A Pilot Implementation Project of Methadone and Suboxone® for Injecting Drug Users in Ho Chi Minh City, Vietnam
Phase: PHASE4
Conditions: Opioid Use Disorder, HIV Infections
Sponsor: University of Pennsylvania

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Protocol 
 
Title of the project: A Pilot Implementation Project of Methadone and Suboxone® for 
Injecting Drug Users in Ho Chi Minh City, Vietnam 
 
Grant Reference: R01- DA033671-01  
 
PI: Charles O'Brien, MD, PhD - University of Pennsylvania, PA, USA 
Co-PI: Le Truong Giang, MD, PhD - HCMC AIDS Committee 
 
Investigators 
Jean-Pierre Daulouède, MD, Bizia, Bayone, France 
David Metzger, PhD, University of Pennsylvania, PA, USA 
Vincent Trias, Expertise France, Paris  
Lisa Huang, MD, Expertise France, Paris 
 
Project director at the University of Pennsylvania: Cécile Denis, PhD 
 
Project period:  AUG- 01- 2012 to JUL- 31-2017 

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Abstract 
HIV continues to spread around the world and new infections in Asia are one of the most 
important areas for prevention among drug using populations.  There is strong and consistent 
evidence from several countries that while injection drug users (IDU) continue to be a source 
of new infections, treatment of opiate addiction is an effective prevention measure against 
further spread.  Among those IDU already infected, substance abuse treatment can improve 
access and adherence to HAART therapy and promote sustained viral suppression.  The 
proposed project will take place at the Go Vap HIV clinic in Ho Chi Minh City (HCMC), 
Vietnam.  Vietnam is an original PEPFAR country and has experienced a major HIV 
epidemic that has been propelled by injection drug use.  While the country has begun the scale 
up of methadone maintenance treatment (MMT), coverage remains inadequate and the rate of 
expansion of new treatment programs clearly needs to be accelerated to have meaningful 
impact on the epidemic.  For heroin (and other opiate) dependent individuals, methadone 
maintenance has limited availability and there are currently no buprenorphine/naloxone 
(Suboxone®) treatment programs in Vietnam.  This newer medication has the possibility of 
making treatment available to more patients because of the efficiency of three times per week 
dosing and given the high prevalence of HIV among drug users in HCMC, fewer interactions 
with antiretroviral medications.  The current project will support and evaluate the expansion 
of drug treatment to both HIV positive and negative IDUs as a model prevention program.  
The project will begin with the implementation of a comprehensive training program on 
addiction and Medication Assisted Treatment (MAT).  Following this training the project will 
introduce MMT at the Go Vap clinic.  At month 18, daily methadone will continue to be 
available and new patients will be given the opportunity to be treated with Suboxone® 
progressing from daily to thrice weekly observed treatment.  All participants also will be 
engaged in behavioral drug and risk counseling. During the project, the study project enrolling 
up to 500 IDUs into MAT treatment program co-located with the Go Vap clinic.  The 
investigators are not proposing a comparison between methadone and Suboxone®.  Both are 
safe and effective medications.  The project will demonstrate feasibility and evaluate 
participant, clinic, and community factors that promote or inhibit program implementation.  
The study will measure costs and identify factors that are associated with treatment success 
for each medication and for positive and negative participants. Importantly, the program is 
being implemented in partnership with the Provincial AIDS Committee of HCMC and will 
contribute to their goal of expanding access to both drug abuse and HIV treatment. 
 
Objectives 
Overall objectives 
The proposed project will evaluate the implementation of a Medication Assisted Treatment 
(MAT) program (both methadone and buprenorphine/naloxone) integrated within an HIV 
treatment setting.  This will be the first project to establish and evaluate the implementation a 
buprenorphine/naloxone (Suboxone®) treatment program in Vietnam.  Following project 
start-up, the investigators will enroll a total of up to 500 injection drug users using structured 
community-based outreach strategies.  All subjects will be enrolled in the integrated MAT 
program that will include drug and risk counseling, and for those who are HIV positive, HIV 
treatment.  At one year following enrollment, participant’s treatment success will be assessed 
based upon retention in MAT treatment, continued drug use, criminal behavior and 
employment. For those who are HIV positive the study will also assess medication adherence 
and suppressed HIV viral load.  The study will carefully assess barriers to implementation 
and, using qualitative methods, measure awareness and perceptions of the program among 
local community-based organizations, governmental agencies, and drug users.  The 

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medication assisted treatments will use well established protocols and will be monitored by 
investigators from the HCMC team, EXPERTISE FRANCE and University of Pennsylvania 
Center for Studies of Addiction (PennCSA).  
Importantly, the work represents a collaboration between the Provincial AIDS Committee 
(PAC) of HCMC, EXPERTISE FRANCE, the French led initiative to expand access to HIV 
prevention and treatment services, and the PennCSA all of whom will support the 
implementation and evaluation to be done by the HCMC clinical and research team.  The goal 
of this collaboration will be to conduct implementation research in a resource limited setting 
with a high prevalence of intravenous drug use and HIV infection.  The current project 
proposes to establish the feasibility of the use of Suboxone®.  Primary measures will consist 
of facilitators and barriers to implementation and retention in MAT generally and Suboxone® 
treatment specifically.  The following specific aims will be evaluated: 
• Establish a new integrated MAT treatment program within and HIV 
treatment setting in HCMC. 
• Evaluate barriers and facilitators to implementation of integrated 
MAT/HIV treatment. 
• Evaluate patient retention and medication adherence in integrated 
MAT/HIV Care. 
• Estimate the costs and benefits of MAT treatment strategies.  
 
Primary outcome variable(s) 
1) Qualitative assessment: acceptability, barriers, and facilitators to implement medication-
assisted treatment for opiate addiction within an HIV-treatment setting; 2) Treatment retention 
at 6 and 12-month follow-ups; 3) Treatment adherence: Methadone, Suboxone®, HIV 
treatment, counseling sessions; 4) Cost-effectiveness ratios calculated at the end of the study 
 
Secondary outcome variable(s) 
1) Drug use and severity of addiction assessed by the ASI scores; 2) Risk taking behaviors: 
scores from the RAB at 6 and 12-month follow-ups 
 
 
Background 
The significance of the proposed study lies in its focus on providing data that can be used to 
facilitate and expand the public heath response to a very serious epidemic of HIV/AIDS 
among opiate dependent drug users in Ho Chi Minh City (HCMC), Vietnam.  As described 
below, Vietnam is experiencing a significant AIDS epidemic fueled in large part by injection 
drug use.  An important component of the response to this epidemic has been the initiation 
and initial scale up of methadone treatment.  The significance of the proposed project lies in 
the potential to demonstrate strategies that can help to expand an integrated HIV and drug 
treatment system in Vietnam and to contribute to the attainment of the country’s national plan 
for HIV prevention.  The proposed project will carefully evaluate the implementation of a 
Medication Assisted Treatment (MAT) program that is fully integrated with PEPFAR 
supported HIV treatment.  The project will also be the first to evaluate the feasibility and 
acceptability of buprenorphine/naloxone treatment in Vietnam.  
Clearly, the significance of the work is rooted in the AIDS epidemic in Vietnam.  HIV 
prevalence in Vietnam is estimated at 0.53% (WHO) and the number of PLWHAs reported is 
290,000 (UNAIDS 2009).  Vietnam is still at a concentrated stage with a high HIV prevalence 
amongst injecting drug users (IDUs) and female sex workers (FSWs).  As a result, Vietnam’s 
national prevention strategy focuses on harm reduction pilot interventions targeting drug 

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injection and high-risk sex. Current interventions include education, needle and syringe 
exchange programs, social marketing of condoms, voluntary counseling, and testing, and STI 
diagnosis and management. Methadone maintenance therapy (MMT) for IDUs started as a 
pilot program in 2008 in Haiphong and HCMC, two of the highest prevalence provinces for 
injecting drug use.  In HCMC, where 51.8 % of IDUs are HIV positive (HCMC Provincial 
Aids Committee PAC, 2009), MMT pilot program started in three districts in May 2008 
(district 4, 6 and Binh Thanh).  On December 2009, 784 patients were under MMT and 235 
were receiving ARV.  30% of patients under MMT are HIV+ (HCMC PAC, 2009).  A 
conference held in HCMC on July 2009 concluded positively on the results of the pilot 
program in terms of 1) Improvement of drug adherence for patients receiving ART; 2) 
Improvement of social rehabilitation; and, 3) Decrease in drug use (heroin) and risk of HIV 
transmission.  According to interviews conducted and information provided by HCMC health 
authorities, there are around 15,000 active drug users in the City. Heroin appears to be the 
main drug used but opium is also widely consumed (mostly among (“old addicts”) and there 
is a rapid spread of methamphetamine use, frequently through intravenous (IV) route.  
Consequently, the HIV transmission rate due to needle sharing is high.  Between 50% and 
70% of drug users are also infected with HCV and an elevated rate of tuberculosis has been 
reported.  
 
