1. IAS Conference on HIV Science 25 July 2017
HIV-Specific Broadly-Neutralizing Monoclonal Antibody, VRC01, Minimally Impacts Time to Viral Rebound Following Treatment Interruption in Virologically-Suppressed, HIV-Infected Participants who Initiated Antiretroviral Therapy during Acute HIV Infection
Trevor A. Crowell, Donn J. Colby, Suteeraporn Pinyakorn, Jintana Intasan, Khunthalee Benjapornpong, Kamonkan Tanjnareel, Nicolas Chomont, Lydie Trautmann, Sodsai Tovanabutra, Shelly Krebs, Diane Bolton, Adrian McDermott, Robert Bailer, Nicole Doria-Rose, Bijal Patel, Robert J. Gorelick, Brandie A. Fullmer, Pornsuk Visudhiphan, Robert J. O’Connell, Randall Tressler, John Mascola, Nelson L. Michael, Merlin L. Robb, Nittaya Phanuphak, and Jintanat Ananworanich for the RV397 and RV254/SEARCH010 Study Groups.
IAS Conference on HIV Science 25 July 2017
Thank you for the opportunity to present these data from the RV397 clinical trial of VRC01 administration to participants who initiated antiretroviral therapy during acute HIV infection. I am happy to present these data on behalf of my co-authors and the RV397 and RV254 study groups.

2. Background and Rationale
ART Initiation during Acute HIV Infection:
Limits reservoir establishment (Ananworanich, EBioMedicine 2016)
Enhances HIV reservoir decay (Buzon, J Virol 2014)
Limits viral diversity (Chamberland, Int J STD AIDS 2011)
Induces post-treatment control in some individuals (Saez-Cirian, PLoS Pathog 2013)
VRC01:
Protects against SHIV rectal and vaginal challenges (Pegu, Sci Transl Med 2014; Gautam, Nature 2016)
Reduces acute SHIV viremia and limits reservoirs (Bolton, J Virol 2015)
Decreases plasma HIV in viremic participants (Lynch, Sci Transl Med 2015)
Delays viral rebound after ART interruption (Bar, N Engl J Med 2016)
For reasons that have been previously described, individuals who initiated ART during acute HIV infection are excellent candidates for the testing of novel therapies with the goal of achieving HIV remission.
VRC01 is such a therapy. It is a broadly-neutralizing HIV-specific monoclonal antibody that targets the CD4 binding site. It’s antiviral activity has been well-established in pre-clinical and clinical trials. In participants with chronic, otherwise untreated HIV, VRC01 decreases plasma HIV RNA. In participants with chronic, treated HIV, VRC01 serial infusions delayed viral rebound after ART interruption as compared to historic controls.
Based on these prior findings, we undertook a randomized, placebo-controlled clinical trial of VRC01 administered to participants who initiated ART during acute HIV infection.

3. Hypothesis and Objectives
Participants receiving VRC01 40 mg/kg q3wk will have a higher rate of viral suppression at 24 weeks following analytic treatment interruption (ATI) as compared to participants receiving placebo
Primary Objectives:
Evaluate safety of VRC01 administered during ATI
Evaluate ability of VRC01 monotherapy to maintain virologic suppression at 24 weeks
Secondary Objectives:
Evaluate impact of VRC01 on viral dynamics, HIV reservoir, host immunity, and clinical outcomes
We hypothesized that participants receiving VRC01 would maintain a higher rate of viral suppression at 24 weeks following analytic treatment interruption as compared to participants receiving placebo.
The primary objectives of this study included evaluation of the safety of VRC01 and the ability of VRC01 monotherapy to maintain virologic suppression after ART cessation.
Secondary objectives included exploration of the impact of VRC01 on viral dynamics, HIV reservoirs, and other endpoints.

