Conditions: Cardiovascular Diseases Hepatitis C Hiv
Keywords: Cardiovascular Disease
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 87
Healthy volunteers: no

Brief summary:
This is an interventional, non-randomized, controlled prospective study to treat HCV in mono-infected and HIV co-infected individuals and compare cardiovascular risk outcomes to HIV mono-infected controls. This pilot study will demonstrate whether functional cure of HCV reduces myocardial injury and risk of cardiovascular disease.

Detailed description:

Arms:
arm 1: Patients infected with HIV only, and not currently or previously infected with hepatitis C. arm 2: Patients infected with Hepatitis C and have no evidence of active HIV or hepatitis B infection arm 3: Patients co-infected with HIV and hepatitis C, and have no evidence of active hepatitis B infection.

Interventions: intervention 1: Elbasvir / Grazoprevir Oral Tablet [Zepatier] intervention 2: Cardiac MRI
Intervention descriptions: intervention 1: All approved direct-acting antivirals for hepatitis C will be used as the intervention. intervention 2: Cardiac MRI to assess for myocardial function and fibrosis

Protocol document:
Prot_SAP_000.pdf: 
CHROME V 10 
January 2,  2020 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Study Protocol 
 
Cardiovascular disease in HIV and Hepatitis C: Risk Outcomes after hepatitis C 
Eradication  
(CHROME) 
 
 
Principal Investigator:  Poonam Mathur, DO 
 
Study No: HP-00081300 
 
Version Number: 10 
 
January 2, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
The information contained herein is the property of IHV and may not be reproduced, 
published or disclosed to others without written authorization. 


CHROME V 10 
January 2,  2020 
 
2 
Study Staff Roster 
Principal Investigator:    
Poonam Mathur, DO  
 
 
 
 
 
Institute of Human Virology (IHV) 
 
 
 
 
 
725 West Lombard Street 
 
 
 
 
 
Baltimore, MD 21201 
 
 
 
 
 
Tel: 443-326-0506 
 
 
 
 
 
 
Sub-Investigators:  
 
Sarah Kattakuzhy, MD, IHV/Special Volunteer NIH 
Elana Rosenthal, MD, IHV/Special Volunteer NIH 
 
 
 
 
 
Joel Chua, MD, IHV 
Angie Price, ARNP, IHV 
Rachel Silk, BSN, MPH, IHV/Special Volunteer NIH 
Rahwa Eyasu, MSN, FNP, IHV/Special Volunteer NIH 
Eleanor Wilson, MD, MHS, IHV 
Amy Nelson, RN, IHV 
Jenny Hoffman, NP, IHV 
Lydia Tang, MD, IHV 
Jennifer Husson, MD, IHV 
Salma Sharaf, IHV 
Ilise Marrazzo, BSN, MPH, IHV 
Amelia Cover, NP, IHV 
Emade Ebah, IHV 
Ashley Davis, NP, IHV 
Henry Masur, MD, NIH/CC/CCMD 
Arlene Sirajuddin, MD NIH/NHLBI 
Mark Ahlman, NIH/CC/LDRR 
 
Research Assistants: 
 
Christopher Brockus, BA, CCMD/NIH 
 
 
 
 
 
Jasmine Stevens, BA, CCMD/NIH 
 
 
 
 
 
Julia Mount, BA, CCMD/NIH 
 
 
 
 
 
 
Epidemiologist/Statistician:  
Benjamin Emmanuel, PhD  
 
Study Sites/Site Collaborators: 
The University of Maryland Institute of 
Human Virology 
 
 
725 W. Lombard St. 
 
 
Baltimore, MD 21201 
 
The University of Maryland Center for 
Infectious Diseases 
300 Armory Place 


CHROME V 10 
January 2,  2020 
 
3 
Baltimore, MD 21201 
 
National Institutes of Health Clinical Center 
Building 10 
10 Center Drive, MSC 1182 
Bethesda, MD 20892 
 
Unity Healthcare System 
1220 12th St. SE, Suite 120 
Washington, DC 20003 
 
 
 
 
 
Laboratory Collaborators:  
Bhawna Poonia, PhD, IHV 
 
Nicholas Mills, MD, PhD, University of 
Edinburgh 
Anoop Shah, PhD, University of Edinburgh 
 
 
 


CHROME V 10 
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4 
Table of Contents 
LIST OF ABBREVIATIONS .............................................................................................................................. 6 
PROTOCOL SUMMARY.................................................................................................................................... 8 
PRIMARY OBJECTIVE:....................................................................................................................................................................... 8 
SECONDARY OBJECTIVES ................................................................................................................................................................ 8 
1 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ................................................. 11 
1.1 
BACKGROUND INFORMATION .................................................................................................................................... 11 
1.2 
INSTITUTIONAL OVERVIEW ........................................................................................................................................ 12 
1.3 
TREATMENT ................................................................................................................................................................... 13 
1.4 
RATIONALE ..................................................................................................................................................................... 14 
2 
STUDY OBJECTIVES ............................................................................................................................. 14 
2.1 
PRIMARY OBJECTIVE .................................................................................................................................................... 14 
2.2 
SECONDARY OBJECTIVES ............................................................................................................................................. 14 
2.3 
EXPLORATORY OBJECTIVES ........................................................................................................................................ 14 
3 
STUDY DESIGN ..................................................................................................................................... 15 
3.1 
DESCRIPTION OF THE STUDY DESIGN ...................................................................................................................... 15 
3.2 
STUDY DRUGS ................................................................................................................................................................. 15 
3.3 
RESEARCH STRATEGY .................................................................................................................................................. 17 
3.4 
PRIMARY HYPOTHESIS ................................................................................................................................................. 17 
4 
STUDY POPULATION .......................................................................................................................... 17 
4.1 
RATIONALE FOR SUBJECT SELECTION ..................................................................................................................... 17 
4.2 
SUBJECT INCLUSION CRITERIA................................................................................................................................... 17 
4.3 
SUBJECT EXCLUSION CRITERIA .................................................................................................................................. 18 
4.3.1 
Justification for Exclusion ................................................................................................................................ 19 
4.3.2 
Incarcerated Participants ............................................................................................................................... 19 
5 
INTERVENTIONS .................................................................................................................................. 20 
5.1 
CONCOMITANT MEDICATIONS AND PROCEDURES................................................................................................ 20 
1.2 
PROHIBITED MEDICATIONS ........................................................................................................................................ 20 
6 
STUDY SCHEDULE ............................................................................................................................... 20 
6.1 
SCREENING /ENROLLMENT ........................................................................................................................................ 20 
6.2 
INTERIM VISIT ................................................................................................................................................................ 21 
6.3 
STANDARD OF CARE HCV TREATMENT ................................................................................................................... 21 
6.4 
STUDY PROCEDURES – HCV TREATMENT............................................................................................................... 21 
CARDIAC BIOMARKER AND SYSTEMIC INFLAMMATION ASSESSMENT.............................................. 21 
CARDIAC MRI .................................................................................................................................................. 21 
6.4.1 
STORED SAMPLE COLLECTION.................................................................................................................................... 21 
6.4.2 
HIV AND HCV MONITORING ...................................................................................................................................... 22 
6.4.3 
VIRAL SEQUENCING....................................................................................................................................................... 22 
6.4.4 
LINKAGE TO CARE.......................................................................................................................................................... 22 
6.5 
EARLY TERMINATION VISIT ....................................................................................................................................... 22 
7 
POTENTIAL RISKS AND BENEFITS .................................................................................................. 22 
7.1 
POTENTIAL RISKS ......................................................................................................................................................... 22 
7.2 
POTENTIAL BENEFITS .................................................................................................................................................. 24 
8 
STORED SAMPLES AND FUTURE RESEARCH ................................................................................ 24 


CHROME V 10 
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5 
8.1 
INTENDED USE: ............................................................................................................................................................. 24 
8.2 
STORAGE: ........................................................................................................................................................................ 25 
8.3 
TRACKING: ...................................................................................................................................................................... 25 
8.4 
DISPOSITION AT THE COMPLETION OF THE PROTOCOL:..................................................................................... 25 
8.5 
REPORTING THE LOSS OR DESTRUCTION OF SAMPLES/SPECIMENS/DATA TO THE IRB: ........................ 25 
9 
ASSESSMENT OF SAFETY ................................................................................................................... 25 
9.1 
RECORDING/DOCUMENTATION ................................................................................................................................ 26 
9.2 
DEFINITIONS................................................................................................................................................................... 26 
9.3 
REPORTING PROTOCOL DEVIATIONS, AES AND DEATHS .................................................................................... 26 
9.3.1 
Expedited Reporting to the IRB..................................................................................................................... 27 
9.3.2 
Waiver of Reporting Anticipated Protocol Deviations, Expected non-UP AEs and Deaths 27 
9.3.3 
Reporting to Sponsor ............................................................................ Error! Bookmark not defined. 
9.4 
ANNUAL REPORTING TO THE IRB ............................................................................................................................ 27 
9.4.1 
Type and Duration of the Follow-up of Subject after Adverse Events......................................... 27 
10 WITHDRAWAL OF A SUBJECT .......................................................................................................... 28 
10.1 
RETURN OF WITHDRAWN/REMOVED SUBJECTS.................................................................................................. 28 
11 REMUNERATION PLAN FOR SUBJECTS .......................................................................................... 28 
12 MONITORING ........................................................................................................................................ 28 
13 STATISTICAL CONSIDERATIONS ..................................................................................................... 29 
13.1 
SAMPLE SIZE JUSTIFICATION AND POWER ............................................................................................................. 29 
13.2 
STATISTICAL ANALYSIS ............................................................................................................................................... 29 
14 ETHICS/PROTECTION OF HUMAN SUBJECTS............................................................................... 29 
14.1 
INFORMED CONSENT PROCESS .................................................................................................................................. 29 
14.2 
ILLITERACY AND CONSENTING .................................................................................................................................. 30 
14.3 
SUBJECT CONFIDENTIALITY........................................................................................................................................ 30 
APPENDIX A: SCIENTIFIC REFERENCES .................................................................................................. 31 
APPENDIX B: STUDY PROCEDURES TABLE ........................................................................................... 33 
APPENDIX C: CARDIAC MRI ....................................................................................................................... 34 
 


