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STEPHANIE NOLEN
From Thursday's Globe and Mail
Globe and Mail
September 20, 2007 at 4:21 AM EDT
JOHANNESBURG ? The volunteers were healthy - Pontiano Kaleebu knew they were healthy. The Ugandan microbiologist could tell that there was nothing wrong with the people who came to his clinic in Entebbe to volunteer to test an HIV vaccine. They felt and looked perfectly well.
But when he screened their blood for markers such as the number of white blood cells, dozens and dozens of would-be volunteers failed the tests. According to the results, they were "sick" and he had no choice but to turn them away - a professional loss, because it's never easy to recruit volunteers to test a product that sounds as scary as an AIDS vaccine. It was also a personal frustration, because Dr. Kaleebu, a widely respected researcher, was certain there was nothing wrong with them.
As it turns out, there wasn't, and unravelling that medical mystery may open the door to faster, more precise research into the treatment and prevention of the biggest killers in the hardest-hit regions.
Until now, researchers in Africa have used "reference ranges" - what are deemed "normal" levels of components of a person's blood - based on North Americans and Europeans. But healthy Africans, a new study shows, have different levels of white blood cells and other blood components. That shouldn't be a surprise, the doctor points out; the only shock is that it took this long for anyone to map out what's "normal" in Africa.
Dr. Kaleebu was part of a team that screened 5,500 clinically healthy, HIV-negative volunteers at a dozen sites across Africa, looking at blood chemistry and kidney and liver function, to develop the new reference ranges. The work was a partnership between the International AIDS Vaccine Initiative, for which Dr. Kaleebu is an investigator, the U.S. military's AIDS research program, and the U.S. Centers for Disease Control and Prevention.
While it is not possible to talk about values that are standard for the people in all 53 sub-Saharan African countries, the results of this two-year study do show that adults in Kenya, Zambia, Uganda and Rwanda have in common some differences from the Western values, including lower levels of lymphocytes, neutrophils - cells that "eat" anything they find that shouldn't be there - and red blood cells. They also had higher levels of eosinophils, which fight infection by parasites.
The findings are important for more than just recruiting volunteers to test AIDS vaccines - they will also be used in trials for treatments of a variety of infectious diseases, including malaria and tuberculosis. Using the results, researchers will now be able to monitor more accurately how volunteers in a trial are doing when they are taking a medication or vaccine. For example, a participant's red blood cell count might show up as "low" and cause worry, but compared against the new range, the cell count would not be deemed a concern. It will also give the researchers a better handle on how effective a treatment is.
Mark De Souza, international lab manager for the U.S. military HIV program, said that in one vaccine trial in Uganda, his staff screened out 58 per cent of potential participants because they had "abnormalities" based on the Western ranges. But when the volunteers were reassessed using values localized for the trial site, the screen-out rate was only 23 per cent, he said. "We were turning away heaps of healthy people," he said in a telephone interview from Bangkok.
There are genetic and environmental factors behind the differences. Compared with people in the West, Africans more commonly have parasites, or anemia, or some level of malaria exposure, which would cause them to test as unhealthy by the Western values even though they are well within the range of normal in their community, explained Pat Fast, the New York-based director of medical affairs for IAVI.
This does raise the question of whether the new reference ranges normalize conditions that are in fact the result of poor access to health care, a potential problem that all the researchers acknowledged, but they said the ranges are a first step toward improved care.
"Maybe if we completely revolutionized the health system, those values would be different," Dr. Fast said. "But it's not within our power to do that ... these people are living their lives and I bet most of them could out-work me."
The goal is to find a vaccine that is safe for people in this environment, and so it is crucial to test in their environment, she said. "It's important as much as possible to shift our locus to the countries we are trying to develop the vaccine for, to shift the way we think, the way we measure."
The new reference ranges may prove particularly relevant to AIDS treatment. Access to anti-retroviral drugs is increasing rapidly in Africa, which is home to 75 per cent of people with HIV. Drawing on Western experience, African patients are typically told to start AIDS treatment when their CD4 count level - a measure of the immune system - drops below 200. But if "normal" is already lower, treatment should perhaps be starting sooner. "A small shift in that curve could really change when you start treatment," Dr. Fast said. "You have to understand the normal before you start to understand disease."
