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

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

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

Test and Treat Hypothesis

Test

Adoption of safer risk behaviors by

HIV+ persons

Treat with ART+

Adherence

Maintain viral suppression

Decrease in HIV Transmission

+

• 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

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

MSM

IDU

HET

*50 States and District of Columbia

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 ColumbiaCourtesy of Kevin Fenton, CDC

9

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.

10

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.

11

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

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

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

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

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

HIV Testing in NYC

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

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

• 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

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

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

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

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)

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

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

26 26

Time from HIV Diagnosis to Care Entry*

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

50%

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”

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

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

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

Current HPTN StudiesExperimental Designs

Potential Future Studies

Current HPTN EffortsFeasibility Studies: HPTN061 and 064

BROTHERS: Community-Based, Multi-component

HIV Prevention Intervention for Black MSM

ISISHIV Seroincidence Study in Women

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

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

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

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,

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

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

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

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

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,

Extra Slides

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

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

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

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

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

Epidemiology of HIV in US: Ethnic and racial disparities

Epidemiology of HIV in US:Geographic Disparities

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)