Antiretroviral Therapy: An HIV Prevention Strategy? by C88S2J

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									  Antiretroviral Therapy:
An HIV Prevention Strategy?

      Wafaa El-Sadr, MD, MPH
          Columbia University
            Harlem Hospital
               New York
        Persons Living with HIV/AIDS 2008
    33.2 million (30.6-36.1 million) worldwide



                                             E. Europe/Central Asia
                             Western &             1.6 million
North America               Central Europe
 1.3 million                  760,000
                                                                E. Asia/Pacific
                                                                   800,000
                              N. Africa/Mid-East
                Caribbean          380,000                                 South/S.E. Asia
                 230,000                                                     4.0 million
                              Sub-Saharan Africa
         Latin America           22.5 million
          1.6 million                                                             Oceana
                                                                                  75,000

                                                   Source: UNAIDS, AIDS Epidemic Update, December 2009
Use of ART for PMTCT
                                          HIV RNA Levels Associated with
                                               HIV Transmission Risk
                                         30
                                                                                                               Male-to-Female                                           Female-to-Male
Transmission rate per 100 Person-Years

                                                       All subjects
                                         25                                                                     Transmission                                             Transmission

                                         20

                                         15

                                         10

                                          5

                                          0
                                                                  3500-9999




                                                                                                                           3500-9999




                                                                                                                                                                                    3500-9999
                                                       400-3499




                                                                                                                400-3499




                                                                                                                                                                         400-3499
                                                <400




                                                                                                        <400




                                                                                                                                                                 <400
                                                                                              >50 000




                                                                                                                                                       >50 000




                                                                                                                                                                                                                >50 000
                                                                              10 000-49 999




                                                                                                                                       10 000-49 999




                                                                                                                                                                                                10 000-49 999
                                         Viral load (HIV-1 RNA copies/ml) and HIV transmission
                                              Quinn TC, et al. NEJM 2000; Fideli U, et al. AIDS Res Hum Retrovir 2001
  Impact of Antiretroviral Therapy (ART)
          on HIV Transmission
• Prospective cohort study of home-based ART
  in a rural community in Uganda (n=926)
• After starting ART
  – Median HIV RNA levels decreased from 122,500
    to <50 copies/mL
  – Estimated HIV transmission rate reduced by 98%
     • From 46 to 1 per 1000 PY
  – Risky sex decreased by 70% (P=0.002)


                          Bunnell R, et al. AIDS. 2006;20(1):85
  Impact of ART on HIV Transmission
• HIV discordant couples (Rwanda and Zambia)
  (n= 2,993 discordant couples)
• HIV+ persons with CD4 <200 cells/mm3on ART
• HIV incidence by partner ART status:
  – Not on ART:      3.4 / 100 PY
  – On ART:          0.7 / 100 PY
     • OR, 0.2; 95% CI, 0.08-0.6



                            Sullivan P, et al. CROI Montreal. 2009
         HIV sexual transmissibility meta-analysis:
        No transmission on ART below 400 copies/ml




Attia S, et al.AIDS 2009 Jul 17;23(11):1397-404.
     Antiretroviral Treatment as Prevention

• Anema A, et al. The use of HAART to reduce HIV incidence at the
  population level. CMAJ 2008; 179:13-4.
• Bateman C. Treat all HIV-positive people--and bury the pandemic
  in 14 years. S Afr Med J 2009; 99:80-2.
• Montaner JS, et al. The case for expanding access to HAART to
  curb the growth of the HIV epidemic. Lancet 2006;368:531-6.
• DeGruttola V, et al. Controlling the HIV epidemic, without a
  vaccine! AIDS 2008; 22:2554-5.
• Dieffenbach CW, Fauci AS. Universal VCT and ART for
  prevention of HIV transmission. JAMA 2009; 301:2380-2
Modeling of Test and Treat




                    Lancet 2009; 373:48-57
          Model Assumptions

• High uptake of annual testing by all >15 year
  old individuals
• All HIV+ individuals start ART immediately,
  irrespective of stage of HIV disease
• 99% decrease in infectiousness
• High adherence with ART
• Low failure with first line ART
              Estimated number of new HIV infections by
                   transmission category, 1977-2006
                                       *50 States and District of Columbia



                          MSM




                           IDU

                                 HET




Courtesy of Kevin Fenton, CDC
HIV Prevalence for Selected Countries in Sub Saharan
   Africa and Subpopulations in the United States
             Test and Treat
     Test                    Treat with ART

