HIVNET 015: The Explore Trial

Susan Buchbinder, MDDirector, HIV Research Section

San Francisco Dept. of Public Health

Spread of HIV in sub-Saharan Africa, 1987

Spread of HIV in sub-Saharan Africa, 1987

Estimated percentage of adults

(15–49) infected with HIV

Estimated percentage of adults

(15–49) infected with HIV

16.0% – 32.0%

8.0% – 16.0%

2.0% – 8.0%

0.5% – 2.0%

0% – 0.5%

trend data

unav ailable

outside region

16.0% – 32.0%

8.0% – 16.0%

2.0% – 8.0%

0.5% – 2.0%

0% – 0.5%

trend data

unav ailable

outside regionWorld HealthOrganizationWorld HealthOrganization UNAIDS–Addis–May 1999UNAIDS–Addis–May 1999

Spread of HIV in sub-Saharan Africa,1997

Spread of HIV in sub-Saharan Africa,1997

Estimated percentage ofadults(15–49) infected with HIV

Estimated percentage ofadults(15–49) infected with HIV

16.0% – 32.0% 8.0% – 16.0% 2.0% – 8.0% 0.5% – 2.0%

0% – 0.5%trend data

unavailableoutside region

16.0% – 32.0% 8.0% – 16.0% 2.0% – 8.0% 0.5% – 2.0%

0% – 0.5%trend data

unavailableoutside region

World HealthOrganizationWorld HealthOrganization UNAIDS–Ad dis–M ay 1999UNAIDS–Ad dis–M ay 1999

Prevalence of HIV in US MSMNHBS: MMWR 2005;54:597-601

40

19 18 1824

0

5

10

15

20

25

30

35

40

HIV Prevalence (%)

Baltimore LA Miami NYC SF

HIV Prevalence in South American CitiesS Montano, JAIDS 2005; 40:57-64

Country Number of MSM HIV prevalence

Columbia 660 19.7%

Ecuador 490 14.5% - 27.8%

Peru 7041 13.7%

Bolivia 234 14.6% - 23.7%

Paraguay 92 13.0%

Uruguay 317 21.8%

Argentina 742 15.4%

Estimated number of adults and childrennewly infected with HIV during 2004

Total: 4.9 (4.3 – 6.4) million

Western & Central Europe21 00021 000

[14 000 – 38 000][14 000 – 38 000]

North Africa & Middle East92 00092 000

[34 000 – 350 000][34 000 – 350 000]

Sub-Saharan Africa3.1 million3.1 million

[2.7 – 3.8 million][2.7 – 3.8 million]

Eastern Europe & Central Asia210 000210 000[110 000 – 480 000][110 000 – 480 000]

East Asia290 000290 000

[84 000 – 830 000][84 000 – 830 000]South & South-East Asia

890 000890 000[480 000 – 2.0 million][480 000 – 2.0 million]

Oceania5 0005 000

[2 100 – 13 000][2 100 – 13 000]

North America44 00044 000

[16 000 – 120 000][16 000 – 120 000]

Caribbean53 00053 000

[27 000 – 140 000][27 000 – 140 000]

Latin America240 000240 000

[170 000 – 430 000][170 000 – 430 000]

Estimated US Cases HIV/AIDS by year of diagnosis

33 areas with name-based HIV infection reporting

0

2000

4000

6000

8000

10000

12000

14000

16000

2000 2001 2002 2003

MSM

Hetero

IDU

MSM+IDU

MMWR 2004;53:1106-10MMWR 2004;53:1106-10

Background

• HIV epidemic throughout Americas (except parts of Caribbean) most concentrated in MSM HIV prevalence 10-30%; HIV seroincidence 2-4%

despite ongoing risk reduction counseling

• Biomedical interventions (vaccines, PREP, STD rx, microbicides) being developed, but still years away

• Behavioral interventions needed both as stand-alone and to complement biomedical interventions

EXPLORE

• First behavioral intervention powered to address impact of intensive intervention on HIV seroincidence

• “Cadillac version” of behavioral intervention intended to maximize effects, likelihood for success

• Use of ACASI to get most accurate measures of risk, correlate change in risk with change in seroincidence

Study Design

• Multi-site “RCT” (randomized controlled trial) efficacy trial

• Eligibility: (range of risk behaviors) Male, > 16 yo Any anal sex with man in last year Not in mutually monogamous relationship > 2 yrs

• Intervention 10 individualized sessions w/ boosters q 3 mos

• Control Project Respect risk reduction counseling q 6 mos

Intervention modules

Modules Content

1-3 Introductory and individual risk assessment, provide basic risk reduction skills

4-5 Sexual communication (serostatus, facilitators/barriers)

6 Sex, drinking and drugs

7-9 Triggers for risk (places/events, partners, emotions)

10 Maintenance plan

Measurements

• HIV antibody q 6 months

• Interviewer administered Demographics STD history

• ACASI (audio computer-assisted self interview) Sexual risk Drug use

Outcomes

• Primary endpoint: HIV infection rates

• “Phase IIB” or screening efficacy trial If efficacy < 10%, discard or reformulate If 10-35%, plausibly efficacious, more study If > 35%, efficacious & implement

• Because Phase IIB are smaller than full efficacy trial, less precision in measure

