Hepatitis C: A Hepatologist s Approach to an Infectious Disease

Transcription

1 CLINICAL PRACTICE Ellie J. C. Goldstein, Section Editor INVITED ARTICLE Hepatitis C: A Hepatologist s Approach to an Infectious Disease Peter M. Rosenberg Department of Medicine, St. John s Health Center, and University of California, Los Angeles Santa Monica Medical Center, Santa Monica, California The evaluation and management of hepatitis C differ from those of other infectious diseases in important ways. In this review, the roles of liver biopsy, virus load determination, and genotyping in the pretreatment evaluation and monitoring of patients with hepatitis C are discussed from a hepatologist s perspective. Hepatologists, rather than infectious disease specialists, currently manage the majority of patients with hepatitis C virus (HCV) infection. This practice pattern is likely the result of infectious disease specialists limited familiarity with liver biopsy and with chronic liver disease. To some extent, it may also reflect an implicit model of hepatitis C as a liver disease, rather than a systemic infection. From a historical perspective, the development of this model might be partly attributable to the long lag between the recognition of chronic non-a, non- B hepatitis as a clinical syndrome and the identification of its etiologic agent [1]. It is clear that future progress in the field of hepatitis C will require increasing communication and cooperation between hepatologists and infectious disease specialists. Therefore, it is the purpose of this review to discuss the elements of a hepatologist s approach to hepatitis C that may be somewhat different from the approach to other infectious diseases. Specifically, the roles of liver biopsy and virus load determination will be discussed. THE ROLE OF LIVER BIOPSY It has become almost axiomatic among hepatologists that all patients with chronic hepatitis C should undergo liver biopsy prior to treatment. The biopsy is the only accurate way of determining the degree of fibrosis and of necroinflammatory Received 26 January 2001; revised 1 June 2001; electronically published 10 October Reprints or correspondence: Dr. Peter M. Rosenberg, 2001 Santa Monica Blvd., Ste. 360-W, Santa Monica, CA (pr838@yahoo.com). Clinical Infectious Diseases 2001; 33: by the Infectious Diseases Society of America. All rights reserved /2001/ $03.00 activity in such patients. Biopsies are typically performed percutaneously, with or without sonographic guidance; transjugular biopsies are reserved for patients with coagulopathy or ascites. The risk of complications is small but not negligible. Bleeding, the most common serious complication, occurs in!1% of patients; the overall mortality rate among patients undergoing liver biopsy is 1 death per 10,000 persons [2]. Other complications, such as bile leak, hemobilia, intestinal perforation, and pneumothorax, are exceedingly rare. Several different grading systems have been developed for the evaluation of histologic specimens obtained from patients with chronic hepatitis. The first numerical scoring system was developed by Knodell et al. [3] in 1981; it uses scores for portal, periportal, and lobular necrosis, inflammation, and fibrosis, to generate a histological activity index. This system has proved quite useful in clinical trials, but it tends to be too cumbersome and complex for routine clinical use. More recently, the French METAVIR group developed an alternative system that, in a simplified form, has become standard in most clinical practices. According to this simplified scoring system, histological specimens are graded on a scale of 0 4, signifying the degree of necrosis and inflammation, and staged on a similar scale, signifying the degree of fibrosis or scarring [4]. The grade of necroinflammatory activity is determined by assessing 2 major parameters: the severity of periportal inflammation and the degree of focal parenchymal necrosis (table 1). Periportal or interface hepatitis, formerly known as piecemeal necrosis, refers to inflammation immediately surrounding the portal tracts. Parenchymal injury refers to the presence of apoptotic bodies, degenerating or ballooned hepatocytes, and inflammatory cell aggregates in the hepatic lobule itself. Grade 1 hepatitis corresponds to the somewhat outdated category of 1728 CID 2001:33 (15 November) CLINICAL PRACTICE

2 Table 1. Histologic grading of chronic hepatitis C. Grade 0 Inflammation is absent Histologic description 1 Inflammation is confined to the portal tract 2 Both periportal (interface) inflammation and parenchymal injury are mild 3 Either periportal inflammation or parenchymal injury is moderate 4 Either periportal inflammation or parenchymal injury is severe chronic persistent hepatitis, in which inflammation is confined to the portal tract itself with minimal spillover into the periportal and lobular regions. Grades 2 4, in contrast, correspond to the previously used category of chronic active hepatitis, and patients with at least grade 2 inflammation are those known to be at risk for progressive liver injury. Although abnormal serum alanine aminotransferase (ALT) levels signify the presence of some degree of hepatic inflammation, the degree of enzyme elevation correlates poorly with the degree of histologic inflammation [5]. Moreover, a significant number of patients with normal ALT levels have significant histologic evidence of liver injury [6]. Neither the ALT nor any other noninvasive test can accurately determine the level of active hepatic inflammation and injury. Therefore, the