Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection

Abstract

Background: Human 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.

Methods: Patients 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).

Results: In 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.

Conclusions: The 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.