Global AIDS 2014

Myron S. Cohen, MD

Yeargan-Bate Eminent Professor
Medicine, Microbiology and Public Health
Director, Institute for Global Health & Infectious Diseases
Associate Vice Chancellor for Global Heath
The HIV Pandemic
Where are we now??
How did we get here??
Where are we going??


GRID: GAY-RELATED IMMUNE DEFICIENCY
Source: The New York Times, 1980
Hubei Medical College, 1980
ME
WHERE ARE WE NOW?

Status of the global HIV epidemic - 2011

34.2 million living with HIV, 2.5 million new infections, 1.7 million deaths
Source: UNAIDS 2012
Eastern Europe
& Central Asia
1.5 million
[1.3 million 1.8 million]
East Asia
830 000
[590 000 1.2 million]
Oceania
530 000
[47 000 60 000]
Sub-Saharan Africa
23.5 million
[22.2 million 24.7 million]
Middle East
& North Africa
330 000
[250 000 450 000]
North America
1.4 million
[1.1 million 2.0 million]
Caribbean
230 000
[200 000 250 000]
Latin America
1.4 million
[1.1 million 1.7 million]
South &South-East Asia
4.2 million
[3.1 million 4.7 million]
CDC: More Americans HIV-positive
than previously believed
ATLANTA, Georgia (CNN) -- There are more new cases of
Americans infected with HIV, the virus that causes AIDS, than
previously believed, the Centers for Disease Control and Prevention
said Saturday

About 56,000 people became infected with HIV in the past year,
which translates to about 40 percent more cases than officials had
estimated, said Dr. Kevin Fenton, director of the CDC's National
Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention.

Previous CDC estimates suggested about 40,000 new people were
infected each year. But those estimates used "limited data and less
precise methods," said the center, which is now using technology
capable of determining when someone was infected.


The new method can indicate whether someone has been infected with HIV during the previous five
months, rather than relying on statistical models.

Diagnosis of HIV can occur years after infection, he said.

"The fact that 56,000 Americans each year are contracting HIV for the first time is a wake-up call for
all of us in the U.S., Fenton said

"These numbers are a scathing indictment of how profoundly U.S. and CDC HIV prevention efforts
have failed," said Michael Weinstein, president of AIDS Healthcare Foundation, which calls itself
"the nation's largest provider of HIV/AIDS medical care."

A woman uses the Oraquick rapid HIV testing
device at a New York health clinic in 2006.
2006 Report on the
global AIDS epidemic
Fig
06/06 e
Where is HIV Going Next?

HIV is decreasing in Africa
HIV spread in China is modest
HIV in Eastern Europe in PWID
India??
What will actually happen next?
HOW DID WE GET HERE?

Epidemic Spread of Disease
Ro = bDC
When Ro >1 epidemic is sustained
b = Efficiency of transmission
D = Duration of infectiousness
C = Number of people (partners) exposed
Anderson and May, 1966
Transmission of Infectious Diseases:
Biological Requirements

Infectious Susceptibility
Inoculum (concentration) Hereditary resistance
Phenotypic factors Innate resistance
Acquired (immune)
resistance

*communicability and virulence are different
HIV Transmission
Sexual
Blood and Blood Products
Mother to child (vertical transmission)
-prepartum
-intrapartum
-peripartum
-postpartum (breast feeding)
semen
Lamina Propria
Dendritic Cells

CD4+
CCR5+
alpha 7 beta 4
HIV-1
SWARM
T cell
CD4
CCR5 DC-SIGN
migration
to lymphoid organs
A Single R5 Virus from A SWARM Infects
Donor
(variable)
Mucosa
Recipient

Abortive
Less fit or attenuated
Abortive
Abortive
Time (days)
0 7 21 14 28
Cohen , NEJM in press
McMichael, A . et al. Nature Reviews in Immunology, 2010
Composite Alignment of the Earliest Innate and Adaptive Immune
Responses Detected After HIV-1 Transmission
? Delay
Opportunistic Infections Over
the Course of HIV Infection
0
100
200
300
400
500
600
700
800
0 1 2 3 4 5 6 7 8 9 10 11
C
D
4

