Enhancing HIV Pre-Exposure Prophylaxis (PrEP) by Targeting Hazardous Alcohol Use and Concurrent Conditions
Phase: NA
Conditions: Hazardous Alcohol Use
Sponsor: Centre for Addiction and Mental Health

 
Version 1.0. February 27, 2020 
 
Page 1 of 13 
 
Study Protocol 
 
Name of Study: PrEP and Alcohol 
 
Responsible Investigators: 
 
Principal Investigator: Dr. Paul Shuper, Centre for Addiction and Mental Health (CAMH). 
 
Co-Investigators: 
Dr. Isaac Bogoch, Toronto General Hospital. 
Dr. John Cunningham, CAMH. 
Dr. Mona Loutfy, Maple Leaf Medical Clinic. 
Dr. Jürgen Rehm, CAMH. 
 
 
NOTE: This research is based on an NIH/NIAAA UH2/UH3 grant mechanism that involves a 
two-phased approach (i.e., UH2 Phase: Years 1-2; UH3 Phase: Years 3-5). REB approval for 
UH2 phase (years 1-2) was initially obtained on October 2, 2017 (CAMH REB# 101/2017; UHN 
REB#18-5014).  Recruitment for this phase is now completed. The present protocol covers 
studies for the second phase of the grant, UH3, which was funded in September 2019 and has an 
anticipated end date of August 2022.   
 
I. Introduction and Background 
 
HIV continues to pose a significant public health concern in Canada, with recent estimates 
indicating approximately 75,500 Canadians living with HIV.1 Within the context of this 
epidemic, HIV disproportionately impacts gay, bisexual, and other men who have sex with men 
(MSM), who comprise approximately half of all new and existing HIV infections in Canada.2 
 
HIV-negative (HIV-) MSM have traditionally been reliant on condoms as their primary method 
of preventing HIV acquisition through sexual contact. More recently, however, biomedical 
strategies have moved to the forefront of prevention, with HIV pre-exposure prophylaxis (PrEP) 
offering those who are HIV- an effective new method of protection from the virus. PrEP entails 
taking a daily dose of tenofovir disoproxil fumarate/emtricitabine, which prevents HIV from 
replicating and taking hold inside one’s body. Empirical support for PrEP has been strong, with 
several randomized controlled trials (RCTs) providing evidence for its efficacy; showing a 
reduction in the rate of HIV infection by 44%-86%.3-7   
 
Although PrEP is an effective tool in preventing the acquisition of HIV,3-7  its effectiveness has 
been shown to be dependent on a number of key behaviors, including adherence to the treatment, 
4,6-9 attendance in follow-up care, and the continued use of condoms.  
 
Hazardous alcohol use is prevalent among PrEP users in Canada,10 which in turn has the 
potential to contribute to suboptimal PrEP adherence, poor retention in PrEP care, and 
condomless sex/STIs while on PrEP (e.g.,11-17). The impact of alcohol on these PrEP-related 
behaviours may also become exacerbated in the presence of concurrent issues such as substance 
use and depression, thus reflecting a potential syndemic effect (i.e., the combined presence of 

 
Version 1.0. February 27, 2020 
 
Page 2 of 13 
 
multiple issues leads to a greater detrimental impact).18 Substance use and depression frequently 
co-occur with alcohol consumption among MSM populations.19 Addressing hazardous alcohol 
use and concurrent conditions in PrEP-prescribed hazardous MSM-drinkers is therefore crucial 
for maximizing the HIV-preventive benefits of PrEP treatment. 
 
II. Rationale and Study Objectives 
This investigation follows a syndemic approach and seeks to explore whether a brief, stand-
alone, alcohol-reduction intervention (with modules on substance use and depression) would be 
feasible, acceptable, and potentially efficacious within the context of PrEP treatment.  The 
impact of traditional alcohol-reduction interventions on HIV-related outcomes has been variable, 
potentially because other concurrent conditions that can adversely impact health outcomes may 
have remained unaddressed. Our proposed intervention will distinctly target alcohol 
consumption and address key concurrent conditions among hazardous drinking, PrEP-prescribed 
MSM; thereby attending to, and accounting for, the potential synergistic detrimental impact that 
these concurrent conditions may have on PrEP-related behaviors. As there is a high prevalence 
of these concurrent conditions among MSM populations, the comprehensiveness and uniqueness 
of our intervention will be particularly well-suited for MSM who rely on PrEP as an HIV risk-
reduction strategy. 
 
Findings from this research will have the potential to guide future initiatives to address 
hazardous alcohol use and concurrent conditions within the context of PrEP treatment. 
Improving PrEP treatment outcomes could ultimately help reduce the likelihood of HIV 
acquisition among this population. 
 
