Viremia Increases During Treatment Interruption After Long Term Virologic Failure.
RM Grant*, T Wrin, J Barbour, T Liegler, C Petropoulos, N Hellmann, and S Deeks.
Gladstone Institute of Virology and Immunology; University of California, San Francisco; ViroLogic, South San Francisco.
BACKGROUND:Immunological and clinical failure of protease inhibitor containing regimens is still rare despite high rates of virological failure in clinical practice. Persistent partial suppression of viremia after the appearance of drug resistant HIV-1 correlates with the amount of CD4+ preservation. METHODS: To study the virological basis of persistent partial virological responses, we prospectively followed subjects in long term virological failure who either discontinued (N=18) or continued antiretroviral therapy (N=6). RESULTS: Subjects had received PI containing therapy for a median 35 months and had been in virologic failure for a median 28 months. Prior to stopping antiretroviral therapy, these subjects had substantial levels of viremia (median 4.55 log10 cpm) that remained lower than their pre-protease inhibitor baseline (median -0.31 log10 cpm; range -0.61 to +0.02). Subjects typically had multi-drug resistant HIV-1 prior to stopping therapy, which was overgrown by drug sensitive variants after median 5.5 weeks (IRQ 4-7 weeks) in 17/18 subjects, demonstrating decreased fitness of the drug resistant HIV-1 in vivo. Greater degree of viral suppression at baseline and lower PI resistance were independently associated with more rapid overgrowth of wild-type HIV-1. Viremia increased after stopping therapy (median change +0.48 log10 cpm) and prior to loss of drug resistance suggesting that antiretroviral therapy had continued partial activity against the resistant HIV-1 population. After overgrowth of drug resistant HIV-1, viremia increased an additional median +0.48 log10 cpm, despite marked decreases in circulating CD4+ target cells, demonstrating the increased capacity of drug sensitive HIV-1 to achieve high level viremia. MODELING: A simple mathematical model in which drug resistant and sensitive HIV-1 populations, that differ with respect to infectivity, compete for target CD4+ cells was developed. Preliminary analysis of this model indicates that resistant virus infectivity that is substantially less than wild-type could account for the data, including 0.4 log10 persistent suppression of resistant viremia during therapy and a 5 week delay to wild-type rebound after treatment interruption. CONCLUSION: These data indicate that partial viremia suppression and persistent CD4+ gains after virological failure of PI containing regimens is dependent on continued exposure to antiviral therapy that are partially active against drug resistant HIV-1 and maintain selection for less fit viral populations.
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