Relation of Interferon Therapy and Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

  1. Yasuharu Imai, MD;
  2. Sumio Kawata, MD;
  3. Shinji Tamura, MD;
  4. Iwao Yabuuchi, MD;
  5. Shuzo Noda, MD;
  6. Masami Inada, MD;
  7. Yuichi Maeda, MD;
  8. Yasuhiro Shirai, MD;
  9. Takaaki Fukuzaki, MD;
  10. Itaru Kaji, MD;
  11. Hideki Ishikawa, MD;
  12. Yukihiko Matsuda, MD;
  13. Masahiro Nishikawa, MD;
  14. Kouichi Seki, MD; and
  15. Yuji Matsuzawa, MD
  1. For the Osaka Hepatocellular Carcinoma Prevention Study Group. From Osaka University Medical School, Osaka, Japan. Acknowledgment: The authors thank Hideaki Tsukuma, MD, for his comments on the manuscript. Requests for Reprints: Sumio Kawata, MD, Second Department of Internal Medicine, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan. Current Author Addresses: Drs. Imai and Nishikawa: Department of Internal Medicine, Ikeda Municipal Hospital, 3-1-18 Johnan, Ikeda, Osaka 563, Japan.
     
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    Abstract

    Background: The effect of interferon therapy on the incidence of hepatocellular carcinoma in chronic hepatitis C is poorly defined.

    Objective: To compare the incidence of hepatocellular carcinoma in interferon-treated patients with chronic hepatitis C to that of historical controls and to examine whether response to therapy is related to incidence of hepatocellular carcinoma in patients with chronic hepatitis C.

    Design: Retrospective cohort study.

    Setting: One university hospital and seven university-affiliated hospitals.

    Patients: 419 consecutive patients with chronic hepatitis C who started interferon therapy between January 1992 and December 1993 (interferon group) and 144 patients with chronic hepatitis C who had liver biopsy between January 1986 and December 1989 and did not receive interferon (controls).

    Intervention: Patients in the interferon group received human lymphoblastoid interferon, recombinant interferon-α 2a, or recombinant interferon-α 2b for 6 months.

    Measurements: The end point was development of hepatocellular carcinoma on abdominal ultrasonography or computed tomography. Sustained response was defined as persistent normalization of alanine aminotransferase (ALT) levels during interferon therapy and follow-up. Relapse was defined as a normal serum ALT level at the end of treatment with an increase to an abnormal level after cessation of treatment. Nonresponse included all other ALT patterns.

    Results: Median follow-up in the interferon and control groups was 47.6 and 46.8 months, respectively. During follow-up, hepatocellular carcinoma was found in 28 interferon-treated patients and 19 controls. Cox proportional-hazards regression analysis that included all patients revealed that interferon therapy (P = 0.041), older age (P = 0.003), greater histologic activity (P = 0.029), and higher histologic stage (P = 0.049) were independent factors associated with the development of hepatocellular carcinoma. The risk ratios for development of hepatocellular carcinoma in patients with sustained response, relapse, and nonresponse were 0.06 (95% CI, 0.01 to 0.46), 0.51 (CI, 0.20 to 1.27), and 0.95 (CI, 0.48 to 1.84), respectively, compared with controls.

    Conclusions: The incidence of hepatocellular carcinoma was lower in patients with sustained response to interferon therapy than historical controls and nonresponders. Interferon therapy may decrease the risk for hepatocellular carcinoma in patients with chronic hepatitis C.

    Hepatocellular carcinoma, a major cause of death in patients with cirrhosis, is one of the most prevalent malignant tumors worldwide, and its incidence is increasing [1-5]. After isolation of hepatitis C virus (HCV), most patients with chronic hepatitis and those with cirrhosis of unknown origin were found to be positive for anti-HCV [6-8]. Evidence suggests that HCV-related chronic liver disease plays a role in the development of hepatocellular carcinoma [9-13]. A high proportion of patients with hepatocellular carcinoma have anti-HCV, although the prevalence varies geographically. The highest rate of anti-HCV is in southern Europe and Japan, where about 70% of patients with hepatocellular carcinoma are positive for anti-HCV [5].

    Interferon has been widely used to treat chronic HCV infection. A series of clinical trials showed that some patients who received interferon had sustained normalization of serum aminotransferase levels and elimination of serum HCV RNA [14-17]. Histologic improvement was also seen in patients who received interferon [14, 18-20]. It is important to determine whether interferon treatment also lowers the incidence of hepatocellular carcinoma in patients with chronic hepatitis C, but the recognized benefits of interferon make a randomized, controlled trial to address this question unethical.

