Understanding mucosal immunity and HIV transmission: the way to new prevention technologies

1. Understanding mucosal immunity and HIV transmission: the way to new prevention technologies AIDS 2010, Vienna Robin Shattock Centre for Infection, Division of Cellular & Molecular Medicine, St George’s University of London, UK

2. Mechanisms of transmission Infection of macaques after vaginal exposure to cell-associated simian immunodeficiency virus. Sallé B, Le Grand R.J et al. Infect Dis. 2010 ;202(3):337-44.

3. Drug penetration For any prevention technology, success will depend on maintaining protective inhibitor concentrations at the mucosal portals of entry.

4. State of the pipeline for microbicides. • First generation concepts (successfully tested) but lacked potency • Drive for more potent products (Anti-Retroviral ARV) products • Systematic testing of the biological plausibility of different targets in primate models • Drug distribution and tissue activity studies in NHP and human studies (PK/PD) • Proof of concept for first ARV candidate (TFV gel) • Current need to better understand dosing relationship (coital/non coital) • Prioritization of new formulations that maximize adherence • Development of combination products will increase in importance • Prioritize (product/dosing) and acceleration of additional clinical trials

5. Microbicide Time Viral binders CCR5 antagonists Inhibit entry Hours Days Weeks Inhibit reverse transcription NRTI (TDF) NNRTI (DPV/UC781) Inhibit Integrase & protease Integrase inhibitors Protease inhibitors PrEP Haase T., Ashley, 11 March 2010, Nature, v. 464, p. 217-223.

6. Building on the ART of HIV-1 therapy – and success of CAPRISA 004 Nucleos(t)ide Reverse Transcriptase Inhibitors (NRTIs) Protease Inhibitors (PIs) Amprenavir (APV) Atazanavir (ATV) Darunavir (DRV) * Fosamprenavir (FPV) Indinavir (IDV) Lopinavir/ritonavir (LPV/r) * Nelfinavir(NFV) Ritonavir (RTV)* Saquinavir (SQVhgc)* Tipranavir (TPV) Zalcitabine (ddC) Zidovudine (ZDV) 3TC/ABC 3TC/ABC/ZDV 3TC/ZDV FTC/TDF* Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC)* Lamivudine (3TC)* Stavudine (d4T) Tenofovir (TDF)* Nonnucleoside RTIs (NNRTIs) Delavirdine (DLV) Efavirenz (EFV) , MIV-150* Nevirapine (NVP), Dapivirine (TMC-120)* Fusion Inhibitors (FIs) Enfuvirtide (ENF) Multiple Class Combinations Chemokine Receptor 5 (CCR5) Inhibitors EFV/FTC/TDF Integrase Inhibitors Maraviroc (MVC)* Raltegravir* *current candidates for PrEP and/or microbicides

7. Compounds protective in monkey models R5 virus challenges b12: MAb, SHIV-162P4, vaginal. PSC-, 6P4-, 5P12-RANTES: Modified chemokine, SHIV-162P3, vaginal. BMS-806: Small molecule to gp120, SHIV-162P3, vaginal. C52L: Peptide to gp41, SHIV-162P3, vaginal. T1249: Peptide to gp41, SHIV-162P3, SIVmac251, vaginal. CMPD 167: Small molecule to CCR5, SHIV-162P3, vaginal. Maraviroc: Small molecule to CCR5, SHIV-162P3, vaginal. TDF (tenofovir gel): NRTI, SIVmac251, vaginal + rectal (up to 3 days post application) *. L-870812, Integrase inhibitor, SHIV-162p3, vaginal. NCp7Nucleocapsid protein inhibitors (ZFI), SHIV-162P3+SHIV89.6, vaginal Griffithsin: Protein lectin, SHIV, SIVmac, vaginal PC-815: Carrageenan/MIV-150 (NNRTI), RT-SHIV, vaginal PC-1005: Carrageenan/MIV-150/ZInc, SHIV-RT, vaginal X4 virus challenges CAP: Polyanion, SHIV-33A, vaginal. Cyanovirin-N: Protein lectin, SHIV-89.6P, vaginal + rectal. SPL7013: Polyanion, SHIV-89.6P, vaginal PRO-2000: Polyanion, SHIV-89.6PD, vaginal. AMD3465:Small molecule to CXCR4, SHIV-189.6P, vaginal. • >20 studies demonstrating biological plausibility • TFV gel now becomes the bench mark. • PK now needs to be related to protection