III. Specific Aims 
 
The specific aims of this study are to: 
 
1) Assess the feasibility and acceptability of implementing an alcohol-focused brief 
intervention with a sample of hazardous drinking, PrEP-prescribed MSM. 
 
2) Assess the preliminary impact of an alcohol-focused brief intervention on reducing 
alcohol consumption among a sample of hazardous drinking, PrEP-prescribed MSM. 
 
3) Assess the preliminary impact of an alcohol-focused brief intervention on improving 
PrEP adherence and retention in PrEP-related care among a sample of hazardous 
drinking, PrEP-prescribed MSM. 
 
4) Assess the preliminary impact of an alcohol-focused brief intervention on reducing 
condomless sex and STIs among a sample of hazardous drinking, PrEP-prescribed MSM. 
 
 
IV. Study Design  
 
We will conduct a pilot randomized controlled trial (RCT) of an alcohol-focused brief 
intervention with supplementary modules that focus on concurrent substance use and depression. 

 
Version 1.0. February 27, 2020 
 
Page 3 of 13 
 
A total of 120 PrEP-prescribed MSM who are hazardous drinkers will be recruited from two 
medical clinics, Toronto General Hospital (TGH) and Maple Leaf Medical Clinic (MLMC), 
located in downtown Toronto. Participants will be randomly assigned to either the intervention 
condition or treatment as usual (TAU) based on a 2:1 intervention:TAU ratio. All participants 
will complete biological and behavioral measures at baseline and at 3- and 6-months post-
baseline to assess PrEP-related behaviors, alcohol consumption, substance use, and depression. 
An overview of the trial design is depicted in Figure 1. 
 
Figure 1. Pilot RCT design overview. 
 
 
Eligibility Criteria 
 
To be included in the study, participants must be (a) aged 18 years or older, (b) be a patient of 
TGH or MLMC, (c) be a man who identifies as a gay or bisexual, and/or a man who has sex with 
other men, (d) have been prescribed PrEP for at least 3 months, and (e) meet the criteria for 
hazardous drinking, (i.e., based on a score of ≥4 on the Alcohol Use Disorders Identification Test 
– Consumption measures (AUDIT-C))20 
Participants will be excluded if they do not meet all of the above-mentioned inclusion criteria.  
 
Study Procedures and Measures 
Men presenting for routine PrEP-related care at TGH and MLMC will be made aware of the 
study either through TGH/MLMC clinic staff members (e.g., doctors, nurses, clinic research 
staff) or via study information cards and/or posters (see “Recruitment Ad” attachment) at their 
respective clinics. Interested individuals will be referred to a CAMH research staff member. The 
CAMH research staff member will provide additional information about the study (see “Pre-
Screening Script” attachment) and answer any questions that the individual may have. 
Individuals who indicate that they would like to participate will complete either a brief, self-
administered tablet-based eligibility screener or an over-the-phone screener (see “Pre-Screening 
Questionnaire” attachment), and qualifying individuals will be offered participation and asked to 
provide informed written consent (see “Consent Form” attachment). Potential participants will be 
encouraged to take as much time as they need to review the information and only give consent 
when they are ready to participate. The study comprises of a baseline session, and two follow-up 
visits at 3- and 6- months post initial visit. Designated CAMH staff members will conduct and 
oversee all study procedures. 

 
Version 1.0. February 27, 2020 
 
Page 4 of 13 
 
 
Pre-Screening 
A CAMH research staff member will introduce the study to the potential participant using the 
pre-screening script (see “Pre-Screening Script” attachment). Individuals interested to take part 
in the study will complete an eligibility pre-screening questionnaire (see “Pre-Screening 
Questionnaire” attachment)  Pre-screening will take approximately 5 minutes to complete and 
will be conducted over the phone or in person. Questions in the screener ask participants about 
their age, time on PrEP, sexual orientation, and alcohol consumption patterns. 
Baseline Session 
During their baseline session, participants will provide samples of dried blood spots (DBS) via 
finger prick (see “Dried Blood Spot Testing” below and “Dried Blood Spot” attachment) and 
complete a self-administered tablet-based survey. The survey, which is based on the previously-
approved survey that was employed in the first phase of this project (CAMH REB# 101/2017; 
UHN REB#18-5014), will include measures assessing PrEP-related behaviors and other key 
factors including alcohol use, substance use, and depression (see “Measures” below and the 
“Survey” attachment). Upon completion of the survey, the tablet-based program will randomly 
assign participants to either the intervention condition or TAU based on a 2:1 intervention:TAU 
ratio. Intervention condition participants will receive a one-time, alcohol-focused brief 
behavioural personalized feedback intervention delivered seamlessly on the same tablet, which 
will also embed supplementary modules focused on substance use and depression when 
necessary (see “Intervention” below and the “Intervention” attachment). 
 
