Hepatology, May 1999, p. 1573-1580, Vol. 29, No. 5
Prospective Study of Interferon Therapy for Compensated Cirrhotic Patients With Chronic Hepatitis C by Monitoring Serum Hepatitis C RNA
From the 1Department of Internal Medicine (II), University of Tokyo, Tokyo, Japan; the 2First Department of Internal Medicine, Chiba University School of Medicine, Chiba, Japan; the 3Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan; the 4Department of Gastroenterology, Mito Saiseikai Hospital, Ibaraki, Japan; the 5Department Gastroenterology, JR Tokyo General Hospital, Tokyo, Japan; the 6Department of Medicine, Mitsui Memorial Hospital, Tokyo, Japan; the 7Department of Gastroenterology, Institute of Adult Disease, Asahi Life Foundation, Tokyo, Japan; the 8Department of Medicine, Tokyo Kosei-Nenkin Hospital, Tokyo, Japan; the 9Department of Medicine, Tokyo Metropolitan Police Hospital, Tokyo, Japan; the 10Department of Gastroenterology, Kanto Chuo Hospital, Tokyo, Japan; the 11Department of Gastroenterology, Kawasaki Chuo Hospital, Kanagawa, Japan; the12Department of Medicine, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan; and the 13Department of Epidemiology and Biostatistics, University of Tokyo, Tokyo, Japan.
Because interferon therapy exhibits low efficacy for cirrhotic patients infected with hepatitis C virus, this prospective study was conducted to determine effective interferon regimens tailored to treatment response by monitoring HCV RNA status. A total of 157 cirrhotic patients were enrolled to receive 9 million units (MU) of interferon three times a week. The HCV RNA values were drawn 8 weeks apart and the patients were randomized to a further 16 or 32 weeks of treatment after two sequential findings of negativity for HCV RNA. A total of 73 out of 157 patients (46%) proceeded to randomization to different durations of treatment, 37 short-course and 36 long-course (duration: 38 ± 8 and 49 ± 13 weeks; total amount of interferon: 940 ± 240 and 1130 ± 390 MU, respectively). The remaining 84 patients without two sequential negative serum HCV RNA determinations received 44.8 ± 27.4 weeks of interferon (IFN) therapy with total amount of 993 ± 633 MU. Of these 157 patients, sustained virological and biochemical response was shown in 32 (20%) and 37 patients (24%), respectively. Sustained virological and biochemical response rate in the randomized patients was significantly higher than in nonrandomized patients (41% vs. 2%, and 38% vs. 11%; each P < .01). Of the 73 randomized patients, the rate of sustained virological response in patients with long-course treatment (50%) was significantly higher than that of patients with short-course treatment (32%) (P = .026: log-rank test), and in patients with early disappearance of HCV RNA especially within 8 weeks, in patients with low virus load (106.3 copies/mL) and with HCV 2a. Multivariate analysis revealed that HCV RNA level and subtypes were the most important factors contributing to sustained virological response. Interferon is effective even in cirrhotic patients with low viral load and HCV 2a, but requires a longer course of administration. (HEPATOLOGY1999;29:1573-1580.)
Chronic hepatitis C is a very common disease that is often asymptomatic and mild, but may slowly progress to cirrhosis and eventually to hepatocellular carcinoma (HCC).1-4 Interferon (IFN) was first reported to have beneficial effects for chronic hepatitis C in the mid-1980s,5 and IFN is the only substance that has been shown to be effective for treatment of this disease. Early studies reported the use of biochemical response to assess the efficacy of IFN therapy.6-8However, biochemical response during IFN administration cannot predict sustained response.9 When IFN therapy was discontinued, serum ALT concentrations rose to pretreatment values in at least 50% of patients who responded to the drug, resulting in a sustained response rate of only 15% to 25%.
Factors predictive of sustained response to IFN have been extensively studied,i.e., short duration of disease, young age, absence of cirrhosis, low HCV RNA levels, HCV subtype 2a, and low hepatic iron stores.10-12 In contrast, patients with a high HCV RNA level and HCV genotype 1b exhibited a low response rate.11-15 A longer course of therapy results in a higher rate of sustained response, rising from approximately 15% with a 6-month course to greater than 25% with a 12- to 24-month course.16-18 Recent meta-analyses indicate that therapy for 12 months generates a significantly higher response rate.19However, the longer course is more expensive and causes more discomfort than the 6-month course, and relapse still occurs.