Enrollment by site

Site N

Boston 729

Chicago 624

Denver 726

New York 737

San Francisco 736

Seattle 743

Recruitment Sources

Source %

Clubs, bars, public venues 23

Advertisements 15

Mailings 14

Friend/acquaintances 13

Street outreach 11

Clinics, MDs 10

Other studies, CBOs, forums 14

Baseline Demographics Intervention Standard N % N % p-value Age (years) 16-19 43 2 50 2 0.97 20-25 359 17 362 17 26-30 450 21 463 22 31-35 458 21 452 21 36-40 376 18 379 18 >40 458 21 445 21 Race/ethnicity White 1559 73 1553 72 0.77 Latino 322 15 330 15 Black 131 6 150 7 Asian/Pacific Isl. 63 3 53 2 Native American 17 1 14 1 Other/unknown 52 2 51 2

Baseline Partners

In last 6 months: Intervention StandardN % N % p-value

No. male partners 0 25 1 17 1 0.26 1 142 7 164 8 2-5 678 32 704 33 6-9 393 18 357 17 >10 904 42 908 42

Female sex partner 86 4 92 4 0.66

HIV+ male partner 595 28 620 29 0.43

Baseline Sexual Practices

In last 6 months Intervention (%)

Standard

(%)

P value

Unprotected receptive anal 48 49 .47

Unprotected insertive anal 53 57 .04

Unprotected anal with HIV positive or unknown partner

47 49 .16

Unprotected receptive anal with HIV+/unknown partner

28 29 .74

Adherence to initial sessions

No. of initial session-modules % completing

0 1

1-3 12

4-6 5

7-9 7

10+ 75

Retention

Months Intervention (%) Standard (%) P value

6 93.0 95.5 .0003

12 93.0 95.5 .0003

18 91.4 94.1 .0005

24 89.9 93.2 .0001

30 88.9 91.9 .0003

36 87.3 90.4 .0054

42 86.0 89.9 .0065

48 85.8 91.8 .0062

RetentionGroup Final visit retention (%)

Race/ethnicity

White 89.5

Af-Am/Latino/API/NAm/oth 83.9

Age (years)

< 25 80.0

26+ 89.8

Female partners

No 88.5

Yes 74.2

Unprotected anal

No 89.0

Yes 86.7

Intervention sessions completed

<9 63.6

9+ 92.2P<0.05 for all comparisons

HIV SeroincidenceOverall seroincidence = 2.1 (1.9, 2.4) per 100 py

Pe

rce

nt f

ree

of H

IV

0.9

00

.92

0.9

40

.96

0.9

81

.00

Months 6 12 18 24 30 36 42 48

OR 0.67 0.61 0.83 1.17 0.73 1.32 0.75 1.05

.918

.931

OR 0.67 0.61 0.83 1.17 0.73 1.32 0.75 1.05

Intervention

Control

Efficacy: 18.2% (-4.7, 36.0)

Adj Efficacy: 15.7% (-8.4, 34.4)

Pre-set cutpoints for efficacy

• Efficacy 18.2% (95% CI: -4.7 to 36%)

• Adjusted efficacy 15.7% (95% CI: -8.4 to 34.4%)

• If lower bound 95% CI > 10%: declare efficacious Didn’t meet this cutpoint

• If upper bound 95% CI < 35%: no substantial efficacy Meet cutpoint to say no efficacy?

Sexual behavior outcomes: UA, SDUA & SDURA

Unadjusted AdjustedEfficacy Efficacy

In last 6 months: (95% CI) (95% CI)

Unprotected anal(UA)

13.9(5.6, 21.5)

13.2(4.8, 20.9)

Unprotected analwith +/unk. statuspartner (SDUA)

14.8(6.5, 22.4)

13.2(4.8, 20.9)

Unprotectedreceptive anal with+/unk. status partner(SDURA)

20.5(10.9, 29.0)

22.5(13.3, 30.7)

Surrogate True ClinicalEndpoint OutcomeDisease

True ClinicalOutcome

SurrogateEndpoint

Disease

Time

Surrogate HIV Endpoint Infection

Intervention

Risk

HIVInfection

SurrogateEndpoint

Risk

Intervention

Time

Self reported HIV6 mo. UA effects Infection

Intervention

Risk

• Potential Differences between self reported risk behaviors and true risk behaviors

• Alternative Pathways for risk of HIV infection

• Durability of effect

Time

Conclusions

• First study of impact of behavioral intervention for MSM on HIV seroincidence

• Recruitment of large cohort, excellent retention

• Modest reduction in HIV seroincidence Can rule out substantial efficacy At cusp between discarding and pursuing further

• Significant reduction in self-reported risk behaviors Implications for using self-reported risk as endpoint in

intervention trials?

Future directions

• Rationale for further analysis and modification Significant reduction in risk Possibility of early effects Likelihood that control condition exceeds usual care

• Precautions Problems retaining young, diverse, risky MSM Unwieldy intervention

• Plans for exploratory analyses Subgroup analyses Focus groups w/ men of color Many other analyses (HSV2, HHV8, risk factors for infection)

Explore Study Team

• Co-chairs: Margaret Chesney Thomas Coates Beryl Koblin

• Site Principal Investigators Susan Buchbinder/Grant

Colfax Connie Celum Frank Judson Beryl Koblin Ken Mayer David McKirnan