AIDS Cure Research- Moving Into the Clinic Matt Sharp Long-term Survivor and AIDS Cure Activist San Francisco

Outline Perspective Cure-related clinical trial issues Cure-related clinical enrolling Zinc finger nuclease approach My clinical experience Results SB-728 Issues Remaining questions

Perspective HIV cure-related research has progressed relatively quickly since the first clinic case report of Timothy Brown, who is considered now functionally cured after five years Despite many unknowns the field is moving rapidly towards remarkable advances in HIV Eradication/functional cure has become a new direction in HIV research and is already moving into the clinic requiring study volunteers New drugs, vaccines, gene therapy, drug intensification trials and immune-based therapies are now being studied in humans

Cure-related clinical trial issues Recruitment in the age of effective ARV therapy Are trials ethical? What risks are reasonable? Protection from research injury Informed consent Challenging trial designs-ATI, invasive procedures Reimbursement Product continuation after trial completion Grass-roots outreach and education Community Advisory Boards to provide input into informed consents

Cure-related clinical trials now enrolling Trials now enrolling as of June 2012* 6 immune-based or cell therapeutic 8 therapeutic vaccine 8 reservoir-related Several others are being planned (ACTG, industry, etc.) *clinicaltrials.gov

Clinical background Dx in 1988 with HIV w/ 409 CD4 Sequential monotherapy throughout 90’s Consented to be in dozens of clinical trials Salvage patient developing multi-drug resistance First reached undetectable 2007 w/ RAL+DRV/r yet T-cells never rebounded Currently virally suppressed on stable HAART Immunologic non-responder

ZFN approach A kinder, gentler approach to making HIV-resistant Gene modification through zinc finger nuclease technology Disrupts the CCR5 gene in leukapheresised CD4 cells Cells modified with zinc finger nuclease introduced with adeno virus vector Modified CD4 cells; then expanded and frozen Infusion

SB-728 phase 1 safety trial First safety trial in virally suppressed immunologic non- responders Screened and consented for SB-728 in June 09 Apheresis procedure July 09 “product” development-aprx. 6 weeks Single infusion September 09 Monthly blood draws, urine 6 rectal biopsies-20 snips each procedure One lymph node biopsy-off protocol

My results Results after one year: Baseline CD4 294; CD4% 14.7; CD4/CD8; Month 12 CD4 458; CD4% 21.2; CD4/CD8; Average annual CD4 488; CD4% 21.2; CD4/CD8; Month 18 CD4 350; CD4%; CD4/CD8 CD4CD4%CD8CD4/CD8 Baseline 8/ mo Average mo % of total cells were modified CCR5 cells Modified cells found in gut No clinical events (not analyzed) No upper respiratory infections

apheresis

Issues Rectal biopsies Reimbursed $2000 over the course of one year 5 protocol amendments w/new lengthy informed consents No drug continuation for study volunteers yet No safety issues Immune system benefit?

Science 13 May 2011: Vol. 332 no pp

Remaining questions Cure-related clinical trials will require many patients Will healthy HIV+ people participate and enroll?If so, will participants understand informed consents? Will product continuation be built into protocols if a benefit is found in the absence of a cure? What is the best way to inform the community of complex and rapidly evolving scientific information? On the road to the goal of a cure, will immunologic non- responders, long-term survivors and others be forsaken? While there are risks there also may be benefits for INR

We must not see any person as an abstraction. Instead, we must see in every person a universe with its own secrets, with its own treasures, with its own sources of anguish, and with some measure of triumph. -Elie Wiesel The Nazi Doctors and the Nuremberg Code Henrietta Lacks

Imagine a World without AIDS