CHROME V 10 
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6 
List of Abbreviations 
 
AE 
 
 
Adverse Event/Adverse Experience 
ART  
 
Antiretroviral Therapy  
CCMD 
 
Critical Care Medicine Department 
CD4 
 
Cluster of Differentiation 4 
CD8 
 
Cluster of Differentiation 8 
CD38 
 
Cluster of Differentiation 38 
CHROME 
 
Study short name 
Co-Infection  
Identifier for those with both HIV and hepatitis C  
CXCL 9 
 
Chemokine ligand 9 
CXCL 10 
 
Chemokine ligand 10 
CXCL 11 
 
Chemokine ligand 11 
DAA  
 
Directly Acting Antiviral 
DC PFAP 
 
DC Partnership for HIV/AIDS Progress 
EDTA  
 
Ethylenediaminetetraacetic acid 
ELISPOT 
 
Enzyme-Linked Immunospot assay 
HCV  
 
Hepatitis C Infection 
HIPAA 
 
Health Insurance Portability and Accountability Act 
HIV 
 
 
Human Immunodeficiency Virus 
HLA-DR+ 
 
Human Leukocyte Antigen-antigen D related 
HRPP  
 
Human Research Protection Program 
hsCRP 
 
High Sensitivity C-reactive protein 
hsTRP 
 
High Sensitivity Troponin 
IFN-g  
 
Interferon-gamma 
IHV 
 
 
Institute of Human Virology 
IL-6 
 
 
Interleukin 6 
IRB 
 
 
Institutional Review Board 
MRI 
 
 
Magnetic Resonance Imaging 
MTA  
 
Materials Transfer Agreement 
N 
 
 
Number (typically refers to number of subjects/sample size) 
NIH 
 
 
National Institutes of Health 
NK 
 
 
Natural Killer (cells) 
PD-1  
 
Programmed Cell Death Protein 1 
PEG-IFN-a  
Pegylated interferon-alpha 
PWID  
 
People who inject drugs 
PI 
 
 
Principal Investigator 
PRO  
 
Patient Reported Outcomes 
RNI 
 
 
Reportable New Information 
SAE  
 
Serious Adverse Event/Serious Adverse Experience 
SOC  
 
Standard of Care 
SOM  
 
School of Medicine 
SVR  
 
Sustained Virologic Reponse 
TIM-3  
 
T Cell Immunoglobulin and Mucin Domain 3 
TNF-α  
 
Tumor Necrosis Factor alpha 
UP 
 
 
Unanticipated Problem 


CHROME V 10 
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UPnonAE 
 
Unanticipated Problem that is not an Adverse Event 
 
 


CHROME V 10 
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8 
Protocol Summary 
Full Title: 
Cardiovascular disease in HIV and Hepatitis C: Risk 
Outcomes after hepatitis C Eradication 
Short Title: 
CHROME 
Conducted by: 
Institute of Human Virology, University of Maryland 
Principal Investigator: 
Poonam Mathur, DO 
Sample Size: 
N= 90; 60 on hepatitis C treatment; will consent up to 200 for 
screening 
Study Population: 
Adults infected with HIV and/or HCV 
Accrual Period: 
12 months 
Study Design: 
 
This is a pilot, intervention, non-randomized, controlled 
prospective study. We will enroll 90 patients into 3 groups. 
Patients with HCV mono-infection (Group 1) or HIV/HCV co-
infection (Group 2) will receive therapy with DAAs. Patients 
with HIV mono-infection (Group 3) will be followed 
throughout the study and laboratory work and imaging will be 
obtained.  
Study Duration: 
 
Start Date: September 2018  
 
 
End Date: July 2021 
Primary Objective: 
Determine the change in cardiovascular risk from baseline to 
after functional cure of hepatitis C among HCV monoinfected 
and HIV/HCV-coinfected patients, using high-sensitivity C-
reactive protein. 
Secondary Objectives:1) Determine the difference in change (pre vs. post 
functional cure) in cardiovascular risk among HCV 
monoinfected and HIV/HCV coinfected patients compared to 
HIV monoinfected patients, using high-sensitivity C-reactive 
protein. 
 
 
2) Compare the difference in levels of cardiac biomarkers 
between HCV monoinfected, HIV/HCV coinfected, and HIV 
monoinfected patients at baseline. 
 
 
3) Determine the difference in change (pre vs. post 
functional cure) in cardiac biomarkers among HCV 
monoinfected and HIV/HCV coinfected patients, compared 
to HIV moninfected patients.   
Exploratory Objectives:  
 
 
1) Compare the difference in cardiac MRI between HCV 
monoinfected, HIV/HCV coinfected, and HIV mono-infected 
subjects at baseline. MRI parameters that will be assessed 


CHROME V 10 
January 2,  2020 
 
9 
are the native myocardial T1, myocardial T2, and myocardial 
extracellular volume fraction (to look for myocardial 
inflammation and small vessel disease). Gadolinium 
enhacement will be used to look at macroscopic fibrosis. 
 
 
2) Determine the difference in change (pre vs. post 
functional cure) in cardiac MRI in HCV monoinfected and 
HIV/HCV coinfected patients, compared to HIV 
monoinfected patients. MRI parameters that will be 
assessed are listed in objective 1. 
 
 
3) Determine the relationship between immune markers of 
activation, cardiac biomarkers, and MRI in HIV positive and 
negative subjects. MRI parameters that will be assessed are 
listed in objective 1.  
 
 
4) Compare the difference in levels of cellular and soluble 
immune markers of activation between HCV monoinfected, 
HIV/HCV coinfected, and HIV monoinfected subjects at 
baseline. 
 
 
 
 
5) Determine the difference in change (pre vs. post 
functional cure) in cellular and soluble immune markers of 
activation HCV monoinfected and HIV/HCV coinfected 
patients, compared to HIV moninfected patients.   
 
 
 
 
 
 
 
 


CHROME V 10 
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10 
Précis 
 
Among people living with HIV (PLWH), there is a 50% increased risk of acute  
myocardial infection compared to the general population(1). Although the advent of  
highly active antiretroviral therapy (HAART) has had several benefits for PLWH, 
including increased life expectancy(2), the longer life span has also made this 
population apt to develop comorbidities seen in age-matched individuals  
without HIV, including cardiovascular disease. In addition, HAART itself is a risk factor 
for cardiovascular disease (CVD)(3), and persistent inflammation and chronic 
immune activation caused by HIV and ART results in a proinflammatory state that also  
increases the risk for cardiovascular disease(4).  
 
Hepatitis C (HCV) is another chronic viral infection with significant morbidity and 
mortality. The development of directly acting antivirals (DAAs) has dramatically 
improved the cure rate of HCV treatment. However, besides the effects on the 
liver, chronic infection with HCV leads to numerous extrahepatic manifestations that are  
associated with morbidity and mortality, including cardiovascular disease(5, 6).  
Therefore, patients co-infected with HCV and HIV have a magnified cardiovascular risk  
than that of the general population (7). If treatment of HCV can lower the risk of CVD  
among HIV and HCV co-infected patients, then this would provide an indication for early  
HCV treatment in this population. 
 
As such, we propose a pilot, intervention, non-randomized, controlled prospective  
study to treat HCV in mono-infected and HIV co-infected individuals and compare  
cardiovascular risk outcomes to HIV mono-infected controls. This pilot study will  
demonstrate whether functional cure of HCV reduces myocardial injury and risk of  
cardiovascular disease.  
 
 
 
 
 
 
 
 
 


CHROME V 10 
January 2,  2020 
 
11 
1 Background Information and Scientific Rationale 
1.1 Background Information 
 
Rates of cardiovascular disease (CVD) are over twice as high in HIV-infected 
individuals compared to matched uninfected controls, with rates anticipated to increase 
as this population ages(8).  Factors contributing to increased risk of CVD in HIV-infected 
patients remain unclear, but there is considerable evidence suggesting that concurrent 
viral disease, especially HCV, is an important contributing factor. With the advent of 
direct acting antivirals (DAA), HCV is now a factor that can be easily eliminated. 
Hepatitis C (HCV) co-infection occurs in approximately one-third of all patients infected 
with human immunodeficiency virus (HIV) in the U.S(9). The early treatment of HCV in 
this population could be an important intervention to reduce the burden of liver disease; 
thus far, early treatment has been a controversial intervention in patients with no fibrosis 
given the cost of HCV treatment. Moreover, chronic HCV is an important model for 
understanding the role of chronic viruses in accelerating inflammation and organ 
dysfunction in multiple anatomic sites. 
While some studies have strongly suggested that hepatitis C (HCV) co-infection 
is associated with increased rates of CVD in HIV-infected patients, results in all studies 
have not been consistent. However, several of these larger cohort studies included 
predominantly Caucasian and male participants in the pre-antiretroviral therapy era(8).  
Given that HIV, HCV, and atherosclerosis are all associated with chronic inflammation 
and immune activation, it can be challenging to understand relative disease 
pathogenesis when found concurrently in individual patients. Identifying predictors of 
CVD progression from overlapping pathways has the potential to suggest novel 
preventive and therapeutic intervention strategies to mitigate CVD progression. If HCV 
confers additional risk for CVD among HIV-infected patients, this would provide further 
impetus to treat HCV early and aggressively in this population.   
 