L
y
m
p
h
o
c
y
t
e

C
o
u
n
t

Years
Pneumocystis Pneumonia
Toxo encephalitis
Crypto meningitis
MAC Bacteremia
CMV Retinitis
TB
Shingles/Hairy Leukoplakia
Thrush/Herpes
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August 27, 2014 19
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Associated dramatic increase
in TB incidence
Chaisson et al 2008
How Did the Epidemic
Get This Big?
Infection is unrecognized (D)
Transmission efficiency (variable Beta)
-and a misguided belief that HIV
transmission is rare


Routes of Exposure and H.I.V.
INFECTION ROUTE RISK OF INFECTION
Sexual Transmission
a. Female-to-male transmission..1 in 700 to 1 in 3,000 (??)
b. Male-to-female transmission...1 in 200 to 1 in 2,000 (??)
c. Male-to-male transmission...1 in 10 to 1 in 1,600
d. Fellatio??...0 (CDC) or 6% (SF)

Parenteral transmission
a. Transfusion of infected blood..95 in 100
b. Needle sharing..1 in 150
c. Needle stick...1 in 200
d. Needle stick /AZT PEP1 in 10,000

Transmission from mother to infant
a. Without AZT treatment...1 in 4
b. With AZT treatment.....Less than 1 in 10


Royce, Sena, Cates and Cohen, NEJM 336:1072-1078, 1997
2.6%
9.4%
2.0%
6.0%
2.1%
4.0%
3.6%
4.1%
2.3%
11.0%
12.2%
7.9%
5.8%
13.8%
4.1%
14.4%
31.2%
25.0%
28.9%
26.3%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
55%
Age 15
Males
Females
95% Confidence Interval
Age 16 Age 17 Age 18 Age 19 Age 20 Age 21 Age 22 Age 23 Age 24
HIV Prevalence by Age and Gender among
South African youth age 15-24 years
Pettifor A, et al. AIDS 2005, 19: 1525-1534.
Coital Frequency per Month by Age

10.02
8.98
9.11
7.44
15-24 25-29 30-34 35-59
Age
4
5
6
7
8
9
10
11
C
o
i
t
a
l

f
r
e
q
u
e
n
c
y

p
e
r

M
o
n
t
h

Amplified Transmission of HIV-1
Susceptibility
Genital ulcers
Inflammatory STDs
Cytokine profile
Lack of circumcision
Cervical ectopy
HLA Haplotype
Hormonal contraception?
Infectiousness
Blood Viral Load
Genital Tract Viral Load
-Inflammatory STDs
Viral clade
ACUTE INFECTION
Contraception and HIV Acquisition
Long acting hormonal contraception prevents
pregnancy and saves lives
Macaques treated with progesterone become
susceptible to mucosal SIV
Some observational studies suggest risk from
hormonal contraception
Clinical trials?
WHO Summary February 2012
A clinical trial STAY TUNED
H
I
V

R
N
A

i
n

S
e
m
e
n

(
L
o
g
1
0

c
o
p
i
e
s
/
m
l
)

2
3
4
5
1/1000 -
1/10,000
1/500 -
1/2000
1/100-
1/1000

Risk of Transmission
Reflects Genital Viral Burden
1/30-
1/70
Sexual Transmission of HIV
H
I
V

R
N
A

i
n

S
e
m
e
n

(
L
o
g
1
0

c
o
p
i
e
s
/
m
l
)

2
3
4
5
Acute HIV/STD co-infection:
Lethal Synergy?
1/30 or greater odds of transmission
to a susceptible partner per coital act
How do STDs increase
HIV-1 transmission?
Reducing physical/mechanical barriers
Increasing HIV in genital lesions, semen
or both
Evoking a more infectious HIV variant
Increasing the number of receptor cells or
the density of receptors per cell
Malawi Overview
Population 10 million
90% rural
Per Capita income $190

