Computer-based Alcohol Reduction Intervention for Alcohol-using HIV/HCV+ Russian Women in Clinical Care
Phase: NA
Conditions: Human Immunodeficiency Virus, Hepatitis C, Alcohol Abuse
Sponsor: New York University

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Title 
Computer-Based Alcohol Reduction Intervention for Alcohol-Using HIV/HCV Co-Infected Russian Women in 
Clinical Care: Study Protocol for a Randomised Controlled Trial 
 
Trial registration:  ClinicalTrials.gov, NCT03362476. Registered 5 December 2017, 
https://clinicaltrials.gov/ct2/show/NCT03362476 
 
Document date: February 1, 2021 
 

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Abstract 
Background: Russia has a high prevalence of (human immunodeficiency virus) HIV infections. In 2018, over 
one million persons were living with HIV (PLWH); over a third were women. A high proportion of HIV-infected 
women are co-infected with Hepatitis C virus (HCV), and many consume alcohol, which adversely affects 
HIV and HCV treatment and prognosis. Despite the triple epidemics of alcohol use, HIV and HCV, and the 
need for interventions to reduce alcohol use among HIV/HCV co-infected women, evidence-based alcohol 
reduction interventions for this vulnerable population are limited. To address this gap, we developed a 
clinical trial to evaluate the efficacy of a computer-based intervention to reduce alcohol consumption among 
HIV/HCV co-infected women in clinical care.  
 
Methods: In this two-arm parallel randomized clinical trial, we propose to evaluate the efficacy of a culturally-
adapted alcohol reduction intervention delivered via a computer for HIV/HCV co-infected Russian women. 
The study population consists of women 21-45 years old with confirmed HIV/HCV co-infection who currently 
use alcohol. Intervention efficacy is assessed by a novel alcohol biomarker, ethyl glucuronide (EtG), and 
biomarkers of HIV and HCV disease progression. Women are randomized to trial conditions in a 1:1 
allocation ratio, using a computer-generated algorithm to develop the assignment sequence and 
concealment of allocation techniques to minimize assignment bias. Women are randomized to either: (1) 
standard-of-care, clinician-delivered MET, plus a computer-based MET intervention, or (2) standard-of-care 
plus clinician-delivered motivational enhancement therapy (MET). We will use an intent-to-treat analysis and 
logistic and linear generalized estimating equations to evaluate intervention efficacy, relative to the standard-
of-care, in enhancing the proportion of women with a laboratory-confirmed negative EtG at each research 
study visit over the 9-month follow-up period. Additional analyses will evaluate intervention effects on HIV 
(viral load and CD4+ levels) and HCV markers of disease progression (FibroScan). 
 
Discussion: The proposed trial design and analysis provides an appropriate conceptual and methodological 
framework to assess the efficacy of the computer-based intervention. We propose to recruit 200 participants.   
The intervention, if efficacious, may be an efficient and cost-effective alcohol reduction strategy that is 
scalable and can be readily disseminated and integrated into clinical care in Russia to reduce women’s 
alcohol consumption and enhance HIV/HCV prognosis. 
 
 
Keywords 
HIV, Hepatitis C virus, HIV/HCV co-infection, Russia, women, service integration, alcohol reduction 
intervention, computer-delivered alcohol intervention, randomised controlled trial  
 
 
 

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Introduction 
 
Background and rationale 
The human immunodeficiency virus (HIV) and hepatitis C virus (HCV) epidemics are interrelated with 
increasing prevalence in Russia. As of 2018, over one million persons were living with HIV (PLWH) in the 
Russian Federation (Russia).2 Women made up 37% of new HIV diagnoses, almost tripling the 2006 
prevalence rate.2  
 
The severity of the HIV epidemic is compounded by the intersecting HCV epidemic. Eastern Europe has the 
largest proportion of PLWH with serological evidence of HCV infection (27%).3 The prevalence of HIV/HCV 
co-infection is markedly higher among individuals with a history of injection drug use (PWID). A recent review 
estimated an HCV prevalence of 69% among PWID compared to 4.6% among PLWH without a history of 
injection drug use in Russia.4 Among HIV-infected women in Saint Petersburg, Russia, a study by our group 
observed that 57.1% were HCV co-infected.5 Behaviours related to injection drug use, such as needle 
sharing, have contributed to the rapid spread of HIV/HCV co-infection among PWID globally,6 including in 
Saint Petersburg, Russia.7-9  
 
Alcohol use poses a significant and persistent health threat to women living with HIV/HCV co-infection. 
Despite substantial reductions in alcohol use over the past two decades,10 problem alcohol use is prevalent 
in Russia and adversely impacts the treatment and prognosis of women living with HIV/HCV by accelerating 
HIV and HCV progression.11 A recent meta-analysis estimated that 55% [95% confidence interval (CI): 16%-
88%] of Russian participants engaged in heavy episodic drinking and 58% (95% CI: 49%-67%) met 
diagnostic criteria for alcohol use disorder.12 A World Health Organization study estimated that among 
Russian women, 43.7% of those who drank were heavy episodic drinkers compared to 19.9% in Europe as a 
whole.13 A recent study among PLWH in Saint Petersburg found that, overall, 45.3% of women reported 
drinking in the past week. Of those, 21.6% reported at least one heavy episodic drinking episode (4 or more 
drinks).14 
 
Among HIV/HCV co-infected individuals, alcohol use may also lead to various adverse health outcomes. 
HIV/HCV co-infected individuals develop liver disease earlier and are diagnosed with more severe liver 
disease than those who are HIV mono-infected.15-17 Excessive alcohol consumption is a significant 
contributor to liver-related mortality among persons with HIV/HCV co-infection.18 The adverse impact of 
alcohol use may be worse for women, who are more prone to rapid fibrosis progression and cirrhosis than 
men.19 In addition to direct health complications, alcohol may heighten health risks to PLWH by interacting 
with antiretroviral (ARV) therapy. For example, alcohol and ARV interactions may contribute to hepatoxicity 
and liver disease,15,17 which may be accelerated by co-morbid HCV infection.20 Furthermore, a history of 
alcohol use may impede persons with HIV/HCV co-infection from benefiting from the new generation of HCV 
treatments, such as direct acting anti-HCV drugs.21 Current recommendations are for individuals with 
HIV/HCV co-infection to abstain from alcohol use given that safe drinking levels have not been defined for 

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this population.22 There is conflicting evidence concerning the health effects of moderate alcohol 
consumption among HCV mono-infected and HCV/HIV co-infected persons, with some studies finding that 
even moderate amounts of alcohol may accelerate disease progression, while other studies identify no such 
association.23,24 
 
Despite the need for interventions to reduce alcohol use among HIV/HCV co-infected women, few evidence-
based interventions are available.25,26 A recent review of interventions to reduce alcohol consumption among 
PLWH identified limited evidence that interventions reduced binge drinking frequency, alcohol use disorders, 
or alcohol dependence symptoms.25 Furthermore, most of the interventions did not target alcohol use 
exclusively, but addressed other high-risk behaviours (e.g., reducing sexual risk behaviours) or focused on 
substance use more broadly. In addition, the majority of interventions were conducted in the U.S.; to our 
knowledge, none were implemented and evaluated in Russia.25 
 
In this two-arm parallel randomized clinical trial, we propose to evaluate the efficacy of a brief, culturally-
adapted, computer-delivered alcohol reduction intervention for Russian women with HIV/HCV co-infection. 
The intervention includes modules utilizing cognitive behavioural and motivational enhancement principles to 
reduce alcohol consumption. Brief interventions based on cognitive behavioural therapy that include 
personalized feedback about alcohol use, the establishment of personal drinking goals, and tracking of goal 
progress coupled with behavioural strategies to reduce alcohol use are efficacious.27,28 
 
The proposed intervention will be brief and delivered via a computer-platform. Computer-delivered alcohol 
reduction interventions effectively lower problematic alcohol use, albeit with small effect sizes29,30 and may 
be more cost-effective and feasible to integrate into clinical care settings than existing interventions delivered 
by experienced, trained clinical providers. A mounting body of evidence points to the promise of integrating 
treatment for alcohol use within comprehensive HIV-care services.31 If efficacious, our intervention may be a 
scalable and cost-effective strategy to reduce alcohol use among women with HIV/HCV co-infection within 
the framework of comprehensive HIV care, in line with current strategies to strengthen HIV-care delivery. 
 
Objectives 
The study objectives are: 
1. To evaluate the efficacy of a standard-of-care, clinician-delivered MET, plus a computer-based MET 
intervention, relative to the standard of care plus clinician-delivered MET condition, in enhancing the 
proportion of HIV/HCV co-infected women detected with laboratory-confirmed negative alcohol 
biomarker over a 9-month follow-up period. 
2. To evaluate the efficacy of a computer-based MET intervention condition, relative to the standard of 
care plus clinician-delivered MET condition, in reducing HIV/HCV co-infected women’s HIV and HCV 
biomarkers of disease progression over a 9-month follow-up period. 
 
Trial design 

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The proposed study is a parallel two-arm randomized control trial to evaluate the efficacy of a culturally-
adapted computer-based alcohol reduction intervention for HIV/HCV co-infected Russian women in clinical 
care.  
 
Following receipt of informed consent and enrolment in the study, 200 women are randomized to one of two 
conditions following a 1:1 allocation ratio: (1) standard-of-care, the clinician-delivered MET, plus the adapted 
computer-based intervention condition (n=100), or (2) the standard-of-care plus clinician-delivered MET 
(n=100).  
 
Data are collected at baseline, before randomization, and at 3-, 6- and 9-month follow-up during scheduled 
research visits via self-report surveys. In addition, biological markers are collected at baseline and at each 
follow-up assessment to obtain objective and quantifiable measures of alcohol use and HIV and HCV 
disease status. The proposed trial design provides an appropriate conceptual and methodological framework 
to determine the intervention’s efficacy in reducing alcohol use and HIV and HCV disease progression (see 
Figure 1). 
 
Methods: Participants, interventions and outcomes 
Study setting 
The intervention is implemented in HIV clinical care facilities in Saint Petersburg, Russia. Saint Petersburg is 
the second largest city in Russia, with a population of approximately 5 million. It has a high concentration of 
PWID, a critical risk behaviour associated with HIV/HCV acquisition.7 An estimated 40,000 PLWH live in 
Saint Petersburg, with about 2000 new cases diagnosed annually.32 There is a high prevalence of HCV 
infection among Russian PLWH.5 The current study includes women seeking HIV care at two clinical care 
sites. Both sites offer comprehensive HIV care, including mental health care, for HIV-infected women. 
 
Eligibility criteria 
Eligible participants must: 1) be women ages 21-45 years; 2) have chart-documented HIV and HCV 
infection; 3) be currently prescribed ARV therapy; 4) have a positive point-of-care ethyl glucuronide (EtG) or 
self-report alcohol use in the past 30 days. Women who are medically, cognitively, or psychologically 
incapable of study participation, as assessed by a research clinician, are excluded, as those who do not 
provide written informed consent to participate. 
 
Who will take informed consent? 
A research staff member explains the study, reviews the consent form with participants, and answers any 
questions before women provide written consent to participate in the study. All eligible participants must 
complete consent procedures before enrolment and randomisation. Measures are being implemented to 
protect study participants. Study staff are instructed to highlight confidentiality and assure participants that 
their responses would not be shared with clinic staff or adversely affect service provision.  
 

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Compensation 
Participants receive a 1000-ruble (~16 United States Dollars, USD) valued gift card at baseline and at the 9-
month follow-up visit and a 500-ruble (~8 USD) valued gift card for each completed intermediary 
assessments (3- and 6-month research visits). 
 
Additional consent provisions for collection and use of participant data and 
biological specimens 
The consent form explains to participants that de-identified data will be part of a general dataset that may be 
shared with other researchers. In terms of biological specimens, the consent form explains that if participants 
choose to join the study, they will be donating their samples and study information. If they withdraw from the 
study, data and samples collected may still be used for this study. Participants are informed that study 
records can be opened by court order and may be provided in response to a subpoena or a request for the 
production of documents. Further study records may be shared with regulatory authorities, such as the IRB, 
government agencies and study funders. 
 
Interventions 
Explanation for the choice of comparators 
This trial compares the efficacy of clinician-delivered alcohol reduction MET counselling to a computer-
delivered MET-based alcohol use reduction intervention. We hypothesize that the computer-delivered 
intervention may be less costly, less demanding on human resources and more feasible to integrate into 
clinical care than the current standard-of-care, with comparable results. 
 
Intervention description 
 
Standard-of-care condition plus clinician-delivered MET plus computer-based MET counseling 
 
Women in the intervention condition receive a brief computer-based intervention to reduce alcohol use 
guided by cognitive behavioural principles. The computerized intervention includes modules to: (a) provide 
an overview of the intervention and information regarding the impact of alcohol use on disease progression; 
(b) assess current levels of drinking and provide feedback on alcohol use; (c) set alcohol reduction goals and 
enhance motivation to modify drinking behaviours; (d) address challenges associated with achieving drinking 
goals; and (e) provide strategies to reduce alcohol use. The computerized intervention was adapted to be 
culturally appropriate and incorporates vignettes to illustrate intervention content. After each computer-based 
session, a study clinician meets with participants to establish drinking goals and discuss strategies to 
achieve these goals during a brief one-on-one motivational enhancement session. Participants randomized 
to the intervention condition also continue to receive the standard of care for alcohol use provided in the 
clinic plus clinician-delivered MET. 
 

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Standard-of-care condition plus clinician-delivered MET 
 
Women receiving treatment for HIV/HCV at the two clinical care sites are routinely asked about their alcohol 
and other substance use and counselled using MET approaches to avoid alcohol and other substances by 
clinical staff. When the treating clinician deems it appropriate, women are referred to community-based care 
for substance use treatment. In addition, all women receive an educational brochure with information 
describing the adverse effects of alcohol use for persons with HIV/HCV co-infection and a list of community-
based resources to seek further help.  
 
Criteria for discontinuing or modifying allocated interventions 
A staff psychiatrist assesses women’s mental health as part of routine care and as requested by a treating 
clinician and refers women diagnosed with alcohol dependence to substance use treatment. The psychiatrist 
may recommend discontinuing participation in the trial if a participant is deemed psychologically incapable of 
continued participation. 
 
Strategies to improve adherence to interventions 
The intervention consists of taking a brief computer-based program; therefore, the key strategy to promote 
adherence is the outreach efforts to invite women back to the clinic to complete the first and follow-up 
sessions. To improve adherence, research staff will call participants to schedule visits, using the contact 
information on file at the clinical sites.  
 
Relevant concomitant care permitted or prohibited during the trial 
All routine treatment procedures for women in care for HIV and HCV, as deemed appropriate by the patient’s 
treating clinicians, are permitted during the trial. 
 
Provisions for post-trial care 
Trial participation does not present more than minimal risk to subjects beyond those encountered as part of 
routine care. Therefore, no special provisions for post-trial care were included. 
 
Outcomes 
Biomarkers (EtG and phosphatidylethanol, PEth) are used to assess the efficacy of the intervention on 
alcohol use patterns and two associated health outcomes, HIV and HCV, as described below.  
 
The primary outcome measure used to evaluate the efficacy of the adapted computer-based alcohol 
reduction intervention condition plus the clinician-delivered MET, relative to the standard of care plus 
clinician-delivered MET condition alone, will be the proportion of women who test EtG negative at each of the 
follow-up assessments over 9-months. 
 

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HIV disease progression is evaluated based on changes in HIV viral load and CD4+ count over the 9-month 
follow-up period in the intervention arm relative to the control arm. HCV disease progression is assessed 
using two non-invasive biomarkers collected routinely as part of ongoing HCV care. The first is FibroTest 
which uses six different biomarkers (α2-macroglobulin, haptoglobin, γ-glutamyl transpeptidase, 
apolipoprotein A1, alanine transaminase, and total bilirubin) to generate a score that is correlated with the 
degree of liver damage.33 The second is FibroScan, a specialized ultrasound that measures the degree of 
fibrosis and steatosis in the liver, providing objective and quantifiable measures of HCV-associated liver 
damage.34 The procedure is painless and performed at point-of-care. 
 
Sample size 
The sample size of 200 women (1:1 allocation ratio) was arrived at based on a power analysis. The most 
conservative hypothesis compares differences between trial conditions in the proportion of participants 
detected with a negative EtG test over the 9-month follow-up. EtG was selected for the power analysis 
because it is a sensitive biological test of alcohol use and has a broad alcohol detection window (5 days). 
The power calculations for the negative EtG test were based on our previous pilot study in which 30% of 
HIV/HCV-infected Russian women were identified with a negative alcohol use biomarker.35 Our study is 
powered to detect a small effect (delta = -0.2; odds ratio = 0.3) in the number of women testing EtG negative 
under a repeated measures logistic regression analysis framework, assuming an intra-cluster correlation of 
0.10 and 10% loss-to-follow-up. Analyses were conducted in Stata 15.1 (Stata Corporation LP, College 
Station, TX). 
 
Recruitment  
Recruitment is conducted at two affiliated clinical sites that provide comprehensive HIV care. The study 
coordinator in Russia, a medical doctor with specialization in infectious diseases, reviews medical records to 
assess potential eligibility. A clinician at each clinic then invites participants to the study and schedules a 
follow-up visit with a research staff member.  
 
Assignment of interventions: allocation 
Sequence generation  
A computer algorithm is used to generate a random allocation sequence prior to the study initiation.  
 
Concealment mechanism  
We use concealment of allocation techniques to promote unbiased randomization.36 Predetermined 
allocations are sequentially numbered. 
 
Implementation  

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The random allocation sequence is generated in the U.S. and shared with Russian staff to implement. Only 
the Russian-based study coordinator has the list of allocations generated in the U.S. and informs other 
researchers of the allocation following participant screening and enrolment. 
 
Assignment of interventions: Blinding 
Who will be blinded  
Because the intervention entails completing a computer-based program, neither providers nor participants 
are blinded to the intervention assignment; however, the statisticians conducting the efficacy analyses will be 
blinded to allocation. Research members in Russia will assign a code to each of the two arms, which will be 
undisclosed to U.S.-based data analysts. 
 
Procedure for unblinding if needed  
The design is an open label, so unblinding will not occur. 
 
Data collection and management 
Plans for assessment and collection of outcomes  
Data for efficacy assessment is collected at baseline and 3-, 6- and 9-months post-intervention initiation 
using multiple data-capture modalities. Participants complete a brief self-report survey assessing basic 
demographics, and history of alcohol and other substance use. In addition to basic demographics, such as 
age, education and income, the brief survey includes validated self-report measures of alcohol use (e.g., 
alcohol use frequency and quantity, and heavy episodic drinking).37 The trained attending clinicians, one at 
each clinic, collect two biomarkers: 1) a urine sample from each woman at each study visit for EtG analysis, 
which assesses recent alcohol use; and 2) a dried blood spot at the 9-month follow-up for PEth analysis, 
which measures alcohol use over the past 21-days. A research staff member abstracts via medical record 
review the following data: (a) length of HIV and HCV infection, (b) HIV viral load, (c) cluster of differentiation 
4 cells (CD4+) count, (d) FibroTest score (based on liver function biomarkers, such as apolipoprotein A1, 
alanine transaminase, and total bilirubin, etc.), (e) prescribed ARV regime, and (f) HCV treatment. Research 
staff consisted of clinicians experienced in the care of PLWH who received training on implementation of 
study procedures, including on EtG administration at point-of-care.  
 
EtG is an ethanol metabolite widely used to detect any alcohol consumption in the past 24 hours.38 When 
measured in urine at point-of-care, it is estimated to have a sensitivity of 100% and a specificity of 97%.39 
PEth is a well-established marker of past 3-week alcohol use,40 including among PLWH.41,42  Among PLWH, 
the sensitivity for any detectable PEth has been estimated at 88% and the specificity at 89%.42 Collecting 
three different alcohol use measures –EtG, PEth, and self-reported use– will allow us to triage the 
information and assess measurement errors and reporting biases. FibroTest is a scoring system based on 

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biochemical markers to evaluate the stage of fibrosis among patients with HCV and is considered a safe, 
non-invasive alternative to liver biopsy.43,44 FibroTest has satisfactory predictive validity of fibrosis staging, 
with Areas Under the Curve ranging from 73% to 80% depending on liver disease progression compared to 
biopsy results.44 
 
Plans to promote participant retention and complete follow-up  
Based on a previous trial in this population45 and on pilot work during adaptation of the computerized 
intervention, we expect loss-to-follow-up to be minimal and not to exceed 10%. Factors to improve 
intervention adherence and prevent loss-to-follow-up over the 9-month follow-up period are that all research 
personnel and clinical staff are highly qualified and trained in working with PLWH; that most patients have a 
trusting relationship with study clinicians; and that all research staff is from Saint Petersburg. In addition, staff 
will call participants to schedule subsequent research visits. Participants’ contact information is on file at the 
clinical care sites. 
 
Data management  
In accordance with the National Institutes of Health (NIH) requirements, the clinical trial established a data 
and safety monitoring plan to ensure participants’ privacy and confidentiality during the trial and as part of 
data collection and storage. The plan is overseen by a four-member committee composed of the principal 
investigators and a study coordinator in Russia.  
 
The data safety and monitoring plan stipulates that all records pertaining to the study and all original and 
electronic data files are to be securely stored off-site, in a locked metal file cabinet, accessible only to one of 
the Russian-based principal investigators. This is also true for completed and signed consent forms. To 
ensure participants’ safety and the data’s validity and integrity, only staff with extensive experience in the 
area of HIV/HCV treatment will be hired. All research staff will receive training on data collection, 
management and storage procedures (including of survey data and biomarkers), maintaining confidentiality, 
and research ethics. On an ongoing basis, the Russian-based study coordinator will review the data to 
ensure data quality, including checking the range of values, and identifying any inconsistencies in the data. 
No names or other identifying information appears on data documents or in data files. Pen and pencil 
surveys will also contain no identifiers. Only designated staff will have access to the data at each site. 
Presentations and publications will not disclose the names of the clinical sites where the research was 
implemented. When the final dataset is made publicly available, data will not contain identifying information. 
 
The data safety and monitoring plan stipulates the following data management procedures, as described in 
this protocol: data entry is the responsibility of the study coordinator, who enters all data onto an Excel 
worksheet. The Excel worksheet includes screening information but not randomisation information, which is 
kept in a separate password-protected file. Research personnel at two sites in Russia are in charge of 
screening procedures and administering the paper-based surveys and of collecting the biomarkers for 
analysis after randomization. The study coordinator is responsible for assigning allocations based on trial 

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condition assignments generated in the U.S. All surveys and biomarkers are marked with a trial identification 
number, assigned by the study coordinator, to ensure anonymity. One person at each study site is 
responsible for personally delivering the surveys and the biomarkers to the study coordinator. The study 
coordinator extracts information from the paper-based surveys, from medical records, and from lab reports to 
populate the database. The coding used on the general dataset for data entry is based on the survey: each 
survey item includes numeric codes, and these are used for data entry. The de-identified general database 
will be password protected and shared periodically with researchers in the U.S. for a range of data value 
checks. 
 
 
Confidentiality {27} 
All data collected during the study will be kept strictly confidential and only accessed by research staff, 
unless requested by the research sites’ IRB members or by the sponsor. Participants are assigned a trial 
identification number. Only the study coordinator has the list linking identifying information with the 
identification number; this list is password-protected and stored on her personal computer, also password-
protected. The de-identified dataset will be available to the rest of the research staff, and after analyses and 
publication of primary findings will be made available to other researchers upon request. 
 
Plans for collection, laboratory evaluation and storage of biological specimens for 
genetic or molecular analysis in this trial/future use {33} 
At baseline and each follow-up assessment, women provide a urine sample, which is analysed for EtG at the 
[redacted]. The limit of detection is >500 nanograms/millilitre (ng/mL). In addition, at the 9-month follow-up, 
clinicians collect dried blood spot samples, which will be analysed for PEth using U.S. Drug Testing 
Laboratory standardized procedures (USDTL, Des Plaines, IL). The PEth samples are analysed at the 
[redacted] in Irkutsk, Russia. The limit of detection is 8 ng/mL; any result above this threshold is considered 
positive for alcohol consumption within the last 21 days. Urine samples will be disposed of immediately 
following analysis at point-of-care. The dried blood spot cards will be labelled with a participant number to 
protect the participants’ identity and stored at -30 degrees Celsius at the main clinical site until shipped to 
Irkutsk for processing. These biological specimens will be destroyed after processing. 
 
Statistical methods 
Statistical methods for primary and secondary outcomes {20a} 
We will use an intent-to-treat analysis and logistic and linear generalized estimating equations to evaluate 
intervention efficacy, relative to the standard-of-care, in enhancing the proportion of women with a 
laboratory-confirmed negative EtG over the follow-up period, thus assessing whether there was a significant 
reduction in alcohol use in the intervention group, compared to the control group. Given that there is no 
consensus regarding safe levels of alcohol use among HIV/HCV-infected individuals46,47 and current 

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recommendations are to abstain from alcohol use,48 a key outcome is the proportion of women who test EtG 
negative (<500 ng/mL) over the 9-month follow-up in each trial condition. To triage results with self-reported 
patterns of alcohol use patterns and EtG, we will also use a novel alcohol use biomarker, PEth collected 
once at follow-up. We will conduct multilevel regression analyses to account for clustering effects at the two 
clinical sites, and between- and within-subject variation. Following the conventions in most trials, we will 
model treatment differences as a fixed-effect and use random effects for modelling the clustering effects of 
cohort and repeated measures data. 
 
We will utilize a similar analysis to assess whether the intervention resulted in differences in liver disease 
progression by evaluating changes in indirect serum markers of liver function based on mean FibroTest 
scores and direct biomarker of disease progression, FibroScan, and whether the intervention affected HIV 
disease progression by assessing changes in mean viral load and CD4+ levels between the two conditions. 
 
Oversight and monitoring 
Composition of the coordinating centre and trial steering committee {5d} 
 
A five-member steering committee was formed, composed of the principal investigators in the U.S. (RJD, 
JLB) and in Russia (NB, VR) and the Russian-based study coordinator (EB). The committee’s role is to 
assess progress and ensure quality and compliance with recruitment and study procedures. The committee 
meets virtually monthly to evaluate project progress, review modifications, and monitor compliance with 
guidelines from the relevant institutional ethics committees and The Office for Human Research Protections 
of the U.S. Department of Health and Human Services. VR supervises the trial operations in Russia. EB is 
the project coordinator and oversees all aspects of screening, recruitment, consent, and study protocols 
implementation at the two study sites. EB and LVG are in charge of the identification, screening of potential 
participants and recruitment. NBK, a psychiatrist with expertise in treating patients with chronic infectious 
diseases, interviews and administers the survey to participants. EB and LVG are in charge of collecting the 
biomarkers. The Russian team (NB, VR, EB, LVG and NKB) hold coordination meetings weekly.  
 
Composition of the data monitoring committee, its role and reporting structure {21a} 
 
The data monitoring committee is composed of EB, JLB and AC. The role of the committee is to conduct 
quarterly data checks to identify potential errors. In addition, the committee routinely assesses if proper 
procedures are in place to ensure that data remain confidential and that there are no data breaches. If any 
problems are identified, the data monitoring committee informs members of the trial steering committee, who 
depending on the type of problem, file a report to the respective IRBs and/or the sponsor. The committee is 
independent of the sponsor and none of the members have competing interests to declare.  
 
Adverse event reporting and harms {22} 

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A system for monitoring and reporting adverse events was established. All research team members were 
trained on recognizing and documenting any unusual events or circumstances that may occur during data 
collection. Researchers will record their observations on comment cards that will be reviewed by the study 
coordinator. Should a serious adverse event occur, the study coordinator will immediately inform the 
principal investigators who, in turn, will immediately notify New York University’s Institutional Review Board 
(IRB). If an adverse event appears to be research-related, it will be reported to the Office for Human 
Research Protections of the U.S. Department of Health and Human Services and the funding institution 
project officer, along with summaries of discussions concerning the event. The funding institution project 
officer will be informed of any IRB action taken concerning any adverse event. Research staff will be 
monitored closely by the principal investigators and the study coordinator. Staff deficits will be addressed via 
additional training, close monitoring for proficiency, and if not adhering to established protocols and 
procedures, will be terminated.  
 
Frequency and plans for auditing trial conduct {23} 
The principal investigators will conduct semi-annual field visits to assess that procedures are being 
implemented as planned at all sites. These audits are independent of the sponsor and will entail observation 
of data collection efforts. The trial steering committee meets monthly to assess progress. Any issues 
identified during semi-annual field visits or during weekly meetings of the Russian-based field team will be 
immediately reported to the trial steering committee for a full investigation. In addition, members of the data 
monitoring committee will meet every six-months to conduct data checks. Ad hoc emergency meetings of the 
committee will be called if a data breach or data errors are identified. 
 
Plans for communicating important protocol amendments to relevant parties (e.g., 
trial participants, ethical committees) {25} 
Changes to the proposed protocol will require a re-submission to the IRB of both institutions and updates to 
the trial registry. If changes to the protocol are different from what was explain to participants during consent, 
participants will be duly informed of the modifications and re-consented by research staff before continuing in 
the study.  
 
Dissemination plans {31a} 
Trial results will be shared in peer-reviewed, open-access publications and at national and international 
research and policy conferences. The final data set will be available through an open access data repository. 
 
Discussion 
If efficacious in reducing alcohol use, this brief computer-delivered intervention for alcohol using HIV/HCV 
co-infected women in Russia would have several advantages. First, the computer-based platform affords 

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participants greater confidentiality, thus encouraging participants to set realistic goals without perceiving 
pressure from healthcare providers. The digital platform offers greater flexibility of administration, for 
example, participants can go through the program at their own pace. Importantly, the participants’ ability to 
replay segments of the intervention as needed may reinforce risk reduction by enhancing learning and 
alcohol reduction messages. 
 
The proposed intervention is novel in several ways. First, it is delivered through a computer-based platform. 
Computer-delivered alcohol reduction interventions effectively reduce problematic alcohol use, albeit with 
small effect sizes,29,30 and may be more cost-effective than existing interventions delivered by experienced 
clinical providers. A computer-based platform offering a brief intervention is less labour- and cost-intensive 
than traditional interventions and has the potential to be more feasible for integration into the clinical care 
setting. Third, the study collects two alcohol use biomarkers to assess intervention efficacy, rather than 
relying on self-report, which is prone to reporting biases. Data from a previous study with this population 
indicated that alcohol use was often underreported.49 It will also utilize objective markers of liver function and 
HIV and HCV disease progression.  
 
As the HIV and HCV epidemics continue to grow, increasing the number of people in care, the computerized 
intervention program may allow for more patients to receive critical messages related to alcohol use while 
reducing the burden on trained healthcare providers in an already heavily demanding clinical care setting. A 
computer-based intervention may be as or more efficacious (the objective of this trial is to assess efficacy 
relative to the standard of care) than other service delivery modalities but less labour intensive and less 
costly to implement and sustain. Because of the ubiquity and affordability of Wi-Fi and portable technology in 
clinical care settings in Russia and the limited demand of the intervention on healthcare providers’ time, this 
computer-based intervention may be a feasible and cost-effective option for scale-up and dissemination to 
other HIV centres in Russia, and even to different clinical settings where alcohol use may be problematic, 
such as at obstetrician-gynaecologist clinics and maternity hospitals. If efficacious, the intervention may be a 
feasible and cost-effective way to reach women with problematic drinking patterns at point-of-care and to 
integrate an alcohol use intervention into comprehensive HIV-delivery services. 
 
Trial status 
All women have completed the baseline assessment and we are currently working on scheduling women for 
follow-up assessments. The protocol is version number 6, dated October 29, 2019. Recruitment began in 
January 2018 and was completed in October 2019. The protocol was submitted after the end of recruitment 
but before the end of the last patient visit. No significant modifications were made to the protocol following 
the end of recruitment. 
 
 
Abbreviations 

Page 15 of 21 
ARV 
antiretroviral 
CI 
confidence interval 
CD4+ cluster of differentiation 4 cells 
EtG 
ethyl glucuronide 
HCV  
hepatitis C virus 
HHS  
U.S. Department of Health and Human Services 
HIV 
human immunodeficiency syndrome 
ICPSR  Inter-University Consortium for Political and Social Research 
IRB  
institutional review board 
ng/mL nanograms/millilitre 
NIH 
National Institutes of Health 
NYU 
New York University 
OHRP Office for Human Research Protections 
PEth 
phosphatidylethanol 
PLWH person living with HIV/AIDS 
PWID person who injects drugs 
USD 
United States Dollars 
USDTL U.S. Drug Testing Laboratory standardized procedures 
 
Declarations 
Acknowledgements 
Not applicable. 
 
Authors’ contributions {31b} 
RJD, JLB are the US-based principal investigators who conceived the study and led the proposal and 
protocol development, and were responsible for quality assurance and oversight. VR and NB led protocol 
development and implementation, as well as quality assurance in Russia. 
EB was the Russian project coordinator, monitoring data collection, and in charge of patient follow-up. 
LVG and NBK are the clinicians in contact with patients and in charge of collecting data  
AC, NR, and JMS supported protocol implementation and U.S.-based coordination support 

Page 16 of 21 
AC wrote the first draft of the manuscript. RJD and JLB edited and made substantial contributions to the 
manuscript. 
All authors read and approved the final manuscript. 
 
Funding {4} 
Research reported in this publication was supported by the National Institute on Alcohol Abuse and 
Alcoholism of the National Institutes of Health under Award Number R01AA025882 (MPI: RJD, JLB) and by 
a grant 17-54-30014 from the Russian Foundation for Basic Research (PI: SP). 
 
The funding body had no role in the study’s design; collection, analysis, and interpretation of data; or in 
writing the manuscript. 
 
Availability of data and materials {29} 
We will deposit the final data set and codebook with the Inter-University Consortium for Political and Social 
Research (ICPSR) located at the University of 
Michigan. ICPSR confidentiality requirements will be followed 
(http://www.icpsr.umich.edu/irb/index.html). ICPSR will make the data permanently available to over 
700 academic member institutions, permitting other researchers to conduct secondary analyses using the 
data set. Data availability will be announced on the ICPSR website.  
 
Ethics approval and consent to participate {24} 
The institutional review boards of New York University (number IRB-FY2019-2519) and Saint Petersburg 
State University (number 02-186) approved all study protocols. Written informed consent to participate is 
obtained from all participants. 
 
 
Consent for publication {32} 
Not applicable. 
 
Competing interests {28} 
The authors declare that they have no competing interests. 
 
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Page 20 of 21 
FIGURE 1. Trial flow diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Clinical Sites: North-West District 
AIDS Center and affiliated clinic  
Consent Eligible Patients   
Baseline Assessment: 
1) Self-Report Survey 
2) Biological Specimen Collection: POC EtG (urine) 
3) Medical Chart Review: ARV regimen, HIV viral load, CD4+ count, HCV 
treatment, FibroTest score (liver function: ALT, bilirubin, etc.), FibroScan 
Eligible  
Computer Randomization to Trial Conditions (N=200) 
Screening Visit 
- Chart review: HIV/HCV co-infection, 
female, 21-45 years old, prescribed ART 
- Alcohol use: Biologically confirmed POC 
EtG positive (>500ng/mL) or any self-
reported past-month alcohol use 
- Interview with psychologist: no 
neurological or mental health impairment 
 
3-, 6- & 9-month follow-up assessments: 
1) Self-Report Survey 
2) Biological Specimen Collection: POC EtG (urine) 
3) Medical Chart Review: ARV regimen, HIV viral load, CD4+ count, HCV 
treatment, FibroTest score (liver function: ALT, bilirubin, etc.), FibroScan (last one 
at 9-month follow-up only) 
Intervention Condition (n=100): 
1) Intervention session:  
• Brief computer-based intervention 
• Psychological counseling (Patient-tailored) 
• Facilitated referral (e.g., community-based alcohol treatment) 
• Information brochure with list of resources 
2) Brief telephone booster session 
3) Repeated intervention session: 3 & 6-month follow-up 
 
Control Condition (n=100): 
1) Standard of Care: 
• Psychological counseling (Patient-tailored) 
• Facilitated referral (e.g., community-based alcohol 
treatment) 
• Information brochure with list of resources 
 
Not Eligible: 
- One or more 
eligibility 
criterion not met 

Page 21 of 21 
Figure 2.  Standard Protocol Items; Recommendations for Interventional Trials (SPIRIT) 
schedule of enrolment, interventions, and assessments 
 
 
Enrolment 
Allocation 
Post-allocation 
 
T0 
T0 
T1 
T2 
T3 
ENROLMENT: 
 
 
 
 
 
Eligibility screen 
X 
 
 
 
 
Informed consent  
X 
 
 
 
 
Allocation 
 
X 
 
 
 
INTERVENTIONS: 
 
 
 
 
 
Standard of care 
 
 
X 
 
 
Computer based 
intervention 
 
 
X 
X 
X 
ASSESSMENTS: 
 
 
 
 
 
Socio-
demographic data 
X 
 
 
 
 
ETG 
X 
 
X 
X 
X 
PEth 
 
 
 
X 
X 
FibroScan 
X 
 
X 
X 
X 
HIV viral load 
X 
 
X 
X 
X 
CD4+ count 
X 
 
X 
X 
X 
Self-reported 
alcohol use 
X 
 
X 
X 
X 
ARV regime 
X 
 
X 
X 
X