1. Why an HIV vaccine? Catherine Hankins MD MSc FRCPC Chief Scientific Adviser to UNAIDS Office of the Deputy Executive Director Journalist training, HIV vaccine research National Press Foundation and Global HIV Vaccine Enterprise Atlanta, Georgia, September 27 th, 2010

2. Why an HIV Vaccine? Global epidemic (facts and figures) –Know Your Epidemic/Know your Response Economic burden –Funding trends and resource needs New prevention technologies –Male circumcision, microbicides, pre- exposure prophylaxis

3. Global estimates for adults and children, 2008 People living with HIV33.4 million [31.1 – 35.8] New HIV infections in 2008 2.7 million [ 2.4 – 3.0] Deaths due to AIDS in 2008 2.0 million [1.7 – 2.4] Almost half of people living with HIV are women Of the 7400 new infections per day in 2008, about 1200 were in children under 15 years of age

4. UNAIDS epidemic update 2009 * National household surveys 4 HIV: a stabilized epidemic (incidence/deaths)  spread of HIV peaked in 1996 at 3.5 new infections (2008: 2.7 million)  new infections have dropped by 17% since 2001  deaths peaked in 2004 at 2.2 million (2008: 2 million) Number of patients newly infected with HIV

5. UNAIDS epidemic update 2009 5 HIV: a stabilized epidemic (prevalence)  Almost 60 million people have been infected by HIV and 25 million have died of HIV-related causes  2008: stabilized HIV prevalence is the result of reduced new infections and the effect of antiretroviral therapy Adult HIV prevalence

6. Know your epidemic and response synthesis process Epidemiological Review: Drivers/ country specificity Incidence data (modelled or otherwise) Prevention policies, response and strategic info review Review of resources for prevention SYNTHESIS ANALYSIS OF EPIDEMIC ANALYSIS OF RESPONSE

7. 7 April 2010 Incidence by mode of HIV transmission in East and Southern Africa Source: MOT country reports available at http://www.unaidsrstesa.org/hiv-prevention-modes-of-transmission

8. Collectively we’ve made remarkable progress in many aspects of the response to HIV… … incidence of new infections, antiretroviral treatment, human rights

10. The number of AIDS-related deaths has declined by over 10% over the past five years… Since 1996 the availability of effective treatment, has saved some 2.9 million lives… Treatment benefits are clear….

11. People in the poorest places have access to life- prolonging medicines

12. Why we need a prevention revolution # people accessing antiretroviral treatment has increased 12-fold in just 6 years 2010 WHO guidelines for treatment initiation (CD4 count of 350 cells) increased # in need by 50% Globally, 2 of every 3 people who need treatment are not accessing it - 10 million people are waiting now Globally, new infections are outstripping expansion of treatment availability - for every 2 people who start taking antiretroviral drugs, another 5 are newly infected Great progress but not only are we not keeping up, we are increasingly behind Need a prevention revolution to break the trajectory of the epidemic

13. Young people are leading the prevention revolution by taking definitive action to protect themselves from HIV Young people are leading the prevention revolution by taking definitive action to protect themselves from HIV HIV prevalence in young people aged 15-24 has declined in 22 high burden countries in sub-Saharan Africa:  delaying onset of sex  fewer partners  correct & consistent condom use

14. Human rights issues and the AIDS movement “Gay couple freed by Malawi presidential pardon return to home villages” Human rights campaigner says men have not been reunited amid fears for their safety Recent advances include the decision of the Delhi high court to strike down an anti-sodomy law dating back to the early days of the British Raj China’s launching of needle exchange and methadone programmes for people who inject drugs need to be multiplied Lifting of travel restrictions: USA, China

15. One of the biggest human rights issues facing the AIDS movement is funding

16. TOTAL annual resources available for AIDS in low and middle income countries, 1996-2009

17. $0.10 - $1 per capita > $10 per capita$1 - $10 per capita < $0.10 per capita Spending per capita for HIV Source: UNAIDS global report 2008, Annex 2

18. International AIDS Assistance: Trends in G8/EC & Other Donor Government Assistance, 2002-2009 USD billions Commitments (Enacted Amounts) Disbursements Sources: KFF and UNAIDS, Financing the response to AIDS in low- and middle- income countries: International assistance from the G8, European Commission and other donor Governments in 2009, July 2010

