Download Four Prevention Opportunities

Prevention of the Sexual
Transmission of HIV-1:
A view from the 21st century
Myron S Cohen
The University of North Carolina
Chapel Hill, USA
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
Circumcision
Condoms
YEARS
HOURS
72h
YEARS
Let’s Accept the Idea that …
Coates et al Lancet 2008
1)
Abstinence or total monagomy in a
SERONEGATIVE couple are effective, but difficult
to achieve (…and beware concurrency)
2)
Barrier Methods Work
a) Condoms (serve as a reversible barrier)
b) Circumcision ( form an irreversible and
imperfect barrier)
3)
HIV prevalence has fallen in many communities so
some behavioral interventions work
4)
Combination multilevel behavioral and structural
approaches may ultimately prove very effective,
and they certainly need continued effort
But When Primary Prevention Fails…
Risk of a Transmission Event Develops
Cohen and Galvin, Nat Micro Rev 2004
Infectious
Susceptible
Inoculum (concentration)
Phenotypic factors
Hereditary resistance
Innate resistance
Acquired resistance
Viral Concentration Really Matters
Probability of transmission
Chakraborty et al., AIDS 2001
0.016
0.012
0.008
0.004
3
3.5
4
4.5
5
5.5
Log10 Seminal HIV RNA in one ejaculate
A Single R5 Virus from “A SWARM” Infects
Keele et al., PNAS 2008
Donor
Mucosa
(variable)
Recipient
Abortive
Abortive
Abortive
Less fit or attenuated
0
7
14
21
28
Time (days)
Estimating HIV Transmission:
Have the methods confused the message?
Powers et al Lancet ID, 2008
HIV Transmission is often estimated as 1/500-1000
episodes of intercourse but only when…
•
•
•
•
Acute transmission in couples cannot be measured
STDs are RARE in the study population(s)
Condom usage cannot be readily measured
Anal intercourse is not generally practiced
SEXUAL TRANSMISSION MUST ON MANY
OCCASIONS BE FAR MORE EFFICIENT …
HIV Transmission Efficiency By Cofactor
Powers et al Lancet ID, 2008
Amplified Transmission of HIV
HIV RNA In Semen
(Log10 copies/mL)
10
8
6
4
2
0
1/30 or greater odds of transmission
to a susceptible partner per coital
act
What about…“The STD Paradox”?
Gray and Wawers, Lancet 2008
Only 1/7 STD intervention RCTs have led to reduced
transmission of HIV
So… either STDs do not “amplify” HIV transmission OR (MORE
LIKELY) the interventions are inadequate??
BUT Successful intervention requires that…..
 The “RIGHT” STD(S) are treated
 At JUST the right time
 In JUST the right people (HIV positive or negative)
 With VERY EFFECTIVE drugs(s)
 For the RIGHT duration of time
And treating STDs has a benefit far BEYOND the
effects of HIV prevention
Four Prevention Opportunities
Cohen et al, JCI, 2008
Cohen IAS 2008
UNEXPOSED
EXPOSED
(precoital/coital)
Behavioral,
Structural
Vaccines
ART PrEP
EXPOSED
INFECTED
(postcoital)
Microbicides
Vaccines
ART PEP
HOURS
72h
Treatment Of HIV
Reduced Infectivity
Circumcision
Condoms
YEARS
YEARS
HIV-1 Transmission Event
Adapted from Johnston and Fauci, NEJM,2007.
Virus Concentration in Extracellular Fluid
or Plasma (Log10 Copies/ml)
Window of Opportunity??
8
7
6
5
4
3
eclipse
2
1
0
-1
-2 Transit
-3
-4
-5
0
Transmission
5
10
Established Infection
Symptoms
Set Point
Reservoir
Limit of detection for HIV RNA
HIV-1 Integration and
Viral Dissemination
15
20
25
30
35
40
Time Post Exposure (days)
45
50
55
60
65
70
When Transmission is Imminent
Biological prevention options at exposure……
1. Modification of Innate Immunity
2. Acquired Immunity (A VACCINE)
a) Neutralizing antibodies
b) Cell mediated immunity
3. Antiretroviral therapy
Strategies for an HIV Vaccine
Transmission
Vaccine Success
no protection
protection against HIV
sterilizing immunity!
