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Role of Explant Tissue Infection Assays

This presentation discusses the use of explant tissue infection assays in HIV clinical trials, including the challenges, benefits, and bridging data to clinical efficacy. Different tissue types and models are explored, as well as examples of studies and assay variability. The importance of standardization and the need to evaluate pharmacokinetic data alongside pharmacodynamic data are emphasized.

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Role of Explant Tissue Infection Assays

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  1. Role of Explant Tissue Infection AssaysIan McGowan MD DPhil FRCPUniversity of Pittsburgh, PA, USA26th July, Paris, France

  2. Disclosures • Consultant • ABIVAX • Novicol Health Sciences • Employment • 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 • 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 Fletcher P et al. AIDS 2006 Abner SR et al. JID 2005

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

  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? Dezzutti C et al. 2014 PLoS ONE

  10. Biopsy Site & Explant Infection Dezzutti C et al. 2014 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 • 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

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