Top Ten Research Reports of 2003
7. Continued Reverse Transcriptase Inhibitor Therapy Is Sufficient to Maintain Short-Term Partial Suppression of Multi-Drug Resistant Viremia
Deeks S. G., Martin J. N., Hoh R. et al. Continued Reverse Transcriptase Inhibitor Therapy Is Sufficient to Maintain Short-Term Partial Suppression of Multi-Drug Resistant Viremia. Presented at: 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Mass. Abstract 640.
BackgroundJust when we thought we understood the fundamentals of HIV drug resistance, along comes a study that teaches us how much we still have to learn. We do know for a fact that it is not uncommon to observe patients on treatment who have viral loads well below their pre-therapy levels and CD4 cell counts that remain improved, yet who have low-level viremia and mutations to their current regimen.
A possible explanation for this common phenomenon is that the mutations the virus has developed have come at a cost to viral pathogenicity (i.e., the virus becomes less fit and therefore less able to replicate). This also explains why, when an antiretroviral regimen is discontinued in such patients, their viral load typically shoots up, their CD4 cell count plummets and resistant virus is supplanted by more pathogenic, wild-type virus -- Darwinian evolution over the course of a few weeks.
What Is New Here?In a study presented at CROI 2003, Steven Deeks and colleagues closely observed what occurred when 20 patients with persistent, detectable, multi-drug-resistant viremia, while on stable antiretroviral therapy with a protease inhibitor and nucleosides for at least one year, either stopped their PI (n=15) or their nucleosides (n=5). The choice of which therapy was to be discontinued was based on the toxicity a patient was experiencing at the time of study entry.
What happened next will explain why this is one of 2003's most critical studies: 13 of the 15 patients who stopped their PI had both stable viral loads and CD4 cell counts after 16 weeks. Their toxicities improved, as did their lipids. PI mutations were no longer seen on genotype testing, since the selective pressure from the PI was gone and the risk of accumulation of new PI-associated resistance was reduced. In contrast, the five subjects who discontinued their NRTIs experienced a significant rise in their viral loads and an average 97-cell drop in their CD4 cell counts.
The Bottom LineThis study overturns many of our assumptions about resistance. Few would have accurately predicted the outcome observed by the investigators. The implication here is that the nucleosides may be doing more than we have ever recognized, even when resistance to these drugs is present. Practically speaking, these data suggest that for similar patients, the removal of a protease inhibitor and the maintenance of the nucleosides may be an option to prevent the cultivation of further PI resistance and limit toxicity. Periodic PI administration may help keep viral loads down and inevitable nucleoside failure at bay. In addition, continuation of "failing" nucleosides, as is commonly done with 3TC, may be a prudent approach to salvage therapy.
On a theoretical level, these preliminary data help us appreciate that resistance is not black and white, that partial antiviral effects may persist and that the impact of resistance on viral fitness may increasingly play a role in our treatment decision making.
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