Dig Dis Sci DOI 10.1007/s10620-014-3361-6
ORIGINAL ARTICLE
Lower Incidence of Hepatocellular Carcinoma and Cirrhosis in Hepatitis C Patients with Sustained Virological Response by Pegylated Interferon and Ribavirin Chansoo Moon • Kyu Sik Jung • Do Young Kim • Oidov Baatarkhuu • Jun Yong Park • Beom Kyung Kim • Seung Up Kim • Sang Hoon Ahn Kwang-Hyub Han
•
Received: 23 May 2014 / Accepted: 8 September 2014 Ó Springer Science+Business Media New York 2014
Abstract Background To elucidate the benefits of successful antiviral therapy in chronic hepatitis C (CHC) patients Methods A total of 463 CHC patients who underwent pegylated interferon alfa and ribavirin therapy were classified as sustained virological response (SVR) or non-SVR based on response to antiviral therapy. We investigated disease progression to cirrhosis in non-cirrhotic patients, development of cirrhosis-related complications such as ascites, variceal bleeding, and hepatic encephalopathy in patients with cirrhosis, and development of hepatocellular carcinoma (HCC). Results Three hundred patients achieved SVR, and 163 were classified into the non-SVR group. The overall SVR rates were 64.8 %, and multivariate analysis showed that younger age, non-cirrhosis, HCV genotype 2 or 3, lower HCV RNA level (\800,000 IU/mL), and lower body weight were independent factors associated with SVR (all P \ 0.05). During a median follow-up of 36.1 months, non-cirrhotic patients with SVR had significantly lower Chansoo Moon and Kyu Sik Jung have equally contributed to this work.
Electronic supplementary material The online version of this article (doi:10.1007/s10620-014-3361-6) contains supplementary material, which is available to authorized users. C. Moon K. S. Jung D. Y. Kim (&) O. Baatarkhuu J. Y. Park B. K. Kim S. U. Kim S. H. Ahn K.-H. Han Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea e-mail: [email protected] O. Baatarkhuu Department of Infectious Diseases, Health Sciences University, Ulaanbaatar, Mongolia
risk of progression to cirrhosis compared with patients with non-SVR (P \ 0.001). Moreover, SVR was related to a reduced risk of HCC development (P = 0.017). Conclusions SVR resulted in significantly more favorable long-term outcomes, such as lower risk of progression to cirrhosis and HCC occurrence compared with non-SVR. Keywords Hepatitis C Cirrhosis Hepatocellular carcinoma Antiviral therapy Sustained virological response
Introduction Hepatitis C virus (HCV) is one of the leading causes of liver diseases with 180 million people infected worldwide and a prevalence of approximately 2.8 % [1]. In the USA, the prevalence was about 1.6 % from 1999 to 2002 [2]. In Korea, 0.78 % of the population is known to be anti-HCV antibody-positive [3]. Once patients are infected with HCV, more than half (55–85 %) will progress to chronic hepatitis. Data show that 5–20 % of patients with chronic hepatitis progress to cirrhosis over 20–25 years [4]. Patients with cirrhosis have an increased risk of hepatic decompensation and hepatocellular carcinoma (HCC) compared with patients without cirrhosis. Therefore, appropriate antiviral treatment of HCV must be emphasized to ensure a better prognosis for chronic hepatitis C (CHC) patients. The primary goal of anti-HCV treatment is to achieve sustained virological response (SVR), defined as HCV being undetectable in the blood, both at the end of treatment and at 24 weeks after cessation of treatment. The current standard care of antiviral therapy is a combination of pegylated interferon (PEG-IFN) alfa and ribavirin. It is
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reported that about 55 % of patients who receive combination of PEG-IFN alfa and ribavirin achieve SVR ([40 % in genotype 1 or 4, [80 % in genotype 2 or 3) [5–7]. If patients achieve SVR, the recurrence of HCV is extremely rare. Thus, SVR is a powerful surrogate marker for clinical cure of HCV [8]. Previous studies reported that SVR could prevent histological deterioration and result in further improvement of liver histology [9]. In addition to histological outcomes, it is important to know the long-term clinical outcomes, such as liver disease-related morbidity and mortality after achievement of SVR, since real improvement in quality of life likely depends on such clinical outcomes. Two clinical end points have to be considered in the analysis of long-term outcomes after antiviral therapy in CHC patients. The first one is that whether SVR can reduce the risk of progression to cirrhosis in non-cirrhotic patients. If these patients enter a cirrhotic state, the probability of liver-related morbidity or mortality becomes higher than non-cirrhotic patients. The other end point is that whether SVR decreases the incidences of cirrhosis-related complications and HCC when patients achieve SVR by successful antiviral therapy. Thus, the aim of this study is to elucidate the benefits of successful antiviral therapy in terms of clinical outcomes in patients who achieved SVR compared with those with nonSVR.
Patients and Methods Patients and Study Design This study included 463 CHC patients who underwent pegylated interferon alfa and ribavirin therapy at Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, from January 2004 to December 2010. All data of patients were retrospectively reviewed. CHC was diagnosed when serum HCV antibody was positive for more than 6 months. Patients received combination therapy of PEG-IFN alfa-2a or PEG-IFN alfa-2b and ribavirin according to the current guidelines [1]. Patients with HCV genotype 1 or 4 received therapy for 48 weeks, while patients with genotype 2 or 3 received therapy for 24 weeks. The following clinical characteristics were obtained: age, sex, liver disease status (cirrhosis or non-cirrhosis), HCV genotype, HCV RNA quantitation, platelet counts, hemoglobin (Hb), white blood cell counts (WBC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, total bilirubin, alpha-fetoprotein (AFP), body weight, previous alcohol history, and history of diabetes mellitus (DM) before antiviral therapy. In our study, DM was diagnosed according to WHO
