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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Protocol for Interferon Treatment
  5. Results
  6. Discussion
  7. References

Acute hepatitis C often progresses to chronic infection. We undertook a randomized controlled trial to determine whether short-term therapy with interferon (IFN) during acute hepatitis C is effective in preventing the development of chronic hepatitis. Thirty patients with acute hepatitis C were randomized into 1 of 2 treatment groups. IFN therapy was initiated 8 weeks after the onset of acute hepatitis in the early-intervention group and after 1 year of observation in the late-intervention group. Short-term therapy consisted of natural IFN-alfa (6 million units) administered on consecutive days for a period of 4 weeks. Any signs of recrudescence of disease were immediately followed by interval IFN therapy (3 times weekly for 20 weeks). In the early-intervention group, short-term therapy was associated with a sustained virological response in 13 of 15 patients (87%). Follow-up treatment was associated with a sustained virological response in both of the remaining 2 patients (100%). The sustained virological response rate was significantly higher in the early-intervention group (87%, 13 of 15 patients after short-term therapy alone, and 100%, 15 of 15 patients after short-term with or without follow-up therapy) than in the late-intervention group (40%, 6 of 15 patients after short-term therapy alone, and 53%, 8 of 15 patients after short-term therapy with or without follow-up therapy, P = .021 and P = .006, respectively). In conclusion, short-term (4 weeks) IFN treatment of patients with acute hepatitis C may be associated with satisfactory results, if initiated at an early stage of the disease. (HEPATOLOGY 2004;39:1213–1219.)

Acute hepatitis that develops after infection with the hepatitis C virus (HCV) is often followed by chronic hepatitis, which may progress eventually to cirrhosis and hepatocellular carcinoma (HCC).1, 2 In the past, the primary causes of infection with HCV were blood transfusion and various medical procedures. Today, blood products in Japan are aggressively screened for HCV and disposable medical devices are in widespread use; there has been a reduction in the incidence of HCV infection. However, patients with acute hepatitis C resulting from treatment-related accidents (needle-stick injury), intravenous drug abuse, sexual contact with HCV-positive partners and unknown causes still occasionally present.3–5 Interferon (IFN) therapy in patients with chronic hepatitis C has considerable potential for preventing the development of HCC, either by eradicating HCV, or by decreasing the activity of hepatitis.6–9 However, the therapeutic effects of IFN vary depending on the HCV genotype and viral load.10, 11

Although much research has already been undertaken on IFN therapy for acute hepatitis C, findings in trials that relate to the effectiveness of this therapy have not been particularly favorable. Possible reasons include differences in types of IFN, differences in study populations, and inclusion of patients with posttransfusion hepatitis.12–17 However, Jaeckel et al.3 reported that a 24-week course of IFN therapy was effective, and that the response to IFN treatment was more favorable in acute hepatitis C than in chronic hepatitis C. Although randomized controlled trials have been used to study the effects of IFN therapy on acute hepatitis C, so far there have been no reports on the most suitable duration of IFN treatment or timing of its initiation.

Short-term (4 weeks) IFN therapy was administered at an early stage of acute hepatitis in patients who met strict diagnostic criteria for acute hepatitis C. The objective was to corroborate the effectiveness of short-term IFN therapy in the treatment of this condition. A randomized controlled trial was designed to determine the appropriate duration of treatment and the timing of initiation of treatment with IFN therapy for acute hepatitis C. The results indicated that it should not be necessary to treat all patients with acute hepatitis C with the 24-week course of treatment that is most commonly administered for chronic hepatitis C in Japan.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Protocol for Interferon Treatment
  5. Results
  6. Discussion
  7. References

Patients.