8. Drug distribution and tissue activity studies seen as critical (PK/PD) • Non human primate studies are now being configured to relate drug distribution (Systemic, tissue, topical) to protection, providing a bridge to human studies (pharmacokinetics (PK)) – how much drug is needed and where is it need to provide protection? • Parallel human studies are being performed to determine drug distribution following application • Most importantly, studies to determine tissue drug activity are being developed as potential surrogate markers of protection (pharmacodynamics (PD)) – is the drug active at the site were it should work These are now seen as critical tools for product development Application of the tools to TFV gel may be critical in determining dosing regimes (coital/daily) and providing a bench mark for other candidates

9. Prioritization of new formulations that maximize adherence Prevention Treatment and Care Prior to Exposure Time of Exposure Prior to Exposure Point of Transmission Anti-retroviral therapies Rights driven behavior change Male and female Condoms and lube Opportunistic infection therapies VCT Cervical barriers? STI treatment Male circumcision Prevention for positives Pre-exposure prophylaxis Basic care Vaccines Education and behavioral change Microbicides

10. Target cells must be protected at the time of viral exposure Critical parameters – turnover of target cells entering and exiting mucosal tissue in steady state and inflammation - Potential entry of infected donor cells 1% gadolinium 1:100 in a sterile system with Dextrin sulphate gel, 2hrs post application (C. Lacey, Imperial College)

11. Coitally dependent, daily and sustained delivery Sex acts, A, B, C Semi-solid formulation, coitally independent Vaginal ring reservoir Gel formulation, coitally dependent Gel formulation, coitally dependent Adapted from Karl Malcolm - Queen’s University Belfast

12. Biological questions raised by CAPRISA 004 • 54% protection in those with >80% compliance. • Why not higher? – if measured compliance = real compliance • Concentration of drug – would more be better (more TDF, or additional drug combinations) • Spacing of dosing (BAT 24 – pre and post) • Better adherence – alternative dosage forms/regimes • Target cell turnover (inflammation, co-infection) • Potential differences in efficacy against cell free vs cell associated virus?

13. Facing the problem of resistance to microbicides: when and how? • Risks of resistance for topical ARV microbicdes are hypothetical. • Risks may differ between products • Topically applied drug may prevent transmission of resistant isolates • Resistant virus may have reduced fitness for transmission • In a clinical trial the risk/benefit ratio is likely to be low • No resistance seen in CAPRISA 004 trial – but too early to asses impact on treatment • ARV approach likely be initially implemented as a prescription only • Resistance continued to be monitored with wider introduction • If identified, enhanced emphasis would be placed on combinations

14. Product prioritization • Mechanism of action: NRTI, NNRTI, CCR5 PI, II etc • Stage of development – human data, manufacture • Appropriateness for combinations • Pharmacokinetics/pharmacodynamics (PK/PD) • - NHP/human – TFV comparison • Ability to be delivered in multiple dosage forms

15. HSV-2 Treatment - Infectiousness Index Partner Treatment Microbicide - BufferGel, PRO2000 Microbicide - Tenofovir Gel CAPRISA 004 Microbicide - Dapivirine gel & ring Oral TDF & Truvada & Tenofovir gel - VOICE Microbicide - PRO2000 Oral TDF -MSM US (Ph II) Oral Truvada - MSM (iPrEx) Oral TDF, Truvada - Partners PrEP Oral Truvada – Heterosexual Botswana Oral Truvada - FemPrEP Oral TDF - IDU Thailand Sustaining Accelerating progress in a changing prevention landscape Treatment Vaccine - Prime/Boost Thailand Vaccine - DNA Prime/Ad5 Boost US New Vaccine concept(s) Vaccines Microbicides PrEP TMC 278 - UK (Ph I/II) 2011+ 2010 2015+ 2009

16. ARV protection Immunological protection Can they be combined?

17. How might new prevention options work together? Combining microbicides or PreP with vaccines may deliver even better protection – the window for placebo controlled trials my be closing • Provides protection during the immunization period • Reduces infectious challenge. • Boosts local immunity (virus/antigen) • Broadening localized immunity through protected exposure to prevalent virus. • Converting high risk challenge to low risk challenge (RV144) • Vaccine induced immunity may cover intermittent compliance, break through virus and prevent resistance evolution

18. Pathways to reversing the epidemic A comprehensive approach to prevention ARV microbicide ARV Prep HIV incidence Partially effective vaccine highly effective vaccine Time

19. Thank you for your attention NIH U19 award AI060614–01