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criteria [10]. Shortly, DM was diagnosed when (1) fasting plasma glucose level C126 mg/dl, (2) 2-h plasma glucose C200 mg/dL during an oral glucose tolerance test (OGTT), and (3) random plasma glucose C200 mg/dL with classic symptom of hyperglycemia. A significant alcohol intake was defined as C40 mg/day. Cirrhosis was defined by histological information or clinical criteria [11]. When liver biopsy was performed, fibrosis stage was evaluated according to the Metavir scoring system [12]. When the histological information was not available, cirrhosis was defined as follows: (1) platelet count \1,000,000/lL and ultrasonographic findings suggestive of cirrhosis, including blunted, nodular liver edge accompanied by splenomegaly ([12 cm); (2) esophageal or gastric varices; or (3) overt complications of cirrhosis, such as ascites, variceal bleeding, and hepatic encephalopathy [13, 14]. The progression to cirrhosis was defined as newly diagnosed cirrhosis during follow-up in patients who had not been cirrhotic at the time of enrollment. All adverse events reported during the treatment period were reviewed. We investigated whether new laboratory abnormalities occurred in patients who had no laboratory abnormalities before treatment. Hematologic adverse events included neutropenia (mild 750 mm3 B absolute neutrophil count [ANC] \ 1,500/mm3; moderate 500/mm3 B ANC \ 750 mm3; and severe ANC \ 500/mm3), thrombocytopenia (platelet count \ 50,000/mm3), and haemolytic anemia (hemoglobin \ 10 g/dL). The other adverse events included influenza-like symptoms, dermatologic symptoms, neuropsychiatric symptoms, and so on. Before and after antiviral therapy, every patient visited our clinic regularly and received HCC surveillance using serum AFP and ultrasonography every 6 months, regardless of achievement of SVR or not. Together with HCC surveillance, progression to cirrhosis and occurrence of overt cirrhotic complication were monitored. Definition of Treatment Response Patients were classified as SVR or non-SVR based on the response to antiviral therapy. SVR was defined as the absence of detectable serum HCV RNA after 24 weeks of treatment. Serum HCV RNA was measured by a COBAS Amplicor HCV Test (Roche Diagnostics, NJ, USA) (\600 IU/mL) until 2010 and thereafter by the Cobas AmpliPrep/Cobas TaqMan HCV Quantitative Test (Roche Molecular Systems; Pleasanton, CA, USA) (\12 IU/mL). Non-SVR was defined when patients did not achieve undetectable HCV RNA at 24 weeks after cessation of treatment. Treatment failure was defined as failure to achieve SVR despite complete antiviral therapy for 48 weeks in genotype 1 or 4, and 24 weeks in genotype 2 or 3. Factors associated with achievement of SVR were
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analyzed. All patients were followed up until the last visit before April 2013. The follow-up duration was calculated from the end of IFN treatment to the day of last follow-up. End Point of Study The primary end point of this study was to evaluate clinical outcomes of combination of PEG-IFN alfa and ribavirin treatment regarding progression to cirrhosis, occurrence of HCC, and cirrhosis-related complications. Secondly, the other end point was to compare such clinical outcomes between patients with SVR and those without. Statistical Analyses Statistical analyses included the Student’s t test and Mann– Whitney test for continuous variables and the chi-square test for categorical variables. Logistic regression analysis was used to analyze the factors associated with SVR. Kaplan–Meier curve analysis with log-rank test was performed to compare long-term clinical outcomes, such as cirrhosis progression and HCC development, between SVR and non-SVR groups. A P value \ 0.05 was considered significant. Data were analyzed by SPSS version 20.0.0 for Windows (IBM Corporation, Armonk, New York, USA).
Results Patient Characteristics A total of 494 CHC patients underwent antiviral therapy from January 2004 to December 2010. Of those, 463 patients with available medical records were recruited in this study. Among 404 patients who had completed standard antiviral therapy of PEG-IFN alfa and ribavirin, 300 patients achieved SVR. The treatment failure group consisted of 71 relapsers and 33 non-responders. The 59 patients who did not complete treatment were defined as the treatment stop group. None of the patient in treatment stop group achieved SVR after 24 weeks after the end of the treatment, and none of non-SVR group was re-treated. Thus, 163 patients with non-SVR were divided into the treatment failure (n = 104) and treatment stop groups (n = 59) (Fig. 1). Table 1 shows the baseline characteristics of the SVR and non-SVR groups. The mean age of all patients was approximately 50 years at the beginning of treatment (50.9 ± 11.5 years). In our cohort, liver biopsy prior to treatment was performed in 46 of 436 (9.9 %) patients. Thirty-nine patients (84.8 %) belonged to B F2 stage (F1, n = 19, 41.3 %; F2, n = 20, 43.5 %), three patients
Fig. 1 A flowchart showing study design. A total of 463 patients with CHC were included in this study. Three hundred patients achieved SVR, and 163 patients were classified as non-SVR group. CHC chronic hepatitis C, SVR sustained virological response, Tx treatment
(6.5 %) to F3 stage, and four (8.7 %) patients to F4 stage. Except those 4 patients with histologically confirmed cirrhosis, 78 patients were diagnosed as cirrhosis by clinical criteria. Therefore, a total of 82 patients were diagnosed as cirrhosis at enrollment, and all cirrhotic patients had preserved liver function (Child pugh A). The most common genotype was 1 (n = 262, 57.2 %), followed by genotype 2 (n = 188, 41.0 %). The median viral load of HCV RNA was 1,210,000 IU/mL (interquartile range [IQR]: 253,750– 2,675,000), and the mean ALT was 86.4 IU/L. Ten (2.3 %) patients had history of previous conventional IFN treatment. The baseline AFP levels were available in all patients, and mean AFP levels were 11.8 ng/mL. When comparing patients with SVR and those with nonSVR, patients with SVR were significantly younger (49.0 ± 12.0 vs. 54.4 ± 9.6 years, P \ 0.001) and had higher platelet count (194.7 ± 62.3 vs. 162.3 ± 61.11,000/ mm3, P \ 0.001) and albumin levels (4.5 ± 0.3 vs. 4.3 ± 0.4 mg/dL, P \ 0.001) than those with non-SVR, whereas patients with non-SVR had a significantly higher proportion of the presence of cirrhosis (32.5 vs. 9.7 %, P \ 0.001) and HCV genotype 1 (74.2 vs. 48.7 %, P \ 0.001), baseline HCV RNA level (1,540,000 vs. 1,005,338 IU/mL, P \ 0.001), and baseline AFP level (19.3 ± 34.5 vs. 7.1 ± 14.9, P = 0.001) than those with SVR. The median follow-up duration was 36.1 months (IQR: 16.0–100.0), and there was no significant difference in follow-up duration between patients with SVR and those with non-SVR (median 37.0 vs. 34.6 months, P = 0.515).