To date, there has been no large-scale expansion of drug treatment or harm reduction 
programs for drug users.  Compulsory admission to a rehabilitation center is still the main 
method used by Vietnamese authorities to fight against drug use and nationally, about 20,000 
persons are currently enrolled in such centers.  However, five pilot outpatient clinics (OPC) 
with access to methadone have been recently opened in HCMC, with the technical assistance 
of CDC and Family Health International (FHI) and funding from the American President’s 
Emergency Plan for AIDS Relief (PEPFAR).  For the past three years EXPERTISE 
FRANCE, the French led initiative to expand access to HIV prevention and treatment 
services, has been working with Government and Non-Government Organizations in Vietnam 
to establish an integrated HIV/drug treatment capacity.  The PI of this application (O’Brien) 
has worked closely with many of the investigators from the EXPERTISE FRANCE group for 
over 20 years and his Center, the Penn Center for Studies of Addiction has been a leader in 
conducting and participating in research to show that drug treatment is HIV prevention 
(Metzger, Woody, and O’Brien, 2010).  
 
Drug Treatment as HIV Prevention 
 
The research literature of the past 20 years provides a strong “proof of concept” that 
methadone treatment is an effective HIV prevention intervention. Specifically, individuals 
who participate in methadone treatment have been found to significantly reduce the frequency 
of their opiate use (Haverkos 1998; Hubbard et al. 1989; Ball et al. 1988; Ball and Ross 1991; 
Hubbard et al. 1997; Gowing et al. 2006; Hartel et al. 1998; Lawrinson et al. 2008;).  This 
finding has been observed when methadone patients have been compared to their community 
counterparts who are not in treatment (Capplehorn and Ross 1995; Metzger et al. 1993; Qian 
et al. 2008) and when patient’s opiate use during treatment has been compared to their pre- 
and post-treatment use (Ball et al. 1988).  Further, significantly lower rates of opiate use have 
been observed when patients with regular methadone program attendance have been 
compared to those with poor attendance (Wong 2003), and when patients receiving minimal 
ancillary services were compared to those receiving more intensive services (McLellan et al. 
1993; Avants et al. 1999).  Consistent with the observed reductions in opiate use, available 
data suggests that methadone patients participate in 40 to 60 percent fewer instances of opiate 
injection and needle sharing events.  This finding has been reported in cross-sectional, 
prospective and retrospective designs comparing methadone patients to heroin users who are 

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not in treatment (Hubbard et al. 1997; Capplehoren and Ross 1995; Booth et al. 1996; 
Kwiatkowski 2001; Qian et al. 2008) and in studies focused on measuring changes in cohorts 
of methadone patients during treatment (Avants et al 1999; Gossop et al. 2002).  Findings 
have also been reported showing significantly lower rates of injection among patients who 
remain in treatment when compared to patients who left treatment (Metzger et al. 1993; 
Thiede et al. 2000).  Perhaps most importantly, from a public health perspective, research has 
documented strong associations between methadone participation and lower rates of HIV 
prevalence and incidence.  Heroin users who remained in methadone treatment during periods 
of rapid HIV transmission in their surrounding communities were found to have a 
dramatically lower prevalence of infection (CDC 1984; Novick et al. 1986; Barthwell 1989; 
Novick et al. 1990; Blix et al. 1991).  HIV prevalence rates have also been correlated with 
length of time in treatment.  In both prospective and retrospective studies, the incidence of 
new HIV infections has been found to be significantly associated with participation in 
(Metzger et al. 1993; Hartel et al. 1998; Wong et al. 2003) and duration of, methadone 
treatment (Moss et al. 1990; Serpelloni et al. 1994; Hartel et al. 1998).  Although no 
randomized controlled trials have yet been conducted (due primarily to ethical concerns 
regarding the random assignment of individuals to no treatment or other treatment 
modalities), the consistency of findings from the observational and case controlled studies 
cited here provide a preponderance of evidence suggesting that sustained treatment with 
methadone is strongly associated with protection from HIV infection (Metzger et al. 1998; 
Sorensen et al. 2000; Farrell et al 2005; Sullivan et al. 2005; Metzger et al. 2010).   
 
ARV Treatment as HIV Prevention 
 
The second tool to reduce HIV transmission among drug users is the use of HAART.  
Indeed, an undetectable viral load is associated with a very low risk of HIV transmission.  
Recent results (Wood et al 2009) have shown a dramatic decrease in HIV transmission in the 
community of drug users where a high coverage of ART was reached. Therefore, there is a 
consensus on the positive impact of linking MAT and HAART in the treatment of HIV-
infected drug addicts (Roux et al. 2008; Roux et al. 2009).  The treatment of addiction leads to 
a significant improvement in adherence, with ARV adherence being required for antiviral 
efficacy and reduction of transmission.  In this respect, the objective of HCMC health 
authorities to improve and expand access to opiate substitution treatment is extremely 
important and supported by data. 
 
Medication Assisted Treatment for opiate addiction 
 
The current project will evaluate the implementation of methadone and Suboxone®.  
Our work is guided by an understanding that no single treatment strategy can meet the needs 
of all opiate dependent drug users.  The investigators believe methadone to be a safe and 
effective method for MAT when prescribed by trained clinicians and in conjunction with 
meaningful counseling.  However, the exclusive use of methadone has several drawbacks.  
First, its full agonist effect raises overdose risks, especially in a context of poor access to drug 
treatment.  This lack of access to treatment can increase the likelihood of diversion and fatal 
overdoses.  Secondly, the metabolic interactions of methadone with ARVs may decrease the 
effectiveness of methadone by decreasing methadone blood levels and requiring significantly 
higher methadone dosages to achieve effects equal to those without ARVs.  Finally, as 
mentioned earlier, it is a medication that requires daily administration.   For these reasons, it 
would be most useful to complement the current system of care with buprenorphine/naloxone 
(Suboxone®).  Buprenorphine, a partial agonist with a ceiling effect of agonist activity and a 
partial antagonist effect (on kappa receptors), reduces considerably the overdose risks (2). The 
addition of naloxone (full opiate antagonist) to buprenorphine leads to a major decrease in 

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misuse, especially in a population that almost exclusively uses full agonists (heroin, opium):  
injection or snorting of Suboxone® causes very unpleasant opioid withdrawal syndromes, 
discouraging diversion. On the opposite, when buprenorphine is used sublingually, as it 
should, naloxone is not absorbed, and buprenorphine exerts its full substitution effect.  
Suboxone® has also been shown to have fewer interactions with ARV medications and 
requires fewer dose adjustments when the medications are taken together.  Finally, another 
important characteristic of Suboxone® is that it allows for three times per week dispensation 
instead of daily administration, reducing the staff and infrastructure needs as well as the costs. 
 
