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Pre-ExposureProphylaxis:

How to PrEP with Models of Men and

Women

Robert M Grant,

MD, MPH

Sept 24, 2010

HIV Prevention

• 3 new infections for every person starting ART• Few Concepts Known

– Condoms, Education, Clean Needles, VCT, MTCTp, Circumcision for Heterosexual Men, Treatment

– All underutilized, most controversial

• Multiple Concepts Failed– Acyclovir, Diaphragms, Mass STI Treatment, Intensive

Counseling, Polyanion Microbicides

• No Surrogate Markers Known• Adherence can run ½ reported levels• Potential Beneficiaries

– Would often rather stay in bed then “advocate” for prevention

"We are really groping in the dark"

Salim S. Abdool KarimQuoted in the Washington Post, November 1, 2007

Finding The Way Out of The Dark:

Listen

What I Heard(I may have been mistaken)

• Pills are for sick people– We are not sick

• HIV is one of many problems– Certainly NOT the most urgent– Violence, Poverty, Isolation are More Urgent

• If you want to study us– Use our names– Studying sex workers in an era when “sex

work” was a forbidden term was a non-starter

Treatment and PreventionSimilar Technology

• Treatment may prevent transmission

• Prevention enables treatment

• Both may use pills– Indeed, the same pills

• Evaluated with Randomized Clinical Trials– Intention to treat is primary

Prevention And Treatment Are Different in Respects

That Bear Directly on Adherence

Prevention is Not Treatment:1) No Patients

• Healthy people, notwithstanding…

• Language That Pathologizes People– “risk groups” and “vulnerable groups” vs– gay men, transexuals, sex workers, etc

• Language that Pathologizes Acts– “risk behavior” vs– Sex or work or community or procreation

Prevention is Not Treatment:2) No regimens

• Treatment regimens can be optimized– In vitro activity suggest target level– Pharmacokinetics suggest dosing interval– Phase II studies narrow to few options– Phase IIb/III select the best option– Phase IV explore alternatives

• Optimization Made possible by – Surrogate markers, small sample size

Prevention is Not Treatment:2) No Regimens

• No surrogate markers for HIV prevention– Immune correlates not known– Minimum protective level not known– Target cells for activity not known– Safety parameters not always clear

• Prevention Trials Are Large – few options evaluated

Counseling When There is No Regimen

• “Adherence” to an optimized regimen – Does not apply to PrEP

• In Prevention, we do not say – “Don’t use condoms unless you can use them

everytime”

• Also Applies to… – Communication with Partners– Use of HIV Tests

• May Apply to Pill use as well.

Prevention is not Treatment3) Drug Resistance?

• In treatment, the virus population has many billions of opportunities to generate resistance– partial adherence to nnRTIs/3TC allows replication to

generate drug resistant mutants– Partial adherence to PIs may not be sufficient to

select the drug resistant mutants.• In Prevention, the virus population clings to a

few mls of genital secretions– it is unknown whether new mutations can be

generated.– Starting PrEP in the window period of infection will

select resistance

Daily PrEP Selected M184I/V Resistance in 2/6 Animals

Garcia-Lerma et al, 2008

Wild type Not testedResistent

Absence of drug resistance in macaques failing iPrEP with oral Truvada (2 weekly doses)

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Garcia-Lerma et al, 2009

Adherence and

Resistance

Bangsberg et al 2004

Resistance and AdherenceConcerns For PrEP

• Starting or Restarting PrEP – during the RNA+/Ab- window”– Expected to select resistance

• Non-adherence to the daily regimen– Unclear effect on resistance– Depends on efficacy, drug levels, selection

• Fear of resistance drives a high bar– People who miss doses may give up– People who miss doses when highly exposed

may be told to give both up (sex and PrEP)

Prevention is Not Treatment:4) We undermine adherence in prevention

These messages have been quoted back to us during qualitative research, as reasons for deferring pill use until efficacy is proven.

Prevention is Not Treatment:5) Synergies expected

• Treatment Choices Are Often Exclusionary– TDF/FTC vs AZT/3TC– EFZ vs NVP– Selecting A means not selecting B

• Prevention Choices Are Typically Complementary– Condom is useful for HIV/ contraception/ STIs– PrEP may protect weak vaccine responses– PrEP may attract people into STI Care

Reported Risk Behavior

Declined With

Open-LabelPost-Exposure

Prophylaxisand

Counseling

Martin et al., AIDS 2004

Conclusion from SF: PEP and Risk Compensation

Martin et al., AIDS 2004

Air Bags and Seat Belts

• Antagonisms assumed initially, but

• Airbags and seat belt innovations are now motivators for purchase of new cars

• Safety conscious people demand both.

