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Conflicts of Interest Nothing to disclose. Conflicts of Interest Nothing to disclose.

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Presentation on theme: "Conflicts of Interest Nothing to disclose. Conflicts of Interest Nothing to disclose."— Presentation transcript:

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2 Conflicts of Interest Nothing to disclose

3 HIV Remission Trials: Correlates of Rebound
Carlo Sacdalan, MD, MBA Clinical Research Physician SEARCH, The Thai Red Cross AIDS Research Centre Share your thoughts on this presentation with #IAS2019

4 Outline HIV remission trials overview HIV remission trials –results
Factors associated with rebound during ATI

5 HIV Treatment interruption Trials (2000-2017)
100 Nonintervention studies 59 Intervention studies Lau, AIDS April 2019

6 Trials done at Thai Red Cross AIDS Research Centre
HIV Treatment interruption trials with intervention done from 2014 to 2017 22 4* Trials done at Thai Red Cross AIDS Research Centre * Plus RV405 study presented in Keystone Symposia 2019 Lau, AIDS April 2019

7 RV254 and HIV Remission Trials
RV254/SEARCH010 Acute infection cohort with early ART RV411 (n=8) Fiebig I ATI, Single arm Early ART in Fiebig I Real-time screening of 343,663 samples in Thailand Remission trials RV409 (n=15) Fiebig III/IV VHM+ART (n=9) vs. ART (n=5) Latency Reversal Acute HIV infection (n=614 enrolled/781 detected) Monitoring VL q3-7 days ART resumption VL > 1000 copies Outcomes Safety VL control 24 weeks post ATI Modifying Immune Response RV397 (n=18) Fiebig I to III VRC01 (n=13) vs. placebo (n=5) Immediate ART (n=609) RV405 (n=27) Fiebig I to IV Ad26/MVA (n=18) vs. placebo (n=9) ATI: analytical treatment interruption VHM: vorinostat+hydroxychloroquine+maraviroc

8 Analytic treatment interruption studies from the RV254 cohort (n=67)
Acute infection Stop ART/ monitor rebound On ART No Intervention N=27 n=8 Fiebig I RV411 Vorinostat n=9 Fiebig III/IV hydroxychoroquine + maraviroc RV409 n=5 Fiebig III Control Intervention pre-ATI N= 27 VRC01 n=13 Fiebig I-III RV397 n=5 Fiebig II/III Placebo Intervention post-ATI N= 13 Ad26 MVA n=18 Fiebig II-IV RV405 n=9 Fiebig I-III Placebo Kroon, IAS, 2016; Colby, Nature Medicine, 2018; Crowell, Lancet HIV 2019, Slide courtesy of Nicolas Chomont

9 RV411: Early ART in Fiebig I
ART resume at VL > 1000 c/ml Median time to viral load rebound >20 copies/ml: 26 days (range days) Very early ART alone is inadequate to achieve HIV remission Colby, Ananworanich, Nature Medicine 2018 Intervention: Early ART in Fiebig I

10 HIV Reservoir Size in Fiebig I
Pre-ATI total HIV DNA (median 1 copy/106CD4) vs. Time to VL rebound Total HIV DNA in CD4 From pre-ART to ATI to ART resumption Reservoir size (total HIV DNA in CD4) at VL rebound - smaller than at acute infection Pre-ATI HIV DNA was not significantly associated with time to VL rebound Leyre, Pagliuzza Chomont (U Montreal) Intervention: Early ART in Fiebig I

11 Pre-ATI CD4/CD8 ratio and time to VL rebound
RV411: CD4/CD8 ratio ≤ 1 faster rebound n=3 n=5 p=0.004 All studies, (n = 67): no difference Colby, Ananworanich, Nature Medicine, 2018 Intervention: Early ART in Fiebig I

12 RV409: Vorinostat, HCQ, Maraviroc (VHM) +ART vs ART
ART resume at VL > 1000 c/ml Median time to first VL detection: 22 days (range 14 to 77 days) No difference between active and non active study arms Kroon, de Souza, IAS 2016 (manuscript submitted) Intervention: Vorinostat

13 Potential for improved response with better and multiple bNAbs
RV397: VRC01 vs Placebo Trend toward delayed virologic rebound with VRC01 in people suppressed during acute HIV infection Potential for improved response with better and multiple bNAbs Crowell, Colby, Ananworanich, 2017 IAS Intervention: VRC01 vs Placebo

14 RV405: Ad26/MVA vs Placebo Ad26/MVA Placebo P Value
Time to VL >20 copies/mL 23 days (11-46) 17 days (13-182) P=0.26 Time to VL >1000 copies/mL 26 days (13-46) 21 days (13-252) P=0.36 ART resume at VL > 1000 c/ml Median time to VL > 20 copies/ml for all participants: 20 (11-182) days No acute retroviral syndrome or new resistance mutations Post-treatment controller was HLA B5701+1 25 of 26 participants resumed ART and had VL suppression by median of 28 (IQR 19-33) days Colby, Ananworanich, Keystone Symposium (X8), 2019 Intervention: Ad26/MVA vs Placebo

