PREVENTION OF HIV-1
Myron S. Cohen, MDInstitute for Global Health
The University of North Carolina
Transmission of HIV-1Biological Requirements
Infectious SusceptibilityInoculum (concentration) Hereditary resistancePhenotypic factors Innate resistance
Acquired (immune)resistance
semenSI HIV (T-tropic)
NSI HIV (M-tropic)
Lamina PropriaDendritic Cells
CD4+CCR5+ Α4 β7+
HIV-1 “SWARM”
T cell
CD4
CCR5DC-SIGN
migrationto lymphoid organs 99% R5, 82% 1 variant
.
HIV-1 Transmission Model Cohen et al, NEJM, 2011
Inoculum
MucosaRecipient
Less fit, attenuated or stochastic event (R0<<1)
Less fit virus (R0~1)
~109 infection events
>106 virions/ml plasma
Time (days)0 3 10 7 14-28
Defective virus
X
Defective virus
(Most fit virus R0>>1)
10-510-4
10-3
10-2
10-10
101
102
103
104105
106
107
108
Transmission
Viru
s Con
cent
ratio
n in
Ext
race
llula
r Fl
uid
or
Plas
ma
(Cop
ies/
ml)
Time Post Exposure (days)
0 5 10 15 20 30 3525 40 45 50 55 60 65 70
Reservoir Vi
rus
disse
mina
tion
Transit
eclipse?
T0
Acute Phase ReactantsDays -5 to-7
Immune ComplexesDay 9
Onset cytokinesapoptosis, Day 7 Free Antibody, Day 13
CD8 T CellResponses
CTL Escape
AutologousNeutralizing Antibody
AutologousNeutralizing
Antibody Escape
Acute HIV-1 Infection Cohen et al, NEJM, 2011
Hollingsworth et al 2008
Hayes & White 2006*
Pinkerton & Abramson 1996**
Kretzschmar & Dietz 1998**†
Xiridou et al 2004
Jacquez et al 1994
Abu-Raddad & Longini 2008†
Salomon & Hogan 2008*
Koopman et al 1997**
Pinkerton 2007
Prabhu et al 2009
* 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.
Powers et al 2010
Effect of Acute and Early HIV Infection on Spread Cohen et al, NEJM, 2011
Four Prevention Opportunities
YEARS
Treatment Of HIVReduced Infectivity
INFECTED
YEARS
UNEXPOSED
Behavioral,Structural
StructuralCircumcisio
nCondoms
STDs
Cohen et al, JCI, 2008Cohen IAS 2008
HOURS
VaccinesART PrEP
Microbicides
EXPOSED (precoital/coital)
72h
VaccinesART PEP
EXPOSED (postcoital)
ART to Prevent Sexual Transmission of HIV
• Post-exposure Prophylaxis (PEP) • Pre-exposure prophylaxis (PrEP) • Treatment of the infected person
Pre-Exposure Prophylaxis
• Study Effect• CAPRISA (TDF Gel) 39-50% • iPREX (Daily TDF) 44%• FEM-PrEP (Daily TDF) Stopped• Partners (TFV/TDF) >70%• Botswana (TDF) >60% • Others in Progress
ART Concentrations Rectal vs. Female Genital Tract TFV/FTC (Truvada®) PO QD
Patterson, Cohen, Kashuba et al WAC 2010
Concentration 24h After a Single Dose of Truvada
RECTAL VAGINAL CERVICAL
TFV
C24
h (n
g/g)
1
10
100
1000
10000
RECTAL VAGINAL CERVICAL
TFV
AU
C (d
*ng/
g)
1
10
100
1000
10000
RECTAL VAGINAL CERVICAL
TFV
-DP
C24
(fm
ol/g
)
102
103
104
105
106
RECTAL VAGINAL CERVICAL
TFV
-DP
AU
C (d
*fm
ol/g
)
102
103
104
105
106
AUC over 14 Days After a Single Dose of TruvadaConcentration 24h After a Single Dose of Truvada
RECTAL VAGINAL CERVICAL
FTC
C24
h (n
g/g)
1
10
100
1000
10000
RECTAL VAGINAL CERVICAL
FTC
AU
C (d
*ng/
g)
1
10
100
1000
10000
RECTAL VAGINAL CERVICAL
FTC
-TP
C24
(fm
ol/g
)
102
103
104
105
RECTAL VAGINAL CERVICAL
FTC
-TP
AU
C (d
*fm
ol/g
)
102
103
104
105
AUC over 14 Days After a Single Dose of Truvada
NotDetected
Concentration 24 Hours After a Single Dose of Truvada®
TFV
TFV-DP
FTC
FTC-TP
CAPRISA 004: TFV 1% Gel BAT24Tenofovir Concentrations
single dose oral and topical administration
Time Post-Dose (hr)0 4 8 12 16 20 24
Teno
fovi
r Con
cent
ratio
n (n
g/m
L)
100
101
102
103
104
105
106
107
Gel Cervicovaginal Fluid
Gel Vaginal Tissue
Tablet Cervicovaginal Fluid
Tablet Blood Plasma
Gel Blood Plasma
Dumond, Kashuba et al 2007; Schwartz, Kashuba et al IAS 2009
Extracellular Tenofovir Concentrations
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
YEARS
Treatment Of HIVReduced Infectivity
INFECTED
YEARS
UNEXPOSED
Behavioral,Structural
StructuralCircumcisio
nCondoms
Cohen et al, JCI, 2008Cohen IAS 2008
HOURS
VaccinesART PrEP
Microbicides
EXPOSED (precoital/coital)
72h
VaccinesART PEP
EXPOSED (postcoital)
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?
POSITIVE RESULTS:• Bunnell (JAIDS, 2007)• Sullivan (IAS 2008)• Donnell (Lancet, 2010) • Romero (BMJ, 2010)
NEGATIVE RESULTS:• Wang (IAS, JAIDS, 2010)
•
HPTN 052
1763 discordant heterosexual couples
9 countries, 13 sites
Immediate ART350-550cells/uL
Deferred ART CD4 <250AZT+3TC+EFV
Endpoints: i) HIV Transmission to partners ii) OIs and clinical Events iii) ART toxicity
Randomization
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• 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
p<0.001
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 PreventionThe “Test and Treat” MovementTHE 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
VACCINE
COUNSELING
ARV TREATMENT
ARV TOPICAL PrEP
STD TREATMENT?
CIRCUMCISION ARV ORAL PrEP
ACUTE HIV INFECTION?
HIV Prevention
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