                      +
Adoption of safer
  behaviors by                  Maintain viral
  HIV+ persons                   suppression



        Decrease in HIV Transmission
        HPTN TNT-Plus Study Concept

             Test                         Enroll in Care
 Increase                                               Initiation
                                                          of ART
in Testing
                                         Treat with ART

         HIV Positive      Linkage                    Support of
 Positive                  to care                    adherence
Prevention                   sites
                                     Maintain viral suppression
   Adopt safer behaviors



               Decrease in HIV Transmission
Testing
                            Coverage of ART among
                         eligible people living with HIV
                                Kenya (2007 KAIS)



          39% know                                              57% Unaware of
           status,                                               status, not on
           on ART               39%                                   ART

                                                  57%

  4% know status, not
       on ART
                                     HIV test
                  Among those who knew status and were eligible 92% were on ART
Mohammed, CROI 2009
      Percentage HIV Tested
Country         % Tested in preceding 12 months
                    Woman               Men
Congo                  6.5               4.8
Cote d’Ivoire         3.7               3.2
Ethiopia              2.3               2.3
Namibia              10.6              17.6
Rwanda               12.0              11.0
Swaziland            21.9               8.9
Uganda               12.0              10.4
Zambia               18.5              11.7
Zimbabwe              7.0               7.0
United States                  10%
New AIDS Cases and “Late Testers”
                   Persons newly diagnosed with AIDS, and
  proportion first diagnosed with HIV within 12 months, 2001-2006 (N=4,640)


                992


                            842
                                       780

    668        54.0%
                                                             692
                           30.3%
                                                  666
                                                                         646
                                       32.3%

                                                              37.1%
   43.3%                                           37.8%
                                                                          33.9%




                            69.7%
                                       67.7%
               46.0%                                          62.9%
                                                   62.2%
   56.7%                                                                  66.1%




                                                                                  20
            Late Diagnosis of HIV
• NYC: 27% of persons newly diagnosed with HIV had
  concurrent diagnosis of AIDS in 2005
• First CD4+ count performed within 12 months after HIV test
   – CD4+<200:       31.7%
   – CD4+ 200-350: 8.2%
   – CD4+ 351-500: 6.9%
   – CD4+ >500:      8.8%
   – Missing:        44%
• Concurrent HIV/AIDS diagnosis (1 month)
   – More than twice risk of death within 4 months
      HR: 2.27 (95% CI 1.94-2.65)

                                         NYC DOHMH surveillance 2007
                                         Hanna et al 2008
Positive Prevention
          Positive Prevention Interventions
Intervention Healthy             CLEAR            WILLOW           SUMIT          Options
Name         Relationship                                          Enhanced
                                                                   Peer-Led
Study Size   328                 175              366              811            497

Setting      Community           Community        Study site and   Study site     HIV care
             AIDS Service        agency,          HIV service                     clinic
             Organization        residence or     clinic
                                 community site
Unit of      Group               Individual       Group            Group          Individual
Delivery

Deliverer    Male and            Licensed         HIV+ peer     HIV+ MSM          HIV
             female              therapist or     educators and peer              physicians
             community           social worker    health        facilitators
             facilitators                         educators
Outcome      UAI, UVI, AI, VI,   Condom Use       UVI; condom      UAR with non   UAI, UVI,
Measure      with non-HIV+                        use; STI         HIV+ partner   UAR, UVR,
             partners:                                                            UIO
             condom use
Linkage to Care
Time from HIV Diagnosis to Care Entry*

      1,340   1,827   1,635   1,502   1,342   1,510




                                                      50%




                                                      25
        Factors Associated with Delayed
                Initiation of Care
• Of 1,928 patients,
   – 1,228 (63.7%) initiated care within 3 months of HIV
     diagnosis
   – 369 (19.1%) initiated care >3 months
   – 331 (17.2%) never initiated care
• Predictors of delayed initiation of care:
   –   Diagnosis at community testing site (HR: 1.9, 95%CI 1.5-2.3)
   –   Diagnosis in corrections, STI or TB clinic (HR:1.3, 95% CI; 1.1-1.6)
   –   Non-white race/ethnicity (HR: 1.8; 95% CI 1.5-2.0)
   –   Injection drug use (HR: 1.3; 95% CI1.1-1.5)
   –   Foreign born (HR: 1.1; 95% CI 1.0-1.2)

