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

Nancie M Archin, Manzoor Cheema, Daniel Parker, Ann Wiegand, Ronald J Bosch, John M Coffin, Joseph Eron, Myron Cohen, David M Margolis, Nancie M Archin, Manzoor Cheema, Daniel Parker, Ann Wiegand, Ronald J Bosch, John M Coffin, Joseph Eron, Myron Cohen, David M Margolis

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.

Conflict of interest statement

Competing Interests: Dr. Margolis and Dr. Eron have received academic honoraria from Merck Research Laboratories. No patents related to this study are pending.

References

    1. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, et al. The Challenge of a Cure for HIV Infection. Science. 2009;2009 323:1304–1307.
    1. Quivy V, Adam E, Collette Y, Demonte D, Chariot A, et al. Synergistic activation of human immunodeficiency virus type 1 promoter activity by NF-kappaB and inhibitors of deacetylases: potential perspectives for the development of therapeutic strategies. J Virol. 2002;76:11091–11103.
    1. Ylisastigui L, Archin N, Lehrman G, Bosch RJ, Margolis DM. Coaxing human immunodeficiency virus type 1 from resting CD4+ T cells: can the reservoir of HIV be purged? AIDS. 2004;18:1101–1108.
    1. Bowman MC, Archin NM, Margolis DM. Pharmaceutical approaches to eradication of persistent HIV infection. Expert Rev Mol Med. 2009;11:e6.
    1. Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, et al. Depletion of latent HIV infection in vivo. Lancet. 2005;36:549–555.
    1. Siliciano JD, Lai J, Callender M, Pitt E, Zhang H, et al. Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. Journal of Infectious Diseases. 2007;195:833–836.
    1. Sagot-Lerolle N, Lamine A, Chaix ML, Boufassa F, Aboulker JP, et al. Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. AIDS. 2008;22:1125–1129.
    1. Archin NA, Eron JJ, Palmer S, Hartmann-Duff A, Martinson JA, et al. Standard ART and Valproic Acid Have Limited Impact on the Persistence of HIV Infection in Resting CD4+ T Cells. AIDS. 2008;22:1131–1135.
    1. Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, et al. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol. 2003;41:4531–4536.
    1. Nettles RE, Kieffer TL, Kwon P, Monie D, Han Y, et al. Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART. JAMA. 2005;293:817–829.
    1. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15:893–900.
    1. Gandhi R, Bosch R, Aga E, Albrecht M, Adams E, et al. No Evidence for Decay in the Latent Reservoir in HIV-infected Patients Receiving Intensive Enfuvirtide-containing ART. 2009. 16th Annual Conference on Retroviruses and Opportunistic Infections, Montreal PQ; abstr. 424.
    1. Dinoso JB, Kim SY, Wiegand AM, Palmer SE, Gange SJ, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 2009;106:9403–8.
    1. Ghandi R, Zheng S, Bosch R, Chan E, Margolis D, et al. Raltegravir (RAL) intensification does not reduce low-level residual viremia in HIV-1-infected patients on antiretroviral therapy (ART): Results from ACTG A5244. 2009. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa.
    1. Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, et al. Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res Hum Retroviruses. 2009;25:207–12.
    1. Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, et al. Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem. 2009;284:6782–9.
    1. Archin NM, Keedy KS, Espeseth A, Dang H, Hazuda DJ, et al. Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors. AIDS. 2009;23:1799–806.
    1. Keedy KS, Archin NM, Gates AT, Espeseth A, Hazuda DJ, et al. A limited group of class I histone deacetylases acts to repress human immunodeficiency virus type 1 expression. J Virol. 2009;83:4749–56.
    1. Coiras M, López-Huertas MR, Pérez-Olmeda M, Alcamí J. Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Nat Rev Microbiol. 2009;7:798–812.
    1. Colin L, Van Lint C. Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies. Retrovirology. 2009;6:111.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera