HIV Risk Reduction With Buprenorphine- Naloxone or Methadone: Findings From A Randomized Trial G. 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):

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 Washington VA Puget Sound Health Care System Seattle, WA U10 DA Donovan and Roll (PIs) NIDA Clinical Trials Network: Pacific Northwest Node

Disclosures Supported by National Institute on Drug Abuse Clinical Trials Network Supported by National Institute on Drug Abuse Clinical Trials Network Reckitt Benckiser provided Suboxone Reckitt Benckiser provided Suboxone

Objectives 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. PRIMARY Compare changes in liver enzymes related to treatment with BUP/NX to changes in liver enzymes related to treatment with MET. SECONDARY Identify 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 1920Number screened for participation 1269Randomized 740Buprenorphine/Naloxone529Methadone 340Evaluable 400 Failed to remain on assigned medication for 24 wks 0Failed to provide ≥ 4 LT samples 391Evaluable 136Failed to remain on assigned medication for 24 wks 2Failed to provide ≥ 4 LT samples 261 Completed 32-week follow-up330 Completed 32-week follow-up

Outcome 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/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) Females238 (32.2%)170 (32.1%) Age37.5 (11.2)37.3 (10.9) Injected in past 30 days508 (68.6%)368 (69.6%)

Participant Characteristics BUP/NX (n=740)MET (n=529) Hispanic Ethnicity125 (16.9%)81 (15.3%) White514 (69.5%)392 (74.1%) African American63 (8.5%)47 (8.9%) Other Race163 (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 Opioids81.3 (32.1) (31.6) 100 Cocaine10.7 (23.5) (23.3) 0 Alcohol4.6 (14.8) 05.8 (17.2) 0 Benzodiazepines2.1 (8.5) 01.8 (8.6) 0 Cannabis10.4 (26.5) 08.4 (22.8) 0

Baseline Substance Use % Positive Urine Drug Screen BUP/NX (n=740)MET (n=529) Opiates644 (87.0%)459 (86.8%) Oxycodone103 (13.9%)78 (14.7%) Cocaine252 (34.1%)222 (42.0%) Benzodiazepines141 (19.1%)95(18.0%) Cannabis187 (25.3%)113 (21.4%)

Dosing Highest Dose in mg MeanSDMedian BUP/NX (buprenorphine) MET  % dispensed ranged from 95.1% week 1 to 83.4% week 24  total dose years for BUP/NX  total dose years for MET

Treatment Retention

Opiate Positive UDS (%) GEE Analysis Bup*time χ 2 =92.41, p<.0001

Cocaine Positive UDS (%) GEE Analysis Bup*time χ 2 =40.55, p<.04

HIV Injection Risk Behavior Risk Behavior Survey completed at baseline, week 12, week 24 Risk Behavior Survey completed at baseline, week 12, week 24 Needle Sharing in Past 30 Days among Week 24 Completers: Baseline (%)Week 24 (%)p Bup/Nx (n=340) <.0001 MET (n=391) <.0001

HIV Sexual Risk Behavior Risk Behavior Survey completed at baseline, week 12, week 24 Risk Behavior Survey completed at baseline, week 12, week 24 Multiple Sexual Partners in Past 30 Days among Week 24 Completers: Baseline (%)Week 24 (%)p Bup/Nx (n=340)6.85.2<.04 MET (n=391)8.25.1<.04

Table 2: Injection drug use and needle risk behavior during the last 30 days VariableBUPMETP values a, b Baseline12 wk. FU24 wk. FUBaseline12 wk. FU24 wk. FUTx Time (Visit) Tx*time Mean number of times injected cocaine Mean number of times injected heroin < Mean number of times injected speedball < Mean number of times injected other opiates Mean number of times injected Amphetamines Mean number of times injected Total < % Shared needles < % Didn’t clean shared needles w/ bleach < % Shared cooker < % Front/back load (any) < % Needle risk composite <.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. VariableBUPMETP values c Baseline 12 wk. FU 24 wk. FU Baseline 12 wk. FU 24 wk. FU Tx Time (Visit) Tx*time % Multiple (>1) partners % Unsafe sex (without condom) % Sex risk composite c PROC GENMOD (GEE) for binary variables

Table 4a: Sexual risk behavior for male VariableMale BUPMETP values Baselin e (n=242 ) 12 week FU (n=234) 24 week FU (n=234) Baselin e (n=253) 12 week FU (n=243) 24 week FU (n=245) Tx Time (visit) Tx*tim e % Multiple (>1) partners % Unsafe sex (without condom) % Sex risk composite

Table 4b: Sexual risk behavior for female VariableFemale BUPMETP values Baselin e (n=98) 12 week FU (n=92) 24 week FU (n=96) Baseline (n=138) 12 week FU (n=131) 24 week FU (n=130) Tx Time (visit) Tx*tim e % Multiple (>1) partners % Unsafe sex (without condom) % Sex risk composite

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 Sex risk low in both groups

Summary (continued) Sex risk significantly lower in male methadone patients, but h igher in male bup patients Sex risk significantly lower in male methadone patients, but h igher in male bup patients Consistent with differences in gonadal suppressing effects of methadone vs bup Consistent with differences in gonadal suppressing effects of methadone vs bup For females, sex risk risk significantly lower in both methadone and bup patients 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 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 If consider differential dropout, conclusion is that methadone resulted in better HIV risk reduction Because more methadone pts. stayed in rx 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 If consider only those that stayed in treatment, methadone and bup both produced equal and marked reduction in injecting risk Recommendations for patients? 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 Node Bi-Valley Medical Clinic, and the California/Arizona Node Connecticut Counseling Centers Hartford Dispensary, and the New England Node NET Steps, and the Delaware Valley Node Bay Area Addiction Research & Treatment Matrix Institute, and the Pacific Region Node Addiction Research & Treatment Corp, and the New York Node Medical University of South Carolina - Genetics University of Pennsylvania – Genetics Rutgers Cell and DNA Repository UCLA - Retention Duke Clinical Research Institute (DSC) EMMES Corporation (CCC) & our CCTN liaisons‘ and NIDA Sponsor!