HIV Infections, Opioid-Related Disorders
Conditions
Keywords
HIV Seronegativity, Opiate Addiction, Opiate Dependence
Brief summary
Drug abuse and HIV/AIDS are serious global health problems. Injection drug use is currently the major mode of transmission of HIV in many countries. The purpose of this study is to determine the effectiveness of drug and risk reduction counseling combined with either substitution drug treatment with buprenorphine/naloxone (BUP/NX) or short-term detoxification with BUP/NX in preventing HIV transmission among injection drug users. Participants will be recruited for this study in China and Thailand.
Detailed description
Effective HIV prevention among injection drug users (IDUs) requires educating the at-risk population about HIV transmission and risky behavior, and providing the means for behavior change. Current treatment for opiate dependence focuses on reducing the frequency of drug use. BUP/NX is a combination pill currently used to treat opiate-dependent individuals. This trial will evaluate the effectiveness of two therapies in preventing HIV transmission among IDUs. Drug and risk reduction counseling combined with either long term medication assisted treatment (LT-MAT) with BUP/NX or short term medication assisted treatment (ST-MAT) with BUP/NX will be compared in preventing the transmission of HIV among opiate-dependent individuals. This study will last 4.5 years. Participants in this study will be randomly assigned to one of two treatment arms. Group 1 will receive LT-MAT with BUP/NX. Group 2 will receive ST-MAT with BUP/NX. An initial 4-week safety and feasibility phase will involve the first 50 participants at each site and will last approximately 30 weeks. Study visits will occur every week and will include a physical exam and blood and urine collection. The main treatment phase of the study will last 52 weeks. Participants in Group 1 will receive BUP/NX under the tongue, at first daily and then three times a week for 52 weeks. Participants assigned to Group 1 will take part in a BUP/NX reduction phase, which will occur between Weeks 47 and 52. Participants in Group 2 will receive short-term BUP/NX; dosage and length of treatment will be determined by the investigator. Participants assigned to Group 2 will receive BUP/NX for a maximum of 18 days; detoxification may be repeated at Week 26 if the participant is still injecting opiates. After Week 4 of the safety phase and Weeks 26 and 52 of the overall study, participants will complete an intervention acceptability assessment. In addition, participants in both groups will attend drug and risk reduction counseling weekly. After the first 12 weeks, participants will return every 4 weeks for 10 more counseling sessions. HIV testing, hepatitis C testing, risk assessment, and urine tests for opiates will occur at screening and at Weeks 26, 52, 78, 104, 130 and 156. Plasma from blood samples will be stored at each of these visits. Hepatitis B testing will occur at Week 26. Participants in China will attend study visits through approximately Week 104, and participants in Thailand will attend study visits through approximately Week 156. Participants in China who have been incarcerated may participate in an optional substudy, which is examining the withdrawal effects from BUP/NX after incarceration. Participants who agree to take part in the substudy will attend one study visit and will complete a questionnaire.
Interventions
DRUGBuprenorphine/Naloxone
Oral tablet
Sponsors
National Institute on Drug Abuse (NIDA)
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* HIV-uninfected within 28 days of enrollment * Meets DSM-IV criteria for opiate dependence * Positive urine test for opiates * Injected opiates at least 12 times in the 28 days prior to enrollment, according to self-report * Willing to use acceptable forms of contraception for the first 12 months of the study * Able to provide contact information and willing to be contacted by study staff as necessary * Available for study visits for at least 2 years
Exclusion criteria
* Current treatment with methadone, morphine, levo-alpha-acetyl-methadol (LAAM), naltrexone, or nalmefene * Currently enrolled in another HIV prevention or drug use intervention study * Known sensitivity to buprenorphine or naloxone * Requires immediate medical attention for dependence on alcohol, benzodiazepines, or other substances. People who are dependent on tobacco are not excluded. * Currently injecting drugs of abuse other than opiates, more than twice in the last 28 days, according to self-report * Psychological disturbance or cognitive impairment that may interfere with the study * Acute or chronic kidney failure * Certain abnormal laboratory values * Any other medical or psychiatric condition that, in the opinion of the investigator, would make participation in this study unsafe * Pregnant or breastfeeding Inclusion Criteria for Substudy: * Current or former participant in HPTN 058 study in Xinjiang who was actively in the long-term treatment arm on stable maintenance dose of Suboxone when detained/arrested (last dose within 2 days of incarceration), resulting in immediate cessation of Suboxone without tapering * Currently released from detention * Willing to complete one-time questionnaire * Willing to sign informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evidence of HIV-1 Infection or Death for Visits up to 104 Weeks | For visits up to week 104 | The primary endpoint for the study was cumulative HIV infection or death after a second year of follow-up (i.e. at week 104), one year after completion of the treatment phase, designed to test a durable intervention effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Self-report of Continued Injection Opiate Use in the Last 30 Days | Measured through Week 104 | All participants completed interviewer-administered assessments of injection and non-injection drug use at baseline and at semi-annual visits. |
