Transcript Document

PREVENTION OF HIV-1
Myron S. Cohen, MD
Institute for Global Health
The University of North Carolina
Transmission of HIV-1
Biological Requirements
Infectious
Susceptibility
Inoculum (concentration)
Phenotypic factors
Hereditary resistance
Innate resistance
Acquired (immune)
resistance
NSI HIV (M-tropic)
SI HIV (T-tropic)
semen
Lamina Propria
Dendritic Cells
HIV-1
“SWARM”
CD4+
CCR5+
Α4 β7+
CD4
DC-SIGN
migration
to lymphoid organs
CCR5
T cell
99% R5, 82% 1 variant
.
HIV-1 Transmission Model
Cohen et al, NEJM, 2011
Mucosa
Recipient
Inoculum
>106 virions/ml plasma
(Most fit virus R0>>1)
~109 infection events
Defective virus
Less fit virus (R0~1)
Defective virus
X Less fit, attenuated or
stochastic event (R0<<1)
0
3
7
Time (days)
10
14-28
Acute HIV-1 Infection
Cohen et al, NEJM, 2011
Onset cytokines
apoptosis, Day 7
Virus Concentration in Extracellular Fluid
or
Plasma (Copies/ml)
Acute Phase Reactants
Days -5 to-7
Free Antibody, Day 13
Immune Complexes
Day 9
Autologous
Neutralizing Antibody
108
107
106
105
104
?
Reservoir
eclipse
103
102
101
0
CTL Escape
CD8 T Cell
Responses
10-1
10-2
Transit
10-3
Autologous
Neutralizing
Antibody
Escape
T0
10-4
10-5
0
Transmission
5
10
15
20
25
30
35
40
Time Post Exposure (days)
45
50
55
60
65
70
Effect of Acute and Early HIV Infection on Spread
Cohen et al, NEJM, 2011
Pinkerton & Abramson 1996**
Kretzschmar & Dietz 1998**†
Powers et al 2010
Hayes &
White
2006*
Jacquez et al 1994
Salomon &
Hogan
2008*
Koopman et al 1997**
Xiridou et al 2004
Pinkerton 2007
Prabhu et al 2009
Abu-Raddad
& Longini 2008†
Hollingsworth
et al 2008
* Range of estimates reflects the proportion of all transmissions during an individual’s entire infectious period that occur during EHI. The extent to which this
proportion corresponds with the proportion of all transmissions that occur during EHI at the population level will depend on the epidemic phase and the distribution
of sexual contact patterns in the population.
** Transmission probabilities were drawn from the population category shown, but the reported estimates result from a range of hypothetical sexual behavior
parameters that do not necessarily reflect a specific population.
† The range of estimates shown was extracted from the endemic-phase portion of graphs showing the proportion of new infections due to EHI over calendar time.
Four Prevention Opportunities
Cohen et al, JCI, 2008
Cohen IAS 2008
UNEXPOSED
EXPOSED
EXPOSED
INFECTED
(precoital/coital) (postcoital)
Behavioral,
Structural
Structural
Circumcision
Condoms
STDs
YEARS
Vaccines
ART PrEP
Microbicides
HOURS
Vaccines
ART PEP
72h
Treatment Of HIV
Reduced Infectivity
YEARS
ART to Prevent Sexual Transmission
of HIV
• Post-exposure Prophylaxis (PEP)
• Pre-exposure prophylaxis (PrEP)
• Treatment of the infected person
Pre-Exposure Prophylaxis
•
•
•
•
•
•
•
Study
CAPRISA (TDF Gel)
iPREX (Daily TDF)
FEM-PrEP (Daily TDF)
Partners (TFV/TDF)
Botswana (TDF)
Others in Progress
Effect
39-50%
44%
Stopped
>70%
>60%
TFV/FTC (Truvada®) PO QD
Patterson, Cohen, Kashuba et al WAC 2010
Concentration 24 Hours After a Single Dose of Truvada®
Concentration 24h After a Single Dose of Truvada
AUC over 14 Days After a Single Dose of Truvada
Concentration 24h After a Single Dose of Truvada
10000
FTC
TFV
1000
10
1
RECTAL
VAGINAL
100
10
10
1
1
106
106
10
Not
Detected
102
RECTAL
VAGINAL
CERVICAL
105
5
104
FTC-TP C24 (fmol/g)
10
10
3
1
FTC-TP
TFV-DP AUC (d*fmol/g)
TFV-DP C24 (fmol/g)
104
10
105
TFV-DP
10
100
RECTAL RECTAL
VAGINAL VAGINAL
CERVICALCERVICAL
CERVICAL
5
FTC AUC (d*ng/g)
100
1000
1000
FTC C24h (ng/g)
TFV AUC (d*ng/g)
TFV C24h (ng/g)
1000
100
10000
10000
FTC-TP AUC (d*fmol/g)
10000
104
103
104
103
3
102
102
102
RECTAL RECTAL
VAGINALVAGINAL
CERVICAL
CERVICAL
CAPRISA 004: TFV 1% Gel BAT24
107
Tenofovir
Concentrations
Extracellular
Tenofovir
Concentrations
single dose oral and topical administration
Tenofovir Concentration (ng/mL)
106
105
Gel Cervicovaginal Fluid
104
Gel Vaginal Tissue
103
102
Tablet Cervicovaginal Fluid
Tablet Blood Plasma
101
100
0
4
8
12
Gel Blood Plasma
16
20
24
Time Post-Dose (hr)
Dumond, Kashuba et al 2007; Schwartz, Kashuba et al IAS 2009
Pre-Exposure Prophylaxis?
