Treatment of Chronic Hepatitis C Virus Infection: Some Remaining Obstacles in the United States
Liver International
Accepted Articles, Accepted manuscript online: 13 JAN 2014
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Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)
Review Article
Gloria Searson
1, Ellen S. Engelson
2, Damaris Carriero
1,3, Donald P. Kotler
1,2,*
DOI: 10.1111/liv.12467
This article is protected by copyright. All rights reserved.
Publication History
Accepted manuscript online: 13 JAN 2014 01:05AM EST
Manuscript Accepted: 6 JAN 2014
Manuscript Revised: 25 DEC 2013
Manuscript Received: 27 JUN 2013
Keywords: effectiveness research; health disparities; substance abuse; alcoholism; chronic liver disease
Abstract
Hepatitis C infection is an important problem in inner city neighborhoods, which suffer from multiple health disparities. Important factors in this population include alcoholism and substance abuse, mental illness, and homelessness, which may be combined with mistrust, poor health literacy, limited access to health care, and outright discrimination. Systemic barriers to effective care include a lack of capacity to provide comprehensive care, insufficient insurance coverage, poor coordination among caregivers and between caregivers and hospitals, as well as third party payers. These barriers affect real world treatment effectiveness as opposed to treatment efficacy, the latter reflecting the world of clinical trials. The components of effectiveness include efficacious medications, appropriate diagnosis and evaluation, recommendation for therapy, access to therapy, acceptance of the diagnosis and its implications by the patient and adherence to the recommended therapy. Very little attention has been given to assisting the patient to accept the diagnosis and adhere to therapy, i.e., care coordination. For this reason, care coordination is an area in which greater availability could lead to greater acceptance/adherence and greater treatment effectiveness
These are exciting times in the field of Hepatitis C virus (HCV) infection. After many years of
ominous predictions, the outlook fo
r HCV-infected patients has im
proved substantially with the
introduction of direct acting agents (1, 2). However,
it is too soon to declare victory. It has even
been said that we are only ‘at the end of the beginning’ of the struggle (3). There are several
remaining obstacles. The purpose of this paper is to enumerate and discuss some of the
remaining barriers to effective HCV treatment in the United States, predominantly from an inner
city perspective.
The medical and economic burdens of HCV have
been increasing for the past 3 decades
(4, 5), and will continue to rise for the next 15 years. The burden of managing HCV-infected
patients will fall increasingly on
public institutions, i.e., inner
city hospitals, clinics and
community health centers, and the costs will shift progressively to public payers, such as
Medicaid and Medicare (5). Official estimates of
disease prevalence in the United States range
from around 4 million (6) to as high at 7 million (7
). The largest subgroup, comprising almost
80%, was born between 1945 and 1965 (8). Other cohorts of HCV-infected individuals exist,
including immigrants, patients with sexually transmitted HCV infection, plus other routes of
transmission, including nosocomial. A majority
are unaware of their HCV serostatus (9).
There are multiple obstacles to access of effective antiviral therapy in all countries, with
variations within and between them for different
subgroups of patients. The barriers can be
classified as virologic, host, and systemic. Virologic factors will not be considered here. Host
factors may be modifiable or non-modifiable.
In addition to age, sex and HIV co-infection,
genetic factors exist, such as the IL28B polym
orphism, which partially explain the observed
racial variation in treatment re
sponse (15). While hepatitis C has its highest prevalence in a
cohort defined by birth year, it is an especially important problem
in African-American
communities. The authors’ institutions treat
residents of Harlem and surrounding neighborhoods
in New York City, which have high prevalence rates for HCV infection and other co-morbidities
(10). Similar conditions exist in many inner-city environments in the US.
