1. IAS 2010 20July 1 The Caprisa 004 result in context Sheena McCormack Clinical Scientist MRC Clinical Trials Unit

2. IAS 2010 20July 2 Outline The RCTs that did and didn’t demonstrate significant reduction in HIV incidence Strength of evidence in context of results to date The pipeline for PrEP and microbicide effectiveness What’s missing

3. IAS 2010 20July 3 40 trials of 33 interventions Type of intervention Beneficial Effect Adverse Effect No Effect Total Behaviour & microfinance 88 STI intervention189 Circumcision314 Diaphragm11 Non-ARV microbicides 11112 ARV microbicides11 ARV oral11 Vaccines134 Adapted from Padian et al AIDS 2010, 24:621

4. IAS 2010 20July 4 In context of results to date It is exciting  Proof of concept for ARV prophylaxis  Proof of concept for microbicides Is it sufficient evidence to roll out globally?

5. IAS 2010 20July 5 Size of effect and strength of evidence Mwanza STI intervention 3 circumcision trials RV144 vaccine trial Caprisa 004 In context of results to date

6. IAS 2010 20July 6 Caprisa strengths and limitations Strengths:  Greater protection (54%) in more adherent users  Protection against HSV2 (51%)  Consistency across analyses  Consistent with ARVs preventing MTCT  Caprisa and non-Caprisa PK/PD supportive  Intermittent macaque challenge (with PK) supportive Parikh et al J Virol Oct 2009:10358 Limitations:  Lower bound of 6% / p=0.017  Single trial population

7. IAS 2010 20July 7 Effectiveness in the pipeline 2010-11  iPrEx: oral, TDF/FTC, daily, MSM, Global  CDC4370: oral, TDF, daily, IDU, Thailand 2012-13  Ptnrs PrEP:oral, TDF & TDF/FTC, daily, couples, Kenya and Uganda  FEMPrEP: oral, TDF/FTC, daily, women, 5 countries in sub-Saharan Africa including SA  VOICE: oral & vaginal, TDF & TDF/FTC (oral combination only), daily, women, US and 4 countries in sub-Saharan Africa including SA

8. IAS 2010 20July 8 What’s missing from RCTs? Effectiveness (or otherwise) of intermittent vaginal dosing in more diverse populations, and with a single dose - before OR after How long the intervals can be between testing without unacceptable risk of resistance Rectal safety and effectiveness

9. IAS 2010 20July 9 What else is missing? Long term (>3yrs) genital safety, safety in pregnancy, adolescents, those have frequent sex Better understanding of PK/PD in sexually active couples Safest way to promote correct and consistent use

10. IAS 2010 20July 10 Concluding remarks (1) Excited – yes! Ready to roll out – no! Proof of concept on two counts  ARV as prophylaxis  Microbicides as route of delivery (we already know that women and their partners like them) The window for placebo controlled trials is open, but could be closing, and prioritising the questions is URGENT

11. IAS 2010 20July 11 Concluding remarks (2) Can’t ignore the challenge of delivering effective treatment to those that need it in resource limited settings Managing the risk of resistance whether from non-adherence to treatment, or PrEP ‘monotherapy’ will determine the shape of the epidemic Consultation, especially with communities, ethics committees and governments will be critical to success

12. IAS 2010 20July 12 the Caprisa 004 participants their partners the dedicated study team the communities that supported the trial the donors, reviewing authorities Thank you to…