HIV remission after discontinuing ART: is it achievable? Jintanat Ananworanich, MD, PhD Associate Director for Therapeutics Research US Military HIV Research Program Maryland, USA jananworanich@hivresearch.org The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or the Department of Defense.
What is HIV remission and how common is it?
Goals of HIV cure research Eradication (Sterilizing Cure) Elimination of all HIV capable of replicating Without ART Remission (Functional Cure) Undetectable VL Healthy No increased risk of transmission
Sustained remission off ART is rare but achievable < 2months Boston A 3 months Circulating virus ART Boston B 8 months Mississippi child 28 months Limit of detection SPARTAC and Visconti Timothy Brown 0 1 2 3 6 7 From Nicolas Chomont, 2015 IAS Plenary, Vancouver Hütter, NEJM 2009; Persaud, NEJM 2013; Luzuriaga NEJM 2015; Henrich, JID 2013; Henrich, Ann Intern Med 2014; Stöhr, Plos One 2013; Hocqueloux, AIDS 2010; Saez-Cirion, Plos Path 2013; Adapted from Cohen, Science 2015.
Transplantation with CCR5 Δ32/Δ32 donor cells: only 1 person is cured and alive Berlin patient (Timothy Brown) CCR5 Δ32 homozygous transplantation Aggressive chemoablative therapy and total body irradiation Graft vs. Host Disease High mortality rate posttransplantation All 8 patients died from complications HIV was not detected in 1 adult and 1 child CXCR4 minority strain depends on CCR5 for replication Hutter NEJM, 2009, Allers K, Blood 2011, Yukl SA, Plos Pathogens 2013, Simons J, CID 2014 Hutter G, NEJM 2014 Duarte RF, Lancet HIV 2015 Timothy Schacker (personal communication)
VISCONTI: Largest and longest HIV remission cohort (post-treatment controllers) 14 people ART in first 3 months Control VL after stopping ART Why are these patients able to control HIV without ART? HIV reservoir amount and location? Low HIV DNA In shorter-lived CD4 cells Saez-Cirion A, Plos Pathogens 2013
Post-treatment controllers (PTC) are different from elite controllers (EC) Viremia ART Saez-Cirion A, Phil Trans R Soc B 2014
HIV remission is uncommon even in early treated people VISCONTI n=14 (15%) SPARTAC n=4 (9%) Swiss 1 n=3 (9%) CASCADE n=11 (5%) Primo- SHM n=4 (5%) ACTG mixed n=1 (5%) Seattle n=1 (5%) San Diego 0% Swiss2 0% A371 0% Ped case reports VISCONTI (Hocqueloux L, 2010; Saez-Cirion A, 2013): SPARTAC (Fidler S, 2013, Stohr 2013); Swiss 1 (Gianella S, 2011) Primo SHM (Grijsen ML, 2012); Cascade (Lodi S, 2012) Seattle (Maenza J, 2015); ACTG mixed (Li J, CROI 2015) San Diego (Gianella S, 2015); Swiss 2 (von Wyl V, 2011); A371 (Volberding P, 2009); Ped (Ananworanich J, 2015)
Why is it difficult to achieve HIV remission?
