Download Addressing the Unique Needs of Military Veterans With Chronic

A CME/CE Certified Supplement to
Addressing the Unique Needs
of Military Veterans
With Chronic
HCV Infection
Introduction.......................................................................... 3
Meeting the HCV Care Needs of an
Evolving VHA Patient Population................... 3
Best Practices in Screening,
Diagnosis, and Treatment Along
the Veteran Health Administration's
Cascade of HCV Care.................................................. 7
Assessing the Characteristics
of HCV Treatment Regimens
to Individualize Therapy to
Optimal Effect............................................................... 11
Chronic HCV and Its Late-Stage
Complications and Comorbidities.............. 15
Post-Test and Evaluation.................................... 20
Faculty
Alexander Monto, MD, Chair
Director, Liver Clinic, San Francisco Veterans Affairs Medical Center
Professor of Medicine, San Francisco School of Medicine
University of California
San Francisco, California
Pamela S. Belperio, PharmD, BCPS
National Public Health Clinical Pharmacist
Department of Veterans Affairs
Los Angeles, California
Patient Care Services/Population Health
Veterans Affairs Palo Alto Healthcare System
Palo Alto, California
Hashem B. El-Serag, MD, MPH
Gastroenterology and Hepatology
Michael E. DeBakey Veterans Administration Medical Center
Baylor College of Medicine
Houston, Texas
Rachel Gonzalez, MPH
Health Science Specialist
Program Manager, National Hepatitis C Resource Center
Long Beach, California
Original Release Date: February 1, 2017
Expiration Date: February 1, 2018
Estimated Time to Complete Activity: 1.5 hours
Jointly provided by
Fasiha Kanwal, MD, MSHS
Professor of Medicine, Interim Chief, Gastroenterology and Hepatology
Baylor College of Medicine
Houston Veterans Affairs HSR&D Center of Excellence
Michael E. DeBakey VA Medical Center
Houston, Texas
Timothy Morgan, MD
Chief, Hepatology, VA Long Beach Healthcare System
Long Beach, California
Angela Park, PharmD, CACP
Clinical Pharmacy Specialist
Pharmacy Process Improvement Program Manager
New England Veterans Engineering Resource Center
Boston, Massachusetts
Supported by an educational grant from
Merck and Company
David B. Ross, MD, PhD, MBI
Director of HIV, Hepatitis, and Related Conditions Programs
Department of Veterans Affairs
Washington, DC
A CME/CE Certified Supplement to
Term of Offering
This activity was released on February 1, 2017, and is
valid for one year. Requests for credit must be made no
later than February 1, 2018.
Inquiries may be directed to Global Academy for
Medical Education at [email protected] or
(973) 290-8225.
At the conclusion of this program, participants should
be better able to:
• Recognize the special characteristics of the patient
population with chronic HCV infection whose care is
managed within the US VHA, including risk factors
and medical and psychiatric comorbidities
• Identify opportunities for improving HCV screening,
diagnosis, and testing among the veteran population
• Develop comprehensive individualized management
strategies for patients with chronic HCV infection
• Compare and contrast risks and benefits of
currently available drug regimens for treating
chronic HCV infection
• Describe practical approaches for improving
the continuum of care for veterans with chronic
HCV infection.
Accreditation Statements
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Method of Participation
Addressing the
Unique Needs of
Military Veterans
With Chronic
HCV Infection
This continuing education supplement
was developed from interviews with
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Suzanne Bujara, in the development
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2 Learning Objectives
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the activity in its entirety, and complete the online posttest and evaluation. Upon completing this activity as
designed and achieving a passing score on the post-test,
you will be directed to a Web page that will allow you to
receive your certificate of credit via e-mail or you may
print it out at that time.
The online post-test and evaluation can be accessed
at: http://tinyurl.com/HCVA17
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Target Audience
This journal supplement is intended for gastroenterologists, infectious disease specialists, family practitioners,
internists, nurse practitioners, physician assistants, and
other clinicians who treat patients with chronic hepatitis C (HCV) infection, including those with end-stage
renal disease (ESRD), within the United States Veterans
Health Administration (VHA).
Educational Needs
The prevalence of chronic HCV infection among
patients in the Veterans Health Administration (VHA) is
approximately 4 times that of the general population.
Approximately 50,000 US military veterans are infected
with HCV, but their infection has not been diagnosed. The
VHA is uniquely suited to treat HCV infection as well as to
address its significant mortality and morbidity. However,
infected veterans—as well as the VHA clinicians who
manage these patients on a regular basis—face many
barriers to diagnosis, testing, and treatment, barriers that
in many ways are unlike those encountered in the private
sector. To address those barriers, in recent years the
VHA has made a substantial commitment to providing
HCV care, as reflected in expanded funding, the establishment of Veterans Integrated Service Network–level
HCV Resource Centers and Hepatitis C Innovation
Teams (HITs), and other steps aimed at providing efficient, effective care. The expanding armamentarium of
direct-acting antiviral (DAA) agents for HCV infection
means that approximately 95% of treated individuals can
experience sustained virologic response—essentially, a
cure. Clinicians within the Department of Veterans Affairs
(VA) system need education to raise their awareness of
screening protocols, the need to evaluate HCV genotypes
and the possible presence of resistance-associated
polymorphisms, the selection of often complex drug regimens, and the importance of managing comorbidities,
including psychiatric illness, substance abuse-related
problems, and liver conditions such as cirrhosis and
hepatocellular carcinoma.
Global Education Group requires instructors, planners,
managers, and other individuals and their spouse/life
partner who are in a position to control the content of
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used as the basis for content, and appropriateness of
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The faculty reported the following financial relationships or relationships to products or devices they or
their spouse/life partner have with commercial interests
related to the content of this CME activity:
Alexander Monto, MD, Chair; Dr Monto’s wife has been
a consultant for Gilead Sciences, Inc.
Pamela S. Belperio, PharmD, BCPS, has nothing to
disclose.
Hashem B. El-Serag, MD, MPH; Grant/Research Support:
Gilead and Wako Pure Chemical Industries, Ltd.
Rachel Gonzalez, MPH, has nothing to disclose.
Fasiha Kanwal, MD, MSHS; Grant/Research Support:
Gilead.
Timothy Morgan, MD; Grant/Research Support: Abbvie
Pharmaceuticals, Inc., Bristol-Myers Squibb Company,
Genentech, Gilead, Hoffman-LaRoche, Merck & Co.
Angela Park, PharmD, CACP, has nothing to disclose.
David B. Ross, MD, PhD, MBI, has nothing to disclose.
The planners and managers reported the following financial relationships or relationships to products or devices
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Sylvia H. Reitman, MBA, DipEd; Mike LoPresti;
Shirley V. Jones, MBA; Ron Schaumburg; Tom Garry;
and Suzanne Bujara hereby state that they or their
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of any amount during the past 12 months.
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Laura Gilsdorf, have nothing to disclose.
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globalacademycme.com/gastroenterology • Addressing the Unique Needs of Military Veterans With Chronic HCV Infection
Introduction
A
s the largest provider of care for patients with chronic hepatitis C virus (HCV) infection in the United States, the
Veterans Health Administration (VHA) is in a unique position to address the challenges posed by the disease. As I discuss
in more detail in this supplement, the VHA has made a substantial commitment to providing HCV care, and the results
of that commitment have led to improved outcomes for thousands of individuals.
By the end of 2016, more than 70% of veterans in the 1945-1965 birth cohort had been screened for HCV. Once identified,
however, these patients need to be guided to ensure that they make (and keep) follow-up appointments, fill prescriptions, and
complete their course of treatment—a process known as linkage to care. As Dr. Ross et al explain in their article, the Department
of Veterans Affairs (VA) has established Hepatitis C Innovation Teams that use a data-driven approach to establish an efficient
path to screening, diagnosis, and treatment. Readers will discover strategies they can implement in their own practices and
centers to improve outcomes in their patients with HCV.
For years, clinicians committed to the treatment of patients with HCV have been frustrated by the lack of efficacy of available
drugs. The clinical picture changed radically with the advent of direct-acting antiviral (DAA) agents, which allow for shorter
treatment durations, fewer side effects, and result in very high rates of sustained virologic response after just 12 weeks, even in
patients with compromised renal function or cirrhosis. Seldom in medicine are we able to use the term “cure,” but use of the
right DAAs against the right HCV genotype in the right patients leads to cure in roughly 95 out of 100 cases. In her article,
Dr. Belperio succinctly summarizes the various available DAA regimens and the factors that drive selection of treatment to
optimize outcomes.
Management of patients with HCV is not solely a question of eradicating the virus. Complications such as infections,
hepatocellular carcinoma, and psychiatric and substance abuse disorders must also be addressed as part of the overall treatment
strategy. Dr. El-Serag’s section of this supplement reviews the most common long-term complications of HCV and describes
successful strategies developed and deployed within the VA system for monitoring—and mitigating—these concerns.
Despite recent achievements, there are still opportunities to improve the treatment of patients with HCV within the VHA.
The information in this supplement will provide clinicians with evidence-based, practical strategies for achieving this important goal.
Alexander Monto, MD, Chair
Meeting the HCV Care Needs of an
Evolving VHA Patient Population
Alexander Monto, MD
H
overall HCV population.5 (See article by
Dr. El-Serag and Dr. Kanwal in this supplement.) More cirrhosis and more comorbidities lead to a higher risk for mortality
but also provide the opportunity to
achieve greater reductions in mortality and
morbidity with successful treatment.
Third, the VHA has made a substantial
commitment to providing HCV care, as
reflected in expanded funding,7 the establishment of Veterans Integrated Service
Network ( VISN)–level Hepatitis C
Innovation Teams (HITs), as described in
the article by Dr. Ross et al in this publication, and other steps to provide efficient,
effective care.
Given the availability of direct-acting
antiviral (DAA) agents that provide rates
of sustained virologic response (SVR)
well over 90%, involve shorter treatment
courses, and have fewer side effects than
older agents, the VHA is well positioned
to significantly reduce the toll of HCV.
The potential scope of that reduction
is suggested by a longitudinal study that
examined how treatment with interferonalpha—a far less effective agent than the
DAAs now available—affected survival in
a cohort of 2,211 patients with HCV at
11 Department of Veterans Affairs (VA)
medical centers who were followed for an
average of 8.5 years.8 As shown in Table 1,
patients treated with an interferon alphabased regimen had significantly lower
mortality than untreated patients, despite
having more cirrhosis.8
Real-world VA rates of SVR with the
current DAA agents are shown in Figure 1.
For those gains to be realized, however,
VHA clinicians will need to adapt their
approach to care to stay in step with the
changing nature of the health care system’s
population. This article examines several
aspects of the evolution of the VHA’s HCV
patient population and the accompanying
implications for care.
Addressing the Unique Needs of Military Veterans With Chronic HCV Infection • globalacademycme.com/gastroenterology 3
epatitis C is a leading cause of death
from infectious disease in the United
States, responsible for approximately
19,000 deaths in 2014.1
Three factors make the Veterans Health
Administration (VHA) uniquely suited to
limiting the mortality and morbidity associated with chronic hepatitis C virus (HCV)
infection. First, the VHA is the single
largest provider of HCV care in the United
States. Of the 2.7 million to 3.9 million
Americans estimated to have chronic HCV
infection,2,3 almost 234,000 were VHA
patients in 2013,4 which translates into
6% to 8.6% of the nation’s total chronic
HCV population. Similarly, while 1.0% to
1.5% of the US population is chronically
infected with HCV, the prevalence among
VHA patients has varied over time between
approximately 3.3%5 and 4.1%.6
Second, patients within the VHA with
chronic HCV tend to have more advanced
liver disease and more medical and psychosocial comorbidities compared with the
Figure 1. SVR by HCV Genotype and Treatment Regimen Among Patients Treated in
the VHA, January 2014-June 2015
Percentage of Patients Treated With Regimen (%)
100
94.3 95 94.6
92.9
95.8
98.1
96.3 100
97
89.9
90.9
100
82.6
90
76.1
80
SVR (%)
70
60
50
40
30
20
10
0
LDV/SOF
LDV/SOF+RBV
PrOD
PrOD+RBV
SOF+RBV LDV/SOF+RBV SOF+PEG+RBV
Genotype 1
8 weeks of treatment
Genotype 2
Genotype 3
12 weeks of treatment
SOF+RBV LDV/SOF+RBV PrOD±RBV
Genotype 4
24 weeks of treatment
HCV=hepatitis C virus; LDV/SOF=ledipasvir/sofosbuvir; PEG=pegylated interferon; PrOD=paritaprevir/ritonavir/ombitasvir and
dasabuvir; RBV=ribavirin; SVR=sustained virologic response; VHA=Veterans Health Administration.
Source: Used with permission. Ioannou GN, Beste LA, Chang MF, et al. Effectiveness of sofosbuvir, ledipasvir/sofosbuvir, or
paritaprevir/ritonavir/ombitasvir and dasabuvir regimens for treatment of patients with hepatitis C in the Veterans Affairs
national health care system. Gastroenterology. 2016;151(3):457-471.e5.9
An Older—and Sicker—
HCV Patient Population
Although the prevalence of HCV is
expected to decline by as much as 50% by
the year 2030, the population infected with
HCV will grow older and sicker during
those years.10 Data for the period illustrate
this trend with the increasing proportion
of HCV patients with cirrhosis and hepatocellular carcinoma (HCC) (Figure 2).11
As Dr. El-Serag has published extensively10 and discussed in this publication,
the significant increase in the proportion
of patients with cirrhosis and HCC will
pose a particular challenge to the VHA.
That challenge includes the need for VHA
clinicians to give careful, evidence-based
consideration to the optimal timing of
treatment to prevent the complications
of cirrhosis, such as HCC. This will
entail treating many patients before they
develop cirrhosis.
Timely diagnosis of HCV is the
prerequisite to timely treatment, further
underscoring the importance of birth
cohort screening. The VHA has made
considerable progress in this regard
since the Centers for Disease Control
and Prevention’s 2012 recommendation
to screen all patients born from 1945
through 1965. 12 However, as of 2014,
roughly one-third of veterans in this birth
cohort who were in VHA care still had
not been screened.13 Policies and procedures that make it easier to screen, such as
those related to consent requirements, are
key to further progress in this area.