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Dig Dis Sci Table 1 Baseline characteristics of patients according to treatment response
Variable
a
Median (IQR)
SVR (N = 300)
Non-SVR (N = 163)
P value \0.001
Age (years)
50.9 ± 11.5
49.0 ± 12.0
54.4 ± 9.6
Male, n (%)
221 (47.7)
141 (47.0)
80 (49.1)
0.669
Cirrhosis, n (%)
82 (17.7)
29 (9.7)
53 (32.5)
\0.001
HCV genotype
267:188:8
146:148:6
121:40:2
\0.001
1:2:3, n (%)
(57.2:41.0:1.7)
(48.7:49.3:2.0)
(74.2:24.5:1.2)
HCV RNAa (IU/mL)
AFP alpha-fetoprotein, ALT aspartate aminotransferase, AST alanine aminotransferase, DM diabetes mellitus, Hb hemoglobin, HCV hepatitis C virus, SVR sustained virological response
All patients (N = 463)
1,210,000
1,005,338.5
1,540,000
(253,750–2,675,000)
(155,750–2,482,500)
(562,000–3,067,500)
Platelet (1,000/mm3)
183.5 ± 63.7
194.7 ± 62.3
162.3 ± 61.1
\0.001
Hb (g/dL)
13.8 ± 1.6
13.8 ± 1.6
13.8 ± 1.6
WBC (/mm3)
5,549.3 ± 1,805.3
5,617.1 ± 1,815.1
5,419.8 ± 1,785.3
0.274
AST (IU/L) ALT (IU/L)
68.8 ± 52.5 86.4 ± 75.9
67.5 ± 51.6 89.9 ± 76.8
71.4 ± 54.3 80.0 ± 74.0
0.453 0.186
Albumin (g/dL)
4.4 ± 0.3
4.5 ± 0.3
4.3 ± 0.4
0.840
\0.001
Total bilirubin (mg/dL)
0.8 ± 0.5
0.8 ± 0.5
0.8 ± 0.4
0.834
AFP (ng/mL)
11.8 ± 25.0
7.1 ± 14.9
19.3 ± 34.5
0.001
Weight (kg)
62.6 ± 10.5
62.2 ± 10.1
63.5 ± 11.2
0.300
DM, n (%)
41 (8.9)
24 (8.0)
17 (10.4)
0.379
Alcohol [ 40 g/day, n (%)
101 (58.0)
68 (57.6)
33 (58.9)
0.871
Follow-up duration, months
36.1 (16.0–100.0)
37.0 (18.0–94.0)
34.6 (16.0–100.0)
0.515
Achievement of SVR and Associated Factors The overall SVR rates for all patients were 64.8 % (300/ 463) by intention-to-treat analysis and 74.3 % (300/404) by per-protocol analysis. SVR was achieved in 142 of 262 patients with genotype 1, which was significantly lower compared with genotype 2 or 3, where 158 of 201 patients achieved SVR (54.2 vs. 78.6 %, P \ 0.001). When 300 patients with SVR were compared with 163 patients with non-SVR, age, liver disease status, HCV genotype, HCV RNA quantitation level, platelet count, albumin level, AFP, and body weight were significantly related to SVR in univariate analysis (Table 2). In a subsequent multivariate analysis, which included the variables which had a statistical significance in univariate analysis (P \ 0.05), age younger than 40 years, non-cirrhosis, HCV genotype 2 or 3, low HCV RNA level (\800,000 IU/mL), and lower body weight were found to be independent factors associated with SVR. Most patients who achieved SVR were maintained with long-term virological response, so only three patients (3/300, 1.0 %) had late relapse. The time points of viral relapse in those three patients were 6, 37, and 46 months after confirming SVR. Two of them were genotype 1 infection, and one was genotype 2. All three patients were cirrhotic at the time of therapy and had high baseline HCV RNA loads. However, the patients did
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\0.001
not have other risk factors related to late HCV relapse such as immunosuppression. Adverse Events Adverse events of any degree occurred in 385 of 463 patients (83.2 %) who underwent antiviral therapy with PEG-IFN and ribavirin. Adverse events are summarized in Supplementary Table 1. Dose reduction was performed in 106 of 404 (26.2 %) patients who completed antiviral treatment. The most common reason for dose reduction was neutropenia (n = 42, 39.6 %), followed by anemia (n = 39, 36.8 %) and thrombocytopenia (n = 25, 23.6 %). Fifty-nine patients stopped antiviral treatment. The reasons for withdrawal of antiviral treatment were as follows: patient’s denial due to intolerance (e.g., general weakness) (n = 54), anemia (n = 2), depression (n = 2), and drug-induced hyperthyroidism (n = 1). Long-Term Outcomes The long-term clinical outcomes were compared between patients with SVR and those without (Table 3). During the follow-up, progression to cirrhosis occurred in 17 (36.7 %) of 463 patients. Among all 17 patients, progression to cirrhosis was diagnosed histologically in four patients. In
Dig Dis Sci Table 2 Univariate and multivariate analysis to identify factors associated with SVR
Univariate analysis Unadjusted OR
Multivariate analysis
(95 % CI)
P value
Adjusted OR
(95 % CI)
P value
Age \40 years
1 (Reference)
C40 years
0.15
0.06–0.39
\0.001
0.16
0.04–0.71
0.016
Male
0.89
0.57–1.39
0.598
1.57
0.67–3.66
0.301
Cirrhosis
0.16
0.09–0.28
\0.001
0.21
0.09–0.49
\0.001
2.81–8.39
\0.001
6.41
2.91–14.15 \0.001
0.24–0.66 1.01–1.02
\0.001 \0.001
0.36 1.00
0.17–0.76 1.00–1.01
0.007 0.112
2.29
0.76–6.94
0.143
0.94
0.90–0.98
0.006
HCV genotype 1
1 (reference)
2 or 3
4.85
HCV RNA (IU/mL) \800,000 C800,000 Platelet (1,000/mm3)
AFP alpha-fetoprotein, ALT aspartate aminotransferase, AST alanine aminotransferase, DM diabetes mellitus, Hb hemoglobin, HCV hepatitis C virus, OR odds ratio, SVR sustained virological response
1 (Reference) 0.40 1.01
Hb (g/dL)
1.01
00.87–1.16
0.927
WBC (/mm3)
1.00
1.00–1.00
0.051
AST (IU/L)
1.00
0.99–1.00
0.762
ALT (IU/L)
1.00
1.00–1.01
0.150
Albumin (g/dL)
4.72
2.26–9.83
\0.001
Total bilirubin (mg/dL)
0.88
0.56–1.38
0.575
AFP (ng/mL)
0.97
0.96–0.99
0.006
DM
1.50
0.72–3.12
0.278
Body weight (kg)
0.97
0.95–0.99
0.018
Alcohol [ 40 g/day
0.97
0.48–1.95
0.926
remaining 13 patients, it was diagnosed by laboratory and imaging results. Progression to cirrhosis occurred more frequently in patients with non-SVR than those with SVR (12 of 110 patients [10.9 %] vs. 5 of 271 patients [1.8 %], P \ 0.001). Annual rate of progression to cirrhosis was also significantly higher in non-SVR group (4.16 event/ year) compared with SVR group (1.62 event/year). In Kaplan–Meier graph, the cumulative incidence of progression to cirrhosis was higher in patients with SVR than those without (Fig. 2a, log-rank test, P \ 0.001). During the follow-up, HCC developed in 12 patients at the median of 46.7 months (range 9–84 months) after the end of antiviral treatment. The patients with non-SVR had a significantly higher incidence of HCC (9 of 163 [5.5 %] patients vs. 3 of 300 [1.0 %] patients, P = 0.005), and annual incidence of HCC development of non-SVR group (3.12 event/year) was significantly higher than those of SVR group (0.97 event/year). The cumulative incidence of HCC occurrence was also higher in patients with SVR than those without (Fig. 2b, log-rank test, P = 0.017). In patients who already had cirrhosis at baseline, cirrhosis-related complications developed in six patients during follow-up. Two patients had variceal bleeding and ascites developed in four patients. The incidence of
cirrhosis-related complications as well as those of HCC occurrence was not significantly different between patients with SVR and those without (Table 3). Table 4 presents the characteristics of 12 HCC patients. Six patients had no evidence of cirrhosis at the time of enrollment, and progression to cirrhosis occurred in 2 of 6 patients until HCC development. Among 6 HCC patients with cirrhosis at baseline, one patient belonged to SVR group and other 5 patients to non-SVR group.