• Differerences in studies
-Gels vs. Pills?
-Adherence?
• PrEP next steps
-Infrastructure (testing requirements)?
-Dosage schedules?
-Different agents?
-PrEP for whom?
Four Prevention Opportunities
Cohen et al, JCI, 2008
Cohen IAS 2008
UNEXPOSED
EXPOSED
EXPOSED
INFECTED
(precoital/coital) (postcoital)
Behavioral,
Structural
Vaccines
ART PrEP
Microbicides
Vaccines
ART PEP
Treatment Of HIV
Reduced Infectivity
Structural
Circumcision
Condoms
YEARS
HOURS
72h
YEARS
HIV “Treatment as Prevention”?
• Compelling biological plausibility: ART
reduces HIV in genital secretions
• Five observational reports
What is the magnitude and durability of ART
for prevention?
Does early ART (for prevention) benefit an HIV
infected person?
HPTN 052
1763 discordant heterosexual couples
9 countries, 13 sites
Randomization
Immediate ART
350-550cells/uL
AZT+3TC+EFV
Deferred ART
CD4 <250
Endpoints: i) HIV Transmission to partners
ii) OIs and clinical Events
iii) ART toxicity
HPTN 052 Modified
• April 28, 2011 (DSMB meeting #11)
Recommendation:
“Make the results available to the public (and
study subjects) as soon as possible”
HPTN 052 is ongoing with all HIV infected
subjects offered ART, regardless of CD4 count
HPTN 052 Prevention Results
 39 total infections, 35 in the delayed arm (p<.0001)
– 28 linked infections (by 3 independent methods)
• 27 delayed arm
p<0.001
• 1 immediate arm
o 17 of 27 infections in delayed arm occurred when the index
participants’ CD4 was >350
– 7 unlinked infections
• 4 delayed arm (ALL NOW PROVEN UNLINKED)
• 3 immediate arm (ALL PROVEN UNLINKED)
– 4 infections still being analyzed (ALL IN THE DELAYED ARM)
– The details of 1/27 transmissions are being evaluated
HPTN 052 Clinical Results
 105 morbidity and mortality events (p<.01)
– 65 in delayed arm
– 40 in immediate arm
 20 cases of extrapulmonary TB (p= 0.0013)
– 17 in delayed arm
– 3 in immediate arm
 23 deaths (NS)
– 13 in delayed arm
– 10 in immediate arm
HPTN 052 Implications
• For discordant couples?
• For the Test and Treat Movement?
The Economist
June 4, 2011
Treatment as Prevention
The “Test and Treat” Movement
THE HORSE IS OUT OF THE GATE
•
•
•
•
Botswana cohort study (Essex, MP3)
US HPTN 065 in NYC, DC, (El-Sadr)
ANRS South Africa (Newell, Dabas)
Combination Prevention Competition:
– CDC September, 2011
– HPTN August, 2011
HIV Prevention
ARV TOPICAL PrEP
COUNSELING
ARV TREATMENT
CIRCUMCISION
ARV ORAL PrEP
VACCINE
ACUTE HIV
INFECTION?
STD TREATMENT?