The Quest for a Cure Matt Sharp Project Inform/ATAC Tim Horn aidsmeds.com/ATAC

Overview Treatment vs. Cure Treatment vs. Cure Sterilizing Cure Sterilizing Cure Functional Cure Functional Cure Preventive Vaccines Preventive Vaccines Treatment as Prevention Treatment as Prevention Funding Funding Advocacy Advocacy 2

Treatment vs. Cure 3

4 Why A Cure? Chronic and manageable disease? Chronic and manageable disease? HIV drugs, though essential for life in the absence of a cure, take a potentially lethal toll on the bodies of people with HIV, precipitating problems ranging from liver cancer to heart attacks HIV drugs, though essential for life in the absence of a cure, take a potentially lethal toll on the bodies of people with HIV, precipitating problems ranging from liver cancer to heart attacks

5 More and more people will be taking antiretroviral medications as treatment guidelines shift and treatment-for- prevention programs begin rolling out More and more people will be taking antiretroviral medications as treatment guidelines shift and treatment-for- prevention programs begin rolling out Treatment fatigue will become a growing concern as well as cumulative toxicities Treatment fatigue will become a growing concern as well as cumulative toxicities

6 Antiretroviral drugs work well for most people but… Antiretroviral drugs work well for most people but… –Some have discordant or inadequate responses for a variety of known and unknown reasons –There are some people who have run out of treatment options despite the number of approved medications

7 Antiretrovirals are only available to 40% of people who need them around the world Antiretrovirals are only available to 40% of people who need them around the world Providing antiretroviral therapy for every person with HIV/AIDS, for the rest of their lives, is financially and logistically problematic Providing antiretroviral therapy for every person with HIV/AIDS, for the rest of their lives, is financially and logistically problematic

8 The ultimate goal for research on any disease is a cure but… The ultimate goal for research on any disease is a cure but… –HIV cure research continues to face many challenges and complexities

9 A cure would save federal dollars A cure would save federal dollars –The US currently spends $11 billion annually on caring for people with AIDS in the US, and in 2008 spent $6 billion on its successful US global AIDS program Would also allow some of the one million people living with HIV in the US to return to work and paying taxes Would also allow some of the one million people living with HIV in the US to return to work and paying taxes

10 Different Possible “Cures” Sterilizing cure: eliminating all HIV from the body Sterilizing cure: eliminating all HIV from the body Functional cure: permanent viral suppression without therapy Functional cure: permanent viral suppression without therapy Preventive vaccines Preventive vaccines Treatment as prevention: universal, widespread use of treatment to radically reduce risk of HIV transmission Treatment as prevention: universal, widespread use of treatment to radically reduce risk of HIV transmission

Sterilizing Cure 11

12 The Hope 1995: David Ho and others suggest HIV eradication with early use of drug combinations, much like approach used to cure diseases like TB and leukemia 1995: David Ho and others suggest HIV eradication with early use of drug combinations, much like approach used to cure diseases like TB and leukemia One and a half to three years of treatment necessary to kill off two HIV compartments: One and a half to three years of treatment necessary to kill off two HIV compartments: –Free HIV and actively infected CD4s –chronically infected cells (macrophages and dendritic cells)

The Reality 1997: Three teams discover third compartment 1997: Three teams discover third compartment –Resting, latently infected CD4 memory T- cells potentially lasting a lifetime –Resting, latently infected CD4 memory T- cells potentially lasting a lifetime 13

Ongoing viral replication Ongoing viral replication –Intensifying treatment further reduces VL –Chronic inflammation What’s causing this? What’s causing this? –Incomplete viral suppression? –Intermittent production by stable cells? –Anatomical reservoirs (brain, gut, etc.) 14

Treatment Intensification Older Approaches Ziagen (abacavir) Ziagen (abacavir) Protease inhibitor Protease inhibitor NNRTI NNRTI Newer Approaches Maraviroc Maraviroc Selzentry Selzentry 15

Purging the Reservoir Older Approaches IL-2 IL-2 IL-2 and interferon-  IL-2 and interferon-  OKT3 and IL-2 OKT3 and IL-2 Newer Approaches IL-7 IL-7 HDAC inhibition HDAC inhibition –Valproic acid Prostratin Prostratin HMBA HMBA 16

17 D. D. Richman et al., Science 323, (2009)

Therapeutic Vaccines Activate transcription of proviral DNA in the presence of ARV treatment Activate transcription of proviral DNA in the presence of ARV treatment 18

19 Gene Therapy Berlin bone marrow transplant case Berlin bone marrow transplant case Anti-HIV ribozymes Anti-HIV ribozymes Antisense Antisense siRNA siRNA Zinc-finger nucleases Zinc-finger nucleases TRIM5  TRIM5  Note: Myleoablative conditioning likely required Note: Myleoablative conditioning likely required

20 Is HIV eradication practical? With advances in HIV therapy, is striving for HIV eradication in more than a few specific cases worth the drastic interventions likely to be required to accomplish this? With advances in HIV therapy, is striving for HIV eradication in more than a few specific cases worth the drastic interventions likely to be required to accomplish this? Are there simpler approaches? Are there simpler approaches?

