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Deadly Synergy

A Keystone Symposium on TB and HIV emphasized the need to tackle the diseases in tandem

By Andreas von Bubnoff

Although tuberculosis (TB) is thought to be the leading cause of death among people with HIV/AIDS, scientific conferences often focus on these two deadly diseases separately. This changed recently, when over 300 scientists and clinicians gathered in Arusha, Tanzania, from October 20-25 at a Keystone Symposium on “Overcoming the Crisis of TB and AIDS.”

Tuberculosis, a disease caused by a bacterial infection, is responsible for between one-third to a half of AIDS deaths, and at least a quarter of the approximately two million people who died of TB last year were co-infected with HIV, conference co-organizer Anne Goldfeld of Harvard Medical School said in the opening session. “Each infection and its solution cannot be separated from each other,” she added. “By bringing together scientists and clinicians who work at the cutting edge of each disease, it’s the aim of this conference to serve as a catalyst to generate new ideas and to identify new ways of solving our global humanitarian disaster.”

The presentations at the symposium spanned many topics including the mechanism of the synergy between HIV and TB, and the treatment and prevention of both diseases.

A lethal dance

Given that the meeting convened both TB and HIV experts, one central topic was how the two infections interact and synergize in individuals that are HIV/TB co-infected. Each infection enhances the other infection’s ability to cause disease: HIV by compromising the immune system and weakening the body’s defenses against other pathogens like the bacterium that causes TB, and TB by driving HIV’s ability to replicate or produce more virus.

Goldfeld showed the results of test-tube studies that address how TB infection increases the quantity of HIV circulating in blood, known as viral load, by enhancing the ability of HIV to replicate. Her data suggest that TB infection in certain kinds of white blood cells induces a protein—one of several—that stimulates HIV replication.

Goldfeld is also involved in the CAMELIA clinical trial in Cambodia that is studying the timing of HIV therapy in co-infected individuals who have already begun therapy for TB. When to initiate highly active antiretroviral therapy (HAART) in co-infected people is a conundrum for scientists and clinicians. Starting co-infected people on HAART too late results in higher mortality because the immune systems of these individuals become too compromised by HIV and therefore they cannot withstand the onslaught of many infections that people with healthy immune systems can typically control. Yet there have also been concerns that starting HAART early might result in adverse drug reactions and interactions. “[There] was a tremendous bias that people couldn’t take seven different types of medicines at once,” Goldfeld said. “So the recommendation was to wait until after the intensive phase of TB therapy was finished to initiate HAART.”

In addition, TB symptoms can sometimes worsen when HAART is initiated. For reasons scientists don’t completely understand, some co-infected individuals develop immune reconstitution inflammatory syndrome or IRIS, an inflammatory disease thought to be associated with an increase in the number of infection-fighting immune cells—known as CD4+ T cells—that, ironically, is one of the benefits of HAART. Goldfeld said that IRIS typically kicks in six to eight weeks after initiation of HAART.

The aim of the CAMELIA trial, which just finished enrolling 661 co-infected volunteers, is to see if early HAART initiation will increase survival in co-infected, immune-compromised individuals despite the perhaps more complex initial clinical management of issues such as IRIS, Goldfeld said. In the trial, some co-infected volunteers start HAART two weeks after starting TB therapy, while others delay initiation of HAART until two months after starting TB therapy. Results of the trial, which evaluates survival one year after initiation of TB therapy, are expected in mid-2010.

Some volunteers enrolled in CAMELIA are also enrolled in another trial called CAPRI-T, which is designed to evaluate whether certain characteristics of CD4+ T cells are involved in causing IRIS. Investigators are analyzing blood samples from participants at several time points after they start TB therapy and at the time IRIS occurs, if this condition develops. Results of this trial are also expected in 2010.

Alan Sher, chief of the laboratory of parasitic diseases at the US National Institute of Allergy and Infectious Diseases (NIAID), presented data from a study in mice that suggest IRIS depends less on the quantity of CD4+ T cells than on their activity.

Sher first infected mice deficient in T cells with Mycobacterium avium, which causes a TB-like infection in the animals. When given CD4+ T cells from a normal mouse, to mimic the increase in CD4+ T cells that would occur as a result of HAART, the mice indeed got a rapid IRIS-like disease and died. But the injected T cells did not expand more in infected mice compared to uninfected mice. Instead, they produced molecules that may lead to the recruitment of other types of white blood cells to tissues including the lungs, where they can cause damage. He believes that intervening in this process might be a possible way to prevent IRIS in humans.

Insights on HIV transmission

The meeting also featured presentations that dealt with HIV and TB separately, including some that focused on HIV transmission. Much has been learned in recent years about HIV transmission. This includes information about the specific viruses that get transmitted from an infected person to an uninfected person. For example, researchers have found that about 80% of heterosexual HIV infections can be traced back to one transmitted virus variant (see VAXApril 2009 Primer on Understanding the Transmitted Virus). This is true even though there are numerous HIV variants circulating in the already infected partner. This led researchers to conclude that there is some sort of bottleneck that occurs in HIV transmission that severely limits the number of viruses that can establish an infection. However, how much of a bottleneck there is depends on the route of HIV transmission. Researchers have observed that in men who have sex with men (MSM) and injection drug users (IDUs), there are often more HIV variants that get transmitted and establish a new HIV infection.

George Shaw, a professor of medicine and microbiology at the University of Alabama, and one of the pioneering scientists documenting these early events in HIV transmission, said that recent studies in IDUs indicate that at least 17 different transmitted viruses have now been found to be responsible for establishing infection. “There [are] so many we can’t count [precisely],” he said. This suggests that some routes of transmission may be fundamentally more difficult to protect against.

Antibody PrEP

A much-discussed strategy to prevent HIV transmission is the administration of antiretroviral therapy to HIV-uninfected individuals prior to exposure to the virus, an approach known as pre-exposure prophylaxis (PrEP; see VAX November 2008 Spotlight article, PrEP Work). David Ho, a professor at Rockefeller University and director of the Aaron Diamond AIDS Research Center, is developing a novel PrEP strategy which involves giving people an antibody rather than antiretroviral therapy. The antibody, called Ibalizumab, binds to a molecule on the surface of CD4+ T cells that HIV uses to get inside. By binding to this molecule, the antibody prevents HIV from infecting CD4+ T cells, the virus’ main target.

Ibalizumab is currently being tested in Phase IIb clinical trials as an HIV therapy, but Ho thinks the antibody should also be tested in uninfected people to see if it has any utility as an HIV prevention strategy. He said this prevention strategy would require less frequent dosing than with antiretroviral therapy and is also typically associated with fewer adverse events.

However, administration of Ibalizumab is not necessarily risk free. One concern with antibodies that bind to this molecule on the surface of CD4+ T cells is that they could inhibit the normal function of these important immune cells. But Ibalizumab doesn’t seem to interfere with normal immune function, Ho said.

Ho is now testing Ibalizumab in nonhuman primates to see it if it can prevent HIV infection, and he is planning to launch a Phase I study in healthy volunteers. He also plans to further improve the antibody so that it would only need to be administered every few months.

Regina McEnery contributed to this article.