Retrospective Evaluation of Treatment Durability Among Treatment-naive HIV-infected Individuals Initiated First-line ART in Russia
Conditions: HIV-1-infection
Sponsor: MSD Pharmaceuticals LLC

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THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., KENILWORTH, NJ, 
U.S.A. 
 
SPONSOR:  
MSD Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc.  
(hereafter referred to as the Sponsor or Merck)  
Timura Frunze Street 11, building 1 
Business Center Demidov,  
Moscow, 119021, Russian Federation  
 
TITLE: 
Retrospective evaluation of treatment durability among treatment-naive HIV-infected 
individuals initiated first-line ART in Russia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Summary of changes 
 
Protocol Section 
Change 
Protocol Summary 
“between February 01 and April 30, 2017” 
replaced with  
“February 01 and June 30, 2017” 
3 METHODOLOGY 
3.1   Summary of Study Design 
 
“The study is to be conducted in 6 investigational sites across 
Russia with up to 200 patients recruited per site.” 
replaced with 
“The study is to be conducted in up to 8 investigational sites 
across Russia with up to 200 patients recruited per site.” 
“All patients must have initiated ART between February 01 
and April 30, 2017”  
replaced with  
“All patients must have initiated ART between February 01 
and June 30, 2017” 
3 METHODOLOGY 
3.3 Inclusion Criteria 
“ • Initiated their first-line ART between February 01 and 
April June 30, 2017”  
replaced with  
“ • Initiated their first-line ART between February 01 and 
June 30, 2017” 
5 STUDY PROCEDURES OF 
DATA COLLECTION 
5.3. Retrospective Data Collection 
“Data will be retrospectively collected from 6 investigational 
sites with up to 200 patients recruited per site.” 
replaced with 
“Data will be retrospectively collected from up to 8 
investigational sites with up to 200 patients recruited per 
site.” 
11 Attachments  
Updated External Adverse Event and Product Quality 
Complaint Form 
 
 
 
 
 
 
 
 
 

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Table of contents 
SPONSOR CONTACT INFORMATION .................................................................................................. 5 
SUPPLIER CONTACT ............................................................................................................................... 5 
LIST OF ABBREVIATIONS ...................................................................................................................... 6 
PROTOCOL SUMMARY ........................................................................................................................... 7 
1 BACKGROUND AND RATIONALE ..................................................................................................... 8 
1.1   BACKGROUND ..................................................................................................................................... 8 
1.2   RATIONALE ......................................................................................................................................... 9 
2 OBJECTIVES AND HYPOTHESES ...................................................................................................... 9 
2.1   PRIMARY OBJECTIVE .......................................................................................................................... 9 
2.2   SECONDARY OBJECTIVES .................................................................................................................... 9 
3 METHODOLOGY ...................................................................................................................................10 
3.1   SUMMARY OF STUDY DESIGN ............................................................................................................10 
3.2   STUDY POPULATION...........................................................................................................................11 
3.3   INCLUSION CRITERIA .........................................................................................................................11 
3.4   EXCLUSION CRITERIA ........................................................................................................................11 
3.5   SUBGROUPS OF STUDY POPULATION ...................................................................................................11 
4 VARIABLES AND OUTCOMES ...........................................................................................................12 
4.1 PATIENT DEMOGRAPHICS ....................................................................................................................12 
4.2 CLINICAL VARIABLES ..........................................................................................................................12 
4.3   OUTCOMES .........................................................................................................................................13 
4.3.1. Treatment Durability..................................................................................................................13 
4.3.1. Time on therapy .........................................................................................................................13 
4.3.2. Association between of patients characteristics and treatment durability .................................13 
5 STUDY PROCEDURES OF DATA COLLECTION ...........................................................................13 
5.1   GENERAL INFORMED CONSENT ..........................................................................................................15 
5.2 WITHDRAWAL/DISCONTINUATION ......................................................................................................15 
5.3 RETROSPECTIVE DATA COLLECTION (CLINICAL ASSESSMENTS) .........................................................15 
5.4 INTERIM STATISTICAL ANALYSIS ........................................................................................................15 
6 SAFETY REPORTING AND RELATED PROCEDURES .................................................................16 
6.1   ADVERSE EVENT AND PRODUCT QUALITY COMPLAINT REPORTING ..................................................16 
6.1.1   INVESTIGATOR RESPONSIBILITY: .......................................................................................16 
6.2   DEFINITIONS ..................................................................................................................................17 
6.2.1   Adverse Event (AE) ...................................................................................................................17 
6.2.2   Adverse Reaction (AR); also referred to as Adverse Drug Reaction (ADR) .............................17 
6.2.3   Serious Adverse Event (SAE)/Serious Adverse Reaction (SAR) ................................................17 
6.2.4   Non-serious Adverse Reaction (NSAR) .....................................................................................17 
6.2.5   Special Situations ......................................................................................................................17 
6.2.6    Health Outcome of Interest (HOI) ...........................................................................................18 
6.2.7    Product Quality Complaint (PQC) ..........................................................................................18 
6.2.8    Malfunction ..............................................................................................................................18 
6.2.9   Sponsor's Product .....................................................................................................................18 
6.2.10   Causality Assessment ..............................................................................................................18 
7 STATISTICAL ANALYSIS PLAN ........................................................................................................18 
7.1   STATISTICAL METHODS .....................................................................................................................18 

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7.1.1 Primary Objective: ......................................................................................................................19 
7.1.2 Secondary Objectives:.................................................................................................................19 
7.1.3 Subgroup analysis .......................................................................................................................20 
7.1.4 Interim Statistical Analysis .........................................................................................................20 
7.2   BIAS ...................................................................................................................................................20 
7.2.1   Methods to Minimize Bias .........................................................................................................21 
7.2.3   Limitations ................................................................................................................................21 
7.3   Sample Size and Power Calculations ...........................................................................................21 
8 ADMINISTRATIVE AND REGULATORY DETAILS .......................................................................21 
8.1   CONFIDENTIALITY ..............................................................................................................................21 
8.1.1   Confidentiality of Data ..............................................................................................................21 
8.1.2   Confidentiality of Subject Records ............................................................................................22 
8.1.3   Confidentiality of Investigator Information ..............................................................................22 
8.2   COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS ...........................................................22 
8.3   COMPLIANCE WITH LAW, AUDIT AND DEBARMENT ...........................................................................23 
8.5   QUALITY MANAGEMENT SYSTEM ......................................................................................................24 
8.6   DATA MANAGEMENT .........................................................................................................................25 
9 PUBLICATIONS ......................................................................................................................................26 
10 REFERENCES .......................................................................................................................................26 
11 ATTACHMENTS ...................................................................................................................................28 
12 SIGNATURES ........................................................................................................................................30 
 
 
 
 
 
 
 

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Sponsor Contact Information 
 
Ekaterina Lukyanova 
Medical Affairs Director of MSD Pharmaceuticals LLC  
ekaterina.lukyanova@merck.com  
 +7 495 916 71 00 
Timura Frunze Street 11, building 1 
Business Center Demidov,  
Moscow, 119021, Russian Federation 
 
Supplier Contact 
 
Mikhail Groubman 
 
General Manager of Atlant Clinical Ltd. 
 