Thirty-nine patients with acute hepatitis C who attended Shin-Kokura Hospital between January 1994, and December 2000, were studied. Criteria for the diagnosis of acute hepatitis C were: (1) At the onset of acute hepatitis, serum alanine aminotransferase (ALT) levels at least 7 × upper limit of the normal range (ULN), HCV-RNA positive and anti-HCV negative; or (2) negative HCV-RNA at the time of a needle-stick accident, but subsequent HCV-RNA positive and ALT levels at least 7 × ULN. All of the patients with acute hepatitis C had no history of blood transfusion. The patients were negative for both immunoglobulin M anti–hepatitis A virus and antinuclear antibody. Patients infected with the human immunodeficiency virus were not included in the study. Two patients were hepatitis B surface antigen positive, and 3 patients had been drinking at least 80 g of alcohol daily; these 5 patients were excluded from the study. At the onset of acute hepatitis, 20 of the remaining 34 patients had symptoms such as general malaise, loss of appetite, and a feeling of abdominal fullness; 14 patients were asymptomatic. The 20 symptomatic patients were diagnosed with acute hepatitis C when they developed symptoms. In 8 of the 14 asymptomatic patients, the diagnosis was made during follow-up after a needle-stick injury. Of the 10 patients followed after needle-stick injury, 8 were asymptomatic and 2 developed symptoms. The remaining 6 asymptomatic patients were diagnosed with acute hepatitis C, as a result of regular tests conducted during clinic visits for other diseases, such as diabetes mellitus.

For 8 weeks after developing acute hepatitis C, 34 patients were tested once weekly for serum ALT and once monthly for HCV-RNA. Of these, 4 patients cleared HCV-RNA during the 8 weeks of initial observation. In 3 of 20 patients with symptoms at onset, clearance of HCV-RNA occurred within 8 weeks. Total bilirubin increased to levels greater than 3.0 mg/dL in 3 of 34 patients during the 8-week follow-up period. In 2 of these 3 patients with jaundice, HCV-RNA clearance occurred within 8 weeks. One patient was positive for HCV-RNA after 8 weeks and was treated with IFN. A total of 30 patients, who were HCV-RNA positive and had ALT levels of at least 7 × ULN at 8 weeks, were enrolled in the study. The route of infection was needle-stick accident in 10 patients, intravenous drug use in 3 patients, sexual contact with an infected partner in 4 patients, and unknown in 13 patients. The time from exposure to onset of hepatitis was 7.3 ± 2.1 weeks (mean ± SD) (range, 5-12 weeks) in 10 the patients who had had a needle-stick injury and who were followed from the time of infection until the time symptoms appeared. Of the 5 patients in the early-intervention group, the time from infection to the start of treatment was 15.6 × 2.7 (range, 13-20) weeks.

Thirty patients were randomized at enrollment into 1 of 2 treatment groups using an enrollment sheet method; there were 15 patients per group. IFN therapy was initiated 8 weeks after acute hepatitis was diagnosed in the early-intervention group, and after 1 year of follow-up in the late-intervention group. The initial plan in this study, which was designed in 1994, was to recruit 30 patients. Characteristics of the patients studied are shown in Table 1. The patients included 19 men and 11 women, whose ages ranged from 22 to 59 years; the mean age was 40.4 years in the early-intervention group and 37.6 years in the late-intervention group. There was no significant difference in sex ratio and age between the two groups. Viral load was measured immediately before IFN therapy, using an Amplicor-HCV monitor assay (Roche Molecular Diag., Tokyo, Japan). Patients were designated as having a low viral load (less than 105 copies/mL), or a high viral load (105 copies/mL or greater). There was no significant difference in viral load between the early-intervention group and the late-intervention group. The genotype of HCV was 1b in about 80% of patients; there was no significant difference in the frequency of this genotype between the two groups. The ULN for serum ALT was set at 40 IU/L.

Table 1. Patient Baseline Characteristics
 Early-Intervention Group N = 15Late-Intervention Group N = 15Total N = 30
  • Abbreviation: y, years.

  • *

    HCV load: low (<1 × 105 copies/mL), high (≥ 1 × 105 copies/mL)

  • Copies/mL refers to HCV-RNA.

