Working to End the HIV Pandemic:
Glimmers of Hope
Myron S. Cohen, MD
Director, 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
HIV-1 Transmission Model (CHAVI)
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
10
14-28
Time (days)
1
Probability of HIV Transmission?
~1/1000 episodes for couples??
(Most recently Hughes et. al. JID)
1/1000 IS AN UNDERESTIMATE??
- “exposed uninfected” partners
- benefits of counseling
- missing amplification factors
Amplified Transmission of HIV-1
Infectiousness
Susceptibility
Blood Viral Load
Genital ulcers
Genital Tract Viral Load
Inflammatory STDs
Cytokine profile
-Inflammatory STDs
Lack of Circumcision
Viral clade
Cervical ectopy
ACUTE INFECTION (!!)
HLA Haplotype
Hormonal Contraception(??)
Acute HIV-1 Infection
Cohen et al, NEJM, 2011
Onset cytokines
apoptosis, Day 7
Acute Phase Reactants
Days -5 to-7
idu
lF
ra
ull
ec
art
xE
in ro
no
it
art
enc
no
C
su
ri
V
)l
/m
se
pio
(C
a
m
sa
lP
108
107
106
105
104
103
102
101
0
10-1
10-2
10-3
10-4
10-5
Free Antibody, Day 13
Immune Complexes
Day 9
Autologous
Neutralizing Antibody
?
Reservoir
eclipse
CTL Escape
CD8 T Cell
Responses
Transit
0
Transmission
5
Autologous
Neutralizing
Antibody
Escape
T0
10
15
20
25
30
35
40
45
50
55
60
65
70
Time Post Exposure (days)
2
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
Treatment Of HIV
Reduced Infectivity
72h
YEARS
Behavioral Interventions?
• No single tool to reduce HIV incidence
Padian, AIDS 2010
• But…HIV incidence has fallen!
• HPTN 043..Effects of mobile VCT
-Cross sectional HIV incidence
STAY TUNED
ART to Prevent Sexual Transmission
of HIV
• Post-exposure Prophylaxis (PEP)???
• Pre-exposure prophylaxis (PrEP) ????
• Treatment of the infected person ???
3
Antiretroviral Exposure at Mucosal Surfaces
Rectal Tissue, CVF, Semen Exposure Relative to Blood
1000
CCR5
Integrase Nonnucleoside
Receptor Inhibitors RT Inhibitors
Antagonists
Nucleoside(tide)
RT Inhibitors
Protease
Inhibitors
Matrix:Blood Plasma Ratio
RAL (150)
100
TFV (46)
MRV (27)
RTV (13)
10
3TC (6)
ETR (8)
FTC/
3TC (4)
MRV (4)
1
MRV (0.6)
RAL (2)
ETR (1.3)
RAL (1)
NVP (0.8)
EVF (0.6)
TFV (5)
D4T (3.5)
FTC (2.6)
ZDV (2) ZDV (2)
TFV (1) ABC (1.5)
NVP (0.7)
DDI (0.21)
ETR (0.15)
ABC (0.08)
LPV/NFV
(0.05)
SQV & RTV
(0.03)
SQV (ND)
0.01
CCR5 RA
RECTAL TISSUE
INSTI
NNRTI
CERVICOVAGINAL FLUID
IDV (1)
LPV (0.08)
D4T (0.05)
EFV (0.03)
IDV (2)
APV (0.5)
RTV (0.3)
APV (0.2)
ATV (0.18)
DRV (0.17)
DLV (0.2)
0.1
DRV (2.7)
NRTI
SEMEN
PI
ARV Class
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
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
4
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”?
HPTN 052 Study Design
Stable, healthy, serodiscordant couples, sexually active
CD4 count: 350 to 550 cells/mm3
Randomization
Immediate ART
CD4 350-550
Delayed ART
CD4 <250
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 Timeline:
The Fast Track?
