February 6, 2001
Persistence of HIV in long-lived viral reservoirs remains one of the main obstacles to the goal of viral eradication, as well as providing a site for potential virus evolution and resistance, even with "suppressive" antiretroviral therapy. In addition, it has been observed that intermittent viremia -- "blips" -- correlate with a slowing of the decay of this pool of virus. In this study, treatment intensification -- adding drugs to an already successful regimen -- was evaluated as a means potentially to reduce the size of the latent reservoir.
Ten subjects were studied. Five who were receiving treatment with AZT/3TC plus either nelfinavir or ritonavir/saquinavir had intensification of their therapy with abacavir (four patients) or both abacavir and efavirenz (one patient). A group of five additional patients served as controls. (The study was non-randomized.) Treatment intensification lasted for a mean of 14 months, with measurements during this time being viral load and latent reservoir as measured by infectious units per million peripheral blood mononuclear cells (IUPM).
In four out of five of the patients, the frequency of intermittent viremia decreased from a mean of 3.3 episodes/year to 0.7/year, while remaining unchanged in the group who did not have intensification. In addition, the half life of the latent reservoir decreased from a mean of 31 months to 10 months, with again no change in the group whose treatment remained unchanged.
What are the implications of this small study for clinical practice? It is clear that current standard antiretroviral therapy does not fully suppress viral replication, and that this ongoing replication contributes to the incurable nature of HIV disease. However, despite the reduction in viral reservoir seen here with treatment intensification, the immediate clinical effect of such a strategy is likely to be limited to the adverse effects of the added drugs, since patients with very low viral loads and occasional "blips" are at extraordinarily low risk for complications of HIV disease. In other words, the viral reservoir alone does not (as far as we know) cause anyone to feel directly sick from HIV. One can therefore think of this as a "proof of concept" study, where with potentially more potent and less toxic drugs we could again even begin to consider the prospect of viral eradication.
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