12/1 Krivokolennyi Lane,  
 
 
101000, Moscow, Russia 
 
 
+7 (495) 628 3802 
 
 
mikhail.groubman@atlantclinical.com 
 
 
 
 

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List of Abbreviations 
 
AE 
Adverse event 
SAE 
Serious adverse event 
IRB 
Independent Review Board 
IEC 
Independent Ethics Committee 
WHO 
World Health Organization 
MoH 
Ministry of Health 
HIV 
AIDS 
Human Immunodeficiency Syndrome 
Acquired Immunodeficiency Syndrome 
PLWH 
People living with HIV 
MSM 
Men having sex with men 
ART 
Antiretroviral therapy 
cART 
Combined antiretroviral therapy 
PI 
Protease inhibitors 
bPI 
Boosted protease inhibitors 
NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
EFV 
ZDV 
Efavirenze 
Zidavudine 
TDF 
Tenofovir 
3TC 
Lamivudine 
FTC 
Emtricitabine 
ABC 
Abacavir 
CV  
CK  
CNS  
CD 
Cardiovascular 
Chronic kidney (disease) 
Central nervous system 
Cluster of differentiation 
SAR 
NSAR 
HOI  
MAH 
PQCs 
CD  
EDC 
eCRF 
Serious adverse reaction 
Non-serious adverse reaction 
Health outcomes of specific interest 
Market authorization holder 
Product quality complaint 
Calendar day 
Electronic data capture 
Electronic clinical reporting form 
CI 
Confidentiality interval 
SOP 
Standard Operating Procedure 
 
 
 

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PROTOCOL SUMMARY 
Title 
Retrospective evaluation of treatment durability among treatment-naive HIV-
infected individuals initiated first-line ART in Russia 
Supplier 
Atlant Clinical Ltd 
Rationale 
Treatment durability is an important factor in HIV disease management since 
HIV infected individuals need to take ART life-long. To date, there is limited 
data on treatment durability in HIV infected individuals initiating ART in 
Russia. Understanding the durability of treatment is essential for improving 
medical care of patient living with HIV.  
Primary Objective 
To evaluate the 48 weeks treatment durability among treatment naive HIV-
infected individuals determined as a percentage of patients remained on initial 
therapy 
Study Design 
A non-interventional retrospective study.  
Study Population 
Treatment-naive at the time of initiation of ART with NNRTI plus two NRTIs 
or PI boosted by ritonavir with 2 NRTIs per usual standard of care of the 
investigator in AIDS clinics of Russia. 
Study Duration 
Up to 24 months will be dedicated to retrospective data collection and analysis 
from treatment-naïve HIV-infected patients who initiated their first-line ART 
between February 01 and June 30, 2017  
Exposure and 
Outcome 
Initial ART per usual standard of care in AIDS clinics of Russia: NNRTI plus 
2 NRTIs or PI boosted by ritonavir with 2 NRTIs. Treatment durability 
determined as a percentage of patients continuing their first-line for 48 and 96 
weeks without changes (switch or withdrawal) evaluated retrospectively 
Statistical Methods 
Data will be presented descriptively as follows: the number of observations, 
mean and standard deviation, median, first and third quartiles, minimum and 
maximum for continuous variables, and the absolute frequencies and 
percentage of patients presenting the given feature for qualitative variables. 
The results on the study endpoints (proportion of patients who remain on first-
line ART at 48 and 96 weeks) will be presented with two-sided 95% confidence 
intervals. Univariate and multivariate logistic regression will be used to study 
the association between patients’ baseline demographic and clinical 
characteristics and treatment discontinuation status. 
Sample Size and 
Power Calculations 
1000 patients. The assumed 1-year (approximately 48 weeks) discontinuation 
rate, based on published research, is 30% [20] therefore the assumed 
proportion of patients who remain on the first line ART regimen at 48 
weeks is 70%. Inclusion of 1000 patients will allow the estimation of this 
proportion with 95% CI: Lower bound - 67.2%, Upper bound – 72.8%, Actual 
width (precision) - 5.7% (±2.8%). 
Limitations 
In this a retrospective study the quality of the data is important. And the 
potential issue of missing data is a limitation of the study. Therefore, it is 
important for the sponsor or designee to monitor data completion and perform 
quality checks during the study. To minimize missing data, a set of core 
variables is required to be available at enrollment as part of inclusion criteria. 
 
 

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1 Background and Rationale 
 
1.1   Background 
Human 
immunodeficiency 
virus 
infection 
and 
acquired 
immune 
deficiency 
syndrome (HIV/AIDS) is a spectrum of conditions which interfere with increasing the risk 
of developing common infections such as tuberculosis, as well as other opportunistic 
infections, and tumors that rarely affect people who have working immune 
systems.[1] These late symptoms of infection are referred to as acquired immunodeficiency 
syndrome (AIDS).[2] From the time AIDS was identified in the early 1980s to 2017, the 
disease has caused an estimated 35 million deaths worldwide.[3] In 2016, about 36.7 
million people were living with HIV and it resulted in 1 million deaths.[4] Unlike most 
countries, Russia’s HIV epidemic is growing, with the rate of new infections rising by 
between 10 and 15% each year. It is estimated that over 250 people become infected with 
HIV every day. [5, 6] By mid-2017, 1.16 million people had been diagnosed with HIV in 
Russia. However, this does not equate to the number of people currently living with HIV 
as it does not account for AIDS-related deaths or people who have HIV but are 
undiagnosed. Although Russia has collected extensive data on HIV since 1987, official 
estimates for these measures remain under reported and inconsistent. A 2017 data analysis 
suggests the numbers of AIDS-related deaths are rising. From January to June 2017, 14,630 
AIDS-related deaths were recorded, a 13.5% increase over the previous six-month period. 
HIV is one of the top 10 causes of premature death in Russia. [7, 8] 
Life expectancy of people living with HIV (PLWH) increased substantially with the 
introduction of combined active antiretroviral therapy (cART) [9]. Consequently, assessing 
long-term treatment outcomes and regimen durability has become increasingly relevant. 
Patients still experience treatment modifications and interruptions for reasons that may 
include virological failure, adverse events, or poor adherence [10, 11]; and treatment 
modifications or interruptions may be associated with increased costs or adverse clinical 
outcomes. Efavirenz (EFV) and other NNRTIs are the preferred options for the third 
component in first antiretroviral regimens (first-line ART) to treat HIV infection, according 
to the World Health Organization Consolidated Guidelines (WHO) [12] and Russian 
National cART guidelines [13].  
In most clinical trials, before the introduction of integrase strand transfer inhibitors 
(INSTIs), NNRTIs showed better efficacy or non-inferiority in suppressing HIV 
replication when compared with other regimens [14–16]. Randomized clinical trials, 
however, are typically conducted over 48- to 96-week periods and evaluate primarily rates 
of virological suppression in populations selected with stringent criteria [17]. A recent 
meta-analysis using pooled data of 29 clinical trials evaluated the risk of death [17], AIDS 
progression, and treatment discontinuation in ART-naive patients comparing non-
nucleoside reverse transcriptase inhibitors (NNRTIs), including EFV-based regimens, with 
boosted protease inhibitor (bPI)–based regimens, and it showed no statistically significant 
differences between regimens in any of the individual and combined outcomes. 
 