4. Analytic Treatment Interruption (ATI)
Study Design
Study Week -6 -4 2 6 24 32 48
VRC01 40mg IV q3wk (n=18)
Randomized 3:1
Placebo IV q3wk (n=6)
PI*
ART
Analytic Treatment Interruption (ATI)
Participants for this study were recruited from the RV254 cohort in Bangkok, Thailand. The study targeted enrollment of 24 adults who initiated suppressive ART during Fiebig stages I-III and whose HIV had been well-controlled for at least 2 years.
1) On the day of each participant’s first study infusion, ART was discontinued. Participants were randomized in a 3:1 ratio, stratified by Fiebig stage, to receive either VRC01 or placebo every 3 weeks for up to 24 weeks.
2) At 24 weeks, participants received their final study infusion and the study’s primary endpoint—virologic control with HIV RNA <50 copies/mL—was assessed.
3) Participants who demonstrated virologic control at week 24 continued observation off all therapies for up to another 24 weeks.
4) Throughout the study, participants were closely monitored for rebound viremia and other indications for ART resumption.
Volunteers from Thai Red Cross (RV254)
20-50 years old
Started on ART during AHI (FI-FIII)
Prescribed ART for ≥24 months
HIV-1 RNA <50 copies/mL
CD4 >400 cells/mm3
Primary Endpoint:
Virologic control (RNA <50 copies/mL)
Secondary Endpoints:
HIV Reservoirs
Inflammatory markers
CD4 count
= HIV RNA Assessment
Any positive HIV RNA prompts repeat quantitative testing at least every 3 days until negative or ART resumed
*4-week PI substitution for participants prescribed NNRTI

5. ART Resumption Criteria
Confirmed HIV RNA >1,000 copies/mL
Single HIV RNA >10,000 copies/mL
HIV RNA rise ≥0.5 log10copies/mL/day
Confirmed CD4 <350 cells/mm3
CD4 decline >50% from baseline prior to ATI
Clinical progression to CDC Category B or C disease
Acute retroviral syndrome
Pregnancy
Participant request for re-initiation of ART
The protocol stated that ART would be resumed for any of the reasons listed here.
Ultimately, every participant who restarted ART did so because of this first criterion, plasma HIV RNA above 1,000 copies/mL on two separate measurements at least one day apart.

6. Participant Flow Enrolled (N=23) Randomized (N=19) Placebo (N=5) VRC01
4 participants withdrawn prior to randomization
Randomized
(N=19)
Placebo
(N=5)
VRC01
(N=14)
This study had a target enrollment of 24 participants. However, enrollment was halted early because of barriers to the importation of study product into Thailand that developed after the study had started.
Nineteen participants were randomized and one of these participants experienced severe generalized urticaria during the first study infusion. The study infusion was discontinued and this participant did not undergo treatment interruption.
1 participant withdrawn due to SAE (generalized urticaria)
Treatment Interruption
(N=5)
Treatment Interruption
(N=13)

7. Participant Characteristics
VRC01
(n=13)
Placebo
(n=5)
Age, years
32 (21-50)
25 (23-48)
Duration of ART, years
3.1 ( )
2.7 ( )
CD4, cells/mm3
769 ( )
562 ( )
CD4/CD8 ratio
1.1 ( )
0.9 ( )
Fiebig Stage at ART Initiation, n (%)
I/II
8 (62%)
3 (60%)
III
5 (38%)
2 (40%)
Eighteen male participants did undergo treatment interruption and received all study infusions according to the protocol. Their characteristics are summarized here.
All characteristics presented as median (range) except for Fiebig stage

8. VRC01 Pharmacokinetics VRC01 40 mg/kg IV every 3 weeks
Target VRC01 trough: 50 μg/mL
Serum VRC01 levels at various timepoints are shown here. For all participants randomized to the VRC01 arm of the study, serum VRC01 levels were consistently above the target trough level of 50 micrograms/mL.
Additionally, functional assays demonstrated expected neutralization activity against tier-1 and tier-2 viruses when mixed with participant serum throughout the dosing interval.
VRC01 levels were in the target range even at the time of viral rebound in participants who experienced viral rebound during the infusion phase of the study.

