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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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Presentation on theme: "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."— Presentation transcript:

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

2 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

3 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

4 Test and Treat Hypothesis Test Adoption of safer risk behaviors by HIV+ persons Treat with ART + Adherence Maintain viral suppression Decrease in HIV Transmission +

5 In US = Localized into geographic and population hotspotsIn US = Localized into geographic and population hotspots No definitive evidence yet of risk/benefits of early ARTNo definitive evidence yet of risk/benefits of early ART  For treatment: START; HPTN052/ACTG5245  For prevention: HPTN 052/ ACTG5245 Challenges in bridging to care and in long-term maintenanceChallenges in bridging to care and in long-term maintenance  ART adherence and HIV suppression Conceptual Framework █ and obstacles █ for a TNT Strategy Identify HIV (+) persons unaware of their HIV statusIdentify HIV (+) persons unaware of their HIV status Risk reduction among persons testing HIV (+)Risk reduction among persons testing HIV (+) Bridge to care for ARTBridge to care for ART  Eligibility from current guidelines, or  ART for all with HIV infection Maintenance of high ART adherence rates for maximal RNA suppressionMaintenance of high ART adherence rates for maximal RNA suppression Decrease in HIV transmission from virally suppressed personsDecrease in HIV transmission from virally suppressed persons

6 Epidemiology of HIV/AIDS in the US Disparities  in race/ethnicity  in geography  in sexual exposure

7 7 Estimated number of new HIV infections by transmission category, MSM IDU HET *50 States and District of Columbia

8 8 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 Columbia Courtesy of Kevin Fenton, CDC

9 9 American Indian/Alaska Native Asian/Pacific Islander Hispanic Black, not Hispanic White, not Hispanic Estimated AIDS Cases among Adult and Adolescent MSM, by Region and Race/Ethnicity, 2006—50 States and DC ,000 1,500 2,000 2,500 3,000 3,500 NortheastMidwestSouth West No. of cases n=3,220n=2,150n=6,939 n=3,765 Note. The data have been adjusted for reporting delay and cases without risk factor information were proportionally redistributed.

10 10 Estimated HIV/AIDS Cases among MSM, Aged 13–24 years, by Race/Ethnicity, 2001–2006—33 States ,200 1,600 2, Year of diagnosis No. of cases White, not Hispanic Black, not Hispanic Hispanic Asian/Pacific Islander American Indian/Alaska Native 2006 Note. The data have been adjusted for reporting delay and cases without risk factor information were proportionally redistributed.

11 11 Total Tested HIV Prevalence No. % Unrecognized HIV Infection No. % Age Group (yrs) (14)45(79) (17)37(70) (29)83(49) (37)41(30) ≥ (31)11(34) Race/Ethnicity White616127(21)23(18) Black444206(46)139(67) Hispanic466 80(17)38(48) Multiracial 86 16(19) 8(50) Other139 18(13) 9(50) Total1,767450(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

12 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

13 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

14 Persons are being tested in clinical settings Private doctor/HMO 44%53% Hospital, ED, Outpatient 22%18% Community clinic (public) 9% HIV counseling/testing 5% Correctional facility 0.6%0.4% STD clinic 0.1% Drug treatment clinic 0.7%0.4% National Health Interview Survey

15 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 to 23 jurisdictions with the highest number of AIDS cases among Black Americans  Increased to 25 jurisdiction in 2008

16 HIV Testing in NYC

17 FY ’07FY ’08 City-Sponsored Tests: 143,719209,194 (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 12/31/08 From: Blayne Cutler, MD PhD, NYC Dept of Health & Mental Hygiene

18 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 From: Blayne Cutler, MD PhD, NYC Dept of Health & Mental Hygiene

19 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

20  Test every Bronx resident who has never been tested (focus on 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

21 Why the Bronx? Epidemiology In 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

22 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

23 HIV Testing in Washington, DC From: Shannon Hader, MD, Washington DC Dept of Health 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 One-third to one-half of people (locally) may be unaware of their HIV status (Source: NHBS data)

24 24 DC HIV/AIDS Prevalence Rates by Race/Ethnicity and Sex, % Black Females 0.7% Hispanic Females White Males White Females 2.6% % Black Males 6.5% Hispanic Males 0.2% Proportion of DC Residents Diagnosed and Living with HIV/AIDS % 3.0 % Overall DC Prevalence

25 25 HIV Rapid Testing Expansion in DC 68.4% increase in number of tests done N=43,271N=72,864 97% of new HIV positives were identified in clinical settings 94% of new HIV positives were identified in clinical settings

26 26 Time from HIV Diagnosis to Care Entry* 1,3401,8271,6351,5021,3421,510 50%

27 Key Research Questions in this Field 1.Does an HIV+ person who is treated aggressively transmit less to an HIV(-) sexual partner? HPTN Does expanded HIV testing reduce HIV transmission in a given community? HPTN 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”

28 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

29 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

30 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

31 Current HPTN Studies Experimental Designs Potential Future Studies

32 Current HPTN Efforts Feasibility Studies: HPTN061 and 064 BROTHERS: Community-Based, Multi-component HIV Prevention Intervention for Black MSM ISIS HIV Seroincidence Study in Women

33 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

34 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

35 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

36 COMMUNITY LEVEL Intervention Control Intensive testing Standard t esting HIV-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,

37 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

38 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

39 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 effectiveness Variables would include: all program costs, population proportion tested, treated, suppressed, breaking through, living longer, behaviors as changing over time

40 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

41 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,

42 Extra Slides

43 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

44 Community-level RCTs AdvantagesIntervention 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

45 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

46 Two Level Factorial Community RCT Study Design: One example Expansion of Testing Earlier Treatment at higher CD4+ cell YES NO YES Expanded testing with earlier ART Expanded testing with standard ART NO Standard testing with earlier ART Standard testing with standard ART

47 Factorial Community-level RCT AdvantagesIntervention 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

48

49 Epidemiology of HIV in US: Ethnic and racial disparities

50 Epidemiology of HIV in US: Geographic Disparities

51 % 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, (N=4,640)


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