It has been estimated that approximately 25% 46% of. Chronic Hepatitis C in Patients With Persistently Normal Alanine Transaminase Levels

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4: Chronic Hepatitis C in Patients With Persistently Normal Alanine Transaminase Levels MITCHELL L. SHIFFMAN,* MOISÉS DIAGO, ALBERT TRAN, PAUL POCKROS, ROBERT REINDOLLAR, DANIELE PRATI, #, ** MARIBEL RODRÍGUEZ TORRES, PILAR LARDELLI, STEVEN BLOTNER, and STEFAN ZEUZEM *Virginia Commonwealth University Medical Center, Richmond, Virginia; Hospital General de Valencia, Valencia, Spain; Hôpital de L Archet, Nice, France; The Scripps Clinic, La Jolla, California; Carolinas Center for Liver Disease, Charlotte, North Carolina; # IRCCS Ospedale Maggiore, Milan, Italy; **Ospedale A. Manzoni, Lecco, Italy; Fundación de Investigación de Diego, Santurce, Puerto Rico; Roche, Basel, Switzerland; Roche, Nutley, New Jersey; and Saarland University Hospital, Homburg/Saar, Germany See editorial on page 564. Background & Aims: Many patients with chronic hepatitis C virus (HCV) have persistently normal serum alanine transaminase (ALT) levels. We compared characteristics of chronic hepatitis C patients with patients with normal and elevated ALT levels using data from 3 randomized phase III trials of peginterferon alfa-2a (40 kda). Methods: The characteristics of 480 patients with normal ALT values (on >3 occasions without any increases in ALT level over a 6- to 18-month period) and 1993 patients with elevated ALT levels were compared. Sixtyeight of the 480 patients with normal ALT levels were randomized to no treatment and monitored for 72 weeks. Results: More patients with normal ALT levels than patients with elevated ALT levels were women (59% vs 32%; P <.01). The serum HCV RNA titer was significantly lower in patients with normal ALT levels (P <.01 vs in patients with elevated ALT levels). Patients with normal ALT levels had significantly lower inflammation and fibrosis scores on liver biopsy examination than patients with elevated ALT levels, but almost two-thirds had portal fibrosis and 10% had bridging fibrosis. No correlation between baseline ALT activity, HCV RNA level, and liver histology was observed in patients with normal ALT levels. During the 72-week follow-up period, ALT activity elevated above the upper limit of normal in 53% of the untreated patients with normal levels of ALT. None became HCV RNA undetectable. Conclusions: Chronic hepatitis C patients with normal ALT levels should be evaluated in a similar manner as patients with elevated ALT levels because they are at risk for developing significant liver disease. The decision to treat with peginterferon alfa and ribavirin should be based on multiple factors, rather than on ALT levels alone. It has been estimated that approximately 25% 46% of patients with chronic hepatitis C virus (HCV) infection have persistently normal serum alanine transaminase (ALT) activity. 1 3 Traditionally, such patients were considered to have mild liver injury and a low risk for developing advanced fibrosis or cirrhosis. 2 In contrast, several studies conducted over the past several years have shown clearly that liver histology in patients with normal ALT levels may not be mild, and in some reports 2% 10% of these patients were found to have bridging fibrosis or even cirrhosis. 4 8 In addition, other studies have shown that when patients with a normal serum ALT level were investigated more closely, many were found to have prior increases in serum ALT levels above the defined limit of normal, or to have developed increases in their ALT level during ongoing follow-up evaluations Understanding the significance of the ALT value in patients with chronic HCV infection is important for deciding if interferon treatment is warranted. For example, previous studies have shown that some patients with chronic HCV infection and normal values for serum ALT levels developed elevation in ALT level above the limits of normal while receiving interferon therapy This observation appeared to support the philosophy that such patients should not receive therapy. In contrast, several studies, including a large randomized, multinational, phase III trial of peginterferon alfa-2a (40 kda) plus ribavirin, have shown clearly that the response to interferon-based therapy is similar in patients with normal and elevated serum ALT levels, both overall and when compared according to HCV genotype. In the phase III study, 52% of patients with chronic HCV infection and normal ALT levels who were treated with peginterferon alfa-2a (40 kda) plus ribavirin achieved a sustained virologic response, whereas no patient Abbreviations used in this paper: ALT, alanine transaminase; HAI, Histologic Activity Index; HCV, chronic hepatitis C virus; ULN, upper limit of normal by the American Gastroenterological Association Institute /06/$32.00 doi: /j.cgh

