HCV Care by Liver Specialists or Community-Based Practices: Pro & Con

The American Journal of Gastroenterology
September 2007

PRO: Management of Hepatitis C by Liver Disease Specialists

Jorge L. Herrera, M.D., F.A.C.G.11University of South Alabama College of Medicine Mobile, Alabama
1University of South Alabama College of Medicine, Alabama

INTRODUCTION

An estimated 1.8% of the adult American population test positive for anti-hepatitis C virus (HCV) antibody (1). Most of these individuals are viremic and asymptomatic. While great progress has been made in public education and increased awareness among health care providers, many patients are being diagnosed after they enter the symptomatic phase of the disease, reflecting advanced liver damage. Early diagnosis of hepatitis C infection is crucial, as chronic hepatitis C is a leading cause of cirrhosis, liver failure and hepatocellular carcinoma.

Fortunately, effective therapy is available and can help over 50% of patients with chronic hepatitis C when diagnosed early. The treatment of hepatitis C has evolved rapidly, with the ability to achieve a sustained response increasing from 10% in 1992 to over 50% in 2006 (2). While this improved efficacy is in great part due to the development of more effective medications, the ability to provide patient support, specialized care, aggressive management of side effects, and individually tailored therapy is crucial in maximizing response. This type of care can only be delivered by specialists in liver disease or a practice devoted to the treatment of hepatitis.

INITIAL DIAGNOSIS AND DECISION TO TREAT

The initial diagnosis of hepatitis C infection usually causes great concern for patients. Most patients have a multitude of questions regarding their illness, the prognosis, safety of those around them and options for therapy (3). Accurate answers for these questions requires an up to date knowledge of the natural history and treatment of viral hepatitis and a practice setting that allocates sufficient time and resources for patient education. It is not surprising that, in a recent study of hepatitis C patients, 28% of patients reported poor communication skills of their physicians resulting in feelings of being rushed, ignored, or misunderstood. Similarly, 23% reported a sense of physician incompetence in the diagnosis and management of their liver disease (4).

Up to 40% of patients diagnosed with chronic HCV are reported to suffer from mood disorders or psychiatric diseases (5), and more frequent and severe emotional distress is reported among HCV infected patients without known psychiatric disease compared with uninfected populations (6). These findings highlight the importance of referring newly diagnosed HCV patients to a practice dedicated to the treatment of liver disease that can meet their needs. Substantial knowledge deficits regarding HCV infection among practicing physicians who do not specialize in the care of liver disease have been reported (7) and likely contribute to communication problems between patients and physicians.

Many patients are diagnosed with hepatitis C after advanced liver fibrosis has developed. Patients with bridging fibrosis or cirrhosis on liver biopsy are the ones most likely to benefit from successful antiviral therapy, however, these patients are also less likely to respond and more likely to develop side effects. Experienced practitioners that specialize in the treatment of liver disease are able to carefully weigh the benefits and risks of treating advanced fibrosis with antiviral agents and are also able to provide the meticulous comprehensive care and monitoring necessary for patients with cirrhosis including counseling on lifestyle modifications, preventive measures, and surveillance for esophageal varices, hepatocellular carcinoma and other complications of cirrhosis (8).

The decision to treat hepatitis C infection is not easy and should be a mutual decision of the patient and the healthcare provider. Multiple prognostic factors need to be considered to assess likelihood of response, and this needs to be weighed against the potential side effects of therapy. In many patients, liver histology findings are crucial in deciding whether or not to proceed with therapy. A clear understanding of hepatic pathology, the prognostic implications of histologic findings and an open and ongoing dialogue with the pathologist, are necessary in order to counsel the patient as to the best course of action. Practices that are not devoted to hepatology often lack the knowledge, resources or time to carefully evaluate all the positive and negative predictive factors, integrate them with the liver biopsy findings and then present the information in a clear and practical way to the patient to arrive at a rational decision regarding therapy.