Age (y, mean ± SD)40 ± 1138 ± 1039 ± 10
Gender (male/female)10/59/619/11
Baseline test values (before IFN therapy)   
 Serum ALT (IU/L, mean ± SD)491 ± 181431 ± 143460 ± 161
 HCV-RNA (low/high)*8/79/617/13
 (105 copies/mL, mean ± SD)2.91 ± 2.412.56 ± 2.782.74 ± 2.66
 Genotype (1b/others)12/313/225/5
Mode of HCV Infection   
 Needle-stick injury5510
 Intravenous drug use123
 Sexual contact with HCV-positive partners224
 Unclear7613

Protocol for Interferon Treatment

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Protocol for Interferon Treatment
  5. Results
  6. Discussion
  7. References

Initial Interferon Therapy (Short-term Interferon Therapy).

Patients in the early-intervention group were treated with 6 million units (MU) of natural IFN-alfa (human lymphoblastoid interferon [HLBI], Sumitomo Pharmaceutical, Osaka, Japan) by intramuscular injection, once daily for 4 consecutive weeks during the early stage of acute hepatitis. The clinical course of patients in the late-intervention group was monitored for 1 year; patients continuing to be HCV-RNA positive after 1 year were treated with 6 MU of HLBI by intramuscular injection once daily for a period of 4 consecutive weeks.

Follow-up Interferon Therapy.

Following completion of 4 the initial weeks of IFN therapy, all patients were followed-up, and HCV-RNA and serum ALT were monitored. Additional IFN therapy was administered to patients who were HCV-RNA positive after completion of the initial course of IFN therapy or who relapsed and became HCV-RNA positive again after completion of the initial course of IFN therapy. IFN therapy was 6 MU of HLBI injected intramuscularly, 3 times weekly, for 20 weeks. For all patients, IFN therapy was administered at Shin-Kokura Hospital.

Serological and Virological Assays.

Serum ALT levels were measured once weekly during the initial 4-week period of treatment, and once every 4 weeks during follow-up IFN therapy and monitoring after treatment. During initial treatment, HCV-RNA was measured at Week 1, Week 2, and upon completion of treatment. In addition, these measurements were also undertaken at 4, 8, 12, 16, 20, and 24 weeks after completion of the initial course of treatment or follow-up IFN therapy. Anti-HCV antibodies were determined at the onset of hepatitis and 24 weeks after completion of IFN therapy, using a second-generation enzyme immunoassay. Effective IFN therapy was considered to be the induction of a sustained virological response—that is, HCV-RNA remaining negative for 24 weeks after completion of the initial course or the follow-up course of IFN therapy. HCV-RNA was measured using 2 methods, nested polymerase chain reaction and Amplicor-HCV assay, version 2.0 (Roche Molecular Diag., Tokyo, Japan), 24 weeks after completion of the initial or follow-up course of IFN therapy. Negative results of both tests were required to infer a sustained virological response. Those patients who were not classified as having undergone a sustained virological response were considered to be nonresponsive. Patients who underwent a sustained virological response were followed for at least 2 years after treatment, and HCV-RNA was measured again at the end of the 2-year period of follow-up, using the Amplicor-HCV assay, version 2.0. HCV genotyping was undertaken as previously described.18

Informed Consent.

The study protocol was approved by institutional ethics committees. All patients gave written informed consent to participate in this study. The study was conducted in accordance with ethical guidelines of the Declaration of Helsinki and the International Conference on Harmonization guidelines for good clinical practice. No patient withdrew informed consent to participate in the study.

Statistical Analysis.

The early-intervention and late-intervention groups, and the sustained virological response and nonresponsive groups were compared using the unpaired Student t test or Fisher exact test. All P values reported in this study were 2-tailed. P values less than .05 were considered to be statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Protocol for Interferon Treatment
  5. Results
  6. Discussion
  7. References

Effect of Early- vs. Late-Intervention IFN Therapy.

