good about giving options to the positive mothers and explaining each option and its risks and benefits. Due to the staff’s willingness to counsel and inform the HIV positive pregnant mothers of treatment options, a majority of these women decide to take part in a course of HIV/AIDS treatment in order to help themselves and to prevent the transmission of HIV to their babies.

Although record-keeping is sparse and sometimes hard to find and evaluate, some records for the PMTCT program proved helpful in evaluating the program’s success over the years. From March of 2005 to September of 2007 (before HIV testing was mandatory), 1,205 women attended an antenatal care appointment to sign up for the PMTCT program and of these 1,205 women, only 35 women or about 3% refused the HIV test. Of the 1,170 women who agreed to be tested, 24.4% tested positive for HIV. This statistic is quite high, but reflects the belief that about 1/3 to ¼ of Mwandi’s population is infected with HIV. Because the PMTCT program was in place, the HIV positive women were able to learn their status, get treatment, and prevent (for the most part) the transmission of HIV to their babies during pregnancy, delivery, and breastfeeding.

Mwandi’s PMTCT program has changed drug regimens in order to stay current with the most effective treatments. Originally, the program was based on a single dose of nevirapine given to the mother during delivery and to the baby right after birth. In April of 2006, the PMTCT program switched to a dual therapy involving both nevirapine and AZT for both mothers and babies. Starting in November of 2007, Mwandi updated its treatment regimen to the most current and effective triple therapy drug treatment. This drug therapy involves a mixture of AZT, 3TC, and NVP for the mother and baby. This new therapy has proven to be very effective and the PMTCT program workers approximate that transmission from mother-to-child rates have decreased to less than 10% and possibly even as low as 6% or 7%.

Possibly the most enticing aspect of the PMTCT program for pregnant women is the free formula feeding program provided to HIV-negative babies of HIV-positive mothers. Breastfeeding is the most common type of mother-to-child HIV transmission, so by providing free formula for those babies who test negative (after 6 weeks of age), the worry of transmission by breastfeeding can be alleviated. Currently there are over 100 babies receiving infant formula and most, but not all, are HIV-negative babies of HIV-positive mothers who participated in the PMTCT program. The program has never resulted in a case of child dysentery, a common negative outcome of formula feeding programs, which is often a result of incorrectly boiled water used to make the formula. This clean record is a result of the care and attention put forth into teaching the mothers how to correctly make the formula and clean the bottles.

Compared to many other Sub-Saharan African PMTCT programs, Mwandi’s program is doing a very good job of keeping the program advancing, as far as the number of women being treated and the updates to newer forms of drug therapies. The program could however still make larger strides in incorporating more women from far out in the catchment area and by possibly providing more rural village outreaches for the sole purpose of PMTCT.