While there are few absolute contraindications to the use of interferon and ribavirin, the list of relative contraindications is extensive, and becomes shorter as the experience of the healthcare provider treating hepatitis C grows. Practices that devote the majority of their time to the treatment of liver disease are more likely to "push the envelope" and safely treat patients that would otherwise be considered ineligible by other less experienced practices. In many instances, the patients with relative contraindications are the ones most likely to benefit from therapy, such as the patient with cirrhosis and moderate thrombocytopenia or neutropenia, or patients with advanced liver fibrosis and well-compensated psychiatric illnesses.

MONITORING DURING TREATMENT

Adherence is one of the most important elements to achieve success when treating chronic hepatitis C infection (9). The treatment for hepatitis C infection is toxic and patients soon realize that they feel better if they skip their medications. Physicians who are not used to treating patients with chronic hepatitis C are more likely to treat side effects by reducing the treatment dose or allowing "drug-holidays" rather than aggressively treating the side effects to prevent dose reductions. Familiarity with the use of growth factors for managing cytopenias and the treatment of uncomplicated psychiatric problems such as mild to moderate depression, irritability, or anxiety are necessary skills for practices taking care of hepatitis C patients.

In many cases, the management of the side effects caused by antiviral therapy is more an art than science, an art that can only be perfected in practices dealing with a high volume of hepatitis C patients and are dedicated to their care. Most practices dedicated to the treatment of liver disease have nurses and physician extenders with expertise in the care of hepatitis C patients; their role in providing patient support and maximizing adherence cannot be overemphasized and is often lacking in practices not dedicated to liver diseases.

The understanding of viral kinetics following initiation of antiviral medications has opened the new field of "individualized therapy". Analysis of viral kinetics allows the clinician to detect early during treatment those patients likely to fail with continued therapy, those that can achieve success with short duration therapy and those that will require extending therapy beyond 48 wk to maximize chances for sustained response (10). Gone are the days of "cookbook medicine" that assigned treatment for a total of 24 or 48 wk based solely on the patient's genotype. The concepts of rapid viral response (RVR), complete early viral response (EVR) and incomplete EVR require frequent and careful monitoring of viral counts at set points during therapy and a clear understanding of the implications of viral kinetics. By using these sophisticated parameters, clinicians experienced in treating a high volume of hepatitis C patients can avoid unnecessary toxicity by early discontinuation of therapy in patients with no hope for response and by shortening therapy in those with early viral clearance and favorable prognostic parameters. This type of intensive monitoring can only be provided by practices that specialize in the care of liver patients and have developed the infrastructure needed to assure carefully timed laboratory evaluations and patient monitoring.

DIFFICULT TO TREAT PATIENTS

Despite effective therapy for hepatitis C, nearly 50% of patients do not respond or relapse after successful therapy. Options for nonresponders are limited but careful evaluation of the prior treatment course by experienced physicians can uncover deficiencies that can be corrected upon retreatment. A careful analysis of viral response during the prior course of therapy may shed light on ways to modify treatment and maximize response. Novel approaches including daily interferon therapy and higher weight-based doses of ribavirin are more likely to be offered to patients who seek care in practices that specialize in the care of liver disease and may be the only hope for the patient to achieve a sustained response.

FUTURE THERAPIES

As we learn more about the hepatitis C virus biology, newer therapies are being developed. Protease and polymerase inhibitors have emerged as potent, specifically-targeted therapies against hepatitis C infection, but will need to be used in combination with interferon and probably ribavirin to minimize resistance. Their introduction into practice will add complexity to the treatment of HCV infection. Potential for resistance, cross reactions with other medications and proper timing for the introduction of these compounds relative to interferon and ribavirin therapy are factors that will need to be individualized according to patient's needs and viral kinetics, requiring experienced physicians with intimate knowledge of how these compounds act in inhibiting viral replication to maximize their efficacy.