Intervention 
The primary intervention component is The Check Your Drinking (CYD) intervention, a brief 
and personalized online intervention designed to assess and provide feedback on quantity and 
frequency of drinking, as well as the severity of hazardous drinking.21 CYD has been previously 
approved by CAMH REB [Protocol # 075/2016].  In the intervention, after completing the 
alcohol assessment, participants will be provided with a personalized drinking feedback report 
that compares their drinking with other Canadian males of the same age. This report also 
includes other relevant feedback, including an assessment of severity of alcohol use, and 
provides recommendations for safe levels of alcohol consumption. The development of the CYD 
was led by CAMH Senior Scientist Dr. Cunningham (Co-Investigator), and it has been subjected 
to five randomized trials from two independent research groups, all of which displayed a 
significant impact of the intervention to reduce hazardous alcohol consumption compared to 
controls.21-25   
An additional module will be appended to the CYD intervention and will appear for participants 
for whom a potential substance use- and/or depression-related issue is reflected in their self-
reported survey responses. The module will be similar to components used in a previously 
validated, electronically-delivered ART adherence promotion intervention that the PI of the 
proposed research helped develop.26 For the present trial, the module will include a list of local 
resources and support services for mental health and addictions concerns, along with contact 
information, web links, and other details for each of these entities.  Participants in this arm only 
(intervention arm) can decide whether to include an email address of their choice if they would 

 
Version 1.0. February 27, 2020 
 
Page 5 of 13 
 
like to receive an electronic copy of their personalized drinking feedback report and/or a list of 
local services for mental health- and substance-related concerns. Providing an email address will 
be completely voluntary. All email addresses collected will be deleted after the data have been 
downloaded to the CAMH secure server. To ensure participants are aware that their email 
address will be connected to their data, we have included the following text in the consent form: 
“It is recommended that for the report, you use an email address that does not identify you (for 
example, that you use an email that does not include your first or last name or other information 
that could identify you). This is because the email address you provide for the report will be 
temporarily stored in a secure Qualtrics database and will be connected with your data.  If you 
use identifiable information in your email, the Qualtrics database may be able to link you to the 
data you provide (i.e., your data will be identifiable in the Qualtrics database). The choice is 
yours, and the research team would like to make you aware of this.” TAU participants will 
receive no intervention. 
Follow Up Sessions 
At 3-month and 6-month follow-up visits, all participants will complete similar questionnaires to 
the baseline survey/screener measuring the same constructs in order to identify any changes in 
outcomes over time. DBS samples from finger prick will also be obtained at these follow up 
visits to test PrEP adherence and alcohol use biomarkers (see “Dried Blood Spot Testing” and 
“Measures” below, as well as the corresponding attachments). For participants in the intervention 
arm only, an additional questionnaire will be included at the end of the 6-month assessment to 
evaluate the perceived acceptability of the intervention (included in the “Survey” attachment). 
With participants’ explicit written consent, retrospective chart reviews will be conducted by 
CAMH research staff for aspects pertaining to PrEP treatment-related factors; alcohol, substance 
use, and mental health-related aspects; incident STIs; and other relevant clinical indicators (see 
“Chart Review” attachment). Chart review items were previously approved in the first phase of 
this study (CAMH REB# 101/2017-03; UHN REB# 18-5014.3).   
Dried Blood Spot Testing 
Participants in both intervention and TAU arms will provide samples of dried blood spots (DBS) 
via finger prick to assess biomarkers of PrEP adherence and heavy alcohol consumption (see 
“Measures” below and “Dried Blood Spot” attachment). Samples will be sent to a lab in the 
United States for testing as there are no labs in Canada that conduct the tests. Tests will be 
performed on a fee for service basis. The samples will be identifiable only by participant ID 
number, with no personal identifiers. The US lab will be required to only use the samples for the 
purposes as defined by CAMH and the REB protocol; destroy the samples after the services are 
complete; and provide confirmation to the PI/designated CAMH project personnel that the 
samples have been destroyed. DBS testing for alcohol (PEth) will be done at USDTL laboratory 
located at 1700 S Mt Prospect Rd, Des Plaines, IL 60018, USA. PrEP testing will be done at one 
of the following three labs in the United States, 1) University of Colorado Denver located at: 
12850 E. Monteview Blvd, Aurora; CO 80045; or 2) CPAC located at: 120 Mason Farm Road; 
University of North Carolina at Chapel Hill; NC 27599; or 3) University of Nebraska Medical 
Center located at: 42nd and Emile, Omaha, NE 68198. Detailed instructions on DBS collection, 
based from USDTL and University of Colorado protocols, are attached with this application (see 
“Dried Blood Spot” attachment).  
 