 

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1.2   Rationale 
The Russian MoH has recently initiated a national program aimed to increase the 
proportion of HIV diagnosis and linkage to care of HIV infected individuals. Treatment 
durability is an important factor in HIV disease management since HIV infected 
individuals need to take ART for many years. [5] To date, there is limited data on treatment 
durability in HIV infected individuals initiating ART in Russia. Understanding the 
durability of treatment is essential for improving patient management in order to achieve 
the goals set by the Russian MoH and the HIV elimination goals set by the WHO.  
According to the robust clinical studies data, there was significant increase of CNS AEs in 
groups of patients treated with EFV [14]. As with other NNRTIs, drug interactions and a 
low resistance barrier have to be considered. Novel NNRTis such as etravirine and 
rilpivirine were implemented in routine clinical practice in Russia recently and have higher 
cost which may influence access and therefore durability to this third drug medications. 
Observational studies, in contrast to clinical trials, have the potential to offer valuable 
additional information with respect to real-life settings, such as durability of the regimen 
over longer periods of time. Cohort studies have evaluated the reasons for change of first-
line regimen in the short term [10, 18] and long term [19] and the prevalence of use of 
different NNRTIs and PIs in first-line [12]. Nevertheless, durability of first-line ART and 
prognostic factors (either positive or negative) measured in current study, such as the 
probability of requiring ART switch, may have significant economic and public health 
relevance. Also durability can be highly influenced by local circumstances. Therefore, in 
this study, the durability of initial ART will be evaluated according to the third component 
in a cohort from Russia and association of baseline patient characteristics with treatment 
durability over a long period of time will be explored. 
2 Objectives and Hypotheses 
2.1   Primary Objective 
• 
To evaluate the 48 weeks treatment durability among treatment naive HIV-infected 
individuals initiated ART (NNRTI, PI) determined as a percentage of patients 
remained on initial therapy without change of the NNRTI or PI agent 
2.2   Secondary Objectives  
• 
To evaluate the estimated time on therapy without change of the NNRTI or PI agent 
at 48 weeks among treatment naive HIV-infected individuals initiated ART 
(NNRTI, PI) 
• 
To describe baseline clinical and demographic characteristics of treatment naive 
HIV-infected individuals initiated ART (NNRTI, PI) 
• 
To assess association between clinical and demographic characteristics of patients 
and treatment durability at 48 weeks 

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• 
To evaluate the 96 weeks treatment durability among treatment naive HIV-infected 
individuals initiated ART (NNRTI, PI) determined as a percentage of patients 
remained on initial therapy without change of the NNRTI or PI agent 
• 
To evaluate the estimated time on therapy without change of the NNRTI or PI 
agent at 96 weeks among treatment naive HIV-infected individuals initiated ART 
(NNRTI, PI) 
• 
To assess association between clinical and demographic characteristics of patients 
and treatment durability at 96 weeks 
3 METHODOLOGY 
3.1   Summary of Study Design 
This study is a non-interventional retrospective study. Data from patients who signed 
informed consent form will be collected through retrospective chart or medical records 
review. Patients have been receiving treatment and diagnostic procedures according to 
daily clinical practice conducted by his/her physician. There are no procedures that are 
required as part of this study. 
The study is to be conducted in up to 8 investigational sites across Russia with up to 200 
patients recruited per site. Each investigational site will be a dedicated HIV clinic or an 
HIV department in clinic of infectious diseases. It is planned that the first half of the study 
population (500 patients) will be enrolled during the first 6-9 months and the second half 
of the study population (500 patients) during the second 6-9 months of the study.   
HIV-infected patients with no experience of therapy at time of initiation of ART with 
NNRTI plus two NRTIs or PI boosted by ritonavir with 2 NRTIs will be enrolled and 
followed retrospectively for up to 96 weeks with data collection at the approximate time 
points of baseline (pre-treatment) and at 48 and 96 weeks after start of treatment.  
The following ARV drugs are considered according to the standards of care: 
• NNRTIs: efavirenz (EFV), nevirapine (NVP), rilpivirine (RPV), ETR (etravirine) etc. 
• PIs: LPV (lopinavir), DRV (darunavir), ATV (atazanavir), FPV (fosamprenavir) etc. 
All patients must have initiated ART between February 01 and June 30, 2017. A time 
window for the retrospective visits at baseline, 48 and 96 weeks is envisaged as 
approximately ± 8 weeks.  
Patients will be retrospectively screened and selected according to inclusion and exclusion 
criteria prior to enrollment in each investigational site starting the day of its initiation. The 
study sites will maintain a list of all screened patients. All patients eligible according to the 
inclusion/exclusion criteria and after signing the informed consent form are to be 
consequently enrolled for their demographic and clinical data collection through 
retrospective chart or medical records review. The enrollment will continue until the 
recruitment goal is reached. 

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Baseline and follow-up data will be extracted through retrospective chart or medical 
records review, if available at each investigational site. No additional interventional tests 
or medical procedures such as additional blood samples, X-ray or other technical 
investigations will be performed as a part of this study. If any data element is not available, 
it will be reported as missing.  
At baseline, demographic and clinical data on age, gender, employment status, marital 
status, substance abuse, HIV diagnosis duration, route of infection, AIDS stage, viral load, 
CD4 count, concomitant medication, comorbidities (noted diagnosis by physician) are to 
be collected through retrospective chart or medical records review.   
At 48 and 96 weeks of retrospective follow-up, the investigators will assess through the 
medical records whether the patient was still on treatment with initiated ART (NNRTI, PI) 
and evaluate the estimated time on therapy without change of the NNRTI or PI agent within 
the class or without change of the NNRTI or PI agent to a different class.  
 
3.2   Study Population 
All patients enrolled must be treatment naive at the time of initiation of ART with NNRTI 
plus two NRTIs or PI boosted by ritonavir with 2 NRTIs per the usual standard of care of 
the investigator in AIDS clinics of Russia. 
 