20. Assessing Fair Share 2: Donor Rank by Disbursements for AIDS per US$1 Million GDP*, 2009 Sources: KFF and UNAIDS, Financing the response to AIDS in low- and middle- income countries: International assistance from the G8, European Commission and other donor Governments in 2009, July 2010

22. Eastern Europe and Central Asia Latin America and the Caribbean Sub-Saharan Africa South East Asia and the Pacific DONOR 3.5 BILLION DONOR 2 BILLION DONOR 21 MILLION DONOR 8 MILLION International Assistance for HIV, domestic spending, and financing gaps

23. Resources needed to provide ART under two CD4 eligibility criteria (New WHO ART guidelines) 23 0 2,000 4,000 6,000 8,000 10,000 12,000 201020112012201320142015 US$ Millions CD4 <350 CD4 <200

24. 24 Investing in AIDS: linked to individual and societal benefits essential for attainment of MDG 3, 4, 5, 6 saves money in the long term Millennium development goals (AIDS+MDGs) 1. Eradicate extreme poverty and hunger 2. Achieve universal primary education 3. Promote gender equality and empower women 4. Reduce child mortality 5. Improve maternal health 6. Combat HIV/AIDS, malaria and other diseases 7. Ensure environmental sustainability 8. Develop a global partnership for development

25. Worst case scenarios if funding decreases: Increased mortality and morbidity Greater transmission risks Treatment interruption Increased burden on health systems Reversal of economic and social gains

26. How much is too much? -255075100125150175200 Cost of war in Iraq in 2008 Amounts spent on Valentine's day Bonus paid to London Financial staff at Christmas 2006 Bilateral Aid for AIDS in 2008 US$ billion 2010 estimated need: 26.8 billion US$. Available: 15.9 billion US$ Is the 11 billion USD gap that we are trying to close too much?

27. Resource mobilization action! Financing options Increase domestic funding Fair share from bilaterals Corporate Partnerships Framework Agreement on Debt2Health Airline ticket tax BRICS governments becoming donors Huge accumulation of wealth (Sovereign Wealth Funds, HNI) Robin Hood Tax (take a look at the videos on http://robinhoodtax.org.uk/) 27

28. Why an HIV Vaccine? Global epidemic (facts and figures) –Know Your Epidemic/Know your Response Economic burden –Funding trends and resource needs New prevention technologies –Male circumcision, microbicides, pre- exposure prophylaxis

29. HIV Prevention at the Crossroads Behaviour change can be effective need tailored, sustainable strategies Structural interventions need better understanding of underlying determinants Biomedical interventions with partial efficacy male circumcision in HIV- heterosexual men (clinical trial) antiretroviral therapy (observational & ecologic data) pre-exposure prophylaxis trials underway modest protective efficacy in the Thai RV144 vaccine trial proof of concept for antiretroviral-containing topical microbicides in CAPRISA 004 No single strategy will work alone: biomedical, behavioural, and structural approachesmulti-component, integrated, biomedical, behavioural, and structural approaches: rights-based, evidence-informed combination HIV prevention approaches

30. What works for HIV prevention: Results from randomised controlled trials with HIV incidence endpoints Efficacy Study Effect size (CI) STD treatment (Mwanza) 42% (21; 58) Circumcision (Orange Farm, Rakai, Kisumu) 57% (42; 68) : M-A HIV Vaccine (Thai RV144) 31% (1; 51) 0% 10 20 30 40 50 60 70 80 90 100% Padian NS, et al. Weighing the gold in the gold standard: challenges in HIV prevention research. AIDS 2010, 24:621–635 Review of 37 HIV prevention RCTs on 39 interventions: PrEP : 1 Behavioural: 7 Microfinance:1 Diaphragm: 1 STI treatment: 9 Vaccines: 4 Microbic: 12 Male Circ: 4 CAPRISA 004 39% (6;60)

