1. The Combined Approach to Preventing HIV Infection Robin Shattock, Mitchell Warren, Sheena McCormack, Catherine Hankins,

2. Outline Approaches to preventing sexual transmission of HIV – what works Biomedical approaches under development to prevent sexual transmission of HIV Opportunities and challenges created by combining partially effective biomedical prevention strategies Conclusions

3. “Successful provision of universal treatment access may be critically dependent on reducing the number of new infections” Annual incidence has declined (19%)3.5- 2.6 million (1996-2009) The total number living with HIV continues to rise HIV prevalence (33 million) constant at 0.8% of global population since 2001 6.6 million are now on antiretroviral treatment (ART) 9 million are waiting to receive it For every person starting ART two people are newly infected 20 million more people predicted to acquire HIV by 2031 increasing potential treatment costs up to $35 billion a year 2. 1. UNAIDS, AIDS at 30: Nations at the Crossroads (2011) 2. R. Hecht et al., Lancet 376, 1254 (2010).

4. Political Declaration on HIV/AIDS: Intensifying our Efforts to eliminate HIV/AIDS (10 June, 2011) The Declaration reaffirms HIV prevention as the cornerstone of national, regional and international responses to the AIDS epidemic expand access to essential HIV prevention commodities, particularly male and female condoms and sterile injecting equipment. intensify national HIV testing campaigns; deploy new bio-medical interventions as soon as they are validated, including earlier access to treatment for prevention HIV prevention strategies inadequately focus on populations at higher risk— specifically men who have sex with men, people who inject drugs and sex workers, and calls on countries to focus their response based on epidemiological and national contexts. Countries committed to working towards: reducing sexual transmission of HIV by 50% by 2015 reducing HIV transmission among people who inject drugs by 50% by 2015 15 million on treatment by 2015

5. What is combination prevention? Coates et al., Lancet 2008 1 2 3 4

6. Prior to exposure Exposure (pre-coital/coital) After infection Oral pre exposure prophylaxis (intermittent PrEP) Coitally dependent topical PrEP (microbicides) Anti-retroviral therapy Immediate treatment of positive partners in discordant couples Treatment for prevention in all who test positive for HIV (T4P) Male circumcision Oral pre exposure prophylaxis (daily PrEP) Topical PrEP (daily gels or intra-vaginal rings (microbicides) Preventive Vaccines Exposure (pre-coital/coital) Oral post exposure prophylaxis (PEP) YEARS HOURS 72 HOURS Opportunities for biomedical interventions All have a behavioral and structural components

7. Study Effect size (CI) Medical male circumcision (MMC) ( Orange Farm, Rakai, Kisumu) 57% (42, 68) Prime-boost HIV Vaccine (Thai RV144) 31% (1, 51) Efficacy 0% 10 20 30 40 50 60 70 80 90 100% TDF/FTC oral-PrEP in MSM (iPrEx, Grant et al 2010) 44% (15, 63) 1% tenofovir gel (Caprisa 004, Karim et al.) 39% (6, 60) *Provisional Immediate ART for positive Partners (HPTN052) 96% (82, 99)* TDF/FTC oral-PrEP in heterosexuals ( TDF2, CDC) TDF oral-PrEP in serodiscordant Partner (Partners PrEP) 63% (22, 83)* TDF/FTC oral-PrEP in serodiscordant Partner (Partners PrEP) 62% (34, 78)* 73% (49, 85)* New biomedical intervention strategies

8. RV144 Acquisition Endpoint: Modified Intent-to-Treat (mITT) Vaccine infections: 51 Placebo infections: 74 p = 0.04 Efficacy: 31.2% 95% CI (OBF): 1.1, 51.2 Placebo Vaccine month612182430 Events1642678295 Efficacy54%60%44%36%

9. CAPRISA 004: HIV infection rates in the tenofovir and placebo gel groups: Kaplan-Meier survival probability p=0.017 (0.017)

10. PrEP for HIV prevention in men who have sex with men

11. What about FEM PrEP? Daily oral TDF/FTC used as PrEP by heterosexual women did not appear to provide benefit in the FEM-PrEP trial Closing early after a planned interim review revealed equal numbers of HIV infections in the active and placebo groups. Findings contrast with those of TDF2 (CDC) and Partners PrEP Differences in dosing, susceptibility and or adherence?