                                                              Torian et al 2008
Treatment with ART
When to Start Antiretroviral Therapy




         Earlier      Later
                 Early versus Later ART
                         Possible Benefits           Possible Risks
Later ART initiation     • Lower medication and      • Lower preservation of
                         monitoring costs            immune function
                         • Lower incidence of long   • Increased risk of
                         term drug toxicity          disease progression
                         • Decrease in               • Risk of HIV
                         development of              transmission prior to
                         resistance                  ART initiation
Earlier ART initiation   • Improved preservation     • Increased medication
                         of immune function          and monitoring costs
                         • Prolonged disease-free    • Increased incidence of
                         survival                    long term drug toxicities
                         • Decreased HIV             • Increased
                         transmission rates          development of drug
                                                     resistant HIV
        INSIGHT START Study
   HIV-infected individuals who are ART-naïve with
             CD4+ count > 500 cells/mm3




Early ART Group                 Deferred ART Group
Initiate ART immediately       Defer ART until the CD4+ count
following randomization        declines to < 350 cells/mm3 or
       N=2,000 for                     AIDS develops
      definitive trial                   N=2,000 for
                                       definitive trial



      Serious AIDS, Non-AIDS Events or Death
                      HPTN 052

          HIV-infected subjects with
CD4 350 to 550cells/µL with discordant partner

                          Randomization

Immediate ART                                    Deferred ART
                         AZT+3TC+EFV
350-550cells/uL                                  CD4 <250>200

         Endpoints: i) HIV Transmission to partners
                   ii) OIs and clinical Events
                   iii) ART toxicity       Thailand, South Africa, Botswana,
                                                Kenya, Malawi, Brazil, India
                            Other Modelling
                                              --- All treated
                                                  Relative infectivity 0.01
                                                  Dropout: 1.5% /year
                                                  14% prevalence in population
                                              --- ART: 65% symptomatic
                                                         20% asympotmatic
                                                  Relative infectivity 0.03
                                                  Dropout: 5% symptomatic
                                                              20% asymptomatic
                                                  Elimination theoretically possible

                                              --- ART: 65% symptomatic
                                                        no ART asymptomatic
                                                  Treated individuals noninfectious
                                                  Dropout: 5%/yr
                                                  HIV remains endemic at 34%
Wagner and Blower, Nature Proceedings, 2009       prevalence and 2%/yr incidence
Adherence
            Adherence to Antiretroviral
                   Treatment


 Percent
reporting
  100%
adherence




             *p<0.01 for difference between months 1 & 4 and months 1 & 8

                                        Mannheimer et al, FIRST Study CPCRA, 2000.
    HPTN 065 TLC-Plus Study
  “Testing Linkage to Care Plus
           Treatment”
                PURPOSE

 To evaluate the feasibility of an enhanced
community-level HIV test, link-to-care plus
         treat strategy in the U.S.
           Study Components
I. Testing
II. Linkage to care
III. Viral suppression
IV. Positive prevention
V. Patient and provider survey
         Study Communities

• Intervention communities
  – Washington DC
  – Bronx, NY
• Comparison communities
  – Houston
  – Philadelphia
  – Chicago
  – Miami
HIV Testing in NYC: The Bronx Knows

                         •Bronx with excess
                         AIDS-related deaths
                         (32% vs. 17% NYC
                         pop.)
                         •1 in 4 diagnosed
                         with HIV & AIDS
                         concurrently in the
                         Bronx
   “The Bronx Knows” Initiative
Test all Bronx residents
ages 18-64 yrs who have
never been tested before
to identify undiagnosed
HIV+ persons
 Link all HIV+ persons to
high quality care and
supportive services
                     Washington, D.C.:
           7 of 8 wards with 1.7-2.8% prevalence

City-wide by
race/ethnicity
and sex
-----------------
WF 0.2%
HF 0.7%
                                                        Population
BF 2.6%                                                 Prevalence
WM 2.6%
HM 3.0%                                                       0.0 - 0.6
                                                              0.7 - 1.2
BM 6.5%                                                       1.3 - 1.8
                                                              1.9 - 2.4
                                                              2.5 - 3.0


                               REF: Shannon Hader. CROI 2009. Abst.57
HIV Rapid Testing Expansion in DC


   68.4% increase in
   number of tests done
   in 1 yr




        97% of new HIV           94% of new HIV
        positives were           positives were
        identified in clinical   identified in clinical
        settings                 settings