Myocardial injury and vascular complications associated with HIV can be 
differentiated by the use of cardiac MRI. Cardiac MRI is an established modality for the 
evaluation of myocardial injury and cardiac function(10, 11). Infarcted regions in the 
myocardium, having undergone scar formation with collagen deposition, have a much 
slower washout rate of gadolinium-based contrast than healthy myocardium, leading to 
significantly increased signal intensity on T1-weighted imaging. Therefore, the presence 
and size of regional myocardial fibrosis due to ischemic heart disease can be accurately 
assessed with delayed contrast enhancement MRI (12). Unlike computed tomography, 
with which Hounsfield units can be used as a reference scale for attenuation, with 
conventional MRI techniques, signal intensity is expressed on an arbitrary scale that 
differs from one imaging examination to another and therefore is unsuitable for direct 
signal quantification. Theoretically, diffusely fibrotic myocardium would accumulate 
contrast in a similar fashion to regional scarring, but calculation of the T1 time is 
required for its quantification, and is a technique that we have expertise with at the NIH. 
Measurement of cardiac function is a well described prognostic tool to evaluate 
myocardial health, and is also an integral component of a complete cardiac MRI 
conducted at the NIH. This modality may be effective in distinguishing variable 
myocardial injury between HIV mono-infected and HIV/HCV co-infected individuals. In 


CHROME V 10 
January 2,  2020 
 
12 
fact, a prior study of 18 patients demonstrated worse cardiac function and morphology 
in HIV/HCV patients who underwent cardiac MRI and spectroscopy for measures of 
cardiac function, myocardial fibrosis, and steatosis which compared to HIV mono-
infected controls(13). However further studies are necessary to reinforce this finding, 
and elucidate underlying mechanisms of injury.  
The objective of this study is to determine the impact of functional cure of HCV 
(sustained virologic response [SVR]) on cardiovascular risk and progression of CVD in a 
population of HCV mono-infected and HIV/HCV-coinfected patients compared to HIV 
mono-infected controls.  
1.2 Institutional Overview 
 
Overview of the DC PFAP Hepatitis Program  
 
In 2008, the National Institutes of Health and the DC Department of Health collaborated 
to establish the DC Partnership for HIV/AIDS Progress (DC PFAP), a partnership for 
community-based clinical care and research whose aim is to reduce the incidence and 
prevalence of HIV/AIDS in the District of Columbia. A plan was developed to create a 
research program to build a sustainable model for urban areas working to reduce the 
HIV/AIDS crisis. A needs assessment within the area’s medical community demonstrated 
a significant deficit in hepatitis C virus care and treatment. This led to the development of 
a Hepatitis branch within DC PFAP, rooted in direct subspecialty medical services and 
clinical research addressing the limitations of standard of care therapy.  
 
The Hepatitis program is currently based at the Institute of Human Virology and operates 
out of three campuses: (1) clinical partners within Washington DC, (2) National Institutes 
of Health, Bethesda, MD and (3) University of Maryland Institute of Human Virology, 
Baltimore, MD. The overarching goals of the programs are to: 
 
• 
establish improved access to subspecialty care for underinsured patients with HIV  
• 
develop access to HIV- and hepatitis-related research for residents of DC 
• 
expand integrated care for hepatitis C in the community HIV clinics  
• 
provide national leadership in the development and delivery of effective, safe, 
convenient therapies, initially focusing on HCV  
 
The clinical aspects of the program are set within partner centers in Washington DC and 
Baltimore City. In the Unity clinic system in Washington DC, we have established 
relationships with the providers and access to a cohort of patients with HIV and Hepatitis 
C. In Baltimore City, the Center for Infectious Disease (CID) provides comprehensive care 
services for a range of infectious diseases, including HIV and hepatitis C. Patients are 
managed by state of the art standard of care as well as offered opportunities to participate 
in clinical research as appropriate. We also have an active clinic at the UMB Drug 
Treatment Center (DTC) treating patients for HCV. To date, over 1240 HIV and HCV 
infected patients have been linked to care and over 900 patients cured of hepatitis C 
through treatment with novel DAA therapy within subspecialty clinics in the Baltimore and 
DC areas. Through direct linkage to care, effective treatment, and continual outcome 


CHROME V 10 
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13 
measurement, the Hepatitis program has developed an effective model for management 
of hepatitis C in an urban setting.   
 
University of Edinburgh: 
Nicholas Mills, MD, PhD, University of Edinburgh, Anoop Shah, PhD, University of 
Edinburgh are laboratory collaborators with Dr. Poonia.   They are experts the field of 
cardiovascular biomarkers and will conduct hsTRP assasy using the samples collected 
from this study.  UMB has a collaborative agreement and MTA between UMB and Univ 
of Edinbugh to support research protocols done at UMB/IHV and Dr. Poonia’s lab.  
 
The National Institutes of Health, Bethesda, MD   
The National Institutes of Health, Bethesda, MD  campus will provide access to 
advanced cardiac MRI imaging and other clinical research resources not available at 
the clinical sites.  Henry Masur, MD is the NIH Intramural site Principal Investigator and 
will oversee the protocol and all the individuals working on it at The NIH Clinical 
Center.  These individuals are listed in the UMD Protocol as Sub-Investigators or 
Research Assistants may include federal employees, special volunteers, and/or 
contractors. Dr. Masur will be authorized to obtain informed consent, have access to 
identifiable data, and participate in data analysis and manuscript preparation/review. 
Research Assistants (Laura Nussdorf, BA; Christopher Brockus, BA) will provide 
research support to the protocol by scheduling imaging, escorting participants to 
radiology appointments the Clinical Center, and data collection as needed. Arlene 
Sirajuddin, MD and Mark Ahlman, MD are expert radiologists in cardiac MRI and will 
provide analysis of all imaging for those participants.  Mary Hall will provide 
regulatory support for the NIH site. She will not obtain informed consent but may have 
access to identifiable data. 
 
Poonam Mathur, Sarak Kattakuzhy, Elana Rosenthal, Rahwa Eyasu and Rachel Silk, 
are UMB sub investigators who are also special volunteers at NIH and are fully 
credentialed and able to see research patients at the NIH.  They are authorized to 
obtain informed consent, have access to identifiable data, see patients at NIH and 
participate in data analysis and manuscript preparation/review. 
 
Data Sharing Among Collaborators 
The PI and DC PFAP study team will have access to all data collected from all sites and 
the NIH will share all the Cardiac MRI data with the DC PFAP. 
 
1.3 Treatment 
Until recently, a major limiting factor in expansion of treatment for HCV has been standard 
of care therapy with pegylated interferon, ribavirin, and for genotype 1 disease, boceprevir 
and telaprevir. These medications have significant side effect profiles, response-based 
dosing regimens of over 6 months, and decreased efficacy in key groups including: those 
with genotype 1 disease, HIV coinfection, and cirrhosis. However, there has been 
dramatic improvement using all oral direct-acting antiviral (DAA) regimens with sustained 
virologic response (SVR) rates over 90%, short-duration therapies and well-tolerated, 


CHROME V 10 
January 2,  2020 
 
14 
simple regimens, including for those with HIV coinfection. Several studies using DAA-
based therapy have shown comparable rates of sustained virologic response (SVR) in 
coinfected patients(14-21). In addition, data suggests that HCV eradication with use of 
antiviral therapy may improve cardiovascular outcomes in mono-infected patients(22). 
However, there is no data on the benefit of cardiovascular risk after HCV eradication in 
co-infected patients.  
1.4 Rationale 
HIV and HCV are diseases of concern in the Baltimore and DC metropolitan areas. New 
DAA treatments allow for effective treatment of chronic HCV and reduction in risk of 
extrahepatic comorbidities, including cardiovascular disease. However, no data exists 
on the role of HCV eradication in mitigating cardiovascular risk in HIV co-infected 
patients, who at baseline have an increased risk of cardiovascular disease due to the 
pro-inflammatory state caused by the virus and the use of ART. This study aims to 
demonstrate that there is a decreased risk of cardiovascular disease after 
eradication of HCV in HCV mono-infected and HIV co-infected patients. The risk 
factors of these patients will be compared to the risk factors for HIV mono-infected 
patients and HCV mono-infected patients who achieve functional HCV cure.  
 
2 Study Objectives 
 
2.1 Primary Objective 
Determine the change in cardiovascular risk from baseline to after functional cure of 
hepatitis C among HCV monoinfected and HIV/HCV-coinfected patients, using high-
sensitivity C-reactive protein. 
2.2 Secondary Objectives  
Determine the difference in change (pre vs. post functional cure) in cardiovascular risk 
among HCV monoinfected and HIV/HCV coinfected patients compared to HIV 
monoinfected patients, using high-sensitivity C-reactive protein. 
Compare the difference in levels of cardiac biomarkers between HCV monoinfected, 
HIV/HCV coinfected, and HIV monoinfected patients at baseline 
Determine the difference in change (pre vs. post functional cure) in cardiac biomarkers 
among HCV monoinfected and HIV/HCV coinfected patients, compared to HIV 
moninfected patients.   
2.3 Exploratory Objectives 
1.  Compare the difference in cardiac MRI between HCV monoinfected, HIV/HCV 
coinfected, and HIV mono-infected subjects at baseline. MRI parameters that will 
be assessed are the native myocardial T1, myocardial T2, and myocardial 
extracellular volume fraction (to look for myocardial inflammation and small 


CHROME V 10 
January 2,  2020 
 
15 
vessel disease). Gadolinium enhacement will be used to look at macroscopic 
fibrosis. 
2. Determine the difference in change (pre vs. post functional cure) in cardiac MRI 
in HCV monoinfected and HIV/HCV coinfected patients, compared to HIV 
monoinfected patients. MRI parameters that will be assessed are listed in 
exploratory objective 1. 
3. Determine the relationship between immune markers of activation, cardiac 
biomarkers, and MRI in HIV positive and negative subjects. MRI parameters that 
will be assessed are listed in exploratory objective 1.  
4. Compare the difference in levels of cellular and soluble immune markers of 
activation between HCV monoinfected, HIV/HCV coinfected, and HIV 
monoinfected subjects at baseline. 
 