Behavioral Drug and Risk Counseling  
Behavioral Drug and Risk Counseling (BDRC) was developed in 2005 by Marek Chawarski, 
Ph.D., and colleagues at Yale University.  This approach is rooted in evidence-based 
cognitive behavioral counseling approaches and is highly structured, manual driven, and 
prescriptive, and focuses on a limited set of immediate problem areas.  In BDRC, the 
counselor guides the participant through the initial stages of the recovery process.  The 
counselor does this by using explicit contracting procedures to engage the participant in a 
comprehensive recovery program that involves medication, counseling, clean and sober 
activities, and lifestyle changes that promote sustained abstinence.  Additional prescriptive 
BDRC components include education about opiate addiction as a chronic medical condition 
and optimal use of all treatment components (e.g., sessions or meetings with counselors, 
doctors, nurses) and other available resources (e.g., psychiatric, medical, social work, 
community resources) to maximize the effectiveness of the treatment.  Finally, BDRC puts 
strong emphasis on HIV prevention including education about drug- and sex-related HIV 
risks and effective HIV prevention strategies.  BDRC combines behavioral contracting with 
an Information-Motivation-Behavioral Skills (IMB) model for reducing HIV risk behaviors 
and illicit drug use that is grounded in social cognitive theory (Bandura 1997) and supported 
by empirical findings in numerous studies and populations (Avants et al. 2004; Carey et al. 
2000; Peipman et al. 2001; Bryan et al. 2000; Fisher and Fisher 2000; Fisher et al. 1999; 
Kalichman et al. 2001; Carroll et al. 2004).  The intensive HIV risk reduction interventions 
provided in BDRC, that includes a personalized assessment of risk (i.e., identification of 
personal, social and environmental factors associated with risky behaviors) in conjunction 
with education and training in skill-building and self-control, may lead to greater reductions 
in both drug and sex related HIV risk behaviors than the more limited, brief counseling 
provided in many clinics, as supported by findings of a recent clinical trial with methadone 
maintained patients (Sorensen and Copeland, 2000) and a meta-analysis regarding the 
effectiveness of HIV risk reduction interventions during drug abuse treatment (Pendergast et 
al, 2001).  BDRC emphasizes a medical model of treatment for drug dependence and is highly 
complementary to and compatible with regular MAT.  Because early abstinence achievement 
is associated with longer term treatment success, BDRC uses short-term behavioral contracts 
to help the patient achieve an initial period of abstinence, take maintenance medications 
regularly, and as prescribed, activate the patient behaviorally to reduce behaviors associated 
with HIV transmission (Schottenfeld et al. 2005).  The accomplishment of specific, short-term 
behavioral goals early in treatment promotes the patient's experience of therapeutic success 
and counters the patient's belief that his/her actions will not lead to success in accomplishing 
goals.  Short-term behavioral goals target a limited number of domains, including achieving 
an initial period of abstinence, increasing activities (primarily vocational, social, or 
recreational) that are not related to drug use, and reducing HIV risk behaviors (e.g., fostering 
consistent condom use, avoiding casual sexual encounters, avoiding IDU or needle or 
equipment sharing) (Chawarski et al. 2003).  BDRC teaches cognitive and behavioral 
strategies for promoting behavioral change, including identifying antecedents of drug use, 

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needle sharing, and high-risk sexual behaviors, and learning strategies to avoid high risk 
situations or cope without engaging in these behaviors.  Skill building exercises (e.g., 
regarding condom use) are used within sessions to learn and practice new skills, and patients 
are encouraged to practice these skills outside the session in their natural environment (Avants 
et al. 2004; Margolin et al. 2003; Kamb et al. 2000; NIMH MHPT 2000; Carroll et al. 1997).  
Findings addressing the efficacy of BDRC are beginning to emerge in the literature.  Of 
relevance to this application is a pilot study of BDRC enhanced treatment in Malaysia 
(Chawarski et al, 2007). After a 2-week buprenorphine induction and stabilization period, 
heroin dependent individuals (n= 24) in Muar, Malaysia were randomly assigned to Standard 
Services (physician administered advice and support, and weekly, non-contingent medication 
pick-up) or BDRC enhanced services (nurse delivered, manual-guided BDRC, and 
abstinence-contingent take-home buprenorphine).  Both groups significantly reduced HIV risk 
behaviors during treatment (p< 0.05), and the proportion of opiates-negative urine tests 
increased significantly over time for both groups (p< 0.001).  However, reductions were 
significantly greater in the BDRC enhanced services group (p< 0.05), with this group 
achieving higher overall proportions of opiate negative urine toxicology tests (87% vs. 69%, 
p= 0.04) and longer periods of consecutive abstinence from opiates (10.3 weeks vs. 7.8 
weeks, p = 0.15) (Chawarski et al, 2007).  More recently the results of a three-arm 
randomized, placebo-controlled trial were reported. In this trial, 126 opiate dependent 
individuals in Malaysia were randomized to received either buprenorphine, naltrexone, or 
placebo (Schottenfeld, Chawarski, and Mazlan, 2008). All participants received BDRC 
counseling. Subjects in all groups showed significant declines in drug and sexual risk 
behaviors while drug use outcomes were superior for the buprenorphine group.  Because of its 
suitability for use in settings that do not have professional therapists, as well as for its 
potential efficacy, manual guided BDRC is being used as the counseling platform provided to 
patients in various research and clinical settings in Malaysia and in the HIV Prevention Trials 
Network (HPTN) protocol 058 in Thailand and China evaluating the efficacy of 
buprenorphine for reducing HIV transmission.  Preliminary data from the first year of 
implementation in Thailand (N=50) shows a high rate of attendance and acceptability for the 
BDRC counseling. Sixty-three percent of the subjects attended all their scheduled sessions 
and 86% attended 75% or greater of their scheduled sessions. 
 
Innovation 
 
Although standard methods of evaluation of program implementation are proposed in 
this application, this effort represents the first time a buprenorphine/naloxone (Suboxone®) 
treatment program will be introduced in Vietnam.  Its location within an HIV treatment 
setting represents another important and innovative feature of the work.  The project is built 
upon two distinct prevention strategies — 1) effective drug treatment for prevention of 
infection among those who begin the study as HIV negative; and 2) sustained viral 
suppression through the effective treatment of those who begin the project already infected.  
The cost of integrated drug and HIV treatment has not been well examined and this also 
represents a unique feature of the proposed project and will provide an opportunity to gauge 
the public health relevance of the program.  The goal of the current project is not to compare 
methadone with Suboxone® but to demonstrate the feasibility of the use of both medications 
within an HIV treatment setting and to document the barriers and facilitators to their 
implementation. 
 
Study design 
Phase 
Not Applicable 

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Design 
This is an open-label follow-up study. The project proposes to enroll up to 500 opiate 
dependent 
individuals 
entering 
Medication 
Assisted 
Treatment 
(Methadone 
or 
buprenorphine/naloxone) at Go Vap Clinic, HCMC, Vietnam.  All participants who appear to 
meet inclusion criteria and who express interest in drug treatment will be invited to be 
screened for participation in the research.  The investigators expect that around 40% of them 
will be also HIV-positive and so will receive appropriate treatment.  All participants will 
receive BDRC sessions (weekly for 12 weeks, monthly thereafter until week 52). 
 
Study duration 
The first 18 months, only methadone will be available as MAT at Go Vap Clinic as 
Suboxone® is not available in Vietnam. The introduction of the Suboxone® treatment will 
follow the establishment of the methadone program at Go Vap, designed to facilitate the 
implementation of Suboxone®.  At Month 18, the investigators plan to begin Suboxone® 
treatment. They anticipate that enrollment of up to participants in methadone treatment will 
occur for 24 months after the first participant's enrollment and they plan to enroll up to 300 
new participants in Suboxone® treatment during the subsequent 36 months.  
 
Resources necessary for human research protection 
All participants who appear to meet inclusion criteria and who express interest in treatment 
will be invited to be screened for participation in the research.  Participants who express 
interest in the study will meet with one of the research staff and be engaged in a conversation 
explaining the details of the study.  Subjects will have the opportunity to have all their 
questions answered and will be given time to discuss the study with family members or others 
with whom they choose to discuss their participation.  Staff will be very clear that 
participation is voluntary, and individuals may withdraw from the study at any time without 
consequence to their treatment participation.  For those who meet inclusion criteria for 
treatment, detailed informed consent procedures will outline the nature of participation, risks 
and benefits, and the schedule for data collection and compensation.  Potential participants 
will then be given a detailed description of the research procedures and all remaining 
questions will be answered.  Subjects will be reminded that they are free to decline or stop 
participation at any time.  The consent form and related discussions will make it very clear 
that a critical feature of the study is the ability to follow study participants for one year 
whether they remain in their treatment program.  The consent will indicate permission from 
the participant to contact them even if they leave treatment.  The locator data collection form 
includes contact information on specific individuals with whom the participant expects to 
maintain contact and for whom contact permission is granted by the participant.  Following 
the completion of informed consent procedures, subjects will be sign the study consent form 
and will be assessed and screened for eligibility using the following inclusion and exclusion 
criteria. 
The Go Vap Clinic is currently an HIV treatment facility supported by the CDC.  The project 
will implement MAT for opiate addiction within this HIV treatment settings.  All participants 
will receive all treatment they need at the Go Vap Clinic.  The Doctors, nurses, psychologists 
and counselors will receive intense training and supervision.  The counseling intervention has 
minimal risk associated with participation.  Study resources are focused on maximizing the 
protection of confidentiality.  The Go Vap clinic has a private room where research 
assessments can be completed. 
The Principal Investigator and Co-Investigators have certifications of completion for required 
education on the protection of human research participants.  Staff who have responsibility for 