CONCLUSIONS

Hepatitis C infection has a variable natural history, the potential for causing severe liver disease, and variable response to current therapy based on pretreatment factors. Patients with HCV infection have special needs and frequent co-morbid psychiatric and mood disorders. The decision to treat hepatitis C is complex and different in each patient. Adherence is crucial and requires extensive patient education and support and medical professionals committed to aggressively treating side effects rather than reducing medication doses. Monitoring during treatment is evolving; frequent and careful assessment of viral kinetics during treatment is needed to individualize therapy and maximize response. All of these variables do not allow for hepatitis C to be treated following a standard protocol or guideline for all patients. Only practices that specialize in the treatment of liver disease have the resources to provide their chronic hepatitis C patients with individualized state of the art therapy and the best chance at sustained viral response.

Jorge L. Herrera, M.D., F.A.C.G

CON: The Management of Hepatitis C in a Community-Based Practice

Farid Naffah, M.D.11Avamar Gastroenterology and Center for Endoscopy Warren, Ohio 1Avamar Gastroenterology and Center for Endoscopy Warren, Ohio

A CHALLENGE FOR SPECIALIZED CENTERS

The notion that patients with chronic viral hepatitis should be managed at tertiary care institutions rests on the presumed lack of expertise outside of specialized centers. Knowledge about hepatitis C has progressed vastly in the past 15 yr. Standards of therapy, which have already witnessed several transformations, continue to evolve at a fairly rapid pace, making it difficult for clinicians to keep up with recent developments, thereby diverting patients to academic centers. Furthermore, the preference for tertiary care institutions is bolstered by the potentially grave side effects of drugs currently in use, interferon and ribavirin, as well as the challenges inherent in certain clinical contexts, such as patients with serious comorbidities, patients coinfected with hepatitis B or HIV (1), patients with extrahepatic syndromes (2), and those having undergone liver transplantation (3). In addition to their ability to handle intricate and precarious cases, tertiary care institutions usually possess the resources for a structured and organized treatment program, including education and follow-up by ancillary staff, a setup not easily achieved in a small community office. For those reasons, many gastroenterologists in private practice have relegated the task of treating patients with chronic hepatitis C to their counterparts at the nearest university hospital or referral center, thereby skirting challenging clinical issues, avoiding potentially difficult medical legal questions, and freeing up time for the exercise of the more routine and lucrative aspects of their practice.

A TASK FOR PRIVATE PRACTICE

A breakdown of the steps involved in managing patients with chronic hepatitis C presents a clearer picture of the matter at hand and unravels many of its perceived complexities (4). A systematic approach to the hepatitis C patient ensures that the job is complete, and simplifies the process. When equipped with a working method, a community-based practice is perfectly suited for the treatment of most cases of hepatitis C. Indeed, the vast majority of patients would not receive superior treatment at a tertiary care institution. Clinical studies conducted in Spain (5) and Germany (6) have reached that same conclusion. Furthermore, many aspects of therapy, particularly those of a pragmatic nature, make it more desirable for patients to be treated in their own communities.

THE NEED FOR CARE CLOSE TO HOME

It is estimated that four million Americans are infected with the hepatitis C virus, but only half a million have been treated (7). The majority have not been identified, but awareness about the disease and its long-term health risks has grown among primary care physicians and in the public at large. Consequently, routine screening of individuals with alanine aminotransferase elevation and those with risk factors for the infection is gaining popularity, yielding increased numbers of diagnosed patients. Their systematic referral for evaluation and treatment to tertiary care centers is likely to result in delays, not to mention inconvenience and potentially higher costs.