    We did a retrospective study to compare the incidence of hepatocellular carcinoma in interferon-treated patients with HCV infection and histologically proven chronic hepatitis or cirrhosis with that in historical controls who did not receive interferon. We also examined the relation between response to interferon therapy and incidence of hepatocellular carcinoma.

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    Methods

    Patients

    The interferon group comprised 419 consecutive patients with chronic hepatitis C who had undergone liver biopsy 1 to 2 weeks before interferon therapy and had started treatment between January 1992 and December 1993. The control group consisted of 144 consecutive patients with chronic hepatitis or cirrhosis who had undergone liver biopsy between January 1986 and December 1989. All patients had histologically proven chronic hepatitis or cirrhosis (Child-Pugh class A) and were positive for anti-HCV.

    Interferon Treatment

    In the interferon group, 176 patients received human lymphoblastoid interferon, 149 received recombinant interferon-α 2a, and 94 received recombinant interferon-α 2b for 6 months. The median total interferon dose was 480 mU (range, 282 to 800 mU). No patient had received interferon therapy before study entry. Contraindications to interferon treatment included pregnancy, presence of hepatitis B surface antigen, other types of liver disease, autoimmune disease, and any other serious illness.

    Efficacy of interferon therapy was categorized as follows. Patients with persistent normalization of alanine aminotransferase (ALT) levels during interferon therapy and follow-up were considered to have sustained response. Patients whose serum ALT level was normal at the end of the treatment but increased to an abnormal level after cessation of treatment were considered to have relapse. All other patients were classified as nonresponders.

    Follow-up

    Abdominal ultrasonography or computed tomography was performed every 4 to 8 months, and serum α-fetoprotein was measured every 2 to 6 months. The diagnosis of hepatocellular carcinoma was confirmed by needle biopsy, by surgically resected tumor specimens, or by typical radiologic findings on hepatic angiography. The starting date of follow-up for patients in the interferon and control groups was defined as the date of liver biopsy. For both groups, the end of follow-up was the development of hepatocellular carcinoma or December 1991 in the control group and the time of the latest abdominal imaging in the interferon group.

    To detect hepatocellular carcinoma, follow-up examinations were done in 85.4% of controls and 90.7% of patients in the interferon group.

    The Osaka Cancer Registry was used [21, 22] to determine whether hepatocellular carcinoma had occurred in patients lost to follow-up. This population-based cancer registry has been operating since December 1962 with the cooperation of the Osaka Medical Association, the Department of Health of Osaka Prefecture, and Osaka Medical Center for Cancer and Cardiovascular Diseases. It covers all of Osaka Prefecture, which had a population of 8.6 million in 1995, and registers cases of cancer by using reports from hospitals and clinics and death certificates collected from health centers. One patient in each group who had been lost to follow-up was listed as having hepatocellular carcinoma in the Osaka Cancer Registry.

    Determination of the Presence of Hepatitis C Virus Antibody and Hepatitis C Virus RNA

    Hepatitis C virus antibody was measured by first-, second-, or third-generation enzyme-linked immunosorbent assays (Ortho Diagnostics, Tokyo, Japan). Serum HCV RNA was measured by reverse transcription polymerase chain reaction or complementary DNA assay, as reported elsewhere [23, 24].

    Assessment of Liver Histologic Findings

    The histologic findings in liver biopsy specimens were scored by three of the authors in a blinded manner by using two scoring methods. For assessment of histologic staging, fibrosis score (F1 to F3 for chronic hepatitis and F4 for cirrhosis) was used; F1 indicated portal fibrous expansion, F2 indicated portal-portal septa without architectural distortion, F3 indicated portocentral septa with architectural distortion, and F4 indicated cirrhosis [25]. For assessment of histologic grading, a total score of histologic activity (components 1 to 3) of the Knodell histologic activity index was used [26].

    Statistical Analysis

    Patients who did not complete the treatment protocol were included for analysis on an intention-to-treat basis. The chi-square test was used to compare the baseline characteristics of both groups. The Wilcoxon rank-sum test was used to assess a significant difference between tumor sizes in the two groups. The Kaplan-Meier method was used to calculate the cumulative incidence of hepatocellular carcinoma, and the log-rank test was used to compare the cumulative incidence of hepatocellular carcinoma between the groups. To estimate independent risk factors for the development of hepatocellular carcinoma, Cox proportional-hazards regression analysis was used. For analysis, interferon therapy, age, sex, serum ALT level, serum α-fetoprotein level, platelet count, histologic staging, and activity scores were used as variables. A P value less than 0.05 was considered statistically significant. Data are expressed as medians and ranges and as risk ratios and 95% CIs.