It is not appropriate to discuss HCV infection in African-Americans without noting the
presence of health disparities in general. In a
recent publication, Williams and colleagues noted
that overall death rates in African-Americans are 30% higher than in Caucasians (11), with
higher death rates for 10 of the 15 leading causes of
death, though not for liver cirrhosis. Health
disparities also exist in HCV infection, in terms
of higher prevalence (6) and poorer response to
therapy (12). Despite these facts, African-Americans have long been under-represented in
clinical trials (13). To identify and reduce such
disparity, the FDA Safety and Innovation Act,
recently passed by Congress, requires the FDA to
report annually on the inclusion of subjects by
age, sex, race, and ethnicity in clinical trials
supporting applications
of new drugs and medical
devices (14).
Important host factors that are potentially modifiable include substance abuse, mental
illness, and homelessness. A co-morbidity that ha
s received very little attention is alcoholism. Alcohol accelerates hepatic fibrosis in mono- and co-infected patients with HCV infection (16,
17). A prospective, case-control study published
in 1999, of chronic viral hepatitis, alcoholism,
and the development of chronic liver disease at Harlem Hospital Center (18) showed that the
combination of HCV infection and heavy alcohol
intake, but not HCV infection or alcoholism
alone, significantly promoted the development of
chronic liver disease. The cohort was followed
for four years and death rates were numerically
higher in the HCV plus alcohol group. The
authors called for greater attention to the management of alcoholism to mitigate the development
of chronic liver disease, even in the absence of
effective anti-HCV therapy at the time. In a
review of HCV-infected patients followed over
a 15-year period in clinics in Scotland, the
fraction of cirrhosis attributable to heavy alcohol intake was estimated at 36%, and at 61% for
heavy drinkers (19). Importantly, since active alcoholism is an absolute contraindication to anti-
HCV therapy, the subgroup at most risk of disease progression often is excluded from treatment. Recent studies from Switzerland and France have demonstrated reasonable rates of sustained
viral response in alcohol-dependent
patients (20,21). Poorer responses to anti-HCV therapy in
the US VA system were felt to be
related more to poorer
treatment adherence than a direct effect
of alcohol intake (22).
Maintaining adherence to treatment may be as important or even a more
important goal than enforcing abstinence. A
study to test this hypothesis would be one
comparing the effects of abstinence and harm
reduction. However, while determining the
relative importance of HCV and
of alcohol intake, including
amount, drinking pattern, and
chronicity, in liver disease progression is of interest, the ultimate goal of therapy should be to
cure both conditions. Other host factors may affect treatment adherence, however. Simoni and colleagues
analyzed 13 studies in HIV infection that used electronic drug monitoring. Demographic
variables such as sex, age, economic status,
education level, plus
depression and substance abuse, did not fully explain a lower level of
adherence observed in African-American subjects
(23). The authors cited evidence that mistrust
, poor health literacy, in
equalities in access to
health care, as well as outright discrimination might be responsible for the differences. Patient
mistrust acts synergistically with nihilism and stigmatization to confound attempts at therapy.
Patients whose clinical problems are related
to socially unacceptably behaviors may be
especially prone to feeling stigmatized, while caregivers may unconsciously express bias. Cultural competence, which involves developing attitudes, behaviors, and
policies that enable
effective work in cross-cultural situations, are routine medical education and core competency
initiatives, but have not overcome the prevailing host barriers.
The host barriers to effective treatment may become institutionalized so that caregivers
do not aggressively promote and
patients do not aggressively seek proven therapies. These
biases may be resistant to change.
A substantial proportion of patients currently presenting for
HCV testing are aware of their HCV status or of the presence of liver disease (G. Searson,
personal observations). In many cases, patients had
been told by a health care provider one, two,
or three decades ago that they were going to be OK or that their liver tests were relatively normal
and not to worry, and now are being told
that they have a serious disease. It is especially difficult for the medical establishment to engage patients who exist
outside the formal health care system. The Affordable Care Act may be helpful in expanding
coverage to some people, but it will not aid people who harbor a fundamental mistrust in the
health care system. Community-based organizations may be helpful in this situation; fostering
trust by helping people to feel at ease through non-judgmental treatment; creating an
environment where people may be more truthful
about personal matters: self-worth, future
prospects, or even existential concerns.