15 All ATI studies: Time to viral rebound (n=66)
Treatment RV397: VRC01 RV405: Ad26/MVA RV409: Vorinostat RV411: Fiebig I Log-rank P> 0.05 for all Placebo Safety: No acute retroviral syndrome No new resistance to all ART classes post ATI All who resumed ART had VL suppression within 28 days Colby, Ananworanich, Nature Medicine, 2018 Crowell, Lancet HIV , 2019 Kroon, de Souza, IAS, 2016

16 Factors associated with time to viral rebound during ATI:
Days to >20 copies/mL

17 Total HIV DNA pre-ART (acute infection) and time to rebound (n=66)
HIV DNA pre-ART does not predict time to rebound to >20 copies/mL Slide courtesy of Diane Bolton (MHRP) and Nicholas Chomont (U Montreal)

18 Total HIV DNA pre-ATI and time to rebound (n=66)
HIV DNA pre-ATI does not predict time to rebound to >20 copies/mL Slide courtesy of Diane Bolton (MHRP) and Nicholas Chomont (U Montreal)

19 pVL pre-ART (acute infection) and time to rebound (n=66)
0.1 0.4 0.6 0.06 0.04 Time to pVL >1000 copies/ml 0.05 0.2 0.4 0.03 0.01 (-0.31) (rho) Unless all participants are analyzed together, pre-ART VL does not predict time to rebound to >20 copies/mL Pre-ART VL is modestly associated with time to rebound to >1,000 copies/mL Slide courtesy of Diane Bolton (MHRP) and Nicholas Chomont (U Montreal)

20 CRF01 _AE associated with time to viral rebound
HIV subtype and time to rebound Variables tested that do not impact time to rebound: Sex Age CD4-pre ART, pre-ATI CD8-pre ART, pre-ATI CD4/CD8 ratio -pre ART, pre-ATI HIV RNA pre-ART Total HIV DNA pre-ATI CRF01_AE was associated with faster time to viral rebound Slide courtesy of Donn Colby (SEARCH, The Thai Red Cross AIDS Research Centre)

21 What predicts viral rebound after treatment interruption?
Sneller, 2017 Williams, 2014, (SPARTAC) Assoumou, 2015 (ANRS 116) Li, 2014 (ACTG A5197) Li, 2016 (ACTG pooled ATI studies) Image from defeatHIV

22 HIV Remission Trials: Where are we?
Treatment interruption with intervention becoming more frequent Heterogeneity in design Studies inform efficacy/ safety of interventions and future trial design Predictors of rebound may accelerate therapeutics development

23 The study participants
MHRP Jintanat Ananworanich Sandhya Vasan Nelson Michael Merlin Robb Julie Ake Trevor Crowell Sodsai Tovanabutra Linda Jagodzinski Lydie Trautmann Diane Bolton Shelly Krebs Bonnie Slike Michael Eller Leigh Ann Eller Morgane Rolland Rasmi Thomas Suteera Pinyakorn Supranee Buranapraditkun Tsedal Mebrahtu Maddy Ouellette Oratai Butterworth Ellen Turk Case Western Rafick Sekaly Drexel Elias Haddad RTI International Holly Peay UT Houston Netanya Sandler AFRIMS Robert O’ Connell Denise Hsu Rapee Trichavaroj Bessara Nantapinit Siriwat Akapirak U Montréal Nicolas Chomont Remi Fromentin UCSF Victor Valcour Joanna Hellmuth Yale Serena Spudich NIH Irini Sereti Daniel Douek Eli Bortiz Frank Maldarelli Leidos-NCI Frederick Claire Deleage Robert Gorelick Michael Piatak Robin Dewar Adam Rupert U Minnesota Tim Schacker UNC Gail Henderson Jean Cadigan Thai Red Cross Praphan Phanuphak Nittaya Phanuphak Nipat Teeratakulpisarn Mark de Souza James Fletcher Eugene Kroon Donn Colby Phillip Chan Nitiya Chomchey Jintana Intasan Tippawan Pankam Sasiwimol Ubolyam Chulalongkorn University Kiat Ruxrungtham Rungsun Rerknimitr Sukalya Lerdlum Netsiri Dumrongpisutkul Mantana Pothisri Phandee Wattanaboonyongcharoen Ponlapat Rojnuckarin Sopark Manasnayakorn Sunee Sirivichayakul OHSU Jacob Estes U Hawaii Lishomwa Ndhlovu Industry Thai Gov Pharm Organization ViiV Healthcare Gilead Merck Acknowledgements The study participants

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