Table 1. Demographics, Clinical Characteristics, and Outcomes of a VHA HCV Patient Cohort, by Treatment Status
Variable
Treated (n=692)
Untreated (n=1,519)
P Value
Age at study entry (mean ± SD)
49.64 ± 6.29
52.20 ± 8.64
<0.0001
Male
676 (97.7%)
1,488 (98.0%)
0.68
History of incarceration
358 (51.7%)
799 (52.6%)
0.71
1 or 4
484 (71.5%)
932 (71.6%)
0.71
2 or 3
181 (26.7%)
277 (21.3%)
Mixed
12 (1.8%)
92 (7.1%)
HIV positive
73 (10.5%)
225 (14.8%)
0.006
History of heavy alcohol use (>80 g/d) at any time prior to study entry
369 (53.3%)
835 (55.0%)
0.47
51 (7.4%)
192 (12.6%)
0.0002
396 (57.2%)
829 (54.6%)
0.25
Substance abuse contraindicating treatment during study period
59 (8.5%)
271 (17.8%)
<0.0001
Psychiatric condition contraindicating treatment during study period
56 (8.1%)
236 (15.5%)
<0.0001
Cirrhosis at baseline
109 (15.8%)
80 (5.3%)
<0.0001
Cirrhosis ever (baseline through end of study follow-up)
224 (32.4%)
347 (22.8%)
<0.0001
Hepatocellular carcinoma ever
43 (6.2%)
84 (5.5%)
0.52
Years of follow-up (mean ± SD)
9.41 ± 2.23
8.08 ± 3.24
<0.0001
Death during follow-up
112 (16.2%)
488 (32.1%)
<0.0001
HCV genotype
Heavy alcohol use (>80 g/d) within 12 months prior to study
Ever injected drugs
HIV=human immunodeficiency virus; HCV=hepatitis C virus; VHA=Veterans Health Administration.
Source: Used with permission. Cozen ML, Ryan JC, Shen H, et al. Improved survival among all interferon-α-treated patients in HCV-002, a Veterans Affairs hepatitis C cohort of 2211 patients,
despite increased cirrhosis among nonresponders. Dig Dis Sci. 2016;61(6):1744-1756.8
4 globalacademycme.com/gastroenterology • Addressing the Unique Needs of Military Veterans With Chronic HCV Infection
A Growing Proportion of
Difficult-to-Treat Patients?
In addition to the disease burden directly
related to their chronic hepatitis, patients
in the VHA who have HCV often contend
with medical and psychiatric comorbidities and substance abuse disorders that can
complicate everything from their candidacy for certain regimens to their ability to
adhere to or tolerate treatment (Table 2).11
From 1998 through 2008, psychiatric
conditions were the most common
reasons for HCV-infected patients in
VHA care to be admitted to the hospital,
whereas liver disease was responsible for
less than 4% of admissions among HCV
monoinfected veterans.14
As VHA clinicians treat more and more
patients whose overall health, ability to
comply with therapeutic regimens, and
other factors enable them to achieve SVR,
the proportion of more complicated HCV
cases remaining in need of care will grow.
These patients will require a comprehensive approach that manages their overall
health, including comorbid psychiatric
conditions and substance abuse disorders,
and that addresses factors such as homelessness and transportation issues that also
are significant impediments to care.
As Katrak and colleagues14 note in a
2016 paper examining health care utilization among veterans with HCV, human
immunodeficiency virus (HIV ), and
HCV/HIV coinfection, “Psychiatric
disease, CVD [cardiovascular disease],
and non-HIV associated infection are the
primary drivers of inpatient admission
for all groups [studied], emphasizing the
importance of investing in mental health
and primary care services for veterans.”
The work of the HITs and other VISNlevel and national initiatives will be critical
in meeting these challenges.
Addressing Race- and
Gender-Based Disparities
in Care
An analysis of 145,596 HCV-infected
patients receiving care in VHA facilities in
the era of second-generation DAA agents
found evidence of disparities in both evaluation by a specialist and treatment with
a second-generation DAA (Figure 3).15
In particular, African Americans were less
likely than white non-Hispanics to be
treated with a second-generation DAA
(odds ratio [OR], 0.78; 95% confidence
interval [CI], 0.73-0.84). Women were
less likely than men to be evaluated by a
specialist (OR, 0.95; 95% CI, 0.89-1.02)
but were not less likely to receive a secondgeneration DAA.15
The study’s authors, who practice within
the VHA system, noted that the treatment disparity affecting African Americans
persisted after adjusting for other demographic characteristics and for clinical and
virologic factors.15 Their finding of a racebased disparity was also consistent across
age groups, disease severity, mental health
comorbidity, and other factors. In considering potential causes for the disparity, they
noted the higher rates of HIV coinfection,
diabetes, and history of drug and alcohol use
and homelessness among African American
patients relative to white non-Hispanics.
They added that differences in access to care
did not appear to be a factor.15
Figure 2. Rising Prevalence of Cirrhosis and Hepatocellular Carcinoma (HCC)
Among HCV-infected Veterans in VHA Care
18
% with chrrhosis
% with HCC
16
14
12
10
8
6
4
2
0
2009
2010
2011
2012
2013
Veterans with HCV 177,974
viremia in VHA carea
180,182
180,0498
178,819
174,302
Deaths
6,932
7,268
7,913
7,812
6,687
HCV=hepatitis C virus; VHA=Veterans Health Administration.
a
Patients who ever had a positive HCV RNA test, among patients who received VHA care that fiscal year.
Source: Adapted from Beste LA, Ioannou GN. Prevalence and treatment of chronic hepatitis C virus infection in the
US Department of Veterans Affairs. Epidemiol Rev. 2015;37(1):131-143.11
Table 2. Comorbidities and Substance Use Disorders Among HCV-Infected Patients
in VHA Care, 2013
Condition
Percentage of Patients (N=174,302)
Medical comorbidities
Chronic obstructive pulmonary disease
23
Diabetes mellitus, type 2
29
Hypertension
68
Ischemic heart disease
17
Psychiatric comorbidities
Any mental illness
69
Bipolar disorder
13
Depression
60
Neuroses and anxiety states
37
Posttraumatic stress disorder
28
Substance use disorders
Alcohol use
55
Cannabis
26
Opioids
22
Stimulants
35
Tobacco use
66
HCV=hepatitis C virus; VHA=Veterans Health Administration.
Source: Adapted from Beste LA, Ioannou GN. Prevalence and treatment of chronic hepatitis C virus infection in the
US Department of Veterans Affairs. Epidemiol Rev. 2015;37(1):131-143.11
Addressing the Unique Needs of Military Veterans With Chronic HCV Infection • globalacademycme.com/gastroenterology 5
Figure 3. Odds Ratios for VHA Patients Being Treated With Second-Generation DAAs
by Sociodemographic Characteristics
0.78
Odds ratio for African Americans relative
to 1.0 reference for white non-Hispanics
95% confidence interval, 0.73-0.84
0.96
Odds ratio for patients aged >50 years relative
to 1.0 reference for patients aged ≤50 years
95% confidence interval, 0.87-1.06
0.78
Odds ratio for patients with history of homelessness relative
to 1.0 reference for those with no history of homelessness
95% confidence interval, 0.74-0.82
DAA=direct-acting antiviral; HCV=hepatitis C virus; VHA=Veterans Health Administration.
Source: Adapted from Kanwal F, Kramer JR, El-Serag HB, et al. Race and gender in the use of direct acting antiviral agents for
HCV. Clin Infect Dis. 2016;63(3):291-299.15
In examining gender differences in care,
the authors noted that young women were
less likely than men of the same age to
receive DAA agents, even after adjustment
for the severity of liver disease.15 Because
women currently serving in the armed
forces are infected with chronic HCV at
1.23 times the rate of their male counterparts, attention to the HCV-related needs
of younger female veterans will grow in
importance in coming years.15 While this
study did not identify definitive reasons
for race- and gender-based disparities in
HCV care, its findings underscore the
authors’ call for an increased focus on
meeting the needs of African American
and female veterans.
Beyond Recognizable
Future Needs
While the prevalence of HCV is expected
to drop dramatically over the next decade
or more in both the general population
and among VHA patients, the long-term
health care needs of veterans who served
in the years following the 9/11 attacks
have yet to be identified. The current wave
of opioid abuse in the US involves both
intravenous use and pills, so it is possible
that in the next decade or so VHA clinicians will be treating a younger cohort
of HCV-infected veterans. Other unpredictable patient needs and challenges no
doubt will emerge as well, requiring practitioners to be flexible and responsive in
their approach to care.
6 In Summary
The second-generation DAA agents
provide clinicians with a greatly enhanced
ability to achieve SVR in a variety of
patients, including those who did not
respond to earlier treatment and those
with advanced liver disease and significant comorbidities. 16-23 The VHA has
made a substantial commitment to provide
comprehensive care to its HCV-infected
patients, including access to DAAs, and has
provided its clinicians with detailed guidance on individualizing care.24 This effort to
meet specific needs also entails identifying
key patient groups and the factors that
influence the VHA’s ability to screen, diagnose, and treat them in an efficient manner.
As the VHA’s HCV population evolves, the
health care system is poised to move in step
with its patients’ changing needs.
References
1.
Centers for Disease Control and Prevention (CDC).
Hepatitis C kills more Americans than any other
infectious disease. http://www.cdc.gov/media/
releases/2016/p0504-hepc-mortality.html. Published
May 4, 2016. Accessed December 9, 2016.
2. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic
hepatitis C virus infection in the United States, National
Health and Nutrition Examination Survey 2003 to
2010. Ann Intern Med. 2014;160(5):293-300.
3. Armstrong GL, Wasley A, Simard EP, McQuillan GM,
Kuhnert WL, Alter MJ. The prevalence of hepatitis C
virus infection in the United States, 1992 through 2002.
Ann Intern Med. 2006;144(10):705-714.
4. Maier MM, Ross DB, Chartier M, Belperio PS, Backus
LI. Cascade of care for hepatitis C virus infection within
the US Veterans Health Administration. Am J Public
Health. 2016;106(2):353-358.
5. Backus LI, Belperio PS, Loomis TP, Yip GH, Mole LA.
Hepatitis C virus screening and prevalence among US
veterans in Department of Veterans Affairs care. JAMA
Intern Med. 2013;173(16):1549-1552.
6. Dominitz JA, Boyko EJ, Koepsell TD, et al. Elevated
prevalence of hepatitis C infection in users of
United States veterans medical centers. Hepatology.
2005;41(1):88-96.
7. US Department of Veterans Affairs. VA expands
hepatitis C drug treatment. http://www.va.gov/opa/
pressrel/pressrelease.cfm?id=2762. Published March 9,
2016. Accessed December 9, 2016.
8. Cozen ML, Ryan JC, Shen H, et al. Improved survival
among all interferon-α-treated patients in HCV-002,
a Veterans Affairs hepatitis C cohort of 2211 patients,
despite increased cirrhosis among nonresponders. Dig
Dis Sci. 2016;61(6):1744-1756.
9. Ioannou GN, Beste LA, Chang MF, et al. Effectiveness
of sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/
ritonavir/ombitasvir and dasabuvir regimens for treatment of patients with hepatitis C in the Veterans
Affairs national health care system. Gastroenterology.
2016;151(3):457-471.e5.
10. El-Serag HB, Kramer J, Duan Z, Kanwal F.
Epidemiology and outcomes of hepatitis C infection in
elderly US veterans. J Viral Hepat. 2016;23(9):687-696.
11. Beste LA, Ioannou GN. Prevalence and treatment of chronic hepatitis C virus infection in the
US Department of Veterans Affairs. Epidemiol Rev.
2015;37(1):131-143.
12. Smith BD, Morgan RL, Beckett GA, et al; Centers for
Disease Control and Prevention. Recommendations
for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR
Recomm Rep. 2012;61(RR-4):1-18.
13. US Department of Veterans Affairs. State of care for
veterans with hepatitis C 2014. http://www.hepatitis.
va.gov/pdf/HCV-State-of-Care-2014.pdf. Published
September 2014. Accessed December 9, 2016.
14. Katrak S, Park LP, Woods C, Muir A, Hicks C, Naggie
S. Patterns of healthcare utilization among veterans
infected with hepatitis C virus (HCV) and human
immunodeficiency virus (HIV) and coinfected with
HIV/HCV: unique burdens of disease. Open Forum
Infect Dis. 2016;3(3):ofw173.
15. Kanwal F, Kramer JR, El-Serag HB, et al. Race and
gender in the use of direct acting antiviral agents for
HCV. Clin Infect Dis. 2016;63(3):291-299.
16. Afdhal N, Reddy KR Nelson DR, et al; ION-2
Investigators. Ledipasvir and sofosbuvir for previously
treated HCV genotype 1 infection. N Engl J Med.
2014;370(16):1483-1493.
17. Feld JJ, Jacobson IM, Hézode C, et al; ASTRAL-1
Investigators. Sofosbuvir and velpatasvir for HCV
genotype 1, 2, 4, 5, and 6 infection. N Engl J Med.
2015;373(27):2599-2607.
18. Feld JJ, Kowdley KV, Coakley E, et al. Treatment for
HCV with ABT-450/r-ombitasvir and dasabuvir with
ribavirin. N Engl J Med. 2014;370(17):1594-1603.
19. Foster GR, Afdhal N, Roberts SK, et al; ASTRAL-2
Investigators; ASTRAL-3 Investigators. Sofosbuvir and
velpatasvir for HCV genotype 2 and 3 infection. N Engl
J Med. 2015;373(27):2608-2617.
20. Kowdley KV, Gordon SC, Reddy KR, et al; ION-3
Investigators. Ledipasvir and sofosbuvir for 8 or 12
weeks for chronic HCV without cirrhosis. N Engl J
Med. 2014;370(20):1879-1888.
21. Naggie S, Cooper C, Saag M, et al; ION-4 Investigators.
Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):705-713.
22. Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir
plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1
infection and stage 4-5 chronic kidney disease (the
C-SURFER study): a combination phase 3 study.
Lancet. 2015;386(10003):1537-1545.
23. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevirelbasvir combination therapy for treatment-naive
cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized
trial. Ann Intern Med. 2015;163(1):1-13.
24. US Department of Veterans Affairs. Chronic hepatitis
C virus (HCV) infection: treatment considerations.
http://www.hepatitis.va.gov/provider/guidelines/hcvtreatment-considerations.asp. Revised September 22,
2016. Accessed December 9, 2016.
globalacademycme.com/gastroenterology • Addressing the Unique Needs of Military Veterans With Chronic HCV Infection
Best Practices in Screening, Diagnosis, and Treatment Along
the Veteran Health Administration's Cascade of HCV Care
David B. Ross, MD, PhD, MBI; Rachel Gonzalez, MPH; Timothy Morgan, MD; and Angela Park, PharmD, CACP
A
s the nation’s single largest provider
of care to patients with chronic hepatitis C virus (HCV) infection, the
Veterans Health Administration (VHA) is
uniquely suited to identify, implement, and
share best practices in HCV care.1 Those
best practices are informed by the VHA’s
extensive data analysis capabilities and
by practical insights from the day-to-day
experience of thousands of VHA health
care professionals. The VHA’s Corporate
Data Warehouse is a particularly valuable
resource for a data-driven, populationhealth approach to care. In addition, the
Veterans Integrated Service Network
(VISN)–level Hepatitis C Innovation
Teams, or HITs, were formed in the wake
of a revolution in HCV treatment. In
September 2014, at a VHA meeting in
San Antonio, Texas, teams began implementing Lean Process Improvement
methods to augment their clinical expertise and redesign the process of HCV
management. The HITs’ goal was to
structure care delivery of screening, diagnosis, and treatment in the most effective,
efficient way possible for patients. This
article discusses several of the best practices incorporated in that pursuit.