ART for prevention of HIV 1993- THE PRESENT
2000
HPTN 052
Protocol
Development
2002
ACTG 5175
Requirement
2004
HPTN 052
Drug
Procurement
2006
HPTN 052
Pilot
2008
2010
HPTN 052 Enrollment
2012
HPTN 052
DSMB (#10)
April 28,
2011
5
HPTN 052 Recognition
U.S. Sponsors:
• National Institutes of Health (NIH)
• Division of AIDS (DAIDS), U.S. National Institute of
Allergy and Infectious Diseases (NIAID)
HIV Prevention Trials Network (HPTN):
• Network Laboratory, Johns Hopkins University
• Statistical Center for HIV/AIDS Research &
Prevention (SCHARP) and University of
Washington
• Coordinating and Operations Center, Family Health
International (FHI)
• HPTN Leadership
AIDS Clinical Trials Group (ACTG):
• ACTG Leadership and Investigators
Pharmaceutical Companies:
• Abbott Laboratories
• Boehringer Ingelheim Pharmaceuticals, Inc.
• Bristol-Myers Squibb
• Gilead Sciences, Inc.
• GlaxoSmithKline
• Merck & Co., Inc.
Sites (Investigators of Record):
• Porto Alegre, Brazil (Breno Santos)
• Rio de Janeiro, Brazil (Beatriz Grinsztejn)
• Boston, United States (Kenneth Mayer)
• Chennai, India (N. Kumarasamy)
• Pune, India (Sheela Godbole)
• Chiang Mai, Thailand (Suwat Chariyalertsak)
• Gaborone, Botswana (Joseph Makhema)
• Kisumu, Kenya (Lisa Mills)
• Blantyre, Malawi (Johnstone Kumwenda)
• Lilongwe, Malawi (Mina Hosseinipour)
• Johannesburg, South Africa (Ian Sanne)
• Soweto, South Africa (Guy De Bruyn)
• Harare, Zimbabwe (James Hakim)
Study
Participants
UNC and 22 Years in Lilongwe, Malawi
• 12.5 million people
• Half live on less than
$1/day
• Life expectancy:
39 years
• 2 physicians per
100,000 people
6
7
8
9
HPTN 052 Enrollment
10,838 Individuals
Screened
Major reasons for exclusion:
3058 HIV+ but CD4 count out of range
2565 HIV- but HIV+ partner ineligible
308 Seroconcordant couples
155 Ineligible due to sexual history
1763 Couples
(3526 Individuals)
Randomized
Immediate Arm
886 Couples
Delayed Arm
877 Couples
HPTN 052 Enrollment
(Total Enrollment: 1763 couples)
U.S.
Thailand
India
Kenya
Americas
278
Brazil
Botswana
South Africa
Malawi
Zimbabwe
Asia
531
Africa
954
DSMB Recommendation
April 28, 2011 (DSMB 10th Biannual Review)
“The Board recommends that the results of the
trial be announced as soon as possible”
10
HPTN 052: HIV-1 Transmission
Total HIV-1 Transmission Events: 39
Linked
Transmissions: 28
Unlinked or TBD
Transmissions: 11
• 18/28 (64%) transmissions from infected
participants with CD4 >350 cells/mm3, and
VL >50,000 copies/ml at transmission
Delayed
Arm: 27
Immediate
Arm: 1
• 23/28 (82%) transmissions in sub-Saharan
Africa
• 18/28 (64%) transmissions from female to
p < 0.001
male partners
HPTN 052: ADHERENCE MATTERS
100
Proportion of participants with VL<400 at each visit
0
20
40
60
80
Immediate Arm
Delayed Arm (not on ART)
Delayed Arm (on ART)
0
3
6
9
12 15 18 21 24 27 30 33
36 39 42 45
Months
One Transmission Event on ART
Index begins ART
AZT/3TC/EFV
Index VL<400
Partner HIV+ (WB)
28
85
Enrollment
Screening
Days
-14
0 1
Partner VL < 400
Index VL = 87,202
Single Genome Analysis: 1-2 viruses transmitted
Analysis of Transmission: >50 days earlier (84 – 190 days)
11
HIV-1 RNA and CD4 Over Time (ITT)
Immediate
Delayed
HPTN 052: We Are Not Done Yet
• The HPTN 052 study is ongoing
• All HIV infected subjects offered ART
– 93% index cases are now on ART
• Retention is 96% among the index cases and
85% for the discordant couples
• Questions remain:
– Durability of the prevention benefit?
