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Getting a Handle on Cross-Compartmental Viral Replication and Genotypic Resistance
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written by Bruce Polsky, M.D.
published on HIVresistanceWeb: July 24, 1998
The recent paper by Gunthard and colleagues suggests that so-called combination highly active antiretroviral therapy (HAART) results in complete cessation of viral replication in sanctuary sites when plasma HIV RNA levels are measured at less than 20 copies/mL. These investigators studied 10 patients on combination antiretroviral therapy for up to one year, looking at HIV-1 pol sequencing from plasma RNA, peripheral blood mononuclear cell (PBMC) RNA, PBMC DNA, lymph node (LN) RNA, LN DNA, as well as RNA from virus isolated from PBMCs or lymph nodes. They were not able to detect viral replication in any of these compartments when plasma HIV RNA was less than 20 copies/mL. Conversely, in patients with plasma HIV RNA levels between 20 and 400 copies/mL, an evolving pattern of drug resistance mutations was detected, suggesting that ongoing viral replication, albeit at low levels, is occurring in such patients. Patients for whom drug therapy was failing had multiply spliced RNA present, as well as extensive evidence of drug resistance mutations. The authors conclude that there is a significant difference in HIV replication between those patients with low-detectable viral loads and those who are "truly" undetectable.
Though appealing in theory, we have observed that nothing lasts forever. A prime example of this is found in the Italy, The Netherlands, Canada, Australia and (United) States (INCAS) trial, which looked at a triple combination regimen of AZT, ddI and nevirapine (a protease inhibitor-sparing regimen from the pre-protease inhibitor era), compared with dual nucleoside therapy. The INCAS investigators found that drug failure, and the subsequent development of resistance mutations, occurred in a substantial proportion of subjects who had plasma HIV RNA levels of less than 25 copies/mL for over one year. Thus, zero is probably rarely ever truly zero.
On the other hand, the recent findings of Notermans and colleagues indicate that increasing the number of drugs does seem to reduce not only plasma HIV RNA levels, but tonsillar lymphoid tissue RNA levels as well but not to zero. The message: Reduce viral replication by whatever means necessary.
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