12. Oral ARV distribution into the genital tract is complex ADM Kashuba, 2011

13. Patterson, Cohen, Kashuba et al WAC 2010 Not Detected Concentration 24 Hours After a Single Dose of Truvada® TFV TFV-DP FTC FTC-TP

14. Treatment for prevention (T4P) HPTN052 Early use of ART by an HIV-infected individual reduces heterosexual transmission to an uninfected partner by 96% Strengthens previous evidence from a meta-analysis estimating a 92% reduction (11). However in at least 7 of the 39 (18%) infections likely acquired from outside the primary relationship Implementation may be feasible for discordant couples in many settings But offering immediate T4P to all who test HIV-positive is challenging in settings where barely 50% of those medically eligible are currently receiving ART. Even more challenging will be identifying those in acute infection and encouraging them to join treatment programs

15. Time to consider a combination approach to biomedical interventions Possible biomedical prevention combinations: Combined use of oral PREP and microbicides for intermittent dosing– optimal systemic and local drug levels (steady state and bolus) PrEP (oral, topical) for women combined with circumcision + oral PrEP for men T4P combined with ARV PrEP (microbicide or oral for women, oral for MSM) for the HIV-negative partner. Vaccines plus ARV PrEP – specific considerations Underpinned by positive promotion of behavioural and structural interventions: providing a comprehensive package of prevention options

16. Mounting a protective immune response within hours of exposure is a biological challenge, particularly if viral exposure is high

17. 80% of HIV infected subjects are infected with a single virion/single quasispecies Mucosal acquisition may depend on the establishment of one or a few foci of infection Here the balance between infection and protection at mucosal surfaces may be small However, where viral exposure is high and/or susceptibility increased several HIV isolates may establishing multiple foci of infection Here, more than one biomedical technology is likely needed to prevent HIV acquisition (Keele et al., PNAS 105: 7522, 2008) – The Shaw-Hahn model

18. Lessons might be learned from the Thai RV144 vaccine trial The vaccine appeared most effective (60% reduction) at 1 year post vaccination Infection may be reflective of suboptimal immune responses or exposure to a higher and/or more frequent infectious challenge Revaccination (annual/biannual) likely required to have a significant impact on incidence ( Hontelez et al Vaccine June 2011 ) Co-implementation of PrEP (oral, microbicides) and/or MMC might provide conditions that could significantly increase vaccine efficacy This hypothesis could be explored in proposed ALVAC-protein prime-boost trials being discussed in Thailand and S.Africa.

19. Early containment may prevent infection Can containment of the initial events in infection be improved to a state where they are delayed long enough for clearance by adaptive immunity?

20. Immunological protection Are there potential benefits? ARV protection

21. How might (VAXPrEP) deliver better protection? Providing protection during the immunization period Reducing infectious challenge and primary foci of infection Increase eclipse phase prior to systemic dissemination providing an extended opportunity for adaptive immunity to respond Boosting local immunity (virus/antigen) Broadening localized immunity through protected exposure to prevalent virus. Converting high risk challenge to low risk challenge (RV144) Coverage between potential re-vaccination campaigns as immunity wanes Providing immunological coverage of intermittent PrEP adherence, break through virus and resistance evolution

22. Can mucosal exposure in the context of PrEP influence immune response? Detectable CD4 and CD8 responses observed in macaques following protected exposure to SHIV in the context of: Rectal 1% tenofovir gel and single high dose rectal challenge (Cranage et al PLoS Med. 2008;5(8):e157) Oral TDF + FTC and repeated low dose vaginal challenge (Kersh et al, PLoS One. 2011;6(4):e19295) Passive infusion with neutralizing antibody and single high dose rectal challenge (Watkins J., et al PloS One 2011; 6 (3):e18207)

23. Can vaccine candidates be co- formulated with microbicides?

24. Stability analyses of gp140 in microbicide gels Stability in vaginal lavage of gp140 alone (in control gel or buffer), or combined with gel formulations 1 and 2 Western blot gp140 Gp140 degradation products Quantification Sattentau Q, et al PLoS One. 2011;6(1):e15861

25. Can mucosal vaccination boost localized immunity? Group A Serum IgA TitresGroup A Serum IgG Titres Animal E50 Mucosal Antibody Titres 0 20 40 60 80 100 120 -431464115122139 Cervical IgG Vaginal IgG Cervical IgA Vaginal IgA Animal E49 Mucosal Antibody Titres 0 20 40 60 80 100 120 -431464100104111132159 Titre Cervical IgG Vaginal IgG Cervical IgA Vaginal IgA IM IVAG Vaccine. 2011;29(7):1421-30

26. Vaginal ring device comprising single candidate antigen and two lead microbicide candidates gp140 in rod-insert Microbicide ‘A’ in ring body Microbicide ‘B’ in ring body rod-insert ring body gp140 Microbicide ‘A’ Microbicide ‘B’ Days free holes for inclusion of additional microbicide/antigen- loaded solid dosage forms Antiviral Res. 2010 Dec;88 Suppl 1:S55-66

27. Paul McKay, Karl Malcolm, Robin Shattock - Vaginal Ring Inserted - Un-primed - Intra-muscular Prime

28. Can protected mucosal exposure boost localized immunity? = Challenge in the absence of microbicide = Challenge in presence of microbicide (100% protective) = IM (intramuscular) immunization = Assess systemic and local immunity A B = IN (intranasal) immunization = Challenge in presence of microbicide (50% protective) Ideal groups size to give an 80% chance of detecting 50% difference: 20 animals per group