 
5. Determine the difference in change (pre vs. post functional cure) in cellular and 
soluble immune markers of activation HCV monoinfected and HIV/HCV 
coinfected patients, compared to HIV moninfected patients.   
  
3 Study Design 
3.1 Description of the Study Design  
This is a pilot, intervention, non-randomized, controlled prospective study. We will enroll 
90 patients into the following groups. Up to 200 patients will be consented. 
Group 1: HCV mono-infected patients (n = 30) 
Group 2: HIV/HCV co-infected patients (n = 30) 
Group 3: HIV mono-infected patients (n = 30) 
Patients with HCV mono-infection (Group 1) or HIV/HCV co-infection (Group 2) will 
receive therapy with any FDA-approved medication for hepatitis C treatment, per 
standard of care in the AASLD/IDSA HCV Treatment Guidelines and/or the discretion of 
the investigator.  
3.2 Study drugs 
Direct Acting Antivirals (DAAs): For the treatment of chronic HCV, patients will be 
treated with one of the following FDA-approved fixed-dose combination products : 
Elbasvir/Grazoprevir (Zepatier), Sofosbuvir/Ledipasvir (Harvoni), Sofosbuvir/Velpatasvir 
(Epclusa), Glecaprevir/Pibrentasvir (Mavyret), Sofosbuvir/Velpatasvir/Voxilaprevir 
(Vosevi).  Some of these medications require administration of concomitant ribavirin. 
Medication regimens will be administered as standard of care per the AASLD/IDSA 
HCV Treatment Guidelines. Common side effects (those that occurred in more than 5% 
of the patients in clinical trials) of these medications are listed below: 
 
Elbasvir/Grazoprevir (Zepatier): 


CHROME V 10 
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16 
• Fatigue 
• Headache 
Sofosbuvir/Ledipasvir (Harvoni): 
• Fatigue 
• Headache 
• Nausea 
• Diarrhea 
• Insomnia 
 
Sofosbuvir/Velpatasvir (Epclusa): 
• Headache 
• Fatigue 
• Nausea 
• Insomnia 
• Lack of energy 
 
Glecaprevir/Pibrentasvir (Mavyret): 
• Headache 
• Fatigue 
• Nausea 
• Diarrhea 
 
Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi): 
• Headache 
• Fatigue 
• Diarrhea 
• Nausea 
• Insomnia 
• Lack of energy 
 
Ribavirin - Women of childbearing potential who receive ribavirin must commit to 
abstinence from sexual activity, or use two forms of contraception during treatment and 
for the 6 months after completion of ribavirin. Men receiving ribavirin who are sexually 
active with women must commit to abstinence from sexual activity, or they and their 
partner must use two forms of contraception during treatment and for the 6 months after 
completion of ribavirin. The most common side effects (occurring more than 5% of the 
time in clinical trials) are: 
• Fatigue 
• Lack of energy 
• Body aches 
• Fever 
• Headache 
• Anemia 


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• Rash 
3.3 Research Strategy 
A total of up to 200 people will be consented for the study from existing clinical sites 
sites and long-term natural history studies.  The total N for the study is 90, HIV (n = 30), 
HIV/HCV (n=30), and HCV (n=30). The investigators have established clinics and 
networks in DC and Baltimore that have successfully recruited these patient populations 
for studies since 2010, including the ASCEND trial which accrued 600 patients in 10 
months. Study participants will be selected based on inclusion criteria, and will be seen 
for study visits at clinics embedded at one of 2 sites: 
1) Unity Healthcare, Washington, DC 
a. An organization which serves as DC’s largest network of community 
health centers providing comprehensive care services including primary 
care, HIV care, and Hepatitis B and C treatment.  
2) Institute of Human Virology, Clinical Research Unit, Baltimore, MD 
All participants HIV/HCV co-infected or HCV mono-infected patients will be treated for 
chronic HCV with DAAs as per standard of care (see 3.1 and 3.2.).  
 
3.4 Primary Hypothesis 
The primary hypothesis is that treatment and functional cure of HCV in HCV-
monoinfected and HIV/HCV-coinfected patients should lead to decreased 
cardiovascular risk, as measured by at least a 2-fold decrease in high-sensitivity C-
reactive protein (hsCRP) by 12 months post-functional cure of HCV. 
4 Study Population 
Participants are adults (age 18-70) patients infected with HIV, HCV and HIV/HCV. 
4.1 Rationale for Subject Selection 
Subjects of any gender will be considered for inclusion in this study. There will be no 
racial, ethnic, or gender discrimination. Persons in jail or prison are not eligible for this 
study (see 4.3.2). Pregnant and breastfeeding women will not be eligible (see section 
4.3.1). 
4.2 Subject Inclusion Criteria 
To be eligible for participation on this protocol, a participant must satisfy all of the 
following conditions: 
 
1. Age ³18 years old 
2. Able and willing to sign informed consent 


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3. Chronically infected with HCV (any genotype), defined as any individual with 
documentation of positive HCV antibody and positive HCV RNA test (HCV RNA 
of 2,000 IU/mL or greater) 
4. If HIV+, suppressed on a stable, protocol-approved, ARV regimen for ≥ 8 
weeks prior to enrolling in the study 
a. HIV RNA < 50 copies/mL (or < LLOQ if the local laboratory assay’s 
LLOQ is ≥50 copies/mL) prior to Screening. Subjects with an isolated or 
unconfirmed HIV RNA > 50 copies/mL (or > LLOQ if the local laboratory 
assay’s LLOQ is ≥50 copies/mL) are not excluded.  
b. CD4 count >100 cells/mm3  
5. Willing to have samples stored for future use 
6. If tested positive for NS5A resistance-associated polymorphisms or PEG-IFN 
and ribavirin experienced, able to tolerate ribavirin-containing regimen for 16 
weeks. Ribavirin will be administered at the discretion of the PI.  
7. Women of childbearing potential who receive ribavirin will have to be willing to 
commit to abstinence from sexual activity, or use of two forms of contraceptive 
during treatment and for the 6 months after completion of ribavirin. Men 
receiving ribavirin who are sexually active with women will also have to be 
willing to commit to abstinence from sexual activity, or use of two forms of 
contraceptive during treatment and for the 6 months after completion of 
ribavirin. 
4.3 Subject Exclusion Criteria 
A participant will be ineligible to participate in this study if any of the following criteria are 
met: 
1. Decompensated liver disease (Childs Pugh B or C) 
2. Unable to comply with research study visits 
3. Poor venous access not allowing screening laboratory collection 
4. Have any condition that the investigator considers a contraindication to study 
participation  
5. Pregnant or breastfeeding woman 
6. Prior HCV treatment with Direct-Acting Antivirals. Note: Patients who are 
treatment-experienced with PEG-IFN/RBV will not be excluded; their inclusion 
in the study will be considered by the PI.  
7. HIV+ patients with prior HCV treatment who achieved sustained virologic 
response (SVR)/ functional cure 
8. Use of a concomitant medication that is contraindicated with the use of the DAA 
for HCV treatment (per package insert) 
9. Coinfection with HCV and HBV, in partcular HBsAg + patients.  
a. Patients with HBcAb+ will not be excluded, but will have HBV DNA levels 
checked and will be monitored while on DAA therapy and medically 
managed as considered appropriate by the PI. 
10. Have any condition that the investigator considers a contraindication to study 
participation or not eligible per standard of care for HCV treatment  


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11. Patients with the following devices are excluded from participating in the 
cardiovascular MRI study:  
• Central nervous system aneurysm clip 
• Implanted neural stimulator 
• Implanted cardiac pacemaker or defibrillator 
• Cochlear implant 
• Ocular foreign body (e.g. metal shavings) 
• Implanted insulin pump 
• Metal shrapnel or bullet 
12. The following groups of people are also excluded from participating in the 
cardiovascular MRI study: 
• Patients with stable renal disease (estimated glomerular filtration 
rate (eGFR)<30ml/min/1.73m2 body surface area.  The eGFR must 
be within two weeks of the the MRI exam. 
• Patients with acute renal disease. 
13. Patients who choose to have the cardiac MRI and are over 60 years of age, 
have a history of renal failure, or have type I or II diabetes mellitus must have 
laboratory tests the same day as the MRI exam. 
14. Positive urine drug screen at screening. Not all patients with positive drug 
screen will be excluded; decision will be made by the PI. 
 
 
4.3.1 Justification for Exclusion 
 
Pregnancy: Pregnant women are excluded from this study per FDA guidance, as there 
are no studies of DAAs in pregnant women, and no DAA is currently FDA approved for 
use in pregnant women.  
 
Breastfeeding: Breastfeeding women are excluded from this study per FDA guidance 
as there are no studies of DAAs in lactating women, and no DAA is currently FDA 
approved for use in lactating women.  
 
Exclusion of Children: Safety and effectiveness of DAAs have not been established in 
pediatric patients, and as such subjects 18 years of age or younger will be excluded 
from the study. Because insufficient data regarding dosing or adverse events (AEs) are 
available in adults to judge the potential risk in children, this study poses greater than 
minimal risk and does not meet the Department of Health and Human Services 
guideline 45 Code of Federal Regulations (CFR) 46, subpart D, governing the 
participation of children in research. 
4.3.2 Incarcerated Participants 
 


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Participants who become incarcerated during the course of the study may have to be 
withdrawn; continued collection of data from incarcerated subjects would be on a case-
by-case basis after consultation with the IRB. 
 