The prevalence of hepatitis C in small communities makes it important to have competent care locally available. Since elderly patients are rarely treated, the majority of those who qualify for therapy are of working age. Unfortunately, the driving distance to a tertiary care center and the lack of flexibility in scheduling appointments often constitute a disincentive for patients to even initiate an evaluation. A typical workup requires several visits, laboratory and radiographic studies, usually a liver biopsy, and often subspecialty consultations: ophthalmologic, psychiatric, endocrinologic, and others. A single appointment typically implies hours of travel and waiting time. For many patients, that adds up to a day lost from work and a day of lost wages, a situation they cannot afford. The disincentive to go through the initial evaluation is only compounded by that of follow-up visits, which are frequent and may continue for an entire year. Patients who are eliminated from therapy at 12 wk, because of failure to achieve a 2-log reduction in viral load, must still anticipate an average of 10 visits to the referral center. Those who are lucky enough to endure must plan for an average of 20 visits to reach the end point of therapy, even under optimal circumstances, and when the course of their treatment is uninterrupted by complications. In view of the above considerations, determining the value of therapy, i.e., weighing its cost against an overall 50% chance of cure, often leads the average working patient to decide against it, or postpone it indefinitely, particularly if the disease is not advanced and there is no perceived need for immediate action. Indeed, many of the patients we treat may never progress to cirrhosis or hepatocellular carcinoma. Yet patients in earlier stages of disease are more likely to tolerate and respond to therapy. Ten to 20 days of lost wages is a high price to pay. For the majority of patients, that may be entirely avoided if they can receive care in the their own community.

A METHODICAL APPROACH

Delineating the steps involved in the management of patients with hepatitis C ensures that the process is carried through optimally and shows how that can be achieved in a community-based practice. Broadly speaking, those steps include patient selection, education, choice of drug regimen, clinical and laboratory follow-up, recognition and treatment of side effects, dose modifications, and termination of therapy.

The selection of patients who qualify for therapy with interferon and ribavirin is generally straightforward, as strict contraindications are well defined, such as decompensated cirrhosis, advanced cardiac and pulmonary disease, epilepsy, and severe mental illness. Relative contraindications, such as depression, retinopathy, and poorly controlled diabetes mellitus, present some challenge but rarely necessitate the opinion of a tertiary care hepatologist. On the other hand, those situations generally require the input of other specialists, such as endocrinologists, ophthalmologists, and psychiatrists, and their continued participation in the patient's care if therapy is initiated. Fortunately, competent specialists are available in most communities and are often already familiar with the concerned patients. Their geographical proximity to the patientsf dwelling and place of employment improves their accessibility, which may be critical in urgent situations, such as hyperglycemia, loss of vision, or suicidal ideation, to only name a few. Problems can be handled in a timely manner, with a high level of cooperation between physicians, which maximizes patient safety, hence the successful completion of therapy.

Treating hepatitis C entails a fair amount of education about the disease, its manifestations, and progression, and a discussion about the treatment, its prognosis, and side effects (8). The physician's review is supplemented by helpful educational materials, which are readily available from the American Liver Foundation and from pharmaceutical companies. They are routinely supplied to patients in the form of pamphlets and videotapes. Issues regarding contraception, as well as the avoidance of alcohol and street drugs, must be stressed and reinforced throughout the course of therapy. Patients are encouraged to ask questions and report adverse reactions. They may well be more apt to do so, both in person and by telephone, in the familiar environment of their local physician's office, while they may be intimidated by the imposing size and structure of a tertiary care institution. Patients are often discouraged from calling when they cannot get through to their physician, which may lead them to withhold their medication until their next scheduled visit or drop out of treatment altogether.

In the context of a community-based practice, dispensation of medication and instruction in self-injection may be administered by a home health organization, if the treating physician is not equipped to handle those services. My preference, however, is to assume charge of every aspect of the patient's care. That eliminates miscommunication, errors, and delays, particularly when dose reductions and other therapeutic modifications become necessary. A trained nurse on the physician's staff can easily incorporate those tasks into her daily activities. At the same time, that nurse would make herself available to answer routine phone calls and provide patients with appropriate advice concerning common side effects of therapy, such as fatigue, malaise, rashes, and headaches, but alert the physician to potentially serious sequelae (9). The patient's ability to always turn to the physician's team for questions and education mitigates anxiety and enhances confidence, which, in turn, improves compliance.