31.  Courtesy Q. Abdool Karim

32. Impact on HIV incidence: Evidence from observational studies and RCTs Weiss & Hayes Effect size.15.2.3.4.5 1 1.5 Study Effect size (95% CI) Overall 0.42 ( 0.34, 0.52) High-risk groups 0.29 ( 0.20, 0.42) General Population 0.56 ( 0.44, 0.71) South Africa 0.40 ( 0.24, 0.67) Kenya 0.41 ( 0.24, 0.70) Uganda 0.49 ( 0.28, 0.86)

33. Weiss et al. AIDS 2008

34. CROI 2010 17th Conference on Retroviruses and Opportunistic Infections Snapshot of Country Progress, Jan 2010 Botswana Kenya Lesotho Malawi Mozambique Namibia Rwanda South Africa Swaziland Tanzania Uganda Zambia Zimbabwe National Coordinator Task Force Situation Analysis Policy Training Quality Service Assurance Delivery M&E

35. Population-level Impacts by Coverage Hankins et al. Male circumcision for HIV prevention in high HIV prevalence settings: What can mathematical modelling contribute to informed decision making? PLoS Medicine 2009;6, September 8

36. Communicating about partial protection

37.  Courtesy Q. Abdool Karim

38. Pre-exposure prophylaxis (PrEP) PrEP is a strategy for HIV-negative individuals to reduce or prevent their risk of infection by: –taking oral antiretroviral drugs used for HIV treatment or –applying microbicides containing the active antiretroviral agent in the vagina or rectum Dosing can be: –daily –intermittently (e.g. Fridays & Mondays) –episodically (i.e. before & after sex) PMTCT, PEP, animal studies promising

39. Completed/ongoing PrEP studies - safety LocationSponsor/ Funder Population / Primary Goal PrEP AgentStatus Cameroon, Ghana, Nigeria FHI / BMGF936 high-risk women safety TDFCompleted 2006 Safety demonstrated. United States Extended Safety Trial CDC 400 MSM safety TDFCompleted Results Q3 2010 Botswana TDF2 Study CDC1200 heterosexual men and women safety and behaviour FTC/TDFFully enrolled Results Q4 2010 Kenya, Uganda E001/002 IAVI150 MSM, high-risk women, HIV discordant couples safety, acceptability FTC/TDF (daily & intermittent) Fully enrolled Results Q4 2010 United States ATN 082 ATN / NIH99 young MSM safety, acceptability FTC/TDFEnrolling Results 2011 United States HPTN 066 HPTN / NIH60 MSM PK FTC/TDF (different dosing strategies) Planning TBD (Thailand, Africa) HPTN 067 HPTN / NIH360 MSM, women safety, behavior FTC/TDF (intermittent) Planning

40. Characteristics of ongoing PrEP efficacy trials HIV seroconversion is 1° endpoint = event-driven trials –Studies continue until a pre-defined number of endpoints achieved (=timeline uncertain) Safety is co-1° endpoint –Given sample sizes, will provide large amount of safety data Distinct trials –Population/route of exposure: IDUs, heterosexual women & men, MSM –Agent: TDF, FTC/TDF, vaginal tenofovir gel –Location: Africa, Americas, Asia –Follow-up: 1-3 years per person Trials designed to detect ~50-70% efficacy –Larger trials are designed so that lower limit of 95% confidence bound will exclude low efficacy (25-30%) Seroconverters followed for ≥1 year –CD4, HIV-1 RNA, resistance testing

41. Ongoing PrEP studies - efficacy LocationSponsor/ Funder PopulationPrEP AgentStatus Thailand Bangkok Tenofovir Study CDC2400 IDUTDF>95% enrolled Results Q4 2011? South Africa CAPRISA 004 CAPRISA / USAID 900 womenVaginal TDF gel (coitally dep) Completed. Results Q3 2010 Brazil, Ecuador, Peru, S. Africa, Thailand, US iPrEX UCSF/ NIH& BMGF 2499 MSMFTC/TDFFully enrolled. Results end 2010 Kenya, Uganda Partners PrEP Study UW / BMGF 4700 HIV discordant couples TDF, FTC/TDF~75% enrolled Results Q4 2012 Kenya, South Africa (Malawi, Tanzania Zambia) FEM-PrEP FHI / USAID& BMGF 3900 high-risk womenFTC/TDF~20% enrolled Results 2013 South Africa, Uganda, Zimbabwe (Malawi, Zambia) VOICE / MTN 003 MTN / NIH 4200 (  4950) womenTDF, FTC/TDF, Vaginal TDF gel (daily) ~10% enrolled Results 2013