HIV hides in long-lived cells and in tissues From Nicolas Chomont (2015 IAS Vancouver) TW Chun, JID 2008; S. Yukl,ID 2010; M. Churchill, Annals Neur 2010; C. Fletcher, PNAS 2014; M. Perreau, JEM 2013
The size and composition of the latent HIV reservoir is affected by early ART Naïve Ag Stem cell memory Central memory Transitional memory Effector memory Terminally differentiated Chronic infection Years of ART Latent reservoir Acute/Recent infection Years of ART Latent reservoir? Ananworanich, Dube and Chomont, Curr Opinion HIV/AIDS 2015; Buzon MJ, Nature Med 2014; Klatt NR, PLoS Pathogens 2014; Muenchhoff M, Frontiers in Immunology 2014; Sandgaard KS, AIDS 2014; Bunders MJ, Blood 2012 and Sci Rep 2014; Zhang X, Sci Transl Med 2014
What can we do to achieve HIV remission? Goal Delaying time to viral load rebound
Reservoir and Immunity Rapid ART initiation Low HIV DNA and HIV RNA Absence of residual viremia Poor viral replicative fitness Host immunity latent virus Broad T cell responses Less exhausted T cells Strong NK cytotoxicity Williams JP, elife 2014; Etemad B, 2015 CROI; Hurst J, Nature Communications 2015; Frater J, AIDS 2014; Scott-Algara D, 2015 CROI; van Gulck E, Plos One 2012
HIV Remission Strategies ART Shock and Kill Eliminate Infected Cells Acute HIV Infection Chronic HIV Infection Viral Load Suppressed Possible interventions: HIV RNA Latency reversing agents Broadly neutralizing antibody Vaccine Gene-editing therapy
Impact of early ART on HIV persistence (RV254) ART started: during chronic infection <25 days after infection <17 days after infection Very early ART (<2-3 weeks after infection) dramatically reduces the frequency of cells carrying integrated genomes Nicolas Chomont (U Montreal); Ananworanich J, Plos One 2012
Reduction in proviral DNA after PGT121 Broadly Neutralizing Antibody in rhesus monkeys Cell death Viral clearance DNA RNA Control Barouch DH, Nature 2013
DART: Dual-Affinity Re-Targeting Therapy Viral clearance assay of DART CD8 killing of autologous infected CD4 Control DART gp41 DART gp120 Sung and Margolis, JCI 2015
Novel CMV-based vaccine given before exposure may aid in viral control: SIV/macaque model No protection but Virus eradicated in 50% Controllers (n=9) Hansen SG, Nature 2011 and 2013 Time post infection (weeks) Early mucosal immune responses Broad immune responses that did not target immuno-dominant epitopes
Gene therapy to eliminate CCR5 Leukapharesis CD4+ T-cell isolation CCR5- CCR5+ ZFN cut CCR5 gene Viral Load (copies/ml) 10 6 10 5 10 4 10 3 10 2 Treatment interruption VL control in Δ 32 heterozygote LOD 10 1 Re-infuse Tebas P, NEJM 2014 28 56 84 112 140 168 196 224 252 Days 2-3 repeat doses after cyclophosphamide (NCT02225665)
Examples of interventions being studied Reinforce latency Tat inhibitor Disrupt sanctuary sites Anti-CD20 to disrupt B cell follicles in lymph node Accelerate CD4 differentiation to shortlived cells Auranofin (±BSO) Clear infected cells Engineered T cells Chimeric Antigen Receptor Therapeutic vaccine Ad26/MVA - mosaic Dendritic cell Immune checkpoint blocker Block PD1, CTLA-4 Immunotoxins Combination therapy 2-3 bnab LRA + bnab or vaccine Mousseau G, mbio 2015; Richman D, Science 2009; Klatt NR, Immunol Rev 2013; Savarino, Retrovirology 2015; Picker LJ, Annu Rev Med 2012; Lam S, Immunotherapy 2013; Denton PW, Plos Pathogens 2014; Wightman, AIDS 2015; Thornhill J, Curr Opin Infect Dis 2015; Wightman F, AIDS 2015
What might HIV remission treatment look like? Biomarkers Suppressive ART ART ART Daily LRA Repeat doses of bnmab or vaccine Time
A Possible Roadmap to Combination Cure Research for HIV Animal Safety Study 6 12 months Combination A Combination B Combination C Combination D Combination E Control Animal Efficacy Study 12-15 months Combination A Combination B Combination D Control Phase I Human Study 12-15 months Phase 2 Human Study 12-24 months Combination A Combination D Control Parallel social, behavioral and ethics research... Ananworanich J and Barre Sinoussi F, Lancet HIV 2015
Conclusion HIV remission cases are almost exclusively reported in early treated individuals Interplay between low reservoir, strong immunity and unique host factors underlies remission Biomarkers for HIV remission is unknown Interventions aimed at HIV remission include Early ART Reactivate or reinforce latency Immunotherapeutics Gene and cell therapies Combination therapies will likely be needed
Acknowledgements RV254/SEARCH 010 participants study team and sponsors Thai Red Cross Praphan Phanuphak Nittaya Phanuphak MHRP Nelson Michael Merlin Robb Lisa Reilly Jamie Livengood University of Amsterdam Peter Reiss Marcel Levi Fransje van der Waals Joep Lange and Jacqueline van Tongeren University of Montreal Nicolas Chomont Harvard/Beth Israel Dan Barouch Gilead Romas Geleziunas Bangkok 2012