The HVTN is supported by National Institute of Allergy and Infectious Diseases (NIAID). Panel 4: A New Era in HIV Prevention Research HIV Vaccines James Kublin, MD, MPH Executive Director, HVTN Journalist-2-Journalist Program Bangkok, Thailand September 11 th, 2011

New Adult Infections in Low- and Middle- Income Countries by Year and Vaccine Scenario Even a vaccine with low efficacy and limited coverage can impact the epidemic and play a role in preventing future infections Stover J, et al. The impact of an AIDS Vaccine in Developing Countries: A New Model and Initial Results. Health Affairs 26(4): (2007) Potential Impact of a Vaccine

Results from HIV prevention trials Study Effect size (CI) Circumcision (Orange Farm, Rakai, Kisumu) 57% (42, 68) HIV Vaccine (Thai RV144) 31% (1, 51) Efficacy 0% % Siegfried N et al. Male circumcision preventing heterosexual acquisition of HIV in men. Int J Epidemiol 2010; 39: TDF/FTC PrEP (iPrEx, Grant et al 2010) 44% (15, 63) 1% TDF gel (Caprisa, Karim et al.) 39% (6, 60) 1.2 y 3.5 y 2.5 y Length of Study 12 mo effect 60* (22,80) 50 (15,72) Slide: Glenda Gray, HVTN Conference, Nov 2010; modified by Jerome Kim, 2010 *Not a part of the pre-specified analysis 50 (28,66)

Phase 2, Randomized, Placebo-Controlled Trial to Evaluate the Safety and Effect on Post-HIV Acquisition Viremia of a Multiclade HIV-1 DNA Plasmid Vaccine Followed by a Multiclade HIV-1 Recombinant Adenoviral Vector Vaccine in HIV-Uninfected, Adenovirus Type 5 Neutralizing Antibody Negative, Circumcised Men and Male-to-Female Transgender Persons, Who Have Sex with Men (Version 2.0 – December 21, 2009) HVTN 505

VRC Candidate HIV Vaccine Months369 Env A Env B Env C gag B pol B nef B CMV-R promoter Env A Env B Env C gag/pol B rAd5

7 HVTN 505: Primary Viral Load Endpoint Post-infection diagnosis visit schedule Definition of VL setpoint Average of all values at week 10 through week 20 post-infection diagnosis study visit VL values prior to ART initiation 20% is an upper bound for censored VL endpoints Weeks Infection Dx Primary endpoint

FPI to FPI “Who ever crawled across cut glass to make a deal”

Previous modifications to HVTN 505  Version 2.0 incorporated Protocol title change to “MTF transgender persons” Step results updated (added section ) Revised I/E criteria  Upper age limit raised to 50  Autoimmune disease exclusion clarified Revisions per Version 2.0 of DAIDS EAE Manual Updated references to DAIDS AE grading table SICF sections 5-8 reordered and rewritten

 In late 2009, results of the HIV vaccine study RV144 were published, showing a modest reduction in HIV infections among people who received the protocol’s study vaccines. 1 Some of the immune responses to the vaccines in the Thai study were similar to immune responses seen in prior human studies of the HVTN 505 vaccines. 2 New results of non-human primate challenge studies also demonstrated a reduction in HIV acquisition among monkeys that received SIV (simian immunodeficiency virus) versions of the HVTN 505 vaccines. 3  Based upon results from these human and NHP HIV vaccine studies, HVTN 505 has added a third primary objective: Assessing whether the 505 vaccines might protect against HIV infection. Study size was increased from 1350 to 2200 participants in Impact of RV144 on HVTN Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361: Koup RA. Antibody responses to the VRC vaccine: Implications for HVTN 505. HVTN Full Group Meeting, Washington, DC, May 5, Letvin NL, Rao SS, Montefiori DC, et al. Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys. Sci Transl Med. 2011;3:81ra36.

HVTN 505 in Evolving Prevention Landscape  Recent advances in drugs for prevention iPrEx: Pre-exposure prophylaxis in MSM FEM-PrEP: Pre-exposure prophylaxis in women (Truvada) HPTN 052: Treatment of discordant HIV+ partner  Microbicides CAPRISA 004: topical PrEP (Tenofovir gel)  HVTN 505: Opportunity to adapt and incorporate results as other non-vaccine and vaccine prevention studies emerge

Impact of PrEP on HVTN 505  Immediately following the release of iPrEX results communication with participants Ensure awareness and educate Web-based questionnaire to assess significance of results, intent to use/access PrEP, attitude towards participation in 505  Series of consultations with CABs, advocacy members, key opinion leaders What do the results mean to the field and to HVTN 505  Team discussions with DAIDS, VRC, Core, SCHARP and sites Reach a decision about implications of PrEP for HVTN 505

HVTN 505: Feedback from Consultations and Survey Following iPrEx  Many 505 participants considered iPrEx results very important either to them personally or to their community 31% of responders would consider taking PrEP in the next year Minority indicated that taking PrEP would affect willingness to remain on study  Community representatives, CAB and key opinion leaders Excitement about the science Many questions about relevance and applicability to the diverse communities of US-based MSM and transgender women

505: Rationale for Monitoring Prophylactic ART Use  Unknown extent of PrEP uptake in MSM and transgender women communities in US Depend on access to drug, cost, perceived side effects  Knowledge and attitudes towards use of ARTs for prophylaxis are evolving  Distinction between pre- and post-exposure prophylaxis may become less clear Emerging data about optimal timing and frequency of dosing around exposure