Discussion HCV infection is one of the major causes of chronic liver diseases and usually progresses over time, eventually to cirrhosis resulting in increased risk of HCC. The rate of progression to advanced fibrosis is highly variable among patients; however, at least 5–20 % of CHC patients deteriorate to cirrhosis over two decades, and HCV infection is associated with higher disease-related morbidity and mortality. We analyzed data of 463 CHC patients who received standard antiviral therapy using PEG-IFN and ribavirin. The overall SVR rates were 64.8 % by intention-to-treat analysis, and patients with HCV genotype 2 or 3 had higher
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Dig Dis Sci Table 3 Comparison of clinical outcome between patients with and without SVR
Whole population (n = 463)
SVR
Non-SVR
300
163
P value
Median follow-up period (month)
37.0 (18.0–94.0)
34.6 (16.0–100.0)
0.515
HCC occurrence
3 (1.0)
9 (5.5)
0.005
271
110
Patients without cirrhosis at baseline (n = 381) Median follow-up period (month)
35.2 (18.0–94.0)
33.2 (16.0–95.0)
Progression to cirrhosis, n (%)
5 (1.8)
12 (10.9)
29
53
Patients with cirrhosis at baseline (n = 82)
0.204 \0.001
Median follow-up period (month)
38.9 (23.2–70.5)
39.4 (17.5–100.0)
0.196
Cirrhosis-related complication, n (%)
1 (3.4)
5 (9.4)
0.303
Development of ascites
1 (3.4)
3 (5.6)
Development of variceal bleeding Development of HEP
0 0
2 (3.8) 0
HCC occurrence
1 (3.4)
5 (9.4)
0.303
HCC hepatocellular carcinoma, HEP hepatic encephalopathy, SVR sustained virological response
SVR rates after antiviral therapy compared with genotype 1. The clinical factors associated with SVR were non-cirrhosis, age younger than 40 years, HCV genotype (genotype 2 or 3), low HCV RNA level (\800,000 IU/mL), and low body weight, which were consistent with the results of previous studies [5, 6]. In our study, SVR rates were found to be higher than in previous studies from Western countries [5–7]. This might be explained by two reasons. First, the difference of host genetic factors which would have affected the difference of SVR rates between Western and Korean patients. The previous studies also reported higher SVR rate in Korean patients compared with Western population [15, 16]. Recently, single nucleotide polymorphisms near the interleukin (IL) 28B gene was reported to be associated with resistance to HCV infection and treatment response and could be a good predictor of SVR [17, 18]. A better efficacy of antiviral therapy in Koreans than
Fig. 2 The cumulative incidences of progression to cirrhosis (a) and HCC occurrence (b) between patients with SVR and non-SVR. HCC hepatocellular carcinoma, SVR sustained virological response
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in Caucasians would be attributed to favorable IL 28B polymorphisms [19–21]. Second, dose reduction rates of our cohort was lower than those of previous studies, as our study was conducted more recently than previous ones, and the patients were recruited from a single center instead of multiple centers [22–24]. It could be suggested that the standard antiviral therapy might be applied more consistently with close contact and monitoring by an experienced medical team, consequently resulting in higher patient compliance without dose reduction in our study. The most important finding in the present study is that SVR was related to a reduced risk of disease progression from hepatitis C. Patients who had achieved SVR had significantly lower risk of progression to cirrhosis from non-cirrhotic state compared with patients with non-SVR. Furthermore, SVR was also significantly associated with decreasing development of HCC. Recently, several studies
Dig Dis Sci Table 4 Characteristics of patients who developed HCC after antiviral treatment Case
Age
Sex
Treatment response
Liver activity
Cirrhotic change until HCC
Duration to HCC (month)
AFP (ng/ml)
Alcohol
1
45
M
Non-response
Cirrhosis
56
13.7
No
2
56
M
Relapse
Cirrhosis
3
58
M
SVR
No cirrhosis
No
9
11.1
Yes
73
1.8
4
58
M
Non-response
No cirrhosis
Cirrhosis
63
6.2
No Yes
5
59
M
Non-response
No cirrhosis
No
13
10.0
No
6
60
F
Relapse
Cirrhosis
45
6.43
No
7 8
60 63
M M
Relapse SVR
Cirrhosis Cirrhosis
9 34
6.9 5.44
Yes No
9
65
F
Non-response
No cirrhosis
No
84
9.6
No
10
66
M
SVR
No cirrhosis
No
18
7.4
No
11
66
M
Non-response
No cirrhosis
Cirrhosis
73
11.7
Yes
12
67
M
Relapse
Cirrhosis
49
5.28
Yes
AFP alpha-fetoprotein, HCC hepatocellular carcinoma, SVR sustained virological response
evaluated risk factors associated with hepatitis C-related HCC development. In a Japanese study analyzing data of 1,028 patients who received PEG-IFN plus ribavirin therapy, non-SVR was selected as independent risk factors associated with HCC development together with older age, male gender, advanced fibrosis, severe steatosis, lower serum albumin, and higher post-IFN treatment ALT or AFP levels [25]. In another study from Japan, moderate to advanced fibrosis stage, advanced age, alcohol history, AFP elevation were identified as risk factors associated with HCC development [26]. Consistent with previous studies, our data suggested that SVR is a good surrogate marker against HCC development. However, it is also notable that potential risk of developing HCC might still exist even if CHC patient achieved SVR after antiviral therapy. For instance, Yamashita et al. [26] analyzed a cohort of 562 patients achieving SVR after IFN therapy and reported that HCC was detected in 26 % of patients more than 10 years after completing IFN therapy. Interestingly, 42 % of those patients were in early fibrosis stage such as F2. In our study, among 12 patients who developed HCC, there were 3 patients with SVR and two of them had no evidence of cirrhosis until HCC diagnosis. However, because the assessment of fibrosis stage in these 3 patients was made based on clinical criteria, there is a possibility that histological cirrhosis might already exist at the time of HCC occurrence. Additionally, it would be also important to find risk factor of HCC occurrence or progression to cirrhosis in patients who achieved SVR. Unfortunately, our study failed to provide confirmative result regarding these, as HCC or progression to cirrhosis occurred in only a small number of patients. When comparing SVR patients with HCC occurrence than those without, there was no
significant difference of clinical variables between two groups. Although SVR patients with progression to cirrhosis had higher baseline AST and ALT levels than those without (all P \ 0.05), these results need to be interpreted carefully and warrant more studies. Given that mortality of patients with liver disease is determined primarily by complications associated with cirrhosis or HCC, eradication of HCV with successful antiviral therapy may prevent disease progression and HCC development, eventually lowering disease-related mortality in CHC patients. In fact, a recent study in Japan reported that SVR with successful antiviral therapy reduced the risk ratio for overall mortality and disease-related mortality of CHC patients [27]. Regarding the role of SVR in CHC patients, it was reported that patients with SVR had no development of HCC and decompensated liver disease in a cohort of CHC patients who had received combination therapy of IFN alfa and ribavirin at a single center [28]. In that study, 138 CHC patients were followed for a median of 41 months and HCC and decompensated liver disease were not observed in 57 patients with SVR while occurring in 5 of 81 (6.2 %) patients with non-SVR. However, the study included patients who underwent conventional IFN-based therapy, not PEG-IFN, and the results had no statistical significance. Our study showed that SVR with PEG-IFN and ribavirin treatment could reduce the risk of progression to cirrhosis from non-cirrhosis and could potentially lower the development of HCC development. Hence, the current study clearly shows the clinical benefits of successful antiviral therapy using a standard regimen for hepatitis C. Ultimately, it would be possible to reduce the morbidity and mortality of CHC patients by achieving SVR with antiviral therapy. Although all CHC patients may be subject to
