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