 
Version 1.0. February 27, 2020 
 
Page 6 of 13 
 
Outcome Measures 
Feasibility and acceptability. In accordance with Specific Aim 1, feasibility will be determined 
through an examination of 1) rates of eligible hazardous drinking PrEP-prescribed MSM who 
express a willingness to take part in the intervention trial; and 2) rates of those assigned to the 
intervention who subsequently complete it. Acceptability of the intervention will be measured 
using validated instruments,27,28 as well as a small number of items developed by the researchers.  
The acceptability measure will query satisfaction with the intervention, perceived ease of use, 
perceived accuracy of intervention content, and the desire to use the intervention on an ongoing 
basis. 
Alcohol consumption. Behavioral measures and a biomarker test will be employed to evaluate 
Specific Aim 2. The AUDIT,20 included as part of the pre-screening process at baseline, will be 
incorporated into 3-month and 6-month follow-up assessments to identify changes in hazardous 
drinking over time. Two supplemental self-report alcohol items will be included in all 
assessments to measure 1) the number of drinks consumed in a typical week, and 2) the highest 
number of drinks consumed on a single occasion.29 As an objective measure of alcohol use, an 
alcohol derivative, phosphatidylethanol (PEth), will be assessed from dried blood spots (DBS) 
obtained at baseline, 3-months, and 6-months. PEth has been shown to be highly correlated with 
several measures of alcohol consumption;30 it has been used as a clinical marker for chronic 
excessive drinking and binge drinking;30-34 and has been employed as a primary outcome in 
alcohol treatment trials.35,36 The half-life of PEth has an estimated range of 4-12 days, and it has 
demonstrated a high degree of sensitivity (i.e., >95%) and specificity (i.e., 100%) when 
comparing patients presenting for alcohol treatment to those who abstain or only consume 
alcohol at low levels.37-41 PEth levels will be measured using liquid chromatography-tandem 
mass spectrometry, and values will be examined based on a dichotomy using a cut-off of ≥35 
ng/ml to identify hazardous drinking.42 
PrEP adherence. Adherence to PrEP will be assessed at baseline, 3-months, and 6-months using 
a combination of behavioral and biological assessments to evaluate the adherence-focused 
component of Specific Aim 3. The behavioral assessment will be comprised of adapted versions 
of two well-validated measures of adherence,43,44 identifying 1) the number of missed PrEP 
doses over the past seven days; and 2) the percent of PrEP doses taken over the past four weeks. 
These measures have been employed in a number of intervention trials and provide good 
estimates of adherence.45  For both measures, suboptimal adherence will be defined as taking 
<80% of one’s prescribed PrEP doses.11 DBS samples obtained at baseline, 3-, and 6-months will 
be analyzed for quantities of PrEP components (e.g., tenofovir/emtricitabine (TFV/FTC)), using 
a validated liquid chromatography tandem mass spectrometry method widely used in PrEP 
research.6,9,46-55 The half-life of TFV is 15 hours and that of FTC is 10 hours50 which will allow 
the quantification of recent use of PrEP with a single DBS sample. Furthermore, blood plasma 
has been shown to provide a good indication of PrEP use for periods ranging from 24 hours to 
seven days.50,51,54  A cut off for the concentration of  ≤10ng/ml (for either TFV or FTC) will be 
employed, as this has been shown to be indicative of inconsistent PrEP intake.50,51  
Retention in care. Specific Aim 3 includes an additional focus on retention in PrEP-related care. 
Attendance at clinic visits that correspond with 3- and 6-month assessments, and attendance 
during any other regularly scheduled PrEP clinic visits during the 6-month follow-up period, will 
be used as an indicator of retention.  

 
Version 1.0. February 27, 2020 
 
Page 7 of 13 
 
Engagement in condomless sex. In accordance with Specific Aim 4, condomless sex will be 
assessed at baseline and follow-up study visits using an adapted version of a validated MSM-
focused sexual behavior assessment that queries condom use during the past three months.56 
Responses at each time point will be dichotomized to identify participants who engaged in any 
condomless anal sex. As an objective indicator of condomless sex, incident chlamydia, 
gonorrhea, syphilis, and HCV, diagnosed at each time point, will be identified through chart 
extraction. 
 