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the conduct of the study and/or direct contact with human study participants will complete 
certification requirements on ethical principles involved in the conduct of human subject’s 
research by completing the on-line training module on the CITI website, or its equivalent.  
The PI and the local PI will ensure that all project staff are oriented to the study procedures 
during their training period. The local Principal Investigator at the HCMC site, Dr. Le Truong 
Giang was appointed as the local PI by the local health authorities and has considerable 
experience supervising research implementation and data collection.  He will assist Dr. 
O'Brien in the direct supervision of the data collection sites. Protocol monitoring will ensure 
that the research protocol specified is being followed without unauthorized deviations.  
Special emphasis will be placed on ensuring that the consent process is being completed 
properly and that adverse events are being properly reported.  Weekly meetings will be held 
by the local PI to monitor the safety and progress of the trial.  These meetings will involve the 
Principal Investigator, Investigators, and project personnel.  This will help to ensure 
standardized application of the protocol and will serve as an ongoing mechanism by which 
project staff and investigators will communicate to maintain a consistently high quality of 
study conduct.  Concerns identified will be addressed through training and retraining of 
personnel.  Dr. O'Brien will have regular conference calls with the investigators and study 
staff in HCMC.  In addition, Dr. O'Brien will be available by e-mail and Internet telephony.  
 
Characteristics of the study population 
Target population 
All individuals who are 18 or more years of age and who meet the DSM-5 criteria for opiate 
use disorder with or without HIV co-morbidity are considered eligible for the study.  
 
Subjects at Penn 
0 
 
Subjects at Sites Other than Penn 
Up to 500 
 
Accrual 
All participants who appear to meet inclusion criteria and who express interest in drug 
treatment will be invited to be screened for participation in the research.  Participants who 
express interest in the study will meet with one of the research staff and be engaged in a 
conversation explaining the details of the study.  Subjects will have the opportunity to have all 
their questions answered and will be given time to discuss the study with family members or 
others with whom they choose to discuss their participation.  Staff will be very clear that 
participation is voluntary, and individuals may withdraw from the study at any time without 
consequence to their treatment participation.  For those who meet inclusion criteria for 
treatment, detailed informed consent procedures will outline the nature of participation, risks 
and benefits, and the schedule for data collection and compensation.  Potential participants 
will then be given a detailed description of the research procedures and all remaining 
questions will be answered.  Subjects will be reminded that they are free to decline or stop 
participation at any time. The consent form and related discussions will make it very clear that 
a critical feature of the study is the ability to follow study participants for one year whether 
they remain in their treatment program.  The consent will indicate permission from the 
participant to contact them in the community should they leave treatment.  The locator data 
collection form includes contact information on specific individuals with whom the 
participant expects to maintain contact and for whom contact permission is granted by the 
participant.  Following the completion of informed consent procedures, subjects will be 

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signing the study consent form and will be assessed and screened for eligibility using the 
following inclusion and exclusion criteria. 
 
Key inclusion criteria 
• 18 or more years of age 
• Meets DSM-5 criteria for opiate use disorder 
• Positive urine drug screen for heroin or other opiates 
• Interested in methadone maintenance or Suboxone® treatment for opiate use disorder 
• Injected heroin within past 30 days by self-report, documented by “tracks” or puncture 
marks 
• Willingness and ability to give informed consent and otherwise participate 
• Provision of adequate locator information 
 
Key exclusion criteria 
• Clinically significant cognitive impairment, schizophrenia, paranoid disorder, bipolar 
disorder 
• Known neurological, cardiovascular, renal, or other medical disorder that is likely to 
impair or make the patient’s participation hazardous 
• Physiologically dependent on alcohol, benzodiazepines, or other sedative type drugs  
• Pending legal charges with likely incarceration within next 12 months 
 
Vulnerable Populations 
 
Children (refer to SOP 501 for definition of children) Form 
 
Pregnant women (if the study procedures may affect the condition of the pregnant 
 
woman or fetus) Form 
 
Fetuses and/or Neonates Form 
 
Prisoners Form 
X 
Other 
 
None of the above populations are included in the research study 
Populations vulnerable to undue influence or coercion 
Injecting drug users are considered a vulnerable population due to the risks, both perceived 
and real, created as they identify themselves as engaging in illegal activity through the use of 
illegal drugs.  Care will be taken to ensure that they are treated with respect and consideration 
throughout the study process. All research procedures will be conducted within the 
participant's methadone treatment program, an environment considered protective of the 
rights of drug users and supportive of their health and welfare.  All data will be stored in a 
safe and confidential manner at the Go Vap Clinic, HCMC, Vietnam.  
 
Subject recruitment 
Recruitment will utilize street outreach, publicity, and a modified respondent driven sampling 
strategy (snowball method), where IDUs who participate in screening are encouraged to bring 
their IDU friends to the study site.  Outreach workers will primarily carry out recruitment 
activities.  These staff will provide information to a range of individuals and encourage those 
individuals to pass information about the study to others in the community.  Outreach workers 
will be research staff from the community and must be knowledgeable about the community’s 
heath care and drug treatment resources as well as the local criminal justice response to drug 
users.  They will be trained, as part of the study, in methods of approaching and 
communicating with potential participants, personal safety, and the importance of maintaining 
confidentiality.  Outreach workers will identify and develop strategies for accessing venues 

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11 
frequented by drug users.  In these geographic areas and settings, outreach workers will 
disseminate general information about the project verbally and via written materials as 
approved by the IRB.  They will provide information on available drug treatment resources in 
the community and encourage prospective participants to participate in screening activities at 
the study site. 
All participants seeking treatment for opiate dependence at Go Vap Clinic will be invited to 
take part in the study.  The study will be explained to the participant during the intake process.   
 
Subject compensation 
Yes 
 
If there is subject compensation, provide the schedule for compensation per study visit or 
session and total amount for entire participation, either as text or separate document 
Participants will receive the equivalent of US$5 (104,084 VND) for each data collection visit, 
that is, at baseline, 6- and 12-month visits, for a total of an equivalent of US$15 (312,252 
VND). 
 
Study Procedures 
Procedures 
All participants who express interest in participating in the study and consent to participate 
will receive MAT, BDRC and HIV treatment if needed. 
 
Methadone Treatment:  The project will implement a standard treatment protocol in 
accordance with evidence-based practice and Vietnamese policy.  As mentioned previously, 
the program will be co-located in the Go VAP HIV treatment clinic site where care and 
treatment services for HIV/AIDS patients are provided: consultation, ART dispensation, 
home-based care, counseling and testing, social services, TB/HIV care, help groups, 
vocational training (for eligible patients).  The site will be staffed with the following clinical 
professionals: 2 doctors; 2 pharmacists; 2 nurses; and 5 counselors. Importantly the 
methadone treatment process will incorporate the following features: 
• 
Dosage of methadone will follow the Ministry of Health guidelines 
• 
Treatment will be started with low doses (usually 20-30 mg) 
• 
The dose will be increased slowly (usually 5-10 mg every 3 days) to reduce 
the risk of overdose  
• 
Most patients not receiving ARVs will be able to be managed on 60 mgs/day 
In practice, higher doses are often necessary, particularly in patients on ART.   In case of 
difficulties, doctors in charge seek advice from the city technical working group, with whom 
regular meeting are hold. Clinical consultation will also be available from the Investigative 
team for this research. Supervision of the prescribing physician will be provided by the on-site 
PIs and co-investigators, Drs. Le Truong Giang, and Lisa Huang.  Patients receiving 
methadone will attend the Go Vap program daily.  All oral methadone doses are consumed 
daily under direct observation by the pharmacist.  Random observed urine samples are 
obtained at least twice per month tested for opiates and other drugs commonly abused in 
Vietnam.  
Methadone will be provided by the Central Procurement Company (Ministry of Health), with 
strict control from agents from both organizations regarding quality and quantity of the 
methadone delivered.  Monthly reporting of methadone use and request for next month’s 
supply are sent to the Pharmaceutical Department of the HCMC Health Department for 
control and approval.  Used bottles of Methadone are destroyed according to a process 
approved and controlled by the Environmental and Natural Resources of the city.   

