The Quest for a The Quest for a CureCure

Matt Sharp Project Inform/ATACMatt Sharp Project Inform/ATAC

Tim Horn aidsmeds.com/ATACTim Horn aidsmeds.com/ATAC

OverviewOverview

Treatment vs. CureTreatment vs. Cure Sterilizing CureSterilizing Cure Functional CureFunctional Cure Preventive VaccinesPreventive Vaccines Treatment as PreventionTreatment as Prevention FundingFunding AdvocacyAdvocacy

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Treatment vs. CureTreatment vs. Cure

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Why A Cure?Why A Cure?

Chronic and manageable disease?Chronic and manageable disease? HIV drugs, though essential for HIV drugs, though essential for

life in the absence of a cure, take life in the absence of a cure, take a potentially lethal toll on the a potentially lethal toll on the bodies of people with HIV, bodies of people with HIV, precipitating problems ranging precipitating problems ranging from liver cancer to heart attacks from liver cancer to heart attacks

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More and more people will be More and more people will be taking antiretroviral medications taking antiretroviral medications as treatment guidelines shift and as treatment guidelines shift and treatment-for-prevention treatment-for-prevention programs begin rolling outprograms begin rolling out

Treatment fatigue will become a Treatment fatigue will become a growing concern as well as growing concern as well as cumulative toxicities cumulative toxicities

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Antiretroviral drugs work well for Antiretroviral drugs work well for most people but… most people but… – Some have discordant or inadequate Some have discordant or inadequate

responses for a variety of known and responses for a variety of known and unknown reasonsunknown reasons

– There are some people who have There are some people who have run out of treatment options despite run out of treatment options despite the number of approved medications the number of approved medications

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Antiretrovirals are only available Antiretrovirals are only available to 40% of people who need them to 40% of people who need them around the worldaround the world

Providing antiretroviral therapy Providing antiretroviral therapy for every person with HIV/AIDS, for every person with HIV/AIDS, for the rest of their lives, is for the rest of their lives, is financially and logistically financially and logistically problematicproblematic

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The ultimate goal for research on The ultimate goal for research on any disease is a cure but… any disease is a cure but… – HIV cure research continues to face HIV cure research continues to face

many challenges and complexitiesmany challenges and complexities

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A cure would save federal dollarsA cure would save federal dollars– The US currently spends $11 billion The US currently spends $11 billion

annually on caring for people with AIDS annually on caring for people with AIDS in the US, and in 2008 spent $6 billion on in the US, and in 2008 spent $6 billion on its successful US global AIDS program its successful US global AIDS program

Would also allow some of the one Would also allow some of the one million people living with HIV in the million people living with HIV in the US to return to work and paying taxesUS to return to work and paying taxes

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Different Possible Different Possible “Cures”“Cures”

Sterilizing cure: eliminating all HIV Sterilizing cure: eliminating all HIV from the bodyfrom the body

Functional cure: permanent viral Functional cure: permanent viral suppression without therapysuppression without therapy

Preventive vaccines Preventive vaccines Treatment as prevention: universal, Treatment as prevention: universal,

widespread use of treatment to widespread use of treatment to radically reduce risk of HIV radically reduce risk of HIV transmission transmission

Sterilizing CureSterilizing Cure

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The HopeThe Hope

1995: David Ho and others suggest HIV 1995: David Ho and others suggest HIV eradication with early use of drug eradication with early use of drug combinations, much like approach used combinations, much like approach used to cure diseases like TB and leukemiato cure diseases like TB and leukemia One and a half to three years of treatment One and a half to three years of treatment

necessary to kill off two HIV compartments:necessary to kill off two HIV compartments:– Free HIV and actively infected CD4sFree HIV and actively infected CD4s– chronically infected cells (macrophages and chronically infected cells (macrophages and

dendritic cells)dendritic cells)

The RealityThe Reality

1997: Three teams discover third 1997: Three teams discover third compartmentcompartment– Resting, latently infected CD4 Resting, latently infected CD4

memory T-cells potentially lasting a memory T-cells potentially lasting a lifetime  lifetime 

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Ongoing viral replicationOngoing viral replication– Intensifying treatment further reduces VLIntensifying treatment further reduces VL– Chronic inflammationChronic inflammation

What’s causing this?What’s causing this?– Incomplete viral suppression?Incomplete viral suppression?– Intermittent production by stable cells?Intermittent production by stable cells?– Anatomical reservoirs (brain, gut, etc.)Anatomical reservoirs (brain, gut, etc.)

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Treatment IntensificationTreatment Intensification

Older ApproachesOlder Approaches Ziagen (abacavir)Ziagen (abacavir) Protease inhibitorProtease inhibitor NNRTINNRTI

Newer ApproachesNewer Approaches MaravirocMaraviroc SelzentrySelzentry

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Purging the ReservoirPurging the Reservoir

Older ApproachesOlder Approaches IL-2IL-2 IL-2 and interferon-IL-2 and interferon- OKT3 and IL-2OKT3 and IL-2

Newer ApproachesNewer Approaches IL-7IL-7 HDAC inhibitionHDAC inhibition

– Valproic acidValproic acid ProstratinProstratin HMBAHMBA

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D. D. Richman et al., Science 323, 1304 -1307 (2009)

Therapeutic VaccinesTherapeutic Vaccines

Activate transcription of proviral DNA Activate transcription of proviral DNA in the presence of ARV treatmentin the presence of ARV treatment

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Gene TherapyGene Therapy

Berlin bone marrow transplant caseBerlin bone marrow transplant case Anti-HIV ribozymesAnti-HIV ribozymes AntisenseAntisense siRNAsiRNA Zinc-finger nucleasesZinc-finger nucleases TRIM5TRIM5 Note:Note: Myleoablative conditioning Myleoablative conditioning

likely requiredlikely required

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Is HIV eradication practical? Is HIV eradication practical?