5 INTERVENTIONS  
5.1 
Concomitant Medications and Procedures  
All concomitant prescription and over the counter medications taken during study 
participation will be recorded.  For this protocol, a prescription medication is defined as 
a medication that can be prescribed only by a properly authorized/licensed clinician.   
1.2 
Prohibited Medications  
Contraindicated medications will be determined per the package insert of the DAA, per 
standard of care.  
 
6 Study Schedule  
Study visits, including screening, will occur at the Center for Infectious Diseases (CID) 
or Drug Treatment Center (DTC) at the University of Maryland, or a Unity Healthcare 
clinic, based upon scheduling availability to accommodate each treatment group. The 
research coordinators will also oversee research operations in the clinics. See Appendix 
B for a detailed Study Schedule. 
 
All phlebotomy related to the study will be done by a phlebotomist working in the clinic 
or clinic staff. All laboratory studies related to standard of care will be performed as per 
the standard practice at the site. All blood samples for storage for research will be 
couriered to the IHV lab. 
 
All Cardiac MRIs will be performed at the National Institues of Health (NIH).  
 
Participants will be given a calendar of scheduled study visits and will be informed that 
any clinic visits outside of scheduled study visits may be either unscheduled visits or 
non-study visits. Subjects will receive this information when given the visit calendar. 
 
Participants who are no-show for visits will be contacted as per the standard procedure 
for missed visits at each clinic site. 
6.1 
Screening /Enrollment 
Screening will occur at the collocated HCV clinics at the Unviersity of Maryland 
Insistutes of Human Virology, CID or DTC, and the Unity Healthcare Center. Subjects 
who meet inclusion criteria and who consent to the study will be enrolled. Outside labs 
performed within the last 6 months may be used to determine eligibility. Women of 
childbearing potential will have a pregnancy test at screening visit. All screeners will 
submit a urine drug screen. 


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6.2 
Interim Visit 
Up to 36 patients (12 from each group) will have a cardiac MRI performed at the NIH 
after screening but before Day 0 (the start of HCV treatment). See Appendix C for MRI 
procedure and specific inclusion and exclusion criteria.  
6.3 
Standard of care HCV treatment  
All participants with HCV will be started on HCV treatment on Day 0 after confirming 
eligibility. Patients will complete visits and laboratory monitoring as per standard of care 
guidelines. 
6.4 
Study procedures – HCV treatment  
During HCV treatment and in the follow-up period, patients with HCV will undergo 
monitoring for treatment adherence and safety per Standard of Care. Laboratory 
parameters and imaging used as part of the study endpoints are listed below. See 
Appendix B Study Schedule.  
Cholesterol measurements 
Patients’ total cholesterol and LDL cholesterol will be obtained at screening and week 
72 for cardiac risk calculations. 
 
Cardiac biomarker and systemic inflammation assessment 
For all participants, labs will be drawn at screening, week 24, and week 72: high 
sensitivity CRP (hSCRP), high sensitivity TRP (hsTRP), soluble markers of 
inflammation (IFN-ϒ, TNF-α, IL-6, CXCL9, CXCL10, CXCL11) and activated and 
exhausted naïve and memory T cells (percent of CD8+ and CD4+ T-cells which are 
HLA-DR+, CD38+, Tim-3+, or PD-1+).   
 
Cardiac MRI 
A subset of patients will undergo cardiac MRI; up to 12 patients will be recruited from 
each of the three groups to  undergo cardiac MRI at the NIH clinical center at Day -7 
(interim visit) and week 72. Patients who are claustrophobic or cannot tolerate the MRI 
procedure will not be selected for this portion of the study. Cardiac MRI will be utilized to 
assess changes in myocardial injury, degree of post-contrast enhancement, T1 
mapping, and the function of the myocardium. See Appendix C for more details.  
6.4.1 Stored sample collection 
Blood samples for storage and research will be obtained at screening (total of 11 tsp), 
and at weeks 24 and 72 (a total of 9 ½ tsp). Samples collected will include:  
• Serum storage (10 mL) SST/tiger top (2 teaspoons) 
• Plasma storage (6ml) EDTA (1 teaspoon) 
• DNA paxgene will be collected (8.5ml) one time at baseline (1 ½ teaspoon) 
• RNA paxgene will be collected (2.5ml) (1/2 teaspoon) 


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• Peripheral blood mononuclear cells (30 ml) Green top/heparin (6 teaspoons) 
6.4.2 HIV and HCV monitoring 
HCV RNA will be checked per standard of care. HIV VL and CD4 will be checked per 
standard of care for HIV mono- and co-infected patients. HIV antibody/antigen will be 
checked at screening for those who are HCV mono-infected. 
6.4.3 Viral sequencing  
Individuals with new seroconversion to HIV will have sample sent for viral sequencing 
and phylogenetic analysis. Individuals with detectable HCV RNA after completion of 
HCV treatment or new infection during the follow up period will have current sample, 
and baseline stored sample sent for viral sequencing and phylogenetic analysis.  
6.4.4 Linkage to care  
Any participant who seroconverts to HIV+ will be immediately linked to care, in DC or in 
Baltimore. 
6.5 
Early Termination Visit 
Participants who discontinue HCV treatment prior to treatment completion for medical or 
personal reasons will be given the option of being followed as per study schedule for lab 
monitoring. 
 
7 Potential Risks and Benefits 
7.1 
Potential Risks  
Given this investigation is centered on a standard model of care, the main risks are related 
to any blood draw outside of standard of care, and loss of confidential data.  
 
Participants who receive treatment for HCV may experience side effects from the medication 
they receive.  They will receive one of the following medication to treat hepatitis C: 
Elbasvir/Grazoprevir (Zepatier), Sofosbuvir/Ledipasvir (Harvoni), Sofosbuvir/Velpatasvir 
(Epclusa), Glecaprevir/Pibrentasvir (Mavyret), Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi). 
 
Common side effects (those that occured in more than 5% of the patients in clinical trials) each 
medication is listed below: 
 
Elbasvir/Grazoprevir (Zepatier): 
• Fatigue 
Headache 
 
Sofosbuvir/Ledipasvir (Harvoni): 
• Fatigue 


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• Headache 
• Nausea 
• Diarrhea 
• Insomnia 
 
Sofosbuvir/Velpatasvir (Epclusa): 
• Headache 
• Fatigue 
• Nausea 
• Insomnia 
• Lack of energy 
 
 
Glecaprevir/Pibrentasvir (Mavyret): 
• Headache 
• Fatigue 
• Nausea 
• Diarrhea 
 
Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi): 
• Headache 
• Fatigue 
• Diarrhea 
• Nausea 
• Insomnia 
• Lack of energy 
 
 
Other potential risks include risks of phlebotomy that include: pain, bruising, fainting and 
very rarely, infection. These risks will be minimized by having trained staff perform the 
procedure.  
 
There is potential for loss of confidentiality, which will be minimized by providing privacy 
during study visits. In addition, all laboratory specimens, and research records will be 
coded by a number to maintain subject confidentiality. Electronic data will be password 
protected. 
 
Potential risks from MRI are outlined in Appendix C. Of note, the cardiac MRI is 
considered to be greater than minimal risk.  If you elect to have the cardiac MRI, you will 
be required to sign a separate consent form which will explain the procedure and risks 
in more detail. 
 
 
 


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7.2 
Potential Benefits 
Subjects may be cured of hepatitis C during the course of this study. Also, they will 
contribute to the body of scientific research on treatment of hepatitis C and 
cardiodvascular risk in people with living with HIV and/or HCV. Furthermore, by 
achieving functional cure of HCV, subjects will no longer be a potential source of HCV 
transmission in the community. It is possible that subjects will receive no benefit from 
the study participation. 
 
8 Stored Samples and Future Research 
We will study the viral and host immunity to HCV and HIV in all patients. The results will 
be used to characterize each individual with regards to immune status and chronicity of 
disease. Studies on research samples may include the following: 
A] HCV genome sequencing may be performed on plasma using the protocol as 
described and compared for variability and relatedness of sequences. 
 
B] We will screen sera from all patients for differential expression of protein using 
multiplex cytokine arrays, which has the capability of detecting several different 
cytokines and other biologically relevant proteins. 
 
C] We will perform detailed phenotypic and functional evaluation of immune cell types in 
the periphery. This will help us in determining the nature of antiviral immune responses 
in patients who are chronically infected, achieve SVR and acquire new HCV and HIV 
infections. Determination of specific immune defects in these individuals are important 
milestones in deciding future therapeutics and protective immunity to reinfection. 
Exhaustion and activation markers on T, B and NK cells will be quantified. Specific 
immune responses against pooled HCV peptides will be performed using an ELISPOT 
assay and/or  flow cytometry. 
 