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12 
 
Buprenorphine/Naloxone (Suboxone®) Treatment:  At month 18, the investigators plan to 
begin Suboxone® treatment and enroll up to 300 new patients during the subsequent 42 
months. The introduction of Suboxone® following the establishment of the methadone 
program at Go Vap is designed to facilitate implementation.  The project will be expanding an 
existing MAT center and not establishing a new and distinct Suboxone® clinic.  Importantly, 
the same entry point will be used to provide access to care and psychosocial support for HIV-
positive IDUs.  The clinical management of patients on Suboxone® will follow guidelines 
established and used successfully in the long-term treatment arm of the HPTN 058 (Lucas et 
al, In Press).  Manuals for clinical management will be modified and translated for use in this 
project. Reckitt Benckiser, the manufacturer of Suboxone®, has agreed to donate the 
medication for this project. 
Suboxone® tablets are administered sublingually, placed under the tongue until they are 
dissolved.  For doses requiring the use of more than two tablets, participants are instructed to 
either place all the tablets at once or alternatively (if they cannot fit in more than two tablets 
comfortably) place two tablets at a time under the tongue.  Either way, the participant should 
continue to hold the tablet under the tongue until they dissolve; swallowing the tablet reduces 
the bioavailability of the drug. 
To aid clinicians in determining the appropriate dose during the first two-to-three days, the 
study will use the Clinical Opiate Withdrawal Scale (COWS), an instrument measuring 
validated items of physical signs or symptoms of withdrawal, such as gooseflesh, vomiting, 
and sweating, to objectively assess withdrawal in both treatment arms (Wesson and Ling, 
2003).  The total score gives an index of the participant’s withdrawal intensity and can be 
administered over time to track changes and adjust dosing.  On day one, the clinician will wait 
until the participant shows at least mild opiate withdrawal by monitoring with the COWS.  If 
the score indicates at least mild withdrawal (the higher the score the more severe the 
withdrawal), the clinician will give 4 mg for the first dose.  COWS will be repeated in one 
hour; patients will receive further dosing as described below.   
Dosing will begin with a titration over a period of two to three days under supervision in the 
Go Vap clinic using the COWS as described above. On the first day of treatment, patients will 
initially receive a 4 mg dose of buprenorphine/Naloxone (expressed as the amount of 
buprenorphine) to be taken sublingually.  Most participants will begin with a total first day's 
dosage of 8 mg.  On Day 2, up to 16 mg may be given.  Up to 32 mg may be given on Day 3 
and thereafter until three-times-weekly dosing begins. The induction strategy is primarily 
dependent on three factors: 1) time since last opiate use; 2) type of opiate (e.g., long, or short-
acting) used; and 3) degree of physical dependence.  Therefore, each dosing schedule will be 
tailored to the individual participant.  
Individuals will come to the study site daily for direct observation of dosing until they have 
stabilized (for up to three weeks).  After induction and stabilization, participants will be asked 
to come to the site for dosing three-times-weekly. The target dosage schedule for individuals 
whose daily dose was 16 to 24 mg/day is expected to be 32/32/48 mg administered on a three-
times-weekly schedule (e.g., M/W/F); this is also the maximum three-times-weekly dosage. 
On rare occasions, for individuals who require more than 24 mg/day (i.e., 26, 28, 30, or 32 
mg/day), it is unlikely that the 32/32/48 mg dosage schedule will be adequate.  For those 
individuals, as well as for others who received 24 mg or less per day but for whom the 
32/32/48 mg three-times- weekly schedule is not adequate, dosing may be continued daily 
through Week 52 of the study, with take-home doses administered for those days on which in-
clinic dosing is not possible (e.g., 32 mg on M/Tu/W/Th/F/Sat with a take-home 32 mg dose 
on Sun).   

Version 05/16/2012 
 
13 
When dosed daily, the maximum agonist effects of buprenorphine will likely occur in a 
dosage range between 16 to 24 mg/day for most individuals. While increased dosages may not 
produce corresponding increases in agonist effects, they may extend the duration of 
buprenorphine-induced blockade of concurrently administered opiates.  In one study, 
individuals maintained on 8 mg/day of buprenorphine solution were shown to tolerate a 72-
hour dose omission well (Essenberg et al, 1997; Lucas et al, In Press).  
 
Behavioral Drug and Risk-Reduction Counseling Visits (BDRC):  At the enrollment visit, 
participants will be scheduled for the 12 weekly counseling sessions.  Approximately every 
four weeks, participants will be asked to provide urine for drug testing during the counseling 
visits for the first year of enrollment.  Women will have pregnancy testing approximately 
every four weeks during counseling visits.  Monthly counseling sessions will be scheduled 
approximately every four weeks beginning at week 16 through week 52.  At each of these 
sessions, participants will be asked to update their locator information and provide urine for 
drug and pregnancy testing (for women in the substitution treatment arm only).  Monthly 
counseling sessions can also be combined with dispensing and follow-up visits. 
 
Implementation Research Strategy:  To assess implementation and costs, the study will 
collect data from the individual study participants, from the program staff, and from the PAC 
and MOH of HCMC.  The project wants to document the extent to which the program 
achieves the intended goals at the individual level as well as documenting aspects of the 
process that facilitate implementation. The investigators will use a mixed methods approach 
that includes both qualitative and quantitative data collection.  Direct comparison of outcomes 
between methadone patients and Suboxone® patients is not the purpose of this project.  The 
project will not randomly assign patients to their treatments.  In fact, the project will examine 
the response to treatment to look for patient characteristics that are associated with success in 
each modality.   
 
Assessments:  As described below, the assessment interviews for each participant will 
include:  1) the locator questionnaire;  2) a brief study specific questionnaire that will be used 
to capture relevant socio-demographic data, health status, medical and drug treatment history 
and living situation and family relationships; 3) the Addiction Severity Index (ASI), 4) the 
Risk Assessment Battery (RAB); 5) the ICD-10; and, 6) the WHO Quality of Life (QOL) 
scale.  At monthly intervals, urine specimens will be collected for testing evidence of 
continued drug use and blood will be collected for HIV testing at baseline, 6 and 12 months.  
Research staff will also collect data from the program records regarding clinic attendance and 
methadone dosage and will keep a log of all counseling sessions attended, their duration and 
copies of all session content checklists.   
All assessments will be completed by trained research staff (not clinicians or counselors) at 
baseline, and again at 6-, and 12-month post-enrollment.  Importantly, assessments will be 
completed on those who remain in treatment as well as those who leave the program.  The 
investigators anticipate follow-up rates exceeding 90% after 12 months. 
Locator Data Collection:  A basic philosophy of the research approach to be implemented is 
that follow-up begins at recruitment and enrollment.  Thus, a detailed contact sheet (Locator 
Form) will be completed for all subjects as part of the baseline assessment.  This locator form 
will be updated at each subsequent assessment visit.  Participants in the research will also be 
asked to call or visit the research office in the clinic whenever they have questions about 
assessment schedules or have updates to provide regarding changes in contact information. 
Participants will be asked to provide contact information on themselves and three additional 
people with whom they are most likely to stay in contact.  They will also be asked about other 