2 646 SHIFFMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 5 in the untreated group cleared HCV. 15 In addition, patients with a pretreatment ALT level within the limits of normal had a further decrease in serum ALT level after successful antiviral therapy. 15 These observations have led many to question the meaning of a normal ALT level in the setting of chronic hepatitis C, how the normal range is defined, and why the upper limit of normal (ULN) varies so widely between various hospitals and reference laboratories. 16 The goals of the present study were to examine the relationship between serum ALT levels and liver histology, and to elucidate further the natural history of chronic hepatitis C in patients with a normal value for serum ALT. This was accomplished by comparing the clinical, virologic, and histologic characteristics of patients with persistently normal or elevated serum ALT activity using data from 3 randomized, multinational, phase III clinical trials. 15,17,18 In 1 of these studies, 15 a cohort of patients with normal ALT levels were assigned randomly to a 72-week untreated follow-up period, allowing the natural evolution of patients with a normal ALT value to be assessed during this time. Patients and Methods Patients Patients with chronic HCV infection included in this analysis were enrolled in 1 of 3 large, randomized, multinational, phase III clinical trials of peginterferon alfa-2a (40 kda) (PEGA- SYS; Roche, Basel, Switzerland) and ribavirin (COPEGUS; Roche), the main findings of which have been reported elsewhere. 15,17,18 The inclusion and exclusion criteria across the studies were similar, with the exception of those that applied to serum ALT activity and liver histology. Two trials required patients to have had elevated ALT levels documented on at least 2 occasions 14 days apart or more within the 6 months preceding enrollment. 17,18 In contrast, the third trial, which investigated pegylated interferon alfa-2a (40 kda) plus ribavirin in patients with normal ALT levels, 15 restricted enrollment to patients with persistently normal serum ALT levels, defined as at least 3 ALT determinations equal to or below the ULN, a minimum of 4 weeks apart, with 1 value obtained during the screening period and at least 1 value obtained 6 to 18 months before enrollment. 15 The only other major difference in the inclusion criteria related to cirrhosis. In the trials that included patients with elevated ALT levels, patients with marked bridging fibrosis or cirrhosis were eligible for enrollment provided they had compensated liver disease. 17,18 In contrast, patients with transition to cirrhosis or cirrhosis were excluded from participating in the study of normal ALT levels. 15 All patients enrolled in the 3 trials were aged 18 years or older, and had HCV infection documented by a positive anti- HCV antibody test and quantifiable HCV RNA levels in serum (Cobas Amplicor HCV Monitor Test v2.0; lower limit of quantitation, 600 IU/mL; Cobas, Branchburg, NJ). The presence of chronic HCV infection was confirmed by liver biopsy examination obtained within 36 months before the study. Patients with other chronic liver diseases or human immunodeficiency virus co-infection were excluded. None of the patients enrolled in these studies had previously received any form of treatment with any interferon preparation or ribavirin. Study Design For the purposes of this analysis, baseline data from the 2 studies of patients with elevated ALT levels 17,18 were pooled, and compared with baseline data from the study of patients with persistently normal ALT levels. 15 Cirrhotic patients (Knodell fibrosis stage 4) from the 2 trials of elvated ALT levels were excluded from the analysis to ensure that the histologic enrollment criteria were similar for both groups. Baseline liver biopsy specimens in all patients enrolled in the 3 studies were evaluated according to the Histologic Activity Index (HAI) of Knodell et al. 19 The relationship between the ALT quotient, the degree of liver disease (HAI score and fibrosis stage), and the baseline viral titer were analyzed for patients with normal ALT levels. Natural variations in serum ALT levels were studied prospectively over a 72-week period in 68 patients randomized to the untreated control group of the study of patients with normal levels of ALT. 15 Quantitative and qualitative HCV determinations were performed for this patient group at screening, baseline, and weeks 4, 12, 24, 48, 60, and 72 (Cobas Amplicor HCV Test v2.0; detection limit, 50 IU/mL; and Cobas Amplicor HCV Monitor Test v2.0). Clinical and laboratory evaluations were conducted at screening, baseline, and then every 4 weeks until week 12, and every 6 weeks thereafter until the end of the observation period (week 72). Statistical Analysis Differences between the characteristics of patients with persistently normal and elevated ALT levels were compared by unpaired t test for continuous variables and by the 2 test for categoric variables. Correlations between the ALT quotient, the degree of liver disease (HAI score and fibrosis stage), and the baseline HCV RNA titer in patients with normal ALT levels were analyzed by the Pearson correlation coefficient. 20 The ALT quotient was defined as the mean of the patient s qualifying ALT values divided by the ULN. The correlation between ALT activity and the mean HAI and fibrosis scores was performed by dividing pretreatment ALT quotients into quartiles for patients with normal ALT levels and deciles for patients with elevated ALT levels. The broader range in ALT values in the elevated ALT population was the reason why the data were grouped in deciles rather than quartiles for this aspect of the analysis.