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    Results

    Table 1 shows the baseline characteristics of the interferon and control groups. The groups did not differ for age, sex, serum ALT level, or platelet count. In the interferon group, 387 patients (92%) had chronic hepatitis (128 had F1 disease, 138 had F2 disease, and 121 had F3 disease) and 32 (8%) had cirrhosis. In the control group, 124 patients (86%) had chronic hepatitis (30 had F1 disease, 38 had F2 disease, and 56 had F3 disease) and 20 (14%) had cirrhosis (P = 0.005). The proportion of patients with serum α-fetoprotein levels greater than 20 ng/mL was higher in the control group (24%) than in the interferon group (15%) (P = 0.011).

    View this table:
    Table 1. Baseline Characteristics of Interferon-Treated Patients and Historical Controls with Chronic Hepatitis C

    In the interferon group, 151 patients (36%) had sustained response, 120 (29%) had relapse, and 148 (35%) were nonresponders. In the 143 patients with sustained response, serum HCV RNA was measured during follow-up. Sustained absence of serum HCV RNA was noted in 120 (84%) of these patients. Twenty-one patients could not complete the 6-month treatment protocol because of depression (5 patients), severe general fatigue (4 patients), skin eruptions (2 patients), severe reduction of serum platelet count (1 patient), pulmonary tuberculosis (1 patient), interstitial pneumonia (1 patient), severe nausea (1 patient), ischemic colitis (1 patient), cardiomyopathy (1 patient), hyperthyroidism (1 patient), and hypermenorrhea (1 patient). One patient stopped treatment because of his business, and one patient discontinued treatment after 3 months because hepatocellular carcinoma was diagnosed. Only 1 of the 21 patients who did not complete treatment showed sustained response; all others were nonresponders.

    Median follow-up was 47.6 months (range, 3.3 to 65.2 months) in the interferon group and 46.8 months (range, 6.9 to 71.6 months) in the control group. During follow-up, hepatocellular carcinoma was found in 19 controls (4 with F2 disease, 8 with F3 disease, and 7 with F4 disease). In the interferon group, 28 patients developed hepatocellular carcinoma during follow-up (2 patients with F1 disease, 5 with F2 disease, 13 with F3 disease, and 8 with F4 disease). A final diagnosis of hepatocellular carcinoma was made histologically in 17 patients in the interferon group (61%) and 11 controls (58%). In 11 patients (39%) in the interferon group and 8 controls (42%), a final diagnosis was made on the basis of typical angiographic findings. The maximum tumor sizes of hepatocellular carcinoma in the interferon and control groups at the time of discovery on ultrasonography or computed tomography were 20 mm (range, 10 to 52 mm) and 24 mm (range, 10 to 50 mm), respectively (P > 0.2).

    Figure 1 shows the cumulative incidence of hepatocellular carcinoma in the interferon and control groups, estimated by using the Kaplan-Meier method. The 4-year rate of hepatocellular carcinoma incidence was 6.6% in the interferon group and 12.2% in the control group (log-rank test, P = 0.040).

    Figure 1. A log-rank test of the two curves showed a significant difference between the two groups ( = 0.040).
    View larger version:
    Figure 1. A log-rank test of the two curves showed a significant difference between the two groups ( = 0.040). Cumulative incidence of hepatocellular carcinoma (HCC) in interferon-treated patients (dotted line) and historical controls (solid line) with chronic hepatitis C.P

    Cox proportional-hazards regression analysis was performed to identify factors contributing to the development of hepatocellular carcinoma. Interferon therapy (P = 0.041), older age (P = 0.003), greater histologic activity (P = 0.029), and higher histologic stage (P = 0.049) were independent factors for the development of hepatocellular carcinoma (Table 2).

