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Improved Outcomes After SVR, Interferon Therapy
 
 
  Sustained virological response to interferon- is associated with improved outcome in HCV-related cirrhosis: A retrospective study
 
Hepatology March 2007
 
Savino Bruno 1, on behalf of the Italian Association of the Study of the Liver Disease (AISF)
1Liver Unit, Department of Medicine, AO Fatebenefratelli e Oftalmico, Milan
 
"...In conclusion, our data show that, in patients with HCV-related histologically proven cirrhosis, the achievement of a SVR following IFN treatment was associated with a reduction in liver-related mortality and with a lower risk of liver-related complications and occurrence of HCC..."
 
ABSTRACT

The effect of achieving a sustained virological response (SVR) following interferon- (IFN) treatment on the clinical outcomes of patients with HCV-related cirrhosis is unknown.
 
In an attempt to assess the risk of liver-related complications, HCC and liver-related mortality in patients with cirrhosis according to the response to IFNa treatment, a retrospective database was developed including all consecutive patients with HCV-related, histologically proven cirrhosis treated with IFN monotherapy between January 1992 and December 1997.
 
SVR was an undetectable serum HCV-RNA by PCR 24 weeks after IFN discontinuation.
 
HCC was assessed by ultrasound every 6 months. Independent predictors of all outcomes were assessed by Cox regression analysis.
 
Of 920 patients, 124 (13.5%) were classified as achieving a SVR.
 
During a mean follow-up of 96.1 months (range: 6-167) the incidence rates per 100 person-years of those with SVR:
 
-- liver-related complications: 0
-- HCC: 0.66
-- liver-related death: 0.19 among SVR
 
And for those without SVR:
 
-- Liver-related complications: 1.88,
-- HCC: 2.10,
-- Liver-related death: 1.44 among non-SVR
(P < 0.001 by log-rank test).
 
Multivariate analyses found that non-SVR was associated with a higher risk of liver-related complications (hazard ratio, HR, not applicable), HCC (HR 2.59; 95% CI 1.13-5.97) and liver-related mortality (HR 6.97; 95% CI 1.71-28.42) as compared to SVR.
 
Conclusion:
Thus, in patients with HCV-related, histologically proven cirrhosis, achievement of a SVR after IFN therapy was associated with a reduction of liver-related mortality lowering both the risk of complications and HCC development.
 
Irrespective of SVR achievement, all patients should continue surveillance because the risk of occurrence of HCC was not entirely avoided.

 
Patients received IFN monotherapy 3 times weekly with a single dose ranging from 3MU to 6MU for 1 year. Antiviral therapy was stopped in patients not responding after 6 months of therapy, and these patients did not receive maintenance therapy. All centers were required to have a long-term surveillance follow-up program after stopping IFN. In order to ensure that all eligible, consecutive patients were included in the database, all centers had to guarantee the pre-existing registration of the cohort of patients treated during the study period.
 
Article Text
 
While progression of HCV is likely to be slowed in all patients with chronic HCV and mild liver disease achieving a SVR, this is not the case in patients with concurrent cirrhosis.[5][9-12] Patients with cirrhosis have less chance of clearing serum HCV-RNA with IFN than patients with milder liver disease, possibly because of their more advanced age, changes in the liver microcirculation which prevent optimal interaction between IFN and infected liver cells, and low compliance.[13] Moreover, at this stage of the disease, patients with cirrhosis who achieve a SVR are not entirely protected against the risk of developing HCC. This could be attributed to either the persistence of liver cells committed to develop into cancer, or the persisting carcinogenic effect of extensive liver fibrosis. Not surprisingly, 2 meta-analyses of anti-HCV studies demonstrated a limited reduction in the risk of HCC in cirrhotic patients who successfully responded to IFN therapy versus untreated or nonresponsive patients.[14][15] However, these meta-analyses also demonstrated clinical heterogeneity of the patient populations investigated and substantial differences among treatment centres in the management of patients.
 
Therefore, to determine the impact of achievement of a SVR on the clinical outcomes of cirrhosis, we conducted a long-term, retrospective, multicenter analysis of prospectively collected data from a cohort of 920 Italian patients with histologically proven HCV cirrhosis, who were treated with IFN and followed up according to standardized criteria.
 
Outcomes of the Study
 
1. Liver-related complications.

 
The incidence rates of liver-related complications per 100 person-years of follow-up was 0 in SVR patients and 1.88 (95% CI: 1.54-2.27) in non-SVR patients (Table 2). The Kaplan Meyer curves of incidence of liver-related complications according to response to IFN are shown in Fig. 1 (P < 0.01 by log-rank test). Ascites was the most common complication (78 cases, 66.7%), followed by bleeding from gastro-oesophageal varices (26 cases, 22.2%) and hepatic encephalopathy (13 cases, 11.1%). By Cox multiple regression analysis the two variables significantly associated with liver-related complications were the non achievement of SVR (crude and adjusted HR not applicable because the value was zero in one cell of the contingency table) and a low platelet values (Table 3).
 
