1. Myron S Cohen The University of North Carolina Chapel Hill, USA
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

2. Four Prevention Opportunities
Cohen et al, JCI, 2008
Cohen IAS 2008
YEARS
UNEXPOSED
Behavioral,
Structural
Circumcision
Condoms
HOURS
Vaccines
ART PrEP
Microbicides
EXPOSED
(precoital/coital)
72h
Vaccines
ART PEP
EXPOSED
(postcoital)
INFECTED
Treatment Of HIV Reduced Infectivity
Vaccine – neutr antibodies
YEARS

3. Let’s Accept the Idea that … Coates et al Lancet 2008
Abstinence or total monagomy in a SERONEGATIVE couple are effective, but difficult to achieve (…and beware concurrency)
Barrier Methods Work
Condoms (serve as a reversible barrier)
Circumcision ( form an irreversible and imperfect barrier)
HIV prevalence has fallen in many communities so some behavioral interventions work
Combination multilevel behavioral and structural approaches may ultimately prove very effective, and they certainly need continued effort

4. But When Primary Prevention Fails… Risk of a Transmission Event Develops
Cohen and Galvin, Nat Micro Rev 2004
Infectious Susceptible
Inoculum (concentration) Hereditary resistance
Phenotypic factors Innate resistance
Acquired resistance

5. Viral Concentration Really Matters
Chakraborty et al., AIDS 2001
0.016
0.012
Probability of transmission
0.008
Here,
X axis is ….
Y axis is ……
explain three lines ……
Explain the slope change after 4.5 log1- value of RNA values.
0.004 3
3.5 4
4.5 5
5.5
Log10 Seminal HIV RNA in one ejaculate

6. A Single R5 Virus from “A SWARM” Infects
Keele et al., PNAS 2008
Donor
(variable)
Mucosa
Recipient
Abortive
Less fit or attenuated
Time (days) 7 21 14 28

7. Estimating HIV Transmission: Have the methods confused the message?
Powers et al Lancet ID, 2008
HIV Transmission is often estimated as 1/ 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 …

8. HIV Transmission Efficiency By Cofactor
Powers et al Lancet ID, 2008

9. Amplified Transmission of HIV
Acute HIV Infection
& STD Co-infection
STD Episode
AIDS
1/30 or greater odds of transmission to a susceptible partner per coital act 10 8 6 4 2
HIV RNA In Semen
(Log10 copies/mL)

10. 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

11. Four Prevention Opportunities
Cohen et al, JCI, 2008
Cohen IAS 2008
YEARS
UNEXPOSED
Behavioral,
Structural
Circumcision
Condoms
EXPOSED
72h
Vaccines
ART PEP
EXPOSED
(postcoital)
INFECTED
(precoital/coital)
Vaccines
ART PrEP
Microbicides
Treatment Of HIV Reduced Infectivity
Vaccine – neutr antibodies
HOURS
YEARS

12. Limit of detection for HIV RNA
HIV-1 Transmission Event
Adapted from Johnston and Fauci, NEJM,2007.
Window of Opportunity??
Established Infection 8 7
Symptoms 6 5
Set Point 4
eclipse 3
Reservoir
Virus Concentration in Extracellular Fluid or Plasma (Log10 Copies/ml) 2
Limit of detection for HIV RNA 1
HIV-1 Integration and Viral Dissemination -1 -2
Transit -3 -4 -5 5 10 15 20 25 30 35 40 45 50 55 60 65 70
Time Post Exposure (days)
Transmission

13. Biological prevention options at exposure……
When Transmission is Imminent
Biological prevention options at exposure……
Modification of Innate Immunity
Acquired Immunity (A VACCINE)
Neutralizing antibodies
Cell mediated immunity
Antiretroviral therapy

14. Strategies for an HIV Vaccine
Transmission
Vaccine Success
Cell-Mediated Immunity
protection against HIV
sterilizing immunity!
no protection
protection against disease
A reduced HV peak and “set point”
HIV Infection
and RNA set point
initial infection
“controlled”
chronic infection
with low set point
Infection prevented

15. HIV Vaccines: Summary
Walker and Burton, Science, 2008
We do not know how to generate neutralizing antibodies
Cell mediated (CTL) vaccines lower peak viremia and set point in macaques
But, human studies have not yet controlled viremia (STEP Trial)
control
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

16. Using Antiretroviral Agents for Prevention?

17. Pre-Exposure Prophylaxis (PrEP) in Macaques2 4 6 8 10 12 14 25 50 75
100
Number of rectal exposures
% Uninfected animals
Controls (n = 18)
Injectable FTC (n = 6)
High-dose Injectable Truvada (n = 6)
Oral Truvada (n = 6)
Oral TDF (n = 4)
Pre-Exposure Prophylaxis (PrEP) in Macaques
Garcia-Lerma , PLoS Medicine 2008