Future use of the specimens will be based on the scientific merit of the investigation and 
would be decided by the Principal Investigator. They would be related to the study of 
HCV and/or HIV. Other investigators may wish to study these samples and/or data.  In 
that case, IRB approval must be sought prior to any sharing of samples and/or data.  
Any clinical information shared about the sample would similarly require prior IRB 
approval. If approved, and once a Material Transfer Agreement (MTA) has been 
established, the study team may send de-identified samples to the collaborators. 
Investigators will use stored samples only for research.  
8.1 
Intended Use:  
Some blood samples may be stored for future analysis in this research study. These 
samples will be stored by the IHV researchers and may be used in future research to 
learn more about HCV and HIV, the immune system and/or other related medical 
conditions. The blood will be used over time to gain a better understanding of the 
pathogenesis of HCV and HIV.  Genetic testing will be performed. Different analytical 


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25 
and laboratory methods will be employed including but not limited to: PCR, ELISA, 
ELISPOT and immunohistochemistry; RNA/DNA, cytokine and antibody quantitation; 
viral particle detection and identification of genetic markers. The consent will include 
language for specimen storage. 
8.2 
Storage:   
Samples will be kept in secure facilities with limited access. Samples and data will be 
stored using a unique identifier.  Only investigators and study staff will have access to 
the samples and data.  
8.3 
Tracking:   
Extra blood samples will be stored using a unique identifier that only the study team can 
trace back to the participants. These stored samples as well as a linkage file will be 
maintained in a database that will be managed by the Investigators and/or Study 
Coordinators and will be maintained on the IHV server. This database will also be 
stored on the password-protected computer of the Lead-Investigator/Study Coordinator 
in an encrypted and/or password-coded file. 
8.4 
Disposition at the Completion of the Protocol:  
At the completion of the protocol (termination), samples and data will either be 
destroyed, or after IRB approval, transferred to another existing protocol. Final 
disposition of any samples cannot be done without written permission from the PI. 
8.5 
Reporting the Loss or Destruction of 
Samples/Specimens/Data to the IRB: 
 
• Any loss or unanticipated destruction of samples or data resulting in a 
violation that compromises the scientific integrity of the data collected for the 
study will be reported to the IRB.  
• Participants may request at any point not to have their samples stored. In this 
case, the Principal Investigator will destroy all known remaining samples and 
report what was done with the samples to both the participant and to the IRB. 
This decision will not affect the subject’s participation in any other protocols.  
 
Generally, the results from the research stored samples will not be given to the 
participant's primary care provider or appear in the medical record. This is because the 
test results, unlike routine medical testing, may be experimental or preliminary. The 
relevance of these tests to direct patient care may be unknown. At the participant's 
request, the results of any research tests will be discussed with the primary care 
physician by the Investigators. 
 
9 Assessment of Safety  


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26 
As this is a pilot, non-randomized, controlled perspective study involving standard of 
card treatment, with interventions limited to non-standard of care blooddraws and 
cardiac imaging, safety issues are not expected.  Only those reportable Adverse Events 
(AEs) related to the research procedures will be reported or those not expected from 
cardic MRI (expected MRI AEs are Mild allergic reaction to contrast agents; Acute renal 
insufficiency related to iodine-based contrast agent; Subcutaneous injection of contrast 
agents). The PI will review the safety data and report any unexpected events to the IRB 
along with the annual continuing review. 
 
9.1 
Recording/Documentation 
At each contact with the patient, information regarding adverse or unexpected events 
related to research procedures will be elicited by appropriate questioning and 
examinations and will be immediately recorded in electronic progress notes.  Source 
documents will include an electronic health record and laboratory reports. Source 
documents will be reviewed in a timely manner by the research team. 
9.2 
Definitions 
Adverse Event: Any untoward medical occurrence in a human subject, including any 
abnormal sign, symptom, or disease, temporally associated with the subject’s 
participation in research, whether or not considered related to the subject’s participation 
in the research.   
 
Protocol Deviation: Any change, divergence, or departure from the IRB approved study 
procedures in a research protocol. Protocol deviations are designated as serious or 
non-serious and further characterized as: 
• Those that occur because a member of the research team deviates from the 
protocol. 
• Those that are identified before they occur, but cannot be prevented. 
• Those that are discovered after they occur. 
9.3 
Reporting Protocol deviations, AEs and Deaths 
Anticipated deviations in the conduct of the protocol will not be reported to the IRB 
unless they occur at a rate greater than anticipated by the study team. Expected 
adverse events will not be reported to the IRB unless they occur at a rate greater than 
that known to occur in those having phlebotomy procedures normally. If the rate of 
these events exceeds the rate expected by the study team, the events will be classified 
and reported. Deaths related to the natural history of hepatitis will be reported at the 
time of continuing review (see annual reporting to the IRB). If a death occurrs while the 
participant is at the NIH it would be reported to the Clinical Director of the Clinical 
Center, the Clinical Director of NHLBI, and the UMB PI in real time as reported as 
required by UMB IRB. 
 


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27 
9.3.1 Expedited Reporting to the IRB 
Any reportable new information (RNI) will be reported to the IRB within 5 business days. 
This includes: 
1) Information that indicates a new or increased risk, or a safety issue. 
2) Any harm experienced by a subject or other individual, which in the opinion of 
the investigator are unexpected and probably related to the research 
procedures. 
3) Non-compliance with the federal regulations governing human research or 
with the requirements or determinations of the IRB, or an allegation of such 
non-compliance.  
4) Failure to follow the procedure due to the action or inaction of the investigator 
or research staff.  
5) Breach of confidentiality. 
6) Change to the protocol taken without prior IRB review to eliminate an 
apparently immediate hazard to a subject.  
7) Complaint of a subject that cannot be resolved by the research team.  
8) Premature suspension or termination of the research by the sponsor or the 
investigator.   
9) Audit, inspection, or inquiry by a federal agency.  
10) Written reports of study monitors.  
 
The NIH site PI and/or study team will report any RNI to the UMB PI so that they are 
reported within the above timeframe to the UMB IRB. 
9.3.2 Waiver of Reporting Anticipated Protocol Deviations, 
Expected non-UP AEs and Deaths   
Deviations in the protocol that do not rise to the level of serious or continuing non-
compliance, and unanticipated or adverse events that are NOT serious, unexpected 
AND related to research protocols need not be reported in an expedited manner to the 
IRB.  Rather, such RNI should be reported as a group at the time of annual renewal  
(see below) 
9.4 
Annual Reporting to the IRB 
The following items will be reported to the University of Maryland IRB in summary at the 
time of Continuing Review: 
• Serious adverse events or deaths that are not related to the research 
• All adverse events associated with research including expected AEs Protocol 
deviations.  This includes AEs related to phlebotomy within 48 hours of procedure. 
• Serious, continuing, and minor non-compliance 
• Any trends or events which in the opinion of the investigator should be reported 
9.4.1 Type and Duration of the Follow-up of Subject after 
Adverse Events 


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28 
All SAEs and non-serious AEs identified in this study will be followed until resolution or 
until the PI judges the AE/SAE has stabilized and no more follow-up is required.  This 
requirement indicates that the follow-up may be required for some events after the 
participant discontinues participation from the study.  These events will be reported to 
the IRB annually. 
10  
Withdrawal of a Subject 
A participant may withdraw from the study at any time.  As part of their duties to ensure 
that research participants are protected, the IRB, IHV, or other government agencies may 
discontinue the study at any time. Voluntary withdrawal from the protocol may occur at 
any time at the request of either the participant or the PI.  If a request is made to withdraw 
from the protocol, all further planned study procedures will be immediately cancelled and 
further follow-up will be terminated. Samples and data already collected may continue to 
be used. If a patient becomes pregnant during the course of the study, the patient will be 
discontinued from the study.  
 
Of note, women who become pregnant during the study will be withdrawn and hepatitis 
C treatment will be stopped. She will be instructed to see an obstetrician and inform the 
doctor of her specific hepatitis C regimen at the time of conception. If the partner of a man 
on hepatitis C treatment gets pregnant, he will not be withdrawn from the study, but told 
to use condoms during intercourse and instruct his partner to let her obstetrician know of 
his hepatitis C treatment regimen at the time of conception. 
10.1 Return of Withdrawn/Removed Subjects 
A participant who has withdrawn may not return to the study. 
11 Remuneration Plan for Subjects  
Participants will not be renumerated for receiving HCV treatment.  
 
Participants will receive $25 remuneration as gift cards at those visits where stored 
sample blood draws are completed.  Those visits are Screening, week 24, and week 72. 
If additional visits are needed to obtain bloodwork or imaging, this additional visit would 
also warrant a $25 remuneration. We will not exceed a maximum of 3 additional visits 
and will encourage combined visits. 
 
Participants will receive $100 remuneration as gift cards provided by UMB study staff 
whilst working as special volunteers at the NIH site when participants have an MRI. 
These visits are at the time of day -7 (interim visit) and week 72.  Poonam Mathur, 
Sarak Kattakuzhy, Elana Rosenthal, and Rachel Silk, are UMB sub investigators who 
are also special volunteers at NIH and are fully credentialed and able to see research 
patients at the NIH.  They are also authorized to obtain informed consent, provide 
remuneration to subjects visiting the NIH site, have access to identifiable data, see 
patients at NIH and participate in manuscript preparation/review. 
12 Monitoring 


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29 
As this is an observational study with intervention limited to laboratory and radiologic 
data collection, safety issues are not expected. The PI and the study team will conduct 
regular monitoring of safety and report to the IRB as specified in section 9.  
 