Functional Cure 21

22 Learning from LTNPs Lessons from long-term Lessons from long-term nonprogressors and elite controllers –Elite controllers: <1% of PLWHIV –50% have strong HIV-specific CD8 cells –Other possibilities: NK cells, low CCR5 expression, skewed HLA-C expression, low immunoregulatory response

23 Early HIV Treatment ARV therapy started during acute and early HIV infection ARV therapy started during acute and early HIV infection –Can it protect immune function? –Does it result in lower viral load “set point?”

24 Therapeutic Vaccines Training the immune system to better respond to HIV in the absence of ARV treatment Training the immune system to better respond to HIV in the absence of ARV treatment –An effective preventive vaccine could potentially work as a therapeutic vaccine, and vice versa

Older Approaches Whole inactive virus Whole inactive virus –Remune Virus-derived gp160 Virus-derived gp160 Cell-derived gp160 Cell-derived gp160 Canarypox-based Canarypox-based –ALVAC 1452 Newer Approaches Prime-boost (GeoVax) Prime-boost (GeoVax) –HIV DNA primer –MVA (smallpox) booster Vacc-4x (Bionor Immuno) Vacc-4x (Bionor Immuno) 25

26 STIs Encouraging initial results Encouraging initial results –Berlin Patient –Small studies Discouraging follow-up results Discouraging follow-up results –Danger in MDR HIV –No proven benefit –SMART study

Future of STIs Future of STIs –In combination with immune-based therapies? –Will these be allowed by FDA? 27

Preventive Vaccines 28

29 The Big Picture By inoculating populations HIV would be stopped By inoculating populations HIV would be stopped Humoral vs cellular responses Humoral vs cellular responses Several vaccine candidates have failed Several vaccine candidates have failed STEP Merck trial interrupted and discontinued STEP Merck trial interrupted and discontinued RV 144 adenoviral candidate showed 31% efficacy-trials are ongoing RV 144 adenoviral candidate showed 31% efficacy-trials are ongoing Huge, expensive trials with large cohorts and complicated science Huge, expensive trials with large cohorts and complicated science

Treatment as Prevention 30

31 Can universal testing and treatment snuff out HIV? Can universal testing and treatment snuff out HIV? TLC+ framework TLC+ framework

Funding 32

33 National Institutes for Health is the largest funder of AIDS research in the world yet is underfunded National Institutes for Health is the largest funder of AIDS research in the world yet is underfunded

34 Budget of the NIH has essentially been flat funded since 2003, and in constant dollars lost 13.4% of its annual spending power by 2009 due to biomedical inflation Budget of the NIH has essentially been flat funded since 2003, and in constant dollars lost 13.4% of its annual spending power by 2009 due to biomedical inflation

35 President Obama’s 2011 proposed budget would add only 3% to the overall NIH budget, a continued decline in spending power President Obama’s 2011 proposed budget would add only 3% to the overall NIH budget, a continued decline in spending power Due to the current economic crisis, President Obama dedicated $10 billion in Stimulus Package funds to NIH research, and about 1/10 of this was designated to NIAID (National Institute of Allergy and Infectious Diseases). Due to the current economic crisis, President Obama dedicated $10 billion in Stimulus Package funds to NIH research, and about 1/10 of this was designated to NIAID (National Institute of Allergy and Infectious Diseases).

NIAID announced that a portion of these funds would be used for basic research into viral persistence—HIV eradication NIAID announced that a portion of these funds would be used for basic research into viral persistence—HIV eradication Fauci has put cure research as one of the top of the NIAID research agenda Fauci has put cure research as one of the top of the NIAID research agenda 36

Advocacy 37

38 Cure Mobilization Cure Mobilization –education –misinformation –complex information –new Bogus cures Bogus cures More research dollars More research dollars

39 IBT Strategy Group IBT Strategy Group Michael Palm Basic Science, Vaccines & Prevention Project Weblog Michael Palm Basic Science, Vaccines & Prevention Project Weblog Project Inform Project Informwww.projectinform.org HIV Policy Project HIV Policy Project