Additional Measures 
Participant characteristics. Demographic factors to be collected include age, race, educational 
background, and income.  These factors will be queried during the baseline assessment. 
Substance use and Depression. Substance use other than alcohol will be assessed using the 
National Institute on Drug Abuse (NIDA) - Modified Assist Screening Tool (NIDA M-
ASSIST).57 This measure queries lifetime use of a variety of substances, frequency of substance 
use during the past three months, and negative consequences experienced as a result of substance 
use. Participants will be identified as possessing a potential substance use issue based on NIDA 
M-ASSIST scoring. Participants will complete the Center for Epidemiologic Studies Depression 
Scale-10 (CESD-10).58 A score ≥10 will be used as an indicator of the presence of marked 
depressive symptomatology.58 Both measures will be administered at baseline and at the two 
follow-up time points. 
It should be noted that the demographic and behavioral measures (i.e. alcohol consumption, PrEP 
adherence, retention in care and engagement in condomless sex) included in this study were 
previously approved in the first phase of this study (CAMH REB# 101/2017-02; UHN REB# 18-
5014). 
 
Data Analysis 
Statistical power. As this is a feasibility study and not intended as a definitive clinical trial, 
sample size considerations focus on expected effect sizes detectable with the design. The 
following effect size for the variable that likely has the least power (i.e., adherence –Aim 3) can 
be detected based on the following assumptions: there is a combined effect of 1) the suggested 
alcohol intervention on alcohol intake,59 and 2) the effect of lowered alcohol intake on PrEP 
adherence.11 Suboptimal PrEP adherence, defined as taking <80% of all doses, was estimated 
based on the literature11 and assumed to be 30% among heavy alcohol users.8  With the current 
sample size, we would be able to significantly detect Odds Ratios of 3 and higher, and assuming 
confounding with an R2 of other variables on the dependent variable, Odds Ratios of 3.5 and 
higher. We will be able to detect differences in proportions of about 20% with a 95% Confidence 
Interval between 2% and 28%.60 Other factors in Aims 2, 3, and 4 can detect smaller effect sizes. 
Statistical analyses. Analyses pertaining to feasibility and acceptability indicators (Aim 1) will 
be based on descriptive statistics involving frequency counts (e.g., intervention completion rates) 
and mean scores (i.e., acceptability measure). The anticipated patterns pertaining to Aims 2, 3, 
and 4 will be tested with generalized linear mixed effect models including random intercepts for 
every patient,61,62 based on the expectation that the intervention group will have better outcomes 
at both follow-up time points. Mixed effect models have fewer assumptions compared to more 

 
Version 1.0. February 27, 2020 
 
Page 8 of 13 
 
traditional repeated measures of analyses of variance61 with respect to missing values.63,64  
For the quantification of the causal impact of alcohol, we will additionally use path models, 
where alcohol consumption levels will be introduced into the equations, with the hypothesis that 
the introduction of this variable will make the differences between experimental and control 
groups disappear. 
 
 
Reference List 
 
 1.  Public Health Agency of Canada. (2015) HIV and AIDS in Canada: Surveillance Report to 
December 31, 2014. Ottawa: Minister of Public Works and Government Services Canada. 
Available at:  http://www.phac-aspc.gc.ca/aids-sida/publication/epi/2010/index-eng.php.  
Accessed April 13 2017.   
 2.  Public Health Agency of Canada. (2015) Summary: Estimates of HIV Incidence, 
Prevalence and Proportion Undiagnosed in Canada, 2014. Available at: 
http://healthycanadians.gc.ca/publications/diseases-conditions-maladies-affections/hiv-
aids-estimates-2014-vih-sida-estimations/index-eng.php. Accessed April 13 2017.   
 3.  Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in 
heterosexual men and women. N Engl J Med 2012 Aug 2;367(5):399-410. 
 4.  Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV 
prevention in men who have sex with men. N Engl J Med 2010 Dec 30;363(27):2587-99. 
 5.  McCormack S, Dunn DT, Desai M, et al. Pre-exposure prophylaxis to prevent the 
acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a 
pragmatic open-label randomised trial. Lancet 2016 Jan 2;387(10013):53-60. 
 6.  Molina JM, Capitant C, Spire B, et al. On-Demand Preexposure Prophylaxis in Men at 
High Risk for HIV-1 Infection. N Engl J Med 2015 Dec 3;373(23):2237-46. 
 7.  Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral Preexposure Prophylaxis 
for Heterosexual HIV Transmission in Botswana. N Engl J Med 2012;367:423-34. 
 8.  Amico KR, Stirratt MJ. Adherence to preexposure prophylaxis: current, emerging, and 
anticipated bases of evidence. Clin Infect Dis 2014 Jul;59 Suppl 1:S55-S60. 
 9.  Grant RM, Anderson PL, McMahan V, et al. Uptake of pre-exposure prophylaxis, sexual 
practices, and HIV incidence in men and transgender women who have sex with men: a 
cohort study. Lancet Infect Dis 2014 Sep;14(9):820-9. 
 10.  Tan DHS, Leon-Carlyled M, Mills R, Moses E, Carvalhal A. Self-administered screening 
for syndemic mental health problems should be routinely implemented among MSM PrEP 
users. Journal Gay Lesbian Mental Health 2016;20(1):13-20. 