Close follow-up by the physician and nurse clearly optimizes the quality of care. Accessibility of care close to home reduces the likelihood of missed appointments and laboratory work, and minimizes the instances of skipped doses of medication. Unforeseen complications, which require the participation of other specialists, can be managed without delay, through emergency consultation or, sometimes, a brief hospitalization. The net result is improved compliance, a pivotal factor in determining the success of therapy (10). Farid Naffah, M.D

A BALANCING VIEW: We Cannot Do It Alone

Mitchell L. Shiffman, M.D.: Chief, Hepatology Section, Medical Director Liver Transplant Program Virginia Commonwealth University Medical Center Richmond, Virginia: Chief, Hepatology Section, Medical Director Liver Transplant Program Virginia Commonwealth University Medical Center Richmond, Virginia

Chronic HCV is one of the most common causes of chronic liver disease, the most common cause of cirrhosis, liver cancer, and the single most common indication for liver transplantation in this and many other countries throughout the world (1). Successful treatment of chronic HCV is associated with regression in hepatic fibrosis (2), a reduction in the risk of developing hepatocellular carcinoma, and improved long-term survival (3). Despite these compelling data, surveys from market research firms suggest that about 25-30% of the estimated 3-4 million persons with chronic HCV infection in the United States have been identified but less than 10% of those diagnosed (less than 5% of the HCV reservoir) have received treatment. An even more confusing and troubling statistic is that the number of patients initiating HCV treatment has declined by approximately 15% over the past year (4-6).

Market surveys have demonstrated that approximately 80% of all patients with chronic HCV are managed by just 20% of gastroenterologists (7). The majority of these physicians are recognized as specialists in liver disease and for the most part they are located at academic medical centers. In contrast, only 20% of HCV patients are cared for by 80% of the gastroenterology community located in the clinical practice setting. This marked imbalance in the distribution between HCV patients and their health care providers serves as the focus for this month's debate in the Red Section of the American Journal of Gastroenterology.

Dr. Herrera is an academic hepatologist at the University of South Alabama and has spent the majority of his career caring for patients with liver disease. He stresses that managing and treating patients with chronic HCV is a complicated, arduous, and time-consuming task that is best left to the liver disease specialist. Unfortunately, many academic hepatologists and community gastroenterologists agree with this philosophy and this is one of the major reasons for the current imbalance in HCV care today. Let us examine these arguments:

Many newly diagnosed patients are misinformed about the natural history of chronic HCV by their primary care providers and various Internet Web sites. They perceive they have a limited life expectancy without liver transplantation and think they must undergo a liver biopsy, which they are told is both risky and painful. Correctly educating these patients does require time and patience. However, I am not certain that a community-based practicing gastroenterologist has any less time to discuss these issues than a liver disease specialist. Competent and caring physicians will make and take the time required to properly educate patients regardless of their diagnosis or the clinical practice setting.

Assessing which patients with chronic HCV require therapy can at times be challenging. Some patients do not find out they have chronic HCV until they present with symptoms or complications of cirrhosis, neutropenia, and/or thrombocytopenia. Indeed, such patients may be better served and have better outcomes when treated by liver disease specialists at academic medical centers. However, the vast majority of patients with chronic HCV feel well, work full time, do not abuse alcohol or illicit drugs, are otherwise basically healthy, and do not understand why the gastroenterologist who identified and removed their colon polyps cannot also treat their chronic HCV infection.

Approximately 1 in 5 patients receiving peginterferon and ribavirin for treatment of chronic HCV do experience irritability, depression, and/or other psychiatric symptoms, which need to be addressed. A similar percentage of patients develop hemolytic anemia. At times this anemia may require that the dose of ribavirin and/or peginterferon be reduced or that erythropoietin be utilized. Both neutropenia and thrombocytopenia may become problematic in patients with cirrhosis; and many other adverse events have been attributed to these medications. Academic hepatologists do tend to manage the adverse events of peginterferon and ribavirin more aggressively, tolerate a lower level of cytopenia, prematurely discontinue treatment less often, and therefore may achieve higher rates of sustained virologic response (SVR) than community-based gastroenterologists (8, 9). However, large clinical trials have demonstrated that the great majority of patients are able to tolerate and complete HCV treatment without significant psychiatric, hematologic, or other adverse events (10, 11) and could be successfully treated in a community-based practice.