Results of IFN therapy are shown in Table 2. A sustained virological response occurred in 13 out of 15 (87%) patients in the early-intervention group following initial therapy. A recrudescence of disease developed in 2 patients in the early-intervention group 4 weeks after completion of the initial therapy. In these 2 patients a sustained virological response occurred after a 20-week course of follow-up IFN therapy. Thus, sustained virological responses occurred in all 15 patients in this group. In the late-intervention group, serum ALT levels fell below 2 × ULN in 6 patients during the 1-year monitoring period, but all patients were HCV-RNA positive immediately before IFN therapy. A sustained virological response occurred after initial IFN therapy in 6 (40%) patients in this group; a recrudescence of disease occurred in 9 patients. These 9 patients received follow-up IFN therapy, and a sustained virological response subsequently occurred in 2 of them. Thus, 8 of 15 (53%) patients in the late-intervention group had a sustained virological response. The sustained virological response rate was significantly higher in the early-intervention group than in the late-intervention group, after both initial and follow-up therapy (P = .021 and P = .006, respectively). All patients who were considered to have a sustained virological response were monitored for at least 2 years after treatment; during this period, serum ALT levels did not exceed the ULN in any of these patients. In addition, in these patients HCV-RNA remained negative at the end of the 2-year period. All patients seroconverted and became anti-HCV antibody–positive.

Table 2. Results of Interferon Treatment
 Early-Intervention GroupLate-Intervention GroupTotalP Value
SR/N(%)*SR/N(%)*SR/N(%)*
  • Abbreviation: SR: sustained virological response.

  • *

    (%): Rate of sustained virological response.

  • P value for the comparison of early-intervention group to late-intervention group by Fisher exact test (2-tailed).

  • Copies/mL refers to HCV-RNA.

After short-term IFN therapy       
< 1 × 105 copies/mL       
 1b6/6(100)4/7(57)10/13(77)>.1
 others2/2(100)2/2(100)4/4(100) 
 total8/8(100)6/9(67)14/17(82)>.1
≥ 1 × 105 copies/mL       
 1b4/6(67)0/6(0)4/12(33).061
 others1/1(100)0/0(0)1/1(100) 
 total5/7(71)0/6(0)5/13(38).021
Total13/15(87)6/15(40)19/30(63).021
After follow-up IFN therapy       
< 1 × 105 copies/mL       
 1b6/6(100)5/7(71)11/13(85)>.1
 others2/2(100)2/2(100)4/4(100) 
 total8/8(100)7/9(78)15/17(88)>.1
≥ 1 × 105 copies/mL       
 1b6/6(100)1/6(17)7/12(58).015
 others1/1(100)0/0(0)1/1(100) 
 total7/7(100)1/6(17)8/13(62).005
Total15/15(100)8/15(53)23/30(77).006

Results of short-term IFN administration, stratified by viral load and genotype, were as follows. A low viral load in the early-intervention group was associated with a sustained virological response in all patients, regardless of genotype. In the late-intervention group, the sustained virological response rate was 57% (4/7) for patients with genotype 1b. In the early-intervention group, among patients with a high viral load, a sustained virological response occurred in 5 of 7 (71%) patients and in 4 of 6 (67%) of those with genotype 1b. In the late-intervention group, sustained virological responses did not occur in any patient with a high viral load. Thus, the sustained virological response rate was significantly higher in the early-intervention group than in the late-intervention group (P = .021).

After follow-up IFN therapy, sustained virological responses occurred in the 2 patients with a high viral load in the early-intervention group, so that sustained virological responses eventually occurred in all patients in this group. In the late-intervention group, a sustained virological response occurred after follow-up therapy in 1 patient with a low viral load and 1 patient with a high viral load. Results after follow-up indicated that the sustained virological response rate for patients with a high viral load in the early-intervention group was significantly higher than that in the late-intervention group (P = .005).