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antiviral therapy, it might be ideal to select patients for whom antiviral therapy is the most helpful, considering cost-effectiveness and adverse events given by the standard of care. The current antiviral therapy has a limited efficacy, especially in patients with HCV genotype 1; therefore, clinicians should consider the benefits and risks of antiviral therapy before making recommendations for individual patient [1]. In this regards, it might be hopeful that recently there was a substantial progress on antiviral therapy for HCV infection due to the emergence of new drugs, directly acting antiviral agents (DAA) that are selective inhibitors of HCV protease or polymerase. The first-generation DAAs, boceprevir and telaprevir, were approved by the FDA in 2011, and several studies reported that the addition of these new agents to PEG-IFN/ribavirin therapy in HCV genotype 1 infection achieved much higher SVR rate compared with the current PEG-IFN/ribavirin regimen [29–33]. Drugs with other classes such as sofosbuvir and asunaprevir/daclatasvir have also been approved or are under clinical trials and are expected to further increase the SVR rates in the near future. The improvement in SVR with these new drugs will translate into more favorable long-term outcomes in CHC patients. We recognize that several previous studies in Western countries support our finding that SVR leads to good longterm outcomes in CHC patients by decreasing the risk of liver-related morbidity and mortality [34–37]. The latest study was a large, international, multicenter study of 530 CHC patients who were treated with IFN-based therapy in Europe and Canada [38]. SVR had a positive effect on longterm outcomes such as all-cause mortality, liver-related mortality, or liver transplantation and HCC. When 405 nonSVR patients and 125 SVR patients were followed for a median of 8.4 years (IQR: 6.4–11 0.4), SVR significantly reduced the risk of all-cause mortality (hazard ratio [HR] 0.26; 95 % CI 0.14–0.49; P \ 0.001), liver-related mortality and liver transplantation (HR 0.06; 95 % CI 0.02–0.19; P \ 0.001), and HCC (HR 0.19; 95 % CI 0.08–0.44; P \ 0.001). Lastly, it is an interesting finding in our study that 4 of 12 HCC patients had no evidence of liver cirrhosis at the time of HCC occurrence, because HCV-related HCC predominantly occurs in the setting of cirrhosis. In one patient (patient 5), HCC was resected and the histological examination showed F3 stage of background liver, and there was no clinical evidence of cirrhosis in the other three patients. The reason for this is not clearly explained, but recent meta-analysis suggested that HCV also could arise from non-cirrhotic liver [39]. New phenotypic expression of HCV followed by long-standing infection or unknown interaction of HCV protein to host cell, or enhanced hepatocarcinogenesis in non-cirrhotic liver by DM might be a possible explanation [39, 40]. However, it is also possible
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that histological cirrhosis or advanced liver fibrosis already existed without clinical evidence in these patients. We are also aware that this study has some limitations. First, histological information by liver biopsy was available only in 46 of 436 (9.9 %) patients at baseline, and the diagnosis of cirrhosis and progression to cirrhosis were performed by clinical criteria of cirrhosis in many patients. Consequently, estimation of fibrosis status before and after treatment might be inaccurate in our study. Furthermore, a subgroup analysis according to fibrosis stage was not possible. Secondly, this study is a retrospective study, which had a potential of selection bias, and the follow-up period (median 36.1 months) was not long enough. Accordingly, long-term outcomes such as all-cause mortality and liver-related mortality were not investigated. In conclusion, our study showed that successful antiviral therapy results in favorable long-term outcomes by reducing the risk of cirrhosis development and HCC occurrence in CHC patients. If patients have progressed to cirrhosis, they have a higher likelihood of mortality and morbidity than noncirrhotic patients. Therefore, anti-HCV treatment should be considered as early as possible after HCV diagnosis. Conflict of interest
None.
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Dig Dis Sci 10. Anonymous. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26:S5– S20. 11. Suk KT, Baik SK, Yoon JH, et al. Revision and update on clinical practice guideline for liver cirrhosis. Korean J Hepatol. 2012; 18:1–21. 12. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24:289–293. 13. Tchelepi H, Ralls PW, Radin R, et al. Sonography of diffuse liver disease. J Ultrasound Med. 2002;21:1023–1032; quiz 1033-1024. 14. Jung KS, Kim SU, Ahn SH, et al. Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using liver stiffness measurement (FibroScan). Hepatology. 2011;53:885–894. 15. Kim KT, Han SY, Kim JH, et al. Clinical outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C. Korean J Hepatol. 2008;14:36–45. 16. Park SH, Park CK, Lee JW, et al. Efficacy and tolerability of peginterferon alpha plus ribavirin in the routine daily treatment of chronic hepatitis C patients in Korea: a multi-center, retrospective observational study. Gut Liver. 2012;6:98–106. 17. Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–1104. 18. Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461:798–801. 19. Lyoo K, Song MJ, Hur W, et al. Polymorphism near the IL28B gene in Korean hepatitis C virus-infected patients treated with peg-interferon plus ribavirin. J Clin Virol. 2011;52:363–366. 20. Jeong SH, Jung YK, Yang JW, et al. Efficacy of peginterferon and ribavirin is associated with the IL28B gene in Korean patients with chronic hepatitis C. Clin Mol Hepatol. 2012;18: 360–367. 21. Sinn DH, Kim YJ, Lee ST, et al. Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in Asian patients. J Gastroenterol Hepatol. 2011;26:1374–1379. 22. Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology. 2002;36:S237–S244. 23. Kwon JH, Bae SH, Choi JY, et al. Assessment of the efficacy of reducing peginterferon alpha-2a and ribavirin dose on virologic response in Koreans with chronic hepatitis C. Korean J Intern Med. 2009;24:203–211. 24. Lee H, Choi MS, Paik SW, et al. Peginterferon alfa-2a plus ribavirin for initial treatment of chronic hepatitis C in Korea. Korean J Hepatol. 2006;12:31–40. 25. Asahina Y, Tsuchiya K, Nishimura T, et al. Alpha-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C. Hepatology. 2013;58:1253–1262.