| Number of Participants Reported Using Injection Equipment (Needles, Syringes, Cookers, Cottons, and Rinse Water) in the Prior 6 Months | Measured through Week 104 | — |
| Number of Participants With Urinalysis Results Positive for Opiates | Measured through Week 104 | Urine drug screen were assessed monthly and semiannually. |
| Incident Hepatitis C Infections for Thailand and China | Measured through week 156 in Thailand and 104 weeks in China | HCV antibody using two different HCV EIA assays (Ortho HCV antibody version 3.0 and Wantai HCV antibody assay) at baseline and between 26-156 weeks later. If both HCV EIA antibody assays were nonreactive, then the participant was considered not to be HCV infected. If either assay was reactive, then the Ortho HCV assay was repeated in duplicate. If two of 3 Ortho HCV assays were reactive, then the participant was considered to be HCV infected. Samples that were repeatedly reactive for HCV antibody at a follow-up visit were tested for HCV RNA by the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV assay. Not all participants had follow-up testing performed in China due to early closure of the study by the Data Safety Monitoring Board on account of futility due to a low HIV incidence (the primary study endpoint). Analysis was done separately for both countries |
| Incident Hepatitis B Infections | Measured through week 52 | Serum samples were tested at baseline and between 26-52 weeks later for Hepatitis B surface antigen (HBsAg) using a commercial enzyme immunoassay (EIA) (Abbott Murex HBsAg version 3.0). If the HBsAg test was initially non-reactive, then the participant was considered to be negative for HBsAg. If the HBsAg test was initially reactive, then it was repeated in duplicate. If at least two of 3 tests were reactive, then the participant was considered to be positive for HBsAg. |
| Self-reported Number of Injections in the Last Month | Measured through Week 104 | — |
Countries
China, Thailand
Participant flow
Recruitment details
The sites were selected based on prior HIV incidence rates among opiate injectors. At the first scheduled interim analyses, when 25% of the participants had completed 104 weeks on study, the Data Safety Monitoring Board (DSMB) halted the study due to futility as a result of lower than anticipated HIV incidence rates.
Pre-assignment details
The study represented the first use of buprenorphine-naloxone as a treatment for opiate dependence in each community, thus implementation of the study and recruitment of participants included a significant effort devoted to community engagement and education. Each site had an active community advisory board (CAB).
Participants by arm
| Arm | Count |
|---|---|
| Long Term Medication Assisted Treatment (LT-MAT) Participants will receive BUP/NX under the tongue daily for a maximum of three weeks(until dose stabilization) and then three times a week for 52 weeks in addition to weekly drug and risk reduction counseling for 12 weeks, and then every 4 weeks through Week 52
Buprenorphine/Naloxone: Oral tablet | 623 |
| Short Term Medication Assisted Treatment (ST-MAT) Participants will receive short-term BUP/NX; dosage and length of treatment will be determined by the investigator.Additionally, participants will undergo weekly drug and risk reduction counseling for 12 weeks, and then every 4 weeks through Week 52.
Buprenorphine/Naloxone: Oral tablet | 627 |
| Total | 1,250 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Data Safety Monitoring Board (DSMB) halt | 412 | 424 |
Baseline characteristics
| Characteristic | Long Term Medication Assisted Treatment (LT-MAT) | Short Term Medication Assisted Treatment (ST-MAT) | Total |
|---|---|---|---|
| Age, Customized | 33 years | 34 years | 34 years |
| Region of Enrollment China | 522 participants | 527 participants | 1049 participants |
| Region of Enrollment Thailand | 101 participants | 100 participants | 201 participants |
| Sex: Female, Male Female | 49 Participants | 50 Participants | 99 Participants |
| Sex: Female, Male Male | 574 Participants | 577 Participants | 1151 Participants |
| Years of Injection | 7 Years | 7 Years | 7 Years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 623 | 1 / 628 |
| serious Total, serious adverse events | 38 / 623 | 42 / 628 |
Outcome results
Primary
Evidence of HIV-1 Infection or Death for Visits up to 104 Weeks
The primary endpoint for the study was cumulative HIV infection or death after a second year of follow-up (i.e. at week 104), one year after completion of the treatment phase, designed to test a durable intervention effect.
