hptn test and treat (tnt) design issues and implications for a domestic research agenda sten...
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![Page 1: HPTN Test and Treat (TNT) Design Issues and Implications for a Domestic Research Agenda Sten Vermund, Wafaa El-Sadr, Kenneth Mayer on behalf of the HPTN](https://reader036.vdocument.in/reader036/viewer/2022062511/551b7d18550346a6148b5595/html5/thumbnails/1.jpg)
HPTN Test and Treat (TNT)
Design Issues and Implications for a Domestic
Research Agenda
Sten Vermund, Wafaa El-Sadr, Kenneth Mayer
on behalf of the HPTN
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Outline of Presentation
• Conceptual framework for TNT • Unique features of US HIV epidemic• US testing initiatives
The Bronx Knows Initiative Washington DC Initiative Layering research on public health programs
• Experimental Designs: Current Studies BROTHERS and ISIS Interventions in BROTHERS-II and ISIS-Plus
• Key Research Questions Study Designs and study outcomes Next Steps your questions and views
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Model assumes…• Generalized epidemic
High prevalence & incidence
• High population coverage with repeated testing and universal treatment Earlier treatment than current SOC
Lancet 2009; 373:48-57
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Test and Treat Hypothesis
Test
Adoption of safer risk behaviors by
HIV+ persons
Treat with ART+
Adherence
Maintain viral suppression
Decrease in HIV Transmission
+
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• In US = Localized into In US = Localized into geographic and population geographic and population hotspotshotspots
• No definitive evidence yet No definitive evidence yet of risk/benefits of early ARTof risk/benefits of early ART
For treatment: START; For treatment: START; HPTN052/ACTG5245HPTN052/ACTG5245
For prevention: HPTN 052/ For prevention: HPTN 052/ ACTG5245ACTG5245
• Challenges in bridging to Challenges in bridging to care and in long-term care and in long-term maintenance maintenance
ART adherence and HIV ART adherence and HIV suppressionsuppression
Conceptual Framework █ and obstacles █ for a TNT Strategy
• Identify HIV (+) persons Identify HIV (+) persons unaware of their HIV statusunaware of their HIV status
• Risk reduction among Risk reduction among persons testing HIV (+)persons testing HIV (+)
• Bridge to care for ARTBridge to care for ART Eligibility from current Eligibility from current
guidelines, or guidelines, or ART for all with HIV infectionART for all with HIV infection
• Maintenance of high ART Maintenance of high ART adherence rates for adherence rates for maximal RNA suppressionmaximal RNA suppression
• Decrease in HIV Decrease in HIV transmission from virally transmission from virally suppressed personssuppressed persons
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Epidemiology of HIV/AIDS in the US
• Disparities in race/ethnicity in geography in sexual exposure
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Estimated number of new HIV infections by transmission category, 1977-2006
MSM
IDU
HET
*50 States and District of Columbia
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Estimated rates of new HIV Infections, by race/ethnicity, 2006*
Total Male: 34.3 per 100,000
Total female: 11.9 per 100,000
*50 States and District of ColumbiaCourtesy of Kevin Fenton, CDC
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American Indian/Alaska NativeAsian/Pacific IslanderHispanicBlack, not Hispanic
White, not Hispanic
Estimated AIDS Cases among Adult and Adolescent MSM, by Region and Race/Ethnicity, 2006—50 States and DC
0
500
1,000
1,500
2,000
2,500
3,000
3,500
Northeast Midwest South West
No.
of
case
s
n=3,220 n=2,150 n=6,939 n=3,765
Note. The data have been adjusted for reporting delay and cases without risk factor information were proportionally redistributed.
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Estimated HIV/AIDS Cases among MSM, Aged 13–24 years, by Race/Ethnicity, 2001–2006—33 States
0
400
800
1,200
1,600
2,000
2001 2002 2003 2004 2005Year of diagnosis
No.
of
case
s
White, not Hispanic
Black, not Hispanic
Hispanic
Asian/Pacific IslanderAmerican Indian/Alaska Native
2006
Note. The data have been adjusted for reporting delay and cases without risk factor information were proportionally redistributed.