3 May 2006 CHRONIC HEPATITIS C AND NORMAL ALT LEVELS 647 Results A total of 2405 patients with elevated ALT levels were enrolled in 2 studies. 17,18 Data from 412 patients with cirrhosis were excluded, leaving 1993 patients for this analysis. In the study of patients with normal ALT levels, 514 patients were enrolled, and of these 23 withdrew before baseline and 11 were excluded for protocol violations (10 had elevated ALT levels and 1 patient had transition to cirrhosis). 15 The remaining 480 patients with persistently normal ALT levels were included in the analysis. Baseline liver biopsy specimens were available from 475 of 480 patients (99%) with persistently normal ALT levels (baseline histology was unavailable for 4 hemophiliac patients and 1 protocol violator), and 419 of 1993 (22%) noncirrhotic patients with elevated ALT levels. In the latter patient population, only patients with paired biopsy specimens underwent full histologic evaluation according to the Knodell scoring system. Demographics and Hepatitis C Virus Characteristics The demographic and baseline characteristics of the 2 populations are summarized in Table 1. A significantly greater proportion of patients with persistently normal ALT levels were women (P.01 vs patients with elevated ALT levels). The mean body weight and body surface area were significantly lower in patients with normal compared with elevated ALT levels (P.01). Differences were also seen in race, with the normal ALT patient population containing a higher proportion of African American patients and a lower percentage of Asian patients than the elevated ALT patient population. HCV genotype 1 predominated in both groups. A higher incidence of genotype 1a was observed in patients with normal levels of ALT, whereas genotypes 1a and 1b were distributed evenly in patients with elevated ALT levels. A significantly lower incidence of HCV genotype 3 infection was seen in patients with normal ALT levels (8%) relative to those with elevated ALT levels (20%; P.01). The baseline HCV RNA titer was significantly lower in the patients with normal ALT levels when compared with patients with elevated ALT levels (P.01). Extent of Liver Disease Overall, patients with persistently normal ALT levels had less extensive liver disease on biopsy examination (Table 1). The mean Knodell necroinflammatory, fibrosis, and total scores all were significantly lower in the population with normal ALT levels than in patients with elevated ALT levels (P.01). Sixty-five percent of the patients with normal ALT levels had necroinflammatory activity scores less than 5 compared with 11% of patients with elevated ALT levels (P.01). Twentyseven percent of patients with normal ALT levels had a fibrosis score of 0 vs 5% of the patients with elevated ALT levels (P.01). However, 64% of patients with normal ALT levels had portal fibrosis (fibrosis stage 1), and 10% of the patients with normal ALT levels had bridging fibrosis (fibrosis stage 3). There was no significant correlation between baseline HCV RNA titer and baseline fibrosis score (Figure 1). For patients with persistently normal ALT levels, the Pearson correlation coefficients between baseline HCV RNA titer and baseline necroinflammatory activity, fibrosis, and total HAI scores were.20,.06, and.19, respectively. The corresponding values for patients with elevated ALT levels were.10,.10, and.12, respectively. In addition, there was no strong correlation between serum ALT level and the severity of liver disease on biopsy examination in patients with either elevated or persistently normal ALT levels. In patients with normal ALT levels, the Pearson correlation coefficients between baseline ALT quotient and baseline necroinflammatory activity, fibrosis, and total HAI scores were.06,.03, and.08, respectively. In patients with elevated ALT levels the corresponding correlation coefficients were.30,.23, and.34, respectively. Evolution of Hepatitis C Virus RNA and Alanine Transaminase Levels in Patients With Persistently Normal Alanine Transaminase Levels The mean HCV RNA titers remained stable in the 68 untreated patients with normal serum ALT levels who were randomized to no treatment and followed-up prospectively over 72 weeks (Figure 2), and no patient