29. Can biomedical combinations be tested in clinical trials? Design 1: PrEP reduces risk of HIV acquisition (oral 44-73%, microbicide 39%) – assumes PrEP is available to all participants? Two-arm study: PrEP alone Vaccine + PrEP (VAXPrEP) Requires 30 to 60 incident infections to assess the additional benefit of vaccination on risk of infection and setpoint viral load. Main challenge, PrEP as active control arm will reduce incidence and increase trial size Superiority of VAXPREP does not imply vaccine alone is efficacious Lack of superiority does not imply vaccine alone is ineffective (potential antagonism). Excler JL, et al AIDS Res Hum Retroviruses. 2010 Dec 16.

30. Can biomedical combinations be tested in clinical trials? Design 2, PrEP (oral or microbicide) assumed not to be in general use. (closing window of opportunity for use of placebo PrEP) A 4 arm study: 1. Placebo (placebo vaccine + placebo PrEP) 2. PrEP (placebo vaccine + PrEP), 3. Vaccine (vaccine + placebo PrEP), 4. VaxPrEp (vaccine+ PrEP) Requires 60-210 infection to demonstrate direct benefit of vaccination with or without PrEP (fewer infections needed when synergy is present). Potential for adaptive design: assess relative ranking of active arms test for superiority among active arms test for interaction (synergy) of the combination eliminate regimes not better than placebo introduce vaccine boost if needed.

31. Potential challenges to combination trials Increased sample size, trial complexity and cost Additional visits for safety, HIV testing etc Risk compensation and adherence may vary according to perceived efficacy of the individual components of any combination Issue of informed choice become more complex Open-label trials may be the best way to assess concerns about risk compensation while learning about implementation.

32. Can mucosal exposure to virus in the context of PrEP lead to immune response: indicated in animals, yet to be tested in humans Can microbicide delivery technology be used for vaccination: Yes Does vaginal vaccination modify mucosal immunity to HIV: indicated in animals, yet to be tested in humans Can vaccine induced immunity be broadened through protected exposure to prevalent virus: currently being tested in animals. Will VAXPrEp provide better protection than PrEP alone?: currently being evaluated in animal models Can combination prevention be tested in human trials: Yes Summary

33. However, current clinical prevention research is focused on efficacy trials of individual biomedical interventions Vaccine - Prime/Boost Thailand Oral TDF - IDU Thailand Oral Truvada – Heterosexual Botswana Oral TDF -MSM US (Ph II) Oral Truvada - MSM (iPrEx) Oral TDF, Truvada - Partners PrEP Oral Truvada - FemPrEP Microbicide - BufferGel, PRO2000 Microbicide - Tenofovir Gel South Africa Microbicide - PRO2000 Oral TDF & Truvada & Tenofovir gel - VOICE 2009 2010 Index Partner Treatment HSV-2 Treatment - Infectiousness Vaccine - DNA Prime/Ad5 Boost US Additional trials of 1% TFV gel Microbicides PrEP Vaccines Treatment as PX KEY Microbicide - Dapivirine ring 2015+ New Vaccine concept(s) Testing & linkage to care plus (TLC+) 2012-3 2011 Emphasis now needed for combinations that provide the greatest impact on HIV incidence

34. A limited window may exist for placebo (PrEP) controlled trials ARV PrEP combined with vaccines may create lower-risk conditions making a partially efficacious vaccines a viable option Additive or synergistic effects will stimulate incremental reductions in HIV incidence This in turn will raise the bar of evidence required for new approaches (cost-effectiveness and population impact) in RCT Decreasing incidence will necessitate larger and more costly trials with an increased emphasis on adaptive design Placing an intrinsic value on high incidence cohorts Conclusions Summarized in: AIDS. Turning the tide against HIV. Science. 2011 Jul 1;333:42-3

35. Pathway to reversing the epidemic Seeing prevention research/funding as a continuum ARV PrEP (oral, microbicide) HIV incidence Treatment 4 prevention A combined research strategy for biomedical interventions is likely to provide the fastest, most tangible impact on HIV transmission Circumcision Partially effective vaccine highly effective vaccine Behavioral and structural interventions Science. 2011;333:42-3

36. Acknowledgements Catherine Hankins – UNAIDS, Geneva Mitchell Warren - AVAC Sheena McCormack – MRC CTU Paul McKay – St George’s. London Martin Cranage – St George’s. London Karl Malcolm – Queens University, London Quentin Sattentau – Qxford Angela Kashuba – Neil Almond – NIBSC, UK Mark Page – NIBSC, UK Roger Le Grand – CEA, Paris Nathalie Bosquet– CEA, Paris NIH U19 award AI060614–01