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Total Tested
HIVPrevalence
No. %
Unrecognized HIV Infection
No. %Age Group (yrs) 18-24 410 57 (14) 45 (79)25-29 303 53 (17) 37 (70)30-39 585 171 (29) 83 (49)40-49 367 137 (37) 41 (30) ≥ 50 102 32 (31) 11 (34)
Race/EthnicityWhite 616 127 (21) 23 (18)Black 444 206 (46) 139 (67)Hispanic 466 80 (17) 38 (48)Multiracial 86 16 (19) 8 (50)Other 139 18 (13) 9 (50)
Total 1,767 450 (25) 217 (48)
HIV Prevalence Among 1,767 MSM, by Age Group and Race/Ethnicity—Baltimore, LA, Miami, NYC, San Francisco
MMWR June 24, 2005
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US National Health Interview Survey (NHIS)
• Annual, cross-sectional U.S. household probability sample conducted by NCHS/CDC (excludes institutionalized individuals)
• Provides estimates for a broad range of health measures for the U.S. population, including HIV testing
Testing Efforts in the US
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HIV Testing in NHIS: 2006
• U.S. adults estimated to have been tested for HIV 40% (71.5 million) at least once 10.4% (17.8 million) in the
preceding 12 months
REF: Duran et al, MMWR, Aug. 2008
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Persons are being tested in clinical settings
2003 2006Private doctor/HMO 44% 53%Hospital, ED, Outpatient
22% 18%
Community clinic (public)
9% 9%
HIV counseling/testing 5% 5%Correctional facility 0.6% 0.4%STD clinic 0.1% 0.1%Drug treatment clinic 0.7% 0.4%- 2006 National Health Interview Survey
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National Testing Initiative 2007
• Goal: To increase HIV testing opportunities for populations disproportionately affected by HIV Focus on Black Americans unaware of their
status
• Funding: $35 million awarded Sept. 2007 to 23 jurisdictions with the highest number of AIDS cases among Black Americans Increased to 25 jurisdiction in 2008
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HIV Testing in NYC
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HIV Testing in NYC
FY ’07 FY ’08
• City-Sponsored Tests: 143,719 209,194 (Internal & External Programs)
• % Rapid Tests 98.0% 98.7%
• Positive Tests 1,660 2,868
• % Seropositive 1.2% 1.4%
NYC DOHMH BHIV Testing Unit, data reported as of 12/31/08NYC DOHMH BHIV Testing Unit, data reported as of 12/31/08
From: Blayne Cutler, MD PhD, NYC Dept of Health & Mental Hygiene
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NYC Internal Testing Programs
• Routinely offered: STD clinics TB clinics NYC jails
• Field Services Unit Field testing of partners of the newly
diagnosed began Feb. 2008
From: Blayne Cutler, MD PhD, NYC Dept of Health & Mental Hygiene
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• 21 Hospitals/Clinics/CBOs via DOHMH
• 37 Hospitals/Clinics/CBOs via RW funds
• 21 CBOs funded by NY City Council limited testing: only 4,453 tests in FY’08
• 6 CBOs: social network-based testing
From: Blayne Cutler, MD PhD, NYC Dept of Health & Mental Hygiene
NYC External Testing Programs
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Test every Bronx resident who has never been tested (focus on 18-64 y.o) Identify all undiagnosed HIV-positive persons in the Bronx Link all persons who test HIV+ to high quality care and supportive services
“The Bronx Knows” Initiative
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Why the Bronx?Epidemiology In 2006-Almost 25% of all NYC diagnoses in Bronx residents
Over 25% of Bronx residents concurrently diagnosed with HIV and with AIDS
Nearly 1/3 of AIDS-related deaths in Bronx residents
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30.7% Never Tested for HIV, Bronx
Est. Population of the Bronx, 2006: 1.36 M.
Bronx Population, age 18–64 years: 821,000
PLWHA, ages 18–64 yrs: 20,218
No. Adults Eligible for HIV Testing: 800,750
No. Adults To Be Tested for HIV, Bronx: 245,830
How many need to be tested?