spontaneously cleared HCV during this time period. The median ALT levels also remained stable during this period (Figure 3); however, 36 patients (52%) developed an elevation of serum ALT level ( 30 to 300 IU/L) (Figure 4). Increases less than 2 times the ULN ( 30 to 60 IU/L) occurred in 31 patients (45%); 4 patients (6%) had elevation between 2 and 5 times the ULN (60 to 150 IU/L), and 1 patient had an isolated flare in ALT 12 times the ULN. In the single patient with a marked ALT flare, the serum ALT level returned to within the normal range at the next determination 20 days later. This same patient also had a subsequent elevation in ALT to 5 times the ULN, which also returned to within normal limits within 1 month. Of all the factors analyzed, only the prestudy ALT quotient

4 648 SHIFFMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 5 Table 1. Baseline Demographic, Virologic, and Histologic Characteristics of Patients With Persistently Normal ALT Versus Elevated ALT Levels Population with persistently normal ALT levels, n 480 Population with elevated ALT levels, n 1993 Sex: female/male (% female) 285/195 (59) a 646/1347 (32) Mean age, SD a Race, n (%) Caucasian 410 (85) 1732 (87) African American 39 (8) a 75 (4) Asian 12 (3) a 127 (6) Other 19 (4) 59 (3) Mean weight, kg SD a Mean body surface area, m 2 SD a (n 1992) Mode of infection, n (%) Intravenous drug use 150 (32) 717 (36) Transfusion 111 (23) a 336 (17) Other percutaneous 41 (8.5) 122 (6) Sexual exposure 8 (1.6) 31 (2) Vertical transmission 2 ( 1) 1 ( 1) Other 13 (2.7) 78 (4) Unknown 155 (32) 708 (35) HCV RNA titer ( 10 3 copies/ml) Mean SD a (n 1990) Median 1445 a 4005 HCV genotype, n (%) Type (68) a 1218 (61) 1a 189 (39) a 600 (30) 1b 136 (28) 602 (30) Other type 1 2 ( 1) 16 ( 1) 2 90 (19) b 293 (15) 3 40 (8) a 404 (20) 4 19 (4) 60 (3) Other type non-1 4 ( 1) 18 (1) Liver histology (Knodell scores) Necroinflammatory activity, n (%) c n 474 n (65) a 47 (11) (34) a 325 (78) 10 2 ( 1) a 47 (11) Mean necroinflammatory score SD a Fibrosis stage, n (%) d n 475 n (27) a 20 (5) (64) a 298 (71) 3 47 (10) a 101 (24) Mean fibrosis score SD.9.8 a Mean total Knodell score SD e a NOTE. Some percentages do not add up to 100% because of rounding. a P.01 vs elevated ALT level. b P.05 vs elevated ALT level. c Necroinflammatory activity rated as 0 (none), 1, 3, 4, 5, 6, 10 (multilobular necrosis). d Fibrosis stage rated as 0 (none), 1 (portal fibrosis), 3 (bridging fibrosis), or 4 (cirrhosis). e Total Knodell score ranges from 0 to 22 (higher scores indicate more severe abnormalities). showed a correlation with the development of ALT elevation above the ULN during the 72-week observation period (correlation coefficient,.44). The baseline HCV RNA titer, the degree of inflammation, or the degree of fibrosis on liver biopsy examination was not associated with the presence or frequency of ALT elevation above the ULN during the observation period (correlation coefficients,.13,.05, and.03, respectively). Chronic Hepatitis C Virus Infection Related Signs and Symptoms in Patients With Persistently Normal Alanine Transaminase Levels Constitutional signs and symptoms of chronic HCV infection in patients with normal ALT levels at the time of enrollment are summarized in Table 2. The most common

5 May 2006 CHRONIC HEPATITIS C AND NORMAL ALT LEVELS 649 Figure 1. Baseline fibrosis score vs HCV RNA titer (mean standard error)., Persistently normal ALT level;, elevated ALT level. Figure 3. Median ALT levels in 68 patients with persistently normal ALT levels (untreated control group) at baseline and over 72 weeks of close monitoring. Vertical bars represent the interquartile range. symptoms reported before treatment were fatigue, depression, and arthralgia. Up to 52 (76%) of the untreated control patients reported at least 1 adverse event during the 72 weeks of observation, and 31 patients (46%) reported symptoms that were similar to those observed at baseline including fatigue, asthenia, and arthralgia. No significant changes in hematologic parameters were observed in any individual in this group during the study. Discussion The present analysis represents a large comparison of patients with chronic HCV infection and elevated or persistently normal serum ALT