In recent long-term follow-up studies of patients who tested negative for HCV RNA 6 months after treatment, these patients remained in remission with normal liver function and improved histological features; and they may have been cured of infection.20,21 Approximately 20% of patients who have a long-term decrease in serum ALT concentration have evidence of the presence of HCV RNA in serum, and ultimately may suffer late relapse.20 Thus, it may be important to monitor HCV RNA during and after IFN therapy.22
Since cirrhosis is a significant risk factor for HCC,23,24 treatment for these patients may be needed to reduce the incidence of HCC, although the effect of IFN is reported to be poor in these patients.10,11,25,26 Because of the importance of virological response to IFN, a prospective study of the treatment of cirrhotic patients with HCV infection was conducted by monitoring HCV RNA in serum during and after IFN therapy to clarify the effect of IFN duration on sustained response.
MATERIALS AND METHODS
Patients With Compensated Liver Cirrhosis
The design of this prospective study was discussed on November 13, 1992, by a committee comprised of 28 members from 14 participating hospitals and universities. Diagnostic criteria for compensated liver cirrhosis, the IFN regimens, and follow-up protocol were discussed and approved on December 18, 1992.
Diagnosis. Diagnosis of chronic hepatitis C with cirrhosis was made on the basis of elevated serum ALT level for more than 6 months, positivity for anti-HCV antibody by the passive hemagglutination test (Dinabbot, Tokyo, Japan) or the enzyme-linked immunosorbent assay test (Ortho Diagnostic Systems, Tokyo, Japan), and by histology of liver biopsy specimens. The presence of HCV RNA was tested by RT-PCR. The serum HCV RNA level was measured by competitive RT-PCR according to Kato et al,27 and HCV genotype by the method of Okamoto et al.28 Liver biopsy was performed in all patients within 12 months before enrollment and was evaluated according to Desmet et al.29 The enrollment criteria in the present study were based on (1) liver histology indicating fibrotic stage F4 according to the criteria of Desmet, (2) positivity for HCV RNA by RT-PCR, (3) platelet count greater than 50,000/mm3, and (4) white blood cell count greater than 3,000/mm3. Patients with liver cirrhosis of other causes, such as hepatitis B, autoimmune hepatitis, primary biliary cirrhosis, or drug-induced liver disease were excluded from the study.
IFN Therapy. A data sheet for each patient including clinical, biochemical, virological, and histological data with a record of informed consent was submitted to the Supervisory Committee set up at the Department of Epidemiology and Biostatistics, Tokyo University, Japan, and the data were reviewed by the controller (Y.O.) to determine acceptability for the study. Eligible patients were then enrolled. The drug used for therapy was IFN alfa 2a (Nippon Roche K.K., Tokyo, Japan). Patients received 9 million units (MU) of IFN by intramuscular injection three times a week. If patients could not tolerate this dose, the IFN dose could be reduced from 9 MU to 6 MU, and subsequently to 3 MU. Duration of IFN treatment was determined based on HCV RNA status monitored during IFN treatment.
Randomization. Biochemical and hematological tests were performed every 4 weeks, and HCV RNA in serum was tested every 8 weeks by RT-PCR during IFN therapy. More than 103 copies/mL of HCV RNA could be detected by this RT-PCR. The patients negative for HCV RNA in serum twice sequentially were randomized to determine the subsequent duration of IFN (16 or 32 weeks) before completion of 56 weeks of IFN therapy. The patients positive for HCV RNA at 56 weeks were permitted to discontinue IFN treatment because of one of the following reasons: presence of antibody against IFN, positivity for HCV RNA at 56 weeks, or ALT level above twice the baseline value. The patients positive for HCV RNA were allowed to continue IFN therapy for 64 to 88 weeks, if they requested it.
Follow-up. Biochemical and hematological tests were performed every four weeks, and HCV RNA in serum was tested every 8 weeks by RT-PCR for a further 52 weeks after withdrawal of IFN therapy.
Approval. Evaluation for this protocol from the Ethics Committee of each participating institution was approved. Informed consent was obtained from each patient in accordance with the Helsinki declaration.
