Transcript Iniciativa PrEx PrEP Initiative Introduction to the PREP concept Javier R. Lama, MD, MPH Robert M.

Iniciativa PrEx
PrEP Initiative
Introduction to the PREP concept
Javier R. Lama, MD, MPH
Robert M. Grant, MD, MPH
1
Management of
genital infections
(STIs)
Microbicides
Cervical Barriers
HIV
PREVENTION
Condoms
Behavioral
Counseling and
Testing
Vaccines
HSV-2
Suppressive
therapy
Male
circumcision
Chemoprophylaxis
MTCTP
PEP
PrEP
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Prevention Disappointments
• Trials showing no efficacy or harm…
–
–
–
–
–
–
Intensive counseling in MSM (Koblin Lancet 2004)
Microbicides: N-9/Savvy/Cellulose Sulfate
Diaphragms (Padian Lancet 2007)
Mass STI treatment (Wawer Lancet 1999)
Herpes suppression (Celum CROI 2008)
An adenovirus-vectored vaccine (Buchbinder CROI 2008)
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Male
circumcision
Condoms
Behavioral
Counseling and
Testing
(Intensive not
better than
standard)
HIV
PREVENTION
(Not known to
be helpful for
men who have
sex with men)
Chemoprophylaxis
MTCTP
(PEP
PrEP
have unknown
efficacy)
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PrEP Goes Back to Basics
• HIV Infection is The Cause of AIDS
– Not Sex, Not Drugs
– Antiretroviral Agents Target HIV Directly
• People Like Sex
– For Pleasure, Intimacy, Company, Livelihood,
– and Pregnancy....
– Prevention is less used if it alters sex
• Abstinence Programs, Condoms, Diaphragm.
• Microbicides?
• Male circumcision?
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Why Chemoprophylaxis?
• Anti-HIV Drugs
– Inhibit HIV directly
– Are already formulated and mass produced
– Prevent mother to child transmission
• A pill is at least as female controlled as a
topical microbicide
• Chemoprophylaxis is a proven concept
– EG: Malaria, TB pneumonia, meningitis
– A mainstay of prevention if no vaccine
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Why Pre-exposure?
• Pre-exposure dosing increases efficacy
– SHIV exposed nonhuman primates (Garcia Lerma 2008)
• People have difficulty recognizing exposure
– Denial (Schechter JAIDS 2004)
– Substance use
– Imperfect communication with partners
• For those at highest risk
– Pre- and post-exposure periods overlap
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Why FTC/TDF?
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Some Chemoprophylactic Agents
Zidovudine
Therapy
year licensed
1987
Lamivudine
1995
Nevirapine
Tenofovir
1996
2001
Emtricitabine
2003
Entry Inhibitors
1st in 2007
Integrase Inhibitors 1st in 2007
Prevention
Indications
MTCTp
PEP
MTCTp
PEP
MTCTp
PEP
Oral PrEP
Microbicide
MTCTp
PEP
Oral PrEP
PrEP
Microbicide
TBD
Status
licensed
used
used
used
efficacy shown
used
phase II/III
phase II/III
safety
used
phase II/III
primates
primates
TBD
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FTC and TDF have Long Intracellular Half Life
Approved
as BID
Approved
as QD or BID
Approved
Approved
Approved
as QD or BID as QD or BID as QD or BID
50
Approved
as QD
**
>60
45
40
T1/2 (hours)
Approved
as QD
35
30
25
20
24 hours
‡
*
15
10
5
12 hours
§
*
0
ZDV
d4T
ABC
3TC
Serum/Plasma half-life
†Data
ddI
TDF
FTC
Intracellular half-life
from Centers for Disease Control and Prevention. MMWR Recomm Rep. 2002;51(RR-7):1-64 unless otherwise noted
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*Anderson et al. AIDS 2003; 17(15):2159-2168. ‡Piliero et al. 43rd ICAAC, Chicago, 2003.
