Researchers Go Beyond Viral Load to Assess the Complexities of Disease Progression
LifeGuide
[Treatment Horizons]
by Chael Needle
A new study published in JAMA by investigators at the Center for AIDS Research at Case Medical Center, led by Benigno Rodríguez, MD, suggests that relying on an initial viral load measurement—the amount of HIV, in this context, circulating in the blood—is a less accurate indicator of CD4 cell depletion and thus disease progression than once thought.
The impetus of the study evolved in part out of earlier research, in particular, a study led by Dr. John W. Mellors that, in a nutshell, indicated the rate of disease progression as measured by CD4 decline could be predicted by the viral load. This classic study, Dr. Rodríguez points out, looked at groups of people defined by relatively similar viral loads, instead of individuals. Indeed, “if you look at it that way the group of people with the higher viral load will have a faster rate of disease progression whereas the group of people with the lower viral loads will have a slower disease progression,” he says.
Yet Rodríguez and his colleagues were interested in asking whether this association held true on a patient-by-patient basis. Clinical experience had shown them that individual patients often did not fit the rule of high viral load-faster rate of disease progression. Some patients had low viral loads, and still progressed very rapidly and vice versa, he notes. Indeed, the study showed that the viral load could only account for about six percent of the variation in the rate of CD4 cell loss among patients.
Unmooring viral load from its typical association with disease progression can help physicians to treat patients with more complexity, of course. But the research also adds ballast to a paradigm shift in the AIDS science community, one which no longer focuses on initial viral load as a premiere marker of disease progression but takes a multipronged approach that looks to indirect mechanisms that drive disease progression.
One of these mechanisms is immune activation. “One of the characteristics of HIV infection is that there is this uncoordinated, disorderly activation of the immune system, which seems paradoxical since HIV and AIDS are immune deficiency diseases,” he says, going on to explain that the body regulates immune activation, initiating a process that ends in cell death for a majority of these immune-activated cells. If immune activation can cause HIV-associated immune damage at different levels of viral load, then what else might be driving the immune activation? Recently, the research team found elevated levels of certain microbial products in HIV-infected blood. Typically, he says, those microbial products can be traced to the bacteria that normally lives in the gut. Supporting evidence “suggest it is exposure to all those bacterial products that helps drive the persistent immune activation in HIV disease. This is not just coincidental. As a matter of fact, this is caused by HIV itself.” Other research shows that damage to the internal surface of the gut that begins in the very early stages of HIV infection helps release bacterial products into the blood. “You can see how if that damage is relatively permanent or relatively long-standing at least then you can see how [immune activation] can continue even after the viral load has decreased” as a result of, say, successful antiretroviral therapy.
Asked if the existence of HIV reservoirs come into play here, he quickly says, “You bet....Reservoirs are more than likely one of the sources of persistent attacks by HIV, even after adequate control of HIV replication in the blood. More than likely that is not enough to account for this persistent ongoing immune activation. The reason is this: When you look at those cells that I mentioned before, those cells that express markers of immune activation, if it were HIV per se that was causing this immune activation, what you would find is the majority of those cells that are activated are designed to respond specifically to HIV....[But] when you look at those cells you find that the majority of them are not designed to attack HIV. Therefore, it is not HIV itself that is driving this. It is something else. We suspect that these bacterial products play a role in that regard.”
When asked what he suggests treating physicians and patients do with this information, Dr. Rodríguez addresses how others have misinterpreted the study’s significance. First of all, he says, his research team’s work in no way questions the fact that HIV is the cause of AIDS. “It also doesn’t mean that viral load doesn’t have a role in treating and management. It absolutely does. Viral load measurement is very helpful in deciding whether or not a person is responding to antiretroviral therapy. And viral load, as a general guideline, provides information about how quickly a person is going to develop opportunistic infections, for example.”
Chael Needle wrote about adjunctive therapies for neuroAIDS in the November issue.
December 2006
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