Systemic barriers to effective care are multiple and diverse. Perhaps the most important
is the lack of capacity of our system to provide comprehensive care to
our patients. Mental
health issues especially often are unrecognized,
overlooked, or undertreated. In HIV infection,
Ryan White funding allowed the development of
a comprehensive care model, with resources
devoted to social work needs, including food and shelter, as well as mental health needs. Such
support is not available for HCV-infected patients.
Lack of insurance, or insufficient insurance coverage, is common among HCV-infected
patients (24). Poor coordination between caregivers and hospitals and between caregivers and
third party payers may lead to unanticipated treatment interruptions. Few institutions have a
centralized system for toxicity management, relying on standard emergency services. However,
a visit to an Emergency Department or a hospital admission is likely to lead to treatment
interruption for a patient irrespective of the presenting complaint. Few hospitals have direct-
acting anti-HCV agents on formulary and the patient is “supposed to” bring his/her outpatient
medications to the hospital, which may not
occur in the face of an emergency.
There are two ways to evaluate treatment success: efficacy and effectiveness. Most
discussions are centered on the notion of treatment
efficacy, which can be defined as the number
cured/number treated, and which reflects the world
of clinical trials. Inclusion and exclusion
criteria minimize the host factors interfering with therapy while the study design and
pharmaceutical support minimize the
systemic obstacles to therapy.
A more accurate measure of
treatment success from a public health standpoint
is treatment effectiveness, which can be
defined as the number cured/number infected. Its importance is seen in the example of
alcoholism.
As discussed above
, alcoholism increases the risk
for developing chronic liver
disease, but is a contraindication for therapy, including inclusion in clinical trials. For this
reason, alcoholism does not affect measured treatment efficacy though it markedly reduces
treatment effectiveness, as might be measured by the prevention of chronic liver disease. Measured rates of effectiveness for pegylated interferon and ribavirin averaged 3.5% in clinical
experience (25, 26), while the effectiveness in the registration trials ranged from 12-17%, and
efficacy in the same trials aver
aged around 45% (discussed in 25).
Recent and emerging advances in therapy will allow the role of new regimens on
treatment effectiveness to be determined, especially the application of interferon-free regimens.
Treatment efficacy for genotype 1, treatment-naïve
patients in clinical trials averaged 40-50%,
using pegylated interferon and ribavirin (27), compared to around 75% in trials also using a
directing agent (1). However, real world results
in an inner city population in New York City
showed an efficacy of 14% in genotype 1 patient
s. In addition, a recent presentation showed an
SVR rate of 43% using a direct acting agent
in a similar patient
group (28). Treatment
effectiveness, including cost effectiveness will require closing the gap between clinical trials and
real world results. Depending on the specific
community, net effectiveness also may require
improvements in the prevention of
risk behaviors, which may lead
to reinfection after SVR (29). Furthermore, improvements in efficacy are irrelevant for a patient who remains unengaged with
the formal health care system.
One can divide treatment effectiveness into
several components (30). Effective therapy
includes the availability of efficacious medications as well as a system to evaluate patients
appropriately, recommend therapy, provide access to therapy, as well as patient compliance with
the evaluation and recommendations as well as adherence to therapy. Developing efficacious
medications is the task of the pharmaceutical
industry, while making
diagnoses and treatment
recommendations plus providing access to therapy are tasks for the health care system.
Accepting the diagnosis and adhering to therapy is
the job of the patient and patient advocates. While great effort has gone into developing efficacious therapies and an increasing amount of
attention is being given to screening, diagnosis, and evaluation, less attention has been placed on
treatment access and very little attention has been given to assisting the patient to accept the
diagnosis and adhere to therapy, i.e., care coordination. For this reason, care coordination is an
area in which greater availability, supported by
a currently nonexistent funding source, could
lead to greater acceptance/adherence, and greater treatment effectiveness. The elements of care
coordination, which include individual counseling, education, behavioral modification, and other
support, are the same for the management of many diseases.
In summary, if we can overcome the obstacles to care delineated above, then treatment
effectiveness will equal efficacy.
http://onlinelibrary.wiley.com/doi/10.1111/liv.12467/pdf
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