 
Version 1.0. February 27, 2020 
 
Page 9 of 13 
 
 11.  Haberer JE, Baeten JM, Campbell J, et al. Adherence to antiretroviral prophylaxis for HIV 
prevention: a substudy cohort within a clinical trial of serodiscordant couples in East 
Africa. PLoS Med 2013;10(9):e1001511. 
 12.  Haberer JE, Kidoguchi L, Heffron R, et al. Alignment of adherence and risk for HIV 
acquisition in a demonstration project of pre-exposure prophylaxis among HIV 
serodiscordant couples in Kenya and Uganda: a prospective analysis of prevention-
effective adherence. J Int AIDS Soc 2017 Jul 25;20(1):1-9. 
 13.  Martin M, Vanichseni S, Suntharasamai P, et al. The impact of adherence to preexposure 
prophylaxis on the risk of HIV infection among people who inject drugs. AIDS 2015 Apr 
24;29(7):819-24. 
 14.  Mugo PM, Sanders EJ, Mutua G, et al. Understanding Adherence to Daily and Intermittent 
Regimens of Oral HIV Pre-exposure Prophylaxis Among Men Who Have Sex with Men in 
Kenya. AIDS Behav 2015 May;19(5):794-801. 
 15.  Storholm ED, Volk JE, Marcus JL, Silverberg MJ, Satre DD. Risk Perception, Sexual 
Behaviors, and PrEP Adherence Among Substance-Using Men Who Have Sex with Men: a 
Qualitative Study. Prev Sci 2017 Aug;18(6):737-47. 
 16.  van der Elst EM, Mbogua J, Operario D, et al. High acceptability of HIV pre-exposure 
prophylaxis but challenges in adherence and use: qualitative insights from a phase I trial of 
intermittent and daily PrEP in at-risk populations in Kenya. AIDS Behav 2013 
Jul;17(6):2162-72. 
 17.  Marcus JL, Hurley LB, Hare CB, et al. Preexposure Prophylaxis for HIV Prevention in a 
Large Integrated Health Care System: Adherence, Renal Safety, and Discontinuation. J 
Acquir Immune Defic Syndr 2016 Dec 15;73(5):540-6. 
 18.  Wilton J, Noor SW, Schnubb A, et al. High HIV risk and syndemic burden regardless of 
referral source among MSM screening for a PrEP demonstration project in Toronto, 
Canada. BMC Public Health 2018 Feb 27;18(1):292. 
 19.  Marshall BD, Operario D, Bryant KJ, et al. Drinking trajectories among HIV-infected men 
who have sex with men: a cohort study of United States veterans. Drug Alcohol Depend 
2015 Mar 1;148:69-76. 
 20.  Babor TF, Higgins-Biddle JC, Saunders JB, Monteiro MG, World Health 
Organization.Dept.of Mental Health and Substance Dependence. The Alcohol Use 
Disorders Identification Test. Guidelines for Use in Primary Care. 2nd ed. Geneva: World 
Health Organization; 2001. 
 21.  Cunningham JA, Wild TC, Cordingley J, van MT, Humphreys K. A randomized controlled 
trial of an internet-based intervention for alcohol abusers. Addiction 2009 
Dec;104(12):2023-32. 

 
Version 1.0. February 27, 2020 
 
Page 10 of 13 
 
 22.  Cunningham JA, Murphy M, Hendershot CS. Treatment dismantling pilot study to identify 
the active ingredients in personalized feedback interventions for hazardous alcohol use: 
randomized controlled trial. Addict Sci Clin Pract 2015;10:1. 
 23.  Doumas DM, Hannah E. Preventing high-risk drinking in youth in the workplace: a web-
based normative feedback program. J Subst Abuse Treat 2008 Apr;34(3):263-71. 
 24.  Doumas DM, Haustveit T. Reducing heavy drinking in intercollegiate athletes: Evaluation 
of a web-based personalized feedback program. The Sport Psychologist 2008;22:213-29. 
 25.  Doumas DM, McKinley LL, Book P. Evaluation of two Web-based alcohol interventions 
for mandated college students. J Subst Abuse Treat 2009 Jan;36(1):65-74. 
 26.  Fisher JD, Amico KR, Fisher WA, et al. Computer-Based Intervention in HIV Clinical 
Care Setting Improves Antiretroviral Adherence: The LifeWindows Project. AIDS Behav 
2011 Mar 31;15:1635-46. 
 27.  Bauermeister JA, Pingel ES, Jadwin-Cakmak L, et al. Acceptability and preliminary 
efficacy of a tailored online HIV/STI testing intervention for young men who have sex with 
men: the Get Connected! program. AIDS Behav 2015 Oct;19(10):1860-74. 
 28.  NDA-NIH. NIMH Data Archive (NDA).  2020. Ref Type: Online Source 
 
