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					  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)




                          Vaccines
Behavioral,                                 Vaccines         Treatment Of HIV
                          ART PrEP
 Structural                                 ART PEP         Reduced Infectivity
                          Microbicides

           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)           Hereditary resistance
Phenotypic factors                 Innate resistance
                                   Acquired resistance
                                      Viral Concentration Really Matters
                                                            Chakraborty et al., AIDS 2001
Probability of transmission



                              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       Recipient
      (variable)




                               Abortive

                               Abortive



                                      Abortive

                                               Less fit or attenuated



                                                                   Time (days)
                          0      7        14    21      28
      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
                    10
                         1/30 or greater odds of transmission
                    8       to a susceptible partner per coital
HIV RNA In Semen
(Log10 copies/mL)




                            act
                    6

                    4

                    2

                    0
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           EXPOSED          INFECTED
                          (precoital/coital)   (postcoital)




                            Vaccines
Behavioral,                 ART PrEP           Vaccines        Treatment Of HIV
 Structural               Microbicides         ART PEP        Reduced Infectivity


           Circumcision
               Condoms


   YEARS                       HOURS              72h                  YEARS
                                                         HIV-1 Transmission Event
                                                                       Adapted from Johnston and Fauci, NEJM,2007.


                                                   Window of Opportunity??                       Established Infection
Virus Concentration in Extracellular Fluid




                                              8
                                              7                             Symptoms
      or Plasma (Log10 Copies/ml)




                                              6
                                              5                                         Set Point
                                              4
                                              3  eclipse              Reservoir
                                              2                                                        Limit of detection for HIV RNA
                                              1
                                                                    HIV-1 Integration and
                                              0                     Viral Dissemination
                                             -1
                                             -2 Transit
                                             -3
                                             -4
                                             -5
                                               0     5    10   15      20    25    30       35   40    45   50    55     60   65    70



                                    Transmission
                                                                     Time Post Exposure (days)
 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            Cell-Mediated Immunity

  no protection     protection against HIV         protection against disease
                     sterilizing immunity!          A reduced HV peak and “set point”




  HIV Infection                              initial infection       chronic infection
                     Infection prevented
and RNA set point                              “controlled”          with low set point
                  HIV Vaccines: Summary
                                     Walker and Burton, Science, 2008


• We do not know how to                                     control
  generate neutralizing antibodies

• Cell mediated (CTL) vaccines
  lower peak viremia and set
  point in macaques

  But, human studies have not yet                 treated
  controlled viremia (STEP Trial)



                                             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




              100                                                 High-dose Injectable Truvada (n = 6)


                       75
% Uninfected animals




                                                                  Oral Truvada (n = 6)

                       50
                                                                  Injectable FTC (n = 6)
                       25                                         Oral TDF (n = 4)

                                                                  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
                                                             Garcia-Lerma & Heneine (in progress)




                       100
% Uninfected animals




                                                                    -72h/+2h (n=6); p=0.01
                                                                    -22h/+2h (n=6); p=0.008
                       75

                       50                                           -2h/+22h (n=6); p=0.04


                       25

                                                                    Untreated controls (n=27)
                        0
                            0    2    4   6    8   10   12     14
                                 Number of rectal exposures
            Maraviroc (CCR5 blockade) as PrEP?
                                                                               Dumond et al. CROI 2008
                                                      Day 7-10 Mean/SD Profile


                                                                                                   Plasma
                      1000
                                                                                                   CVF
Maraviroc Concentration (ng/mL)




                                                 Vaginal Tissue
                                  100




                                  10




                                                                                   protein-free IC90 = 0.5ng/mL
                                    1
                                        0   12           24         36        48            60            72
   N=12                                                           Time (hr)
   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                (listed in latest stage of development)

                                           Candidate              Status - Phase
                                           PRO 2000             Ongoing – Phase 3
                                         Tenofovir gel          Ongoing – Phase 2B
Reservoir and Matrix Vaginal Rings
                                     PRO 2000/BufferGel®       Ongoing – Phase 2/2B
                                           Dapivirine           Ongoing – Phase I
                                      Ethanol in Emollient      Ongoing – Phase I
                                              Gel
                                            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          EXPOSED          INFECTED
                          (precoital/coital)   (postcoital)




                            Vaccines
Behavioral,                 ART PrEP           Vaccines        Treatment Of HIV
 Structural                Microbicides        ART PEP        Reduced Infectivity


           Circumcision
               Condoms


   YEARS                       HOURS              72h                 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)




                           Vaccines
Behavioral,                ART PrEP         Vaccines         Treatment Of HIV
 Structural               Microbicides      ART PEP         Reduced Infectivity


           Circumcision
               Condoms


   YEARS                     HOURS              72h                 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
                                   ?
                                                      (only 8 weeks)
                                                    AIDS
                                   ?
                                                      (untreated)
INCREASING RISK




                                                    Established infection
                                   ?
                                                    (untreated + STDs)

                         30,000,000 people          Established infection
                       (Fraser et al, PNAS, 2007)     (unrecognized)

                                                    Established infection
                           2.5 million people
                                                           (on ART)
        ART for Secondary Prevention
                                                                 Cohen et al. Annals Int Med 2006

                                                            100




                             Patients (%) with detectable
                                                                                Not on ART
• Strong biological




                              HIV in genital secretions
                                                                                On ART
  plausibility for men and                                  80

  women                                                     60
• Retrospective clinical                                    40
  studies
                                                            20
• Observational studies
  of couples                                                 0

• Ecological population                                                Men                Women
  studies                                                             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                               Deferred ART
350-550cells/uL       AZT+3TC+EFV           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   RCTs Completed RCTs Effective
Behavior change          9              0
Circumcision             4              3
Diaphragms               1              0
Microbicides             9.5            0
PrEP                     1              0
STD Treatment            7              1
Vaccines                 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 multi-
  pronged 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

                                        Millions     Millions of    Millions of   Millions of
 Scenario                               of Total     Infections     Total Adult   Deaths
                                        New Adult    Averted vs.    Deaths        Averted vs.
                                        Infections   Baseline                     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            27.3         10.1
                                                       (55%)                        (27%)
 Combined response (pessimistic)           43.6          8.7            31.6          5.8
                                                       (17%)                        (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

				
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posted:11/24/2011
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