18. Current and Proposed PrEP Trials
Daily TNF
Daily Truvada
Daily TNF Gel
Coitally-dependent TNF Gel

19. Efficacy of Oral Truvada PrEP 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
% Uninfected animals 25
Untreated controls (n=27) 2 4 6 8 10 12 14
Number of rectal exposures

20. Maraviroc (CCR5 blockade) as PrEP?
Dumond et al. CROI 2008
Vaginal Tissue
Cervicovaginal Fluid
Exciting advance in the prevention arena
Blood Plasma
protein-free IC90 = 0.5ng/mL
N=12
N=12

21. TRUVIROC Truviroc Thinking Ahead Truvada + Maraviroc
THE ULTIMATE IN PrEP??? T
Truviroc
…fighting the viral swarm
TRUVIROC
Truvada Maraviroc

22. Topical Approaches for HIV-1 Prevention
Klasse et al Annu Rev Med 2008
Current Microbicide Candidates
(listed in latest stage of development)
Tenofovir Gel
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
UC-781
VivaGel®
Paused – Phase I
ACIDFORM ™
Planned – Phase 3
Invisible Condom™
Planned – Phase 2/3
CAP vaginal soft tablet
Planned – Phase I
Duet®
PC-815
Reservoir and Matrix Vaginal Rings
July 2008

23. Four Prevention Opportunities
Cohen et al, JCI, 2008
Cohen IAS 2008
YEARS
UNEXPOSED
Behavioral,
Structural
Circumcision
Condoms
EXPOSED
72h
Vaccines
ART PEP
EXPOSED
(postcoital)
INFECTED
(precoital/coital)
Vaccines
ART PrEP
Microbicides
Treatment Of HIV Reduced Infectivity
Vaccine – neutr antibodies
HOURS
YEARS

24. 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

25. Four Prevention Opportunities
Cohen et al, JCI, 2008
Cohen IAS 2008
YEARS
UNEXPOSED
Behavioral,
Structural
Circumcision
Condoms
HOURS
Vaccines
ART PrEP
Microbicides
EXPOSED
(precoital/coital)
72h
Vaccines
ART PEP
EXPOSED
(postcoital)
INFECTED
Treatment Of HIV Reduced Infectivity
Vaccine – neutr antibodies
YEARS

26. 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!!

27. The Hierarchy of Transmission Risk.. from ~36-39 Million People with HIV
INCREASING RISK ?
Acute HIV Infection
(only 8 weeks) ?
AIDS
(untreated)
Established infection
(untreated + STDs) ?
30,000,000 people
(Fraser et al, PNAS, 2007)
Established infection
(unrecognized)
Established infection
(on ART)
2.5 million people

28. ART for Secondary Prevention
Cohen et al. Annals Int Med 2006
100
Strong biological plausibility for men and women
Retrospective clinical studies
Observational studies of couples
Ecological population studies
Not on ART
On ART 80 60
Patients (%) with detectable HIV in genital secretions 40 20
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)

29. 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
cells/uL
Deferred ART
CD4 <250>200
AZT+3TC+EFV
As part of our ongoing deliberations we designed a study for RRS that could be used as the basis for statistical simulations to further address the feasibility of conducting a trial in RRS. This slide outlines the proposed trial, similar in initial design to a composite of the two trials proposed by the INSIGHT network.
Endpoints: i) Transmission Events
ii) OIs and Clinical Events
iii) ART Toxicity

30. Prevention of the Sexual Transmission of HIV-1: Results from Randomized Controlled Trials
Wasserheit, WHO, 2007
Intervention
RCTs Completed
RCTs Effective
Behavior change
Circumcision
Diaphragms
Microbicides
PrEP
STD Treatment
Vaccines 9 4 1
9.5 7 2 3
1) RCT results are one measure of success
2) 15 RCTs in progress: new results each year

31. HIV Prevention and Public Health
Potts et al. Science, 2008
Resources must match opportunities?
Failure to implement ideas that work?
Failure to undertake combined multi-pronged and multilevel approaches?

32. Highly Active HIV Prevention
Coates, Richter et al., 2008

33. Great HIV treatment success…
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

34. Modeling Interventions in Sub-Saharan Africa, 2004-2020
Integrating HIV Prevention and Treatment Salomon at al. PLoS Medicine, 2005
Modeling Interventions in Sub-Saharan Africa,
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
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%)

35. 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