The treatment of chronic HCV is indeed evolving. In the past, patients were treated with a "cookbook" regimen and received a fixed dose of peginterferon and ribavirin for a fixed duration based only upon genotype. We now know that HCV patients should be treated for different durations based upon how quickly HCV RNA becomes undetectable and that reducing the dose of these medications, especially after HCV RNA has become undetectable, has little impact on the ability to achieve SVR (12-14). Thus, both the dose and duration of HCV treatment has become "individualized." Dr. Herrera and many other academic hepatologists feel that this "individualized" approach has made HCV treatment even more complicated for the practicing gastroenterologist. However, many others feel that this has actually made therapy more rational and straightforward. Every aspect of medicine evolves as we learn more about the disease process, reevaluate our current treatments, and develop new therapies. This is the basis for continuing medical education (CME) and there are no data to suggest that physicians in a community setting benefit any less from CME activities than their academic counterparts.

Dr. Naffah is a community-based gastroenterologist in Warren, Ohio, a community of roughly 200,000 persons located approximately 1 h southeast of Cleveland. He, like the majority of community gastroenterologists, has a busy endoscopy, hospital, and office-based practice. He readily acknowledges that treating HCV is challenging and time consuming. Nevertheless, he and many other community gastroenterologists who treat chronic HCV have had many successful outcomes and treating this disease has become a rewarding part of their clinical practice.

I applaud Dr. Naffah and the many other community-based gastroenterologists who have made the effort to learn about HCV treatment and incorporate this into their clinical practice. Yes, HCV patients may be challenging and time consuming. However, there are many other challenging and time-consuming diseases which community gastroenterologists routinely manage. Many gastroenterologists have incorporated physician's assistants and/or nurse practitioners into their care team. These medical providers can also be a tremendous asset in the evaluation and treatment of patients with chronic HCV (15).

The treatment of chronic HCV does require some expertise. If the community gastroenterologist and or their mid-level provider has not previously treated very many patients with peginterferon and ribavirin they should become acquainted with the adverse events associated with therapy, the various response characteristics that patients exhibit during treatment, and the terminology utilized to describe these response patterns: rapid virologic response, early virologic response, null response, partial response, breakthrough, relapse, and SVR (16). The American College of Gastroenterology (ACG) has long recognized the need to educate our membership in the various aspects of HCV and its treatment. Expertise can be gained through sessions offered at the postgraduate course, symposia, and breakfast sessions at our annual meeting, at regional meetings, and by participating in various other CME activities offered by the College and other entities. A new membership category in the College for Nurse Practitioners and Physician's Assistants will better enable these individuals to attend our meetings so they can gain this expertise as well.

Dr. Herrera is correct in that some patients with chronic HCV are best cared for by a liver disease specialist. This includes those patients with more advanced liver disease, complications of cirrhosis, those that have previously failed HCV treatment, and those with relative contraindications to peginterferon and ribavirin. Patients who wish to be treated with new innovative therapies in clinical trials should also be referred to an academic medical center for therapy.

However, the numbers speak for themselves. There are simply too many patients with chronic HCV for the limited number of liver disease specialists to care for. Hepatologists frequently have long wait times to see patients, are distracted by the needs of their liver transplant program, and their ability to treat HCV is often restricted by space, personnel, and financial limitations at large academic centers. It is therefore essential that more community-based gastroenterologists begin treating chronic HCV, at least on a limited basis in enthusiastic patients with no contraindications to therapy. We cannot do it alone.

Mitchell L. Shiffman, M.D