Abstract
BackgroundHuman immunodeficiency virus (HIV) infection that persists despite antiretroviral therapy (ART) is a daunting problem. Given the limited evidence that resting CD4+ T cell infection (RCI) is affected by the histone deacetylase (HDAC) inhibitor valproic acid (VPA), we measured the stability of RCI and residual viremia in patients who added VPA with or without raltegravir (RAL), or enfuvirtide (ENF) with or without VPA, to standard ART.MethodsPatients with plasma HIV RNA<50 c/mL added sustained-release VPA (Depakote ER®) twice daily, RAL 400 mg twice daily, or ENF 90 mcg twice daily. Change in RCI was measured by outgrowth assays. Low-level viremia was quantitated by single-copy plasma HIV RNA assay (SCA).ResultsIn three patients on standard ART a depletion of RCI was observed after 16 weeks of VPA, but this effect waned over up to 96 weeks of further VPA. In two patients ENF added to stable ART had no effect on RCI. Simultaneous intensification with ENF and addition of VPA had no effect on RCI frequency in one patient, and resulted in a 46% decline in a second. No significant depletion of RCI (>50%) was seen in six volunteers after the addition of RAL and VPA. In 4 of the 6 patients this lack of effect might be attributed to intermittent viremia, low VPA levels, or intermittent study therapy adherence. Overall, there was no effect of the addition of RAL or ENF on low-level viremia measured by SCA.ConclusionsThe prospective addition of VPA and RAL, VPA and ENF, or ENF failed to progressively reduce the frequency of RCI, or ablate intermittent and low-level viremia. New approaches such as more potent HDAC inhibition, alone or in combination with intensified ART or other agents that may disrupt proviral latency must be pursued.
Highlights
Given the costs and difficulties in maintaining suppression of viremia in the Human immunodeficiency virus (HIV)-infected patients for decades, and the challenges that face effective prevention of HIV infection, interest has reawakened in interventions that might eradicate HIV infection [1]
3 HIV-infected males stably suppressed on antiretroviral therapy (ART) and previously treated with valproic acid (VPA) in whom a significant decline in resting CD4+ T cell infection (RCI) was measured after 16 weeks of VPA agreed to further study on treatment with VPA
Despite continuous ART and VPA, the depletion of RCI seen at week 16 regressed to baseline at 48 and 96 weeks (Table 1)
Summary
Given the costs and difficulties in maintaining suppression of viremia in the HIV-infected patients for decades, and the challenges that face effective prevention of HIV infection, interest has reawakened in interventions that might eradicate HIV infection [1]. Reagents that selectively induce the expression of quiescent proviral genomes but have limited effects on host cell activation and susceptibility to infection might allow outgrowth of latent HIV, and avoid the pitfalls of global T cell activation [2,3]. In one small pilot study RCI was depleted when intensified ART was given in combination with generic VPA, an anticonvulsant and non-selective HDAC inhibitor [5]. Given the limited evidence that resting CD4+ T cell infection (RCI) is affected by the histone deacetylase (HDAC) inhibitor valproic acid (VPA), we measured the stability of RCI and residual viremia in patients who added VPA with or without raltegravir (RAL), or enfuvirtide (ENF) with or without VPA, to standard ART
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