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HIV Might Be Eliminated After Thirty Months Of Combination Therapy
Scientists are moving closer to answering the question of how long the new combination antiretroviral treatments will need to be administered to eradicate HIV-1 infection and if, in fact, this can be accomplished.
In the journal Science, and the journal Nature, AIDS researchers describe the effect of antiretroviral treatment on tissue reservoirs of HIV-1, in which infection may persist long after the virus becomes undetectable in plasma.
Dr. Ashley T. Haase of the University of Minnesota Medical School led a multicenter team that investigated the kinetic response of lymphoid tissue to a three-drug regimen that included a protease inhibitor and two reverse transcriptase inhibitors. For the study, 10 previously untreated HIV-1-positive subjects underwent tonsil biopsy before, during and after treatment began.
Following treatment, the researchers observed that HIV-1 burden was rapidly reduced. Specifically, they noted that the frequency of productive mononuclear cells, as determined by in situ hybridization and quantitative computer analysis, diminished with a half-life of approximately 1 day. Surprisingly, the amount of HIV-1 RNA in virus trapped on follicular dendritic cells decreased almost as quickly. Overall, Dr. Haase's team reports that 6 months of potent therapy controlled active replication and cleared >99.9 percent of virus from the secondary lymphoid tissue reservoir.
If viral clearance continues at this same rate, this extrapolates to elimination of viral RNA within an average of 30 months of triple antiretroviral therapy. They caution, however, that additional studies are needed to establish whether it is possible to completely purge HIV-1 infection from lymphoid tissue, or whether lifelong maintenance therapy will be required after initial 'induction' treatment.
The follicular dendritic cells, where most of the virus is stored, act as an "antigen depot," Dr. Haase stated. "To our surprise, the pool was reduced quite rapidly, and by 6 months, the virus was reduced by about 3000-fold." There are some important caveats, he continued. There are still substantial amounts of virus remaining. Their study simulated an "almost an ideal situation," with previously untreated patients receiving an optimal antiretroviral regimen. The projection of viral elimination within 30 months is based on the current rates of viral depletion, which may change if problems such as drug resistance develop. "Anything can throw a wrench into it," he added.
The next step, he said, will be to continue to follow these patients who are receiving optimal therapy, and to consider how this information can be applied in more practical clinical settings.
Dr. David D. Ho of the Aaron Diamond AIDS Research Center in New York, NY, and colleagues report a similar estimate of the time to eradication of HIV-1 for patients on combination antiretroviral therapy. Based on studies of 8 patients, Dr Ho's group demonstrate an approximate 99% decrease in plasma HIV-1 load within 2 weeks of beginning therapy, which is followed by a slow second phase decay of plasma viremia. They found that the loss of long-lived infected cells is a major contributor to the second phase, whereas the activation of latently infected lymphocytes. is only a minor source.
They estimate that 2.3-3.1 years of a completely inhibitory treatment would be required to eliminant HIV-1 from these compartments. Dr. Ho's group acknowledges the possibility of viral compartments or "sanctuary sites" that are as yet undetected, in which case eradication may take longer.
They add that despite recent progress in treatment of HIV-1 infection, it would be wrong to believe that we are close to a cure for AIDS. Because of the cost and toxicity of prolonged combination antiretroviral therapy, new strategies must be developed to facilitate the extinction of those viral 'embers' that could rekindle the infection.
Work by Dr. Robert F. Siliciano of Johns Hopkins University in Baltimore, Maryland and colleagues has also focused on the importance of tissue reservoirs for HIV-1. They now report on latent viral infection of resting CD4 T cells.
Because they are in an inactivated state, latently infected CD4 T cells are not affected at all by antiretroviral treatment. The "good news" is that the number of these latently infected cells is much smaller than suspected, with only about 10 million total cells in the body. The bad news, he said, is that these memory cells can last for years.
The critical question now is exactly how long it takes for memory CD4 T cells to turn over. To this end, Dr. Siliciano's group plans to continue to follow patients treated with combination antiretroviral therapy. Return to the top of this page
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