1. 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

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

3. 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

4. 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

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

6. The Colorectal Explant Model
Endoscopic biopsies
Absorbable gelatin sponge +

7. Colorectal Explant Infection

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

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

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

11. 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)

12. 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

13. CHARM-01
McGowan I et al. PLoS ONE 2015

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

15. 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

16. 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

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

18. 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

19. 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

20. Thank You