A total of 164 patients, who visited the participating hospitals and gave informed consent, underwent examination of pretreatment HCV RNA status and liver biopsy from January, 1993, to October, 1994. The data sheets of these patients were submitted to the controller to check eligibility for enrollment in this study. Four patients were found not to meet the criteria because of absence of informed consent, or lack of histological data, and three patients withdrew before starting IFN therapy. The remaining 157 patients were enrolled in this prospective study and defined as a full analysis set (intention-to-treat population).
Criteria for Virological and Biochemical Response
Patients who were negative for HCV RNA at 24 weeks after completion of IFN therapy were classified as showing sustained virological response (virological SR), whereas patients who were positive for HCV RNA at 24 weeks after the completion of IFN therapy were classified as showing nonsustained response, even if they were negative for HCV RNA during and/or at the end of IFN therapy. Furthermore, patients who showed a persistent normal ALT after completion of IFN therapy were classified as showing sustained biochemical response (biochemical SR), whereas patients who showed an abnormal ALT were classified as showing nonsustained biochemical response.
We used SAS version 6.08 (SAS Institute Inc., Tokyo, Japan) for statistical analysis. The 2 test or Fisher’s exact test was used for comparison of the distribution of parameters between the groups. The 95% confidence intervals for SR rate were calculated based on exact binomial distribution. Kaplan-Meier lifetables were constructed for HCV RNA negativity with patients being censored. HCV RNA negativities in two different treatment duration regimens were compared using the log-rank test. To test candidates for predictive factors for the efficacy of IFN therapy, we used univariate and multivariate logistic regression with stepwise variable selection and/or all combination analysis. Each continuous variable was transformed into categorical data consisting of two ordinal numbers for univariate and multivariate logistic regression analyses. The median value of each parameter was selected for this purpose. Variables that achieved statistical significance (P<.05) in Wald 2 test for univariate analysis were subjected to multiple logistic regression to determine the significance of the independent predictors.
All comparisons between the two different treatment regimens were performed according to the intention-to-treat method. In the intention-to-treat analysis, none in the 157 patients was excluded, even in cases of noncompliance or missing data: patients without endpoint data were considered as failures.
Response to IFN Therapy
A schematic flow chart of the composition of enrolled patients is shown in Fig. 1. Serum HCV RNA was qualitatively tested every 8 weeks by RT-PCR. Negativity for HCV RNA at 8, 16, 24, and 32 weeks was shown in 47, 61, 72, and 73 patients, respectively. The cumulative HCV RNA negativity rates at 40 weeks reached 54.3 ± 4.3% from Kaplan-Meier lifetable (Fig. 2). Sequential negativity for HCV RNA twice was determined at 16 weeks in 43 patients, at 24 weeks in 13, at 32 weeks in 13, at 40 weeks in 1, and at 48 weeks in 3, respectively. These patients were processed for randomization to determine the duration of treatment: 37 patients for further 16 week treatment (+16-week treatment), and 36 for further 32 week administration (+32-week treatment).
|Fig. 2. Cumulative rate of HCV RNA negativity during interferon administration (Kaplan-Meier test). HCV RNA in serum was measured by RT-PCR, and cumulative rate for HCV RNA negativity was analyzed.|
Demographic features of the patients are shown in table 1. When demographic features of the patients in the +16-week treatment and +32-week treatment groups were compared, no significant differences between these two groups were found with regard to age, gender, history of blood transfusion, biochemical parameters, or viral characteristics (table 1). The mean durations of IFN administration in the former and latter groups were 38.1 ± 8.3 weeks and 49.4 ± 13.0 weeks, respectively, with total amounts of IFN of 937 ± 240 MU and 1130 ± 391 MU, respectively. Nonrandomized patients (84 patients) included 40 patients who dropped out or discontinued IFN therapy before 48 weeks, and 44 patients persistently positive for HCV RNA at 48 weeks. The mean duration of IFN administration in the nonrandomized group was 44.8 ± 27.4 weeks, with total amount of IFN of 993 ± 633 MU.
|table 1. Demographic Features of Patients|
Of the 157 patients, virological end-of-treatment response (ETR) and SR was found in 60 (38%) and 32 (20%), respectively, and biochemical ETR and SR was shown in 46 (29%) and 37 (24%), respectively (table 2). Of the 60 patients with virological ETR, 54 were from the randomized group, and 6 were from the nonrandomized group. Of the 32 patients with virological SR, 30 were from the former group, and 2 from the latter group. Furthermore, of the 46 patients with biochemical ETR, 31 were from the randomized group, and 15 were from the nonrandomized group. Of the 37 with biochemical SR, 28 were from the former group, and 9 were from the latter group. The rate of virological or biochemical ETR and SR in the randomized group was significantly higher compared with the nonrandomized group (each P<.01).
