Science seemed to play second fiddle to politics and policy at the XIII International AIDS Conference in Durban, South Africa. There were no shattering scientific revelations, but a series of generally positive confirmatory findings deepened and broadened our understanding of how to better manage combination therapy.
The mantra of suppressing HIV viral load below a level of detection is softening a bit as evidence of longer-term clinical use of HAART accumulates. New York physician Jeffrey Greene followed 95 patients for three years and found no statistical difference between those who were able to suppress their virus below 50 copies and those who lingered between 50 and 400 copies.
In Washington, D.C., physician Douglas Ward focused on 22 patients who had a transitory "blip" of viremia from undetectable to between 50 and 400 copies. Without changing their drug regimen, 14 returned to undetectable on their next test, while 2 others took a little longer to do so.
The group was largely treatment experienced. Only 4 of the 22 were on their first drug combination and they all were able to regain control of the virus; 12 on a salvage regimen were able to do the same, while 6 were not. Adherence was not evaluated in this study.
These transitory blips are "not necessarily an indication of failure of an antiviral regimen," Ward concluded. His study strongly suggests caution rather than urgency in reacting to the appearance of low levels of viremia in patients whose viral load previously were undetectable. Switches in therapy should be based upon sustained trends not a single test result.
The importance of strict adherence in taking combination therapy in the prescribed manner was reinforced by several presentations. Most notable was a study by A. Carmonal that followed 736 patients on HAART over nearly two years, in Barcelona, Spain. Good adherence meant taking 90 percent or more of the prescribed doses as determined by interviews and pill counts.
Carmonal found that compliant patients were rewarded with a mortality of 1.8 percent, while poor compliance resulted in 8.4 percent rate of death. It was less clear whether or not the illness and debility of advanced disease contributed to poor adherence.
STI vs SIT
"What's in a name?" asked William Shakespeare. At Durban there were the beginnings of a squabble over what to call a planned stoppage of therapy and what it is suppose to accomplish.
Bruce Walker ( Harvard University ) and Franco Lori ( Georgetown University ) have championed structured treatment interruption ( STI ) as a way to boost the body's killer t-cell response to assist in fighting HIV. It is based on the ideas that the immune system needs a relatively high level of exposure to HIV, over an extended period of time, in order to develop that response.
HAART suppresses the virus so successfully that the level of HIV falls below what is necessary to prime t-cells to play that role, and eventually their response fades. Stopping therapy allows the virus to multiply, which reactivates the t-cells. In theory, cycling on and off therapy may stimulate t-cells and build up that response to play a greater role in controlling viremia, perhaps even without therapy for extended periods of time.
Initial research in small numbers of patients offers some evidence that this may be possible for some but probably not for all patients.
At Durban, Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases weighed in with his competing acronym called structured intermittent therapy ( SIT ) .
Waxing unusually philosophical and less data driven, Fauci reviewed how current therapies are not capable of completely eradicating HIV, that reservoirs remain from which virus will continue to emerge, likely for decades.
Side effects associated with current therapies— lipodystrophy, metabolic abnormalities, mitochondrial and liver toxicities—make it "almost certainly not feasible to have people on therapy for an indefinite period of time," he said.
But Fauci was less enthusiastic about the long-term impact of t-cells in controling viremia. His lab has initiated a series of on/off experiments "to find a point where as little drug as possible can be given over a period of time."
Mark Dybul reported on three strategies being tried at NIAID in patients on HAART with undetectable viral loads. A cycle of two days on and five days off did not drive the re-emergent virus back below 50 copies in two of the three patients.
Five patients who alternated one week of therapy and holiday were always able to get their viral load back under 50 copies, at least through the seven cycles of data presented. Their t-cell counts did not change significantly during the trial.
The third group tried a month off therapy and two months back on. Nine patients have made it through two or three such cycles. They showed initial rises in viral load and drops in CD4 count but re-initiation of therapy brought those numbers back to where they were before treatment was stopped. Some showed lower viral rebounds on subsequent interruptions, indicating a possibly juiced up t-cell response.
Just how high the viral load has to rise and how long it has to stay there in order to stimulate the appropriate t-cell response are far from clear. And patient response likely will be highly variable, dependent upon factors such as personal genetics and disease history.
Fauci stressed that these small studies were created to help shape a larger clinical trial. Because of their small numbers, they should not be interpreted as an indication of what should be normal clinical practice.
For patients, the "debate" over nomenclature of STI or SIT bears at least a passing resemblance to the long-running Miller Lite ad campaign of "Taste's great" vs. "Less filling." But, to return to Shakespeare, "a rose ( of fewer toxic drugs ) by any other name would smell as sweet."
Research over the next few years should reveal a better sense of the balancing act between using intermittent therapy and our own immune system to manage chronic HIV infection.
