HPTN Test and Treat (TNT)

1. Design Issues and Implications for a Domestic Research Agenda Sten Vermund, Wafaa El-Sadr, Kenneth Mayer on behalf of the HPTN HPTN Test and Treat (TNT)

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 hotspots No 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 maintenance ART adherence and HIV suppression Conceptual Framework █ and obstacles █ for a TNT Strategy Identify HIV (+) persons unaware of their HIV status Risk reduction among persons testing HIV (+) Bridge to care for ART Eligibility from current guidelines, or ART for all with HIV infection Maintenance of high ART adherence rates for maximal RNA suppression Decrease 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. Estimated number of new HIV infections by transmission category, 1977-2006 *50 States and District of Columbia MSM IDU HET

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 Courtesy of Kevin Fenton, CDC *50 States and District of Columbia

9. White, not Hispanic Black, not Hispanic Hispanic Asian/Pacific Islander American Indian/Alaska Native Estimated AIDS Cases among Adult and Adolescent MSM, by Region and Race/Ethnicity, 2006—50 States and DC 3,500 3,000 2,500 2,000 No. of cases 1,500 1,000 500 0 West Northeast Midwest South n=3,765 n=3,220 n=2,150 n=6,939 Note. The data have been adjusted for reporting delay and cases without risk factor information were proportionally redistributed.

10. Estimated HIV/AIDS Cases among MSM, Aged 13–24 years, by Race/Ethnicity, 2001–2006—33 States 2,000 1,600 1,200 Black, not Hispanic No. of cases 800 White, not Hispanic Hispanic 400 Asian/Pacific Islander American Indian/Alaska Native 0 2001 2002 2003 2004 2005 2006 Year of diagnosis Note. The data have been adjusted for reporting delay and cases without risk factor information were proportionally redistributed.

11. HIV Prevalence Among 1,767 MSM, by Age Group and Race/Ethnicity—Baltimore, LA, Miami, NYC, San Francisco 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) Unrecognized HIV Infection No. % HIV Prevalence No. % Total Tested Race/Ethnicity White 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) 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 - 2006 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. 2007 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. 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% From: Blayne Cutler, MD PhD, NYC Dept of Health & Mental Hygiene NYC DOHMH BHIV Testing Unit, data reported as of 12/31/08

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. 2008 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 NYC External Testing Programs From: Blayne Cutler, MD PhD, NYC Dept of Health & Mental Hygiene

20. “The Bronx Knows” Initiative • 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

21. 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

22. How many need to be tested? 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 30.7% Never Tested for HIV, Bronx No. Adults To Be Tested for HIV, Bronx: 245,830 Minimum Estimate

23. HIV Testing in Washington, DC From: Shannon Hader, MD, Washington DC Dept of Health • 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) Population Prevalence 0.0 - 0.6 0.7 - 1.2 1.3 - 1.8 1.9 - 2.4 2.5 - 3.0 2009 PREVIEW

24. DC HIV/AIDS Prevalence Rates by Race/Ethnicity and Sex, 2007 6.5 % 1.0 % 3.0 Overall DC Prevalence White Females 0.2% Hispanic Females 0.7% Black Females 2.6% White Males 2.6% Hispanic Males 3.0% Black Males 6.5% 24 2009 PREVIEW Proportion of DC Residents Diagnosed and Living with HIV/AIDS

25. HIV Rapid Testing Expansion in DC N=43,271 N=72,864 68.4% increase in number of tests done 97% of new HIV positives were identified in clinical settings 94% of new HIV positives were identified in clinical settings 2009 PREVIEW 25

26. Time from HIV Diagnosis to Care Entry* 1,340 1,827 1,635 1,502 1,342 1,510 50% 2009 PREVIEW 26

27. Key Research Questions in this Field • Does an HIV+ person who is treated aggressively transmit less to an HIV(-) sexual partner? HPTN 052 • Does expanded HIV testing reduce HIV transmission in a given community? HPTN 043 • Can we engage hard-to-reach populations? HPTN 061 (BROTHERS) and HPTN 064 (ISIS) • Should HIV therapy be started earlier than currently recommended? HPTN 052/ACTG 5245 & INSIGHT START • 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 EffortsFeasibility Studies: HPTN061 and 064 BROTHERS: Community-Based, Multi-component HIV Prevention Intervention for Black MSM ISISHIV Seroincidence Study in Women

33. HPTN Feasibility Studies Brothers 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 • 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

34. Research Design Options Community-level RCT Stepped wedge Factorial Quasi-experiment Pseudo-randomized 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) Intervention cities Intervention delivered over 1-2 years Control cities Venue-based time-space sampling of Black MSM • Package of Interventions • Testing • Referral and Linkage • Suppression of viral load HIV incidence estimates

36. 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

38. Process/Output Variables will be measured regardless of design

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

45. Stepped-wedge Community-level RCTs

46. Two Level Factorial Community RCT Study Design: One example

47. Factorial Community-level RCT

49. Epidemiology of HIV in US: Ethnic and racial disparities

50. Epidemiology of HIV in US:Geographic Disparities