AIDS impact
900,000 people living with HIV
15% adult HIV prevalence
STD Clinic: 47% prevalence

Operating Room at KCH
8/27/2014 39
8/27/2014 40
Where Are We Going
TREATMENT
PREVENTION
CURE

Projected life expectancy in African countries
with high HIV prevalence, 19952000
Source: United Nations Population Division
1955 1960 1965 1970 1975 1980 1985 1990 1995 2000
Average life expectancy at birth, in years
65
60
55
50
45
40
35
Zimbabwe
Zambia
Uganda
Botswana
Malawi
Azidotyhmidine (AZT)!!!
ART
Easier, less toxic, and more potent therapy




0

5

10

15

20

25

30

35

40

1995

1996

1997

1998

1999

2000

2001

D
e
a
t
h
s

p
e
r

1
0
0

p
e
r
s
o
n
-
y
e
a
r
s

0

25

50

75

100

P
e
r
c
e
n
t
a
g
e

o
f

p
a
t
i
e
n
t
-
d
a
y
s

o
n

A
R
T

DEATHS

USE OF ART

Mortality vs ART utilization

Palella F, et al. 2001; 8th CROI. Abstract 268b.
AIDS Mortality Rates: 1996-2001
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
End 2002 End 2003 End 2004 End 2005 End 2006 End 2007 End 2008
M
i
l
l
i
o
n
s
North Africa and the Middle East
Europe and Central Asia
East, South and South-East Asia
Latin America and the Caribbean
Sub-Saharan Africa
Number of people receiving ART in low- and
middle-income countries, by region, 2002-2008
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PEPFARs Latest Contributions
Globally, 34 million people live with HIV/AIDS, of which 8 million are
on treatment, and 7 million are eligible for treatment (with current
guidelines) but are not receiving it

Through PEPFAR the U.S. directly supported nearly 5.1 million
people on ART -- up from 1.7 million in 2008, a 200% increase

In FY 2012 PEPFAR programs supported antiretroviral drugs to
prevent mother-to-child transmission for nearly 750,000 pregnant
women living with HIV, which resulted in an estimated 230,000
infant HIV infections averted in 2012 alone. PEPFAR is on track
to reach an additional 1.5 million pregnant women living with HIV by
the end of FY 2013.

PEPFAR supported HIV testing and counseling for more than 49
million in 2012
ADM Kashuba, CROI 2008
HIV Prevention Opportunities
YEARS
Treatment Of HIV
Reduced Infectivity
INFECTED
YEARS
UNEXPOSED
Behavioral,
Structural
lSTDs
Circumcision
Condoms
Cohen and Kashuba, 2008, in press
HOURS
Vaccine,
Topical Mic.,
PrEP
EXPOSED
(precoital/coital)
within 72h 28d
Vaccine
PEP
EXPOSED
(postcoital)
History of Male Circumcision
Circumcision may
be oldest and most
common surgery
performed on
humans. 20-25% of
men circumcised.

A relief on the tomb of Ankh-Mahor
Possible circumcision
protective mechanisms
Circumcision
Anatomic effect by removal
of foreskin
Reduced GUD, reduced cofactor
effects
Reduced Target cells for HIV
Impact of MC on HIV : Evidence
from observational studies and RCTs

85 80 70 60 .50 1
Reduction of risk
(95% CI)
South Africa (RCT) 60 ( 76, 33)
Kenya (RCT)
59 ( 76, 30)
Uganda (RCT) 51 ( 82, 14)
Overall 58 ( 66, 48)
15
1
7
1
1
Reduction of risk (0%)
Bailey et al.
Lancet 2007; 369: 64356
Weiss et al.
AIDS 2000, 14:2361-70
Auvert et al.
PLoS Med 2005(11): e298.2006
Gray et al.
Lancet, 2007, 65766
Medical Male Circumcision
Four Prevention Opportunities
YEARS
Treatment Of HIV
Reduced Infectivity
INFECTED
YEARS
UNEXPOSED
Behavioral,
Structural
Circumcision
Condoms
Cohen et al, JCI, 2008
Cohen IAS 2008
HOURS
Vaccines
ART PrEP
Microbicides

