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Can interferon prolong life?
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Hepatology, 2003;38:493-502. Fumio Imazeki et al. Department of Medicine and
Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
First below is the summary of a study reported in this month's journal Hepatology. This is followed by article "Can Interferon Prolong Life?".
Favorable prognosis of chronic hepatitis C after interferon therapy by long-term cohort study
Hepatology, 2003;38:493-502. Fumio Imazeki et al.
The prognosis of patients with chronic hepatitis C after interferon (IFN) therapy is still poorly defined. The present study evaluated the effect of IFN therapy on
survival in a cohort of such patients. The study included 459 patients with biopsy-proven C-viral chronic liver disease who were followed for 8.2 ± 2.9 years (range, 7-183 months). Survival status was examined by medical records or direct questionnaires. Fifteen (14%) of 104 IFN-untreated patients and 33 (9%) of 355 patients treated with IFN died during follow-up. Among the treated patients, 4 (3%) of 116 with sustained virologic response and 29 (12%) of 239 without sustained virologic response died. Liver-related death was shown in 32 (67%) patients, and hepatocellular carcinoma (HCC) caused 25 (52%) of the 48 deaths. Multivariate Cox proportional regression analysis revealed that IFN treatment decreased the risk ratio for overall death to 0.521 (confidence interval [CI]: 0.263-1.034) and for liver-related death to 0.208 (CI: 0.088-0.495) compared with untreated patients, and sustained virologic response showed a decrease in the risk ratio for overall death to 0.219 (CI: 0.068-0.710) and for liver-related death to 0.030 (CI: 0.003-0.267). IFN treatment showed no association with liver-unrelated death. Furthermore, the standardized mortality ratios for all causes of death and liver-related death were reduced in IFN-treated patients compared with untreated patients (1.4 vs. 2.0
for total death and 7.9 vs. 19.7 for liver-related death). Because this was a retrospective study and some of the baseline characteristics were different between IFN-treated and -untreated groups, our proportional hazards regression model used 15 variables potentially associated with survival including age, sex, fibrotic stage, and comorbidities to minimize the risk of uncontrolled confounding in the analysis. In conclusion, the present data suggest that IFN therapy has a long-term clinical benefit for patients with chronic hepatitis C patients by reducing liver-related death, especially in patients with sustained virologic response. In this study, a virologic sustained response was achieved in only 33% of 355 patients treated with IFN monotherapy. Recent progress in treatment with peginterferon combined with ribavirin showed elimination of serum HCV RNA in over 50% of treated patients,32,33 with much higher rates of sustained virologic response. Based on our current results with standard IFN therapy, further improvement in the sustained virologic response rate from more effective antiviral drugs or combined therapy can be anticipated to provide normal life expectancy to patients with chronic hepatitis C.
Fibrotic stage, IFN treatment, IFN efficacy, AST level, and alcohol consumption were shown to be associated with risk for liver-related death. IFN treatment showed a decrease in the risk ratio for liver-related death to 0.208 (CI: 0.088-0.495) compared with untreated patients. Both virologic sustained and nonsustained responders after IFN therapy showed a decrease in risk ratio, the former to 0.030 (CI: 0.003-0.267) and the latter to 0.257 (CI: 0.108-0.609). The effect of IFN treatment on the risk of liver-related death of cirrhotic patients was also assessed by this method adjusted for sex and age, and there was a reduction in the risk to 0.181 (CI: 0.050-0.663).
REVIEW: Can Interferon Prolog Life?
Hepatology, August 2003, Volume 38, Number 2
Rafael Esteban, M.D. Liver Unit, Department of Medicine, Hospital General Universitario Valle de Hebron, Barcelona, Spain
In the past few years, the prevalence of hepatocellular carcinoma (HCC) has increased in Western countries and currently cirrhosis related to the hepatitis C virus (HCV) is the most common cause of liver transplantation worldwide. Studies projecting future complications of chronic hepatitis C, using mathematic models, are not optimistic. A substantial number of currently asymptomatic patients infected by HCV will progress to cirrhosis and HCC in the coming years, and it is estimated that the number of liver-related deaths will increase by 180%.
Antiviral therapy for patients with chronic hepatitis C has the final objective of decreasing the mortality of infected patients by preventing HCC and decompensation of cirrhosis. Given the difficulties of putting these objectives into practice, we use the sustained virologic response (SVR) as a parameter to measure these goals. SVR is defined as the clearance of virus, which means HCV RNA undetectable by sensitive methods 6 months after discontinuation of therapy. This parameter has proved to be an excellent surrogate marker of the resolution of infection. Follow-up studies have shown that response is durable in the majority of patients and the progression of liver lesions is stopped. It has been shown that liver fibrosis diminishes when the inflammatory activity disappears; this probably is due to the antifibrogenic effect of interferon. It is important to note that even in patients without a sustained virologic response, liver histology may improve by stopping the progression of fibrosis.
In this setting, there are some difficult questions: Can antiviral therapy prevent the development of HCC? Does antiviral therapy prolong the survival of treated
patients? Might therapy be beneficial in nonresponders?