** Hawkins et al. 5th IWCPHT, Rome, 2004 § Wang et al. IAC, 2002, poster #4546.
Drug Exposure in the Male Genital Tract
Percent of Blood Plasma Levels
Kashuba et al. and CROI 13 Abstract 569 (Vourvahis), 13th CROI
Abstracts 396 (Stekler), Abstract 618 (Katzenstein)
0
50%
100%
APV (20%) NVP (70%)
ENF (ND)
150%
ABC (150%)
200%
500%
ZDV (200%)
TDF (500%)
600%
3TC (600%)
IDV (100%)
d4T (2%)
EFV (3%)
SQV (3%)
RTV (3%)
LPV (5%)
NFV (5%)
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NRTI
PI
NNRTI
FI
Mitochondrial DNA Depletion
DDI>DDC>D4T>AZT>Abacavir = 3TC = TDF
(Birkus, Hitchcock, Cihlar. Antimicrob Agents Chemother 2002)
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Preclinical Evaluation of
Tenofovir (TDF) +
Emtricitabine (FTC)
• Either FTC or TDF were protective
– 70% to 100% Effective
• Emtricitabine + Tenofovir
– The combination was 100% effective
– Even after repeated rectal exposures (14)
– Even if given once prior to exposure, and once after
• Protection probably reflects
– High concentrations in genital tissues and fluids
– Long intracellular half life
– Activity in Macrophages
Tsai ‘95; Van Rompay ‘99 ‘00 ‘01 ‘04; Subbarao ’05; Heneine’06 ‘07 ‘08
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FTC/TDF Toxicity Concerns
• TDF
– Few Case Reports of Renal Failure
• Risk Factors: Small Body Size, Overdosage, Concomitant use of DDI
or Kaletra
– Headache, Dizziness, Cramps, Flatulence,
– Small changes in bone density in HIV positives
• FTC
– Skin or nail discoloration (0-8%; blacks>>latinos>whites)
– Never severe; does not lead to stopping medications
• Both
– HBV flare in those stopping
• Risk Factors: baseline cirrhosis, baseline transaminitis, HBeAg+
– Lactic Acidosis?
• All case reports involve other drugs as well (especially D4T or DDI)
• Monitor Anion Gap and Total CO2
– Drug Resistance
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2007
• Conducted between June 2004 and March 2006
• West Africa
• Daily dose of 300 mg oral Tenofovir DF vs. placebo
• All participants received testing, condoms, and counseling.
• Safety evaluated in N=936 including 428 person years
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Findings From the
West African PREP Study
• Safety in seronegatives confirmed
– No increase in grade 1 renal abnormalities
– No grade 2 or greater renal toxicity
– No flares among 23 known to be HBsAg+
• A trend toward efficacy
– 8 seroconversions (2 TDF: 6 Placebo; P=0.34)
– 2 seroconversions after 1 and 2 months of TDF
• No specimens to Rule Out Pre-PREP infection
• No bona fide case of PREP failure yet documented
Peterson, Plos Clinical Trials, 2007
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The iPrEx Study:
Safety, Efficacy, Behavior, and Biology
Sponsored by NIH/NIAID/DAIDS
with co-funding by the
Bill and Melinda Gates Foundation
and drug donated by
Gilead Sciences
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The iPrEx Study:
Safety, Efficacy, Behavior, and Biology
Gladstone Institute
of Virology and
Immunology
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The iPrEx Study
•
•
•
•
Plans to Enroll 3000 High Risk MSM
Randomized 1:1 Daily Oral PREP
FTC/TDF vs Placebo
Followed on Drug for:
–
–
–
–
–
–
–
HIV seroconversion
Adverse Events (especially renal & liver)
Metabolic Effects (Bone, Fat, Lipids)
HBV Flares among HBsAg+
Risk Behavior & STIs
Adherence
If infected
• Drug Resistance
• Viral load
• Immune responses & CD4 Count
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Why MSM?
“We Love You…
Be Part of
Something Big”
INMENSA, Peru
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Why MSM?
• From 2002 to 2004,
– The PREP Agenda Did Not Include MSM
• MSM Bear a Major Burden of the Epidemic
– Throughout the Americas
– In At Least Some Parts of Asia
– The Burden in Africa Is Increasingly Appreciated
• Efficacy Could Be Different After Rectal Exposure
– Higher Efficiency of Transmission
– Possibly Different Tissue Penetration of Virus and Drug
• iPrEx is Still The Only Efficacy Study in MSM
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“Let’s Communicate”
From February 2004, the iPrEx study communicated with participants, activists, government,
sponsors, physicians…
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Lessons Learned
• Ethical Discussions Focus on
–
–
–
–
Autonomy if rich
Benefits if poor
Poverty impinges on autonomy
EG: Visit Reimbursement Rates
• Poor People Want More
• Risk Compensation or “Dis-inhibition”
– Major concern for straight-appearing gay men
– Not mentioned by travesties and others
• Fragile communities rely on delicate practices
for generating income, resisting violence, and
maintaining health
– Any Change is Frightening.