|table 2. Efficacy of IFN Therapy on Cirrhotic Patients|
Randomized Patients. After disappearance of HCV RNA during IFN treatment, HCV RNA was detected again in 14 patients in spite of continuous IFN administration. These patients were considered to exhibit virological breakthrough. At the end of treatment, 27 patients (73%) in the +16-week treatment group and 27 (75%) in the +32-week treatment group were negative for HCV RNA, but sustained virological response was demonstrated in 12 (32%) and 18 (50%) patients, respectively (P = .0262: log-rank test).
Of 30 patients with sustained virological response, 26 (87%) were randomized at 16 weeks, and 4 (13%) were randomized thereafter. When the 43 patients who were randomized at 16 weeks were analyzed by IFN regimens of +16-week treatment or +32-week treatment, the virological SR rate for the latter treatment regimen was 67%, in contrast to 53% for the former treatment regimen (95% CI: 28.9%-75.6% for +16-week treatment vs. 44.7%-84.4% for +32-week treatment).
Nonrandomized Patients. Six patients with virological ETR in this group consisted of 5 patients who discontinued IFN therapy because of adverse events (at 9 [2 patients], 21, 28, and 32 weeks), and 1 patient out of 29 receiving IFN therapy for 64 to 88 weeks. However, virological SR was shown in only two patients who discontinued IFN therapy because of adverse events.
Relationship of Biochemical Responses and Virological Responses
Serum ALT levels were then compared with HCV RNA status during and after IFN therapy (Fig. 3). At the end of IFN treatment, normal ALT level was found in only 42% of the patients with virological ETR. Of the 32 patients with virological SR, normal serum ALT level was shown in 12 (38%) at the end of IFN therapy, but in 25 patients (78%) after 24 weeks.
Characteristics of HCV and Efficacy of IFN Therapy
Pretreatment HCV RNA Level. Efficacy of IFN was analyzed with respect to pretreatment level of HCV RNA excluding the 11 patients in whom pretreatment HCV RNA level was undetermined. HCV RNA negativity at the end of IFN therapy was achieved in 55 patients, including 35 of 62 (56%) patients in whom pretreatment HCV RNA level was less than or equal to 106.8 copies/mL, in contrast to 20 of 84 (24%) patients with greater than or equal to 107.3 copies/mL. However, sustained virological response was shown in 54% (25/46) of patients with less than or equal to106.3 copies/mL, in contrast to 4% (4/97) of patients with greater than or equal to 106.8 copies/mL (Fig. 4, P<.0001: 2 test). Of the 73 randomized patients, SR rate in patients with less than or equal to 105.8copies/mL with the +16-week and +32-week administration regimen was similar (90% and 78%, respectively). However, the SR rate in patients with 106.3 to 106.8 copies/mL with the +32-week treatment regimen was 53%, in contrast to 33% with the +16-week treatment regimen (95% CI: 4.3%-77.7% for the +16-week treatment vs. 26.6%-78.7% for the +32-week treatment).
HCV Subtype. The efficacy of IFN was analyzed with respect to HCV subtype (table 3). Rate of ETR was significantly higher in patients with HCV 2a (67%), compared with patients with HCV 1b (33%) (P = .003). In addition, rate of sustained virological response was also higher in patients with HCV subtype 2a (54%), than in patients with HCV 1b (13%) (P = .0001). The SR rate in patients with HCV 1b was slightly higher with the +32-week regimen (33%) than with the +16-week treatment regimen (26%), but not significantly. The SR rate in patients with HCV 2a with the +32-week regimen was 80%, in contrast to 63% with the +16-week treatment regimen (95% CI: 24.5%-91.5% for the +16-week treatment vs. 44.4%-97.5% for the +32-week treatment).
|table 3. Virological Response in Relation to HCV Subtypes and Treatment Regimens|
Factors Affecting IFN Efficacy
Univariate Logistic Regression Analysis. Effect of IFN therapy among the group was analyzed by several parameters; i.e., age, gender, history of blood transfusion, HCV RNA level, HCV subtype, AST, ALT, albumin, bilirubin, and platelet count. The efficacy of IFN for virological ETR and SR depended on HCV RNA level (P = .0004 for virological ETR, P = .0001 for virological SR) and HCV subtype (P = .0182 for virological ETR, P = .0001 for virological SR).
