1IAS 2010 20July

The Caprisa 004 result in context

Sheena McCormackClinical Scientist

MRC Clinical Trials Unit

2IAS 2010 20July

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

3IAS 2010 20July

40 trials of 33 interventionsType of intervention

BeneficialEffect

AdverseEffect

NoEffect

Total

Behaviour & microfinance

8 8

STI intervention 1 8 9Circumcision 3 1 4Diaphragm 1 1Non-ARV microbicides

1 11 12

ARV microbicides 1 1ARV oral 1 1Vaccines 1 3 4

Adapted from Padian et al AIDS 2010, 24:621

4IAS 2010 20July

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?

5IAS 2010 20July

Size of effect and strength of evidence

60

51

71

72

77

58

39

31

51

53

61

42

6

1

19

22

34

21

0 20 40 60 80 100

Mwanza STI intervention

3 circumcision trials

RV144 vaccine trialCaprisa 004

In context of results to date

6IAS 2010 20July

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

7IAS 2010 20July

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

8IAS 2010 20July

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

9IAS 2010 20July

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

10IAS 2010 20July

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

11IAS 2010 20July

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

12IAS 2010 20July

the Caprisa 004 participants

their partnersthe dedicated

study teamthe communities that supported

the trialthe donors, reviewing authorities

Thank you to…