levels. Data for this analysis were obtained from 3 large, randomized, phase III multinational trials 15,17,18 with similar entry and exclusion criteria. The overall results suggest that there are substantial differences between the 2 patient populations in terms of disease characteristics and liver histology. Figure 2. Mean HCV RNA levels in 68 patients with persistently normal ALT levels (untreated control group) at baseline and over 72 weeks of close monitoring. Vertical bars represent 95% confidence intervals. Figure 4. Maximum ALT elevation in 68 patients with persistently normal ALT levels (untreated control group) during 72 weeks of close monitoring.

6 650 SHIFFMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 5 Table 2. Chronic Hepatitis C Related Symptoms/Signs in Patients With Persistently Normal ALT Levels Sign/symptom n(%) All patients at baseline (n 480) Untreated control patients during the 72-week observation period (n 68) Fatigue 40 (8) 12 (17) Depression 34 (7) 4 (6) Arthralgia 32 (7) 3 (4) Dyspepsia 12 (2.5) - Asthenia 8 (2) 6 (9) Nausea 8 (2) 1 (1) Myalgia 8 (2) 5 (7) Pruritus 5 (1) 1 (1) Abdominal pain 2 ( 1) 4 (6) Hepatomegaly 1 ( 1) - Cryoglobulinemia 1 ( 1) - The analysis found that patients with persistently normal ALT levels were significantly more likely to be women than men and, as would be expected from this observation, have a lower body weight and body surface area. Other investigators have reported a female predominance among patients with normal ALT levels, 4,7,21 24 and have postulated that this imbalance between the sexes may be associated with hormonal influences on the immune response to HCV infection. 7,22 Previous studies have shown that serum ALT levels are related to both sex and race. The lowest mean ALT level generally is found in Caucasian women and the highest ALT level generally is found in African American men. 4,6,7 In this analysis, there was a significantly greater proportion of African American and significantly fewer Asian patients in the population with a normal ALT level than in the population with an elevated ALT level. It is likely that such differences relate to the different geographic locations of the clinical trials used in the analysis. The proportion of African American patients in the study of normal ALT levels 15 ranged from 4% in the untreated control group to 10% in the group that received peginterferon alfa-2a (40 kda) plus ribavirin for 48 weeks. In the study of elevated ALT levels, the proportion of African American patients in each treatment group generally was lower, ranging from 3% in the Hadziyannis et al 18 study to 6% in the Fried et al 17 study. We observed subtle differences in the distribution of HCV genotypes between the 2 populations. The overall incidence of HCV genotype 1 infection was greater in patients with normal than in those with elevated ALT levels (68% vs 61%; P.01). Subtype 1a was more common than 1b in patients with normal ALT levels, whereas these were distributed evenly in patients with elevated ALT levels. Infection with HCV genotype 3 was significantly less prevalent in patients with normal than in patients with elevated ALT levels. Some investigators have observed a lower incidence of genotype 1 infection, 7,25 and a predominance of genotype 2 8 or 3 25 in patients with normal ALT levels. These differences may be associated with geographic area, or be related to the inclusion of patients from different risk groups such as intravenous drug users. 6,26 The lower incidence of normal ALT levels in patients infected with HCV genotype 3 also may be related to an increased incidence of steatosis in this patient group. Unfortunately, grading for steatosis was not performed on the biopsy specimens obtained in these studies 15,17,18 and therefore could not be compared directly in patients with normal and elevated serum ALT levels. In the present analysis, HCV RNA titers were significantly lower in patients with persistently normal ALT levels than in those with elevated ALT levels. Other comparative studies also have suggested that HCV RNA level is significantly lower in patients with normal ALT levels, 6,14 although the observation remains controversial. In our analysis, baseline HCV RNA levels did not correlate