The presence or absence of symptoms at the onset of hepatitis and the efficacy of IFN therapy were investigated. In the early-intervention group, 8 patients were symptomatic and 7 patients were asymptomatic. There was no difference in the sustained virological response rate between symptomatic patients (88%, 7 out of 8 patients) and asymptomatic patients (86%, 6 out of 7 patients) after short-term therapy. In the late-intervention group, 9 patients were symptomatic and 6 patients were asymptomatic. After short-term therapy, the sustained virological response rate was higher in the symptomatic patients (56 %, 5 out of 9 patients) than in the asymptomatic patients (17%, 1 out of 6 patients), but the difference was not significant. After additional therapy, the sustained virological response rate was higher in the symptomatic patients (67%, 6 out of 9 patients) than in the asymptomatic patients (33%, 2 out of 6 patients), but the difference was not significant. There was, therefore, no relationship between the presence or absence of symptoms at the onset of hepatitis and the efficacy of IFN therapy.

Sustained Virological Response and Eradication of HCV-RNA During Initial Therapy.

Table 3 shows the virological state of patients who became negative for HCV-RNA during initial IFN therapy. HCV-RNA became negative at Week 1 after the start of treatment in 13 patients in the early-intervention group and in 5 patients in the late-intervention group; the higher conversion rate for the early-intervention group was significant (P = .008). A sustained virological response occurred after initial treatment in all 18 patients who tested negative for HCV-RNA at Week 1. An additional 5 patients were negative for HCV-RNA at Week 2. Of these, 1 patient from the late-intervention group underwent a sustained virological response at the completion of the initial therapy; a recrudescence of disease occurred in the other 4 patients. After follow-up therapy, all 4 of these patients also underwent a sustained virological response. All 7 patients who continued to be positive for HCV-RNA at Week 2 were in the late-intervention group. These 7 patients continued to be HCV-RNA positive after completion of the initial treatment and continued to be virological nonresponders after follow-up therapy.

Table 3. Patients Becoming HCV-RNA Negative During Short-Term Therapy and Sustained Virological Response
 Early-Intervention Group N = 15Late-Intervention Group N = 15Total N = 30
  • Abbreviation: SR, sustained virological response.

  • *

    P = .008 for the comparison of early-intervention group to late-intervention group by the Fisher exact test (2-tailed)

  • **

    P = .006 for the comparison of early-intervention group to late-intervention group by the Fisher exact test (2-tailed).

  • (%): Rate of sustained virological response.

HCV-RNA negative at Week 1 after starting treatment13*5*18
HCV-RNA negative at Week 2 after starting treatment15**8**23
HCV-RNA negative at the completion of 4-week treatment15**8**23
SR (%) after short-term therapy13 (87%)6 (40%)19 (63%)
SR (%) after follow-up therapy15 (100%)8 (53%)23 (77%)

Factors Influencing the Efficacy of Initial IFN Treatment.

Table 4 shows the results of initial IFN treatment classified according to various factors. Univariable analysis of sustained virological response after initial therapy yielded the following results: age (P = .467), gender (P = .238), pretreatment serum ALT levels (P = .218), HCV load (P = .009), genotype (P = .129), timing of initial treatment (P = .021), and loss of HCV-RNA by Week 1 (P < .001). Significant factors were viral load (low viral load group), the timing of initial treatment (early-intervention group), and loss of HCV-RNA by Week 1.

Table 4. Efficacy of Initial Interferon Treatment Classified According to Factor
 Sustained Virological Response N = 19No Response N = 11P Value*
  • Abbreviation: y, years.

  • *

    P value for comparison with sustained virological response to nonresponse by the Fisher exact test (2-tailed) or the unpaired Student t test.

  • HCV load: low (< 1 × 105 copies/mL), high (≥ 1 × 105 copies/mL).

  • Copies/mL refers to HCV-RNA.

