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Combination therapy with the broadly neutralizing antibody VRC07'523LS and the latency reversal agent Vorinostat fails to substantially reduce latent, resting CD4+ T cell infection or reduce low-level viremia

Title
Combination therapy with the broadly neutralizing antibody VRC07'523LS and the latency reversal agent Vorinostat fails to substantially reduce latent, resting CD4+ T cell infection or reduce low-level viremia
Presenter
David M. Margolis
Authors
D.M. Margolis * (1), K.S. James (1), M. Tuyishime (2), S.D. Falcinelli (1), S.B. Joseph (1), B. Allard (1), J.L Kirchherr (1), M. Clohosey (1), R.J. Gorelick (3), L. Gama (4), R.A. Koup (4), J.R. Mascola (4), M. Floris-Moore (1), G. Ferrari (2), J.J. Eron (1), J.D. Kuruc (1), N.M. Archin (1), C.L. Gay (1)
Institutions
(1) University of North Carolina at Chapel Hill, UNC HIV Cure Center, Chapel Hill, United States, (2) Duke University Medical Center, Department of Surgery, Durham, United States, (3) Frederick National Laboratory for Cancer Research, Frederick, United States, (4) Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, United States

BACKGROUND: Approaches to deplete persistent HIV infection are needed. We investigated the combined impact of the latency reversing agent vorinostat (VOR) and VRC-07-523-LS, a broadly-neutralizing HIV antibody with prolonged half-life, on the HIV reservoir in HIV+ participants on stable antiretroviral therapy (ART).
METHODS: Participants with HIV'1 Infection on ART with a CD4 T cell count '¥ 350 cells/mm3 and viral suppression for '¥ 24 months received two cycles of intravenous VRC07'523LS at 40 mg/kg followed by 10 oral doses of 400 mg VOR every 72 hours. Cycles were separated by at least one month. ART was maintained throughout the study. Change in low-level HIV viremia, resting cell-associated HIV RNA (rca-RNA), Intact Proviral DNA assay (IPDA), and the frequency of resting CD4+ T-cell infection (QVOA; quantitative viral outgrowth assay) was measured at baseline and after the treatment cycles.
RESULTS: No serious treatment-related adverse events were observed among eight participants. Following cycles of VRC07-523LS and VOR, declines of IPDA or QVOA were seen, that did not reach statistical significance. Of note, we observed significant declines of rca-RNA despite exposure to VOR in three participants although non-significant depletions of IPDA and QVOA were observed. Viral isolates recovered from resting CD4 cell outgrowth assays did not acquire increased resistance to VRC-07 during the study. Low-level viremia ('¤50 copies/mL) was absent or barely measurable in most participants. However, one participant maintained viremia of ca. 30 copies/ml throughout the study, despite the lack of evidence of VRC07 resistance.
CONCLUSIONS: VRC07-523LS and VOR were safe and well-tolerated. Downward trends in some parameters of HIV persistence were observed, but a definitive reduction in the HIV reservoir as measured by a 50% decrease in QVOA was not measured. The persistence of low-level viremia in one participant raises the concern that Ab-directed clearance may not be efficient enough to impact small populations of transiently productive infected cells. More efficacious antiviral immune interventions, likely paired with more effective latency reversal approaches that are now emerging, must be developed to clear persistent HIV infection.