3.3   Inclusion Criteria  
• 
Adult patients (>18 years of age) with definite HIV-1 infection based on positive 
lab test and judgement of treating physician according to standards of care 
• Naive to antiretroviral treatment at the time of initiation 
• Viral load of >1000 copies/ml at the time of initiation of ART 
• Initiated their first-line ART between February 01 and June 30, 2017 
• Patients are included, if the third component of their first line ART was either 
NNRTI or boosted PI plus 2 NRTIs  
• Completed follow-up from baseline for at least 96 weeks 
• Signed informed consent 
 
3.4   Exclusion Criteria 
• HIV-2 infection 
3.5   Subgroups of study population 
The study population will be divided to several subgroups based on the baseline 
demographic and clinical characteristic which are the following: 
1) Age: < 40, 40-60, > 60 years; 
2) Gender: male, female, transgender; 

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3) Employment status: employed, unemployed, student, pensioner, incarcerated; 
4) Marital status: married, single, divorced; 
5) Substance abuse: no, alcohol, drugs; 
6) HIV diagnosis duration at baseline: 0-0.5, 0.5-1, 1-2, 2-3, 3-5, >5 years; 
7) Route of infection: IV drug use, homosexual (MSM), heterosexual, other; 
8) HIV stage (if applicable): I-V; 
9) Baseline viral load: <50 000, 50 000-100 000, >100 000 copies/ml; 
10) Baseline CD4 cells count: <50, 50-100, 101-200, 201-350 and >350  cells/μl; 
11) Concomitant medications at baseline: 0, 1-2, 3-5, >5; 
12) Comorbidities at baseline: No, Yes CV disease, diabetes mellitus, CK disease, liver 
disease, viral hepatitis, pulmonary disease, tuberculosis, CNS disease, psychiatric 
disorder; 
13) ART therapy: NNRTI plus two NRTIs; PI boosted by ritonavir with 2 NRTIs. 
4 Variables and Outcomes 
4.1 Patient Demographics 
The following demographic parameters will be retrospectively recorded at baseline: 
• 
Age (years); 
• 
Gender: male, female, transgender; 
• 
Employment status: employed, unemployed, student, pensioner, incarcerated; 
• 
Marital status: married, single; 
• 
Substance abuse: no, alcohol, drugs. 
4.2 Clinical Variables  
The following clinical parameters will be retrospectively recorded at baseline: 
1) HIV diagnosis duration at baseline (years); 
2) Route of infection: IV drug use, homosexual (MSM), heterosexual, other; 
3) HIV stage (if applicable): I-V; 
4) Baseline viral load (copies/ml); 
5) Baseline CD4 cells count (cells/μl); 
6) Concomitant medications at baseline; 
a. Data will be retrospectively captured on medication given for the 
treatment for any disorder/disease but HIV/AIDS at baseline 

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7) Comorbidities at baseline: No, Yes – CV disease, diabetes mellitus, CK disease, 
liver disease, viral hepatitis, pulmonary disease, tuberculosis, CNS disease, 
psychiatric disorder; 
8) ART therapy: NNRTI plus two NRTIs; PI boosted by ritonavir with 2 NRTIs. 
 
It should be noted that demographic and clinical variables collected in this non-
interventional retrospective study are recommended for daily-practice clinical record 
keeping for the management of HIV-infection in Russia. Thus, these variables are available 
for the majority of the HIV-infected patients in regular clinical practice and can be collected 
within locally applicable legal and ethical framework for non-interventional research. 
 
4.3   Outcomes 
4.3.1. Treatment Durability 
Treatment durability is determined as a percentage of patients continuing their first-line 
ART with NNRTI plus 2 NRTIs or PI boosted by ritonavir with 2 NRTIs for 48 and 96 
weeks without change of the NNRTI or PI agent (“anchor” or “third agent”) within the 
class or without change of the NNRTI or PI agent to a different class.  
According to the Primary objective, the treatment durability is to be retrospectively 
evaluated at 48 weeks from the time of initiation.  
According to the Exploratory objective, the treatment durability is to be retrospectively 
evaluated at 96 weeks from the time of initiation.  
4.3.1. Time on therapy 
According to the Secondary objective, the estimated time on therapy (weeks) without 
change of the NNRTI or PI agent (“anchor” or “third agent”) is to be retrospectively 
evaluated at week 48 from the time initiation. 
According to the Exploratory objective, the estimated time on therapy (weeks) without 
change of the NNRTI or PI agent (“anchor” or “third agent”) is to be retrospectively 
evaluated at week 48 from the time initiation. 
4.3.2. Association between of patients characteristics and treatment durability 
According to the Secondary objective, association between clinical and demographic 
characteristics of patients and treatment durability at 48 weeks will be retrospectively 
evaluated. 
According to the Exploratory objective, association between clinical and demographic 
characteristics of patients and treatment durability at 96 weeks will be retrospectively 
evaluated. 
5 STUDY PROCEDURES OF DATA COLLECTION 
The Study Flow Chart and Study Procedures Table summarize the procedures of data 
collection to be performed retrospectively. Individual study procedures of retrospective 
data collection are described in detail below.  

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Study Flow Chart 
 
 
 
 
 
Study Procedures 
Study period 
Screening 
Retrospective clinical data extraction  
through chart or medical records review 
Visit Number 
0 
1 
Screening and chart review 
X 
 
Informed consent 
X 
 
Inclusion/Exclusion criteria 
X 
 
Age at baseline 
 
X 
Gender at baseline 
 
X 
Employment status at baseline 
 
X 
Marital status at baseline 
 
X 
Substance abuse 
 
X 
HIV diagnosis duration at baseline 
 
X 
Route of infection at baseline 
 
X 
HIV stage at baseline 
 
X 
Viral load at baseline 
 
X 
CD4 at baseline 
 
X 
Concomitant medications at baseline 
 
X 
Comorbidities at baseline 
 
X 
Initial ART at baseline  
 
X 
Treatment durability: 
NNRTI or PI continuation at Week 48/96 
 
X 
Estimated time on treatment  
with NNRTI or PI at Week 48/96 
 
X 
Adverse events  
at baseline and at Week 48/96 
 
X 
 
Baseline
(pre-treatment)
Week 48
± 8 weeks
Week 96
± 8 weeks
Screening/ 
Signing ICF
Retrospective 
chart review
• HIV-infected 
• ART naïve 
• Starting ART with 
either NNRTI or 
boosted PI plus 2 
NRTIs 
• 01.02.2017 -  
30.06.2017 
• Daily clinical 
practice 
• HIV-infected 
• ART with either 
NNRTI or 
boosted PI plus 
2 NRTIs 
• Continuation or 
change of the 
NNRTI or PI 
agent 
• HIV-infected 
• ART with either 
NNRTI or 
boosted PI plus 2 
NRTIs 
• Continuation or 
change of the 
NNRTI or PI 
agent 
• Inclusion/ 
Exclusion 
criteria 
• Signing 
Informed 
Consent Form 
• Baseline 
demographic 
and clinical data 
• Treatment 
durability 
• Time on 
treatment  

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5.1   General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before the 
demographic and clinical data are extracted through retrospective chart or medical records 
review.  
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use. The informed consent will adhere to 
IRB/ERC requirements, applicable laws and regulations and Sponsor requirements. 
5.2 Withdrawal/Discontinuation 
The patient may withdraw his/her consent to participate in the study at any time for any 
reason. This decision will not have any consequences for his/her future medical care. 
The sponsor may stop the study at any time. In such case, all investigators will be 
informed in advance. 
 