Multivariate Logistic Regression Analysis. Using the parameters exhibiting significance on univariate analysis among 157 patients, multivariate analysis was performed to clarify independent parameters contributing to virological ETR and SR in patients with liver cirrhosis. Although only HCV RNA pretreatment level exhibited significance for virological ETR (P = .004), both HCV RNA pretreatment level (P = .0001) and HCV subtype (P = .037) exhibited significance for virological SR.
Multivariate logistic regression analysis was performed including a parameter of treatment regimen using 73 randomized patients. Previous analysis using Catmod procedure showed that HCV RNA level and HCV subtype were selected as parameters contributing to virological SR. Using these parameters including a parameter of treatment regimen, multivariate analysis was performed, indicating that viral load (P = .0001) was the only significant determining factor in virological SR, but not treatment regimen (P = .183) nor HCV subtype (P = .282).
Adverse Events, Dose Reduction, and Discontinuation of Therapy
Of the 157 patients, IFN dose was reduced from 9 MU to 6 MU for 38 (24%), and to 3 MU for 16 (10%) (table 4).
|table 4. Adverse Events and Tolerability in the Study|
Of the nonrandomized patients, IFN was discontinued for 55; 38 because of adverse events (13 patients within 16 weeks, 15 during 16-32 weeks, 4 during 32-48 weeks, and 6 after 48 weeks) and 17 because of other reasons of detection of malignancy, the progression of liver disease, and at their request (table 4). In the +16-week treatment group, IFN was discontinued in 2 patients, whereas IFN was discontinued for 8 patients in the +32-week treatment group.
There are many studies including ours, indicating that HCV RNA level, HCV subtypes, and the presence of cirrhosis/fibrosis on pretreatment biopsy are factors that influence response to a 6-month course of treatment.10-14 To date, the majority of studies have evaluated initial therapy using fixed-dose, fixed-duration regimens rather than regimens tailored to treatment response. Since cirrhotic patients are known not to respond well to IFN, the present study was conducted to evaluate the efficacy of IFN therapy in cirrhotic patients by monitoring HCV RNA and by prospectively defining the duration of treatment tailored to treatment response.
The HCV RNA negativity rate in the current study was 50.4% until 24 weeks of IFN therapy, but only slightly increased to 54.3% at most even at week 40. On the other hand, most of the patients positive for HCV RNA who were unresponsive to IFN at week 48 of IFN treatment were persistently positive for HCV RNA thereafter. Thus, most cases of virological response to IFN could be determined within 24 to 32 weeks of IFN administration.
Present study showed that virological ETR and SR was found in 38% and 20% of the 157 cirrhotic patients, respectively, and that biochemical ETR and SR was shown in 29% and 24%, respectively. The rates of virological and biochemical ETR and SR in the randomized group were significantly higher than those in the nonrandomized group.
After randomization of the HCV RNA-negative patients into 2 groups of subsequent 16- and 32-week administration of IFN, excellent results were obtained with the longer treatment schedule, with approximately 50% sustained response with subsequent 32-week treatment, in contrast to 32% with subsequent 16-week treatment, as determined by the intention-to-treat method. The mean duration of IFN administration in the +32-week group was approximately 49 weeks, in contrast to 38 weeks in the +16-week group. These findings are consistent with those of a previous meta-analysis indicating that the best efficacy-risk ratio was obtained with 3 MU of IFN three times per week for at least 12 months in patients with chronic hepatitis C,19 although the IFN dose was higher in our study and administered intramusclarly.
Furthermore, patients with early disappearance of HCV RNA in serum at both 8 and 16 weeks (as who were randomized at 16 weeks) exhibited a significantly higher virological SR rate than those with later disappearance. These results suggest that most of the sustained virological response may be achieved only in those patients with early disappearance of HCV RNA in serum, especially within 8 weeks after initiation of IFN therapy.