biopsy is an important tool in the assessment of disease activity in patients with HCV. Biopsy is even more essential in the evaluation of HCVrelated fibrosis. Analogous to the grading of necroinflammatory activity, the staging of fibrosis is performed on a scale of 0 4 (table 2). Evaluation of fibrosis is performed by use of a Masson trichrome stain. Stage 4 fibrosis constitutes cirrhosis, defined histologically by the presence of discrete nodules of regenerating liver tissue surrounded by fibrous septa. Given that the morbidity and mortality of hepatitis C are related almost exclusively to the development of cirrhosis, the histological stage of fibrosis is the most important predictor of prognosis in this disease. In the majority of patients with hepatitis C, no combination of noninvasive tests can accurately establish the presence or absence of cirrhosis [7]. On average, progression of fibrosis occurs at a rate of 1 stage every 4 years; the actual rate of progression varies widely from one patient to another but appears to be fairly constant within a given patient [8]. Therefore, when the date of initial infection can be established with some certainty, the degree of fibrosis on biopsy and the elapsed time since infection can be used to determine a given patient s rate of fibrosis progression. This information is obviously invaluable in estimating prognosis. In this sense, the role of liver biopsy in patients with HCV infection is analogous to that of CD4 lymphocyte counts in patients with HIV. Just as low CD4 counts portend the onset of opportunistic infections, stage 4 fibrosis portends the onset of complications in hepatitis C, such as ascites, variceal bleeding, hepatic encephalopathy, and hepatocellular carcinoma. Patients with stage 4 fibrosis (i.e., cirrhosis but with no previous complications of cirrhosis) have 91% 5-year and 79% 10-year survival rates. However, once one of these complications has occurred, there is only a 50% likelihood that the patient will survive for 5 years [9]. Unfortunately, no noninvasive analog of the CD4 count exists for HCV. Because it is the only method of reliably estimating the prognosis in patients with HCV, liver biopsy is also the only way of correctly timing various therapeutic interventions in patients infected with HCV, including antiviral therapy, referral for liver transplantation, and various measures to prevent complications of cirrhosis, such as screening for hepatocellular carcinoma and upper endoscopy to rule out esophageal varices. Biopsy is particularly useful in patients who are being considered for therapy of HCV. In addition to providing a pretreatment baseline, liver biopsy aids in selecting patients for treatment, timing the initiation of therapy, and determining likelihood of response. Given that the currently available therapies for HCV are fairly toxic and extremely expensive, appropriate selection of patients for treatment is especially important. Treatment is generally recommended for those patients with at least grade 2 inflammatory activity and stage 1 fibrosis on biopsy, because patients with less active disease progress to cirrhosis only rarely and then very slowly [10]. The ability to estimate the rate of progression of fibrosis, as discussed above, is also extremely useful in timing the initiation of therapy. If a patient has relative contraindications to IFN therapy and demonstrates a relatively slow rate of fibrosis progression, for example, it may be appropriate to withhold therapy and to await the development of less toxic therapies. If, on the other hand, the patient exhibits advanced fibrosis with a relatively short duration of infection, the need for treatment becomes much more urgent. Similarly, if a patient has advanced fibrosis or rapid progression of fibrosis, treatment is more likely to be continued in the event of a potentially manageable side effect. Advanced fibrosis, in addition to being a poor prognostic factor, is associated with a lower likelihood of response to currently available therapies [11]. Therefore, patients with advanced fibrosis are usually treated with a full year of therapy, Table 2. Histologic staging of chronic hepatitis C. Stage Histologic description 0 No fibrosis 1 Fibrous portal tract expansion 2 Periportal fibrosis 3 Bridging or septal fibrosis 4 Cirrhosis CLINICAL PRACTICE CID 2001:33 (15 November) 1729

3 even if they have other favorable indicators of response, such as low virus loads, non genotype 1 infection, young age, and female sex. Furthermore, patients with advanced fibrosis and any complications of liver disease or relative contraindications to therapy may be more appropriate for referral to a transplantation center than for antiviral therapy. In addition to serving the aforementioned functions, the liver biopsy is useful in assaying for and assessing the contribution of other processes, such as steatohepatitis, iron overload, and alcoholic liver disease, to the hepatic injury in patients with hepatitis C. These other diseases clearly worsen the course of liver disease in patients with hepatitis C. Prior to any decision regarding antiviral therapy, any of these conditions should be addressed if present, because they may be the predominant cause of the liver disease and, therefore, require treatment prior to or concomitant with antiviral therapy. Of course, these conditions can, in most cases, be diagnosed accurately by assessment of history and by noninvasive testing. Therefore, the need to exclude these conditions is rarely the primary indication for a liver