5.3 Retrospective Data Collection (Clinical Assessments) 
This retrospective study will only involve Secondary Data Collection by reviewing medical 
chart generated in routine clinical cares. 
Data will be retrospectively collected from up to 8 investigational sites with up to 200 
patients recruited per site. It is planned that the first half of the study population (500 
patients) will be enrolled during the first 6-9 months and the second half of the study 
population (500 patients) during the second 6-9 months of the study.  
Based on the protocol, an electronic data capture (EDC) or electronic clinical reporting 
form (eCRF) will be developed for data collection. Each local center will be asked to enter 
the data into the EDC. All the data collected will be entered into a single database stored 
centrally and analyzed. 
If any reportable safety events are identified during retrospective chart review, it is to be 
ensured they are reported as per section 6 of the protocol. 
5.4 Interim Statistical Analysis 
Interim Statistical Analysis will be performed when data retrospectively collected from at 
least 500 patients during the first 6-9 months of the study. 
 

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6 Safety Reporting and Related Procedures 
Adverse Event Reporting Language for Non-Interventional Study Protocols 
Introduction 
 
This is a non-interventional study based on secondary use of data collected for other 
purposes.  No administration of any therapeutic or prophylactic agent is required in this 
protocol, and there are no procedures required as part of this protocol.  
6.1   Adverse Event and Product Quality Complaint Reporting  
6.1.1   INVESTIGATOR RESPONSIBILITY:  
Although adverse events (AEs) and product quality complaints (PQCs) are not actively 
solicited in this study, there are certain circumstances in which individual AEs and/or PQCs 
will be reported.  For example, during review of medical records or physician notes (paper 
or electronic), to collect data as required by the protocol, if a notation of an AE* or PQC 
to any Merck product is identified, the AE/PQC must be reported according to Table 1.  
  
*For the purposes of this protocol, the term “AE” collectively refers to the following 
reportable events (refer to section 6.2 for definitions):  
• 
Serious adverse reactions (SARs), including death   
• 
Non-serious adverse reactions (NSARs)  
• 
Special situations  
• 
Study-specific Health Outcomes of Interest (HOIs) that meet criteria for 
SAR/NSAR or special situation  
  
AEs, PQCs, and AEs that occur in combination with PQCs, or spontaneously reported 
events, should all be captured using the AE/PQC report form for each patient and reported 
according to Table 1.  
  
Table 1: AE and PQC Reporting Timeframes and Process for Investigators  
 
AEs AND PQCs  
INVESTIGATOR TIMEFRAMES 
Investigator to MSD [1] 
SAR (including study-specific HOIs that meet criteria for SAR  
Serious Special Situation, regardless of causality  
24 hours from receipt 
NSAR (including study-specific HOIs that meet criteria for 
NSAR)  
Non-serious Special Situation, regardless of causality  
10 CD from receipt 
PQC with or without an AE (SAR/NSAR/Special situation)  
24 hours from receipt 
Spontaneously reported AEs/PQCs for Merck products-submit using above timeframes  
Follow-up to any AE/PQC-submit using above timeframes  
BD-Business Day; CD-Calendar Day  

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If the investigator elects to submit AEs/PQCs for non-MSD products, they should be reported to the 
market authorization holder (MAH) for that product or to the health authority according to the 
institution’s policy or local laws and regulations.  
[1] Investigator to MSD: AEs and PQCs for MSD products are submitted to MSD for reporting to 
worldwide regulatory agencies as appropriate.   
Submitting AEs and PQCs to Local Designated Point of Contact (DPOC): All AEs and PQCs 
must be submitted to Local DPOC Mailbox FAX +7 495 228 32 39 in English using the AE/PQC 
reporting form.  
 
  
6.2   DEFINITIONS 
6.2.1   Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
sponsor’s product and which does not necessarily have to have a causal relationship with this 
product.   An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the use 
of the product, whether or not considered related to the product.  Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the product, is also an adverse event. 
6.2.2   Adverse Reaction (AR); also referred to as Adverse Drug Reaction (ADR) 
An AE which has a causal relationship with the product, that is, a causal relationship between the 
product and the adverse event is at least a reasonable possibility. 
6.2.3   Serious Adverse Event (SAE)/Serious Adverse Reaction (SAR) 
An adverse event or adverse reaction that results in death, is life threatening, results in persistent 
or significant disability/incapacity, requires inpatient hospitalization, prolongation of existing 
inpatient hospitalization, is a congenital anomaly/birth defect, or is another important medical 
event.  Other important medical events that may not result in death, may not be life-threatening, or 
may not require hospitalization may be considered an SAE/SAR when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the other outcomes listed previously.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home and blood dyscrasias or convulsions that do not result in inpatient hospitalization. 
6.2.4   Non-serious Adverse Reaction (NSAR) 
An adverse reaction that does not meet any of the serious criteria in 6.2.3. 
6.2.5   Special Situations 
The following special situations are considered important safety information and must be reported, 
regardless of seriousness or causality, if the investigator becomes aware of them: 
• 
Overdose  
• 
Exposure to product during pregnancy or lactation  
• 
Lack of therapeutic effect    
• 
Off-label use, medication error, misuse, abuse, or occupational exposure 
• Suspected transmission via a medicinal product of an infectious agent 