Age (y, mean ± SD)40 ± 1237 ± 8.467
Gender (male/female)14/55/6.238
Baseline test values (before IFN therapy)   
 Serum ALT (IU/L, mean ± SD)493 ± 201406 ± 143.218
HCV load (low/high)14/53/8.023
(105 copies/mL, mean ± SD)1.78 ± 2.244.40 ± 2.81.009
Genotype (1b/others)14/511/0.129
Time of treatment initiation (early-intervention group/late-intervention group)13/62/9.021
HCV-RNA at Week 1 (negative/positive)18/10/11<.001

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Protocol for Interferon Treatment
  5. Results
  6. Discussion
  7. References

Our randomized controlled trial in patients with acute hepatitis C demonstrates that short-term (4 weeks) IFN therapy is effective when the treatment is initiated 8 weeks after the onset of acute hepatitis. In this study, to demonstrate the efficacy of short-term IFN therapy for acute hepatitis C, we applied strict criteria for the diagnosis; patients with posttransfusion hepatitis were excluded. As substantiated by our study, acute hepatitis C is associated with a few subjective symptoms that are easily overlooked by many patients. Diagnosis requires finding elevated serum ALT levels, and conversion from HCV-RNA negative to HCV-RNA positive.

There are no standard methods for treatment of acute hepatitis C. Both IFN-alfa3–5, 13, 15–17 and IFN-beta12, 14 have been used. Previous studies have involved predominantly asymptomatic patients with posttransfusion hepatitis.13–15 Recent studies by European researchers4, 5 have shown that 75% or 68% of patients have jaundice at the onset of acute hepatitis C, but Japanese studies have found that few patients have jaundice at the onset.12, 19 The latter finding is consistent with the results of this study, in which only 3 of 34 patients had jaundice. The reason for this difference in the incidence of jaundice at the onset of acute hepatitis C between Europeans and Japanese is unclear. A recent study of the natural history of acute hepatitis C found spontaneous viral clearance within 5 weeks of the onset of symptoms in a high proportion of patients with symptomatic hepatitis.4 As a 24-week course of IFN therapy starting immediately after the onset of acute hepatitis C was very effective (sustained response of 95%),3 deciding when to start IFN therapy is important; spontaneous clearance of HCV may occur within 5 weeks of the onset of acute hepatitis C. In addition, asymptomatic acute hepatitis C is common in Japan. Therefore, in this study we monitored serum ALT levels and HCV-RNA for 8 weeks before initiating of IFN therapy. Clearance of HCV occurred within this 8-week period in 4 of 34 patients. All patients in the late-intervention group underwent some changes in serum ALT levels during the 1-year period of observation, but none of these patients became HCV-RNA negative after 1 year.

Recent reports of European studies4, 5 indicated a high rate (67%-68%) of spontaneous HCV clearance within 12 weeks of the onset of acute hepatitis C, but the corresponding rate was low in our study (12%). The reason for this difference is unclear, but the fact that we observed our patients for only an 8-week period may have been a contributing factor. In Japan, patients are often referred to a specialist hospital by the doctor who made the initial diagnosis of acute hepatitis, if treatment is considered to be necessary. Since most patients referred do require treatment, it is possible that patients in whom hepatitis resolves spontaneously would have been excluded. Spontaneous clearance of HCV should be investigated in a large group of patients who have been followed from the time of infection to the onset of acute hepatitis C. In our study, spontaneous clearance of HCV was not observed in any patients who had a needle-stick injury and who had been followed from the time of the infection to the onset of acute hepatitis C. The natural history of acute hepatitis C in the Japanese seems to be different from that in Europeans, but there are no data available to indicate whether this is the case.

We found no relationship between the presence or absence of symptoms at the onset of hepatitis and the efficacy of IFN therapy, although spontaneous clearance of HCV occurred in many patients with symptoms at the onset.4, 5 In this study, short-term daily IFN therapy was associated with a high (87%) sustained virological response rate. When a recrudescence of disease occurred in the early-intervention group, patients received an additional 20-week course of follow-up therapy; sustained virological responses occurred in all patients. In this respect our results are similar to those reported by Jaeckel et al.3 It appears that IFN therapy is more effective in acute hepatitis C than in chronic hepatitis C. Due to IFN treatment's high cost and frequency of adverse events, it is desirable to shorten the duration of treatment with IFN as much as is practicable.