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After 3 Years of Preparation,
iPrEx is Enrolling on Schedule
800
700
Enrollment
600
500
400
300
200
100
0
Jun- Jul- Aug- Sep- Oct- Nov- Dec- Jan- Feb- Mar07
07
07
07
07
07
07
08
08
08
25
Ju
n0
Se 7
pDe 0 7
cM 07
ar
-0
Ju 8
n0
Se 8
pDe 0 8
cM 08
ar
Ju 09
n0
Se 9
pDe 0 9
cM 09
ar
-1
Ju 0
n1
Se 0
pDe 1 0
c10
Enrollment
Planned iPrEx Enrollment
3500
3000
2500
2000
1500
1000
500
0
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Why Was iPrEx Expanded?
• To Provide Power to Detect
Cost-Effective Levels of Efficacy
– Cost Effective if >60% Efficacy
– Not Cost Effective if <30% Efficacy
– Efficacy in Practice < Efficacy in Trials
Grant et al, IAS Meeting, Toronto 2006
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Future Optimization
• Requires Non-Inferiority Margins
– Minimal Evidence of Efficacy From A Single
“Proof of Concept” Trial Could Hinder
Future Optimization
• Optimizing The Regimen
– To Minimize Toxicity, Resistance and Costs
• Optimizing Dosing Route and Interval
– To Maximize Convenience and Efficacy
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Adherence
• Measured by
– CASI (quarterly)
– Self Report to Counselor (monthly)
– Pill Count
• Improves After First On-Drug Visit
• Individualized Counseling Strategies Used
– People Go From Pharmacy to Counseling
• Periodic Blinded Drug Levels
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The Importance of CASI
• PREP is a Behavioral Intervention
– Requires Adherence
– Could Alter Risk Behavior
• Behavior is Complicated
– Especially Sexual Behavior
– Numbers of partners, types of partners,
practices with each partner
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Other Possible Effects of PEP/PREP
• Encourages People to PREPare for Sex.
– Take Protection Along.
– Have The Safe Sex Talk Early.
• Serves As A Reminder Of Risk.
– Foster A Vision For An AIDS-free Life.
– Investment In Future Health.
• Builds Stronger Communities.
– Bridge Across Positive And Negative Factions.
– De-stigmatize “At Risk” and infected groups.
• Stabilizes Sexual Relationships.
– By Protecting Those Drawn To Positive Persons.
– By Protecting Those Desiring Pregnancy.
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The Importance of CASI
• Measures Drug Exposure
• Measure Sexual Behavior
– Numbers of Partners
– Types of Partners
– Activities with Each Type of Partner
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Drug Resistance
• Standard Population Genotype
• Standard Population Phenotype
• Allele Specific PCR for Mutations
– Using a ultra-selective enzyme
– And mutation specific primers
– TDF: K65R, K70E
– FTC: M184I/V, K65R
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Will Chemoprophylaxis Have
Immunological Benefits?
PBMCs are for immunological
and virological substudies led by
Douglas Nixon, Oscar Guerra, Esper Kallas, Robert Grant
Viral antigen exposure during
chemoprophylaxis may induce antiviral
immune responses that could provide
future protection,
or,
attenuate the course of infection among
seroconverters.
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Minimum Effective Concentration
of PREP Agents
• The Best We Surrogate Marker of
Protection We Could Have
• PBMC Concentrations Reflect Longer
Term Exposure
• Yet Another Reason PBMC Collection is
Very Important in iPrEx
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“…Señor Ministro de Salud: ¿qué hacer?
¡Ah! desgraciadamente, hombres humanos,
hay, hermanos, muchísimo que hacer!”
LOS NUEVE MONSTRUOS
César Vallejo, 1939
THE NINE MONSTERS
“… Mr. Minister of Health: What to do?
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Ay, unfortunately, fellow humans,
there is, brothers, so much to do!”