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• Unexpected Therapeutic Benefit/Effect 
6.2.6    Health Outcome of Interest (HOI) 
Health Outcomes of Interest (HOIs) are clinical events or outcomes that are collected 
according to the protocol.  HOIs may be represented as diagnoses, treatments or 
procedures.  Examples of HOIs include syncope, disease progression, or hypoglycaemia 
collected as study endpoints.  HOIs may meet the criteria of an SAE/SAR, NSAR or special 
situation, and if so, must be collected as such, in addition to being collected as an HOI. 
Specifically, collected HOI data must be assessed for the criteria described herein and 
reported accordingly.   
6.2.7    Product Quality Complaint (PQC)  
 Any communication that describes a potential defect related to the identity, strength, 
quality, purity or performance of a product identified by an external customer. This 
includes potential device or device component malfunctions.  
 6.2.8    Malfunction  
 The failure of a device (including the device component of a combination product) to meet 
its performance specifications or otherwise perform as intended. Performance 
specifications include all claims made in the labeling for the device.  
6.2.9   Sponsor's Product   
Sponsor’s product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, provided 
by or distributed by the Sponsor for human use.  
6.2.10   Causality Assessment  
A causality assessment is the determination of whether or not there is at least a reasonable 
possibility that a product caused the adverse event.    Causality must be recorded on the AE 
form for each reported event in relationship to a Sponsor's product.  
 Secondary Data Collection  
Only AEs with an explicit and definitive notation (by a healthcare provider) of a causal 
relationship with a product in the medical records or other secondary data being reviewed 
should be reported as NSAR/SARs.  During review of secondary data, causality should 
never be assigned retrospectively.      
7 Statistical Analysis Plan 
7.1   Statistical Methods 
Data will be presented descriptively as follows: the number of observations, mean and 
standard deviation, median, first and third quartiles, minimum and maximum for 
continuous variables, and the absolute frequencies and percentage of patients presenting 
the given feature for qualitative variables. The results on the study endpoints (proportion 
of patients who remain on first-line ART at 48 and 96 weeks) will be presented with two-

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sided 95% confidence intervals. Univariate and multivariate logistic regression will be used 
to study the association between patients’ baseline demographic and clinical characteristics 
and treatment discontinuation status.  
7.1.1 Primary Objective:   
• 
Percentage of HIV-infected patients remained on first-line ART at 48 weeks after 
the start of treatment will be presented descriptively with 95% confidence interval 
by initial ART regimen (NNRTI or boosted PI plus 2 NRTIs) and overall 
7.1.2 Secondary Objectives:   
• 
Time on therapy (weeks) without change of the NNRTI or PI agent at week 48 from 
the ART initiation will be presented in Kaplan-Meier plots 
• 
Demographic and clinical characteristics at baseline will be presented descriptively 
by initial ART regimen (NNRTI or boosted PI plus 2 NRTIs) and overall 
• 
Association between characteristics of patients and treatment durability at 48 weeks 
will be investigated via: 
o Subgroup analysis: number and percent of patients continuing treatment at 
48 weeks will be presented descriptively by demographic and clinical 
characteristics categorized according to 8.1.4 
o Multivariate logistic regression analysis to identify potential risk factors for 
discontinuation of initial ART at 48 weeks. Demographic and clinical 
characteristics categorized according to 8.1.4 will be included into 
multivariate analysis only if they are found significant in univariate logistic 
regression analysis. Unadjusted (univariate model) and adjusted 
(multivariate model) odds ratios will be presented with 95% confidence 
intervals for the parameters included in each of the analyses. 
• 
Percentage of HIV-infected patients remained on first-line ART at 96 weeks after 
the start of treatment will be presented descriptively with 95% confidence interval 
by initial ART regimen (NNRTI or boosted PI plus 2 NRTIs) and overall 
• 
Time on therapy (weeks) without change of the NNRTI or PI agent at week 96 
from the ART initiation will be presented in Kaplan-Meier plots 
• 
Association between characteristics of patients and treatment durability at 96 weeks 
will be investigated via: 
o Subgroup analysis: number and percent of patients continuing treatment at 
96 weeks will be presented by demographic and clinical characteristics 
categorized according to 8.1.4 

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o Multivariate logistic regression analysis to identify potential risk factors for 
discontinuation of initial ART at 96 weeks. Demographic and clinical 
characteristics categorized according to 8.1.3 will be included into 
multivariate analysis only if they are found significant in univariate logistic 
regression analysis (p<0.1). Unadjusted (univariate model) and adjusted 
(multivariate model) odds ratios will be presented with 95% confidence 
intervals for the parameters included in each of the analyses. 
7.1.3 Subgroup analysis 
The study population will be divided to several subgroups based on the baseline 
demographic and clinical characteristics. The following categories will be used for the 
subgroup analysis: 
1) Age: < 40, 40-60, > 60 years; 
2) Gender: male, female, transgender; 
3) Employment status: employed, unemployed, student, pensioner, incarcerated; 
4) Marital status: married, single, divorced; 
5) Substance abuse: no, alcohol, drugs; 
6) HIV diagnosis duration at baseline: 0-0.5, 0.5-1, 1-2, 2-3, 3-5, >5 years; 
7) Route of infection: IV drug use, homosexual (MSM), heterosexual, other; 
8) HIV stage (if applicable): I-V; 
9) Baseline viral load: <50 000, 50 000-100 000, >100 000 copies/ml; 
10) Baseline CD4 cells count: <50, 50-100, 101-200, 201-350 and >350 cells/μl; 
11) Concomitant medications at baseline: 0, 1-2, 3-5, >5; 
12) Comorbidities at baseline: No, Yes CV disease, diabetes mellitus, CK disease, liver 
disease, viral hepatitis, pulmonary disease, tuberculosis, CNS disease, psychiatric 
disorder; 
13) ART therapy: NNRTI plus two NRTIs; PI boosted by ritonavir with 2 NRTIs. 
7.1.4 Interim Statistical Analysis 
Interim Statistical Analysis will be performed when data retrospectively collected from at 
least 500 patients during the first 6-9 months of the study. Since this observational study is 
not aimed at testing any hypothesis, no adjustment on significance level will be applied.  
 
7.2   Bias 
Potential sources of bias are errors in recruitment. 

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7.2.1   Methods to Minimize Bias 
Bias from errors in recruitment of patients can be reduced with rigorous adherence to 
inclusion/ exclusion criteria when recruiting patients for the study. 
7.2.3   Limitations 
In this a retrospective study the quality of the data is important. And the potential issue of 
missing data is a limitation of the study. 
Therefore, it is important for the sponsor or designee to monitor data completion and 
perform quality checks during the study. To minimize missing data, a set of core variables 
is required to be available at enrollment as part of inclusion criteria. 
There is a risk that patients who had already been receiving ART might be enrolled due to 
unavailable medical records from his/her previously clinic which is not a part of the study.  
7.3   Sample Size and Power Calculations 
There is no formal hypothesis testing the current study. Sample size justification is based 
on desired precision for the estimation of the primary variable – proportion of patients who 
continue the first line ART regimen at 48 weeks without changes.  
The assumed 1-year discontinuation rate, based on published research, is 30% [20], 
therefore the assumed proportion of patients who remain on the first line ART regimen at 
48 weeks is 70%. Precision (half-width of the 95% Wald confidence interval for the 
proportion) and 95% confidence intervals (CIs) for the proportion resulting from a range 
of sample sizes are presented in the table below: 
 