42. Systemic versus topical administration in women

43. Past & Current Microbicide Clinical Trials (courtesy of CAPRISA, Durban) Stopped for futility Safe but not effective Increased HIV infection Zena Stein publishes seminal article “HIV prevention: the need for methods women can use” Kenya N-9 sponge trial FHI N-9 film trial UNAIDS COL-1492 trial CONRAD CS trial FHI SAVVY trial PopCouncil Carraguard trial HPTN PRO2000 & BufferGel trial 1 st class: Surfactants eg. N9, SAVVY 2 nd class: Polymers eg. PRO2000, Carraguard, Cellulose Sulfate (CS) 3 rd class: ARVs eg. Tenofovir gel, Dapivirine gel/ring 4 th class: Co-receptor Blockers eg. CD4 blocker, CCR5 Blockers CAPRISA Tenofovir gel trial MDP 0.5% PRO2000 trial ‘90 ‘92 ’98 ’00 ‘03 ‘04 ‘04 ’05 ’05 ’07 ‘10 FHI CS Trial 2% PRO2000 67 MTN 003 VOICE trial IPM Dapivirine gel & ring trial

44. 44 CAPRISA 004 dosing strategy (BAT 24) – based on nevirapine in childbirth BAT 24  Insert 1 gel up to 12 hours Before sex,  insert 1 gel as soon as possible within 12 hours After sex,  no more than Two doses in 24 hours HIVNET 012 nevirapine regimenCAPRISA 004 tenofovir gel regimen asap 72 hrs 12 hrs Onset of labour Delivery

45. CAPRISA Vulindlela Clinic KwaZulu-Natal Midlands CAPRISA eThekwini Clinic Durban City Centre CAPRISA 004: Urban and Rural sites

46. Effectiveness of tenofovir gel in preventing HIV infection 46 TenofovirPlacebo # HIV infections3860 Women-years (# women)680.6 (445)660.7 (444) HIV incidence (per 100 women-years) 5.69.1 Incidence rate ratio: 0.61 (CI: 0.4 to 0.94); p = 0.017 39% lower HIV incidence in tenofovir gel group

47. Impact of adherence on effectiveness of tenofovir gel (overall 39% [6,60]) 47 # HIVN HIV incidence Effect TFVPlacebo High adherers (>80% gel adherence) 363364.29.3 54% Intermediate adherers (50-80% adherence) 201816.310.0 38% Low adherers (<50% gel adherence) 413676.28.6 28%

48. HIV infection rates in the Tenofovir and placebo gel groups: Kaplan-Meier survival probability p=0.017 (0.017) After 12 months of gel use: HIV endpoints: 65 Effectiveness: 50% P-value: 0.007 Tenofovir Placebo

49. Tenofovir gel – Next steps VOICE trial reports in 2013: daily dosing, powered to provide strength of evidence to support licensure of tenofovir gel if it shows at least 58% effectiveness FACTS 001: proposed South African trial 16 to 30 years BAT24 MDP 302: proposed trial in other African countries: BAT24 plus single dose arm CAPRISA 008: implementation trial in HIV-negative women CAPRISA 009: seroconverter study Moral obligation and public health imperative to confirm whether tenofovir gel is a viable HIV prevention option for women Funding need: US$100 million over 3 years ( US$33 million/year) Gap: US$42 million Committed: US$58 million Gap: US$42 million In comparison: US $868 million invested in HIV vaccines in 2009 of US$1.165 billion invested in HIV prevention R& D

50. Acknowledgements Carlos Avila Salim Abdool Karim Helen Weiss Richard Hayes Jared Baeton Connie Celum Quarraisha Abdool Karim Eleanor Gouws Alexandra Calmy Tim Hallett Lynn Paxton Dawn Smith Myron Cohen Toby Kasper Kim Dickson John Stover Tim Farley Elizabeth McGrory

51. hivthisweek.unaids.org Zero new HIV infections Zero discrimination Zero HIV-related deaths