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

IAS July 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

IAS July 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 ARV microbicides11 ARV oral11 Vaccines134 Adapted from Padian et al AIDS 2010, 24:621

IAS July 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?

IAS July 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

IAS July 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

IAS July 7 Effectiveness in the pipeline  iPrEx: oral, TDF/FTC, daily, MSM, Global  CDC4370: oral, TDF, daily, IDU, Thailand  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

IAS July 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

IAS July 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

IAS July 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

IAS July 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

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