Assumed 
Proportion 
Patients 
enrolled 
Patients 
with known 
status 
95% CI  
Lower 
bound  
95% CI  
Upper 
bound 
95% CI Actual 
width (precision) 
70.0% 
250 
250 
64.3% 
75.7% 
11.4% (±5.7%) 
70.0% 
500 
500 
66.0% 
74.0% 
8.0% (±4.0%) 
70.0% 
750 
750 
66.7% 
73.3% 
6.6% (±3.3%) 
70.0% 
1000 
1000 
67.2% 
72.8% 
5.7% (±2.8%) 
70.0% 
1250 
1250 
67.5% 
72.5% 
5.1% (±2.5%) 
70.0% 
1500 
1500 
67.7% 
72.3% 
4.6% (±2.3%) 
8 ADMINISTRATIVE AND REGULATORY DETAILS 
8.1   Confidentiality 
8.1.1   Confidentiality of Data 
By signing this protocol, the investigator affirms to the Sponsor that information furnished 
to the investigator by the Sponsor will be maintained in confidence, and such information 
will be divulged to the Institutional Review Board, Ethics Review Committee or similar or 
expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this study will be considered confidential by the 

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investigator, except to the extent that it is included in a publication as provided in the 
Publications section of this protocol. 
8.1.2   Confidentiality of Subject Records 
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor 
representative), Institutional Review Board/Independent Ethics Committee (IRB/IEC), or 
Regulatory Agency representatives may consult and/or copy study documents in order to 
verify worksheet/case report form data.  By signing the consent form, the subject agrees to 
this process.  If study documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor. 
 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed 
in connection with this study in accordance with all applicable privacy laws, rules and 
regulations. 
8.1.3   Confidentiality of Investigator Information 
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and study site 
personnel, may be used and disclosed for study management purposes, as part of a 
regulatory submissions, and as required by law.  This information may include: 
• name, address, telephone number and e-mail address; 
• hospital or clinic address and telephone number; 
• curriculum vitae or other summary of qualifications and credentials; and 
• other professional documentation. 
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory agencies or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses 
and disclosures. 
 
If this is a multicenter study, to facilitate contact between investigators, the Sponsor may 
share an investigator’s name and contact information with other participating investigators 
upon request. 
 
8.2   Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 

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The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 
21 CFR Part 54, to provide his/her financial interests in and/or arrangements with the 
Sponsor to allow for the submission of complete and accurate certification and disclosure 
statements.  The investigator/subinvestigator(s) further agree to provide this information 
on a Certification/Disclosure Form, commonly known as a financial disclosure form, 
provided by the Sponsor or through a secure password-protected electronic portal provided 
by the Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data. 
 
8.3   Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of 
Good Pharmacoepidemiology Practice and all applicable federal, state and local laws, rules 
and regulations relating to the conduct of the study. 
 
The investigator also agrees to allow monitoring, audits, Institutional Review 
Board/Independent Ethics Committee review and regulatory agency inspection of study-
related documents and procedures and provide for direct access to all study-related source 
data and documents. 
 
The investigator agrees not to seek reimbursement from subjects, their insurance providers 
or from government programs for procedures included as part of the study reimbursed to 
the investigator by the Sponsor. 
 
The Investigator shall prepare and maintain complete and accurate study documentation in 
compliance with Good Pharmacoepidemiology Practice, standards and applicable federal, 
state and local laws, rules and regulations; and, for each subject participating in the study, 
provide all data, and, upon completion or termination of the study, submit any other reports 
to the Sponsor as required by this protocol or as otherwise required pursuant to any 
agreement with the Sponsor. 
 
Study documentation will be promptly and fully disclosed to the Sponsor by the 
investigator upon request and also shall be made available at the investigator’s site upon 
request for inspection, copying, review and audit at reasonable times by representatives of 
the Sponsor or any regulatory agencies.  The investigator agrees to promptly take any 
reasonable steps that are requested by the Sponsor as a result of an audit to cure deficiencies 
in the study documentation and worksheets/case report forms. 
 
The investigator must maintain copies of all documentation and records relating to the 
conduct of the study in accordance with their institution’s records retention schedule which 
is compliant with all applicable regional and national laws and regulatory requirements.   If 
an institution does not have a records retention schedule to manage its records long-term, 
the investigator must maintain all documentation and records relating to the conduct of the 
study for 5 years after final report or first publication of study results, whichever comes 

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later, per GPP guidelines.  This documentation includes, but is not limited to, the protocol, 
worksheets/case report forms, advertising for subject participation, adverse event reports, 
subject source data, correspondence with regulatory authorities and IRBs/ERCs, consent 
forms, investigator’s curricula vitae, monitor visit logs, laboratory reference ranges, 
laboratory certification or quality control procedures and laboratory director curriculum 
vitae.  All study documents shall be made available if required by relevant regulatory 
authorities. The investigator must consult with the Sponsor prior to discarding study and/or 
subject files. 
 
The investigator will promptly inform the Sponsor of any regulatory agency inspection 
conducted for this study. 
 
Persons debarred from conducting or working on studies by any court or regulatory agency 
will not be allowed to conduct or work on this Sponsor’s studies.  The investigator will 
immediately disclose in writing to the Sponsor if any person who is involved in conducting 
the study is debarred or if any proceeding for debarment is pending or, to the best of the 
investigator’s knowledge, threatened. 
 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that site’s IRB/IEC. 
 
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center study (including multinational).  When more than one study 
site is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different sites in that Member State, according to national regulations.  
For a single-center study, the Protocol CI is the principal investigator.  In addition, the 
Sponsor must designate a principal or coordinating investigator to review the study report 
that summarizes the study results and confirm that, to the best of his/her knowledge, the 
report accurately describes the conduct and results of the study in the study’s final report.  
The Sponsor may consider one or more factors in the selection of the individual to serve 
as the Protocol CI and or CSR CI (e.g., availability of the CI during the anticipated review 
process, thorough understanding of study methods, appropriate enrollment of subject 
cohort, timely achievement of study milestones).  The Protocol CI must be a participating 
study investigator. 
 
8.5   Quality Management System  
By signing this protocol, all parties agree to following applicable standard operating 
procedures (SOPs). All parties also agree to ensuring all existing and new study personnel 
are appropriately trained to ensure the study is conducted and data are generated, 
documented, and reported in compliance with the protocol, Good Pharmacoepidemiology 
Practice (GPP), and all applicable federal, state, and local laws, rules and regulations. All 
parties should maintain transparency and open communication in order to effectively 
manage the study and proactively mitigate any risks.   
 

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The Sponsor may conduct routine or for-cause audits to ensure oversight and conduct of 
the study are completed in accordance with the protocol, quality standards (e.g. GPP), and 
applicable laws and regulations. If a significant quality issue (SQI) is identified at any time 
during the conduct of the study, it must be escalated to the Sponsor immediately. A SQI is 
any issue with the potential to negatively impact, either directly or indirectly, the rights, 
safety and well-being of patients or study participants and/or the integrity of the data. In 
the event an audit or SQI results in corrective or preventive actions, all parties are expected 
to appropriately implement the action plan in a timely manner.  
 
