HIV Risk Reduction With Buprenorphine-Naloxone or Methadone: Findings From A

Randomized TrialG. Woody, D. Bruce, P. T. Korthuis, S. Chhatre, M. Hillhouse, P. Jacobs, J.

Sorensen, A. J. Saxon, D. Metzger, W. Ling

Perelman School of Medicine at Univ. of PA; Treatment Research Institute; Yale Univ.; Oregon

Health & Sciences Univ.; Univ. of CA, Los Angeles; Univ. of CA, San Francisco; Veterans Affairs Puget

Sound Health Care System, Seattle, WA

JAIDS 2014; 66(3): 288-293

Protocol: NIDA-CTN-0027

Secondary Analyses of Data from “Starting Treatment with

Agonist Replacement Therapies” (START)

Protocol: NIDA-CTN-0027

Secondary Analyses of Data from “Starting Treatment with

Agonist Replacement Therapies” (START)

Drs. Walter Ling and Andrew Saxon, Lead

Investigators University of WashingtonVA Puget Sound Health Care SystemSeattle, WAandrew.saxon@va.gov206-764-2782

5 U10 DA013714-08 Donovan and Roll (PIs) NIDA Clinical Trials Network: Pacific Northwest Node

Disclosures

Supported by National Institute on Drug Abuse Clinical Trials Network

Reckitt Benckiser provided Suboxone

Objectives of Main StudyObjectives of Main Study

The Food and Drug Administration (FDA) requested a study comparing buprenorphine/naloxone (BUP/NX) and methadone (MET) on indices of hepatic safety.

PRIMARYCompare changes in liver enzymes related to treatment with BUP/NX to changes in liver enzymes related to treatment with MET.

SECONDARYIdentify risk factors at baseline and during treatment that could contribute to interactions with BUP/NX or MET causing liver dysfunction. Assess abstinence from illicit substances. Assess abstinence from alcohol.

START Study Schema

1920 Number screened for participation

1269 Randomized

740 Buprenorphine/Naloxone 529 Methadone

340 Evaluable400 Failed to remain on assigned

medication for 24 wks0 Failed to provide ≥ 4 LT

samples

391 Evaluable 136 Failed to remain on assigned

medication for 24 wks2 Failed to provide ≥ 4 LT samples

261 Completed 32-week follow-up 330 Completed 32-week follow-up

Outcome Measures/AnalysisOutcome Measures/Analysis

• Primary Outcome Changes in liver enzymes (transaminases)

• Primary analysis Descriptive Shift Tables

• ≤2X ULN remain ≤2X ULN• ≤2X ULN then ↑ >2X ULN• >2X ULN then ↓ ≤2X ULN and remain ≤2X ULN• >2X ULN do not ↓ ≤2X ULN or ↑ >2X eligibility value• >2X then ↑ >2X eligibility value

Outcome Measures/AnalysisOutcome Measures/Analysis

• About 10 secondary Outcomes• Among them was HIV risk• Measured by Risk Behavior Survey

• Self-reported injecting and sexual risk behaviors

• Window past 30 days• Done at baseline and at weeks 12 and 24

Participant Characteristics

BUP/NX (n=740)

MET (n=529)

Females 238 (32.2%) 170 (32.1%)

Age 37.5 (11.2) 37.3 (10.9)

Injected in past 30 days

508 (68.6%) 368 (69.6%)

Participant Characteristics

BUP/NX (n=740)

MET (n=529)

Hispanic Ethnicity

125 (16.9%) 81 (15.3%)

White 514 (69.5%) 392 (74.1%)

African American

63 (8.5%) 47 (8.9%)

Other Race 163 (22%) 90 (17%)

Baseline Substance Use

% Reported Days Use Past 4 Weeks

BUP/NX (n=740)M (SD) Median

MET (n=529)M (SD) Median

Opioids 81.3 (32.1) 100

82.5 (31.6) 100

Cocaine 10.7 (23.5) 0

11.6 (23.3) 0

Alcohol 4.6 (14.8) 0

5.8 (17.2) 0

Benzodiazepines 2.1 (8.5) 0

1.8 (8.6) 0

Cannabis 10.4 (26.5) 0

8.4 (22.8) 0

Baseline Substance Use

% Positive Urine Drug Screen

BUP/NX (n=740)

MET (n=529)

Opiates 644 (87.0%) 459 (86.8%)

Oxycodone 103 (13.9%) 78 (14.7%)

Cocaine 252 (34.1%) 222 (42.0%)

Benzodiazepines 141 (19.1%) 95(18.0%)

Cannabis 187 (25.3%) 113 (21.4%)

Dosing

Highest Dose in mg

Mean SD Median

BUP/NX(buprenorphine)

22.3 9.2 24

MET 93.2 43.9 90

% dispensed ranged from 95.1% week 1 to 83.4% week 24175.3 total dose years for BUP/NX197.1 total dose years for MET

Treatment Retention

0

0.2

0.4

0.6

0.8

10 20 40 60 80 10

0

120

140

160

168

Surv

ival

Days in treatment during 24 weeks

Buprenorphine (n=738) Methadone (n=529)

Survival Curves for Buprenorphine Versus Methadone

1

Opiate Positive UDS (%)

GEE Analysis Bup*time χ2=92.41, p<.0001

Cocaine Positive UDS (%)

GEE Analysis Bup*time χ2=40.55, p<.04

HIV Injection Risk Behavior

Risk Behavior Survey completed at baseline, week 12, week 24

Needle Sharing in Past 30 Daysamong Week 24 Completers:

Baseline (%)

Week 24 (%)

p

Bup/Nx (n=340)