HIV Infection
and RNA set point
Infection prevented
Cell-Mediated Immunity
protection against disease
A reduced HV peak and “set point”
initial infection
“controlled”
chronic infection
with low set point
HIV Vaccines: Summary
Walker and Burton, Science, 2008
• We do not know how to
generate neutralizing antibodies
control
• Cell mediated (CTL) vaccines
lower peak viremia and set
point in macaques
But, human studies have not yet
controlled viremia (STEP Trial)
treated
Letvin, Science, 2006
WE HAVE ABSOLUTELY NO CHOICE BUT TO CONTINUE
TO DEVELOP THE SCIENCE REQUIRED FOR AN HIV
VACCINE…NO MATTER HOW LONG IT TAKES
Using Antiretroviral Agents for Prevention?
Pre-Exposure Prophylaxis (PrEP) in Macaques
Garcia-Lerma , PLoS Medicine 2008
% Uninfected animals
100
High-dose Injectable Truvada (n = 6)
75
Oral Truvada (n = 6)
50
Injectable FTC (n = 6)
Oral TDF (n = 4)
25
Controls (n = 18)
0
0
2
4
6
8
10
12
14
Number of rectal exposures
Current and Proposed PrEP Trials
Daily TNF
Daily Truvada
Daily TNF Gel
Coitally-dependent TNF Gel
Efficacy of Oral Truvada PrEP
% Uninfected animals
Garcia-Lerma & Heneine (in progress)
100
-72h/+2h (n=6); p=0.01
-22h/+2h (n=6); p=0.008
75
-2h/+22h (n=6); p=0.04
50
25
0
Untreated controls (n=27)
0
2
4
6
8
10
12
Number of rectal exposures
14
Maraviroc (CCR5 blockade) as PrEP?
Dumond et al. CROI 2008
Day 7-10 Mean/SD Profile
Plasma
1000
Maraviroc Concentration (ng/mL)
CVF
Vaginal Tissue
100
10
protein-free IC90 = 0.5ng/mL
1
0
N=12
12
24
36
Time (hr)
48
60
72
Thinking Ahead
Truvada
+
Maraviroc
T
…fighting the viral swarm
THE ULTIMATE IN PrEP???
Topical Approaches for HIV-1 Prevention
Klasse et al Annu Rev Med 2008
Current Microbicide Candidates
Tenofovir Gel
Reservoir and Matrix Vaginal Rings
(listed in latest stage of development)
Candidate
Status - Phase
PRO 2000
Ongoing – Phase 3
Tenofovir gel
Ongoing – Phase 2B
PRO 2000/BufferGel®
Ongoing – Phase 2/2B
Dapivirine
Ongoing – Phase I
Ethanol in Emollient
Gel
Ongoing – Phase I
UC-781
Ongoing – Phase I
VivaGel®
Paused – Phase I
ACIDFORM ™
Planned – Phase 3
Invisible Condom™
Planned – Phase 2/3
CAP vaginal soft tablet
Planned – Phase I
Duet®
Planned – Phase I
PC-815
Planned – Phase I
www.microbicide.org, July 2008
Four Prevention Opportunities
Cohen et al, JCI, 2008
Cohen IAS 2008
UNEXPOSED
EXPOSED
(precoital/coital)
Behavioral,
Structural
Vaccines
ART PrEP
EXPOSED
INFECTED
(postcoital)
Microbicides
Vaccines
ART PEP
HOURS
72h
Treatment Of HIV
Reduced Infectivity
Circumcision
Condoms
YEARS
YEARS
Post Exposure Prophylaxis
Roland, 2008
•
A clinical trial to PROVE that PEP works cannot
be developed
•
PEP requires emergent usage and a full 28 days
of therapy, and multiple agents
•
Human failures have occurred, especially after
anal exposure and with delayed initiation of ART
•
In several reports health care providers seem to
demonstrate ambivalence about the PEP
strategy
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
HOURS
72h
Treatment Of HIV
Reduced Infectivity
Circumcision
Condoms
YEARS
YEARS
Secondary HIV Prevention
• Transmission from those who do not know their
status is important (Marks, AIDS 2006)
• Transmission in HIV discordant couples represents
an ongoing challenge (Dunkle, Lancet 2008)
HIV TESTING REMAINS A CRITICAL LINK!!
