Abstract

Both immune activation and viral load are reduced within 28 days by VS411, the first antiviral-hyperactivation limiting therapeutic (AV-HALT) - a phase II study

E. Katabira¹, P. Cahn², J. Lange³, R. Maserati⁴, D. Baev⁵, S.A. Calarota⁵, D. De Forni⁵, M.R. Stevens⁶, J. Lisziewicz⁷, F. Lori⁵, for the VS411 Study Group

¹Makerere Medical School, Kampala, Uganda, ²Fundación Huesped, Buenos Aires, Argentina, ³IATEC, Amsterdam, Netherlands, ⁴Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, ⁵ViroStatics srl, Alghero (SS), Italy, ⁶ViroStatics srl, Princeton, NJ, United States, ⁷Genetic Immunity Kft., Budapest, Hungary

Background: Excessive immune activation drives disease progression and HIV-associated pathologies even with successful HAART. A new antiretroviral class, AV-HALTs, reduces both viral load and excessive immune activation. VS411, the first-in-class NRTI-based AV-HALT, combines low-dose, slow-release 2´,3´-dideoxyinosine (ddI) with low-dose hydroxycarbamide (HC) to accomplish both objectives with a favorable toxicity profile.
Methods: Multinational, double-blind, 28-day Phase IIa study: ART-naïve HIV-1-infected adults randomized into five VS411 dose arms. Activation/proliferation markers and HIV-specific T-cell responses analyzed by flow cytometry and ELISPOT. Results analyzed using ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t
tests.
Results: 58 subjects (median RNA: 4.50 log₁₀, CD4: 406.5 cells/mm³, 50% female, 50% black) enrolled and analyzed (ITT-exposed). VS411 produced significant viral load reductions (P< .001), CD4 increases (P=.002), and significant, rapid immune activation marker reductions without suppression of HIV-specific immune responses. There were no SAEs/discontinuations or major differences between arms in clinical/laboratory safety, nor induction of nucleoside resistance.


[VS411 results tables]


Conclusions: VS411 was well-tolerated, increased CD4 counts and reduced VL, T-cell activation, and proliferating (Ki-67+) CD4+ T-cells without suppressing HIV-specific immune responses. The ddI200mg/HC900mg QD formulation (doses lower than traditionally investigated) demonstrated the greatest CD4+ increase (+135 cells), fewest AEs, and VL reduction of -1.47 log₁₀. VS411 represents a new class, AV-HALTs, combining antiviral efficacy with novel, potentially beneficial reductions in the excessive immune system activation associated with HIV disease.
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