Pulse
Clues from Uganda
Local researchers are studying why some patients with AIDS get sicker with treatment
In 2003, while teaching African physicians about AIDS therapies at Makerere University’s Infectious Diseases Institute in Kampala, Uganda, Paul Bohjanen, M.D., noticed that an unusually large number of patients who were taking antiretroviral therapy (ART) for AIDS were having unpredictable responses to the treatment.
Many of those patients had opportunistic infections such as cryptococcal meningitis, a fungal infection in the lining of the brain, when they were initially diagnosed with AIDS. But after they were treated for the meningitis and began ART for AIDS, many showed up at the hospital weeks later with the same symptoms of meningitis—fever, headache, confusion. This time, however, they had no trace of active Cryptococcus organisms in their spinal fluid or blood.
Bohjanen, who now directs the University of Minnesota’s Center for Infectious Diseases and Microbiology Transitional Research, had heard about this response to ART—a phenomenon known as immune reconstitution inflammatory syndrome, or IRIS—but he was perplexed by the large number of patients who had it. “The number of IRIS cases were two to three times that of what we were seeing in the United States,” he recalls, adding that a number of patients who had IRIS died as a result. IRIS affects an estimated 25 percent of Ugandans who are taking antiretroviral medications for AIDS. In the United States, it affects only about 10 to 15 percent of patients, and most of those cases are mild.
Says Bohjanen, “The questions were obviously Why? and What could be done?” Although he had gone to Uganda to teach, Bohjanen decided to see if he could find answers.
The Burden of IRIS
For people with AIDS who are profoundly immunosuppressed, choosing to take an antiretroviral medication can either be life-saving or, in the presence of IRIS, deadly. Up to half of the people who develop IRIS associated with cryptococcal meningitis will die from it.
In a favorable scenario, when a patient begins ART, the immune system recovers and responds to opportunistic infections. But if the patient develops IRIS, the immune system’s checks and balances go haywire. “In patients with IRIS, the mechanisms that control that immune response are so damaged from AIDS that they develop these really exaggerated inflammatory responses to infections when their immune systems improve on antiretroviral therapy,” Bohjanen explains. “And if that exaggerated inflammatory response involves the lining of the brain, it can be deadly.”
How to treat IRIS is, at this point, anyone’s guess. Currently, patients receive anti-inflammatory drugs such as steroids or NSAIDs to suppress the inflammation. “But are we just throwing that at them because we think it will help? No one knows for sure,” says David Boulware, M.D., an assistant professor in the University of Minnesota’s Division of Infectious Diseases who has been studying IRIS with Bohjanen.
Researching an Enigma
In 2005, Bohjanen secured start-up funding from the University of Minnesota’s Academic Health Center to explore why IRIS was so pervasive in Uganda and what, if any, diagnostic criteria could be gleaned from a subset of the Infectious Disease Institute’s patients. To date, Bohjanen and his colleagues, including Boulware, have enrolled in their study about 100 Ugandan patients who are on ART and have been diagnosed with cryptococcal meningitis (the study also includes 50 control patients). Several times a year, participants visit the Infectious Diseases Institute in Kampala, where they receive care and undergo testing for immune response, gene expression, and the presence of certain types of cytokines that are markers for inflammation. Of those in the study group, about 40 percent have had an IRIS-related event. Bohjanen says this is the only study that has evaluated the incidence of IRIS in this subset of patients.
Since the study began, the team has made some interesting observations. For one thing, although the prevalence of HIV in Uganda has dropped from 25 percent in the mid-1980s to about 6 percent in the mid-2000s, more people in Africa are living with very advanced AIDS and receiving ART, thus increasing the probability of IRIS. “A healthy person walking down the street will have a CD4+ count of 1,000 or higher,” Boulware says. “The patients we are seeing in Uganda typically have a CD4+ count of below 50, which makes them profoundly immune-suppressed. And if you have a high burden of disease throughout the body, you have a higher risk for IRIS than if you have a localized infection.”
Second, patients with IRIS have an unusually high number of markers for inflammation. “If we look in the spinal fluid of these patients, we see a lot of inflammatory cells and cytokines being produced,” Bohjanen explains. “In the blood, we see expression of genes that are usually only expressed in activated cells of the immune system.” Such findings, Bohjanen says, can lead to better measurement of the inflammation associated with IRIS—and, ultimately, a more accurate diagnosis of IRIS as well as better treatments for it.
Finally, the evidence of inflammation can be seen in IRIS patients’ cytokine profiles and gene expression long before they get sick. “Researchers had initially suspected that things started happening with IRIS only after HIV therapy began,” notes Boulware. “What we are showing is that there are differences that occur prior to initiation of treatment.”
The Work Continues
As part of what has become an “institutional affiliation agreement” between Makerere University and the University of Minnesota, the work that Bohjanen and others began is benefiting physicians in both the United States and Africa. Physicians from Uganda now come to Minnesota to teach and learn, and about 15 residents and medical and public health students from the university have traveled to Uganda to learn more about HIV and AIDS and do hands-on clinical work.
Since the project was funded in 2005, Bohjanen has returned to Uganda two to three times a year to teach about HIV and ART and to supervise the research. Along with two colleagues at Makerere University, he and Boulware are currently establishing a multisite clinical trial examining the effect of earlier ART on the onset and progression of IRIS.
On average, Bohjanen says, the time between diagnosis of cryptococcal meningitis, which is typically followed by an AIDS diagnosis, and initiation of ART is 35 days in Uganda. He explains that 40 percent of patients die before they receive ART. There is a similar delay between diagnosis and treatment in the United States, he notes, but only 5 percent of patients die. Bohjanen speculates that this is because U.S. patients with cryptococcal meningitis are not as ill when they seek treatment and have access to better care. In the upcoming study, randomized patients will begin therapy either 35 days or 10 to 14 days after diagnosis. “Our hope is that earlier treatment will improve survival for patients. But you have to balance that benefit against the potential for IRIS,” he says.
In the meantime, both Bohjanen and Boulware are confident that the findings from their Uganda investigations will benefit people with AIDS throughout the world—including those in their own backyard. “We could never do this research in Minnesota because most people start on ART earlier here, and there are fewer IRIS cases,” Boulware says. “But the knowledge we gain from our work in Uganda will certainly have broader implications. One day, we will be better able to pick therapies for IRIS based on the science, and that will enable better therapies for Minnesota patients.”—Jeanne Mettner