Transcript How to PrEP: For Models of Man

Pre-Exposure
Prophylaxis:
Robert M Grant,
MD, MPH
Sept 24, 2010
Maurice Cook (EM Designs Group, Inc.)
How to PrEP with
Models of Men and
Women
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 Karim
Quoted 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 Prevention
Similar 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 Treatment
3) 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
Wild type
Garcia-Lerma et al, 2008
Resistent
Not tested
Log10 RNA copies/ml
Log10 RNA copies/ml
Absence of drug resistance in macaques failing
iPrEP with oral Truvada (2 weekly doses)
1800
8
6
4
4
2
2
0
4
8
12
Weeks
16
20
DK40
wt
wt
4
2
0
4
8
12
Weeks
16
20
0
0
4
8
12
Weeks
16
20
DL6V
0
4
2
2
0
0
4
4
8
12
Weeks
16
20
Not tested
8 12
Weeks
16
20
35032
6
4
0
0
8
wt
Wild type
Garcia-Lerma et al, 2009
wt
4
2
6
6
0
6
8
8
DM92X
8
6
wt
0
DM91
8
wt
0
4
8
12
Weeks
16
20
Adherence
and
Resistance
Bangsberg et al 2004
Resistance and Adherence
Concerns 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-Label
Post-Exposure
Prophylaxis
and
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
Motivation
Information
Skills
I
B
Behavior
IMBot
• Specific IMB for Each Action State
• People populated by multiple IMB processes
• Condom use, Test Use, PrEP Use, Reporting
I
B
A situated IMBot socializing with friends
IMBot
navigating
in stormy
waters:
I
B
poverty,
violence,
racism,
homophobia,
addiction,
sexuality.
Oceanic View of Sex and Society
I
B
•
•
•
•
•
•
Dynamic
Complex
Unpredictable
Mysterious
Details matter little
IMBots can learn to
navigate over rough seas
• Rough seas are better
avoided than studied
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 Sex
adapted from Gagnon Sexual Conduct 1973
I
B
• 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
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 AIDSdriven 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
Investigators
Community
Locus of Control
External
Internal
Provider as
Authority
Consultant
Missed Doses
HIV Exposure
Adherence
Patient
Pill Use
Activist
Initiated by
Perception Focus
Desired Behavior
Fostered Social Role
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 Agency
1st Meeting, San Francisco
January 16th and 17th, 2008