14.4 2.4 <.0001

MET (n=391) 14.1 4.8 <.0001

HIV Sexual Risk Behavior

Risk Behavior Survey completed at baseline, week 12, week 24Multiple Sexual Partners in Past 30

Daysamong Week 24 Completers:

Baseline (%)

Week 24 (%)

p

Bup/Nx (n=340)

6.8 5.2 <.04

MET (n=391) 8.2 5.1 <.04

Table 2: Injection drug use and needle risk behavior during the last 30 days

Variable BUP MET P values a, b

Baseline 12 wk. FU 24 wk. FU Baseline 12 wk. FU 24 wk. FU Tx Time(Visit)

Tx*time

Mean number of times

injected cocaine 1.8 1.1 0.77 2.2 1.5 1.2 0.881

30.1861 0.7585

Mean number of times injected heroin

64.6 1.9 2.7 65.3 3.9 4.4 0.6695

< .0001 0.4797

Mean number of times injected speedball

2.3 0.69 0.22 4.1 0.74 0.42 0.5375

< .0001 0.9633

Mean number of times injected other opiates

1.0 0.02 0.01 1.7 0.01 0.02 0.9919

0.0008 0.7064

Mean number of times injected Amphetamines

0.05 0.07 1.9 0.29 0.02 0.22 0.0497

0.6135 0.0363

Mean number of times injected Total

69.7 3.83 5.6 73.5 6.2 6.2 0.8756

< .0001 0.9407

% Shared needles 14.4 2.5 2.4 14.1 2.9 4.8 0.2008

< .0001 0.1029

% Didn’t clean shared needles w/ bleach

10.3 1.8 1.8 9.9 1.6 3.2 0.3692

< .0001 0.3009

% Shared cooker 17.1 2.5 3.0 18.9 4.8 4.5 0.7262

< .0001 0.2959

% Front/back load (any) 21.2 3.1 4.6 20.5 5.9 4.5 0.7049

< .0001 0.5311

% Needle risk composite

25.0 4.2 5.2 24.8 7.2 6.9 0.4022

< .0001 < .1923

a PROC GENMOD (Negative binomial distribution); b PROC GENMOD (GEE) for binary variables

Table 3: Sexual risk behavior during the last 30 days.

Variable BUP MET P values c

Baseline 12 wk. FU

24 wk. FU

Baseline 12 wk. FU

24 wk. FU

Tx Time(Visit)

Tx*time

% Multiple (>1) partners

6.8 7.9 5.2 8.2 4.3 5.1 0.6750 0.0329 0.3539

% Unsafe sex (without condom)

56.5 53.4 58.5 59.9 54.3 54.9 0.1217 0.0544 0.0534

% Sex risk composite

56.5 53.4 58.5 60.4 54.6 55.2 0.0942 0.0425 0.0451

c PROC GENMOD (GEE) for binary variables

Table 4a: Sexual risk behavior for male

Variable Male

BUP MET P values

Baseline (n=242)

12 week FU (n=234)

24 week FU(n=234)

Baseline (n=253)

12 week FU(n=243)

24 weekFU (n=245)

Tx Time(visit)

Tx*time

% Multiple (>1) partners 5.79 8.12 5.13 5.53 3.29 3.27 0.9728 0.1370 0.2931

% Unsafe sex (without condom)

39.26 39.32 44.02 42.29 40.74 41.22 0.2472 0.8370 0.1279

% Sex risk composite 41.32 45.30 47.44 46.25 42.39 44.08 0.1575 0.5554 0.0318

Table 4b: Sexual risk behavior for female

Variable Female

BUP MET P values

Baseline (n=98)

12 week FU (n=92)

24 week FU (n=96)

Baseline (n=138)

12 week FU (n=131)

24 weekFU(n=130)

Tx Time(visit)

Tx*time

% Multiple (>1) partners 9.18 7.61 5.21 13.04 6.11 8.46 0.6989 0.1292 0.9470

% Unsafe sex (without condom)

44.90 42.39 40.63 48.55 41.22 41.54 0.5750 0.1055 0.5598

% Sex risk composite 52.04 46.74 44.79 55.80 45.80 45.38 0.5489 0.0245 0.5433

Summary

BIG and equal reduction in opioid injecting risk in both groups for patients who remained in their assigned condition

Increase in #times amphetamines injected in bup pts.

But, overall level of amphetamine use very low

Sex risk low in both groups

Summary (continued)

Sex risk significantly lower in male methadone patients, but higher in male bup patients Consistent with differences in gonadal

suppressing effects of methadone vs bup For females, sex risk risk significantly

lower in both methadone and bup patients Consistent with reduction in drug use &

leading to less exchanging sex for drugs in females

Summary (continued)

If consider differential dropout, conclusion is that methadone resulted in better HIV risk reduction Because more methadone pts.

stayed in rx If consider only those that stayed in

treatment, methadone and bup both produced equal and marked reduction in injecting risk

Recommendations for patients?

Thanks to the CTN Network that did the trial!

Thanks to the CTN Network that did the trial!

Evergreen Treatment Services, and the Pacific Northwest Node

CODA Inc. and the Oregon Hawaii NodeBi-Valley Medical Clinic, and the California/Arizona Node

Connecticut Counseling CentersHartford Dispensary, and the New England Node

NET Steps, and the Delaware Valley NodeBay Area Addiction Research & Treatment

Matrix Institute, and the Pacific Region NodeAddiction Research & Treatment Corp, and the New York

NodeMedical University of South Carolina - Genetics

University of Pennsylvania – GeneticsRutgers Cell and DNA Repository

UCLA - RetentionDuke Clinical Research Institute (DSC)

EMMES Corporation (CCC)& our CCTN liaisons‘ and NIDA Sponsor!