with the degree of liver disease on biopsy examination, a finding that supports the hypothesis that liver histology and disease progression are a reflection of the host immune response and not HCV infection per se. 9,14,27 Although the proportion of patients with fibrosis stage 0 was significantly greater in the population with a normal ALT level (26% vs 5%; P.01), almost two thirds (63%) had portal fibrosis (fibrosis stage 1) and 10% had bridging fibrosis (fibrosis stage 3). Furthermore, an even higher proportion of patients had evidence of active inflammation, corroborating previous observations that normal ALT levels do not preclude the existence of significant histopathology. Although scores for necroinflammation and fibrosis were significantly lower in the population with normal ALT levels, there was no strong correlation between the pretreatment ALT quotient and the severity of liver disease in either the group with normal ALT levels or with elevated ALT levels. Thus, ALT activity alone should not be used as a marker of histologic damage in patients with chronic HCV. The study of patients with normal ALT levels 15 included a subset of patients who were randomized to no treatment and followed-up prospectively for 72 weeks. During this period, 52% of patients, all of whom met our strict definition of persistently normal ALT levels at baseline, experienced elevation above the ULN. This incidence is considerably higher than previously reported, 8 10 and is likely to

7 May 2006 CHRONIC HEPATITIS C AND NORMAL ALT LEVELS 651 be a reflection of the intensity of surveillance in the present study. 28 A correlation between baseline ALT quotient and the development of ALT elevation was observed in the untreated control group. In contrast, no correlation between baseline HCV RNA titer, HCV genotype, or HAI score, and the development of subsequent ALT increases was observed. Therefore, it seems that these parameters may not be reliable in identifying patients at elevated risk for disease progression. In the study of patients with normal ALT levels, the median ALT values decreased in patients who achieved a sustained virologic response to treatment with peginterferon alfa-2a (40 kda) and ribavirin. 15 In patients who became HCV RNA undetectable during therapy and achieved a sustained virologic response, the ALT level decreased from a mean of 24 IU/L at baseline, which was well within the normal range, to only 8 9 IU/L at the end of the follow-up period. However, patients who initially responded during treatment and subsequently relapsed showed an increase in serum ALT level to the pretreatment baseline level, which still was within the normal range. 15 This observation suggests that the pretreatment ALT activity in these individuals, although within the normal laboratory range, was not the true healthy level of serum ALT for these patients. This finding casts doubt on the validity of the concept of normal ALT levels in patients with chronic hepatitis C, and suggests that, in many cases, patients with chronic HCV infection have an ALT value that exceeds their true healthy baseline level. A considerable proportion of patients with persistently normal ALT levels in the present analysis had nonspecific constitutional signs and symptoms at enrollment or developed symptoms during the follow-up period (some similar to those reported as adverse events associated with interferon-based therapy). Spontaneous clearance of HCV in patients with normal ALT levels rarely has been reported in the literature, 2 and none of the patients in the untreated control group became HCV RNA undetectable during 72 weeks of close monitoring. Taken together, these observations suggest that chronic HCV infection in patients with normal ALT levels is not a benign condition and, thus, a conservative management strategy may be inappropriate. In conclusion, patients with persistently normal ALT levels have some distinct biological and virologic characteristics, but there are currently no parameters that can be used to identify individual patients at elevated risk for progressive liver disease. Therefore, patients with chronic HCV and normal serum ALT levels should be evaluated in the same manner as patients with elevated ALT levels. Combination therapy with pegylated interferon and ribavirin is useful in preventing disease progression and transmission, 15 and is cost effective. 