With advances in HIV therapy, is With advances in HIV therapy, is striving for HIV eradication in striving for HIV eradication in more than a few specific cases more than a few specific cases worth the drastic interventions worth the drastic interventions likely to be required to likely to be required to accomplish this? accomplish this?

Are there simpler approaches?Are there simpler approaches?

Functional CureFunctional Cure

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Learning from LTNPsLearning from LTNPs

Lessons from long-term Lessons from long-term

nonprogressors and elite controllersnonprogressors and elite controllers– Elite controllers: <1% of PLWHIVElite controllers: <1% of PLWHIV– 50% have strong HIV-specific CD8 cells50% have strong HIV-specific CD8 cells– Other possibilities: NK cells, low CCR5 Other possibilities: NK cells, low CCR5

expression, skewed HLA-C expression, expression, skewed HLA-C expression, low immunoregulatory responselow immunoregulatory response

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Early HIV TreatmentEarly HIV Treatment

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

point?”point?”

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Therapeutic VaccinesTherapeutic Vaccines

Training the immune system to Training the immune system to better respond to HIV in the better respond to HIV in the absence of ARV treatmentabsence of ARV treatment– An effective preventive vaccine An effective preventive vaccine

could potentially work as a could potentially work as a therapeutic vaccine, and vice versatherapeutic vaccine, and vice versa

Older ApproachesOlder Approaches Whole inactive virus Whole inactive virus

– RemuneRemune Virus-derived gp160Virus-derived gp160 Cell-derived gp160Cell-derived gp160 Canarypox-basedCanarypox-based

– ALVAC 1452ALVAC 1452

Newer ApproachesNewer Approaches Prime-boost (GeoVax)Prime-boost (GeoVax)

– HIV DNA primerHIV DNA primer– MVA (smallpox) boosterMVA (smallpox) booster

Vacc-4x (Bionor Vacc-4x (Bionor Immuno)Immuno)

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STIsSTIs

Encouraging initial resultsEncouraging initial results– Berlin PatientBerlin Patient– Small studiesSmall studies

Discouraging follow-up resultsDiscouraging follow-up results– Danger in MDR HIVDanger in MDR HIV– No proven benefitNo proven benefit– SMART studySMART study

Future of STIsFuture of STIs– In combination with immune-based In combination with immune-based

therapies?therapies?– Will these be allowed by FDA?Will these be allowed by FDA?

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Preventive VaccinesPreventive Vaccines

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The Big PictureThe Big Picture

By inoculating populations HIV would be By inoculating populations HIV would be stoppedstopped

Humoral vs cellular responsesHumoral vs cellular responses Several vaccine candidates have failedSeveral vaccine candidates have failed STEP Merck trial interrupted and STEP Merck trial interrupted and

discontinueddiscontinued RV 144 adenoviral candidate showed 31% RV 144 adenoviral candidate showed 31%

efficacy-trials are ongoingefficacy-trials are ongoing Huge, expensive trials with large cohorts Huge, expensive trials with large cohorts

and complicated scienceand complicated science

Treatment as PreventionTreatment as Prevention

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Can universal testing and Can universal testing and treatment snuff out HIV? treatment snuff out HIV?

TLC+ frameworkTLC+ framework

FundingFunding

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

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

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President Obama’s 2011 proposed President Obama’s 2011 proposed budget would add only 3% to the budget would add only 3% to the overall NIH budget, a continued overall NIH budget, a continued decline in spending power decline in spending power

Due to the current economic crisis, Due to the current economic crisis, President Obama dedicated $10 billion President Obama dedicated $10 billion in Stimulus Package funds to NIH in Stimulus Package funds to NIH research, and about 1/10 of this was research, and about 1/10 of this was designated to NIAID (National Institute designated to NIAID (National Institute of Allergy and Infectious Diseases).of Allergy and Infectious Diseases).

NIAID announced that a portion of NIAID announced that a portion of these funds would be used for basic these funds would be used for basic research into viral persistence—HIV research into viral persistence—HIV eradicationeradication

Fauci has put cure research as one of Fauci has put cure research as one of the top of the NIAID research agendathe top of the NIAID research agenda

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AdvocacyAdvocacy

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Cure Mobilization Cure Mobilization – educationeducation– misinformationmisinformation– complex informationcomplex information– newnew

Bogus curesBogus cures More research dollarsMore research dollars

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IBT Strategy GroupIBT Strategy Group Michael Palm Basic Science, Michael Palm Basic Science,

Vaccines & Prevention Project Vaccines & Prevention Project Weblog Weblog

Project InformProject Inform

www.projectinform.orgwww.projectinform.org HIV Policy Project HIV Policy Project

www.aidspolicyproject.orgwww.aidspolicyproject.org