26. Yamashita N, Ohho A, Yamasaki A, et al. Hepatocarcinogenesis in chronic hepatitis C patients achieving a sustained virological response to interferon: significance of lifelong periodic cancer screening for improving outcomes. J Gastroenterol. 2013. 27. Maruoka D, Imazeki F, Arai M, et al. Long-term cohort study of chronic hepatitis C according to interferon efficacy. J Gastroenterol Hepatol. 2012;27:291–299. 28. Kim JH, Han KH, Lee KS, et al. Efficacy and long-term follow up of combination therapy with interferon alpha and ribavirin for chronic hepatitis C in Korea. Yonsei Med J. 2006;47:793–798. 29. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–2416. 30. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417–2428. 31. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014–1024. 32. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195–1206. 33. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207–1217. 34. Cardoso AC, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis. J Hepatol. 2010;52:652–657. 35. Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147:677–684. 36. Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology. 2007;45:579–587. 37. Morgan TR, Ghany MG, Kim HY, et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. 2010;52:833–844. 38. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584–2593. 39. Madhoun MF, Fazili J, Bright BC, et al. Hepatitis C prevalence in patients with hepatocellular carcinoma without cirrhosis. Am J Med Sci. 2010;339:169–173. 40. Kawamura Y, Arase Y, Ikeda K, et al. Diabetes enhances hepatocarcinogenesis in noncirrhotic, interferon-treated hepatitis C patients. Am J Med. 2010;123:951–956 e951.
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ORIGINAL ARTICLE
Lower Incidence of Hepatocellular Carcinoma and Cirrhosis in Hepatitis C Patients with Sustained Virological Response by Pegylated Interferon and Ribavirin Chansoo Moon • Kyu Sik Jung • Do Young Kim • Oidov Baatarkhuu • Jun Yong Park • Beom Kyung Kim • Seung Up Kim • Sang Hoon Ahn Kwang-Hyub Han
•
Received: 23 May 2014 / Accepted: 8 September 2014 Ó Springer Science+Business Media New York 2014
Abstract Background To elucidate the benefits of successful antiviral therapy in chronic hepatitis C (CHC) patients Methods A total of 463 CHC patients who underwent pegylated interferon alfa and ribavirin therapy were classified as sustained virological response (SVR) or non-SVR based on response to antiviral therapy. We investigated disease progression to cirrhosis in non-cirrhotic patients, development of cirrhosis-related complications such as ascites, variceal bleeding, and hepatic encephalopathy in patients with cirrhosis, and development of hepatocellular carcinoma (HCC). Results Three hundred patients achieved SVR, and 163 were classified into the non-SVR group. The overall SVR rates were 64.8 %, and multivariate analysis showed that younger age, non-cirrhosis, HCV genotype 2 or 3, lower HCV RNA level (\800,000 IU/mL), and lower body weight were independent factors associated with SVR (all P \ 0.05). During a median follow-up of 36.1 months, non-cirrhotic patients with SVR had significantly lower Chansoo Moon and Kyu Sik Jung have equally contributed to this work.
Electronic supplementary material The online version of this article (doi:10.1007/s10620-014-3361-6) contains supplementary material, which is available to authorized users. C. Moon K. S. Jung D. Y. Kim (&) O. Baatarkhuu J. Y. Park B. K. Kim S. U. Kim S. H. Ahn K.-H. Han Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea e-mail: [email protected] O. Baatarkhuu Department of Infectious Diseases, Health Sciences University, Ulaanbaatar, Mongolia
risk of progression to cirrhosis compared with patients with non-SVR (P \ 0.001). Moreover, SVR was related to a reduced risk of HCC development (P = 0.017). Conclusions SVR resulted in significantly more favorable long-term outcomes, such as lower risk of progression to cirrhosis and HCC occurrence compared with non-SVR. Keywords Hepatitis C Cirrhosis Hepatocellular carcinoma Antiviral therapy Sustained virological response
Introduction Hepatitis C virus (HCV) is one of the leading causes of liver diseases with 180 million people infected worldwide and a prevalence of approximately 2.8 % [1]. In the USA, the prevalence was about 1.6 % from 1999 to 2002 [2]. In Korea, 0.78 % of the population is known to be anti-HCV antibody-positive [3]. Once patients are infected with HCV, more than half (55–85 %) will progress to chronic hepatitis. Data show that 5–20 % of patients with chronic hepatitis progress to cirrhosis over 20–25 years [4]. Patients with cirrhosis have an increased risk of hepatic decompensation and hepatocellular carcinoma (HCC) compared with patients without cirrhosis. Therefore, appropriate antiviral treatment of HCV must be emphasized to ensure a better prognosis for chronic hepatitis C (CHC) patients. The primary goal of anti-HCV treatment is to achieve sustained virological response (SVR), defined as HCV being undetectable in the blood, both at the end of treatment and at 24 weeks after cessation of treatment. The current standard care of antiviral therapy is a combination of pegylated interferon (PEG-IFN) alfa and ribavirin. It is
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reported that about 55 % of patients who receive combination of PEG-IFN alfa and ribavirin achieve SVR ([40 % in genotype 1 or 4, [80 % in genotype 2 or 3) [5–7]. If patients achieve SVR, the recurrence of HCV is extremely rare. Thus, SVR is a powerful surrogate marker for clinical cure of HCV [8]. Previous studies reported that SVR could prevent histological deterioration and result in further improvement of liver histology [9]. In addition to histological outcomes, it is important to know the long-term clinical outcomes, such as liver disease-related morbidity and mortality after achievement of SVR, since real improvement in quality of life likely depends on such clinical outcomes. Two clinical end points have to be considered in the analysis of long-term outcomes after antiviral therapy in CHC patients. The first one is that whether SVR can reduce the risk of progression to cirrhosis in non-cirrhotic patients. If these patients enter a cirrhotic state, the probability of liver-related morbidity or mortality becomes higher than non-cirrhotic patients. The other end point is that whether SVR decreases the incidences of cirrhosis-related complications and HCC when patients achieve SVR by successful antiviral therapy. Thus, the aim of this study is to elucidate the benefits of successful antiviral therapy in terms of clinical outcomes in patients who achieved SVR compared with those with nonSVR.