         N=43,271                 N=72,864

                                                          41
                                                          41
               Study Components
            I. Expanded HIV Testing

This includes
  1- social mobilization, with targeted messaging to
   promote testing
2- universal offer of HIV testing in
    emergency departments (EDs) and
    hospital inpatient admissions
   9%


   8%


   7%


   6%


   5%


   4%


   3%


   2%

   1%

   0%
        Jul-05

                 Sep-05

                          Nov-05

                                   Jan-06

                                              Mar-06




                                                                                                                                                                                                       ED New Dx
                                                       May-06

                                                                Jul-06

                                                                         Sep-06

                                                                                  Nov-06

                                                                                            Jan-07

                                                                                                     Mar-07




                                                                                                                                                                                           IP New Dx
                                                                                                              May-07


                                                                                                                       Jul-07


                                                                                                                                Sep-07


                                                                                                                                           Nov-07


                                                                                                                                                    Jan-08


                                                                                                                                                             Mar-08


                                                                                                                                                                      May-08

                                                                                                                                                                               OP New Dx
                                            OP New Dx                                      IP New Dx                                     ED New Dx


                                                                                                                                                                                                                   43
                  Study Components
                  II. Linkage to Care
This component involves:

  – test site randomization (20 per community)
  – determine feasibility and effectiveness of
         » financial incentives vs.
         » standard of care (SOC)

  Outcome: Proportion of newly identified HIV+ patients from
   HIV test sites who complete two clinical visits at HIV care
   sites
                  Study Components
                 III. Viral Suppression

This component involves:

  – care site randomization (20 per community)
  – determine feasibility and effectiveness of
          » financial incentives vs.
          » standard of care (SOC)

   Outcome: Proportion of patients at HIV care site achieving
    and maintaining viral suppression
                        Financial Incentives

• 2-arm RCT:
       • Information about
         programs
       • Incentives worth up
         to $750 for program
         completion, short-
         term cessation, long-
         term cessation

• Eligibility for incentives tied
to quitting within first 6
months of enrollment                                 p-value for difference < 0.0001



               Volpp, Troxel, Pauly et al, New England Journal of Medicine. 2009; 360(7): 699-709.
              Study Components
         IV. Prevention for Positives
This involves:

  –individual randomization of patients (6 care sites
   per community)

  –determine effectiveness in decreasing risk
   behaviors
        »computer-delivered intervention vs.
        »standard of care (SOC)
            Study Components
          Prevention for Positives
The computer-delivered intervention is:

  –A modification of the Computer Assessment and
   Risk Reduction Education for       HIV-positives
   (CARE+) platform, integrated with an audio-
   narrated self-interview (ACASI)
             Study Components
      V. Patient and Provider Surveys
These surveys aim to determine:

  –knowledge, attitudes and practices regarding
   early initiation of ART

  –knowledge and attitudes regarding financial
   incentives for linkage to care and viral
   suppression
      Study Objectives and Outcomes

• Assesses feasibility and effectiveness outcomes, dependent
  on study component

• Assesses the feasibility of using surveillance data for
  outcomes

• All aim at determining feasibility of overall strategy

• TLC-Plus is not designed to measure a change in HIV
  incidence
       Unique Features of TLC-Plus
• Partnerships
   – Between NIH and CDC
   – Across NIH institutes
   – With departments of health in major cities
   – With diverse stakeholders in communities
• Community (rather than research site) focus
• Combine feasibility and effectiveness outcomes
• Use of routine HIV surveillance data for key outcomes
• Galvanize community support for expanded testing, care and
  treatment
                        Conclusions
• HIV prevention successes have been limited
• Intense interest in use of antiretroviral therapy as a
  prevention strategy
• Success will require:
   – effective implementation of multiple interrelated
     interventions at a broad community level
   – Simple easy to measure outcomes at a community level
• TLC-Plus Study will examine several strategies for:
   –   HIV testing
   –   Linkage from testing to care
   –   Enhanced and maintained viral suppression with ART
   –   Positive prevention intervention
• Lessons learned may help inform larger definitive study of this
  strategy in the US and internationally
          Acknowledgement

CDC: Bernard Branson, Kate Buchacz, Irene Hall
NYC DOHMH: Blayne Cutler and Lucia Torian
Washington, DC DOH: Shannon Hader
Members of the TLC-Plus team and Advisory Group
HIV Prevention Trials Network
Many others

Support by NIH

								
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