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Interferon treatment improves survival in chronic hepatitis C patients showing biochemical as well as virological responses by preventing liver-related death
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Journal of Viral Hepatitis
Volume 11 Issue 2 - March 2004
Kasahara 1 , H. Tanaka 2 , T. Okanoue 3 , Y. Imai 4 , H. Tsubouchi 5 , K. Yoshioka 6 , S. Kawata 7 , E. Tanaka 8 , K. Hino 9 , K. Hayashi 5 , S. Tamura 7 , Y. Itoh 3 , K. Kiyosawa 8 , S. Kakumu 10 , K. Okita 9 and N. Hayashi 11
1Department of General Medicine, Osaka University Graduate School of Medicine; 2Department of Cancer Control and Statistics, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; 3Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kyoto; 4Department of Internal Medicine, Ikeda Municipal Hospital, Ikeda; 5Second Department of Internal Medicine, Miyazaki Medical College, Miyazaki; 6Third Department of Medicine, Nagoya University Graduate School of Medicine, Nagoya; 7Department of Internal Medicine and Molecular Science, Osaka University Graduate School of Medicine, Osaka; 8Second Department of Medicine, Shinshu University School of Medicine, Shinshu; 9First Department of Medicine, Yamaguchi University School of Medicine, Yamaguchi; 10Department of Internal Medicine, Division of Gastroenterology, Aichi Medical University School of Medicine, Aichi; and 11Department of Molecular Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan "...risks of overall and liver-related deaths for chronic hepatitis C patients displaying a sustained virological response were 86 and 96% lower than for untreated patients.
"...The risk reduction for sustained biochemical responders was almost equal to that for sustained virological responders.
"...liver-related mortality for these patients was equivalent to that for the general population.
"...Thus, and as expected, when patients treated with interferon belong to the sustained virological or biochemical response group, they appear to have the highest long-term survival rate.
"...Of nonsustained virological responders, the risk of death from all causes and liver-related diseases for transient biochemical responders was significantly lower than for untreated patients, but higher than for sustained biochemical and virological responders.
"...risk of death from all causes and liver-related diseases was significantly lower for chronic hepatitis C patients for whom interferon was effective in normalizing ALT than for patients who did not receive interferon, even when HCV was not eradicated."
Summary. Interferon therapy for chronic hepatitis C reduces the risk of hepatocellular carcinoma, especially among virological and biochemical responders. However, little is known about the effect of interferon therapy on mortality.
We studied the long-term effect of interferon therapy on mortality in patients with chronic hepatitis C. For this retrospective cohort study, 2954 patients with chronic hepatitis C were recruited, of whom 2698 received interferon therapy and 256 did not. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality data for the general Japanese population and by risk ratio calculated by proportional hazard regression.
Over 6.0 ± 2.2 years follow-up, death from liver-related diseases was observed in 69 (68%) of 101 deaths among interferon-treated patients and in 42 (81%) of 52 deaths among untreated patients. Compared with the general population, overall mortality was high among untreated patients (SMR: 2.7; 95% CI: 2.0-3.6) but not among interferon-treated patients (SMR: 0.9; 95% CI: 0.7-1.1).
Liver-related mortality was extremely high among untreated patients (SMR: 22.2; 95% CI: 16.0-30.0) and less among interferon-treated patients (SMR: 5.5; 95% CI: 4.3-6.9).
The risk of death from all causes was lower for interferon-treated than untreated patients (risk ratio: 0.47; 95% CI: 0.261-0.836; P = 0.01). The risk of death from liver-related diseases was significantly lower for sustained virological responders (risk ratio: 0.04; 95% CI: 0.005-0.301; P = 0.002) compared with untreated patients, but not for nonsustained virological responders.
Sustained biochemical responders (risk ratio: 0.03; 95% CI: 0.004-0.230; P < 0.001) and transient biochemical responders (risk ratio: 0.18; 95% CI: 0.063-0.532; P = 0.002) showed a significantly reduced risk of death from liver-related death, whereas biochemical nonresponders did not.
Hence interferon treatment improved survival in chronic hepatitis C patients showing a biochemical as well as a virological response by preventing liver-related deaths.