29 Treatment decisions therefore should be based on a global evaluation of the individual patient and influenced by factors that predict successful outcomes, rather than on ALT levels alone. 2,30,31 References 1. Bacon BR. Treatment of patients with hepatitis C and normal serum aminotransferase levels. Hepatology 2002;36(Suppl 1): S179 S Ahmed A, Keeffe EB. Chronic hepatitis C with normal aminotransferase levels. Gastroenterology 2004;126: Alberti A, Noventa F, Benvegnù L, et al. Prevalence of liver disease in a population of asymptomatic persons with hepatitis C virus infection. Ann Intern Med 2002;137: Puoti C, Magrini A, Stati T, et al. Clinical, histological, and virological features of hepatitis C virus carriers with persistently normal or abnormal alanine transaminase levels. 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Therapy of hepatitis C: patients with normal aminotransferase levels. Hepatology 1997;26: 133S 136S. 15. Zeuzem S, Diago M, Gane E, et al. Peginterferon alfa-2a (40KD)

8 652 SHIFFMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 5 and ribavirin in patients with normal aminotransferase levels. Gastroenterology 2004;127: Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002;137: Fried MW, Shiffman ML, Reddy KR, et al. Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection. N Engl J Med 2002;347: Hadziyannis SJ, Sette H, Morgan TR, et al. Peginterferon alfa-2a and ribavirin combination therapy in chronic hepatitis C. A randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140: Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1: Pearson WH. Estimation of a correlation coefficient from an uncertainty measure. Psychometrika 1966;31: Mathurin P, Moussalli J, Cadranel JF, et al. Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity. Hepatology 1998;27: 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: Piton A, Poynard T, Imber-Bismut F, et al. Factors associated with serum alanine transaminase activity in healthy subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis C. MULTIVIRC Group. Hepatology 1998;27: Sakugawa H, Nakasone H, Nakayoshi T, et al. Alanine aminotransferase (ALT) levels in a normal population and interferon therapy in chronic hepatitis C patients with normal ALT. Hepatogastroenterology 2003;50: Silini E, Bono F, Cividini A, et al. Differential distribution of hepatitis C virus genotypes in patients with and without liver function abnormalities. Hepatology 1995;21: Prati D, Capelli C, Zanella A, et al. Influence of different hepatitis C virus genotypes on the course of asymptomatic hepatitis C virus infection. Gastroenterology 1996;110: Dincer D, Okten A, Kaymakoglu S, et al. Persistently normal alanine transaminase levels in chronic C hepatitis: what does it tell us? Hepatogastroenterology 2001;48: Rumi MG, De Filippi F, Donato MF, et al. Progressive hepatic fibrosis in healthy carriers of hepatitis C virus with a transaminase breakthrough. J Viral Hepat 2002;9: Hornberger J, Farci P, Prati D, et al. The economics of treating chronic hepatitis C patients with peginterferon alfa 2a (40KD) plus ribavirin presenting with persistently normal aminotransferase. J Viral Hepat 2006 (in press). 30. National Institutes of Health. Consensus development conference statement: management of hepatitis C: 2002 June 10 12, Hepatology 2002;36(Suppl 1):S3 S Strader DB, Wright T, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39: Address requests for reprints to: Mitchell L. Shiffman, MD, Hepatology Section, Virginia Commonwealth University Medical Center, Box , Richmond, Virginia mshiffma@vcu.edu; fax: (804) Supported by Roche (Basel, Switzerland). Dr Tran was an Investigator for the study. Dr Pockros received research grants, was involved with CME programs, is a Consultant for, and is on the Speaker s Bureau for Roche. Dr Reindollar has associations with Hoffmann LaRoche, Shering-Plough, Intermune, and Vertex. Drs Lardelli and Blotner are employees of Hoffmann LaRoche. Dr Zeuzem is a Consultant for, is on the Speaker s Bureau, and is a Clinical Investigator for Shering-Plough and Hoffmann LaRoche.