biopsy. Occasionally for example, when the suspicion of active alcohol abuse is extremely high in the face of repeated denials by the patient a liver biopsy may be indicated to assess the relative contributions of alcohol and hepatitis C to the patient s liver disease. The routine use of pretreatment liver biopsy is currently being reexamined. A recent cost-effectiveness analysis found that routine pretreatment liver biopsy increased cost without improving outcome [12]. When more-effective and less toxic treatments for hepatitis C become available, of course, treatment may be offered to all chronically infected individuals. Over time, therefore, the importance of liver biopsy in the pretreatment evaluation may decline. To some extent, this has already occurred in the subset of HCV patients with non genotype 1 infection. Given the excellent response rates of these patients to even short courses of currently available therapy, many hepatologists now offer treatment to all patients with non genotype 1 infection without performing a pretreatment liver biopsy. Serial liver biopsies are rarely performed in patients with HCV. After a course of therapy, virologic and biochemical measures are adequate to determine whether a response has been achieved, and histologic improvement correlates with these markers. Therefore, posttreatment biopsy rarely adds any information to that provided by noninvasive testing. The principal reason for serial biopsy, therefore, is to follow patients who have not been treated. It is reasonable to perform additional biopsies for such patients at intervals of 5 years, to rule out progression of fibrosis in patients with early-stage or lowgrade disease on initial biopsy [13]. THE ROLE OF HCV RNA QUANTITATION The application of molecular virology to the study of HCV has yielded several new and potentially powerful tools for the diagnosis and monitoring of this infection. These include qualitative and quantitative HCV RNA determinations (by either reverse transcriptase PCR or branched DNA assay) and genotype assays. The ability to quantify serum levels of HCV RNA has made it possible to approach anti-hcv therapy from a more infectious disease viewpoint. Eradication of viremia as measured by these assays has clearly become the litmus test for HCV treatment; 95% of patients with undetectable HCV RNA 6 months after a course of treatment remain HCV RNA negative, with normal ALT levels, during 5 10 years of follow-up [14]. Qualitative HCV RNA testing has become a valuable addition to the diagnostic evaluation of the patient with potential HCV infection. Although the majority of HCV-seropositive individuals are indeed chronically infected with HCV, a significant minority (10% 20%) of patients with antibody to HCV clear the infection. Especially in patients with normal ALT levels, therefore, qualitative HCV RNA testing is invaluable in establishing the diagnosis of chronic HCV infection. Even in a small number of HCV-seropositive patients with abnormal ALT, qualitative PCR for HCV RNA may be negative, which reflects the presence of other forms of liver disease in patients with resolved HCV infections. HCV RNA quantitation is quite useful in planning the duration of antiviral therapy and in predicting the likelihood of response to treatment. Patients with high HCV RNA levels (12 million copies/ml) tend to respond less well to IFN and ribavirin than do patients without high HCV levels, but lengthening the course of therapy to 48 weeks more than doubles the response rate, which results in rates nearly equal to those seen in patients with lower virus loads [15]. Assays for HCV RNA are also useful in monitoring treatment. Studies with IFN monotherapy have suggested that clearance of HCV RNA after 3 months of therapy predicts a sustained response, whereas failure to clear viremia by that time point predicts treatment failure [16]. Therefore, the National Institutes of Health Consensus Conference recommended cessation of therapy after 3 months in patients with persistent viremia [17]. However, experience with combination therapy (IFN plus ribavirin) has been somewhat different; cessation of therapy on the basis of the presence of HCV RNA at 3 months would have led to withholding therapy from 11% of patients who went on to achieve a sustained response [15]. The current recommendation is to assay for HCV RNA by qualitative PCR after 6 months of therapy and to discontinue therapy only if persistent viremia is detected at that time. There are several important caveats regarding HCV RNA testing. First, the assays themselves have been plagued by poor 1730 CID 2001:33 (15 November) CLINICAL PRACTICE

4 precision and by variability from one laboratory to another. Therefore, it is often difficult to determine whether changes in HCV RNA levels are truly meaningful or whether they reflect the variability of the assay itself. Overuse of these assays is expensive and potentially misleading, given that many of the changes seen may be artifactual and not clinically significant. The principal caveat in interpreting HCV RNA levels, however, is that they do not correlate with the natural history of the disease. This is in sharp contrast to the situation with HIV, in which the virus load is the principal factor determining the rate of disease progression. HCV RNA levels do not correlate with either grade or stage of disease on liver biopsy [18]. Therefore, HCV RNA quantitation has no role in predicting prognosis and, as discussed above, has only a limited role in selecting patients for treatment. Its principal role, as