Figure 1. The VHA Cascade of Care
for HCV Infection
Estimate Number of Patients
With Chronic HCV
Diagnose Patients With Chronic HCV
Link Diagnosed Patients to HCV Care
Treat With HCV Antivirals
Achieve Sustained Virologic Response
HCV=hepatitis C virus; VHA=Veterans Health Administration.
Source: Figure adapted from Maier MM, Ross DB,
Chartier M, Belperio PS, Backus LI. Cascade of care for
hepatitis C virus infection within the US Veterans Health
Administration. Am J Public Health. 2016;106(2):353-358.5
A Cascade-of-Care Model
Population-health approaches to chronic
diseases such as diabetes mellitus, human
immunodeficiency virus (HIV ), and
HCV often use a cascade-of-care model
to identify delays in patients’ progression from one key step to another, such
as from screening to definitive diagnosis,
from diagnosis to presentation for care,
and from initiation of care to adjustment
of the treatment regimen or achieving the
desired outcome.2-4
In the VHA system, the 5 steps highlighted in Figure 1 constitute the chief
components of the cascade of care for
HCV.5 The first step in this process entails
defining the scope of the challenge—the
number of affected patients—as reliably as
possible.5 Maier and colleagues drew upon
the VHA’s Corporate Data Warehouse
to identify those patients with chronic
HCV infection and estimate additional
cases based on projected prevalence (from
HCV antibody-positive patients who had
not received confirmatory RNA testing
and the untested population). As a result,
these investigators estimated that just
under 234,000 VHA patients had chronic
HCV in 2013.5
HCV Screening
and Diagnosis
The projections used to estimate HCV
prevalence speak to 2 changes made by
the VHA in recent years that impact
timely diagnosis. The first change affected
patients who received positive results on
HCV antibody screening but who did
not have the confirmatory RNA testing
that is necessary for making a diagnosis of
current HCV infection.5
Prior to 2009, it was standard practice
in the VHA—and in other non-VA health
care institutions—to use an entire serum
sample for HCV antibody testing only.
Patients with a positive antibody result
would need to return to the facility to
provide a second blood sample to test for
the presence of HCV RNA. At best, this
constituted an avoidable delay in obtaining
the data needed to make a diagnosis and to
start formulating a management plan. At
worst—and not infrequently—it meant
that the patient did not receive the testing
required to reach a definitive diagnosis of
HCV infection.
Addressing the Unique Needs of Military Veterans With Chronic HCV Infection • globalacademycme.com/gastroenterology Beginning in 2009, however, the VHA
implemented a policy that required laboratories to save a portion of the blood
sample provided for HCV antibody
testing and, in the event of a positive
result, to automatically proceed to test
that retained specimen for HCV RNA.
This change in the process provided an
efficient and patient-centered approach
to the HCV screening and diagnosis
testing sequence (Figure 2).6 As a result,
providers who order HCV screening now
receive results that indicate whether or
not the patient has an HCV infection,
without the need for another blood draw.
In 2013, initial positive HCV screens
were followed by confirmatory testing in
96% of cases.7
The second policy change within the
VHA, which affected a large portion of
patients who had yet to be tested for HCV,
was brought on by a change in Centers for
Disease Control and Prevention (CDC)
recommendations. In 2012, the CDC
recommended that all people born from
1945 through 1965 be screened for HCV
infection regardless of their risk-factor
status. To reduce the number of untested
patients, the VHA went beyond the CDC
recommendations by providing HCV
screening to any patient who requested
it, without that patient having to identify
specific risk factors that would support
screening. In part as a result of this
approach, between 2002 and 2013, the
proportion of veterans with at least one
VHA outpatient visit who had received
HCV screening more than doubled, from
27% to 56%. By October 2013, 65% of
veterans in the 1945-1965 birth cohort
had received HCV screening,7 and recent
efforts by the HITs have resulted in annual
increases of 3% to 4%.
Linkage to Care and
Initiating Treatment
With HCV Antivirals
Linkage to HCV care can be defined in its
most narrow sense by an outpatient visit in
which HCV was included on the patient’s
problem list. By this measure, according
to 2013 data, the VHA’s HCV cascade of
care functioned well: 89% of patients diagnosed with chronic HCV had a linkage to
care that year, as illustrated in Figure 3.5
7
Figure 2. Hepatitis C Screening and Diagnosis Testing Sequence
HCV
Antibody
Nonreactive
Reactive
HCV
RNA
Not Detected
No HCV Antibody Detected
STOPa
Detected
No Current HCV Infection
Current HCV Infection
Additional Testing as Appropriateb
Link to Care
HCV, hepatitis C virus.
a
For persons who might have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up testing for HCV
antibody is recommended. For persons who are immunocompromised, testing for HCV RNA can be considered.
b
To differentiate past, resolved HCV infection from biologic false positivity for HCV antibody, testing with another HCV antibody
assay can be considered. Repeat HCV RNA testing if the person tested is suspected to have had HCV exposure within the past
6 months or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen.
Source: Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2013;62(18):362-365.6
As a practical matter, however, linkage
to care entails far more, particularly given
the high burden of comorbidities that can
preclude or detract from successful HCV
treatment. Almost 70% of HCV-viremic
veterans under care within the VHA in
2013 had at least one serious mental illness,
such as schizophrenia, bipolar disorder,
posttraumatic stress disorder (PTSD),
anxiety, and depression.8 Similarly, 55% of
HCV-viremic veterans in care that year had
a history of problematic alcohol use, which
poses a further significant clinical challenge, given that alcohol has been shown to
facilitate progression of liver disease in the
setting of HCV infection.8-10 In addition to
comorbid psychiatric and substance abuse
diagnoses that can adversely affect treatment, HCV-infected veterans are often also
contending with serious infectious disease
and general medical conditions, some of
which can limit the choice and efficacy
of HCV therapeutic regimens (Table 1).8
(For more information about complications of HCV infection, especially in the
later stages of the disease, see the article by
Dr. El-Serag and Dr. Kanwal on page 15.)
Figure 3. Cascade of HCV Care in the VHA in 2013
No. of Patients (thousands)
250
233,898
(100%)
181,168
(77%)
200
160,794
(69%)
150
100
39,388
(17%)
50
77%
89%
24%
41%
15,983
(7%)
0
Chronic HCV (estimated)a Diagnosed With Chronic HCVb Linked to HCV Carec
Treated With HCV Antiviralsd
Achieved SVRe
Cascade Steps
HCV=hepatitis C virus; SVR=sustained virologic response; VHA=Veterans Health Administration.
The proportion of patients in each step of the cascade from the patients in the preceding step is presented in the arrows
between each bar.
a
Chronic HCV was estimated from the sum of those already identified as having chronic HCV plus estimated additional cases
from projected prevalence among HCV antibody-positive patients who had not had RNA testing, plus estimated additional
cases from projected prevalence among the untested population.
b
“Diagnosed with chronic HCV” was defined as ever having a detectable HCV RNA or genotype.
c
“Linked to HCV care” required an outpatient visit in 2013, entry in the VHA’s HCV registry, and HCV entered on the patient’s
medical record problem list.
d
“Treated with HCV antivirals” was defined as ever receiving HCV antivirals from the VHA as of December 31, 2013.
e
“Achieved SVR” was defined as undetectable HCV RNA on all tests after end of treatment, including at least 1 test at least 12 weeks
after the end of treatment, with the SVR rate among those evaluable for SVR applied to those without definitive SVR status.
Source: Used with permission. Maier MM, Ross DB, Chartier M, Belperio PS, Backus LI. Cascade of care for hepatitis C virus
infection within the US Veterans Health Administration. Am J Public Health. 2016;106(2):353-358.5
8 Patients face overlapping and often overwhelming challenges when seeking linkage
to care. The overarching theme of many
of the best practices developed to provide
such care is “It takes a therapeutic village.”
Within the VHA system, we are fortunate
to have primary care physicians, mental
health professionals, advanced practice
clinicians, nursing care coordinators,
clinical pharmacists, and others with deep
expertise in meeting the needs of patients
with HCV infection. Treating prescribers
are encouraged to draw on these tremendous resources, both before and during
antiviral therapy aimed at achieving a
sustained virologic response (SVR).
Addressing as many background health
issues as possible can help to enhance the
patient’s readiness for treatment, the likelihood of being adherent with the therapeutic
regimen, and in some cases, the efficacy of
therapy. It is also important that clinicians
be aware of their patients’ nonmedical
issues that can pose obstacles to successful
therapy, such as transportation challenges
and patient concerns or attitudes about
treatment. Enlisting the assistance of VHA
social workers can be an invaluable step in
overcoming logistical impediments to care.
Among the treating provider’s responsibilities is the need to ensure that the patient is
fully aware of what the therapeutic regimen
entails, including the risks and benefits of
treatment. One key step in doing so is to
connect a patient with a fellow veteran who
has received the same or similar treatment.
Such psychosocial support can be invaluable in assuaging patients’ concerns and
perhaps prompting them to ask questions
they may be hesitant to ask their clinicians.
The complexity of our patients’ health
status, coupled with their needs in addition
to medical care, can at times make clinical
decision making seem daunting. But by
following 2 well-established best practices,
clinicians can better manage the many variables involved in HCV management in an
efficient and effective manner.
The first of those best practices is to
take a step-wise approach to assessing
the various factors that will shape decisions on initiation of treatment and
choice of regimen. The 2012 recommendations from the US Department
of Veterans Affairs (VA) Hepatitis C
Resource Center Program and National
Hepatitis C Program Office serve as an
example of this thorough approach, as
detailed in Table 2.11 Components of this
globalacademycme.com/gastroenterology • Addressing the Unique Needs of Military Veterans With Chronic HCV Infection
pretreatment assessment checklist have
since been updated, given current treatment practices. Updated HCV treatment
recommendations are available at http://
www.hepatitis.va.gov/provider/guidelines/
hcv-treatment-considerations.asp.12
The VA has expanded its budget for
HCV drugs from $696 million in fiscal
year (FY) 2015 to roughly $1 billion
in FY 2016. 13 Clinicians are obligated
to make prudent use of these public
resources, and HCV resistance testing in
appropriate patients (which helps assure
optimal treatment selection) is one way
to do so.
The need to make the most informed
choice possible when selecting an initial
HCV therapy means drawing on the
services of 2 members of the VHA HCV
care team whose roles are too often
underappreciated: the laboratorian and
the clinical pharmacist. By working with
laboratory personnel to obtain critical
information on viral load, presence of
resistance-associated polymorphisms
(RAPs), and other crucial data, HCV
providers are able to select the optimal
HCV therapy for their patients. While
the value of “patient-facing” members
of the HCV care team has long been
recognized—thanks in part to research
showing that nonphysician providers
(NPPs) can achieve HCV treatment
outcomes comparable to those of physicians 14—the laboratorian is a subject
matter expert (SME) whose counsel
should be regularly obtained and highly
regarded. Meanwhile, as experts on the
safety and efficacy of HCV direct-acting
antivirals (DAAs), pharmacokinetics and
pharmacodynamics, and drug interactions, the VHA’s clinical pharmacists play
an integral role in efforts to achieve SVR
in as many patients, and at the lowest rate
of adverse effects, as possible. Clinical
pharmacists’ scope of practice allows
them to act as treating providers and
manage patients through HCV therapy,
expanding the VHA’s overall capacity to
treat patients.
The Pursuit of SVR
In 2013, the VHA initiated treatment with
HCV antivirals in 24% of the HCV-viremic
patients who were linked to VHA care. In
turn, approximately 41% of those patients
receiving treatment achieved SVR, a
proportion generally consistent with SVR
rates in that year before introduction of the
latest generation of more effective DAAs.5
While the data for 2015-2016 showed
SVR rates of more than 90%, one best
practice related to treatment will remain:
Assessing patient response approximately
12 weeks after initiating therapy. Various
VISNs have demonstrated that steps as
simple as sending a reminder letter can
increase patients’ rate of compliance with
follow-up appointments. These steps, while
basic, are essential.
As discussed by Dr. Belperio in this
supplement, the newer DAAs provide a
greatly enhanced ability to achieve SVR
even among patients who have failed prior
therapy or who have advanced liver disease.
By sharing and adopting best practices for
screening, diagnosis, and treatment, VHA
clinicians can extend the benefits of these
agents to an ever-increasing proportion of
America’s HCV-viremic veterans.
Table 1. Prevalence of Selected Infectious Disease and General Medical Conditions
in HCV-Viremic Veterans Receiving Care From the VHA, 2015a
Condition
Ever Diagnosis of Condition, N (%)
Anemia
43,215(25)
Cardiac conduction disorders/dysrhythmias
23,883(14)
Chronic obstructive pulmonary disease
40,333 (23)
Diabetes mellitus, type 2 or unspecified
50,131 (4)
Human immunodeficiency virus infection
5,733 (3)
Hepatitis B virus infection
12,233 (7)
Hypertension
120,685 (69)
Ischemic heart disease
29,790 (17)
Renal failure, acute
17,446 (10)
Renal failure, chronic
15,557 (9)
HCV=hepatitis C virus; VHA=Veterans Health Administration.
a
Number of HCV-viremic veterans in care in 2013 used as denominator, 174,302.
Source: Adapted from US Department of Veterans Affairs. State of care for veterans with hepatitis C 2014.
http://www.hepatitis.va.gov/pdf/HCV-State-of-Care-2014.pdf. Published September 2014. Accessed December 5, 2016.8
Table 2. Pretreatment Assessments in Patients With Chronic HCV Infection
Necessary Assessments
Medical history, including complications of liver disease, presence of significant extrahepatic disease,
and symptoms of chronic HCV that may diminish quality of life
Psychiatric history, including past or ongoing psychiatric and substance use disorders
Screening for depression and alcohol use
Previous antiviral therapies and response
ECG in patients with pre-existing cardiac disease
Biochemical markers of liver injury and assessment of hepatic function, including serum ALT and
AST, serum albumin, total protein, alkaline phosphatase, serum bilirubin (including direct bilirubin),
and prothrombin time
Hemoglobin, hematocrit, WBC with differential, and platelet count
Serum creatinine
Serum glucose
Quantitative HCV RNA measurement
HCV genotype
Serum ferritin, iron saturation, and serum ANA
If using ribavirin, pregnancy test (in women of childbearing age)
HIV serology
Serum HBsAg, anti-HBc, anti-HBs, anti-HAV (total)
ALT=alanine transaminase; ANA=antinuclear antibody; anti-HAV=antibody to hepatitis A virus; anti-HBc=antibody to hepatitis B
core antigen; anti-HBs=antibody to hepatitis B surface antigen; AST=aspartate aminotransferase; ECG=electrocardiogram;
HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; WBC=white blood cell.
Source: Yee HS, Change MF, Pocha C, et al; Department of Veterans Affairs Hepatitis C Resource Center Program; National
Hepatitis C Program Office. Update on the management and treatment of hepatitis C virus infection: recommendations from
the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J
Gastroenterol. 2012;107(5):669-689.11
Addressing the Unique Needs of Military Veterans With Chronic HCV Infection • globalacademycme.com/gastroenterology 9
The VHA’s Greatest HITs: Best Practices for Improving HCV Care
Untreated hepatitis C virus infection has
significant population-health implications,
including chronic liver disease, liver cancer,
and risk of transmission leading to new
infections. Since 2014, second-generation
DAAs have demonstrated increased efficacy in producing sustained viral response,
or cure, with fewer side effects, albeit at
a dramatically increased cost. These new
medicines allow nearly all patients to be
treated. To meet the increased demand for
treatment, the VA committed to timely identification of patients with hepatitis C and
organization of care in the most patientcentered manner.
Recognizing the unique opportunity to
improve care for approximately 200,000
veterans, the HIV, Hepatitis and Public
Health Pathogens Programs (HHPHP)
directed the National Hepatitis C Resource
Center (NHCRC), in partnership with the
Veterans Engineering Resource Center
(VERC), to create the Hepatitis C Innovation
Team (HIT) Collaborative. Multidisciplinary
HITs formed in each VA region, with
members from gastroenterology, infectious
disease, case management, information
technology, nursing, pharmacy, psychology,
process improvement, and public and
population health. Teams apply Lean
methods to improve access and quality of
HCV care. The HIT Collaborative provides a
clinically focused foundation to share best
practices across and within teams.
Strong practices for improving HCV
care emerged from a multitude of strategies employed by the HITs. Testing all baby
boomers (per CDC recommendations)
and patients at risk for HCV infection is a
critical first step for improving HCV care for
veterans. Testing veterans is particularly
vital because the prevalence of HCV in this
group is almost triple that of the general
population. To ensure screening of at-risk
patients, HITs partnered with primary
care providers and Housing and Urban
Development–VA Supportive Housing (HUD/
VASH) programs to educate veterans about
HCV risk. For example, one team created
an automated system inviting veterans
born from 1945 through 1965 to be tested
for HCV, streamlining the process and eliminating the need for a veteran to complete
a full clinical visit to access testing. Other
teams are adopting these practices as loweffort, high-impact interventions.
Patients newly diagnosed with HCV
infection, as well as those who were
already aware of their HCV status, need to
connect with providers who can evaluate
their liver disease and deliver appropriate
treatment. To overcome patient-, provider-,
and system-level barriers, HITs shifted
the health system’s traditional approach:
Rather than rely on referrals from primary
10 care, HCV care providers implemented
direct outreach to patients. HITs leveraged
the VA’s electronic health records to create
population-management tools, ensuring
that patients with HCV were identified and
that those with the most advanced liver
disease were contacted by phone and/or
by mail. This strong practice was adopted
by all teams, with HIT members from
every discipline committing extra time to
contacting patients and making veterans
aware of new treatment options.
HITs recognized that, despite active
outreach, some patients remained uncertain about pursuing evaluation or treatment.
One team responded by engaging peer
counselors (who are veterans themselves)
as part of the HCV care team. These peersupport specialists can address veterans’
concerns through different pathways than
clinicians, increasing patient activation and
empowerment to engage in HCV care.
The need for multiple blood tests and
evaluation procedures, which require
several visits, was identified as a barrier to
evaluation and treatment. As HITs worked
to continuously improve their patients’
experience, many teams developed sameday service for completion of clinical labs,
imaging, vibration-controlled transient elastography (FibroScan®), care management,
and treatment initiation. To expand capacity
and offer patients better options for care,
other teams established such services as
Saturday clinics, group treatment clinics,
and shared medical appointments. For
veterans for whom transportation or
distance is a major barrier, HITs promoted
use of telemedicine. Through Specialty Care
Access Network–Extension for Community
Healthcare Outcomes (SCAN-ECHO),
specialty providers supported colleagues
working in locations more accessible to
patients. The decrease in the number of
required in-person visits and increased
use of virtual care has increased access
and improved the patient-centered care
experience. Programming is also under
way to better serve homeless veterans and
veterans with multiple comorbid conditions.
Successful efforts by the 20 regional
teams led to the identification of best practices in several different focus areas. As
these strategies were tested and refined,
HITs disseminated results and helped each
other export these practices across regions.
These multidisciplinary teams learn from
each other to address day-to-day concerns
and tackle complex challenges, ultimately
increasing access to care, improving
veterans’ experience, and facilitating
the initiation of HCV treatment for nearly
70,000 veterans in the past 2 years.
References
1. US Department of Veterans Affairs. Viral hepatitis. http://www.hepatitis.va.gov/about-index.asp.
Updated August 26, 2016. Accessed December 5,
2016.
2. Ali MK, Bullard KM, Gregg EW, del Rio C.
A cascade of care for diabetes in the United States:
Visualizing the gaps. Ann Intern Med. 2014;
161(10):681-689.
3. MacCarthy S, Hoffman M, Ferguson L, et al. The
HIV care cascade: model, measures, and moving
forward. J Int AIDS Society. 2015;18(1):19395.
4. Yehia BR, Schranz AJ, Umscheid CA, Lo Re V III.
The treatment cascade for chronic hepatitis C virus
infection in the United States: A systematic review
and meta-analysis. PLoS One. 2014;9(7):e101554.
5. Maier MM, Ross DB, Chartier M, Belperio
PS, Backus LI. Cascade of care for hepatitis C
virus infection within the US Veterans Health
Administration. Am J Public Health. 2016;106(2):
353-358.
6. Centers for Disease Control and Prevention
(CDC). Testing for HCV infection: an update of
guidance for clinicians and laboratorians. MMWR
Morb Mortal Wkly Rep. 2013;62(18):362-365.
7. Veterans Health Administration (VHA). HIV,
Hepatitis, and Public Health Pathogens Programs
annual stakeholders report. http ://www.
hepatitis.va.gov/pdf/stakeholders-report-2015.pdf.
Published May 2015. Accessed December 5, 2016.
8. US Department of Veterans Affairs. State of care
for veterans with hepatitis C 2014. http://www.
hepatitis.va.gov/pdf/HCV-State-of-Care-2014.pdf.
Published September 2014. Accessed December 5,
2016.
9. Poynard T, Bedossa P, Opolon P. Natural history
of liver fibrosis progression in patients with
chronic hepatitis C. The OBSVIRC, METAVIR,
CLINIVIR , and DOSVIRC groups. Lancet.
1997;349(9055):825-832.
10. Ostapowicz G, Watson K J, Locarnini SA,
Desmond PV. Role of alcohol in the progression of
liver disease caused by hepatitis C virus infection.
Hepatology. 1998;27(6):1730-1735.
11. Yee HS, Chang MF, Pocha C, et al; Department
of Veterans Affairs Hepatitis C Resource Center
Program; National Hepatitis C Program Office.
Update on the management and treatment of
hepatitis C virus infection: recommendations
from the Department of Veterans Affairs Hepatitis
C Resource Center Program and the National
Hepatitis C Program Office. Am J Gastroenterol.
2012;107(5):669-689.
12. US Department of Veterans Affairs. Chronic
hepatitis C virus (HCV) infection: treatment considerations. http://www.hepatitis.va.gov/provider/
guidelines/hcv-treatment-considerations.asp. Revised
September 22, 2016. Accessed December 5, 2016.
13. US Department of Veterans Affairs. VA expands
hepatitis C drug treatment. http://www.va.gov/
opa/pressrel/pressrelease.cfm?id=2762. Published
March 9, 2016. Accessed December 5, 2016.
14. Backus LI, Belperio PS, Shahoumian TA, Mole LA.
Impact of provider type on hepatitis C outcomes
with boceprevir-based and telaprevir-based regimens.
J Clin Gastroenterol. 2015;49(4):329-335.
globalacademycme.com/gastroenterology • Addressing the Unique Needs of Military Veterans With Chronic HCV Infection
Assessing the Characteristics of HCV Treatment Regimens
to Individualize Therapy to Optimal Effect
Pamela S. Belperio, PharmD, BCPS
S
ince 2014, clinicians treating chronic
hepatitis C virus (HCV) infection
have been able to use direct-acting
antiviral (DAA) agents, which offer
benefits such as shorter treatment duration, fewer side effects, and higher rates of
12-week posttreatment sustained virologic
response (SVR12), or cure, compared with
previous HCV therapies.1
The number of newer agents available
and the differences in their efficacy and
safety profiles in specific patient populations provide the opportunity—and
obligation—to carefully weigh treatment
regimens and patient characteristics to
individualize HCV care so as to achieve
optimal effect. This article reviews the
clinical data on the DAA regimens most
commonly used in the Veterans Health
Administration (VHA) system. It then
outlines a stepped approach to considering
factors such as genotype, comorbidities,
drug interactions, stage of liver disease,
and patient treatment history in selecting
a course of therapy.
Elbasvir and Grazoprevir
(EBR/GZR)
In January 2016, the US Food and Drug
Administration (FDA) approved elbasvir/
grazoprevir (EBR/GZR) with or without
ribavirin for treatment of HCV genotypes
(GT) 1 and 4 in adults.2 The oral therapy
is available as a fixed-dose combination of
50 mg EBR, an NS5A inhibitor, and 100
mg of GZR, an NS3/4A protease inhibitor.3 The FDA approval followed trials
in which study subjects received EBR/
GZR, with or without ribavirin (RBV),
once daily for 12 or 16 weeks. SVR12 rates
in patients with GT1 HCV ranged from
94% to 97%, and patients with GT4 infections had SVR12 rates of 97% to 100%.4
The ranges in efficacy reflect differences in
duration of treatment and adjunctive use
of ribavirin determined by prior treatment
history, presence or absence of resistanceassociated polymorphisms (RAPs), and
GT subtype (1a or 1b). 2 Determining
GT subtype, and testing GT1a-infected
patients for RAPs, are essential steps before
initiating treatment, because the presence
of baseline polymorphisms is a key factor
in determining duration of therapy and
whether the addition of RBV is warranted.5
In clinical trials, the most common
adverse effects of EBR/GZR when used
without ribavirin were fatigue, headache, and nausea. When the combination
therapy was administered with ribavirin,
anemia and headache were the most
frequent adverse effects.2 Drugs contraindicated with EBR/GZR include the
anticonvulsants phenytoin and carbamazepine, the immunosuppressant cyclosporine,
and several HIV therapies for human
immunodeficiency virus (HIV). 3 (See
Table 5 for more information on contraindicated drugs and drug interactions for
EBR/GZR and the other agents discussed
in this article.)
EBR/GZR can be used in patients with
renal impairment, including those receiving
dialysis, without dosage adjustment.3 In the
phase 3 C-SURFER study of the combination therapy in 224 patients with GT1
HCV and stage 4 or 5 chronic kidney
disease (CKD), with or without dialysis, a
12-week regimen of EBR/GZR resulted in
SVR rates of 100% in patients with stage 4
CKD, 93% in patients with stage 5 CKD,
and 93% in patients receiving dialysis.3,6
In an evidence-based document, Chronic
Hepatitis C Virus (HCV) Infection:
Treatment Considerations, published by the
US Department of Veterans Affairs (VA)
in September 2016, VA HCV expert panel
members identify EBR/GZR as a treatment option for the patients and clinical
scenarios outlined below (Table 1).5
Ledipasvir and Sofosbuvir
(LDV/SOF)
The fixed-dose combination of the NS5A
inhibitor ledipasvir and the HCV nucleotide analog NS5B polymerase inhibitor
sofosbuvir (LDV/SOF), taken once daily
in coformulated tablets containing 90 mg
LDV and 400 mg SOF, is indicated with
or without ribavirin for treating HCV
genotypes 1, 4, 5, and 6.7 In a study of
treatment-naïve, noncirrhotic patients
with GT1 HCV, 94% of subjects receiving
an 8-week course of LDV/SOF achieved
SVR12, as did 96% of patients receiving
a 12-week course of therapy.7,8 In another
randomized, open-label trial, 94% of
treatment-naïve, GT1-infected patients
with cirrhosis achieved SVR12 after
12 weeks of LDV/SOF, as did 99%
of noncirrhotic GT1 treatment-naïve
patients.7,9 LDV/SOF also has demonstrated efficacy in GT1 patients who have
failed prior therapy with peginterferon/
ribavirin with or without an NS3/4A
protease inhibitor, achieving SVR12 rates
of 94% and 99% following 12 weeks and
24 weeks of treatment, respectively. 7,10
Table 1. Elbasvir/Grazoprevir (EBR/GZR) ± Ribavirin (RBV): Options for Individualizing Patient Care
Treatment Regimen
HCV Genotype; Treatment History
Cirrhosis Status
EBR/GZR, 12 wk
GT1a without baseline NS5A polymorphisms; treatment-naïve or prior PEG-IFN/RBV
GT1b; treatment-naïve or prior PEG-IFN/RBV, prior NS3/4A inhibitor + PEG-IFN/RBV,
or prior SOF + RBV ± PEG-IFNa
GT4; treatment-naïve
Noncirrhotic or cirrhotic CTP A
EBR/GZR + RBV, 12 wk
GT1a without baseline NS5A polymorphisms; prior NS3/4A inhibitor + PEG-IFN/RBV,
or prior SOF + RBV ± PEG-IFNa
Noncirrhotic or cirrhotic CTP A
EBR/GZR + RBV, 16 wk
GT1a with baseline NS5A polymorphisms; treatment-naïve or prior PEG-IFN/RBV, prior NS3/4A
inhibitor + PEG-IFN/RBV, or prior SOF + RBV ± PEG-IFNa
GT4; prior PEG-IFN/RBV
Noncirrhotic or cirrhotic CTP A
CTP=Child-Turcotte-Pugh; EBR/GZR=elbasvir and grazoprevir; GT=genotype; HCV=hepatitis C virus; PEG-IFN=pegylated interferon; RBV=ribavirin; SOF=sofosbuvir.
a
EBR/GZR + RBV is not FDA approved for prior SOF + RBV ± PEG-IFN failures.
Source: US Department of Veterans Affairs. Chronic hepatitis C virus (HCV) infection: treatment considerations. http://www.hepatitis.va.gov/provider/guidelines/hcv-treatment-considerations.asp.
Revised September 22, 2016. Accessed November 3, 2016.5
Addressing the Unique Needs of Military Veterans With Chronic HCV Infection • globalacademycme.com/gastroenterology 11
Table 2. Ledipasvir/Sofosbuvir (LDV/SOF) and LDV/SOF + Ribavirin: Options for Individualizing Patient Care
Treatment Regimen
LDV/SOF, 8 wk
LDV/SOF, 12 wk
HCV Genotype; Treatment History
Cirrhosis Status
GT1; treatment-naïve with HCV RNA <6 million IU/mL, and HCV monoinfected
GT1; treatment-naive (cirrhotic or non-cirrhotic), or prior PEG-IFN/RBV (non-cirrhotic)
GT4; treatment-naïve or prior PEG-IFN/RBV
Noncirrhotic
Noncirrhotic or cirrhotic CTP A
GT1; prior PEG-IFN/RBV
Cirrhotic CTP A
GT1; prior NS3/4A inhibitor + PEG-IFN/RBV, or prior SOF + RBV ± PEG-IFNa
LDV/SOF + RBV, 12 wk
Noncirrhotic or cirrhotic CTP A
GT1; treatment-naïve or prior PEG-IFN/RBV, NS3/4A inhibitor + PEG-IFN, or prior SOF +
RBV ± PEG-IFN
Initiate at 600 mg/d, increasing by 200 mg/d every 2 weeks as tolerated
If RBV is contraindicated or cannot be tolerated, extend LDV/SOF treatment to 24 weeks
Cirrhotic CTP B, C
GT4; treatment-naïve or prior PEG-IFN/RBVa
Initiate treatment at 600 mg/d, increasing dosage as tolerated
LDV/SOF, 24 wk
GT1; treatment-naïve or prior PEG-IFN/RBV, NS3/4A inhibitor + PEG-IFN, or prior SOF +
RBV ± PEG-IFN in patients who cannot tolerate or have contraindications to RBV
Initiate at 600 mg/d, increasing by 200 mg/d every 2 weeks as tolerated
Cirrhotic CTP B, C
CTP=Child-Turcotte-Pugh; GT=genotype; HCV=hepatitis C virus; LDV/SOF=ledipasvir and sofosbuvir; PEG-IFN=pegylated interferon; RBV=ribavirin.
a
LDV/SOF + RBV is not FDA approved for prior SOF + RBV ± PEG-IFN failures. Further LDV/SOF is not approved for use with RBV in GT4 patients who are treatment-naïve or who have failed
PEG-IFN/RBV and who have CTP B, C cirrhosis.
Source: US Department of Veterans Affairs. Chronic hepatitis C virus (HCV) infection: treatment considerations. http://www.hepatitis.va.gov/provider/guidelines/hcv-treatment-considerations.asp.
Revised September 22, 2016. Accessed November 3, 2016.5
Table 3. Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir (PrOD), PrOD + Ribavirin (RBV), Paritaprevir/Ritonavir/Ombitasvir
(PrO) + RBV: Options for Individualizing Patient Care
Treatment Regimen
PrOD, 12 wk
PrOD + RBV, 12 wk
HCV Genotype; Treatment History
Cirrhosis Status
GT1b; treatment-naïve or prior PEG-IFN/RBV
Noncirrhotic or cirrhotic CTP A
GT1a; treatment-naïve or prior PEG-IFN/RBV
(consider 24 weeks of treatment for cirrhotic patients, prior null responders)
Noncirrhotic or cirrhotic CTP A
GT4; prior PEG-IFN/RBV
PrO + RBV, 12 wk
GT4; prior PEG-IFN/RBV
Noncirrhotic or cirrhotic CTP A
CTP=Child-Turcotte-Pugh; GT=genotype; HCV=hepatitis C virus; PEG-IFN=pegylated interferon; PrO=paritaprevir, ritonavir, and ombitasvir; PrOD=paritaprevir, ritonavir, ombitasvir, and dasabuvir;
RBV=ribavirin.
Source: US Department of Veterans Affairs. Chronic hepatitis C virus (HCV) infection: treatment considerations. http://www.hepatitis.va.gov/provider/guidelines/hcv-treatment-considerations.asp.
Revised September 22, 2016. Accessed November 3, 2016.5
Table 4 . Sofosbuvir/Velpatasvir (SOF/VEL) and SOF/VEL + Ribavirin: Options for Individualizing Patient Care
Treatment Regimen
SOF/VEL, 12 wk
HCV Genotype; Treatment History
GT2; treatment-naïve
Noncirrhotic or cirrhotic CTP A
GT3; treatment-naïve
Noncirrhotic
GT3; treatment-naïve without Y934 RAP or prior PEG-IFN/RBV, without Y934 RAP
GT3; prior PEG-IFN/RBV. Test for NN5A RAPs; add RBV if Y93H RAP is present
GT2; prior SOF treatment
Cirrhotic
Noncirrhotic
Noncirrhotic or cirrhotic CTP A
GT2; treatment-naïve or prior SOF + RBV ± PEG-IFN. Initiate RBV at lower dose as clinically
indicated, considering factors such as baseline hemoglobin level
GT3; treatment-naïve with Y93H RAP
SOF/VEL + RBV, 12 wk
Cirrhosis Status
GT3; treatment-naïve. Initiate RBV at lower dose as clinically indicated, considering factors such
as baseline hemoglobin levels
GT3; prior PEG-IFN/RBV with Y93H RAP or prior SOF experience
GT3; prior SOF or PEG-IFN/RBV. Initiate RBV at lower dose as clinically indicated, considering
factors such as baseline hemoglobin levels
Cirrhotic CTP B, C
Cirrhotic CTP A
Cirrhotic CTP B, C
Noncirrhotic or cirrhotic CTP A
Cirrhotic CTP B, C
CTP=Child-Turcotte-Pugh; GT=genotype; HCV=hepatitis C virus; PEG-IFN=pegylated interferon; RAP=resistance-associated polymorphism; RBV=ribavirin; SOF/VEL=sofosbuvir/velpatasvir.
Source: Epclusa (sofosbuvir and velpatasvir) tablets, for oral use [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; June 2016.18
12 globalacademycme.com/gastroenterology • Addressing the Unique Needs of Military Veterans With Chronic HCV Infection
LDV/SOF achieved SVR12 rates ≥90%
in patients infected with genotypes 4, 5,
or 6. Among patients with GT1 and GT 4
coinfected with HIV-1, LDV/SOF had an
SVR12 rate of 96% in 327 GT1 patients
and 100% in 8 GT4 patients.7,11
The 8-week course of LDV/SOF can be
valuable in treating eligible patients whose
time obligations or other obstacles to adherence could make it difficult for them to
complete a longer regimen (see Table 2).5
There is some evidence to suggest that
African Americans may not do as well with
this 8-week regimen.12 The VHA’s treatment considerations indicate that LDV/
SOF should be combined with RBV for a
12-week course in treatment-experienced
GT1 patients with CTP A cirrhosis, or any
patient who has CTP B, C cirrhosis. For
such patients who cannot tolerate RBV, a
24-week course of LDV/SOF can be used
as an alternative.5 In clinical trials, the
adverse events most frequently reported
were fatigue, headache, and nausea.7
Paritaprevir, Ritonavir,
Ombitasvir, and
Dasabuvir (PrOD)
Another coformulated combination therapy
for treating GT1 HCV consists of 200 mg
of dasabuvir (non-nucleoside NS5B palm
polymerase inhibitor), 8.33 mg of ombitasvir
(NS5A inhibitor), 50 mg of paritaprevir
(NS3/4A protease inhibitor), and 33.33 mg
of ritonavir (CYP3A inhibitor) taken as
3 tablets once daily.13 The FDA indication for the regimen, known as PrOD,
encompasses treatment of patients with
GT1b without cirrhosis or with compensated cirrhosis and—in combination with
ribavirin—treatment of GT1a HCV in
patients without cirrhosis or with compensated cirrhosis. 13 The most commonly
reported side effects of PrOD include
nausea (8%), pruritus (7%), insomnia
(5%), and asthenia (4%).13
In studies of GT1b-infected subjects
without cirrhosis, ≥99% of treatmentnaïve and treatment-experienced patients
on a 12-week regimen of PrOD achieved
SVR12.14 In addition, among 60 treatment-naïve and treatment-experienced
patients with GT1b and cirrhosis, 100%
achieved SVR12.15 Treatment-naïve and
treatment-experienced GT1a patients
without cirrhosis receiving 12 weeks of
PrOD and ribavirin achieved SVR12
rates of 96%, whereas those with cirrhosis
achieved overall SVR12 rates of 89%.16,17
Extending treatment to 24 weeks resulted
in higher SVR12 rates of 94%.
PrOD can be used in patients with renal
impairment, including those receiving
dialysis, without dosage adjustment. 13
In a study of the combination therapy in
20 patients with GT1 HCV and stage 4 or
5 CKD, with or without dialysis, a 12-week
regimen of PrOD (with RBV for GT1a
patients) resulted in SVR rates of 90%.
PrOD is contraindicated in patients
with moderate to severe hepatic impairment.13 PrOD also is contraindicated for
concomitant use with several medications
(see Table 5), necessitating a careful review
of drug interactions prior to treatment
initiation. Furthermore, ritonavir is also an
HIV-1 protease inhibitor, and it can select
for HIV-1 protease inhibitor resistance–
associated substitutions. As a result, the
prescribing information for PrOD notes
that any HCV/HIV-1–coinfected patient
treated with the regimen should also be on
a suppressive antiretroviral drug regimen.13
As a practical matter, use in patients coinfected with HIV is typically avoided due
to these resistance-related concerns and the
potential for complex drug interactions.
The VHA’s treatment considerations
document outlines scenarios for using
PrOD with or without RBV in treating
GT1 HCV.5 It also outlines options for
using PrOD with RBV and a combination
of paritaprevir, ritonavir, and ombitasvir
(PrO) with RBV in the treatment of GT4
HCV (Table 3) .5
Table 5. Noteworthy Drug Contraindications and Drug Interactions With DAA Regimens
Treatment Regimen
Drug Contraindications
Drug Interactions
Elbasvir/grazoprevir (EBR/GZR)
Atazanavir, carbamazepine, cyclosporine,
darunavir, efavirenz, lopinavir, phenytoin, rifampin,
saquinavir, St. John’s wort, and tipranavir
Atorvastatin, bosentan, etravirine, fluvastatin, ketoconazole,
modafinil, nafcillin, rosuvastatin, simvastatin, tacrolimus
Ledipasvir/sofosbuvir (LDV/SOF)7
No contraindications specific to LDV/SOF
Coadministration of LDV/SOF with amiodarone is not recommended.
Because ledipasvir solubility decreases as pH increases, commonly
used acid-reducing agents may decrease ledipasvir concentrations.
To minimize the potential for this interaction, it is recommended
to separate doses of antacids and LDV/SOF administration by
at least 4 hours. H2-receptor antagonists can be administered
either simultaneously with LDV/SOF or separated by 12 hours;
proton pump inhibitors should be administered under fasted
conditions at the same time as LDV/SOF
Paritaprevir, ritonavir, ombitasvir,
and dasabuvir (PrOD)13
Coadministration with drugs that are highly
dependent on CYP3A for clearance; moderate
or strong inducers of CYP3A or strong inducers
of CYP2C8; and strong inhibitors of CYP2C8.
Specific agents include carbamazepine, cisapride,
dronedarone, ethinyl estradiol, ranolazine,
rifampin, sildenafil, St. John’s wort, and triazolam
Amiodarone, amlodipine, candesartan, fluticasone, ketoconazole,
metformin, quetiapine, verapamil
Sofosbuvir/velpatasvir (SOF/VEL)18
No contraindications specific to SOF/VEL
Coadministration with amiodarone is not recommended.
Coadministration of proton pump inhibitors (PPIs) is not
recommended. Concomitant use of drugs that are inducers of
P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8,
or CYP3A4 is not recommended. Specific agents include
carbamazepine, phenobarbital, phenytoin, rifampin, and
St. John’s wort
3
DAA=direct-acting antiviral; LDV/SOF=ledipasvir and sofosbuvir; SOF/VEL=sofosbuvir/velpatasvir.
Sources: Zepatier (elbasvir and grazoprevir) tablets, for oral use [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc.; January 20163; Harvoni (ledipasvir and sofosbuvir) tablets, for
oral use [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; June 20167; Viekra XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir) extended-release tablets, for oral use [prescribing
information]. North Chicago, IL: AbbVie Inc.; July 201613; Epclusa (sofosbuvir and velpatasvir) tablets, for oral use [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; June 2016.18
Addressing the Unique Needs of Military Veterans With Chronic HCV Infection • globalacademycme.com/gastroenterology 13
Selecting Optimal Treatment Regimens for George M. –
A Look at 4 Scenarios
George M. is a 67-year-old Vietnam veteran recently diagnosed with the HCV genotype GT1a,
the most common subtype of the virus in the VHA system.
Based on the VHA’s recently published treatment considerations for chronic HCV infection,
therapeutic options for GT1a HCV include EBR/GZR, LDV/SOF, and PrOD, all with or without
RBV.5 To narrow these options in an evidence-based manner, let’s consider which regimens
might be preferable for the patient, based on 4 permutations in his detailed medical history.
Scenario 1: George has been treated
with an NS3/4A inhibitor + PEG-IFN/RBV
and has significant cirrhosis (CTP B).
Consider a 12-week course of LDV/SOF
+ RBV, initiating the RBV at 200 mg/d and
up-titrating every 2 weeks as tolerated.
If George cannot tolerate the RBV, extend
the LDV/SOF-only regimen to 24 weeks.
Alternatively, consider 12 weeks of a
different combination, SOF/VEL + RBV.
Scenario 3: George is treatment-naïve,
does not have HIV or hepatitis B coinfection, does not have cirrhosis, and has
an HCV RNA count <6 million IU/mL. The
patient is a candidate for one of several
regimens but may find an 8-week course of
LDV/SOF preferable because of its brevity.
With coinfection, cirrhosis, or a higher HCV
RNA count, a regimen of longer duration
would be required.
Scenario 2: George has early cirrhosis
(CTP A) and significant renal impairment,
with an estimated glomerular filtration
rate (eGFR) <30 mL/min/1.73 m2. He has
previously been treated with a PEG-IFN/
RBV regimen. EBR/GZR is an attractive
option in this scenario because it does
not require dosage adjustment in the
setting of advanced CKD. However, testing
for NS5A polymorphisms is important in
determining the duration of EBR/GZR treatment; a 12-week course is indicated if that
testing indicates no resistance, whereas
a 16-week course in combination with
RBV is warranted if resistance-associated
polymorphisms are identified at baseline
testing. PrOD could also be considered for
this patient. Conversely, if renal impairment were not an issue but there was
more-advanced liver disease, the balance
of considerations would tilt away from EBR/
GZR or PrOD toward LDV/SOF.
Scenario 4: George is HIV-positive, has
undergone prior treatment with PEG-IFN/
RBV, has CTP A cirrhosis, and takes a
proton pump inhibitor once daily. Although
PrOD is an option in this scenario, careful
review of the patient’s HIV regimen is
necessary prior to initiation to determine
if the patient is on a boosted HIV protease
inhibitor and if the dose of ritonavir used
for boosting the HIV protease inhibitor
requires adjustment. PrOD or EBR/GZR may
be advantageous for this patient, as there
is potential concern about a drug interaction between the proton pump inhibitor
and LDV/SOF. However, if the patient takes
the proton pump inhibitor once daily and
is counseled appropriately on the simultaneous administration of the proton pump
inhibitor and the LDV/SOF under fasting
conditions, this regimen may be acceptable.
Source: US Department of Veterans Affairs. Chronic hepatitis C virus (HCV) infection: treatment considerations. http://
www.hepatitis.va.gov/provider/guidelines/hcv-treatment-considerations.asp. Revised September 22, 2016. Accessed
November 3, 2016.5
SOF/VEL itself, but any contraindications to
RBV apply to its use with that combination.18
In addition to use in the patients and
clinical scenarios outlined above, the VHA
treatment considerations document identifies SOF/VEL as an alternative option
for situations in which contraindications
or tolerability issues preclude use of other
regimens. As one example, a 12-week
course of SOF/VEL may be considered
as an alternative for GT1 treatment-experienced cirrhotic patients who cannot
tolerate or have contraindications to RBV.5
Table 5 provides is a partial listing of
drugs that are contraindicated for use with
the HCV treatment regimens discussed
in this article, as well as drug interactions
with those regimens.3,7,13,18 See the full
prescribing information for each agent or
regimen for a complete listing of contraindications, drug interactions, and warnings
and precautions.
Beyond the drug contraindications listed
below, if a regimen is used in combination
with RBV, any contraindications to RBV
also apply to the combination regimen.
Alternative Options
The VHA treatment considerations
document also identifies several alternative options to the treatment approaches
outlined above. While largely beyond the
scope of this article, those alternatives
include combination therapy with daclatasvir and sofosbuvir (DCV + SOF) with
or without RBV in various patients and
circumstances, as follows5:
• DCV + SOF for 12 weeks in GT2 or
GT3, treatment-naïve, noncirrhotic
patients, and in GT3 noncirrhotic patients
previously treated with PEG-IFN/RBV
• DCV + SOF for 12-16 weeks in GT2,
treatment-naïve patients with CTP A
• DCV + SOF + RBV for 12 weeks in
GT2, noncirrhotic or CTP A patients
previously treated with sofosbuvir and
for treatment-naïve GT2 patients with
CTP B or C (this regimen is not FDAapproved for these patients)
• DCV + SOF + RBV for 12-16 weeks
in GT2 patients who have had prior
therapy with SOF + RBV ± PEG-IFN
(this regimen is not FDA-approved
for these patients); treatmentexperienced GT2 patients with CTP
B or C (this regimen also is not FDAapproved for these patients); treatmentnaïve GT3 patients with CTP A;
noncirrhotic GT3 patients previously
treated with SOF; and cirrhotic GT3
patients with CTP A previously treated
with PEG-IFN/RBV.
continued on page 19
Sofosbuvir and
Velpatasvir (SOF/VEL)
In June 2016, the FDA approved the fixeddose combination of sofosbuvir 400 mg
and velpatasvir 100 mg (SOF/VEL) for the
treatment of HCV genotypes 1-6, making
the agent the first single-tablet regimen for
all HCV genotypes (Table 4).18 The combination of sofosbuvir, an NS5B polymerase
inhibitor, and velpatasvir, an NS5A inhibitor,
is indicated for patients without cirrhosis or
with compensated cirrhosis. When used
with ribavirin, the therapy also is indicated
for patients with decompensated cirrhosis.18
In the phase 3, placebo-controlled
ASTRAL-1 trial of 740 patients with
HCV genotypes 1, 2, 4, 5, and 6, including
approximately 20% of whom had CTP
A cirrhosis, 99% of patients receiving 12
weeks of SOF/VEL achieved SVR12.19
Similarly, in the ASTRAL-3 trial of 552
patients with GT3 HCV, approximately
30% of whom had CTP A cirrhosis, 95%
of subjects receiving a 12-week course of
SOF/VEL achieved SVR12.18,20
The most common adverse events associated with SOF/VEL include headache,
fatigue, and nasopharyngitis.19 No dosage
adjustment for SOF/VEL is needed for
patients with mild, moderate, or severe
hepatic impairment (CTP A-C) or for
patients with mild or moderate renal impairment. There are no contraindications to
14 globalacademycme.com/gastroenterology • Addressing the Unique Needs of Military Veterans With Chronic HCV Infection
Chronic HCV and Its Late-Stage Complications
and Comorbidities
Hashem B. El-Serag, MD, MPH and Fasiha Kanwal, MD, MSHS
H
epatitis C virus (HCV) is one of
the most common blood-borne
infections in the world, affecting
an estimated 150 million people.1,2 In the
United States, approximately 1.3% of the
overall population and 5.4% of Veterans
Health Administration (VHA) enrollees
are infected with HCV.3
Within the VHA system, veterans
born between 1945 and 1965—the “baby
boomer” cohort—are especially vulnerable to HCV infection.1 This cohort was
likely infected during the post–World
War II period, when medical procedures
and blood transfusions did not use the
safeguards that are in place today.4 The
prevalence of chronic HCV increases
the risk for cirrhosis, liver transplant, and
hepatocellular carcinoma (HCC).1 Most
people with HCV do not experience any
symptoms and, hence, the infection may
go unnoticed for decades; some people are
diagnosed only after HCV manifests as
end-stage liver disease or cirrhosis.1
The good news is that, with the advent
of direct-acting antiviral (DAA) agents, the
possibility of curing HCV infection—and
thus reducing the risk for serious, even lifethreatening long-term complications—has
increased significantly.
(SVR), older age (patients achieving
SVR after age 64), diabetes, and infection
with HCV genotype 3.7 In untreated or
uncured patients, these same risk factors
for HCC are present, as well as male sex,
alcohol consumption, diabetes, steatosis,
coinfection with hepatitis B virus (HBV)
or human immunodeficiency virus (HIV),
and more advanced disease (portal
hypertension, aspartate aminotransferaseto-platelet ratio index [APRI] score >2).7,8
Of the veterans diagnosed with
cirrhosis in 2013, 48% had chronic HCV
infection, and >60% also had a chronic
alcohol-related diagnosis.5 Other factors
contributing to cirrhosis among veterans in
this study included alcoholic liver disease
(ALD) in 30% of patients, nonalcoholic
fatty liver disease (NAFLD) in 15%, HBV
in 2.1%, and cryptogenic cirrhosis in 2.9%.
The duration and type of HCV therapy
for patients with cirrhosis depends on
the severity of the cirrhosis and whether
patients are treatment experienced.9 Those
with mild cirrhosis (Child-Turcotte-Pugh
[CTP] score A) receive a 12-week DAA
regimen, which may include ribavirin.
Patients with more severe cirrhosis (CTP B
and C) receive 24-week DAA therapy with
specific agents to avoid adverse events.9
HCV Complications
Hepatocellular Carcinoma
patient-years (746 patients) in 2002 to
45 per 100,000 VHA patient-years
(2,532 patients) in 2012. This upswing
was associated with underlying chronic
HCV infection. The incidence of HCC
related to ALD and NAFLD increased
only slightly during that same period.
In the VHA system, the mortality rate
among patients with HCC rose from 13
per 100,000 patient-years (485 deaths)
in 2001 to 37 per 100,000 patient-years
(2,144 deaths) in 2013.5 In a recent study
by Mittal and colleagues, among the 13%
of VHA patients with HCV who did not
have cirrhosis, NAFLD and metabolic
syndrome were the common risk factors.10
There is insufficient evidence to attribute
the risk of HCC to NAFLD or provide
guidance on screening NAFLD patients
without cirrhosis. Metformin may be a
reasonable strategy for preventing HCC in
patients with nonalcoholic steatohepatitis
(NASH).10
Coinfections
One of the most serious complications of
HCV infection is HCC. As of 2013, there
were 7,670 patients with HCC in VHA
care, 68% of whom had HCV infection
and 61.3% of whom also had an alcoholrelated diagnosis.5 From 2002 to 2013, the
number of HCV-infected veterans diagnosed with HCC increased 9-fold.1
Other factors that increase the risk of
HCC within the VHA system included
NAFLD (13% of patients with both
HCV and HCC ), HBV infection (2.3%),
and cryptogenic cirrhosis (3.2%).5 The
average age of the HCC patients was
64 years; 69% were white, 25% black,
and 10% Hispanic. As was the case with
cirrhosis, 99% of HCC patients in this
study population were male, and the most
common complications were gastroesophageal varices and ascites.5
The 10-year period between 2002 and
2012 saw a significant increase in the rate
of HCC cases, from 17 per 100,000 VHA
Coinfection with HIV is a risk factor for
rapid progression of HCV infection to
hepatic fibrosis.1 There was a slight decline
in the number of veterans coinfected with
HIV, dropping from 6,184 of HCV-viremic
veterans (4.2%) in 2002 to 5,733 (3.3%) in
2013.1 The VHA, however, is not entirely
confident that it has thoroughly accounted
for the number of coinfected HIV veterans;
the cited figures could underestimate the
true number of at-risk veterans.1
The prevalence of coinfection of
HCV with HBV among patients in the
VHA rose 22% between 2002 and 2013,
involving more than 12,000 individuals. As
is the case with HIV coinfection rates, the
VHA noted that there is great variability
in HBV screening rates, so HBV may be
underdiagnosed among veterans.1
DAA therapy is more nuanced in
patients who are coinfected, mostly related
to possible drug interactions in the case of
HIV and reactivation of HBV.11 However,
SVR rates typically are comparable to those
who are HCV monoinfected. Most of the
DAA regimens involve at least 12 weeks of
treatment.9 With the availability of newer
DAA agents, clinicians need more clinical
trial data to guide treatment for the more
complicated cases of patients coinfected
with cirrhosis.
Addressing the Unique Needs of Military Veterans With Chronic HCV Infection • globalacademycme.com/gastroenterology 15
Cirrhosis
From 2002 to 2013, the number of
veterans with HCV who were diagnosed
with cirrhosis increased 138%, with more
than 29,000 veterans receiving treatment for cirrhosis during this period. 1
Decompensated cirrhosis, which involves
ascites, encephalopathy, and variceal hemorrhage, is an important clinical complication
of HCV infection.1 In a study by Beste and
colleagues, the most common cirrhosis
complication was gastroesophageal varices,
seen in approximately one-quarter of
veterans, 6% of whom experienced a variceal hemorrhage. Ascites, the second most
common complication, was reported in
17% of this patient population.5
It is estimated that at least 20% of
veterans with HCV have cirrhosis, which
increases their risk for HCC.6 Risk factors
that contribute to HCC are cirrhosis at
the time of sustained virologic response
How the Houston VHA Tracks HCV
Before the Development of HCC
The Michael E. DeBakey Veterans Affairs
Medical Center (MEDVAMC) in Houston,
Texas, has a mandate to identify in its electronic database those veterans with any
liver disease. With increased congressional
funding for HCV, and given the fact that
the pharmaceutical industry has significantly discounted its prices for DAAs, the
VHA’s imperative is to find veterans with
liver disease and treat them before HCV
complications develop, including HCC and
the need for liver transplantation.36 One
key strategy is to send affected veterans
and their primary care clinicians letters
emphasizing the importance of followup for liver diseases. Using the electronic
database and care coordination, Houston
liver clinics have reached out to more than
1,000 patients with known HCV infection
who were previously unlinked with liver
care. The clinics’ strategy: After 2 phone
calls, they follow up with a letter encouraging patients to seek treatment.
HCV is the country’s number one fatal
infectious disease, involving 19,659
deaths annually—more deaths than HIV,
pneumococcal disease, and tuberculosis
combined.4 Since spring of 2016, the VHA
has been treating an estimated 1,100
veterans weekly, and it hopes to have
doubled that figure by the end of 2016.36
Other Liver Conditions
Although NAFLD is not a major contributor to HCC and cirrhosis, it is becoming
more common due to an increased incidence of obesity and diabetes.5 However,
there are no clear estimates of prevalence
or incidence of NAFLD in the VA.12
Veterans with NAFLD tend to be older (an
average of 59.6 vs 61.2 years for cirrhosis;
60.9 vs 63.1 years for HCC), more obese,
and more likely to have diabetes, and less
likely to have a history of substance abuse
compared to patients with HCV, alcoholic
cirrhosis, or HCC.5
NASH, unlike simple steatosis, is associated with a higher risk of cirrhosis,
progressive fibrosis, liver transplant, and
HCC.13 NASH is diagnosed histologically
with evidence for hepatocyte damage and
fibrosis. NASH is seen in 30% to 60% of
individuals with NAFLD who undergo
biopsy for liver disease.14 Patients with
NASH tend to have a higher prevalence
of obesity, diabetes, hyperlipidemia, and
metabolic syndrome than patients with
NAFLD.13
16 Recognizing that not all VHA system
facilities are equally equipped, the larger
facilities are providing HCV consultations
and education via videoconferencing to
clinicians in remote areas through its
Specialty Care Access Network–Extension
for Community Healthcare Outcomes
(SCAN-ECHO).36 Under such an educational
system, clinicians can share their experiences with patients and learn from experts.
One report found that the median time from
diagnosis to treatment was 6 months for
patients seen by clinicians who had undergone SCAN-ECHO training, compared with
2 years for patients seen by clinicians who
did not receive SCAN-ECHO training.36
As the nation’s largest system for
managing patients with HCV, the VHA has a
key advantage over other health networks:
the availability of large and sophisticated
electronic health records, automated databases, as well as critical ancillary services
such as mental health, addiction rehabilitation, and pharmacy under one roof. Since
1999, approximately 57,500 patients in the
VHA have been cured of HCV, and almost
half (28,084) of those veterans were
cured in 2015 after the advent of effective
interferon-free DAA regimens.37 With its
integrated system, the VHA estimates that
it has the ability to cure all veterans with
HCV within 3 years.37
Managing weight and metabolic disorders is crucial for patients with
NAFLD and NASH. Clinicians need to
check for metabolic syndrome, including
insulin resistance, and hepatic steatosis,
which could worsen hypertension and
dyslipidemia.15
Substance Abuse
Alcohol abuse is the second most common
substance use disorder (after tobacco use)
among veterans with HCV; more than
half (55%) of HCV-viremic veterans in
VHA care have a history of alcohol abuse.1
In HCV-viremic individuals, alcohol can
hasten the progression of liver disease.16
Problematic alcohol use—defined as
>4 drinks per day for men or >3 drinks per
day for women—can also contribute to
treatment nonadherence. Even so, there is
evidence that starting therapy with DAA
agents early is preferable to withholding
treatment (and thus allowing HCV infection to progress while efforts are made to
curtail alcohol use).8,17
Substance abuse involving illicit drugs
should not be an automatic exclusion from
HCV therapy, although the VHA urges
providers to partner closely with other
clinicians providing substance abuse care
to ensure that the patient will adhere to
therapy.9 There are no published randomized controlled trials on the efficacy of
concomitant treatment for substance abuse
and HCV, but effectiveness studies suggest
similar SVR rates.9,18
Psychiatric Disorders
Comorbid mental health conditions
can make HCV treatment more complicated for HCV-infected veterans. In the
interferon era, the presence of major uncontrolled depressive disorder was considered
to be an absolute contraindication for HCV
treatment.19 In cases involving patients who
had certain mental disorders, clinicians
were reluctant to treat HCV, citing concern
about the patients’ ability to remain
adherent to treatment. Due to improved
screening for HCV, there was a 19% increase
in the number of HCV-infected veterans
in VHA care from 2002 to 2013.1 This in
turn led to a disproportionate increase in
the percentage of HCV-infected veterans
with comorbid mental health diagnoses,
the most common being posttraumatic
stress disorder (PTSD), depression, bipolar
disorder, and anxiety disorder. 1 Most
patients with these disorders can now be
safely treated with interferon-free DAA
combinations. The decision to treat a
veteran with severe mental illness should be
based on a consultation with the patient’s
mental health provider.9
Extrahepatic Manifestations
Most of the complications of chronic HCV
are confined to the liver. However, there
have been associations with numerous
extrahepatic manifestations (EHMs)—
from aplastic anemia to uveitis—most of
which are correlated with autoimmune
disorders.20 The hypotheses surrounding
HCV’s contribution to diseases beyond the
liver include the immune system’s inability
to eliminate accumulating chronic infections and the production of monoclonal
rheumatoid factors, which causes mixed
cryoglobulinemia, one of the most common
EHMs.20 Mixed cryoglobulinemia, a form
of systemic vasculitis, produces skin, renal,
and neurologic symptoms.21
Renal Insufficiency
HCV infection is highly prevalent among
patients with end-stage renal disease
(ESRD) and is a serious cause of increased
morbidity and mortality in this group.22
globalacademycme.com/gastroenterology • Addressing the Unique Needs of Military Veterans With Chronic HCV Infection
The risk of HCV is several-fold higher in
patients undergoing dialysis compared to
nonuremic patients.23 Conversely, renal
status needs to be evaluated in patients
undergoing HCV therapy. Treatment
recommendations from the VHA provide
guidance on modifying drug use in patients
with renal insufficiency (see Table).9
Clinicians need to screen veterans for
HCV infection, particularly in the baby
boomer cohort and those with additional risk factors. As these veterans age,
managing their comorbidities such as
diabetes, obesity, renal insufficiency, or
coinfections with HIV or HBV will be
critical in preventing serious complications
of HCV that may lead to liver transplant or
HCC. Now that more patients are eligible
to receive HCV treatment with DAAs,
clinicians are encouraged to form interdisciplinary teams to better manage the
patient’s HCV and any comorbidities.
Successful HCV
Treatment Mitigates
Complications
Before the advent of DAAs, the mainstays
of HCV therapy were pegylated interferon
and ribavirin.24 When both agents were
combined, the rate of SVR was approximately 50%, compared to 17% SVR with
interferon alone.24 However, as shown in a
2005 study of 4,084 veterans with chronic
HCV infection, less than one-third were
considered eligible for treatment with
an interferon-based regimen.25 The most
common reasons for treatment exclusion
included ongoing or recent substance abuse
(20.2%), active psychiatric disease (18.3%),
and comorbid medical disease (17.9%).
(Such medical disorders as advanced liver
disease [5.6%], anemia [7.6%], neutropenia [2.3%], or thrombocytopenia [5.5%]
did not serve as barriers to treatment.25)
Among individuals who did receive treatment, fewer than 10% achieved SVR.24
Fortunately, treatment eligibility criteria
have expanded. And clinicians now speak
of “cure” with the new DAAs, which
confer an SVR in >90% of patients, many
of whom need only 12 weeks of treatment.9
Given the increased efficacy of newly available agents, the VHA system has a mandate
to screen and cure as many HCV-infected
veterans as possible to reduce the risk of
cirrhosis, HCC, liver failure, and liverrelated death, as well as all-cause mortality.
There is evidence that treating all patients,
including those with cirrhosis and other
comorbidities, results in better outcomes.9
Veterans are eligible for treatment if they
want to be treated; no longer are substance
abuse issues or psychiatric conditions automatic exclusions for HCV therapy.9
SVR confers benefits beyond liverrelated mortality and morbidity reduction.
It also improves quality of life and possibly
decreases the risk for extrahepatic manifestations such as renal, dermatologic, and
metabolic complications.8
Patients who achieve SVR have a lower
risk of either overall mortality or liverrelated mortality compared with untreated
HCV-infected patients and patients—
even those with HIV coinfection and
cirrhosis—who fail to achieve SVR with
treatment. In a meta-analysis of 31 studies
involving 33,360 HCV-infected patients
(including 2,604 with cirrhosis and 2,358
with HIV coinfection), SVR reduced
all-cause mortality by approximately
50%, 74%, and 79% compared with not
achieving an SVR in the general, cirrhotic,
and coinfected populations, respectively.26
In SVR nonresponders, the mortality rate
more than tripled across all 3 groups during
the 5-year follow-up period.26
Even among patients with advanced
fibrosis, SVR reduced the risk of liverrelated mortality or transplantation by
94% (hazard ratio [HR], 0.06; 95% confidence interval [CI], 0.02-0.19; P<0.001).
After 10 years, the benefit remained: The
cumulative incidence rate of liver-related
mortality or transplantation was 1.9%
among those with SVR and 27.4% among
those without SVR (P<0.001).27
Left untreated, patients with HCVassociated cirrhosis have a 3% to 5% per
year cumulative incidence of hepatocellular carcinoma. 8 Patients who achieve
SVR with interferon-based therapy have
a long-term HCC risk reduction of 75%.8
In a study of more than 10,000 veterans
who were treated with interferon and
achieved SVR, the overall incidence rate
for HCC was 0.33% per year, which
remained constant for approximately
5 years post SVR.7
When interferon was the mainstay of
HCV therapy, careful patient selection was
essential. Adverse events with interferon
and ribavirin limited the patients who
received—and completed—treatment.
Furthermore, earlier studies excluded
individuals at high risk for reinfection,
such as injection drug users. 8 Narrow
patient selection in earlier SVR trials
may have given the impression that only
interferon had long-term durable efficacy.
First-generation DAAs were not as effective in achieving SVR as was hoped, due
primarily to a low barrier of resistance
and drug interactions.28 Now that more
patients are eligible for treatment, recent
SVR trials may provide conflicting results
with a more heterogeneous patient population than previous SVR trials that included
interferon therapy.
Despite the promise of more patients
achieving SVR and the likelihood of
long-term benefits with the new DAAs,
Table. Modification of Drug Use in Patients With Renal Insufficiency
Treatment
Comment
Grade of Evidence
Dasabuvir
No dosage adjustment needed.
A-I
Elbasvir/grazoprevir
No dosage adjustment needed, including use in hemodialysis patients.
A-I
Ledipasvir
No dosage adjustment needed.
A-I
Paritaprevir/ritonavir/ombitasvir + dasabuvir
No dosage adjustment needed.
A-II
Ribavirin
200 mg daily alternating with 400 mg daily for CrCl 30-50 mL/min
and 200 mg daily for CrCl <30 mL/min, including hemodialysis.
A-I
Simeprevir
Has not been studied in HCV-infected patients with CrCl <30 mL/min.
A-I
Sofosbuvir
Should not be used if CrCl <30 mL/min or ESRD.
A-I
Velpatasvir
No dosage adjustment needed.
A-I
CrCl=creatinine clearance; ESRD=end-stage renal disease; HCV=hepatitis C virus.
Source: US Department of Veterans Affairs. Chronic hepatitis C virus (HCV) infection: treatment considerations. http://www.hepatitis.va.gov/provider/guidelines/hcv-treatment-considerations.asp.
Revised September 22, 2016. Accessed November 11, 2016.9
Addressing the Unique Needs of Military Veterans With Chronic HCV Infection • globalacademycme.com/gastroenterology 17
Even after SVR, regular surveillance is
warranted, as data on the durable longterm effects of DAA therapy emerge. As
the highest-risk cohort ages, comorbidities
and complications will increase, necessitating the use of interdisciplinary teams to
manage the care of veterans with HCV.
At 12 weeks after the end of treatment,
a patient’s HCV RNA levels should be
assessed to determine whether SVR was
achieved.9 It is optional to test HCV RNA
levels again at 24 weeks posttreatment
because 12- and 24-week SVRs are deemed
to be clinically equivalent.9
As the leader of HCV infection care in
the United States, the VHA has stepped
up its efforts to screen for HCC in the
veterans most at risk; by 2013, 65% of
the baby boomer cohort had been tested.
Overall, the VHA has doubled the proportion of screened veterans, from 26.9% in
2002 to 56.0% by 2013.1
Such an aggressive approach to HCC
screening was not always a mandate
within the VHA. Despite the poor HCC
survival rate (overall 5-year survival is
<10%), veterans—even those who have
cirrhosis—have not always received the
requisite surveillance.32,33 Those who do
receive a liver transplant, surgical resection, or tumor ablation for small lesions
have a 5-year survival rate of up to 70%.32
In a study of 126,670 patients with HCV
in the VHA system, only 42% of patients
with cirrhosis had received an HCC
surveillance test within the first year after
their cirrhosis diagnosis.33
Where patients are diagnosed with HCC
also has an impact on their likelihood of
receiving HCC treatment. Veterans who
were diagnosed with HCC during hospitalization were more likely to be linked to
HCC therapy compared with those who
were diagnosed as outpatients, indicating
that the VHA could provide more timely
and seamless referrals to specialty care.32
Proper vigilance for HCC starts before
HCV therapy. We recommend that
patients with HCV preferably undergo
cross-sectional imaging (computed
tomo g raphy, ma g netic resonance
imaging) but at least liver ultrasound as
well as serum α-fetoprotein (AFP) before
starting treatment.9
Subsequent monitoring for patients
with advanced fibrosis (F3-F4) is based
on liver ultrasound imaging at 6-month
intervals combined with biomarker AFP
testing. The recommendations for HCC
diagnosis include dedicated cross-sectional
liver imaging and/or biopsy.34
The preferred noninvasive methods to
monitor liver fibrosis progression, which
may determine the risk and hence need
for continued HCC surveillance, include
vibration-controlled transient elastography (FibroScan® ) and acoustic radiation
force impulse (ARFI) imaging.9 There are,
however, some caveats with imaging: the
findings might differ by population and
body weight, and not every VHA facility
offers these imaging studies.9
In patients who do not have cirrhosis
but who have NAFLD, there is scant guidance on surveillance and prevention of
HCC.35 Given the relationship of diabetes
and obesity with HCC, treatment that
targets these metabolic conditions, such as
metformin in patients with diabetes, may
also reduce the risk for HCC.35
Routine blood tests can predict the
likelihood of developing decompensated
disease or HCC. Fibrosis progression
can be detected with serum markers such
as APRI and Fibrosis-4 (FIB-4).9 Other
noninvasive tests to identify cirrhotic
patients with more advanced disease
include a platelet count of <140,000/
mm3 to 150,000/mm3. If patients have
other conditions that may affect platelet
count such as HIV or idiopathic thrombocytopenia, this test should not be used.
Patients with platelet counts of <100,000/
mm3 have an even greater risk of developing HCC.9
HCV treatment guidelines recommend
that patients with advanced fibrosis (F3 or
F4) receive ongoing follow-up because they
are at risk for liver-related complications
such as HCC and liver decompensation.8 In patients with intermediate-stage
18 globalacademycme.com/gastroenterology • Addressing the Unique Needs of Military Veterans With Chronic HCV Infection
2 European retrospective cohort studies
suggested that HCC may appear or recur
more readily in patients treated with
interferon-free regimens. In patients with
cirrhosis who were treated with curative
(ablation and resection) and palliative
(transcatheter arterial chemoembolization)
treatment and then received DAA therapy,
the HCC recurrence rates were 28% after a
median of 3.5 months post-DAA therapy in
Spain29 and 29% at 6 months after SVR in
Italy.30 Recent preliminary evidence suggests
that de novo HCC may be more common
in HCV patients treated with DAAs.31 In a
study of 2,279 patients with advanced liver
disease and HCV, the HCC incidence was
2.1 per 100 patient-years in a median followup of 224.9 days from DAA treatment
initiation. The most predictive baseline risk
factor for HCC was APRI, which showed a
10% increase for each APRI point.31 These
data need to be confirmed and should not
be used to justify withholding HCV treatment for the time being.
Follow-Up After SVR
fibrosis (F2), hepatologists should be sure
that there is no fibrosis progression before
discharging them to their primary care
clinician. Patients whose fibrosis is mild
(F0 or F1) can receive ongoing follow-up
care outside a hepatology practice as long
as they do not have any liver-associated
complications.8
Patients with cirrhosis who achieve SVR
still need to be monitored for liver-related
complications, including HCC. Post-SVR,
factors that potentially affect progression
of cirrhosis include the severity of persistent portal hypertension, age of the patient
(>65 years), and the presence or development of diabetes.8
Conclusion
HCV management is an interdisciplinary effort. Routine screening for the
virus and linkage to care are essential if
all HCV-infected veterans are to receive
treatment. Once patients achieve SVR,
they still need to be monitored long-term
for liver-related complications, especially if
they already have cirrhosis. Because DAA
therapy is still in its relative infancy, clinicians need longer-term data to guide actual
practice in the years after SVR is achieved.
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for veterans with hepatitis C 2014. www.hepatitis.
va.gov/pdf/HCV-State-of-Care-2014.pdf. Published
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2. World Health Organization. Hepatitis C fact sheet.
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3. Dominitz JA, Boyko EJ, Koepsell TD, et al. Elevated
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5. Beste LA, Leipertz SL, Green PK, Dominitz JA,
Ross D, Ioannou GN. Trends in burden of cirrhosis
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6. Kanwal F, Hoang T, Kramer JR, et al. Increasing
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7. El-Serag HB, Kanwal F, Richardson P, Kramer J. Risk
of hepatocellular carcinoma after sustained virological
response in veterans with hepatitis C virus infection.
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8. Terrault NA, Hassanein TI. Management of the patient
with SVR. J Hepatol. 2016;65(1 suppl):S120-S129.
9. US Department of Veterans Affairs. Chronic hepatitis
C virus (HCV) infection: treatment considerations.
http://www.hepatitis.va.gov/provider/guidelines/hcvtreatment-considerations.asp. Revised September 22,
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10. Mittal S, El-Serag HB, Sada YH, et al. Hepatocellular
carcinoma in the absence of cirrhosis in United States
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Clin Gastroenterol Hepatol. 2016;14(1):124-131.e1.
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13. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y,
Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment
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14. Williams CD, Stengel J, Asike MI, et al. Prevalence
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15. Wong RJ, Gish RG. Metabolic manifestations
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17. National Institute on Alcohol Abuse and Alcoholism.
What’s “at-risk” or “heavy” drinking? https://www.
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18. Ho SB, Monto A, Peyton A, et al; VALOR study team.
Efficacy of sofosbuvir plus ribavirin in veterans with
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23. Selcuk H, Kanbay M, Korkmaz M, et al. Distribution of
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24. North CS, Hong BA, Adewuyi SA, et al. Hepatitis C
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25. Bini EJ, Bräu N, Currie S, et al. Prospective multicenter
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veterans with chronic hepatitis C virus infection. Am J
Gastroenterol. 2005;100(8):1772-1779.