In 1995, a randomized study with a small number of patients was published showing a decrease in the number of HCC cases in patients with cirrhosis caused by HCV treated with interferon versus untreated controls.5 However, the high rate of HCC in the control group made the results doubtful. Since then, numerous studies have been published on this topic. In 1994, a retrospective surveillance study in Japan was started called Inhibition of Hepatocarcinogenesis by Interferon Therapy, which focused on the appearance of new cases of HCC.6 The study included chronic hepatitis C patients who underwent liver biopsies and periodic imaging during follow-up for the diagnosis of HCC. In 1998, data from 2,890 patients, 2,400 treated with interferon and 490 untreated, were evaluated. The results showed a
significant beneficial effect of interferon by reducing the incidence of HCC in treated patients. This effect was greater in patients who achieved a SVR and also in those who normalized alanine aminotransferase levels. In untreated patients, an increase in the incidence of HCC was observed in parallel with the degree of fibrosis, from an annual rate of 0.5% for patients with F0 to F1 to 7.9% in those with F4. Interestingly, the effect of interferon in preventing HCC was more beneficial in patients with F2 or F3 than in patients with F4 (cirrhosis). The incidence of HCC in sustained virologic responders was 0.49%, whereas in nonresponders it was 5.32%. Also in Japan, in 1999, Ikeda et al. published similar results from 1,643 patients of whom 1,191 had received interferon therapy. The incidence of HCC in treated patients was 7.6% after 10 years of follow-up evaluation, compared with 12.4% in untreated patients. Again, patients who normalized alanine aminotransferase levels had a lower incidence of HCC despite the lack of virologic response.
At the same time these studies were performed in Japan, European studies failed to show that interferon had a beneficial effect either on the development of HCC or on the survival of treated patients. In a randomized study with 99 patients followed-up for 3 years, Valla et al.8 observed no difference between controls and treated patients with interferon. In a retrospective study with 384 patients with cirrhosis caused by HCV, Fattovich et al. also found no differences during follow-up. In contrast, in a retrospective study of 103 patients with HCV cirrhosis, Serfaty et al. observed a beneficial effect of interferon on the development of HCC and on survival during a follow-up of 3.5 years.
There are various explanations for the differences in the results of these studies. First, in Japan, the sustained virologic response rate is higher than that observed in Europe and the United States. Almost 30% of patients achieved a SVR after interferon monotherapy. In Western countries, the rate of SVR in patients with advanced fibrosis is lower, only 5%. Second, the incidence of HCC is much higher in Japan. Both factors make it easier to show a preventive effect of therapy. There also are important methodological questions. The majority of the studies are retrospective and nonrandomized, introducing a bias in the selection of patients for therapy. In fact, in the large studies, the baseline clinical characteristics of treated and control patients are different. Factors associated with a higher incidence of HCC and cirrhotic decompensation such as higher age, lower albumin levels, lower platelet counts, and more advanced fibrosis are more frequent in the untreated control
group. Although the majority of studies introduce stratified subgroups to statistically balance the difference, this can be erroneous. In addition, the type, duration, and doses of interferon and follow-up are different between the studies, which further complicates the comparison of the results.
Camma et al.11 performed a meta-analysis that included 3 randomized and 11 nonrandomized studies with a total of 3,109 patients and 356 cases of HCC. In 13 of the 14 studies, interferon reduced the incidence of HCC with a statistical significance in 10 studies. Overall, the differential risk was -12.8 (confidence interval, -8.3 to 17.2; P < .00001) for patients treated with interferon. The effect of treatment was more beneficial in patients who achieved a sustained biochemical response and also in those who showed no cirrhosis in the liver biopsy.
In the current issue, Imazeki et al. present a follow-up study of 459 patients with chronic hepatitis C over 8.2 years to examine the survival rate relative to interferon treatment. The investigators describe the variables associated with mortality: age, sex, degree of fibrosis, interferon treatment, and response to treatment. Cirrhotic patients with a SVR showed a reduction in mortality, differential risk, 0.219 (confidence interval, 0.068-0.710). Only one patient with a SVR developed HCC during the follow-up in contrast to 11 cases in the untreated group and 14 cases in nonresponders. In relation to liver-related mortality, patients who received interferon showed a significant reduction, even nonresponders. This beneficial effect continued after adjusting the data for age and sex. The survival in the overall cohort of hepatitis C patients was reduced compared with the general population (standardized mortality rate, 1.6). The standardized mortality rate for patients with HCC was 12.6 and for those with cirrhosis was 5.9.
Once again, because the study was retrospective and nonrandomized, the interpretation of the results is difficult. Untreated patients were older, with lower levels of serum albumin and high viral load. However, there was no difference in the degree of fibrosis, in genotype distribution, or duration of the infection. The benefits of treatment were maintained after performing a regression analysis, which included 15 variables with statistical significance in the univariate analysis. One notable aspect of this study is that the mortality rate of infected patients was higher than that of the general population, not only in patients with cirrhosis but also in patients with stages F2 and F3, the stages at which therapy can have a stronger preventive effect. Perhaps the conclusion of this study, with similar results to those published by Yoshida et al.,13 is that treated patients who achieve SVR have a higher survival due to the decrease of incidence of HCC and cirrhosis complications and this
should be the aim of therapy. Luckily, with the combination of pegylated interferon and ribavirin, the overall SVR is higher than 50%, particularly in patients with cirrhosis, in whom it is much more efficacious that the old standard interferon monotherapy.
The still unanswered question is whether interferon therapy can be beneficial in nonresponders. Different studies show that patients who achieve a biochemical response with normalization of alanine aminotransferase levels but without a virologic response seem to have a lower incidence of HCC during follow-up evaluation and this could be related to the suppression of fibrosis progression by interferon. If this assumption is correct, the current rule of discontinuation of therapy in nonresponders at week 12 should be revised to benefit a higher number of patients. Whether long-term maintenance therapy with pegylated interferon could be of additional benefit in clinical terms, due to its antifibrogenic effect, still needs to be clarified. The answer will probably be found when the 3 ongoing studies (HALT, COPILOT, and EPIC) with interferon maintenance are completed.
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