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ACTG 5340:The Effect of VRC01 on Viral Kinetics After Analytic Treatment Interruption
Katharine J. Bar1; Linda J. Harrison2; Edgar T. Overton3; Mark Bardsley1; Michael Messer4; Edmund Capparelli5; Barney Graham6; Richard A. Koup7; James A. Hoxie1; Pablo Tebas1; for the AIDS Clinical Trials Group (A5340 team)
1Univ of Pennsylvania, Philadelphia, PA, USA;2Harvard Sch of PH, Boston, MA, USA;3Univ of Alabama at Birmingham, Birmingham, AL, USA;4Univ of Alabama School of Medicine, Birmingham, AL, USA;5Univ of California San Diego, San Diego, CA, USA;6NIAID, NIH, Bethesda, MD, USA;7VRC, NIAID, NIH, Bethesda, MD, USA
Broadly neutralizing anti-HIV monoclonal antibodies (bNAbs) have shown promising results for the prevention and treatment of HIV. We present data evaluating whether high dose passive administration of VRC01, a bNAb targeting the CD4 binding site, can prevent or delay the return of viremia after ART interruption.
ACTG A5340 is an open-label study of the safety, tolerability, pharmacokinetics (PK) and antiviral activity of VRC01 in suppressed HIV-1 infected individuals undergoing a monitored analytical treatment interruption (ATI). We administered VRC01 40 mg/kg by intravenous infusion every 3 weeks for a total of 3 doses starting 1 week before the ATI. Thirteen evaluable participants provided 95% power to detect a 40% difference a rebound probability of 90% at 8 weeks without intervention using a one-sided test and 5% significance level. All participants were on protease (PI) or integrase (INSTI) based ART that was restarted after confirmed HIV RNA ≥200 c/ml.
We enrolled 14 participants; 100% male, 50% African American. Median CD4 count was 896 c/mm3 (IQR 579-1053) and nadir >200 c/mm3 for all participants. Median time on ART was 4.7 years (IQR 3.8-6.0); 71% were on INSTI and 29% on PI regimens at entry. VRC01 was safe and well tolerated. No grade 3 or higher, or grade 2 VRC01-related, adverse events were observed.
One participant was excluded from antiviral activity analysis because he stopped ART before the first VRC01 dose. Despite median trough VRC01 concentrations of 90.4 mcg/ml (range 71.5-135.5) 3 weeks after the first dose, viral rebound occurred before week 8 of the ATI for the majority of participants (Figure). Notably, we detected a delay in rebound when compared to non-NNRTI historical controls from prior ACTG studies; 45% vs 13% were virally suppressed to week 4 (Fisher’s exact p=0.02) and 9% vs 3% to week 8 (p=0.40). Two participants maintained suppression for 7 and 10 weeks in the absence of any other ART. Participants were off ART for a median of 5 weeks and 10/11 (2 participants are still in the ATI phase) resuppressed <50 c/ml within 4 weeks.
Passive immunization with high doses of a single bNAb (VRC01) failed to prevent rebound viremia in the majority of participants, although rebound was delayed when compared to historical controls. We are evaluating the baseline and rebound virus sensitivity to VRC01, PK, immunological and virological parameters. These data will inform the next strategies to utilize bNAbs, alone or in combination.