26. Simmons B, Saleem J, Heath K, Cooke GS, Hill A.
Long-term treatment outcomes of patients infected
with hepatitis C virus: a systematic review and
meta-analysis of the survival benefit of achieving
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2016;65(1 suppl):S130-S142.
Assessing the Characteristics of HCV Treatment Regimens
to Individualize Therapy to Optimal Effect
• Finally, 12-24 weeks of DCV + SOF +
RBV is cited as an alternative option for
GT3 patients with CTP A cirrhosis who
were previously treated with SOF therapy,
and in GT3 treatment-naïve or experienced patients with CTP B or C cirrhosis
and access to transportation needed for
keeping clinic appointments. Cognitive,
substance abuse, and psychiatric issues
should be addressed to the greatest extent
possible before treatment initiation and
are also important factors to consider in
terms of the pill burden and duration of
various regimens.
By being conversant with the data on
available regimens and considering the
6 factors cited above in considering each
patient’s case, clinicians can streamline
decision making in a way that individualizes treatment for optimal effect.
29. Reig M, Mariño Z, Perelló C, et al. Unexpected high rate
of early tumor recurrence in patients with HCV-related
HCC undergoing interferon-free therapy. J Hepatol.
2016;65(4):719-726.
30. Conti F, Buonfiglioli F, Scuteri A, et al. Early occurrence and recurrence of hepatocellular carcinoma in
HCV-related cirrhosis treated with direct acting antivirals. J Hepatol. 2016;65(4):727-733.
31. Romano A, Capra F, Piovesan S, et al. Incidence and
pattern of “de novo” hepatocellular carcinoma in
HCV patients treated with oral DAAs. Hepatology.
2016;64(1)(suppl):10a. Abstract 19.
32. Davila JA, Kramer JR, Duan Z, et al. Referral and
receipt of treatment for hepatocellular carcinoma in
United States veterans: effect of patient and nonpatient
factors. Hepatology. 2013;57(5):1858-1868.
33. Davila JA, Henderson L, Kramer JR, et al. Utilization of
surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States. Ann
Intern Med. 2011;154(2):85-93.
34. Bruix J, Reig M, Sherman M. Evidence-based diagnosis,
staging, and treatment of patients with hepatocellular
carcinoma. Gastroenterology. 2016;150(4):835-853.
35. Mittal S, Sada YH, El-Serag HB, et al. Temporal trends
of nonalcoholic fatty liver disease–related hepatocellular carcinoma in the Veteran Affairs population. Clin
Gastroenterol Hepatol. 2015;13(3):594-601.e1.
36. Graham J. VA extends new hepatitis C drugs to all veterans
in its health system. JAMA. 2016;316(9):913-915.
37. Moon AM, Green P, Berry K, Ioannou GN. Towards
eradication of hepatitis C virus infection in the Veterans
Affairs national healthcare system: a study of 107,079
antiviral treatment regimens administered from 19992015. Hepatology. 2016;64(1)(suppl):120a. Abstract 227.
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1. Maier MM, Ross DB, Chartier M, Belperio PS, Backus
LI. Cascade of care for hepatitis C virus infection within
the US Veterans Health Administration. Am J Public
Health. 2016;106(2):353-358.
2. US Food and Drug Administration. FDA approves
Zepatier for treatment of chronic hepatitis C genotypes
1 and 4. http://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm483828.htm. Published
January 28, 2016. Accessed November 7, 2016.
3. Zepatier (elbasvir and grazoprevir) tablets, for oral use
[prescribing information]. Whitehouse Station, NJ:
Merck & Co., Inc.; January 2016.
4. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevirelbasvir combination therapy for treatment-naive
cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized
trial. Ann Intern Med. 2015;163(1):1-13.
5. US Department of Veterans Affairs. Chronic hepatitis
C virus (HCV) infection: treatment considerations.
http://www.hepatitis.va.gov/provider/guidelines/hcvtreatment-considerations.asp. Revised September 22,
2016. Accessed November 3, 2016.
6. Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir
plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1
infection and stage 4-5 chronic kidney disease (the
C-SURFER study): a combination phase 3 study.
Lancet. 2015;386(10003):1537-1545.
7. Harvoni (ledipasvir and sofosbuvir) tablets, for oral
use [prescribing information]. Foster City, CA: Gilead
Sciences, Inc.; June 2016.
8. Kowdley KV, Gordon SC, Reddy KR, et al; ION-3
Investigators. Ledipasvir and sofosbuvir for 8 or 12
weeks for chronic HCV without cirrhosis. N Engl J
Med. 2014;370(20):1879-1888.
9. Afdhal N, Zeuzem S, Kwo P, et al; ION-1 Investigators.
Ledipasvir and sofosbuvir for untreated HCV genotype
1 infection. N Engl J Med. 2014;370(20):1889-1898.
10. Afdhal N, Reddy KR, Nelson DR, et al; ION-2
Investigators. Ledipasvir and sofosbuvir for previously
treated HCV genotype 1 infection. N Engl J Med.
2014;370(16):1483-1493.
11. Naggie S, Cooper C, Saag M, et al; ION-4
Investigators. Ledipasvir and sofosbuvir for HCV
in patients co-infected with HIV-1. N Engl J Med.
2015;373(8):705-713.
12. Backus LI, Belperio PS, Shahoumian TA, Loomis TP,
Mole LA. Real-world effectiveness of ledipasvir/sofosbuvir in 4,365 treatment-naive, genotype 1 hepatitis
C-infected patients. Hepatology. 2016;64(2):405-414.
13. Viekra XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir) extended-release tablets, for oral use [prescribing
information]. North Chicago, IL: AbbVie Inc.; July 2016.
14. Ferenci P, Bernstein D, Lalezari J, et al; PEARL-III
Study; PEARL-IV Study. ABT-450/r-ombitasvir and
dasabuvir with or without ribavirin for HCV. N Engl J
Med. 2014;370(21):1983-1992.
15. Feld JJ, Moreno C, Trinh R, et al. Sustained virologic
response of 100% in HCV genotype 1b patients with
cirrhosis receiving ombitasvir/paritaprevir/r and
dasabuvir for 12 weeks. J Hepatol. 2016;64(2):301-307.
16. Feld JJ, Kowdley KV, Coakley E, et al. Treatment for
HCV with ABT-450/r-ombitasvir and dasabuvir with
ribavirin. N Engl J Med. 2014;370(17):1594-1603.
17. Poordad F, Hezode C, Trinh R, et al. ABT-450/rombitasvir and dasabuvir with ribavirin for hepatitis C
with cirrhosis. N Engl J Med. 2014;370(21):1973-1982.
18. Epclusa (sofosbuvir and velpatasvir) tablets, for oral
use [prescribing information]. Foster City, CA: Gilead
Sciences, Inc.; June 2016.
19. Feld JJ, Jacobson IM, Hézode C, et al; ASTRAL-1
Investigators. Sofosbuvir and velpatasvir for HCV
genotype 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015;373(27):2599-2607.
20. Foster GR, Afdhal N, Roberts SK, et al; ASTRAL-2
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Addressing the Unique Needs of Military Veterans With Chronic HCV Infection • globalacademycme.com/gastroenterology 19
A Stepped Approach
to Individualizing
Treatment
The various treatment combinations,
permutations, and durations available to
the clinician treating chronic HCV infection constitute a dazzling, and potentially
dizzying, array of options. In narrowing
the choices to best address the individual
patient’s needs, it is helpful to begin with
consideration of 6 core factors that collectively go far toward narrowing treatment
options and determining which may be
preferable for a given patient:
•Genotype
• Treatment history
• Stage of liver disease
•Comorbidities
• Concomitant medications,
contraindications, and potential
for drug interactions
• Potential for resistance
Additionally, practical issues related
to the patient’s willingness and ability to
adhere to a treatment regimen need to be
weighed and warrant attention to such
basic considerations as work obligations
References
Addressing the Unique Needs of Military Veterans With Chronic HCV Infection Post-Test and Evaluation Form
Original Release Date: February 1, 2017 • Expiration Date: February 1, 2018 • Estimated Time to Complete Activity: 1.5 hours
FOR REVIEW PURPOSES ONLY.
MUST BE COMPLETED ONLINE.
To get instant CME/CE credits online, go to http://tinyurl.com/HCVA17. Upon successful completion of the online test and
evaluation form, you will be directed to a Web page that will allow you to receive your certificate of credit via e-mail.
If you have any questions or difficulties, please contact: Global Academy for Medical Education at [email protected] or (973) 290-8225.
POST-TEST CME/CE QUESTIONS
1. The most common reason for hepatitis C virus (HCV)-infected patients in
Veterans Health Administration (VHA) care to be admitted to the hospital is:
A.Advanced liver disease
B.Diabetes and its complications
C.Psychiatric conditions
D.End-stage renal disease
2. Which of the following statements is best supported by the evidence?
A.The prevalence of chronic HCV infection among patients in VHA care is
expected to increase in the next 15 years.
B.The prevalence of advanced liver disease is increasing among HCV-infected
patients in VHA care.
C.The average age of HCV-infected patients in VHA care is expected to decline
over the next decade.
D.The proportion of treated VHA patients achieving sustained virologic response
(SVR) each year is expected to increase steadily over the next decade.
3. Nonphysician providers (NPPs) such as nurse practitioners, physician
assistants, and pharmacists treating HCV-infected patients in the VHA
have achieved SVR rates comparable to those of physicians.
A.True
B.False
4. Necessary pretreatment assessments of VHA patients seeking treatment
for chronic HCV infection include all of the following EXCEPT:
A.Hemoglobin, hematocrit, WBC with differential, and platelet count
B.Human immunodeficiency virus (HIV) serology
C.Biochemical markers of liver injury and assessment of hepatic function
D.Confirmation that the patient is not using alcohol
5. Based on approaches outlined in the VHA 2016 Treatment Considerations,
the presence of baseline resistance-associated polymorphisms (RAPs) in
a treatment-naïve patient with GT1a chronic HCV infection:
A.Precludes use of elbasvir/grazoprevir (EBR/GZR)
B.Has no impact on the standard 12-week course of EBR/GZR for such patients
C.Warrants the addition of ribavirin (RBV) to a 12-week course of EBR/GZR
D.Warrants adding RBV to EBR/GZR and extending treatment from 12 to 16 weeks
6. Which of the following HCV treatment regimens should be accompanied
by a suppressive antiretroviral drug regimen when administered to a
patient coinfected with HIV-1?
A.Elbasvir/grazoprevir (EBR/GZR)
B.Ledipasvir and sofosbuvir (LDV/SOF)
C.Paritaprevir, ritonavir, ombitasvir, and dasabuvir (PrOD)
D.Sofosbuvir and velpatasvir (SOF/VEL)
7. Which risk factor contributes to hepatocellular carcinoma in patients with
chronic HCV infection?
A.Genotype 1b
B.Genotype 4
C.Hypertension
D.Cirrhosis
8. Which veterans are eligible to receive HCV treatment?
A.Those who want to be treated
B.Those with liver failure
C.Those with decompensated cirrhosis
D.Those with comorbid end-stage renal disease and hepatocellular carcinoma
EVALUATION FORM
To assist us in evaluating the effectiveness of this activity and to make recommendations for future educational offerings, please take a few moments to complete this
evaluation form. Your response will help ensure that future programs are informative and meet the educational needs of all participants. CME/CE credit letters and long-term
credit retention information will only be issued upon completion of the post-test and evaluation online at: http://tinyurl.com/HCVA17.
If you do not feel confident that you can achieve the above objectives to some
extent, please describe why not.
___________________________________________________________________
Please indicate your profession/background:
MD/DO MSN/BSN/RN PA APN/NP PharmD/RPh Student
Resident/Fellow Researcher Administrator Other; specify ________________
LEARNING OBJECTIVES
Having completed this activity,
you are better able to:
Recognize the special characteristics of the
patient population with chronic hepatitis C
virus (HCV) infection whose care is managed
within the US Veterans Health Administration
(VHA), including risk factors and medical and
psychiatric comorbidities
Identify opportunities for improving HCV
screening, diagnosis, and testing among the
veteran population
Develop comprehensive individualized
management strategies for patients with
chronic HCV infection
Compare and contrast risks and benefits of
currently available drug regimens for treating
chronic HCV infection
Describe practical approaches for improving
the continuum of care for veterans with
chronic HCV infection
Strongly
Agree
5
5
Agree
4
4
Somewhat
Strongly
Agree Disagree Disagree
3
3
2
2
1
1
5
4
3
2
1
5
4
3
2
1
5
4
3
2
1
Based on the content of this activity, what will you do differently in the care of
your patients/regarding your professional responsibilities? (check one)
Implement a change in my practice/workplace.
Seek additional information on this topic.
Do nothing differently. Current practice/job responsibilities reflect activity recommendations.
Do nothing differently as the content was not convincing.
Do nothing differently. System barriers prevent me from changing my practice/workplace.
If you anticipate changing one or more aspects of your practice/professional
responsibilities as a result of your participation in this activity, please briefly
describe how you plan to do so.
___________________________________________________________________
If you plan to change your practice/workplace, may we contact you in
2 months to see how you are progressing?
Yes. E-mail address: __________________________________________
No. I don’t plan to make a change.
If you are not able to effectively implement what you learned in this activity, please
tell us what the system barriers are (eg, institutional systems, lack of resources, etc).
___________________________________________________________________
OVERALL EVALUATION
The information presented increased my
awareness/understanding of the subject.
The information presented will influence how
I practice/do my job.
The information presented will help me
improve patient care/my job performance.
The program was educationally sound and
scientifically balanced.
Overall, the program met my expectations.
I would recommend this program to my
colleagues.
Pamela S. Belperio, PharmD, BCPS
-Demonstrated current knowledge of the topic.
-Was organized in the written materials.
Hashem B. El-Serag, MD, MPH, et al
-Demonstrated current knowledge of the topic.
-Was organized in the written materials.
Alexander Monto, MD
-Demonstrated current knowledge of the topic.
-Was organized in the written materials.
David B. Ross, MD, PhD, MBI, et al
-Demonstrated current knowledge of the topic.
-Was organized in the written materials.
Strongly
Agree
Agree
Somewhat
Strongly
Agree Disagree Disagree
5
4
3
2
1
5
4
3
2
1
5
4
3
2
1
5
4
3
2
1
5
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2
1
5
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3
2
1
5
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3
2
2
1
1
5
5
4
4
3
3
2
2
1
1
5
5
4
4
3
3
2
2
1
1
5
5
4
4
3
3
2
2
1
1
What topics do you want to hear more about, and what issue(s) regarding your
practice/professional responsibilities will they address?
___________________________________________________________________
Please provide additional comments pertaining to this activity and any
suggestions for improvement.
___________________________________________________________________
The Global Education Group thanks you for your participation in this CME/CE activity. All information provided improves the scope and purpose of our programs and your patient care. © 2017 Global Academy for Medical Education, LLC. All Rights Reserved.