 29.  Romelsjo A, Leifman H, Nystrom S. A comparative study of two methods for the 
measurement of alcohol consumption in the general population. Int J Epidemiol 1995 
Oct;24(5):929-36. 
 30.  Hahn JA, Dobkin LM, Mayanja B, et al. Phosphatidylethanol (PEth) as a biomarker of 
alcohol consumption in HIV-positive patients in sub-Saharan Africa. Alcohol Clin Exp Res 
2012 May;36(5):854-62. 
 31.  Comasco E, Nordquist N, Leppert J, et al. Adolescent alcohol consumption: biomarkers 
PEth and FAEE in relation to interview and questionnaire data. J Stud Alcohol Drugs 2009 
Sep;70(5):797-804. 
 32.  Kip MJ, Spies CD, Neumann T, et al. The usefulness of direct ethanol metabolites in 
assessing alcohol intake in nonintoxicated male patients in an emergency room setting. 
Alcohol Clin Exp Res 2008 Jul;32(7):1284-91. 
 33.  Stewart SH, Reuben A, Brzezinski WA, et al. Preliminary evaluation of 
phosphatidylethanol and alcohol consumption in patients with liver disease and 
hypertension. Alcohol Alcohol 2009 Sep;44(5):464-7. 
 34.  Stewart SH, Law TL, Randall PK, Newman R. Phosphatidylethanol and alcohol 
consumption in reproductive age women. Alcohol Clin Exp Res 2010 Mar 1;34(3):488-92. 
 35.  de BA, Lof E, Walther L, et al. Varenicline for treatment of alcohol dependence: a 
randomized, placebo-controlled trial. Alcohol Clin Exp Res 2015 Nov;39(11):2189-99. 

 
Version 1.0. February 27, 2020 
 
Page 11 of 13 
 
 36.  Papas RK, Gakinya BN, Mwaniki MM, et al. Associations Between the 
Phosphatidylethanol Alcohol Biomarker and Self-Reported Alcohol Use in a Sample of 
HIV-Infected Outpatient Drinkers in Western Kenya. Alcohol Clin Exp Res 2016 
Aug;40(8):1779-87. 
 37.  Hahn JA, Anton RF, Javors MA. The Formation, Elimination, Interpretation, and Future 
Research Needs of Phosphatidylethanol for Research Studies and Clinical Practice. Alcohol 
Clin Exp Res 2016 Nov;40(11):2292-5. 
 38.  Aradottir S, Asanovska G, Gjerss S, Hansson P, Alling C. PHosphatidylethanol (PEth) 
concentrations in blood are correlated to reported alcohol intake in alcohol-dependent 
patients. Alcohol Alcohol 2006 Jul;41(4):431-7. 
 39.  Hartmann S, Aradottir S, Graf M, et al. Phosphatidylethanol as a sensitive and specific 
biomarker: comparison with gamma-glutamyl transpeptidase, mean corpuscular volume 
and carbohydrate-deficient transferrin. Addict Biol 2007 Mar;12(1):81-4. 
 40.  Winkler M, Skopp G, Alt A, et al. Comparison of direct and indirect alcohol markers with 
PEth in blood and urine in alcohol dependent inpatients during detoxication. Int J Legal 
Med 2013 Jul;127(4):761-8. 
 41.  Wurst FM, Thon N, Aradottir S, et al. Phosphatidylethanol: normalization during 
detoxification, gender aspects and correlation with other biomarkers and self-reports. 
Addict Biol 2010 Jan;15(1):88-95. 
 42.  Wurst FM, Thon N, Yegles M, Schruck A, Preuss UW, Weinmann W. Ethanol metabolites: 
their role in the assessment of alcohol intake. Alcohol Clin Exp Res 2015 
Nov;39(11):2060-72. 
 43.  Chesney MA, Ickovics JR, Chambers DB, et al. Self-reported adherence to antiretroviral 
medications among participants in HIV clinical trials: the AACTG adherence instruments. 
Patient Care Committee & Adherence Working Group of the Outcomes Committee of the 
Adult AIDS Clinical Trials Group (AACTG). AIDS Care 2000 Jun;12(3):255-66. 
 44.  Walsh JC, Mandalia S, Gazzard BG. Responses to a 1 month self-report on adherence to 
antiretroviral therapy are consistent with electronic data and virological treatment outcome. 
AIDS 2002 Jan 25;16(2):269-77. 
 45.  Simoni JM, Huh D, Wang Y, et al. The validity of self-reported medication adherence as an 
outcome in clinical trials of adherence-promotion interventions: Findings from the 
MACH14 study. AIDS Behav 2014 Dec;18(12):2285-90. 
 46.  Anderson PL, Glidden DV, Liu A, et al. Emtricitabine-tenofovir concentrations and pre-
exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med 2012 Sep 
12;4(151):151ra125. 