Version 05/16/2012 
 
14 
places where they might be able to be contacted in the future. This instrument will be modeled 
after the Locator form developed in Philadelphia and will be modified and translated by the 
investigators in Vietnam.  
Study Specific Questionnaire:  This questionnaire will be administered by study staff and 
collects demographic information (e.g., age, gender, race and ethnic identity, marital status, 
sexual orientation, educational level, employment status, income and income sources) and 
descriptive information about the subject's living situation, involvement with the criminal 
justice system, drug treatment, and source of needles during the last 6 months.  This 
questionnaire will also include questions about non-study treatment services.   
Addiction Severity Index (ASI):  The ASI is a structured interview developed to assess the 
range of problems seen in drug abusers (McLellan, et al, 1980).  It has been widely used in 
international settings for substance abuse and treatment research.  It combines objective and 
subjective data to produce ratings of problem severity in seven areas: medical, employment 
and support, drug use, alcohol use, legal status, family/social relations, and psychological 
status. The ASI produces severity ratings and composite scores in each of seven areas, and 
each type of score has been assessed regarding validity and reliability (McLellan et al, 
1992b).  Severity ratings and composite scores have demonstrated high levels of inter-rater, 
test-retest, and concurrent reliability.  The Treatnet version of the ASI, developed in 2007 for 
international studies (McLellan and Carise, 2007 - UNODC Treatnet ASI version 3.0).  It will 
be administered at baseline, 6 and 12 months.  
Risk Assessment Battery (RAB):  The RAB provides a brief self-report measure of drug use, 
injection-related risk behavior, and sexual risk and uses the preceding six months as the time 
interval of interest.  The RAB takes an average of 10 minutes to complete.  There are 38 
closed-ended items that cover issues of recent substance use and frequency of use, needle 
sharing and cleaning, and condom use.  The nine drug-use risk items include questions 
concerning whether the participant injected drugs, whether they shared needles, the number of 
people with whom they shared needles, the number of visits to a location where drugs are 
used with others present, the number of times they shared rinse water, cookers, or cottons, and 
the frequency of back loading.  There are eight sex-risk items, which include sexual 
orientation, number of partners (male and female), frequency of exchanges of sex for drugs, 
drugs for sex, sex for money, money for sex, and the consistency of condom use.  Scores from 
the RAB have able to discriminate between cocaine and opiate abusers as well as those who 
seroconverted from those who remained seronegative (Metzger et al, 1993; Navaline et al, 
1994).  The RAB has been used in various international settings including Brazil, Russia, 
Ukraine, Georgia, Israel, and China.  Translation and cultural adaptation have not been 
identified as serious problems primarily because the questions do not involve the 
understanding of complex concepts and are focused on discrete and relatively recent 
behaviors.  The RAB will be translated into Vietnamese. 
ICD-10 and ICD-10 Symptom Checklist for Mental Disorders (psychoactive substance use 
syndromes):  The MINI ICD-10 is a short structured diagnostic interview, developed jointly 
by psychiatrists and clinicians in the US and Europe for ICD-10. With an administration time 
of approximately 15 minutes, it was designed to meet the need for a short but accurate 
structured psychiatric interview for multi-center clinical trials and epidemiology studies. This 
instrument has been translated to Vietnamese. 
WHO QOL-BREF:  For assessing quality of life, the World Health Organization Quality of 
Life (WHOQOL)-BREF will be used. Assessments will be completed at baseline, month 3, 6, 
9, and 12. The World Health Organization Quality of Life (WHOQOL) project was initiated 
in 1991 to develop an international cross-culturally comparable quality of life assessment 
instrument. It assesses the individual's perceptions in the context of their culture and value 
systems, and their personal goals, standards, and concerns. The WHOQOL instruments were 

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15 
developed collaboratively in several centers worldwide and have been widely field-tested.  
The WHOQOL-BREF is a self-administered, standardized instrument used as a measure of 
health outcome and comprises 26 items, which measure the following broad domains: 
physical health, psychological health, social relationships, and environment. The WHOQOL-
BREF is a shorter version of the original instrument that may be more convenient for use in 
large research studies or clinical trials.  It has been used in international settings, including the 
WHO collaborative study of substitution treatment (Lawrinson et al, 2008).   
Urine testing:  Urine drug testing will be done using rapid test kits that test for opiates, 
amphetamines, methamphetamines, benzodiazepines, and cannabis. These will be purchased 
from an approved laboratory in Vietnam.  These kits provide a rapid urine test that is done on 
site and produces a result within five minutes.  In this study, urine testing will be done 
monthly, with collection days being randomly selected. 
HIV Testing:  At the baseline visit rapid HIV testing will be used to determine HIV status and 
need for care.  All participants who are determined to be HIV positive (two rapid positives) 
will be referred directly to Go Vap HIV clinic for initial assessment.  All participants who test 
negative will be scheduled for retesting at 6- and 12-month assessment points.  The test kits to 
be used will be WHO tested and selected in conjunction with the HCMC MOH.   
Drug Abuse Treatment Cost Analysis Program (DATCAP): The cost data will be collected in 
Year three.  This effort will be led by Dr. Julie Becher a health economist from the Penn CSA. 
The program-based DATCAP and Client-based DATCAP are reliable instruments widely 
used by substance abuse treatment programs for the collection and organization of 
programmatic costs and participant-based costs, respectively.  The instruments, by 
standardizing data collection procedures, enable direct comparison of data and cost estimates 
across different drug treatment programs and over time (French et al. 1997).  The program-
based DATCAP is divided into different categories, each one pertaining to a particular area of 
standard universal economic resource and cost variables: personnel (e.g., percentage of time 
devoted to the program, annual salary, total cost of employee benefits, total overtime cost, any 
other personnel cost) supplies and materials (e.g., cost of medications, medical and office 
supplies, value of supplies and materials donated or received free of charge), major equipment 
(e.g., cost of all leased/rented equipment used by program, depreciation expense for 
equipment, value of any equipment donated or received free of charge), contracted services 
(e.g., cost of laboratory services, repairs and maintenance, advertising services), buildings and 
facilities (e.g., size of total usable space in building, percentage of that space used by the 
treatment program, percentage of time it was used by this program, annual lease/rental price 
per square foot), miscellaneous resources and costs (e.g., cost of utilities such as electricity, 
telephone, transportation, staff training, medical waste disposal) not recorded elsewhere.  The 
outpatient-client based DATCAP collects information on costs incurred by participants such 
as expenses related to transportation, child or elder care and lost productivity while 
participating in the treatment program (French et al. 2004; Salome et al. 2003).   
The general categories of “costs” are universal and applicable to different programs in 
different countries.  These instruments were designed to be flexible; individual items within 
each category may be added or deleted depending on specific aspects of a unique drug 
treatment program or geographical characteristics (Salome, French, Miller, & McLellan 
2003).   For example, the DATCAP has been used in Australia, Spain, Romania, and a few 
other countries.  The instrument is in the public domain and usage has not been monitored, so 
there is no readily available list of citations (Michael French, personal communication, 
August 18, 2008).  Time to complete the instruments varies depending on specific 
characteristics of drug treatment programs and participants.  These assessments are highly 
structured and will be completed over the course of three days of interviews conducted by Dr. 
Becher. 

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Together, these assessments will produce serologic, behavioral, and cost measures during the 
project period.  Baseline assessments are expected to last approximately two hours.  Given the 
number and variety of assessment modalities (interview, questionnaire, phlebotomy, pre and 
post-test counseling), the burden of the participants will be minimized through careful 
scheduling and efficient administration of assessments and small refreshments and brief 
breaks will be provided.  Follow-up assessments are expected to take approximately one hour.   
 
Study Retention:  A series of structured activities will be used to maximize completion of 
follow-up appointments. These activities are considered core principles in conducting 
longitudinal studies and have been shown successful in many different cultural settings.   The 
investigators believe that with the intensive and structured efforts described below, the 
proposed project can achieve a 90% retention rate at 12 months. Most importantly, research 
staff will maintain accurate and timely follow-up contact information for all participants 
throughout the study.  A basic philosophy of the work to be implemented is that follow-up 
begins when the initial relationship is established, and the data is collected at the time of 
recruitment and enrollment.  Thus, a detailed locator interview will be completed for all 
subjects following completion of the informed consent at the time of enrollment.  This will be 
updated at all subsequent contacts. All future appointments for research assessments will be 
scheduled on a calendar at the time of enrollment. A copy of this visit schedule will be given 
to the participant.  Ten days prior to all scheduled assessment visit, calls reminding subjects 
about their scheduled assessment will be completed and a note will be left in the methadone 
dispensing area reminding the participant about the time and location of the assessment visit. 
Missed calls will be noted and attempts to contact the participant will continue until contact is 
achieved. For those who are not able to be contacted through the clinic or by phone, staff will 
visit contact locations collected from the participant at the time of enrollment and updated at 
their most recent contact.  Reminder calls will also be made on the day before the scheduled 
appointment. Missed appointments will be responded to immediately.  At the end of each day, 
the designated follow-up staff will attempt to contact all the subjects who missed their 
appointment that day.  For those who unable to be reached by phone, a reminder letter will be 
sent within three days.  Outreach by research staff will also be used to locate missing subjects.  
When unable to make contact after 5 days, research staff members will implement outreach 
procedures, including visiting the subject’s home, contacts, and common “hangouts” reported 
by the subject at the time of their prior visit.  Subjects who are reported to be incarcerated will 
have a note placed in their retention file and staff will periodically update the status of the 
participant through contact with the friend or family member who initially reported the 
incarceration. 
 