Time frame: For visits up to week 104
Population: Data Safety Monitoring Board (DSMB) halted the study on October 4, 2011 due to futility as a result of lower than anticipated HIV incidence rates. See participant flow section for the number of participants who completed visit up to 104 by July 31, 2012.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Long Term Medication Assisted Treatment (LT-MAT) | Evidence of HIV-1 Infection or Death for Visits up to 104 Weeks | # of HIV infections | 2 participants |
| Long Term Medication Assisted Treatment (LT-MAT) | Evidence of HIV-1 Infection or Death for Visits up to 104 Weeks | # of Deaths | 8 participants |
| Short Term Medication Assisted Treatment (ST-MAT) | Evidence of HIV-1 Infection or Death for Visits up to 104 Weeks | # of HIV infections | 5 participants |
| Short Term Medication Assisted Treatment (ST-MAT) | Evidence of HIV-1 Infection or Death for Visits up to 104 Weeks | # of Deaths | 9 participants |
95% CI: [0.7, 2.8]
95% CI: [1.2, 3.7]
p-value: 0.376995% CI: [0.308, 1.562]Regression, Cox
Secondary
Incident Hepatitis B Infections
Serum samples were tested at baseline and between 26-52 weeks later for Hepatitis B surface antigen (HBsAg) using a commercial enzyme immunoassay (EIA) (Abbott Murex HBsAg version 3.0). If the HBsAg test was initially non-reactive, then the participant was considered to be negative for HBsAg. If the HBsAg test was initially reactive, then it was repeated in duplicate. If at least two of 3 tests were reactive, then the participant was considered to be positive for HBsAg.
Time frame: Measured through week 52
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Long Term Medication Assisted Treatment (LT-MAT) | Incident Hepatitis B Infections | 9 participants with HBsAg |
| Short Term Medication Assisted Treatment (ST-MAT) | Incident Hepatitis B Infections | 0 participants with HBsAg |
95% CI: [1.22, 5.08]
95% CI: [0, 10.1]
Secondary
Incident Hepatitis C Infections for Thailand and China
HCV antibody using two different HCV EIA assays (Ortho HCV antibody version 3.0 and Wantai HCV antibody assay) at baseline and between 26-156 weeks later. If both HCV EIA antibody assays were nonreactive, then the participant was considered not to be HCV infected. If either assay was reactive, then the Ortho HCV assay was repeated in duplicate. If two of 3 Ortho HCV assays were reactive, then the participant was considered to be HCV infected. Samples that were repeatedly reactive for HCV antibody at a follow-up visit were tested for HCV RNA by the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV assay. Not all participants had follow-up testing performed in China due to early closure of the study by the Data Safety Monitoring Board on account of futility due to a low HIV incidence (the primary study endpoint). Analysis was done separately for both countries
Time frame: Measured through week 156 in Thailand and 104 weeks in China
Population: Baseline HCV antibody negative participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Long Term Medication Assisted Treatment (LT-MAT) | Incident Hepatitis C Infections for Thailand and China | 41 participants with HCV antibody |
| Short Term Medication Assisted Treatment (ST-MAT) | Incident Hepatitis C Infections for Thailand and China | 8 participants with HCV antibody |
95% CI: [14.7, 31.6]
95% CI: [2, 9]
Secondary
Number of Participants Reported Using Injection Equipment (Needles, Syringes, Cookers, Cottons, and Rinse Water) in the Prior 6 Months
Time frame: Measured through Week 104
Population: Number of participants presented here applies to whom data available at week 104.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Long Term Medication Assisted Treatment (LT-MAT) | Number of Participants Reported Using Injection Equipment (Needles, Syringes, Cookers, Cottons, and Rinse Water) in the Prior 6 Months | 23 participants |
| Short Term Medication Assisted Treatment (ST-MAT) | Number of Participants Reported Using Injection Equipment (Needles, Syringes, Cookers, Cottons, and Rinse Water) in the Prior 6 Months | 28 participants |
p-value: 0.344695% CI: [0.407, 1.369]Regression, Logistic
Secondary
Number of Participants With Urinalysis Results Positive for Opiates
Urine drug screen were assessed monthly and semiannually.
Time frame: Measured through Week 104
Population: Number of participants presented here applies to visit 104 for whom data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Long Term Medication Assisted Treatment (LT-MAT) | Number of Participants With Urinalysis Results Positive for Opiates | 138 participants |
| Short Term Medication Assisted Treatment (ST-MAT) | Number of Participants With Urinalysis Results Positive for Opiates | 141 participants |
p-value: 0.432595% CI: [0.553, 1.289]Regression, Logistic
Secondary
Self-reported Number of Injections in the Last Month
Time frame: Measured through Week 104
Population: Number of participants presented here applies to whom data available at week 104.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Long Term Medication Assisted Treatment (LT-MAT) | Self-reported Number of Injections in the Last Month | 30 injections |
| Short Term Medication Assisted Treatment (ST-MAT) | Self-reported Number of Injections in the Last Month | 30 injections |
p-value: 0.36295% CI: [0.6477, 1.1718]Generalized linear model
Secondary
Self-report of Continued Injection Opiate Use in the Last 30 Days
All participants completed interviewer-administered assessments of injection and non-injection drug use at baseline and at semi-annual visits.
Time frame: Measured through Week 104
Population: Number of participants presented here applies to whom data available at week 104.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Long Term Medication Assisted Treatment (LT-MAT) | Self-report of Continued Injection Opiate Use in the Last 30 Days | 102 participants |
| Short Term Medication Assisted Treatment (ST-MAT) | Self-report of Continued Injection Opiate Use in the Last 30 Days | 107 participants |
p-value: 0.274995% CI: [0.536, 1.194]Regression, Logistic