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Dare We Say "Eradication"?

Dare We Say "Eradication"?


Back in the dog days of summer and long since overshadowed by news of avian flu, an article about HIV in The Lancet cautiously used the word eradication. The claim was not that eradication had been achieved. Rather, the article discussed a proof-of-concept experiment that looked for at least some sort of positive result to encourage a larger investigation. The hypothesis started with the observation that valproic acid, a common drug called Depakote, blocked an enzyme that was important for maintaining resting memory T cells in their dormant state. HIV's persistence in these resting cells is the primary cause for our inability to eliminate the virus with combination therapy. Investigators wanted to see if they could 'awaken' these cells with valproic acid and cause their destruction with treatment. They took four patients whose disease was already fully suppressed by medication, intensified their regimens with Fuzeon for four to six weeks, added valproic acid for the next three months, and then measured the amount of HIV-infected resting T cells. In three of the patients the HIV-infected cells declined by an average of 75%. Was HIV eradicated? No. But it sure was nice to know that folks are still working on it. There are three main reasons HIV persists in patients with fully suppressed viral loads: (1) There is still low-grade replication when virus is undetectable. (2) Some cells that are infected with HIV turn over slowly. These include the resting memory T cells but also resting monocytes/macrophages and follicular dendritic cells in the center of lymph nodes. Our anti-HIV medications block replication of HIV in activated cells, not dormant cells that are just sitting there with HIV integrated into their nuclei. Activated T cells live about 1.6 days, and thus viral loads can drop over 90% in the first two weeks of treatment. But the resting memory T cells have a half-life of 44 months. This means it would take over 60 years of suppression on combination therapy before that population completely turned over. And if low-grade replication is still occurring, then some resting memory T cells may continually be reinfected. (3) HIV hides in sanctuaries, especially the brain, testes, and retina. These areas are harder to reach with antivirals. Various strategies have been tried and continue to be developed with new drugs and in different combinations: ' Intensifying combination therapy by adding a fourth or fifth antiviral can further reduce the low-grade viral replication in people already suppressed to below 50. We see this in studies showing fewer viral blips in those on extra medications. It also appears that the resting cells are not reinfected as much when they turn over in the face of intensified therapy. ''Stimulation of the resting cells can cause them to activate. This causes the integrated HIV to replicate and thus become susceptible to treatment. IL-2, IL-7, and interferon-gamma are some of these stimulators. The downside of these is side effects ranging from barely tolerable to life-threatening. There are also concerns about overwhelming HIV reproduction reinfecting sanctuary sites or producing resistance. ''Boosting the immune response to HIV using therapeutic vaccines or strategic therapy interruptions may help. So far, no vaccine has made it past a phase III trial, and the results of STIs are disappointing. What probably will be done is a mixture of all three approaches with combinations of drugs from each area. For example, IL-2, IL-7, and interferon-gamma each stimulate different resting cells and cause different viral isolates to appear. Eradication strategies are not for the weak of heart, nor should they be created ad lib by individual doctors. Eradication may be a charged word, but we need to charge ahead. Bowers is board-certified in family practice and is a senior partner with Pacific Oaks Medical Group, one of the nation's largest practices devoted to HIV care.

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