HVTN 505: Rationale for Behavioral and Biological Monitoring of Prophylactic ART  ART used as prophylaxis may influence HIV incidence Post-infection disease course Study participation, risk behavior over time, and perception of risk  Important opportunity to ask a number of questions and monitor prophylactic ART use in 505 Lessons can be applied broadly to vaccine field and prevention field

HVTN 505 v3: Modifications  Increased sample size to enable evaluation of HIV-1 acquisition  Modified inclusion and exclusion criteria anticipating increased use of prophylactic ART  Opportunity to evaluate self reported use in correlation with objective measures of drug levels  Opportunity for further education and risk reduction counseling of participants

505: Proposed Assessment of Prophylactic ART Use  Behavioral monitoring: Self report ACASI questionnaire administered very 3 months Describe patterns of use over 3 months with greater precision over past 2 weeks

505: Proposed Assessment of Prophylactic ART Use  Biological monitoring: Plasma drug levels Samples collected and stored every 3 month  Analysis of samples Chosen retrospectively to capture levels on HIV negative individuals reporting ART use Random sampling of HIV negative individuals who do not report prophylactic ART At HIV diagnosis visit and visit with earliest evidence of infection

HVTN 505: Proposed assessment of prophylactic ART use cont’d  Participant counseling and education  At every visit assessment of PEP/PrEP use and risk reduction counseling Inform and educate participants about results of other HIV prevention studies Risk reduction counseling as appropriate for the participant Referrals to services as appropriate

HVTN 505 Protocol Team Chair: Scott Hammer Co-Chairs: Magdalena Sobieszczyk & Michael Yin Protocol Team Leader: Shelly Karuna Biostatisticians: Peter Gilbert & Doug Grove & Holly Janes DAIDS Medical Officers: Adam Sherwat VRC Developer Representatives: Barney Graham & Mary Enama VRC Immunologist: Richard Koup HVTN Laboratory Program: John Hural Clinical Trials Manager: Tamra Madenwald Protocol Development Coordinator: Carter Bentley SDMC Senior Project Manager: Drienna Holman SDMC Project Manager: Marianne Hansen SDMC Clinical Affairs: Hsiu-Ying Huang & Pat Farrell DAIDS Pharmacist: Ana Martinez DAIDS Regulatory Affairs: Michelle Conan-Cibotti HVTN Regulatory Representative: Renee Holt HVTN Pharmacist: Jan Johannessen Community Ed Unit Representative: Gail Broder Communications: Sarah Alexander Community Engagement: Steve Wakefield & Niles Eaton Community Educators/Recruiters: Gavin Morrow-Hall & Coco Alinsug CAB Members: Rick Church & Rich Trevino Clinic Coordinator: Steven Chang HVTN Investigators: Susan Buchbinder, Mike Keefer, Beryl Koblin, & Mark Mulligan Technical Editor: Anya Luke-Killam

Evaluate vaccine with and without oral FTC/TDF or topical TDF 1% gel HVTN – MTN Collaboration (synergy!) Study armNumberStudy products a Month -1 (Day -28 on) b Month 0 (Day 0) Month 1 (Day 28) Month 2 (Day 56) Month 5 (Day 140) Group 1a (Vaccine + Oral PrEP) 40 Vaccine DNA-C NYVAC-C Oral FTC/TDF Daily Vaginal TDF Gel placebo Daily Group 1b (Vaccine Placebo + Oral PrEP) 8 Vaccine placebo placebo Oral FTC/TDF Daily Vaginal TDF Gel placebo Daily Group 2a (Vaccine + Topical PrEP) 40 Vaccine DNA-C NYVAC-C Oral FTC/TDF placebo Daily Vaginal TDF Gel Daily Group 2b (Vaccine Placebo + Topical PrEP) 8 Vaccine placebo placebo Oral FTC/TDF placebo Daily Vaginal TDF Gel Daily Group 3a (Vaccine only) 40 Vaccine DNA-C NYVAC-C Oral FTC/TDF placebo Daily Vaginal TDF Gel placebo Daily Group 3b (All placebos) 8 Vaccine placebo placebo Oral FTC/TDF placebo Daily Vaginal TDF Gel placebo Daily Total 144 (120:24)

Social Science  Social research is the systematic observation of social life for the purpose of finding and understanding patterns among what is observed (Earl Babbie, sociologist)  What is measured is as important as how it is measured.

Potential Priorities for Socio- behavioral Research  Better engagement of communities in the conduct of our trials  Effective informed consent process to achieve what we want it to  Addressing racial and ethnic health disparities in our work  Assessing impact of our trials on participants and communities  Effective risk reduction counseling

 Informs readers about the science of the HVTN, the management of the Network’s many multilateral collaborations, and our outstanding clinical sites.  Current issue includes articles on Epitope Mapping, Adaptive Trial Design, and Exploring Barriers and Facilitators in the Recruitment of Transgender Women. HVTN.org/Science/HVTNews

Acknowledgements  Magda Sobieszczyk  505 Protocol Team  HVTN 505 Sites, Staff and Participants  HVTN Community Education & Communications Team  HVTN 505 PrEP Monitoring Working Groups PK substudy Working Group  John Hural, Peter Gilbert, Carter Bently, Shelly Karuna, Magda Sobieszczyk, Scott Hammer, Adam Sherwat, Angela Kashuba, Jim Rooney, HVTN Lab Behavioral substudy Working Group  Jonathan Fuchs, Beryl Koblin. Ken Mayer, Susan Buchbinder, Al Liu, Michele Andrasik