discussed above, is to establish a pretreatment baseline and to monitor the efficacy of treatment. The temptation to monitor HCV RNA levels in untreated patients, with the assumption that they somehow provide meaningful information regarding the course of the disease, is misguided and often leads to unnecessary, expensive, and misleading testing. Withholding therapy on the basis of low but detectable HCV RNA levels is particularly dangerous and fallacious, because such patients may well go on to develop cirrhosis and die of its complications. THE ROLE OF HCV GENOTYPE DETERMINATION HCV may be divided into at least 6 distinct genotypes. Genotyping that uses the reverse hybridization line probe assay has become a useful clinical tool, although it is not routinely used by all hepatologists. Genotype is the single strongest predictor of response to currently available antiviral therapy. Patients with genotype 1 HCV infection unfortunately, this is overwhelmingly the most prevalent genotype in the United States respond less well to IFN and ribavirin than do patients with other HCV genotypes, with sustained virologic response rates approximately half of those achieved in patients with non genotype 1 infections [15, 19, 20]. Recent data indicate that the response rate to pegylated IFN plus ribavirin in patients with genotypes 2 and 3 is as high as 88%, as opposed to 48% in patients with genotype 1 [21]. As discussed above, the high response rate among patients with virus genotype 2 and 3 has led many hepatologists to question the need for pretreatment biopsy in these patients. From a practical point of view, genotyping is principally useful for determining the duration of antiviral therapy. Among patients with genotype 1 infection, extending treatment from 24 weeks to 48 weeks doubles the response rate to IFN-ribavirin combination therapy [15]. In contrast, patients with genotypes 2 and 3 respond equally well to 24 weeks or 48 weeks of therapy and may therefore be treated with a 24-week course of therapy. The need to determine the duration of treatment appears to be the only indication for genotyping at present, because genotype does not appear to correlate with prognosis in any way other than likelihood of response to treatment. TREATMENT Although a detailed discussion of HCV therapy is beyond the scope of this article, a brief overview of the hepatologist s approach to treatment bears review. IFN-a proved to have activity against HCV in the 1980s, but sustained response rates were only 10% 20% [22, 23]. Typical dosing of IFN for hepatitis C is 3 million units by subcutaneous injection 3 times per week. Pegylated IFN, which results from the attachment of a polyethylene glycol molecule to IFN, has a longer half-life and is typically dosed at 1.5 mg per kg of body weight once per week. In a recently published trial, treatment with pegylated IFN resulted in a 39% sustained response rate, which is double that of standard IFN [24]. The addition of ribavirin, typically at a dosage of mg per day given orally, has also been found to improve virologic response to IFN, although ribavirin monotherapy has little or no anti-hcv activity. Combination therapy with IFN and ribavirin, currently the standard therapy for chronic hepatitis C, gives sustained response rates of 40% [15, 19, 20]. Preliminary data on the combination of pegylated IFN and ribavirin are more promising, with a response rate that approaches 60% [21]. Hepatologists perform a careful pretreatment evaluation of HCV patients that includes history, physical examination, standard laboratory evaluation, HCV RNA quantitation, liver ultrasonography, sometimes genotyping, and usually liver biopsy. Combination IFN-ribavirin therapy is offered to most patients with chronic HCV viremia, abnormal ALT levels, and at least moderate inflammation on a liver biopsy specimen. IFN monotherapy is currently reserved for patients with contraindications to ribavirin, such as severe anemia, ischemic heart disease, and renal failure. Patients with cirrhosis may be candidates for therapy as long as they have not experienced complications of endstage liver disease. Depending on genotype, therapy may be either 24 weeks or 48 weeks in duration. Treatment is usually stopped if no response has been observed after 24 weeks. Lifelong suppressive therapy in nonresponders who have advanced fibrosis may be beneficial, but trials that address this issue are currently ongoing. Combination pegylated IFN and ribavirin therapy is likely quite soon to supplant standard IFN-ribavirin therapy. CLINICAL PRACTICE CID 2001:33 (15 November) 1731

5 CONCLUSION Approximately 4 million people in the United States alone are chronically infected with HCV. Clearly, there is a desperate need for further progress in the field, given that at least 40% of patients with HCV did not respond to currently available therapy. Progress will best be achieved by collaboration between infectious disease and hepatology specialists, especially by applying lessons learned in the treatment of other viral infections to the treatment of HCV. When a truly effective antiviral therapy for HCV exists, it is very likely that the role of infectious disease specialists in managing this disease will expand considerably. Liver biopsy may become less important in the evaluation and monitoring of the disease, and virologic parameters will likely become even more important. Lifelong suppressive regimens may become more common, similar to the use of antiviral medications in HIV. 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