13 Statistical Considerations 
13.1 Sample Size Justification and Power 
The proposal primary outcome for cardiovascular risk is change in hsCRP. The primary 
hypothesis is that HCV eradication will result in at least a two-fold decrease from the 
baseline elevated hsCRP to 12 months post-functional cure in HCV-monoinfected and 
HIV/HCV-coinfected patients, respectively. Based on a previous study, mean hsCRP 
before starting IFN-therapy in HCV-monoinfected patients was 0.97±0.11 mg/L 
compared to 0.07± 0.07 mg/L in healthy controls(23). Among SVR patients the median 
hsCRP at baseline was 0.64 mg/L and decreased to 0.25 mg/L after treatment. With a 
sample size of 30 patients in each group, we assume than 95% will achieve SVR with 
Zepatier (elbasvir/grazoprevir), resulting in a sample size of 28 patients in each group. 
In a paired t-test analysis (from baseline to 12-month post-treatment), with a=0.05, 
power of 90% (1-b), and standard deviation (σ) = 0.15, we will be able to detect a true 
difference in the mean hsCRP response of matched pairs of 0.1 mg/L in each group or 
0.8 mg/L with 80% power. 
13.2 Statistical Analysis  
We will perform univariate analysis to describe the demographic and clinical 
characteristics of the study population. Count with percentages will be calculated for 
categorical variables and mean + standard deviation or median (interquartile range) for 
continuous variables. The independent variable is the three groups of participants with 
HCV, HIV/HCV, and HIV. Separate analysis will be done for each study group for the 
change in the primary outcome of HsCRP, from baseline to 18 months after baseline, in 
a paired t-test analysis, as well as for the secondary outcomes of cardiac biomarkers, 
MRI, and cellular and soluble immune markers of activation. Baseline comparison of 
hsCRP, cardio biomarkers, MRI, and cellular and soluble immune markers of activation 
between the three groups of participants will be performed using one-way or Kruskal-
Wallis analysis of variance (ANOVA) for continuous variables and chi-square test of 
independence or Fisher’s exact test for categorical variables. A linear regression model 
will be used in adjusted analysis for continuous dependent variables, while logistic 
regression model will be used in adjusted analysis for binary dependent variables. All 
analysis will be conducted in SAS, version 9.4 (SAS Institute, Inc., Cary, NC) with a P-
value of less than 0.05 indicating statistical significance. 
 
14 Ethics/Protection of Human Subjects 
14.1 Informed Consent Process 


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Informed consent is a process where information is presented to enable persons 
to voluntarily decide whether or not to participate as a research subject. It is an 
on-going conversation between the human research subject and the researchers, 
which begins before consent is given and continues until the end of the subject's 
involvement in the research. Discussions about the research will provide 
essential information about the study and include: purpose, duration, procedures, 
alternatives, risks and benefits.  Subjects will be given the opportunity to ask 
questions and have them answered.  
The subjects will personally sign and date the informed consent document prior 
to undergoing any research procedures. The subjects may withdraw consent at 
any time throughout the course of the trial.  A copy of the informed consent 
document will be given to the subjects for their records. Consenting process will 
be documented in the record. The rights and welfare of the subjects will be 
protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study.  
Per NIH policy, subjects participating in the MRI portion of the study will be 
consented with a NIH consent for the cardiac MRI that takes into account that the 
NIH is subject to the Privacy Act and is therefore not a HIPAA covered institution.  
 
14.2 Illiteracy and Consenting 
As the majority of the patient populations from which the study participants are 
drawn are literate, written consent will be obtained. Per UMB IRB policy, for 
participants unable to read, the written informed consent and any other written 
information will be read and explained to the participant by the person obtaining 
consent. An impartial third party will be present for the entire consent process.  
Once the subject has orally consented, the participant and witness will sign the 
consent form.  
14.3 Subject Confidentiality 
All records will be kept confidential to the extent provided by federal, state and 
local law. The study monitors and other authorized representatives of the 
Sponsor may inspect all documents and records required to be maintained by the 
Investigator, including but not limited to, medical records. Records will be kept 
locked and all computer entry and networking programs will be done with coded 
numbers only.  Clinical information will not be released without written permission 
of the subject, except as necessary for monitoring by IRB, FDA, the Joint 
Commission or the HHRP. 


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APPENDIX A: Scientific References 
 
1. 
Freiberg MS, Chang CC, Kuller LH, Skanderson M, Lowy E, Kraemer KL, et al. 
HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 
2013;173(8):614-22. 
2. 
Nakagawa F, May M, Phillips A. Life expectancy living with HIV: recent estimates 
and future implications. Curr Opin Infect Dis. 2013;26(1):17-25. 
3. 
Beires MT, Silva-Pinto A, Santos AC, Madureira AJ, Pereira J, Carvalho D, et al. 
Visceral adipose tissue and carotid intima-media thickness in HIV-infected 
patients undergoing cART: a prospective cohort study. BMC Infect Dis. 
2018;18(1):32. 
4. 
Hemkens LG, Bucher HC. HIV infection and cardiovascular disease. Eur Heart J. 
2014;35(21):1373-81. 
5. 
Negro F, Forton D, Craxi A, Sulkowski MS, Feld JJ, Manns MP. Extrahepatic 
morbidity and mortality of chronic hepatitis C. Gastroenterology. 
2015;149(6):1345-60. 
6. 
Soriano V, Berenguer J. Extrahepatic comorbidities associated with hepatitis C 
virus in HIV-infected patients. Curr Opin HIV AIDS. 2015;10(5):309-15. 
7. 
Kakinami L, Block RC, Adams MJ, Cohn SE, Maliakkal B, Fisher SG. Risk of 
cardiovascular disease in HIV, hepatitis C, or HIV/hepatitis C patients compared 
to the general population. Int J Clin Pract. 2013;67(1):6-13. 
8. 
Aberg JA. Aging, inflammation, and HIV infection. Top Antivir Med. 
2012;20(3):101-5. 
9. 
CDC;Pageshttp://www.cdc.gov/hepatitis/populations/pdfs/hivandhep-
factsheet.pdf. 
10. 
Lima JA, Desai MY. Cardiovascular magnetic resonance imaging: current and 
emerging applications. J Am Coll Cardiol. 2004;44(6):1164-71. 
11. 
Pennell DJ, Sechtem UP, Higgins CB, Manning WJ, Pohost GM, Rademakers 
FE, et al. Clinical indications for cardiovascular magnetic resonance (CMR): 
Consensus Panel report. Eur Heart J. 2004;25(21):1940-65. 
12. 
Kwong RY, Chan AK, Brown KA, Chan CW, Reynolds HG, Tsang S, et al. Impact 
of unrecognized myocardial scar detected by cardiac magnetic resonance 
imaging on event-free survival in patients presenting with signs or symptoms of 
coronary artery disease. Circulation. 2006;113(23):2733-43. 
13. 
Chew KW, Liu CY, Ambale-Venkatesh B, Liao D, Horwich TB, Lima JAC, et al. 
Subclinical myocardial disease by cardiac magnetic resonance imaging and 
spectroscopy in healthy HIV/Hepatitis C virus-coinfected persons. J Int Med Res. 
2017;45(6):1693-707. 
14. 
Wyles DL, Ruane PJ, Sulkowski MS, Dieterich D, Luetkemeyer A, Morgan TR, et 
al. Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl 
J Med. 2015;373(8):714-25. 
15. 
Rockstroh JK, Nelson M, Katlama C, Lalezari J, Mallolas J, Bloch M, et al. 
Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients 
with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-
randomised, open-label trial. Lancet HIV. 2015;2(8):e319-27. 


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16. 
Osinusi A, Townsend K, Kohli A, Nelson A, Seamon C, Meissner EG, et al. 
Virologic response following combined ledipasvir and sofosbuvir administration in 
patients with HCV genotype 1 and HIV co-infection. JAMA. 2015;313(12):1232-9. 
17. 
Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al. 
Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J 
Med. 2015;373(8):705-13. 
18. 
Sulkowski MS, Naggie S, Lalezari J, Fessel WJ, Mounzer K, Shuhart M, et al. 
Sofosbuvir and ribavirin for hepatitis C in patients with HIV coinfection. JAMA. 
2014;312(4):353-61. 
19. 
Molina JM, Orkin C, Iser DM, Zamora FX, Nelson M, Stephan C, et al. Sofosbuvir 
plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV 
(PHOTON-2): a multicentre, open-label, non-randomised, phase 3 study. Lancet. 
2015;385(9973):1098-106. 
20. 
Rodriguez-Torres M, Gaggar A, Shen G, Kirby B, Svarovskaia E, Brainard D, et 
al. Sofosbuvir for chronic hepatitis C virus infection genotype 1-4 in patients 
coinfected with HIV. J Acquir Immune Defic Syndr. 2015;68(5):543-9. 
21. 
Sulkowski MS, Eron JJ, Wyles D, Trinh R, Lalezari J, Wang C, et al. Ombitasvir, 
paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in 
patients co-infected with HIV-1: a randomized trial. JAMA. 2015;313(12):1223-
31. 
22. 
Petta S. Hepatitis C virus and cardiovascular: A review. J Adv Res. 
2017;8(2):161-8. 
23. 
Huang CF, Hsieh MY, Yang JF, Chen WC, Yeh ML, Huang CI, et al. Serum hs-
CRP was correlated with treatment response to pegylated interferon and ribavirin 
combination therapy in chronic hepatitis C patients. Hepatol Int. 2010;4(3):621-7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B: Study Procedures Table 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X= HCV mono- and HIV/HCV co-infected 
^= HIV mono-infected
 
 
 
 
 
M6 
M18 
HCV Treatment 
Screening 
Interim 
visit 
(Day -7) 
Day 0 
End of 
Treat-
ment 
Week 24 
Week 
72 
Provider Visit 
X^ 
 
X 
X 
X 
 
HCV SOC 
Labwork 
X 
 
 
X 
X 
 
HCV RNA 
X 
 
 
X 
X 
X 
HCV Ab 
X^ 
 
 
 
 
^ 
HIV 4th gen Ag/Ab 
X 
 
 
 
 
 
HIV SOC Labwork 
^ 
 
 
 
 
 
HBV DNA (for 
HBcAb positive) 
X^ 
 
 
 
 
 
Total Cholesterol 
and HDL 
Cholesterol 
X^ 
 
 
 
 
X^ 
Fibroscan or 
Fibrosure 
X^ 
 
 
 
X^ 
 
hsCRP, hsTRP 
X^ 
 
 
 
X^ 
X^ 
Markers of 
inflammation 
X^ 
 
 
 
X^ 
X^ 
Memory T cells 
X^ 
 
 
 
X^ 
X^ 
Cardiac MRI 
 
X^ 
 
 
 
X^ 
Urine Drug Screen 
X^ 
 
 
 
 
 


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34 
APPENDIX C: Cardiac MRI 
Introduction and MRI Procedure 
Cardiovascular magnetic resonance imaging (MRI) is an excellent imaging 
modality capable of assessing cardiac anatomy, myocardial function, myocardial 
infarction/fibrosis, as well as many other types of myocardial diseases. Patients infected 
with the hepatitis C virus are at increased risk of cardiovascular disease. Cardiac MRI 
can be used to assess for epicardial coronary artery plaque, sequela of epicardial 
coronary artery disease, such as myocardial infarction, as well as microvascular 
disease. 
Each patient participating in the MRI scan will receive an oral and written 
explanation of the purposes, procedures, and risks of this study in language appropriate 
for the individual’s level of understanding.  
All cardiac MRI scans for this study will be performed on an FDA approved 3.0T 
or 1.5T scanner (Aera - Siemens Healthcare, Erlangen, Germany). The radiofrequency 
power levels (SAR limits) will be kept within the FDA established limits. A body coil will 
be used during the exam. A body coil is a noninvasive device external to the body that 
acts as antennae to receive radiofrequency signals out of the body. The body coil used 
during the MRI exam will follow FDA parameters. 
For the cardiovascular MRI exam, patients will receive an intravenous injection of 
gadolinium chelate (Gadavist, 0.15 mmol/kg) via an MRI compatible power injector. 
 