AUTHOR DISCUSSION
We previously demonstrated that interferon treatment could reduce the risk of HCC development in patients with chronic hepatitis C [12]. Following this, five retrospective studies [13-17] showed a similar effect of interferon on the risk of HCC, especially for virological and biochemical responders. These results suggest that interferon therapy for chronic hepatitis C can prevent the development of HCC, possibly leading to improvement in long-term survival. However, only a few previous studies have assessed the effects of interferon therapy on survival [18-24], and whether interferon therapy also reduces mortality from liver-related disease in patients with chronic HCV infection has not been thoroughly investigated. It is also still unclear what type of response to interferon results in the improvement of long-term survival.
To evaluate the effect of interferon therapy on the risk of mortality for chronic hepatitis C patients, a randomized controlled trial should be carried out. However, a prospective randomized trial with untreated control patients is ethically impossible, because interferon therapy has already been established as the standard modality for patients with chronic hepatitis C. Only two randomized controlled trials of a small number of HCV-related cirrhotic cases have evaluated the effect of interferon therapy on mortality [19,21], but with discrepant results. In contrast, large-scale prospective and retrospective cohort studies [23,24] indicate that interferon therapy for HCV-related cirrhosis or chronic hepatitis C improves long-term survival. In particular, Yoshida et al. [24] demonstrated in their recent retrospective cohort study that interferon therapy improved survival of chronic hepatitis C patients by preventing liver-related deaths. However, its beneficial effect was considered to be limited to patients with a sustained virological response.
As ours is a retrospective cohort study, it may be subject to several biases. The interferon-treated and untreated groups had different demographic characteristics, including age and gender. These factors were adjusted for multivariate regression analysis and considered when calculating SMR by applying the corresponding mortality for the general population. Severity of chronic liver disease was adjusted by using the stage of liver fibrosis for multivariate analysis. As the time of liver biopsy of untreated patients was earlier than for interferon-treated patients, mortality for untreated patients may be generally higher than for interferon-treated patients. To avoid this bias, we adjusted the time at liver biopsy for multivariate analysis, and 5-year time-specific mortality rates for the general population were prepared in the SMR analysis. Moreover, the number of untreated patients was small, because most Japanese chronic hepatitis C patients, except for cases with medical problems, have been treated with interferon. However, the relatively small number of untreated patients in comparison with the large number of interferon-treated patients is not likely to have resulted in a substantial overestimation of the effect of interferon therapy on survival as several of the biases already mentioned were controlled in the analyses.
When we compared the observed mortality with the expected mortality for the matched general population by calculating SMR, we were able to demonstrate that chronic hepatitis C patients had higher overall and liver-related mortality than the general population, and that the majority of deaths were liver-related. However, interferon-treated patients had a significantly lower risk of liver-unrelated mortality, whereas untreated patients did not. This may represent a selection bias in the use of interferon therapy, which included patients with no medical problems except for having chronic liver diseases. However, our multivariate regression analysis clearly showed that interferon therapy reduced the risk of liver-related death in virological responders by 96% and in biochemical responders by 82-97%. These findings indicate that a significant reduction in the risk of death from all causes for patients treated with interferon, shown in the analysis of SMR, was not caused by a selection bias but is mainly attributable to the prevention of liver-related death by interferon therapy.
Our multivariate analysis made it clear that the risks of overall and liver-related deaths for chronic hepatitis C patients displaying a sustained virological response were 86 and 96% lower than for untreated patients. The risk reduction for sustained biochemical responders was almost equal to that for sustained virological responders. Similarly, the SMR analyses showed that liver-related mortality for these patients was equivalent to that for the general population. Thus, and as expected, when patients treated with interferon belong to the sustained virological or biochemical response group, they appear to have the highest long-term survival rate.
Of nonsustained virological responders, the risk of death from all causes and liver-related diseases for transient biochemical responders was significantly lower than for untreated patients, but higher than for sustained biochemical and virological responders. The same effects of interferon therapy on survival were observed in the SMR analyses. Although the follow-up period was not sufficiently long for a reliable and accurate examination of mortality, we would like to emphasize that the risk of death from all causes and liver-related diseases was significantly lower for chronic hepatitis C patients for whom interferon was effective in normalizing ALT than for patients who did not receive interferon, even when HCV was not eradicated. However, the risk of death from all causes and liver-related diseases was not reduced in biochemical nonresponders.