– Consequences of delayed ART?
PEPFAR, WHO AND HPTN 052
www.pepfar.gov/documents/organization
www.who.int/hiv/pub/guidelines/9789241
ART for heterosexual discordant couples
Treat HIV before CD4 count falls below 350
Does ART prevent HIV transmission in
MSM couples?
IDU transmission?
12
The Economist
TnT: Aspiration Meets Reality
Smith, Cohen et al. PLOS MED, July 2012
1. Acute Infection?
2. “THE CASCADE”
3. Ecological and observational studies
HIV Rx “Cascade”
Aspiration Meets Reality
80%
77%
66%
89%
77%
Multiplies
to 28%
850,000 HIV+ Americans (72%) lack viral control
Refs: MMWR 2011; see also Gardner CID 2011; Burns CID 2010
13
Black MSM
Undiagnosed HIV
OR, 6.38 (4.33-9.39)
HIV
Detection
Diagnosed HIV+
OR, 3.00 (2.06-4.40)
Health insurance
coverage
OR,0.47 (0.29-0.77)
• 15 X risk for HIV
• Policies that
criminalize
homosexuality
associated with
increased HIV
prevalence
• Safe and culturally
competent access to
care lacking for
black MSM
ART utilization/ access
OR, 0.56 (0.41-0.76)
>200 CD4
cells/mm3 before
ART initiation
OR, 0.40 (0.26-0.62)
ART adherence
OR, 0.50 (0.33-0.76)
HIV suppression
OR, 0.51 (0.31-0.83)
Viral
Suppression
The image cannot be
display ed. Your computer
may not hav e enough
memory to open the
image, or the image may
hav e been corrupted.
Millett AIDS 2012, Lancet
HPTN 065 (TLC-Plus) Provider Survey
Study Population and Participants
• ART-prescribing providers at 38 participating
HPTN 065 care sites in Bronx, NY and
Washington, DC
• Internet-based survey (anonymous)
Kurth et al, TASP 2012
Glimmers of Hope
14
The “Test and Treat” Movement
• US HPTN 065 Linkage in NYC, DC
• ANRS PILOT in South Africa
• THE PEPFAR Combination Prevention Trials:
– CDC- BOTSWANA
– NIH HPTN 071 -South Africa, Zambia
– USAID JHU-Tanzania
HPTN 071 Intervention Package
Community HIV Care Providers (CHiPs team):
•
•
•
•
•
Counselling, condom provision, syndromic STI Rx
Referral of pregnant women for ANC/PMTCT services
Universal voluntary HIV testing house-to-house
HIV-uninfected men offered circumcision
HIV-infected persons
− Arm A: Immediate ART (analogous to HPTN 052)
− Arm B: “Enhanced” Standard of Care (CD4<350)
− Arm C: Standard of Care (CD4<350)
15
Personal Conclusions
• 34,000,000 people with HIV to treat
-for health, and transmission prevention
• Mass treatment of HIV is a “bridge”
-to simpler, modified intervention
-to a “cure”
-to a vaccine
Wishful , magical or aspirational thinking?
Clinton Speech November 8, 2011
16
PPEFAR ROADMAP
• Saving Lives:
– Scale up combination prevention and treatment
• Smart Investments:
– Going where the virus is
• Shared Responsibility:
– Creating an AIDS-Free Generation requires a global effort
• Driving Results with Science:
– Science must continue to guide our efforts
HIV Prevention 2012
ARV TOPICAL PrEP
COUNSELING
ARV ORAL PrEP
CIRCUMCISION
VACCINE
ARV TREATMENT
PMTCT
ACUTE HIV
INFECTION
17