Inclusion Criteria for the Cardiovascular MRI 
18 years of age or older 
Written informed consent 
 
Exclusion Criteria for the Cardiovascular MRI 
Patients with the following devices are excluded from participating in the cardiovascular 
MRI study: 
• Central nervous system aneurysm clip 
• Implanted neural stimulator 
• Implanted cardiac pacemaker or defibrillator 
• Cochlear implant 
• Ocular foreign body (e.g. metal shavings) 
• Implanted insulin pump 
• Metal shrapnel or bullet 
The following groups of people are excluded: 
• Pregnant women 
• Lactating women unless they are willing to discard breast milk for 24 hours 
after receiving gadolinium 
• Patients with stable renal disease (estimated glomerular filtration rate (eGFR) 
< 30ml/min/1.73 m2 body surface area). The eGFR must be within 2 weeks of 
the MRI exam. Patients who are over 60 years of age, have a history of renal 
failure, or have type I or II diabetes mellitus must have laboratories the same 
day as the MRI exam. 


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35 
• Patients with acute renal disease. 
 
Monitoring Patients during the Cardiovascular MRI scan 
The cardiovascular MRI exam is expected to last 60 to 90 minutes in 
duration. The MRI technologist will monitor the exam. Monitoring includes 
continuous ECG-gating. Blood pressure and pulse oximetry will be measured if 
clinically indicated. Patients may elect to withdraw from the MRI scan at any 
point. 
 
Benefits/Risks of the Cardiovascular MRI 
The cardiovascular MRI exam with gadolinium contrast involves greater than 
minimal risk, however may be of direct benefit to the individual patients [45 CFR 
46.102(i)]. A clinical report of the exam will be available for the patients’ physician.  
MRI does not use ionizing radiation, and is extremely safe on a properly 
screened population. There is potential risk related to the magnetic field strength in 
patients with implanted metal devices (cochlear implants, etc), resulting in movement of 
these objects and subsequent harm to the patients. Patients will be screened for these 
objects (see exclusion criteria above) and excluded if they meet any of the exclusion 
criteria. 
Peripheral nerve stimulation is unlikely to occur with our imaging parameters. It 
occurs when the magnetic field gradient switch occurs so fast that it results in peripheral 
nerve depolarization. The patient may feel a twitch or possibly some pain. Patient 
education as well as audio feedback from the patient during the exam will be used for 
the issue of possible peripheral nerve stimulation. 
The scanner is operated within FDA guidelines for radiofrequency power levels. 
However, there is a small chance that a damaged or dysfunctional coil could cause 
some local warming in the body. Thus, for safety purposes, we ask all patients to report 
this sensation so we can modify scans and also verify the integrity of the hardware. 
 
Gadolinium Administration for the Cardiovascular MRI exam 
Patients must have an IV placed for gadolinium administration. Potential risks of 
IV placement include discomfort, bruising/bleeding, and vasovagal reactions. 
The gadolinium agent used for the cardiovascular MRI exam, Gadavist, is commercially 
available and routinely used in hospital radiology practices. Studies in large patient 
populations have shown that gadolinium is safe without side effects in the majority of 
patients. If side effects occur, they are often mild and include headache and nausea. 
Severe reaction such as shortness of breath, wheezing, and hypotension are rare. 
The US Food and Drug Administration has issued a warning that the administration of 
gadolinium (updated September 9, 2010) has been associated with development of a 
disease call nephrogenic systemic fibrosis (NSF). All cases to date have occurred in 
patients with severe renal disease, including patients on dialysis. NSF has been nearly 
eradicated by avoiding gadolinium contrast use in patients with creatinine clearance 
<30cc/min.4-7 
On July 27, 2015, the US Food and Drug Administration issued a safety 
announcement stating that they are investigating the risk of brain deposits of gadolinium 
contrast agents. Several studies have shown a correlation between high signal intensity 


CHROME V 10 
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36 
in the dentate nucleus and globus pallidus of the brain on unenhanced T1-weighted 
images and the number of previous administrations of gadolinum contrast agents in 
both adult and pediatric patients with normal renal function, suggesting deposition of the 
gadolinium contrast agent into the brain. 
More recently, autopsy studies have confirmed that gadolinium deposits in the 
brains of patients with normal renal function as well as in other organs including the 
bones and the skin. Murata et al showed that macrocyclic gadolinium contrast agents 
deposit in the body to a significantly lesser degree than the linear open chain 
gadolinium contrast agents. The effects (adverse or otherwise) of gadolinium deposition 
in patients with normal renal function remains unclear and the FDA investigation is 
ongoing. 
The gadolinium agent used for our cardiovascular MRI exams is Gadavist, which 
is a macrocyclic type of gadolinium contrast based agent. Macrocyclic agents are 
currently considered the safest type of gadolinum based contrast agent available. 
 
References 
1. Niendorf HP, Alhassan A, Geens VR, Clauss W.  Safety review of gadopentetate 
dimeglumine. Extended clinical experience after more than five million 
applications.  Invest Radiol. 1994;  29 Suppl 2:S179-S182 
2. Niendorf HP, Haustein J, Cornelius I, Alhassan A, Clauss W.  Safety of 
gadolinium-DTPA: extended clinical experience.  Magn Reson.Med. 1991;  
22:222-228. 
3. Niendorf HP, Dinger JC, Haustein J, Cornelius I, Alhassan A , Clauss W.  
Tolerance data of Gd-DTPA: a review .  Eur.J.Radiol. 1991;  13:15-20. 
4. Prince, M.R., H. Zhang, Z. Zou, et al., Incidence of immediate gadolinium 
contrast media reactions. AJR Am J Roentgenol, 2011. 196(2): p. W138-43. 
5. Sanyal, S., P. Marckmann, S. Scherer, et al., Multiorgan gadolinium (Gd) 
deposition and fibrosis in a patient with nephrogenic systemic fibrosis--an 
autopsy-based review. Nephrol Dial Transplant, 2011. 26(11): p. 3616-26. 
6. Martin, D.R., S.K. Krishnamoorthy, B. Kalb, et al., Decreased incidence of NSF in 
patients on dialysis after changing gadolinium contrast-enhanced MRI protocols. 
J Magn Reson Imaging, 2010. 31(2): p. 440-6. 
7. Amet, S., V. Launay-Vacher, O. Clement, et al., Incidence of nephrogenic 
systemic fibrosis in patients undergoing dialysis after contrast-enhanced 
magnetic resonance imaging with gadolinium-based contrast agents: the 
Prospective Fibrose Nephrogenique Systemique study. Invest Radiol, 2014. 
49(2): p. 109-15. 
8. Errante, Y., V. Cirimele, C.A. Mallio, et al., Progressive increase of T1 signal 
intensity of the dentate nucleus on unenhanced magnetic resonance images is 
associated with cumulative doses of intravenously administered gadodiamide in 
patients with normal renal function, suggesting dechelation. Invest Radiol, 2014. 
49(10): p. 685-90. 
9. Kanda, T., M. Osawa, H. Oba, et al., High Signal Intensity in Dentate Nucleus on 
Unenhanced T1-weighted MR Images: Association with Linear versus 
Macrocyclic Gadolinium Chelate Administration. Radiology, 2015. 275(3): p. 803-
9. 


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10. Kanda, T., T. Fukusato, M. Matsuda, et al., Gadolinium-based Contrast Agent 
Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: 
Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass 
Spectroscopy. Radiology, 2015. 276(1): p. 228-32. 
11. McDonald, R.J., J.S. McDonald, D.F. Kallmes, et al., Intracranial Gadolinium 
Deposition after Contrast-enhanced MR Imaging. Radiology, 2015. 275(3): p. 
772-82. 
12. Adin, M.E., L. Kleinberg, D. Vaidya, et al., Hyperintense Dentate Nuclei on T1-
Weighted MRI: Relation to Repeat Gadolinium Administration. AJNR Am J 
Neuroradiol, 2015. 36(10): p. 1859-65. 
13. Murata, N., L.F. Gonzalez-Cuyar, K. Murata, et al., Macrocyclic and Other Non-
Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain 
and Bone Tissue: Preliminary Results From 9 Patients With Normal Renal 
Function. Invest Radiol, 2016. 51(7): p. 447-53. 
14. Murata, N., K. Murata, L.F. Gonzalez-Cuyar, et al., Gadolinium tissue deposition 
in brain and bone. Magn Reson Imaging, 2016. 34(10): p. 1359-1365.