HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression

Abstract

Identifying the immunologic and virologic consequences of discontinuing antiretroviral therapy in HIV-infected patients is of major importance in developing long-term treatment strategies for patients with HIV-1 infection. We designed a trial to characterize these parameters after interruption of highly active antiretroviral therapy (HAART) in patients who had maintained prolonged viral suppression on antiretroviral drugs. Eighteen patients with CD4 ؉ T cell counts > 350 cells͞l and viral load below the limits of detection for >1 year while on HAART were enrolled prospectively in a trial in which HAART was discontinued. Twelve of these patients had received prior IL-2 therapy and had low frequencies of resting, latently infected CD4 cells. Viral load relapse to >50 copies͞ml occurred in all 18 patients independent of prior IL-2 treatment, beginning most commonly during weeks 2-3 after cessation of HAART. The mean relapse rate constant was 0.45 (0.20 log 10 copies) day ؊1 , which was very similar to the mean viral clearance rate constant after drug resumption of 0.35 (0.15 log 10 copies) day ؊1 (P ‫؍‬ 0.28). One patient experienced a relapse delay to week 7. All patients except one experienced a relapse burden to >5,000 RNA copies͞ml. Ex vivo labeling with BrdUrd showed that CD4 and CD8 cell turnover increased after withdrawal of HAART and correlated with viral load whereas lymphocyte turnover decreased after reinitiation of drug treatment. Virologic relapse occurs rapidly in patients who discontinue suppressive drug therapy, even in patients with a markedly diminished pool of resting, latently infected CD4 ؉ T cells.HIV-1 infection ͉ antiretroviral drugs ͉ viral load ͉ relapse ͉ CD4

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“…HIV-1-infected individuals on ART with suppressed plasma viral loads progressively lose HIV-1-specific CTLs, suggesting that persistent viremia is required to maintain high frequencies of HIV-specific CTLs. In chronic HIV-1 infection, discontinuation of ART has been uniformly accompanied by a rapid rebound of plasma HIV-1 RNA to pretreatment, steady-state levels, indicating persistence of the HIV reservoir and absence of immune control (8,20,25). For these reasons, immunotherapeutic strategies with the potential to suppress viral replication and with the goal of eliciting broad, robust, and durable HIV-1-specific TH1 and CTL responses are needed.…”

Four days a week or less on appropriate anti‐HIV drug combinations provided long‐term optimal maintenance in 94 patients: the ICCARRE project

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