Analysis Plan 
All data will be collected by research staff based at the Go Vap clinic.  Trained staff will 
review all forms prior to the completion of the study visit to minimize problems associated 
with missing values and incorrect skip patterns.  All assessments will be recorded on final 
version of the Case Reporting Forms (CRFs). CRFs will also be developed to capture the 
results of all biological assessments.  All CRFs will be completed and stored using only 
participant identifying numbers and will not include names, addresses, or other data that could 
possibly be used to disclose the identity of the participant.  All completed CRFs will be filed 
in locked cabinets by ID number.  Consent forms, locator information, and other forms with 
personal identifiers will be securely stored separately. Research staff at the project site will be 
responsible for entering all data into the secure web-based data management system operated 
by the Data Management Unit of the University of Pennsylvania, Center for Studies of 
Addiction (CSA).    

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17 
The data management and the quantitative analyses will be performed by the Center for 
Studies of Addiction data analyst, under the supervision of the PI and Dr. Kevin Lynch, the 
CSA Statistician.  Dr. Becher will supervise the economic analyses. Prior to performing 
analyses, standard data screening and cleaning procedures will be applied (Tabachnik & 
Fidell 2001).  These procedures will (1) screen the data for data-entry errors, (2) check for 
outliers, (3) assess the extent and pattern of missing data, and (4) check that appropriate 
assumptions of normality are met whenever necessary.  
The planned analyses will be sharply focused on providing information able to inform the 
primary aims of the study.     
1) Establish a new integrated MAT treatment program within and HIV treatment setting in 
HCMC.  This aim will be fully documented by descriptive data focused on the numbers of 
patients treated by methadone and Suboxone.  Data to summarize the duration of and 
response to treatment by patients in each of the four groupings—Methadone treated HIV-; 
Methadone treated and HIV+; Suboxone® treated and HIV-; and Suboxone® treated and 
HIV+ will be presented.  The project's goal is not to compare treatment but to provide data 
to demonstrate that these treatments are producing results consistent with “clinical 
expectations” for these approaches and patient populations.   
2) Evaluate barriers and facilitators to implementation of integrated MAT/HIV treatment.  
For this aim the study will carefully document the “events” or “factors” that are identified 
as having an influence on the ability and speed of implementation.  Three stakeholder 
groups will be monitored—the drug using and patient population, the program staff, and 
the local government and non-government organizations. Data will be assembled using a 
monthly implementation log and formally assessed using semi-structured interview 
strategies.  
3) Evaluate patient retention and medication adherence in integrated MAT/HIV Care.  This 
aim will be critically important in documenting the success of implementation of the 
program.  The study will carefully monitor through the baseline, 6- and 12-months 
assessments both retention in treatment and response to treatment.  Retention will include 
measures of medication visit completion for expected methadone and Suboxone® 
administration visits as well as adherence to antiretroviral medication.  Biological markers 
of these measures will also be collected.  Results of monthly urinalyses for all participants 
will be reported and semiannual viral load measures for HIV positive patient will be 
summarized.  
4) Estimate the costs and benefits of MAT treatment strategies.  A cost-effectiveness analysis 
is an economic evaluation technique that may be used to evaluate multiple strategies to 
achieve an outcome.  A cost-utility analysis is a special kind of cost-effectiveness analysis 
that may be used to compare strategies that affect morbidity and mortality (Gold et al. 
1996; Haddix et al. 2003).  One potential barrier to implementation of an enhanced 
intervention is the number of resources that must be devoted to administer the additional 
procedures.  However, resource-intensive interventions may be justified through the 
achievement of better outcomes resulting from administering the enhanced procedures.  
Data Analyses for treatment and outcomes  (Aims 1 and 3): The sample of up to 500 
participants will be split between HIV+ and HIV- participants. The participants will not be 
assigned at random to Suboxone® or methadone. The assignments will be based on clinical 
evaluation, and participants with a longer history of addiction, or with higher numbers of 
previous treatments, or participants who may be at risk for interactions between methadone 
and antiretroviral medications, will be more likely to receive Suboxone®.  The investigators 
anticipate having about 40-50% of the sample receiving one medication, and 60-50% 
receiving the other, so there should be adequate numbers for analyses in each treatment 
stratum.  

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18 
The goal of the analyses for Aims 1) and 3) is to assess the influences of participant 
characteristics on treatment outcome, and to examine whether characteristics of good outcome 
differ across treatment and HIV groups. Thus, the analyses will regard treatment (SUB or 
METH) and HIV status (+ve or –ve) as strata. Participant characteristics, drawn from the 
baseline administrations of the Study Specific Questionaire, ASI, RAB, and ICD-10 
assessments, will be the explanatory variables of interest, while binary factors for treatment 
group and for HIV status will form four strata.  
The outcomes of interest include: (1) the durations of time in treatment, and time to relapse to 
drug use, which will be addressed using Cox proportional hazards models and its extensions; 
(2) measures of psychopathology and drug or sex risk behaviors, drawn from the ASI and the 
RAB at the 6 and 12 month points, which will be analyzed using linear or nonlinear (e.g. 
logistic or ordinal) mixed effects models; (3) self-reported drug use drawn from the ASI, and 
monthly UDS tests, which will also be analyzed using linear or nonlinear mixed effects 
models; (4) overall incidence of HIV among those participants negative for HIV at baseline, 
which will be analyzed using a logistic regression model.     
The analyses will follow the same overall analytic strategy for each set of models. First, the 
participant characteristics will be examined separately. For a given characteristic, the analyses 
will first test for heterogeneity (interaction) between the characteristic and the stratifying 
variables of treatment and HIV status. Two types of heterogeneity are possible: the 
characteristic could have effects that differ across some combination of the treatment and HIV 
groups (three-way interaction) or its effects may be independent of one variable but differ 
across levels of the other (two-way interaction). In either of these cases, stratum-specific 
estimates of the effects will be reported. If no heterogeneity is detected, the adjusted (pooled) 
estimates of effect will be reported. In each case, the estimates on an appropriate scale (e.g., 
odds ratios, or regression coefficients associated with interpretable changes in the level of the 
participant characteristic), together with appropriate confidence intervals will be reported. 
Once the univariate effects of the different characteristics will be assessed, multivariate 
models containing what appear to be the important characteristics will be performed, and 
these models will be implemented and reported in the same way as for the univariate models.  
 
Data Analyses for Economic Outcomes (Aim 4): Standard cost-effectiveness and cost-
utility analyses will compare costs and benefits of the two approaches (Gold et al., 1996; 
Haddix et al., 2003).  The analyses will be carried out from a societal perspective which 
means that all costs and benefits, regardless of who pays or incurs them, will be included.   
Benefits may be considered as reductions in sex risk behaviors (e.g., condom use and 
decreased number of partners) and less risky drug-use practices (e.g., decreased needle 
sharing and works sharing) during follow-up.  In addition, a measure of the quality-adjusted 
life-years (QALYs) of sex partners saved by the intervention versus the standard of care will 
be estimated.  Benefits will be compared to the direct and indirect costs (i.e., lost productivity) 
of the intervention and standard of care procedures.  Relevant costs include time for the 
administration of the HIV counseling and testing, HIV test kits, completion of intervention 
questionnaires, time of staff to collect blood and follow-up assessment data and the time of 
participants to complete the follow-up assessments.   
Incremental cost-effectiveness ratios will be computed to find the additional net cost (costs 
minus benefits) per outcome (e.g., cases of HIV transmission prevented or QALY saved) by 
administering the behavioral intervention over standard procedures.  To check the sensitivity 
of results, univariate and multivariate sensitivity analyses, in which parameter values in the 
mathematical models are varied from baseline values, will be conducted.    
 
Data confidentiality 

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19 
X 
Paper-based records will be kept in a secure location and only be accessible to 
 
personnel involved in the study. 
X 
Computer-based files will only be made available to personnel involved in the study 
 
using access privileges and passwords. 
 
Prior to access to any study-related information, personnel will be required to sign 
 
statements agreeing to protect the security and confidentiality of identifiable 
 
information. 
X 
Wherever feasible, identifiers will be removed from study-related information. 
 
A Certificate of Confidentiality will be obtained because the research could place the 
 
subject at risk of criminal or civil liability or cause damage to the subject's financial 
 
standing, employability, or liability. 
 
A waiver of documentation of consent is being requested because the only link 
 
between the subject and the study would be the consent document and the primary risk 
 
is a breach of confidentiality. (This is not an option for FDA-regulated research.) 
 
Precautions are in place to ensure the data is secure by using passwords and 
 
encryption, because the research involves web-based surveys. 
 
Audio and/or video recordings will be transcribed and then destroyed to eliminate 
 
audible identification of subjects. 
 