• Synergies Prevail

How to PrEP?Models of Men and Women

IMB

I

B

Information Motivation

Skills

Behavior

• Specific IMB for Each Action State• People populated by multiple IMB processes• Condom use, Test Use, PrEP Use, Reporting

IMBot

I

B

A situated IMBot socializing with friends

IMBot navigating in stormy waters:

poverty, violence,racism,

homophobia,addiction,

sexuality.

IB

Oceanic View of Sex and Society

• Dynamic• Complex• Unpredictable• Mysterious• Details matter little• IMBots can learn to

navigate over rough seas• Rough seas are better

avoided than studied

IB

Models of Man

• Herbert Simon(1916-2001)

• Published 1956• “Bounded Rationality”• Not Pathological Within

Social Context• Nobel Prize 1978• APA award 1993

Bounded Rationality and Organizational Decision-making

Organizations. March and Simon, 1958

• Decisions Come From Where People Sit– The Social Situation Governs

• Information availability • Perceptions• Motivation and goals• Learned Skills and Heuristics

Social view of Sexadapted from Gagnon Sexual Conduct 1973

• Sex, both desire and control, are social constructs

• Some safer than others

• Plans may be lost• Behavior

constrained, but not determined.

• Can be studied and understood

I

B

US Traditions in Sex Research

• Kinsey– Biology, Narratives, Outlets

• Sociological (Gagnon & Simon)– Social scripts– Shape both desire and control– National surveys

• Women’s studies/LGBT studies• Development of ED Drugs• AIDS Research

On AIDS Research• John Gagnon• “None of these studies has

been undertaken to understand sexual phenomena, but rather to measure risk of seroconversion and the effectiveness of prevention efforts… Such purely AIDS-driven work forces researchers to follow outbreaks of the epidemic rather than anticipate them.– Disease and Desire. 1989

Where do Prevention Users Sit?

In Their Communities

“Let’s Communicate”

Community Based Prevention

• Ecuador

• Constitutional Protections for LGBT Communities

• Boston

• Specialized Health Care For LGBT Communities

Both Highly Successful iPrEx Sites

Successful Prevention Initiatives

• Condom Use in US Cities Early 1980s• “Love Carefully” Uganda 1990s• SeroPos Seroadaptive Behaviors Late 1990s• Common Characteristics

– Grass Roots Initiatives– The Scripts Changed

• Love Carefully• Be a rubber man

– Acknowledge Sexual Goals

People Learn What They Need to Know:Will Intermittent PrEP Create a Need to Recognize Exposure and Plan for Sex?

(HPTN 067)

Daily Intermittent

Initiated by Investigators Community

Locus of Control External Internal

Provider as Authority Consultant

Perception Focus Missed Doses HIV Exposure

Desired Behavior Adherence Pill Use

Fostered Social Role Patient Activist

Toward More Effective Prevention

• Advocacy for Study Populations– Gay, Lesbian, Transgender– Sex workers– Drug Users– Discordant couples– Abused

• Focus on Use, not Intention• Turn the Oceans into Roadmaps

– Sex, society, violence, poverty– NIH NIS and CDC NCS?

• Focus on Synergies, not Antagonisms

iPrEx Presentations on PrEP Pill Use

• Lorena Vargas, INMENSA, Lima, Peru– Qualitative Research in Andes

• Albert Liu, SF DPH– Qualitative Research in SF

• Rivet Amico, U. Conn– Next Step Counseling

Many Thanks To

• IPREX Pill Use Working Group– Rivet Amico– Albert Liu– Ed Wolf– Pedro Goicochea– Lorena Vargas– Vanessa McMahan

• Social Approaches– Jeff McConnell– John Gagnon– David Halperin

• HPTN 067 Behavioral Working Group– Frits Von Griensven– Rivet Amico– Kata Chillag– Daniela Marks– Michael Stirrat– Andrew Forsyth– Scott Rose

• Sponsors/Funders– Division of AIDS, NIMH, Gates,

CDC

HIV, Risk, Behavior, and Agency1st Meeting, San Francisco

January 16th and 17th, 2008