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Outline Identifying primary HIV infection

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Presentation on theme: "Outline Identifying primary HIV infection"— Presentation transcript:

0 The Future of Early Diagnosis and Intervention During Primary HIV Infection
Jintanat Ananworanich, MD, PhD Associate Director for Therapeutics Research, U.S. Military HIV Research Program Co-director, SEARCH, The Thai Red Cross AIDS Research Center Professor of Internal Medicine, University of Amsterdam Clinical Professor of Pediatrics, University of Maryland, Baltimore

1 Outline Identifying primary HIV infection
RV254 study algorithm Other methods Early ART and HIV remission trials RV254-associated treatment interruption trials Considerations for study designs and interventions After suppression in early treated participants During primary HIV infection

2 RV254/SEARCH010 Real-time screening of 238,963 samples in Thailand
SEARCH clinic, Bangkok Real-time screening of 238,963 samples in Thailand Acute HIV infection (n=481) Immediate antiretroviral treatment (ART) RV254/SEARCH010 Acute infection cohort with early ART de Souza, Ananworanich, AIDS 2015 97% male 26 years old 19 days of infection 39%Fiebig I/II 95% VL < 50 copies/ml by year 3

3 Acute HIV Diagnosis Algorithm in RV254/SEARCH 010 Study
4th generation immunoassay (n=238,963) Reactive (n=16,330) Non-reactive (n=222,633) 3rd or 2nd generation Immunoassay Pooled nucleic acid testing (3-30 samples/pool) Non-reactive (n=444) Positive (n=144) Negative (n=222,489) Reactive Chronic HIV (n=13,744) Acute HIV (n=587) HIV uninfected (n=222,489) Updated from de Souza, Ananworanich, AIDS 2015 Data from 15 April 2009 to 15 July 2017

4 Identifying Primary HIV Infection
High suspicion for HIV infection Febrile illness Repeat testing in 1-2 weeks Frequent testing Home testing Cohort of people at risk for HIV Confirmatory tests Indeterminate/negative results by Bio-Rad Geenius HIV-1/2 confirmatory assay gp41 (HIV-1 ENV) p24 (HIV-1 GAG) gp160 p31 (HIV-1 POL) gp36 (HIV-2) gp140 (HIV-2 ENV) control Ramos EM, J Clin virology 2013; Ngoi, Plos One 2016 Mayaphi, Plos One 2016; Malloch, J Clin Virology 2013; Robb, NEJM 2016

5 Early ART and HIV Remission Trials

6 Time to Viral Load Rebound post-Treatment Interruption in Early Treated People in RV254
Median (Min-Max) time to viral rebound = 22 (9 – 77) days Kroon, 2016 IAS; Colby, 2017 CROI; Crowell, 2017 IAS

7 Time to VL Rebound and Fiebig Stage/Reservoir size
Fiebig stage at ART initiation Pre-ATI Total HIV DNA in CD4 Correlation coefficient -0.18, p=0.15 Fiebig stage at ART initiation and total HIV DNA in CD4 prior to ATI were not associated with time to viral rebound > 20 copies/ml

8 Evaluating HIV Remission Strategies with Treatment Interruption
Biomarkers currently unknown Suppressive ART ART Viral Load immunotherapeutics Time

9 Interventions in Virally Suppressed Early Treated People
Low reservoir and viral escape Virally suppressed, early treated participants Preserved memory and survival potential of HIV-specific T cells Low frequencies of HIV-specific effector cells and antibodies Finding rare latently infected cells through persistent immune surveillance Engineered T cells Vaccines Repeated administrations of antibodies (novel delivery systems such as mRNA, AAV)

10 Interventions in the Context of Early Treatment
During primary infection After viral suppression on ART Adjuvant /LRA Productively infected cell Latently infected cell Dead cell

11 Those not consenting to ATI (continue ART)
Potential Trial Design for Combination Broadly Neutralizing Antibodies during Acute HIV Infection Stage 1 (Study interventions) Stage 2 (Analytical treatment interruption) Arm 1 (n=30) ART+ 2-3 bNAbs 2 4 6 12 24 36 48 50 56 Consent ATI Criteria to resume ART ATI 74 Those not consenting to ATI (continue ART) 74 Arm 2 (n=15) ART+ Placebo Consent ATI ATI Criteria to resume ART 2 4 6 12 24 36 48 50 74 56 Endpoints: Viremic control, reservoir and immunologic markers Sample size of 45 (2:1 randomization) 85% power to detect differences of 55% between arms for VL < 50 copies/ml at 24 weeks post-ATI Assuming control of 75% in active vs. 20% in control arms, and 70% acceptance rate for ATI

12 Trial Design Considerations
Challenges in recruitment and administration of investigational agents during acute infection Exploratory studies Composite endpoints Control arm

13 Conclusion Promising future technologies in engaging people at-risk and diagnosing primary HIV infection Testing interventions for primary HIV infection At time of ART initiation during acute HIV infection After sustained viral suppression Immune adjuvant/LRA and persistent immune surveillance

14 Acknowledgements RV254 participants and investigators Thai GPO
Thai Red Cross Praphan Phanuphak Nipat Teeratakulpisarn Nittaya Phanuphak Eugene Kroon Donn Colby Nitiya Chomchey Carlo Sacdalan James Fletcher Pornpen Tantivitayakul Phillip Chan Jintana Intasan Many more Chulalongkorn Kiat Ruxrungtham SupraneeBuranapraditkun 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 COG Bamrasnaradura Suthat Chottanapund Acknowledgements MHRP Nelson Michael Merlin Robb Julie Ake Sheila Peel Sodsai Tovanabutra Gustavo Kijak Linda Jagodzinski Mark de Souza Lydie Trautmann Suteeraporn Pinyakorn Lisa Reilly Jamie Livengood Diane Bolton Shelly Krebs Leigh Ann Eller Morgane Rolland Rasmi Thomas Trevor Crowell Hiroshi Takata Ellen Turk Madelaine Ouellette Oratai Butterworth COO, DCAC U Montréal Nicolas Chomont Remi Fromentin Louise Leyre Marta Massanella UCSF Victor Valcour Joanna Hellmuth Yale Serena Spudich Leah Le NIH Irini Sereti Daniel Douek Rick Koup Eli Bortiz Frank Maldarelli Leidos-NCI Frederick Jeff Lifson Jacob Estes Claire Deleage Robert Gorelick Robin Dewar UNC Gail Henderson RTI International Holly Peay U Minnesota Timothy Schacker UT Houston Netanya Sandler Case Western Rafick Sekaly Drexel Elias Haddad U Missouri Robert Paul U Hawaii Lishomwa Ndhlovu Napapon Sailasuta U Melbourne Sharon Lewin U PIttsburgh John Mellors Sharon Riddler U Sydney Sarah Palmer RV254 participants and investigators Thai GPO ViiV Healthcare Merck Gilead

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