When we studied the efficacy of IFN therapy in patients in whom HCV-RNA became negative during short-term (4 weeks) treatment, we found that it was necessary for patients to become HCV-RNA negative within the first week of treatment for a sustained virological response to occur. A sustained virological response occurred in all 18 patients, in whom this early event occurred; monitoring for at least the following 2 years indicated that no recurrence of HCV-RNA positivity and no relapse of elevated serum ALT levels occurred in any of these patients. In IFN therapy for chronic hepatitis C, the sustained virological response rate is low if the HCV load does not decrease early after the start of therapy.20 These findings suggest that short-term IFN therapy may be associated with satisfactory results in acute hepatitis C, if patients become HCV-RNA negative within the first week of treatment. Conversion from HCV-RNA positive to HCV-RNA negative within 2 weeks of the start of IFN therapy is one indicator that treatment of chronic hepatitis C may be efficacious.21, 22 We also found that a 20-week course of follow-up IFN therapy may be associated with a sustained virological response in patients who are HCV-RNA negative within 2 weeks of starting treatment.

In this study, significant predictive factors were viral load (low viral load), timing of initial treatment (early-intervention group), and conversion to HCV-RNA negative at Week 1. Although viral load is the best predictor of the efficacy of IFN therapy for chronic hepatitis C,10, 11 it was also found to be a significant predictor of a sustained virological response in patients with acute hepatitis C. Our results suggest that a short course (4 weeks) of IFN therapy for acute hepatitis C may be associated with satisfactory results in patients who have low viral loads, by whom IFN therapy is started early, or who become HCV-RNA negative within one week of the initiation of treatment.

In chronic cases that had been monitored for 1 year, the viral elimination rate was also high for those with a low viral load. As fulminant hepatic failure is rare in acute hepatitis C, it was previously believed that spontaneous clearance of HCV would occur after the hepatitis had spontaneously subsided. Accordingly, patients were followed for 1 year, rather than having costly IFN treatment at an early stage of the disease. However, in this study we found that IFN therapy was more effective when the treatment was initiated at an early stage after the onset of acute hepatitis. We studied 2 groups; treatment was initiated after 8 weeks of monitoring in the early-intervention group and after observation for a year or more in the late-intervention group. However, we were unable to investigate the timing of initiation of IFN therapy after the onset of acute hepatitis C. Hofer et al.4 reported that patients with acute hepatitis C had a high rate of spontaneous viral clearance within one month of onset of symptoms, and that IFN therapy was indicated in patients who failed to clear the virus within 35 days of the onset of symptoms. Gerlach et al.5 observed that spontaneous clearance of HCV usually occurs within 12 weeks of the onset of symptoms; no spontaneous clearance of HCV occurred after 16 weeks. The timing of IFN therapy for acute hepatitis C should, therefore, be investigated in a larger study.