The Hierarchy of Transmission Risk..
from ~36-39 Million People with HIV
Acute HIV Infection
?
INCREASING RISK
?
?
30,000,000 people
(Fraser et al, PNAS, 2007)
2.5 million people
(only 8 weeks)
AIDS
(untreated)
Established infection
(untreated + STDs)
Established infection
(unrecognized)
Established infection
(on ART)
ART for Secondary Prevention
• Strong biological
plausibility for men and
women
• Retrospective clinical
studies
• Observational studies
of couples
• Ecological population
studies
Patients (%) with detectable
HIV in genital secretions
Cohen et al. Annals Int Med 2006
100
Not on ART
On ART
80
60
40
20
0
Men
Women
Vernazza, al., AIDS, 2000
Cu-Uvin et al., JAIDS, 2006
BUT WE DO NOT KNOW THE DEGREE OR DURABILITY OF
BENEFIT FROM ART AS AN HIV-1 PREVENTION WITHIN A COUPLE
(Wilson et al. Lancet, 2008)
HPTN 052…AN RCT UNDERWAY
(www.hptn.org/research_studies/hptn052.asp)
HIV-infected subjects with 350 to 550 CD4 T cells
Randomization
Immediate ART
350-550cells/uL
AZT+3TC+EFV
Deferred ART
CD4 <250>200
Endpoints: i) Transmission Events
ii) OIs and Clinical Events
iii) ART Toxicity
Prevention of the Sexual Transmission of HIV-1:
Results from Randomized Controlled Trials
Wasserheit, WHO, 2007
Intervention
Behavior change
Circumcision
Diaphragms
Microbicides
PrEP
STD Treatment
Vaccines
RCTs Completed RCTs Effective
9
0
4
3
1
0
9.5
0
1
0
7
1
2
0
1) RCT results are one measure of success
2) 15 RCTs in progress: new results each year
HIV Prevention and Public Health
Potts et al. Science, 2008
• Resources must match opportunities?
• Failure to implement ideas that work?
• Failure to undertake combined multipronged and multilevel approaches?
Highly Active HIV Prevention
Coates, Richter et al., 2008
The Big Challenge NOW
Great HIV treatment success…
– 22 antiretroviral agents available
– More than 2 million people receiving ART
But 2.5 million new HIV infections/yr
HIV prevention lags behind and has not
married treatment except for MTCT!!
HIV prevention MUST marry treatment NOW:
With the community…a unified strategy
Integrating HIV Prevention and Treatment
Salomon at al. PLoS Medicine, 2005
Modeling Interventions in Sub-Saharan Africa, 2004-2020
Scenario
Millions
of Total
New Adult
Infections
Millions of
Infections
Averted vs.
Baseline
Millions of
Total Adult
Deaths
Millions of
Deaths
Averted vs.
Baseline
Baseline
52.3
NA
37.4
NA
Treatment-centered (optimal effects)
49.2
3.0 (6%)
32.4
5.0 (13%)
Treatment-centered (mixed effects)
57.4
-5.1 (-10%)
33.9
3.5 (9%)
Prevention-centered
33.2
19.1 (36%)
32.6
4.8 (13%)
Combined response (optimistic)
23.4
28.8
(55%)
27.3
10.1
(27%)
Combined response (pessimistic)
43.6
8.7
(17%)
31.6
5.8
(16%)
THANK YOU
• To the organizers
• To many collaborators over 25 years
• To faculty and staff at UNC-CH, and UNC
Projects in Malawi, China, Madagascar and
other countries
• To patients and volunteers who participated in
many clinical trials
• To NIH, CDC, USAID, and others for funding