Minimum Estimate
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HIV Testing in Washington, DCFrom: Shannon Hader, MD, Washington DC Dept of Health
0.0 - 0.60.7 - 1.21.3 - 1.81.9 - 2.42.5 - 3.0
Population Prevalence
• 15,120 persons reported living with HIV/AIDS in the District as of 12/31/07
• 7,432 new HIV/AIDS cases reported between 2003-2007
• One-third to one-half of people (locally) may be unaware of their HIV status (Source: NHBS data)
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2424
DC HIV/AIDS Prevalence Rates by Race/Ethnicity and Sex, 2007
3.0%
BlackFemales
0.7%HispanicFemales
WhiteMales
WhiteFemales
2.6%
1.0
2.6%
BlackMales
6.5%
Hispanic Males
0.2%
Proportion of DC Residents Diagnosed and Living with HIV/AIDS
% 3.0% Overall DC Prevalence
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2525
HIV Rapid Testing Expansion in DC
68.4% increase in number of tests done
N=43,271 N=72,864
97% of new HIV positives were identified in clinical settings
94% of new HIV positives were identified in clinical settings
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26 26
Time from HIV Diagnosis to Care Entry*
1,340 1,827 1,635 1,502 1,342 1,510
50%
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Key Research Questions in this Field
1. Does an HIV+ person who is treated aggressively transmit less to an HIV(-) sexual partner? HPTN 052
2. Does expanded HIV testing reduce HIV transmission in a given community? HPTN 043
3. Can we engage hard-to-reach populations? HPTN 061 (BROTHERS) and HPTN 064 (ISIS)
4. Should HIV therapy be started earlier than currently recommended? HPTN 052/ACTG 5245 & INSIGHT START
5. Can a combination of expanded testing and bridging to good HIV/AIDS care reduce HIV incidence? “TNT”
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What might we test in TNT?• Any or all of these to make an impact on
community-level HIV incidence:
– Expanded testing and bridging to care• Peer navigators
– Improved adherence counseling and mnemonics within care
• Treatment “buddies”
– Positive prevention messages for persons in care
– Social marketing of prevention messages
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In whom would we measure outcome?
• Seroincidence from sentinel sites– STD clinics? People come for symptoms
– ANC? People come to have babies
– Discard syphilis tests? Mix of routine tests and assessment of risks or symptoms
• Seroincidence from population-based samples– General? MSM? IDU? High risk women?
– National surveys like NHBS as complements to targeted testing
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How would we measure outcome?
• BED-CEIA to screen
– Avidity in BED (+)• Modeling to adjust for ART, VL, CD4
• Acute infection surveillance
• Modeling from changes in seroprevalence among new IDUs and/or adolescents
• Complemented by behavioral surveillance, process/output measures
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Current HPTN StudiesExperimental Designs
Potential Future Studies
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Current HPTN EffortsFeasibility Studies: HPTN061 and 064
BROTHERS: Community-Based, Multi-component
HIV Prevention Intervention for Black MSM
ISISHIV Seroincidence Study in Women
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HPTN Feasibility Studies
Brothers• Feasibility of recruitment
of Black MSM
• Feasibility of recruitment of their sexual/social networks
• Feasibility of HIV testing of index cases and network members
• Feasibility of peer navigation for prevention and care
ISIS• Accurate estimation of
HIV incidence in US women at risk for HIV
• Feasibility of follow-up of cohort of at risk women
• Feasibility of HIV as the primary outcome for prevention study in US women
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Research Design Options
1. Community-level RCT
2. Stepped wedge
3. Factorial
4. Quasi-experiment
1. Pseudo-randomized
2. Before-After
Note: Process indicators would accompany any design
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Proposed Design of BROTHERS-II
Community-level randomization (12 to 30 cities for full RCT)
Package of Interventions• Testing
• Referral and Linkage• Suppression of viral load
Control cities
Venue-based time-space sampling of Black MSM
HIV incidence estimates
Intervention cities
Intervention delivered over 1-2 years
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COMMUNITY LEVEL
Intervention Control Intensive testing Standard testingHIV-Women (individual-level)
Experim. Intervention (combination behavioral
interventions)
Control Intervention
WI-CI WI-CC
WC-CI
WC-CC
ISIS-Plus: Two Level Factorial Design
WI = women’s intervention group, WC = women’s control group CI = Community Intervention group, CC = Community control group,
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Quasi-experimental design