A previous study revealed a breakthrough phenomenon during IFN therapy, in which ALT level become temporarily normal and then abnormal again during treatment.30 We also found a virological breakthrough in 14 (19%) of the 73 cirrhotic patients responding to IFN during treatment, in which HCV RNA become temporarily undetectable , but was detected again even during treatment. There is an evidence that breakthrough may be related to the development of viral quasispecies or neutralizing antibody to IFN.31
In the present study, biochemical response during IFN therapy did not reflect virological response. There was a relative high percentage (62%) of virological SR patients with elevated ALT values at the end of therapy, which corrected in most of these patients after therapy was stopped. Although there may be a possibility that hyperlipidemia during IFN may explain this phenomenon, triglyceride levels were not different between the patients with normal ALT and those with elevated ALT in this study (data not shown). These features contrast with those of patients with chronic hepatitis, in whom the discrepancy of HCV RNA status and biochemical response was only 10% to 15% during IFN therapy.32 Thus, monitoring of HCV RNA may be more important than monitoring of biochemical parameters during IFN treatment especially in cirrhotic patients.
When the results of the present study were analyzed with respect to HCV RNA load and subtypes, it was found that virological SR could be efficiently achieved in patients with low viral load (106.3 copies/mL) and with HCV subtype 2a. On univariate analysis, the pretreatment level of HCV RNA and HCV subtype exhibited significance for virological ETR and SR. Multivariate analysis revealed significance of HCV RNA and HCV subtype for virological SR. Furthermore, the predominant importance of HCV RNA level among these parameters was shown by the analysis using 73 randomized patients, not treatment regimen.
When these findings are compared with those of our previous study,14,33 it was found that virological SR could be achieved in half of the cirrhotic patients with 106.3 HCV RNA copies/mL, but with a longer treatment regimen (38 to 49 weeks). Furthermore, it is interesting that the difference in SR rate between shorter- and longer-course of treatment was mainly brought by patients presenting HCV RNA load between 106.3 and 106.8 copies/mL. This may have occurred in part because an efficient amount of IFN in the cirrhotic liver might be less than the expected amount by the fibrotic process of the liver and need longer duration of treatment.34 Thus, a longer course of treatment may be needed to achieve a high rate of efficacy with IFN in cirrhotic patients.
Although higher doses of IFN result in a higher virological SR rate, they are often poorly tolerated.35, 36 In fact, IFN dose was reduced from 9 MU to 6 or 3 MU in 34% of the patients in the present study. Furthermore, long-term therapy is poorly tolerated, especially in unresponsive patients. Severe adverse events were observed among these cirrhotic patients, and one patient died because of subarachnoid hemorrhage in the present study. Because cirrhotic patients are older than patients with chronic hepatitis, they often suffer from various diseases of hypertension, hypercholestemia, ischemic heart diseases, diabetes mellitus, etc. These patients should thus be treated with great care. Consistent with previous studies,16, 17 a longer course of therapy resulted in a higher rate of sustained response. However, the longer course of treatment is more expensive and causes more discomfort than the 6-month course. Thus, monitoring the level of HCV RNA may be a more accurate method for assessing the response to therapy, and IFN therapy may be discontinued in patients unresponsive to IFN.
In conclusion, the present study strongly suggested that HCV RNA level and HCV subtypes are important factors contributing to the efficacy of IFN therapy even in cirrhotic patients, and that sustained virological response rate can be increased by a longer course of IFN treatment. Thus, before starting IFN therapy for patients with chronic hepatitis, especially those with cirrhosis, the fibrotic stage of the liver should be evaluated to select treatment regimens to obtain higher efficacy of IFN therapy. For patients who begin initial therapy with IFN, treatment effectiveness must be determined by monitoring HCV RNA during therapy, and IFN may be discontinued in unresponsive patients. Recent studies found an improvement in liver histology in patients with virological SR.21 In addition, a decreased incidence of development of hepatocellular carcinoma was demonstrated in cirrhotic patients after IFN therapy.37-39 Thus, effective therapy for cirrhotic patients with HCV infection might reduce the incidence of development of HCC after treatment.
HCC, hepatocellular carcinoma; IFN, interferon; HCV-RNA, hepatitis C virus RNA; ALT, alanine transaminase; RT-PCR, reverse transcription polymerase chain reaction; MU, million units; SR, sustained response; ETR, end-of-treatment response.
Received August 25, 1998; accepted February 2, 1999.
Address reprint requests to: Yasushi Shiratori, M.D., Department of Internal Medicine (II), University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. Fax, 81-3-3814-0021.
Copyright © 1999 by the American Association for the Study of Liver Diseases.