Table 2. Number and Rate of Events Developed During Follow-up in 883 Patients with HCV-Related Histologically Proven Cirrhosis Stratified According to Response to IFN
In the table you see there were 7 HCC cases among 124 patients (Rate/100 Person Yrs: 0.66) who achieved SVR and 122 cases of HCC among 759 patients without an SVR (rate/100person yrs: 2.10).
 

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2. HCC Incidence.
 
The incidence rates of HCC per 100 person-years of follow-up were 0.66 (95% CI: 0.27-1.37) for SVR and 2.10 (95% CI: 1.75-2.51) for non-SVR patients (Table 2). Thus, patients who did not achieve a SVR had 2.59-fold higher rate of HCC than SVR patients. The Kaplan Meyer curves of HCC development in the 2 groups of patients are shown in Fig. 1 (P < 0.01 by log-rank test). In multivariate analysis, age older than 54 years, male gender, low platelet count, and non-SVR status were independent predictors of the likelihood of HCC occurrence (Table 3).
 
Figure 1. Cumulative incidence of liver-related complications (A) and HCC (B) in 883 patients with HCV-related histologically proven cirrhosis stratified according to response to IFN (P = 0.001 by log-rank test). SVR: sustained virological response.
 

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3. Mortality.
 
The incidence rates of liver-related mortality per 100 person-years of follow-up were 0.19 (95% CI: 0.02-0.71) in SVR and 1.44 (95% CI: 0.14-1.78) in non-SVR patients (Table 2). The Kaplan Meyer curves of liver-related mortality according to response to IFN are shown in Fig. 2 (P < 0.001 by log-rank test). By Cox-regression model, the HR of liver-related death was 6.97-fold higher in non-SVR patients (Table 3). In contrast, the incidence rates for non-liver related mortality per 100 person/years of follow-up were similar in SVR and non-SVR patients (Table 2).
 
Analysis of Heterogeneity
The results of analysis of heterogeneity across treatment centres according to the rate of SVR are summarized in Table 4. No significant differences were observed between the centres in the rate of HCC development both in patients with or without SVR (Fig. 3).
 
DISCUSSION
This study shows, in a large Caucasian population, a significant reduction in the rates of liver-related complications, HCC and liver-related mortality in patients with HCV-related cirrhosis who achieved a SVR following IFN monotherapy. During a mean follow-up period of 8 years, the risk of HCC was 2.6-fold higher and that of liver-related deaths was approximately 7-fold higher, respectively, in those failing to clear HCV after IFN therapy.
 
This analysis included the largest ever cohort of patients with histologically-proven cirrhosis. Patients were subjected to prospective follow-up. The study was adequately powered to exclude over-fitting biases and the study population is likely to accurately represent Italian patients with HCV-related cirrhosis, since treatment centres throughout the country participated. A limited number of patients were lost to follow-up in both treatment groups, and the sensitivity of the study was increased by the longer follow-up observed in SVR patients, which reduced the underestimation of outcomes in this population at lower risk of events.
 
The study enrollment period (1992-1997) was selected because, at that time, IFN was the only available antiviral drug to treat HCV infection; ribavirin was later introduced into clinical practice. The influence of HCV genotypes on IFN response was unknown at that time. Thus, there was greater likelihood of including patients who had received homogenous treatment.
 
We planned a delay of at least 6 years between the last enrollment (end of 1998) and the end of follow-up (June 2005), to guarantee the observation of a large number of outcomes in a population with a low risk of events. The reliability of HCV-RNA tests were ensured by the use of annual viral assessments over the entire study period.
 
Previous studies aimed at assessing the anti-HCV activity of IFN were not able to demonstrate reduced liver decompensation rates in IFN recipients.[22][23] The only study suggesting a cause-effect relationship between IFN, HCV eradication and the prevention of clinical decompensation did not conduct separate analyses for patients with cirrhosis versus those with chronic hepatitis.[24] Indeed, it is expected that IFN therapy might also lower the risk of HCC in patients with chronic HCV infection, since this drug combines antiviral and antiproliferative properties. Although IFN therapy prevented HCC in selected, it is not clear whether or not the achievement of a SVR might lower the risk of liver cancer in patients with complete cirrhosis.[9] A retrospective analysis and a prospective study of patients followed up for 6.8 years conducted in Japan showed that HCC risk was reduced, but not abolished, in patients with cirrhosis.[5][25] However, the overall reduction in HCC risk in SVR cirrhotic patients was limited as it did not exceed 20% with respect to untreated or non-responder patients.[14][15]
 