9. Safety Outcomes One serious adverse event in VRC01 arm
Severe generalized urticaria during first study infusion
Infusion-related AEs included fatigue, nausea, infusion site pain, headache and infusion site bruising
One moderate bruising in VRC01 arm; all other AEs mild
No hospitalizations
No acute retroviral syndrome
No new drug resistance mutations
No anti-VRC01 antibodies
All participants re-suppressed after ATI
There was one serious adverse event in the study, which was the severe generalized urticaria that was previously mentioned. Most other adverse events were mild and rates were not substantially different between the VRC01 and placebo groups.
There were no hospitalizations, no cases of acute retroviral syndrome, and no participants with new drug resistance mutations at the time of viral rebound.
All participants were tested for anti-VRC01 antibodies at various timepoints, including at the time of ART resumption, and no anti-VRC01 antibodies were observed.
Once ART was reinitiated, all participants achieved virologic resuppression within about five weeks and many did so in considerably less time.

10. Viral Load After Treatment Interruption
This figure shows viral load measurements for the 18 study participants who underwent treatment interruption. The black lines represent participants in the VRC01 arm and the red lines represent those in the placebo arm. You can see that many participants in the placebo arm had detectable viremia at week 2 after ART was stopped. In the VRC01 arm, there appears to be a modest delay in the time to viral rebound.
(1) There is one participant, Participant 009 in the VRC01 arm, who maintained an undetectable viral load through week 42. This participant just experienced a detectable qualitative HIV RNA on Thursday.
Participant 009

11. Participant 009 24yo MSM, Fiebig III, TDF/3TC/EFV x 3.1 years
VRC01 Concentration: μg/mL
Total HIV DNA: copies/106 CD4
Participant 009 is a 24-year-old Thai man who has sex with men. He initiated ART during Fiebig stage III and had been virologically suppressed on tenofovir, lamivudine, and efavirenz for about 3 years at the time of entry into RV397. Serial viral load assessments for this participant were as shown.
Additional assessments via the ultrasensitive single copy assay reveal low-level viremia up to 1.5 copies/mL during the study period without progression to detectable viremia on standard clinical assays.
Total HIV DNA was measured in peripheral CD4 cells at multiple time points prior to treatment interruption and was in the range of 5-79 copies/106 cells.
VRC01 concentrations were well above the target trough of 50 mcg/mL throughout this participant’s dosing.
Single Copy HIV RNA: < copies/mL

12. Time to Virologic Rebound
(A) Time to HIV RNA >20 copies/mL
(B) Time to HIV RNA >1000 copies/mL
Log-rank Test: p=0.051
Log-rank Test: p=0.010
Overall, there is a trend toward delayed virologic rebound among participants receiving VRC01. This slide presents Kaplan-Meier curves evaluating time to rebound using two different threshold viral load levels.
On the left, 20 copies/mL is used, representing the lower limit of detection for the clinical HIV RNA assay used in this study. Participants in the placebo group experienced their first detectable viral load at a median of 14 days after treatment interruption, whereas participants in the VRC01 group experienced their first detectable viral load at a median of 26 days.
On the right side of the slide, the same analysis is presented using a higher threshold for viral rebound of 1000 copies/mL. Here we see a statistically significant delay in the time to viral rebound in the VRC01 group as compared to placebo.
Median (Range)
Median (Range)
Placebo 14 (14-29) days
Placebo 14 (14-32) days
VRC01 26 (9-65) days
VRC01 33 (13-67) days

13. Total HIV DNA All Participants (n=17) Placebo (n=5) VRC01 (n=12)
Correlation coefficient: -0.39
p=0.042
p=0.028
p=0.043
p=0.209
Viral rebound was associated with a small but statistically significant increase in total HIV DNA in the placebo group but not the VRC01 group.
In both groups, the overall frequency of infected cells remained low at all time points as compared to what is observed in individuals who initiated ART during the chronic phase of HIV infection.
Total HIV DNA at the time of treatment interruption was significantly, but not strongly, correlated with the time to rebound viremia.

