Friday, January 17, 2014

Treatment of Chronic Hepatitis C Virus Infection: Some Remaining Obstacles in the United States

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 Searson1, Ellen S. Engelson2,  Damaris Carriero1,3, Donald P. Kotler1,2,*
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

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.


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