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Effect of Infusion of Broadly Neutralizing Antibody VRC01 on HIV Plasma Rebound
Tae-Wook Chun1; Michael Sneller2; Catherine Seamon1; Jesse S. Justement1; Mary E. Petrone1; Eric Refsland1; Julie Ledgerwood3;Katherine Clarridge1; Susan Moir1; Anthony S. Fauci1
1NIAID, NIH, Bethesda, MD, USA;2National Insts of Hlth, Bethesda, MD, USA;3VRC, NIAID, NIH, Bethesda, MD, USA
Recent advances in immunogen and antibody cloning technologies have led to the isolation of several highly potent and broadly neutralizing HIV-specific antibodies (bNAb) from B cells of infected individuals. Among these, VRC01 has proven to be effective in neutralizing diverse strains of HIV in vitro and in animal models and has the capacity to suppress plasma viremia in infected individuals. However, the ability of VRC01 to suppress plasma viral rebound in HIV-infected patients following cessation of antiretroviral therapy (ART) remains unclear.
An exploratory, open-label clinical trial was conducted to examine the effect of passive transfer of VRC01 on plasma viral rebound following discontinuation of ART in HIV-infected individuals who initiated ART during the chronic phase of infection and who suppressed plasma viremia >3 years with CD4+ T cell count > 450 cells/mm3 at enrollment. Subjects received VRC01 (40mg/kg) 3 days prior to and 14 and 28 days following interruption of ART, and monthly thereafter for up to 6 months. Levels of plasma viremia and VRC01 were measured at day -7, -3, 0, 3, 7, 14, 21, and 28 and biweekly thereafter. In addition, the capacity of VRC01 and other bNAbs to neutralize autologous infectious HIV prior to and following infusions of the antibody was examined.
10 subjects were enrolled in the study. Mean duration of ART was 10.6 years. Mean CD4+ and CD8+ T cell counts at baseline were 796 and 768 per mm3, respectively. Multiple infusions of VRC01 were safe and well tolerated. 9/10 subjects experienced plasma viral rebound (>40 copies/ml) between 11-54 days (median 39) following cessation of ART; 8 subjects reinitiated ART per protocol. Plasma concentration of VRC01 ranged between 142-352 µg/ml (median 160) at time of first detectable plasma viremia. Preliminary analyses of autologous replication-competent viral isolates revealed the existence of VRC01-resistent virus prior to infusion of antibody in several subjects; further assessment of prior and post-treatment resistance is ongoing.
While multiple infusions of VRC01 were safe and well-tolerated, the majority of patients experienced plasma viral rebound despite adequate levels of antibody in plasma. Therefore, therapeutic strategies involving passive transfer of bNAbs may require a combination (s) of Abs and/or resistance prescreening in order to achieve sustained virologic control in HIV-infected individuals upon withdrawal of ART.