Role of Explant Tissue Infection Assays Ian McGowan MD DPhil FRCP University of Pittsburgh, PA, USA 26th July, Paris, France Wednesday October 7th 15 minutes + 5 minutes for questions

Disclosures Consultant Employment ABIVAX Novicol Health Sciences Chief Medical Officer at AELIX Therapeutics

Overview The explant model of HIV infection Tissue Virus Use of the explant model in clinical trials Challenges of the model Bridging explant data to clinical efficacy

The Explant Model Tissue types Challenge model Cervical (S, NS) Vaginal (S, NS) Penile (S) Tonsil (S, NS) Colorectal (S, NS) Challenge model Human NHP S: surgical; NS: nonsurgical

The Explant Model Polarised model Non-Polarised model Abner SR et al. JID 2005 Fletcher P et al. AIDS 2006

The Colorectal Explant Model Endoscopic biopsies Absorbable gelatin sponge +

Colorectal Explant Infection

PCR as An Alternative Endpoint HIV-1BaL HIV-1CHO77 Janocko L et al. AIDS Research & Human Retroviruses 2015

Surgical or Endoscopic Tissue? Replication of HIV JR-CSF better in flex sig tissue than surgical. No difference with Bal Dezzutti C et al. 2014 PLoS ONE

Biopsy Site & Explant Infection Dezzutti C et al. 2014 PLOS ONE

Clinical Studies with Explant PD RMP-01 (Topical UC781) RMP-02 (Oral TDF & Topical TFV) CHARM-01 (Topical TFV) MWRI-01 (IM TMC278) MTN-017 (Oral TDF & Topical TFV) HPTN-069 (Oral MVC, FTC, & TDF) CHARM-03 (Oral MVC & Topical MVC) MTN-026 (Topical DPV)

Examples of Study Data CHARM-01 MWRI-01 HPTN-069 Phase 1 rectal microbicide study MWRI-01 Phase 1 LA rilpivirine PK/PD HPTN-069 Phase 2 Study of four oral PrEP regimens

CHARM-01 McGowan I et al. PLoS ONE 2015

MWRI-01 Ex vivo / in vitro1 In vitro2 1McGowan I et al. Lancet HIV 2016; 2Dezzutti C et al. AAAC 2016

HPTN-069 (P<0.05) (P<0.05) HIV-1 p24 (pg/mL/mg) Important caveat: MVC rapidly disassociates from explant tissue1 1Coll J et al. AIDS 2015 McGowan I et al. CROI 2016

Challenges with Using the Explant Model in Trials Choice of virus Generally HIV-1BaL Challenge inoculum Viral incubation period Choice of virological endpoint Standardization of model across sites in multicenter trials

Explant Assay Variability Richardson-Harman N et al. AIDS Research & Human Retroviruses 2016

Bridging Explant Data to Clinical Efficacy Increased need to standardize protocols and reagents to reduce assay variability PD data should always be evaluated with PK data Despite assay limitations HPTN-069 colorectal explant data supports Phase 2B/3 effectiveness data for FTC/TDF MTN-013/IPM 026 cervical explant data supports Phase 2B/3 effectiveness data for dapivirine

Acknowledgements The study participants >1,000 flexible sigmoidoscopies and 20,000 biopsies in Pittsburgh1 My explant colleagues but especially Charlene Dezzutti and Nicola Richardson-Harman Funding from NIH/NIAID/DAIDS and the Bill and Melinda Gates Foundation Chiu WK et al. AIDS Research & Human Retroviruses 2017

Thank You