Patients and Methods Patients and Study Design This study included 463 CHC patients who underwent pegylated interferon alfa and ribavirin therapy at Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, from January 2004 to December 2010. All data of patients were retrospectively reviewed. CHC was diagnosed when serum HCV antibody was positive for more than 6 months. Patients received combination therapy of PEG-IFN alfa-2a or PEG-IFN alfa-2b and ribavirin according to the current guidelines [1]. Patients with HCV genotype 1 or 4 received therapy for 48 weeks, while patients with genotype 2 or 3 received therapy for 24 weeks. The following clinical characteristics were obtained: age, sex, liver disease status (cirrhosis or non-cirrhosis), HCV genotype, HCV RNA quantitation, platelet counts, hemoglobin (Hb), white blood cell counts (WBC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, total bilirubin, alpha-fetoprotein (AFP), body weight, previous alcohol history, and history of diabetes mellitus (DM) before antiviral therapy. In our study, DM was diagnosed according to WHO
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criteria [10]. Shortly, DM was diagnosed when (1) fasting plasma glucose level C126 mg/dl, (2) 2-h plasma glucose C200 mg/dL during an oral glucose tolerance test (OGTT), and (3) random plasma glucose C200 mg/dL with classic symptom of hyperglycemia. A significant alcohol intake was defined as C40 mg/day. Cirrhosis was defined by histological information or clinical criteria [11]. When liver biopsy was performed, fibrosis stage was evaluated according to the Metavir scoring system [12]. When the histological information was not available, cirrhosis was defined as follows: (1) platelet count \1,000,000/lL and ultrasonographic findings suggestive of cirrhosis, including blunted, nodular liver edge accompanied by splenomegaly ([12 cm); (2) esophageal or gastric varices; or (3) overt complications of cirrhosis, such as ascites, variceal bleeding, and hepatic encephalopathy [13, 14]. The progression to cirrhosis was defined as newly diagnosed cirrhosis during follow-up in patients who had not been cirrhotic at the time of enrollment. All adverse events reported during the treatment period were reviewed. We investigated whether new laboratory abnormalities occurred in patients who had no laboratory abnormalities before treatment. Hematologic adverse events included neutropenia (mild 750 mm3 B absolute neutrophil count [ANC] \ 1,500/mm3; moderate 500/mm3 B ANC \ 750 mm3; and severe ANC \ 500/mm3), thrombocytopenia (platelet count \ 50,000/mm3), and haemolytic anemia (hemoglobin \ 10 g/dL). The other adverse events included influenza-like symptoms, dermatologic symptoms, neuropsychiatric symptoms, and so on. Before and after antiviral therapy, every patient visited our clinic regularly and received HCC surveillance using serum AFP and ultrasonography every 6 months, regardless of achievement of SVR or not. Together with HCC surveillance, progression to cirrhosis and occurrence of overt cirrhotic complication were monitored. Definition of Treatment Response Patients were classified as SVR or non-SVR based on the response to antiviral therapy. SVR was defined as the absence of detectable serum HCV RNA after 24 weeks of treatment. Serum HCV RNA was measured by a COBAS Amplicor HCV Test (Roche Diagnostics, NJ, USA) (\600 IU/mL) until 2010 and thereafter by the Cobas AmpliPrep/Cobas TaqMan HCV Quantitative Test (Roche Molecular Systems; Pleasanton, CA, USA) (\12 IU/mL). Non-SVR was defined when patients did not achieve undetectable HCV RNA at 24 weeks after cessation of treatment. Treatment failure was defined as failure to achieve SVR despite complete antiviral therapy for 48 weeks in genotype 1 or 4, and 24 weeks in genotype 2 or 3. Factors associated with achievement of SVR were
Dig Dis Sci
analyzed. All patients were followed up until the last visit before April 2013. The follow-up duration was calculated from the end of IFN treatment to the day of last follow-up. End Point of Study The primary end point of this study was to evaluate clinical outcomes of combination of PEG-IFN alfa and ribavirin treatment regarding progression to cirrhosis, occurrence of HCC, and cirrhosis-related complications. Secondly, the other end point was to compare such clinical outcomes between patients with SVR and those without. Statistical Analyses Statistical analyses included the Student’s t test and Mann– Whitney test for continuous variables and the chi-square test for categorical variables. Logistic regression analysis was used to analyze the factors associated with SVR. Kaplan–Meier curve analysis with log-rank test was performed to compare long-term clinical outcomes, such as cirrhosis progression and HCC development, between SVR and non-SVR groups. A P value \ 0.05 was considered significant. Data were analyzed by SPSS version 20.0.0 for Windows (IBM Corporation, Armonk, New York, USA).
Results Patient Characteristics A total of 494 CHC patients underwent antiviral therapy from January 2004 to December 2010. Of those, 463 patients with available medical records were recruited in this study. Among 404 patients who had completed standard antiviral therapy of PEG-IFN alfa and ribavirin, 300 patients achieved SVR. The treatment failure group consisted of 71 relapsers and 33 non-responders. The 59 patients who did not complete treatment were defined as the treatment stop group. None of the patient in treatment stop group achieved SVR after 24 weeks after the end of the treatment, and none of non-SVR group was re-treated. Thus, 163 patients with non-SVR were divided into the treatment failure (n = 104) and treatment stop groups (n = 59) (Fig. 1). Table 1 shows the baseline characteristics of the SVR and non-SVR groups. The mean age of all patients was approximately 50 years at the beginning of treatment (50.9 ± 11.5 years). In our cohort, liver biopsy prior to treatment was performed in 46 of 436 (9.9 %) patients. Thirty-nine patients (84.8 %) belonged to B F2 stage (F1, n = 19, 41.3 %; F2, n = 20, 43.5 %), three patients
Fig. 1 A flowchart showing study design. A total of 463 patients with CHC were included in this study. Three hundred patients achieved SVR, and 163 patients were classified as non-SVR group. CHC chronic hepatitis C, SVR sustained virological response, Tx treatment
(6.5 %) to F3 stage, and four (8.7 %) patients to F4 stage. Except those 4 patients with histologically confirmed cirrhosis, 78 patients were diagnosed as cirrhosis by clinical criteria. Therefore, a total of 82 patients were diagnosed as cirrhosis at enrollment, and all cirrhotic patients had preserved liver function (Child pugh A). The most common genotype was 1 (n = 262, 57.2 %), followed by genotype 2 (n = 188, 41.0 %). The median viral load of HCV RNA was 1,210,000 IU/mL (interquartile range [IQR]: 253,750– 2,675,000), and the mean ALT was 86.4 IU/L. Ten (2.3 %) patients had history of previous conventional IFN treatment. The baseline AFP levels were available in all patients, and mean AFP levels were 11.8 ng/mL. When comparing patients with SVR and those with nonSVR, patients with SVR were significantly younger (49.0 ± 12.0 vs. 54.4 ± 9.6 years, P \ 0.001) and had higher platelet count (194.7 ± 62.3 vs. 162.3 ± 61.11,000/ mm3, P \ 0.001) and albumin levels (4.5 ± 0.3 vs. 4.3 ± 0.4 mg/dL, P \ 0.001) than those with non-SVR, whereas patients with non-SVR had a significantly higher proportion of the presence of cirrhosis (32.5 vs. 9.7 %, P \ 0.001) and HCV genotype 1 (74.2 vs. 48.7 %, P \ 0.001), baseline HCV RNA level (1,540,000 vs. 1,005,338 IU/mL, P \ 0.001), and baseline AFP level (19.3 ± 34.5 vs. 7.1 ± 14.9, P = 0.001) than those with SVR. The median follow-up duration was 36.1 months (IQR: 16.0–100.0), and there was no significant difference in follow-up duration between patients with SVR and those with non-SVR (median 37.0 vs. 34.6 months, P = 0.515).