Advantages Intervention Attributes Needed
Disadvantages
- Roll-out approach; more realistic and acceptable politically
- Pseudo-randomization may increase strength of evidence
Cities or areas that could be matched for similar characteristics
Less rigorous than community-randomized trial
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Process/Output Variables will be measured regardless of design
Advantages Intervention Attributes Needed
Disadvantages
- Power issues less daunting
- Builds public health infrastructure
- Standard approach to any program expansion:
# tested,
# bridged to care,
# virally suppressed, “community” VL
- Much less rigorous such that TNT impact question will not be answered
- Standardization challenging
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Modeling
• Build models based on US HIV epidemic
• Assess effectiveness of various interventions over time
• Identify interventions most likely to be effective based on various assumptions
• Model cost effectivenessVariables would include: all program costs, populationproportion tested, treated, suppressed, breaking through, living longer, behaviors as changing over time
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Next Steps
• Establish partnership with CDC, NYC DOH, DC DOH, and others to:
Determine methods to utilize routinely collected data to determine effect of HIV testing and other public health initiatives
Assess various programmatic components
• Continue efforts to determine feasibility of enrollment of prevention cohorts in the US
• Design definitive TNT trial, preparing for anticipated USG investments
• Utilize modeling to assist in choice of interventions and anticipate their effect
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Your CRITICAL comments are most welcome!!
• Wafaa, Ken, and Sten acknowledge… Protocol chairs and investigators
• ISIS and BROTHERS • HPTN 043 and 052
Tom Coates, Jessica Justman, Bernie Branson, Shannon Hader, Blayne Cutler,
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Extra Slides
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Routinely Collected Data(DOHMH-Funded Testing Programs)
• Routinely-collected data for all persons tested (+/-) Tests conducted and tests results Whether previously tested for HIV Self-reported HIV status prior to testing Demographics of persons tested
• Age and Sex (including transgender)• Race, Ethnicity, Zip code
• Additional Data for HIV(+) Persons Risk Factors CD4+ cells and VL
• All results for each individual Concurrent AIDS diagnosis, if any STAHRS-based seroincidence estimates from WBs
• Available Aggregate Data Index of “community VL” Median, mean, range CD4+ cells % linked to care within 3 months % with concurrent AIDS diagnosis % of new diagnoses that are recent infections
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Community-level RCTs
Advantages Intervention Attributes
Needed
Disadvantages
Most rigorous design
Robust and effective intervention(s)
- Politically unpalatable to those assigned to control group
- Control communities will still institute new programs
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Stepped-wedge Community-level RCTs
Advantages Intervention Attributes Needed
Disadvantages
- More politically palatable than traditional community-level trial
- May reduce the likelihood that new interventions will be introduced in the control phase communities
- Robust and effective intervention(s)
- Ability to turn intervention on rapidly and consistently
- Cost in power vs. RCT
- Puts premium on ability to “turn on” the intervention quickly
- Needs more immediate impact than TNT likely to provide
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Two Level Factorial Community RCT Study Design: One example
Expansion of Testing
Earlier Treatment at higher CD4+ cellYES NO
YES Expanded testing with earlier ART
Expanded testing with standard ART
NO Standard testing
with earlier ARTStandard testing with standard ART
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Factorial Community-level RCT
Advantages Intervention Attributes Needed
Disadvantages
Permits identification of efficacy of specific components of an intervention
Interventions that are not dependent on one another
- May increase power needed in both intervention arms, if multiple components of an intervention are additive or multiplicative
- May be unpopular in the standard ¼ group
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Epidemiology of HIV in US: Ethnic and racial disparities
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Epidemiology of HIV in US:Geographic Disparities
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5151
668 692666
780842
992
646
43.3%
46.0%
54.0%
69.7%
30.3%
67.7%
32.3%
62.2%
37.8%
62.9%56.7%
37.1%
66.1%
33.9%
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)