In conclusion, the findings reported here indicate that interferon therapy improves long-term survival in chronic hepatitis C patients showing a biochemical as well as a virological response by preventing liver-related deaths.
Patients
We recruited chronic hepatitis C patients from four previous studies which were conducted to assess the effect of interferon therapy on the incidence of HCC. All patients meeting the following criteria were included in this study: (i) histological diagnosis of chronic hepatitis or cirrhosis; (ii) no history of clinical signs at entry into the study of complications of cirrhosis, i.e. ascites, jaundice, encephalopathy, or variceal bleeding; (iii) no evidence of HCC at entry into the study as assessed by ultrasonography and/or computed tomography; (iv) absence of serum hepatitis B surface antigen; (v) absence of co-existing liver diseases such as autoimmune hepatitis or primary biliary cirrhosis; (vi) absence of excessive alcohol consumption (>80 g/day); and (vii) absence of human immunodeficiency virus antibodies, as described previously. A total of 3025 patients who met these criteria and whose initial sera tested positive for anti-HCV as determined by either first- or second-generation ELISA (Ortho Diagnostics, Tokyo, Japan) and HCV RNA were included in the study. The sera of patients who had been diagnosed as non-A, non-B hepatitis before anti-HCV testing became available (i.e. before 1989) had been frozen at 80 °C and were retrospectively assayed.
Of the 3025 chronic hepatitis C patients, 2762 had received interferon after 1987, when interferon became available in Japan. Interferon-treated patients received a 4-12-month course of interferon therapy, which was initiated within 1 month of liver biopsy. The remaining 263 patients did not undergo interferon therapy or any other antiviral therapy, including almost all patients with biopsy-proven chronic hepatitis who had refused interferon treatment due to adverse effects, lack of time for therapy, or their inability to undergo treatment as a consequence of depression, severe diabetes mellitus or other medical conditions.
Criteria for biochemical and virological responses to interferon therapy
The biochemical response during the follow-up up to 6 months after the completion of interferon therapy was defined according to previously described criteria with minor modifications. In the sustained response group, ALT levels decreased to the normal range during therapy and remained within that range up to 24 weeks after therapy without any abnormal elevation. In the transient response group, ALT levels decreased to the normal range by the end of therapy, remained normal during therapy but returned to abnormal levels during the 24 weeks following interferon therapy. In the no-response group, ALT levels did not decrease to the normal range, or fluctuated during therapy and the subsequent 24 weeks. Both biochemical transient and nonresponders were designated as nonsustained biochemical responders.
A sustained virological response was defined as HCV RNA negativity at more than 6 months after the cessation of interferon therapy. Patients showing positive HCV RNA at the same time were designated as nonsustained virological responders.
Histological evaluation
Liver biopsy was carried out before interferon therapy in all cases. Specimens were fixed in formaldehyde and embedded in paraffin. The sections were stained with haematoxylin-eosin and Azan-Mallory and analysed by two pathologists without any knowledge of the clinical and laboratory data. Histological findings were scored according to the classification of Desmet et al.
Follow-up
The starting date of the follow-up for both the interferon-treated and untreated groups was defined as the date of liver biopsy. Biochemical examinations including -fetoprotein and abdominal ultrasonography were carried out before interferon therapy and every 3-6 months thereafter at the outpatient clinic of the respective hospitals. The end of the follow-up was the date of death or the latest confirmation of survival. Follow-up data on the patients were obtained from the participating hospitals. Follow-up data that were not available from the hospitals were collected from the resident registry of the local municipal office. Death from liver-related disease was defined as death from HCC, liver failure determined by the presence of one or more of ascites, jaundice and hepatic encephalopathy, or variceal bleeding diagnosed on the basis of endoscopic findings of patients presenting with upper gastrointestinal haemorrhage.
Five untreated patients were observed for over 162 months, which corresponded to the longest period of observation of those treated with interferon. In these subjects, only the follow-up data up to 162 months were considered. Seventy-one patients whose follow-up period was shorter than 12 months were excluded from the study. The final numbers of study subjects were 2698 for the interferon-treated group and 256 for the untreated group.
Informed consent was obtained from each patient included in the study. The study protocol was in accordance with the Helsinki Declaration of 1975 (revised in 1983) and approved by the Ethical Committee of the Osaka University Graduate School of Medicine.
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