From Thursday's Globe and Mail
Globe and Mail
September 20, 2007 at 4:21 AM EDT
JOHANNESBURG ? The volunteers were healthy - Pontiano Kaleebu knew they were healthy. The Ugandan microbiologist could tell that there was nothing wrong with the people who came to his clinic in Entebbe to volunteer to test an HIV vaccine. They felt and looked perfectly well.
But when he screened their blood for markers such as the number of white blood cells, dozens and dozens of would-be volunteers failed the tests. According to the results, they were "sick" and he had no choice but to turn them away - a professional loss, because it's never easy to recruit volunteers to test a product that sounds as scary as an AIDS vaccine. It was also a personal frustration, because Dr. Kaleebu, a widely respected researcher, was certain there was nothing wrong with them.
As it turns out, there wasn't, and unravelling that medical mystery may open the door to faster, more precise research into the treatment and prevention of the biggest killers in the hardest-hit regions.
Until now, researchers in Africa have used "reference ranges" - what are deemed "normal" levels of components of a person's blood - based on North Americans and Europeans. But healthy Africans, a new study shows, have different levels of white blood cells and other blood components. That shouldn't be a surprise, the doctor points out; the only shock is that it took this long for anyone to map out what's "normal" in Africa.
Dr. Kaleebu was part of a team that screened 5,500 clinically healthy, HIV-negative volunteers at a dozen sites across Africa, looking at blood chemistry and kidney and liver function, to develop the new reference ranges. The work was a partnership between the International AIDS Vaccine Initiative, for which Dr. Kaleebu is an investigator, the U.S. military's AIDS research program, and the U.S. Centers for Disease Control and Prevention.
While it is not possible to talk about values that are standard for the people in all 53 sub-Saharan African countries, the results of this two-year study do show that adults in Kenya, Zambia, Uganda and Rwanda have in common some differences from the Western values, including lower levels of lymphocytes, neutrophils - cells that "eat" anything they find that shouldn't be there - and red blood cells. They also had higher levels of eosinophils, which fight infection by parasites.
The findings are important for more than just recruiting volunteers to test AIDS vaccines - they will also be used in trials for treatments of a variety of infectious diseases, including malaria and tuberculosis. Using the results, researchers will now be able to monitor more accurately how volunteers in a trial are doing when they are taking a medication or vaccine. For example, a participant's red blood cell count might show up as "low" and cause worry, but compared against the new range, the cell count would not be deemed a concern. It will also give the researchers a better handle on how effective a treatment is.
Mark De Souza, international lab manager for the U.S. military HIV program, said that in one vaccine trial in Uganda, his staff screened out 58 per cent of potential participants because they had "abnormalities" based on the Western ranges. But when the volunteers were reassessed using values localized for the trial site, the screen-out rate was only 23 per cent, he said. "We were turning away heaps of healthy people," he said in a telephone interview from Bangkok.
There are genetic and environmental factors behind the differences. Compared with people in the West, Africans more commonly have parasites, or anemia, or some level of malaria exposure, which would cause them to test as unhealthy by the Western values even though they are well within the range of normal in their community, explained Pat Fast, the New York-based director of medical affairs for IAVI.
This does raise the question of whether the new reference ranges normalize conditions that are in fact the result of poor access to health care, a potential problem that all the researchers acknowledged, but they said the ranges are a first step toward improved care.
"Maybe if we completely revolutionized the health system, those values would be different," Dr. Fast said. "But it's not within our power to do that ... these people are living their lives and I bet most of them could out-work me."
The goal is to find a vaccine that is safe for people in this environment, and so it is crucial to test in their environment, she said. "It's important as much as possible to shift our locus to the countries we are trying to develop the vaccine for, to shift the way we think, the way we measure."
The new reference ranges may prove particularly relevant to AIDS treatment. Access to anti-retroviral drugs is increasing rapidly in Africa, which is home to 75 per cent of people with HIV. Drawing on Western experience, African patients are typically told to start AIDS treatment when their CD4 count level - a measure of the immune system - drops below 200. But if "normal" is already lower, treatment should perhaps be starting sooner. "A small shift in that curve could really change when you start treatment," Dr. Fast said. "You have to understand the normal before you start to understand disease."