In conclusion, short-term (4 weeks) IFN therapy at an early stage of acute hepatitis C may be associated with satisfactory results, especially when HCV-RNA becomes negative within the first week of treatment. If the patient remains HCV-RNA positive after Week 1 of IFN treatment, a 24-week course of IFN therapy is recommended to try to achieve a satisfactory result.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Protocol for Interferon Treatment
  5. Results
  6. Discussion
  7. References
  • 1
    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; 22: 825832.
  • 2
    Takano S, Yokosuka O, Imazeki F, Tagawa M, Omata M. Incidence of hepatocellular carcinoma in chronic hepatitis B and C: a prospective study of 251 patients. HEPATOLOGY 1995; 21: 650655.
  • 3
    Jaeckel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M, et al. German Acute Hepatitis C Therapy Group. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001; 15: 14521457.
  • 4
    Hofer H, Watkins-Riedel T, Janata O, Penner E, Holzmann H, Steindl-Munda P, et al. Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load. HEPATOLOGY 2003; 37: 6064.
  • 5
    Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung MC, Ulsenheimer A, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 2003; 125: 8088.
  • 6
    Ikeda K, Saitoh S, Arase Y, Chayama K, Suzuki Y, Kobayashi M, et al. Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: a long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis. HEPATOLOGY 1999; 29: 11241130.
  • 7
    Kasahara A, Hayashi N, Mochizuki K, Takayanagi M, Yoshioka K, Kakumu S, et al. Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Osaka Liver Disease Study Group. HEPATOLOGY 1998; 27: 13941402.
  • 8
    Imazeki F, Yokosuka O, Fukai K, Saisho H. Favorable prognosis of chronic hepatitis C after interferon therapy by long-term cohort study. HEPATOLOGY 2003; 38: 493502.
  • 9
    Arif A, Levine RA, Sanderson SO, Bank L, Velu RP, Shah A, et al. Regression of fibrosis in chronic hepatitis C after therapy with interferon and ribavirin. Dig Dis Sci 2003; 48: 14251430.
  • 10
    Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 26: 975982.
  • 11
    Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958965.
  • 12
    Omata M, Yokosuka O, Takano S, Kato N, Hosoda K, Imazeki F, et al. Resolution of acute hepatitis C after therapy with natural beta interferon. Lancet 1991; 338: 914915.
  • 13
    Viladomiu L, Genesca J, Esteban JI, Allende H, Gonzalez A, Lopez-Talavera JC, et al. Interferon-alpha in acute posttransfusion hepatitis C: a randomized, controlled trial. HEPATOLOGY 1992; 15: 767769.
  • 14
    Takano S, Satomura Y, Omata M. Effects of interferon beta on non-A, non-B acute hepatitis: a prospective randomized, controlled-dose study. Gastroenterology 1994; 107: 805811.
  • 15
    Lampertico P, Rumi M, Romeo R, Craxi A, Soffredini R, Biassoni D, et al. A multicenter randomized controlled trial of recombinant interferon–alpha 2b in patients with acute transfusion-associated hepatitis C. HEPATOLOGY 1994; 19: 1922.
  • 16
    Hwang SJ, Lee SD, Chan CY, Lu RH, Lo KJ. A randomized controlled trial of recombinant interferon alpha-2b in the treatment of Chinese patients with acute post-transfusion hepatitis C. J Hepatol 1994; 21: 831836.
  • 17
    Ohnishi K, Nomura F, Nakano M. Interferon therapy for acute post-transfusion non-A, non-B hepatitis: response with respect to anti-hepatitis C virus antibody status. Am J Gastroenterol 1991; 86: 10411049.
  • 18
    Simmonds P, Alberti A, Alter HJ, Bonino F, Bradley DW, Brechot C, et al. A proposed system for the nomenclature of hepatitis C virus genotypes. HEPATOLOGY 1994; 19: 13211324.
  • 19
    Oketani M, Higashi T, Yamasaki N, Shinmyozu K, Osame M, Arima T. Complete response to twice-a-day interferon-beta with standard interferon-alpha therapy in acute hepatitis C after a needle-stick. J Clin Gastroenterol 1999; 28: 4951.
  • 20
    Jessner W, Gschwantler M, Steindl-Munda P, Hofer H, Watkins-Riedel T, Wrba F, et al. Primary interferon resistance and treatment response in chronic hepatitis C infection: a pilot study. Lancet 2001; 358: 12411242.
  • 21
    Nomura H, Kimura Y, Morita C, Tada H, Okamoto O, Shiraishi G, et al. Usefulness of HCV-RNA assays in efficacy evaluation of interferon treatment for chronic hepatitis C: Amplicor HCV assay and branched DNA probe assay. J Infect 1997; 34: 349355.
  • 22
    Yamaji K, Hayashi J, Kawakami Y, Furusyo N, Sawayama Y, Kishihara Y, et al. Hepatitis C viral RNA status at two weeks of therapy predicts the eventual response. J Clin Gastroenterol 1998; 26: 193199.