    View this table:
    Table 2. Risk Factors for Hepatocellular Carcinoma in Patients with Chronic Hepatitis C according to Cox Proportional Hazards Regression Analysis

    Of the 28 patients in the interferon group who developed hepatocellular carcinoma, 1 had sustained response, 7 had relapse, and 20 were nonresponders. Figure 2 shows Kaplan-Meier estimates of the cumulative incidence of hepatocellular carcinoma in the patients with sustained response, relapse, and nonresponse (log-rank test, P < 0.001). The 4-year incidence of hepatocellular carcinoma was 0.9% in patients with sustained response, 6.1% in patients who had relapse, and 12.8% in nonresponders. Risk ratios for hepatocellular carcinoma in the interferon group compared with the control group were 0.06 (95% CI, 0.01 to 0.46; P = 0.007) in patients with sustained response, 0.51 (CI, 0.20 to 1.27; P = 0.150) in patients with relapse, and 0.95 (CI, 0.48 to 1.84; P > 0.2) in nonresponders (Table 3).

    Figure 2. A log-rank test of the three curves showed a significant difference between these groups (P<0.001).
    View larger version:
    Figure 2. A log-rank test of the three curves showed a significant difference between these groups (P<0.001). Cumulative incidence of hepatocellular carcinoma (HCC) in interferon-treated patients with chronic hepatitis C categorized by sustained response (dashed line), relapse (dotted line), and non-response (solid line).
    View this table:
    Table 3. Risk Ratios for Hepatocellular Carcinoma by Response to Interferon Therapy

    Twelve of the 176 patients (6.8%) who received human lymphoblastoid interferon, 10 of the 149 patients (6.7%) who received recombinant interferon-α 2a, and 6 of the 94 patients (6.4%) who received recombinant interferon-α 2b developed hepatocellular carcinoma. This suggests that the type of interferon does not affect the incidence of hepatocellular carcinoma.

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    Discussion

    After interferon therapy was reported to have beneficial effects in patients with chronic non-A, non-B hepatitis [27], many clinical trials confirmed the efficacy of interferon therapy in patients with chronic hepatitis C [14-17]. Recently, Nishiguchi and colleagues [28] reported that interferon therapy decreased the incidence of hepatocellular carcinoma in a small number of patients with chronic active hepatitis C with cirrhosis. Mazzella and coworkers [29] showed that interferon-α decreased the risk for hepatocellular carcinoma in patients with HCV-related cirrhosis. In contrast, Bruno and associates [30] found that interferon therapy was not an independent risk factor for hepatocellular carcinoma in anti-HCV-positive patients with cirrhosis. A European group also did not find a significant benefit of interferon-α in preventing hepatocellular carcinoma in patients with compensated type C cirrhosis [31]. Thus, the effect of interferon treatment on the incidence of hepatocellular carcinoma in patients with HCV-related cirrhosis is controversial. Moreover, the effect of interferon therapy on the incidence of hepatocellular carcinoma in patients with HCV-related chronic hepatitis has not been reported. In this large retrospective study, we compared the incidence of hepatocellular carcinoma in anti-HCV-positive patients with biopsy-proven chronic hepatitis and cirrhosis after interferon treatment with that in historical controls.

    In our study, the cumulative incidence of hepatocellular carcinoma was significantly lower in interferon-treated patients than in historical controls (P = 0.040). Because the baseline characteristics of the two groups, including histologic stage and serum α-fetoprotein level, were not similar (Table 1), Cox proportional-hazards regression analysis was done to evaluate the effect of interferon therapy on the incidence of hepatocellular carcinoma. Interferon therapy was shown to be an independent factor associated with development of hepatocellular carcinoma in chronic hepatitis C. Despite the inherent limitations of a retrospective study, the result of Cox proportional-hazards regression analysis suggests that interferon is associated with a decrease in the incidence of hepatocellular carcinoma.

    Among anti-HCV-positive patients with chronic hepatitis or cirrhosis proven by biopsy, only 1 of 151 patients who showed sustained normalization of the ALT level during follow-up developed hepatocellular carcinoma. In addition, the risk ratio for development of hepatocellular carcinoma in patients with sustained response was low (0.06 [CI, 0.01 to 0.46]) compared with that in the control group. These results suggest that the patients who responded to interferon treatment were at very low risk for developing hepatocellular carcinoma. The finding that patients with sustained response have a low incidence of hepatocellular carcinoma has important implications for screening programs for hepatocellular carcinoma because those patients may need less frequent screening. It also provides additional impetus for conducting a cost–benefit analysis of interferon treatment of chronic hepatitis C.