Subject Confidentiality 
All data will be collected by research staff at Go Vap Clinic, HCMC, Vietnam.  Trained staff 
will review all forms prior to the completion of the study visit to minimize problems 
associated with missing values and incorrect skip patterns.  All assessments will be recorded 
on final version of the Case Reporting Forms (CRFs).  CRFs will also capture the results of 
all biological assessments.  All CRFs will be completed and stored using only participant 
identifying numbers and will not include names, addresses, or other data that could possibly 
be used to disclose the identity of the participant.  Research staff at the Go Vap Clinic will be 
responsible for entering all data into the secure web-based data management system operated 
by the Data Management Unit of the University of Pennsylvania, Center for Studies of 
Addiction (CSA).  After the final data set is sealed (approximately 6 months after the final 
data collection session) all identifying information will be destroyed. 
 
Subject Privacy 
Privacy refers to the person's desire to control access of others to themselves. Privacy 
concerns people, whereas confidentiality concerns data.  Describe the strategies to protect 
privacy considering the following:  The degree to which privacy can be expected in the 
proposed research and the safeguards that will be put into place to respect those boundaries. 
The methods used to identify and contact potential participants. The settings in which an 
individual will be interacting with an investigator. The privacy guidelines developed by 
relevant professions, professional associations and scholary disciplines (e.g., psychiatry, 
genetic counselling, oral history, anthropology, psychology). 
All potential subjects will be recruited at the GoVap clinic.  Research staff will speak with 
those interested in the study.  Only research staff, not clinic staff, will collect data for the 
study.  Clinic staff will not have access to the study data. All research assessments will be 
performed in private offices within the clinic.  For follow-up research visits, staff will attempt 
to leave appointment notes for participants when they attend the clinic.  For those who have 
left treatment, staff will use information collected on the locator form to telephone 
participants or mail letters to them. 
Data Disclosure 

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Staff supervised by the Key Personnel will have access to the data in order to perform study 
duties. 
 
Data Protection 
X 
Name 
X 
Street address, city, county, precinct, zip code, and equivalent geocodes 
X 
All elements of dates (except year) for dates directly related to an individual and all 
 
ages over 89 
X 
Telephone and fax number 
 
Electronic mail addresses 
 
Social security numbers 
 
Medical record numbers 
 
Health plan ID numbers 
 
Account numbers 
 
Certificate/license numbers 
 
Vehicle identifiers and serial numbers, including license plate numbers 
 
Device identifiers/serial numbers 
 
Web addresses (URLs) 
 
Internet IP addresses 
 
Biometric identifiers, incl. finger and voice prints 
 
Full face photographic images and any comparable images 
 
Any other unique identifying number, characteristic, or code 
 
None 
 
Tissue Specimens Obtained Specimens Obtained as Part of Research* 
Are Tissue Specimens being obtained for research? 
No 
 
Tissue Specimens - Collected during regular care* 
Will tissue specimens be collected during regulator clinical care (for treatment or diagnosis)? 
No 
 
Tissue Specimens - otherwise discarded* 
Would specimens otherwise be discarded? 
No 
 
Tissue Specimens - publicly available* 
Will tissue specimens be publicly available? 
No 
 
Tissue Specimens - Collected as part of research protocol* 
Will tissue specimens be collected as part of the research protocol? 
No 
 
Tissue Specimens - Banking of blood, tissue etc. for future use* 
Does research involve banking of blood, tissue, etc. for future use? 
No 
 
Genetic testing 
If genetic testing is involved, describe the nature of the tests, including if the testing is 

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predicative or exploratory in nature. If predictive, please describe plan for disclosing results to 
subjects and provision of genetic counseling. Describe how subject confidentiality will be 
protected Note: If no genetic testing is to be obtained, write: "Not applicable." 
N/A 
 
Consent 
1. Consent Process 
Overview 
The study will be described to the participant during the intake process.  Participants who 
express interest in the study will meet with one of the research staff and be engaged in a 
conversation explaining the details of the study.  Subjects will have the opportunity to have all 
their questions answered and will be given time to discuss the study with family members or 
others with whom they choose to discuss their participation.  Staff will be very clear that 
participation is voluntary, and individuals may withdraw from the study at any time without 
consequence to their treatment participation.  For those who meet inclusion criteria for 
treatment, detailed informed consent procedures will outline the nature of participation, risks 
and benefits, and the schedule for data collection and compensation.  Potential participants 
will then be given a detailed description of the research procedures and all remaining 
questions will be answered.  Subjects will be reminded that they are free to decline or stop 
participation at any time.  The consent form and related discussions will make it very clear 
that a critical feature of the study is the ability to follow study participants for one year 
whether they remain in their treatment program.  The consent will indicate permission from 
the participant to contact them in the community should they leave treatment. 
 
Children and Adolescents 
N/A 
 
Adult Subjects Not Competent to Give Consent 
N/A 
 
2. Waiver of Consent 
Waiver or Alteration of Informed Consent* 
No Waiver Requested 
 
Minimal Risk* 
NA 
Impact on Subject Rights and Welfare* 
NA 
Waiver Essential to Research* 
NA 
Additional Information to Subjects 
NA 
Written Statement of Research* 
No 
 
If no written statement will be provided, please provide justification 
 
Risk / Benefit 
 
Potential Study Risks 

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Both Methadone and Suboxone® (buprenorphine/naloxone) treatment have a long 
history of effectiveness and safety as a therapy for opiate addiction.  However, since they are 
highly potent drug, an improper prescription and/or their misuse can be harmful or even fatal.  
Some patients could experience some minor side effects such as headache, stomach pain, 
nausea, vomiting, constipation, warmth or tingly feeling, increased sweating, weakness, back 
pain, increased of anxiety and/or depression symptoms, sleep problems (insomnia) or runny 
nose.  These symptoms usually occurred at the beginning of the treatment.  Serious side 
effects are linked to the properties of any narcotic medicines that could slow the patient's 
breathing and in some case conduct to death.  However, serious side effects appeared mostly 
with misuse/ inappropriate use of the medication or when the medication is combined with 
any other non-prescribed drug (alcohol, benzodiazepine).  To avoid any serious side effects, 
the patients should strictly follow the prescription as the dose of the medication is established 
by the doctor on an individual basis.  Clinical signs and patient-reported symptoms of either 
overmedication or withdrawal, along with drug craving and/or continuing illicit-opiates use, 
are vital indicators for achieving dose adequacy.  All the doctors have received an extensive 
training to adequately prescribe both medications and so reduce all the serious side-effects.  
 
There are a few risks associated with HIV testing.  The participant's finger (and arm if 
confirmatory testing is required) may become bruised or sore following the collection of 
blood for the HIV testing.  Also, if the tests determine that the participant is infected with 
HIV, they may have an emotional reaction and become depressed or angry. If this happens, 
the research staff will help by providing counseling and making a referral for follow-up 
counseling services.  Although the research staff will work very hard to protect privacy and 
the confidentiality of the test results, it is possible that someone may discover the results of 
their testing.  Also, participants may be embarrassed by some of the personal questions that 
the research staff will ask.  Finally, it is possible that someone could find out about an 
individual's participation in the study and determine that they are in treatment for drug 
dependence. 
 
Potential Study Benefits 
Any direct benefit to individuals participating in this study can not be promised.  The 
information gained from this study will provide information that may help to implement other 
programs for opiate addiction within an HIV treatment program.  The HIV test will provide 
important information about the participants health status.  For those who are determined to 
be uninfected with HIV, counseling will be focused on developing ways to avoid infection in 
the future.  Although the impact of the counseling is not certain, it is possible that the 
counseling may help participants gain a better understanding of drug addiction.  The 
counseling may also help participants become more successful patients in medication assisted 
treatment for opiate addiction and, if they are HIV infected, more adherent to their HIV 
treatment. Finally, the counseling sessions may give participants effective strategies to 
improve relationships with family and friends. 
 
Alternatives to Participation (optional) 
 
Data and Safety Monitoring 
This study will be monitored by the principal investigator and the DSMB of the University of 
Pennsylvania Center for Studies of Addiction.  
 
Risk / Benefit Assessment 
The investigators cannot say that participation in the trial will have direct personal benefits to 
the participants. However, the trial procedures pose a minimal risk to participants, as they are 

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not greater, considering probability and magnitude, than those ordinarily encountered in daily 
life or during the performance of routine physical and psychological examinations or tests. At 
the same time, this trial will provide information that will have potential importance in the 
development of enhanced medication assisted treatment outcomes.