14. Conclusions VRC01 was generally safe and well-tolerated
Trend toward delayed virologic rebound with VRC01
VRC01 monotherapy was insufficient to maintain viral suppression
Next steps:
Test combination therapy with monoclonal antibodies
Investigate factors that contributed to delay in rebound
In this small experience, VRC01 was generally well-tolerated when administered during intensely monitored interruption of antiretroviral therapy.
This randomized study demonstrated that VRC01 administration was associated with a trend toward delayed virologic rebound when given to participants who initiated ART during acute HIV infection.
However, VRC01 monotherapy was insufficient to maintain viral suppression, even in this carefully selected population. Mechanisms investigating breakthrough viremia require further investigation.
The efficacy signal observed in this study gives hopes that combination therapies, particularly ones with the next generation of more potent and long-lasting agents may be more efficacious.
Further research is needed to investigate mechanisms of virologic control and factors that impact time to viral rebound, particularly in the one person with sustained virologic control.
This study also adds to the body of evidence that treatment interruption studies can be safely conducted and future studies may also consider allowing for more prolonged periods of viremia prior to ART re-initiation in order to better observe the virologic effects of novel interventions.

15. Acknowledgments: Study participants! MHRP Nelson Michael Merlin Robb
Julie Ake
Jintanat Ananworanich
Sheila Peel
Sodsai Tovanabutra
Lydie Trautmann
Linda Jagodzinski
Diane Bolton
Shelly Krebs
Leigh Anne Eller
Mike Eller
Morgane Rolland
Rasmi Thomas
Hiroshi Takata
Supranee Buranapraditkun
Suteeraporn Pinyakorn
Ellen Turk
Madelaine Ouellette
Oratai Butterworth
COO
DCAC
Many more
Thai Red Cross
Praphan Phanuphak
Nipat Teeratakulpisarn
Nittaya Phanuphak
Eugène Kroon
Donn Colby
Mark de Souza
Nitiya Chomchey
Carlo Sacdalan
James Fletcher
Pornpen Tantivitayakul
Phillip Chan
Jintana Intasan
Khunthalee Benjapornpong
Kamonkan Tanjnareel
Many more
Chulalongkorn
Kiat Ruxrungtham
Sunee Sirivichayakul
Rungsun Rerknimitr
Sukalya Lerdlum
Phandee
Wattanaboonyongcharoen
Ponlapat Rojnuckarin
Sopark Manasnayakorn
AFRIMS
Robert O’ Connell
Kirsten Smith
Sandhya Vasan
Alexandra Schuetz
Siriwat Akapirak
Denise Hsu
Tanyaporn Wansom
Rapee Trichavaroj
Bessara Nantapinit
Pornsuk Visudhiphan
COG
U Montréal
Nicolas Chomont
Remi Fromentin
Louise Leyre
Amélie Pagliuzza
UCSF
Victor Valcour
Joanna Hellmuth
Jennifer Daniels
Yale
Serena Spudich
Leah Le
NIH
Anthony Fauci
John Mascola
Barney Graham
Carl Dieffenbach
Sarah Read
Richard Koup
Julie Ledgerwood
Adrian McDermott
Robert Bailer
Nicole Doria-Rose
Randall Tressler
Irini Sereti
Daniel Douek
Eli Boritz
Frank Maldarelli
Bijal Patel
Leidos-NCI Frederick
Jeff Lifson
Jacob Estes
Claire Deleage
Robert Gorelick
Robin Dewar
Brandie Fullmer
U Minnesota
Timothy Schacker
Drexel
Elias Haddad
U Missouri
Robert Paul
U Hawaii
Lishomwa Ndhlovu
Napapon Sailasuta
UNC
Gail Henderson
RTI International
Holly Peay
I would like to thank the dedicated and engaged volunteers who participated in this study as well as the extensive team of investigators who made this work possible. I am happy to answer any questions you may have.
Funding and Medication Support Provided by: U.S. Department of Defense, NIH, Thai GPO, ViiV Healthcare, Merck, Gilead