The Third D: Long Term Solutions to End the Epidemic Mitchell Warren Executive Director, AVAC 12 February 2014
Key clinical trial milestones: HIV vaccine research First HIV vaccine trial opens Phase II Step and Phambili studies halted HVTN 505 stopped for futility Results of Phase III Thai Trial (RV144) 1980 1990 2000 2010? HIV identified VaxGen candidate fails in Phase III trials
Vaccine efficacy trials: Hopes in 2006
Vaccine efficacy trials: realities in 2014 `
Advocacy to Develop Public health effect of an HIV vaccine will depend much less on behavior than any other option We need a combination of options Challenge for advocates: Have ready answers for why we should spend millions on research with unclear results and timelines
So what about Adenovirus vectors?! Ad5 Adenovirus type 5 was used as a vector in vaccines tested in three major efficacy trials, all having no prevention effect! Some evidence that these candidates may have primed the immune system to be more vulnerable to HIV infection What we can do:! Push the field to closely monitor trials of candidates of vaccines using adeno-based vectors! Come to consensus on how to explain efficacy trial results, need for more research, and potential effects of vectors! Develop clear communication on the long-term nature of vaccine research to manage expectations
So what about the P5?! Following RV 144 can we move this or a similar product to licensure? But RV 144 ended in 2009!! Trials planned for Thailand and South Africa. Why not elsewhere?! Timelines: follow on efficacy trial in South Africa now estimated to begin in 2016, originally planned 2014/2015 What we can do! Push research groups, product developers, and others about why timelines are slipping! Start conversations about what results from these trials will mean for other countries that need a vaccine
So what about standard of prevention?! In 2016, PrEP will be part of a high quality prevention package in many countries! VMMC is effective; coverage numbers are picking up! TasP is being recommended in many countries for discordant couples and, now, other populations! Microbicide results in coming years What we can do! Build advocates capacity about standard of prevention in trials! Ensure trial community representatives and other advocates have a seat at the protocol table before decisions are made
So what about neutralizing antibodies?! Prior to 2009, only a handful of broadly neutralizing antibodies (bnabs) against HIV identified! New techniques led to identification of many hundreds of new bnabs between 2009-2013! Mapped shape & structure of bnabs and identified points of contact and binding between antibody and the virus a key for vaccine development! Not yet clear how to generate these antibodies with a candidate vaccine! Early, small trials underway to move some of the bnabs into Phase I human trials of safety and tolerability, and discussions of passive immunization trials
http:// 3pathstoacure.org
Cure in the News Four Key Cases AIDS 2012: French Cohort Treated during Primary Infection Appears to Control HIV without ART Bone marrow 'frees men of HIV drugs'
Some More Language Reservoir pool of HIV-infected cells that have become latent (T-cells, tissues, macrophages in the central nervous system) Latency maintenance in host genome of integrated viral DNA where infectious virus is not produced from the cell Elite controller an individual who can naturally control the HIV virus without anti-retroviral therapy Functional cure no detectable virus using viral load standards and no transmission of infection (remission) Sterilizing cure no detectable virus and no reservoir
How could an HIV cure work? Change the immune system Through stem cell transplant (bone marrow) Gene therapy Shock and kill Reactivate the infected cells and kill them Target the latent cells Don t reactive just kill Enhance immune control Therapeutic vaccination Immune modulators
Berlin Patient HIV-positive diagnosis in 1995 Controlled with ARVs Acute Myeloid Lukemia (AML) in 2007 Received two bone marrow transplants (2007, 2008) from the same donor who is naturally immune Off ARVs without a problem since 2008 Seems to have sterilizing cure
Mississippi Baby Mother found HIV positive on giving birth; had not been receiving HIV treatment Infant given ARVs within 30 hours of birth Lost to care at 18 months Presented again at 24 months Looks to be at least functionally cured, if not completely cured
Visconti Cohort! A subset of patients consisting of 14 individuals put on treatment within 10 weeks of infection! Taken off treatment under physician supervision! Some seem to have become spontaneous controllers Meaning they do not seem to have the same genetic protection that elite controllers have
Boston Patients Two men in Boston both had HIV controlled through ARV therapy and lymphoma (blood cancer) Received bone marrow transplantations for their cancer and were kept on ARVs Taken off of HIV treatment by physician Remained off ARVs for several months without indication of HIV infection Clinical indication of infection returned
No what? Cure patients prove concepts are possible Need much more clinical research and it s tough Need more basic research on cure concepts Functional cure doesn t mean HIV-free Virus is undetectable in the blood, but still exists in reservoirs Infection from latent virus can reoccur at any time A functional cure is closer to remission in cancer
What can advocates focus on? Where is the research happening, and where should it happen Need to involve women Ensure affected communities can be part of the research agenda Develop mechanisms for community engagement and GPP within trials Funding maintain support for the develop agenda, even if answers are complex and a long way off