8.6   Data Management 
The investigator or qualified designee is responsible for recording and verifying the 
accuracy of subject data.  By signing this protocol, the investigator acknowledges that 
his/her electronic signature is the legally binding equivalent of a written signature.  By 
entering his/her electronic signature, the investigator confirms that all recorded data have 
been verified as accurate. 
For an outsourced study the institutional policies of the supplier should be followed for 
development of data management plans.  However, the supplier should ensure compliance 
with Good Pharmacoepidemiology Practice, and all applicable federal, state, and local 
laws, rules and regulations relating to the conduct of the study.  
 

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9 Publications 
The Risk Management Subteam (RMST) Lead /Clinical Safety Risk Manager (CSRM) Physician 
will be notified if any safety data are generated in the final study report or any interim report. The 
safety and conclusion sections of the final study report or interim report must be reviewed by the 
RMST Lead/CSRM Physician prior to finalization of the report.  The review by the CSRM 
Physician must occur prior to any release of results to the public domain in the form of abstracts, 
posters, presentations or manuscripts. 
The study results will be submitted as abstract submission to relevant international and local HIV 
congresses. A manuscript will be drafted and submitted for publication in local/international 
scientific/professional journal. 
10 References 
 
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on February 17, 2016. Retrieved February 11, 2016. 
2. "About HIV/AIDS". CDC. December 6, 2015. Retrieved February 11, 2016. 
3. "Fact sheet - Latest statistics on the status of the AIDS epidemic". www.unaids.org. 
UNAIDS. Retrieved 2018-03-16. 
4. Fact sheet – Latest statistics on the status of the AIDS epidemic | UNAIDS". 
www.unaids.org. Archived from the original on July 13, 2017. Retrieved July 21, 
2017. 
5. Ministry of Healthcare of the Russian Federation (2016) ‘Approving the State 
Strategy to Combat the Spread of HIV in Russia through 2020 and beyond’ 
6. 2. In 2017, 100,000 people in Russia became infected with HIV, 26,000 more than 
in 2010, a 35% rise.UNAIDS (2018) UNAIDS 'Data Book' [pdf] 
7. Clark, F. (2016) ‘World Report: Gaps remain in Russia's response to HIV/AIDS’ 
The Lancet, Vol 388, No. 10047, p857–858, 27 August 2016 
8. Beyrer C, Wirtz AL, O’Hara G, L?on N, Kazatchkine M (2017) ‘The expanding 
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9. Palella FJ Jr, Delaney KM, Moorman AC et al. Declining morbidity and mortality 
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10. Cesar C, Shepherd BE, Krolewiecki AJ et al; Caribbean, Central and South 
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12. WHO.The use of antiretroviral drugs for treating and preventing HIV infection 
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Team Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial 
treatment of HIV-1. Ann Intern Med 2011; 154:445–56. [PMC free article] 
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15. Echeverr?a P, Negredo E, Carosi G et al. Similar antiviral efficacy and tolerability 
between efavirenz and lopinavir/ritonavir, administered with abacavir/lamivudine 
(Kivexa), in antiretroviral-na?ve patients: a 48-week, multicentre, randomized 
study (Lake Study). Antiviral Res 2010; 85:403–8. [PubMed] 
16. Mir? JM, Manzardo C, Pich J et al; Advanz Study Group Immune reconstitution in 
severely immunosuppressed antiretroviral-naive HIV type 1-infected patients using 
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17. Borges H, Lundh A, Tendal B et al. Nonnucleoside reverse-transcriptase inhibitor- 
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18. Tuboi SH, Schechter M, McGowan CC et al. Mortality during the first year of 
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19. Cesar C, Shepherd BE, Jenkins CA et al; Caribbean, Central and South America 
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20. De La Torre-Lima J, Aguilar A, Santos J et al. Durability of the first antiretroviral 
treatment regimen and reasons for change in patients with HIV infection. HIV Clin 
Trials 2014; 15:27–35. 
 
 

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11 Attachments 
 
External Adverse Event and Product Quality Complaint Form 
 
 
 

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General Guidance for completing External Adverse Event and Product Quality Complaint 
Form 
 
 
 
 
 

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12 SIGNATURES 
 
 
 
12.1 
Sponsor's Representative 
 
PRINTED NAME 
 
TITLE 
 
SIGNATURE 
 
DATE SIGNED 
 
 
 
 

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12.2 
Investigator 
 
I agree to conduct this study in accordance with the design outlined in this protocol and to abide by 
all provisions of this protocol (including other manuals and documents referenced from this 
protocol); changes from the protocol are acceptable only with a mutually agreed upon protocol 
amendment.  I agree to conduct the study in accordance with generally accepted standards of Good 
Pharmacoepidemiology Practice.  I also agree to report all information or data in accordance with 
the protocol and, in particular, I agree to report any serious adverse experiences as defined in 
Section 6 – Safety and Product Quality Complaint Reporting and Related Procedures.  I understand 
that information that identifies me will be used and disclosed as described in the protocol, and that 
such information may be transferred to countries that do not have laws protecting such information.  
Since the information in this protocol is confidential, I understand that its disclosure to any third 
parties, other than those involved in approval, supervision, or conduct of the study is prohibited. I 
will ensure that the necessary precautions are taken to protect such information from loss, 
inadvertent disclosure, or access by third parties. 
 
 
PRINTED NAME 
 
TITLE 
 
SIGNATURE 
 
DATE SIGNED 
 
 
 
 

VEAP ID NO: 8370 
02 July 2020 
              15-Nov-2019 DB_TB6 Restricted  Confidential – Limited Access 
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12.3 
Supplier  
 
I agree to conduct this study in accordance with the design outlined in this protocol and to abide by 
all provisions of this protocol (including other manuals and documents referenced from this 
protocol); changes from the protocol are acceptable only with a mutually agreed upon protocol 
amendment.  I agree to conduct the study in accordance with generally accepted standards of Good 
Pharmacoepidemiology Practice.  I also agree to report all information or data in accordance with 
the protocol and, in particular, I agree to report any serious adverse experiences as defined in 
Section 6 – Safety and Product Quality Complaint Reporting and Related Procedures.  I understand 
that information that identifies me will be used and disclosed as described in the protocol, and that 
such information may be transferred to countries that do not have laws protecting such information.  
Since the information in this protocol is confidential, I understand that its disclosure to any third 
parties, other than those involved in approval, supervision, or conduct of the study is prohibited. I 
will ensure that the necessary precautions are taken to protect such information from loss, 
inadvertent disclosure, or access by third parties. 
 
 
PRINTED NAME 
 
TITLE 
 
SIGNATURE 
 
DATE SIGNED