 
Version 1.0. February 27, 2020 
 
Page 12 of 13 
 
 47.  Baxi SM, Liu A, Bacchetti P, et al. Comparing the novel method of assessing PrEP 
adherence/exposure using hair samples to other pharmacologic and traditional measures. J 
Acquir Immune Defic Syndr 2015 Jan 1;68(1):13-20. 
 48.  Castillo-Mancilla JR, Zheng JH, Rower JE, et al. Tenofovir, emtricitabine, and tenofovir 
diphosphate in dried blood spots for determining recent and cumulative drug exposure. 
AIDS Res Hum Retroviruses 2013 Feb;29(2):384-90. 
 49.  Corneli A, Perry B, Agot K, Ahmed K, Malamatsho F, Van DL. Facilitators of adherence 
to the study pill in the FEM-PrEP clinical trial. PLoS ONE 2015;10(4):e0125458. 
 50.  Liu A, Glidden DV, Anderson PL, et al. Patterns and correlates of PrEP drug detection 
among MSM and transgender women in the Global iPrEx Study. J Acquir Immune Defic 
Syndr 2014 Dec 15;67(5):528-37. 
 51.  Liu AY, Yang Q, Huang Y, et al. Strong relationship between oral dose and tenofovir hair 
levels in a randomized trial: hair as a potential adherence measure for pre-exposure 
prophylaxis (PrEP). PLoS ONE 2014;9(1):e83736. 
 52.  Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-based preexposure prophylaxis 
for HIV infection among African women. N Engl J Med 2015 Feb 5;372(6):509-18. 
 53.  Matthews LT, Heffron R, Mugo NR, et al. High medication adherence during 
periconception periods among HIV-1-uninfected women participating in a clinical trial of 
antiretroviral pre-exposure prophylaxis. J Acquir Immune Defic Syndr 2014 Sep 
1;67(1):91-7. 
 54.  Minnis AM, van der Straten A, Salee P, Hendrix CW. Pre-exposure Prophylaxis Adherence 
Measured by Plasma Drug Level in MTN-001: Comparison Between Vaginal Gel and Oral 
Tablets in Two Geographic Regions. AIDS Behav 2016 Jul;20(7):1541-8. 
 55.  Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection 
among African women. N Engl J Med 2012 Aug 2;367(5):411-22. 
 56.  The Explore Team. Effects of a behavioural intervention to reduce acquisition of HIV 
infection among men who have sex with men: the EXPLORE randomised controlled study. 
Lancet 2004;364:41-50. 
 57.  National Institute on Drug Abuse. (2012) Resource Guide: Screening for Drug Use in 
General Medical Settings. Available at: https://www.drugabuse.gov/publications/resource-
guide. Accessed April 13, 2017.   
 58.  Andresen EM, Malmgren JA, Carter WB, Patrick DL. Screening for depression in well 
older adults: evaluation of a short form of the CES-D (Center for Epidemiologic Studies 
Depression Scale). Am J Prev Med 1994 Mar;10(2):77-84. 

 
Version 1.0. February 27, 2020 
 
Page 13 of 13 
 
 59.  Riper H, Blankers M, Hadiwijaya H, et al. Effectiveness of guided and unguided low-
intensity internet interventions for adult alcohol misuse: a meta-analysis. PLoS ONE 
2014;9(6):e99912. 
 60.  Newcombe RG. Interval estimation for the difference between independent proportions: 
comparison of eleven methods. Stat Med 1998 Apr 30;17(8):873-90. 
 61.  Detry MA, Ma Y. Analyzing Repeated Measurements Using Mixed Models. JAMA 2016 
Jan 26;315(4):407-8. 
 62.  Rabe-Hesketh S, Skrondal A. Multilevel and Longitudinal Modeling Using Stata. 3rd ed. 
College Station, Texas: Stata Press.; 2012. 
 63.  Ma Y, Mazumdar M, Memtsoudis SG. Beyond repeated-measures analysis of variance: 
advanced statistical methods for the analysis of longitudinal data in anesthesia research. 
Reg Anesth Pain Med 2012 Jan;37(1):99-105. 
 64.  Newgard CD, Lewis RJ. Missing Data: How to Best Account for What Is Not Known. 
JAMA 2015 Sep 1;314(9):940-1.