A clear-cut relationship between SVR and drop of HCC risk in Caucasian patients with cirrhosis has not been established. A multicentre retrospective study in Europe showed a slight reduction in HCC risk in patients with HCV-related cirrhosis treated with IFN as compared to untreated ones. The difference, however, disappeared when patients were analysed on the basis of the liver disease severity at entry.[22] Conversely, our database provides evidence that HCC risk was reduced, even though not abolished, among Caucasian patients with cirrhosis who successfully responded to IFN therapy.
 
The occurrence of HCC in patients with cirrhosis achieving a SVR, however, is not unprecedented.[6][9][26] Cirrhosis is the main independent risk factor for HCC development,[9][27] and residual viremia, i.e., HCV-RNA not detected by the currently available commercial PCR assays, may explain the risk of HCC in these patients.[28] The finding that male subjects aged >54 years have a higher risk of developing HCC suggests that host-related factors and/or the duration of the disease might enhance the risk of HCC. Therefore, our results support the need of screening/surveillance programs despite viral eradication in patients with cirrhosis as recently stated.[29] (MRI)
 
Our data suggest that the reduction of liver-related mortality among SVR patients resulted from the combined efficacy of IFN against decompensation or bleeding and HCC, because these complications are the leading causes of death in patients with early cirrhosis due to HCV.[30][31] Data indicate that IFN may prevent the worsening of the disease by suppressing HCV-related liver inflammation which favors hepatocellular failure and the progression of portal hypertension, and by modulating several cell factors involved in neoplastic transformation, such as RNA-dependent PKR and 2,5 oligo adenyl synthetase.[32] In murine models, IFN inhibits liver cell proliferation and stimulates apoptosis of preneoplastic hepatocytes.[33][34] Our findings, which show that the rates of non-liver related mortality were similar in SVR as in non-SVR patients, confirm that IFN activity was specifically addressed toward lowering liver-related mortality among SVR patients.
 
This study may be affected by some methodological weaknesses. First, in cohort studies with no control group, prognostic factors other than treatment might hamper the validity of the obtained results. However, given that we only compared patients who received treatment, both groups (SVR and non-SVR) were likely to have been exposed to similar selecting factors. The enrollment of homogeneous patients with a diagnosis of cirrhosis obtained by liver biopsy and treated with similar schedules of antiviral therapy helped to lower both the hidden differences in terms of the severity of the disease and avoid the confounding effect of inclusion of patients with chronic hepatitis without cirrhosis, as observed in previous reports.[5][6]
 
Also, we performed univariate and multivariate analyses to determine whether the different outcomes among SVR and non-SVR patients could have been influenced by different baseline disease severity. Statistical analyses showed that the platelet count cut-off point of 109,000/mmc emerged as an independent predictor of decompensation as well as HCC and liver-related mortality. This indicates that the degree of portal hypertension, of which the platelets are a reliable surrogate marker, as described,[35] is a powerful indicator of cirrhosis outcome. Despite the fact that the platelet count was significantly lower in the non-SVR group, its value did not influence the impact of SVR as an independent predictor of all outcomes in multivariate analysis. Hence, the risk that the better outcomes observed in the SVR group were attributable to the presence of less severe disease at entry was reduced.
 
The lack of the heterogeneity between centers as evaluated by main outcomes of the study (rate of SVR, incidence of HCC) indicated that all participating centers had similar competence and satisfactory skills in the management of these patients. Furthermore, when we assessed the association between the response to treatment and the clinical outcomes, all factors identified as being independent predictors of response to IFN (i.e., HCV genotype) were taken into account as potential confounding variables. Of interest, platelet count was not associated with the likelihood of achieving SVR. This suggests that hematological side effects and adherence to therapy may be similar in the 2 groups, thus reducing the probability that premature treatment discontinuation was more frequent in the non-SVR group.
 
The retrospective nature of this study may have represented a potential source of selection bias. However, the rates of SVR in our study is consistent with those obtained in similar patients using this schedule of treatment,[36] and might be justified by the sole inclusion of a cohort of patients with early stage of cirrhosis with moderate of portal hypertension and, of a high proportion of patients infected by easy-to-treat genotype 2.[37]
 
In conclusion, our data show that, in patients with HCV-related histologically proven cirrhosis, the achievement of a SVR following IFN treatment was associated with a reduction in liver-related mortality and with a lower risk of liver-related complications and occurrence of HCC.
 
 
 
 
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