    Interferon treatment has been reported to improve liver histologic characteristics, including inflammatory activity and liver fibrosis, in patients with chronic hepatitis C [14, 18-20]. The decrease in histologic activity after interferon therapy seems substantial in patients with normal ALT levels [18]. Cox proportional-hazards regression analysis showed that high histologic activity and advanced histologic stage were independent risk factors for the development of hepatocellular carcinoma. It seems likely that suppression of histologic activity by interferon therapy might decrease the occurrence of hepatocellular carcinoma.

    As have others [4, 11, 30], we found that age and histologic stage were independently associated with development of hepatocellular carcinoma. However, we did not find male sex and α-fetoprotein level, which have been shown to be related to the development of hepatocellular carcinoma [4, 30], to be independent risk factors for this disease. As mentioned above, we showed that high histologic activity of the liver biopsy specimens was another independent risk factor for development of hepatocellular carcinoma. Long-term chronic inflammation may be related to carcinogenesis.

    Our study had limitations. Because it was a retrospective cohort study done by using historical controls, lead-time bias may have occurred. However, tumor sizes were similar in historical controls and interferon-treated patients. It seems likely that the screening program for hepatocellular carcinoma in historical controls was similar to that in interferon-treated patients. Even if detection of hepatocellular carcinoma was less effective in historical controls than interferon-treated patients, we may have underestimated the effect of interferon on the incidence of hepatocellular carcinoma. We chose patients with chronic hepatitis C who had undergone liver biopsy between 1986 and 1989 because interferon treatment was not a standard treatment then in Japan. In addition, a historical comparison group rather than a concurrent control group of patients not treated with interferon seems less likely to be biased with respect to the occurrence of hepatocellular carcinoma.

    Another limitation of our study is the wide 95% CIs for interferon therapy and histologic stage and activity seen in Cox proportional-hazards regression analysis. The result suggests that the effect of interferon on the incidence of hepatocellular carcinoma was not very strong. We evaluated the response of interferon by measuring serum ALT levels, not serum HCV RNA levels. Only one patient who showed sustained normalization of serum ALT levels developed hepatocellular carcinoma. This patient also showed sustained elimination of serum HCV RNA. A longer observation period may be needed to determine whether elimination of serum HCV RNA is important in the prevention of hepatocellular carcinoma.

    Third, insufficient data on alcohol use precluded the inclusion of this information in our analyses. Finally, response to interferon was determined by measuring ALT levels rather than by doing polymerase chain reaction, and we did not have data on HCV genotype.

    In conclusion, we showed that interferon-treated patients with chronic hepatitis C had a low incidence of hepatocellular carcinoma and that patients who showed sustained normalization of serum ALT levels after interferon therapy were at low risk for development of hepatocellular carcinoma. Interferon therapy seems to lower the risk for hepatocellular carcinoma in patients with chronic hepatitis C.

    Drs. Kawata, Tamura, Matsuda, and Matsuzawa: Second Department of Internal Medicine, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan.

    Dr. Yabuuchi: Department of Internal Medicine, Otemae Hospital, 1-5-34 Otemae, Chuo-ku, Osaka 540, Japan.

    Dr. Noda: Department of Internal Medicine, Suita Municipal Hospital, 2-13-20 Katayama-cho, Suita, Osaka 564, Japan.

    Dr. Inada: Department of Internal Medicine, Toyonaka Municipal Hospital, 4-14-1 Shibahara-cho, Toyonaka, Osaka 560, Japan.

    Dr. Maeda: Department of Internal Medicine, Kawanishi City General Hospital, 5-21-1 Higashiuneno, Kawanishi, Hyogo 666-01, Japan.

    Dr. Shirai: Department of Internal Medicine, Izumisano Municipal Hospital, 2-23 Rinku-oraikita, Izumisano, Osaka 598, Japan.

    Dr. Fukuzaki: Department of Internal Medicine, Izumiotu Municipal Hospital, 16-1 Gejo-cho, Izumiotsu, Osaka 595, Japan.

    Dr. Kaji: Department of Gastroenterology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 3-3 Nakamichi 1-chome, Higashinari-ku, Osaka 537, Japan.

    Dr. Ishikawa: Department of Cancer Epidemiology, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, 3-3 Nakamichi 1-chome, Higashinari-ku, Osaka 537, Japan.

    Dr. Seki: Department of Internal Medicine, Hyogo Prefectural Nishinomiya Hospital, 13-9, Rokutanji-cho, Nishinomiya, Hyogo 662, Japan.

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    1. Ann Intern Med July 15, 1998 vol. 129 no. 2 94-99
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