EXPOSED
72h
Vaccines
ART PEP
EXPOSED
(postcoital) (precoital/coital)
Antiretroviral Therapy
Effect on HIV Transmission

?
ART to Prevent Sexual
Transmission of HIV
Pre-Exposure Prophylaxis (PrEP)

Post Exposure Prohylaxis (PEP)

Treatment of the infected person

PrEP Utilization
Cohen and Baden, NEJM 2012
TDF/FTC (Truvada) PrEP FDA approved
- MSM
- Discordant Couples
- High Risk People (???)

Strategy, Infrastructure, Demand?
CDC Interim Guidance August 11,2012




CAPRISA 004: Tenofovir Gel
Tenofovir gel is a clear, colorless,
and odorless viscous gel in
single-dose plastic applicators
Topical HIV-1 Prevention
Klasse et al Annu Rev Med 2008
www.microbicide.org, July 2008
Tenofovir Gel
Reservoir and Matrix Vaginal Rings
Candidate Status - Phase
Tenofovir gel Mixed Results
Dapivirine Ring Ongoing clinical trial
Current MicrobicideCandidates
(listed in latest stage of development)
Four Prevention Opportunities
YEARS
Treatment Of HIV
Reduced Infectivity
YEARS
UNEXPOSED
Behavioral,
Structural
Structural
Circumcision
Condoms
Cohen et al, JCI, 2008
Cohen IAS 2008
HOURS
Vaccines
ART PrEP
Microbicides
EXPOSED
(precoital/coital)
72h
Vaccines
ART PEP
EXPOSED
(postcoital)
INFECTED
HIV-RNA HIV-DNA
0
20
40
60
80
100
P
a
t
i
e
n
t
s

(
%
)

w
i
t
h

d
e
t
e
c
t
a
b
l
e

H
I
V

i
n

s
e
m
e
n

n=55
n=114
Controls (drug naive)
Potent ART
p<0.0001
p=0.025
Semen HIV with HIV Treatment
Vernazza, Cohen et al., AIDS, 2000
Treatment as Prevention
The Four Questions
1) Do ART drugs prevent HIV transmission?

2) What do we tell infected people?

3) Can we reduce population HIV incidence ?

4) Barriers to Treatment as Prevention?
Reduce HIV in sexual fluids and reduce
contagion? Another benefit of ART?
Try to prevent HIV transmission in
heterosexual discordant couples?
A SIMPLE PREVENTION IDEA
Stable, healthy, serodiscordant couples, sexually active
CD4 count: 350 to 550 cells/mm
3
Primary Transmission Endpoint
Virally linked transmission events

Primary Clinical Endpoint
WHO stage 4 clinical events, pulmonary tuberculosis,
severe bacterial infection and/or death
HPTN 052 Study Design
Immediate ART
CD4 350-550
Delayed ART
CD4 <250
Randomization
HPTN 052 Enrollment
(Total Enrollment: 1763 couples)
U.S.
Brazil
South Africa
Botswana
Kenya
Thailand
India
Americas
278
Africa
954
Asia
531
Zimbabwe
Malawi
APRIL 28, 2011, 10
TH
BIANNUAL REVIEW

The Oversight Board
recommends that the results of
the trial be made public.
HPTN 052
Bruce Alberts, Editor of
Science, explains the
importance of this work:
The results have
galvanized efforts
to end the worlds
AIDS epidemic in a
way that would
been inconceivable
even a year ago
Clinton speech November 8, 2011 at
US National Institutes of Health
11- 11- 12 10:02 AM PEPFAR: Worki ng Toward an AIDS- Free Generat i on
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