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Dig Dis Sci Table 1 Baseline characteristics of patients according to treatment response
Variable
a
Median (IQR)
SVR (N = 300)
Non-SVR (N = 163)
P value \0.001
Age (years)
50.9 ± 11.5
49.0 ± 12.0
54.4 ± 9.6
Male, n (%)
221 (47.7)
141 (47.0)
80 (49.1)
0.669
Cirrhosis, n (%)
82 (17.7)
29 (9.7)
53 (32.5)
\0.001
HCV genotype
267:188:8
146:148:6
121:40:2
\0.001
1:2:3, n (%)
(57.2:41.0:1.7)
(48.7:49.3:2.0)
(74.2:24.5:1.2)
HCV RNAa (IU/mL)
AFP alpha-fetoprotein, ALT aspartate aminotransferase, AST alanine aminotransferase, DM diabetes mellitus, Hb hemoglobin, HCV hepatitis C virus, SVR sustained virological response
All patients (N = 463)
1,210,000
1,005,338.5
1,540,000
(253,750–2,675,000)
(155,750–2,482,500)
(562,000–3,067,500)
Platelet (1,000/mm3)
183.5 ± 63.7
194.7 ± 62.3
162.3 ± 61.1
\0.001
Hb (g/dL)
13.8 ± 1.6
13.8 ± 1.6
13.8 ± 1.6
WBC (/mm3)
5,549.3 ± 1,805.3
5,617.1 ± 1,815.1
5,419.8 ± 1,785.3
0.274
AST (IU/L) ALT (IU/L)
68.8 ± 52.5 86.4 ± 75.9
67.5 ± 51.6 89.9 ± 76.8
71.4 ± 54.3 80.0 ± 74.0
0.453 0.186
Albumin (g/dL)
4.4 ± 0.3
4.5 ± 0.3
4.3 ± 0.4
0.840
\0.001
Total bilirubin (mg/dL)
0.8 ± 0.5
0.8 ± 0.5
0.8 ± 0.4
0.834
AFP (ng/mL)
11.8 ± 25.0
7.1 ± 14.9
19.3 ± 34.5
0.001
Weight (kg)
62.6 ± 10.5
62.2 ± 10.1
63.5 ± 11.2
0.300
DM, n (%)
41 (8.9)
24 (8.0)
17 (10.4)
0.379
Alcohol [ 40 g/day, n (%)
101 (58.0)
68 (57.6)
33 (58.9)
0.871
Follow-up duration, months
36.1 (16.0–100.0)
37.0 (18.0–94.0)
34.6 (16.0–100.0)
0.515
Achievement of SVR and Associated Factors The overall SVR rates for all patients were 64.8 % (300/ 463) by intention-to-treat analysis and 74.3 % (300/404) by per-protocol analysis. SVR was achieved in 142 of 262 patients with genotype 1, which was significantly lower compared with genotype 2 or 3, where 158 of 201 patients achieved SVR (54.2 vs. 78.6 %, P \ 0.001). When 300 patients with SVR were compared with 163 patients with non-SVR, age, liver disease status, HCV genotype, HCV RNA quantitation level, platelet count, albumin level, AFP, and body weight were significantly related to SVR in univariate analysis (Table 2). In a subsequent multivariate analysis, which included the variables which had a statistical significance in univariate analysis (P \ 0.05), age younger than 40 years, non-cirrhosis, HCV genotype 2 or 3, low HCV RNA level (\800,000 IU/mL), and lower body weight were found to be independent factors associated with SVR. Most patients who achieved SVR were maintained with long-term virological response, so only three patients (3/300, 1.0 %) had late relapse. The time points of viral relapse in those three patients were 6, 37, and 46 months after confirming SVR. Two of them were genotype 1 infection, and one was genotype 2. All three patients were cirrhotic at the time of therapy and had high baseline HCV RNA loads. However, the patients did
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\0.001
not have other risk factors related to late HCV relapse such as immunosuppression. Adverse Events Adverse events of any degree occurred in 385 of 463 patients (83.2 %) who underwent antiviral therapy with PEG-IFN and ribavirin. Adverse events are summarized in Supplementary Table 1. Dose reduction was performed in 106 of 404 (26.2 %) patients who completed antiviral treatment. The most common reason for dose reduction was neutropenia (n = 42, 39.6 %), followed by anemia (n = 39, 36.8 %) and thrombocytopenia (n = 25, 23.6 %). Fifty-nine patients stopped antiviral treatment. The reasons for withdrawal of antiviral treatment were as follows: patient’s denial due to intolerance (e.g., general weakness) (n = 54), anemia (n = 2), depression (n = 2), and drug-induced hyperthyroidism (n = 1). Long-Term Outcomes The long-term clinical outcomes were compared between patients with SVR and those without (Table 3). During the follow-up, progression to cirrhosis occurred in 17 (36.7 %) of 463 patients. Among all 17 patients, progression to cirrhosis was diagnosed histologically in four patients. In
Dig Dis Sci Table 2 Univariate and multivariate analysis to identify factors associated with SVR
Univariate analysis Unadjusted OR
Multivariate analysis
(95 % CI)
P value
Adjusted OR
(95 % CI)
P value
Age \40 years
1 (Reference)
C40 years
0.15
0.06–0.39
\0.001
0.16
0.04–0.71
0.016
Male
0.89
0.57–1.39
0.598
1.57
0.67–3.66
0.301
Cirrhosis
0.16
0.09–0.28
\0.001
0.21
0.09–0.49
\0.001
2.81–8.39
\0.001
6.41
2.91–14.15 \0.001
0.24–0.66 1.01–1.02
\0.001 \0.001
0.36 1.00
0.17–0.76 1.00–1.01
0.007 0.112
2.29
0.76–6.94
0.143
0.94
0.90–0.98
0.006
HCV genotype 1
1 (reference)
2 or 3
4.85
HCV RNA (IU/mL) \800,000 C800,000 Platelet (1,000/mm3)
AFP alpha-fetoprotein, ALT aspartate aminotransferase, AST alanine aminotransferase, DM diabetes mellitus, Hb hemoglobin, HCV hepatitis C virus, OR odds ratio, SVR sustained virological response
1 (Reference) 0.40 1.01
Hb (g/dL)
1.01
00.87–1.16
0.927
WBC (/mm3)
1.00
1.00–1.00
0.051
AST (IU/L)
1.00
0.99–1.00
0.762
ALT (IU/L)
1.00
1.00–1.01
0.150
Albumin (g/dL)
4.72
2.26–9.83
\0.001
Total bilirubin (mg/dL)
0.88
0.56–1.38
0.575
AFP (ng/mL)
0.97
0.96–0.99
0.006
DM
1.50
0.72–3.12
0.278
Body weight (kg)
0.97
0.95–0.99
0.018
Alcohol [ 40 g/day
0.97
0.48–1.95
0.926
remaining 13 patients, it was diagnosed by laboratory and imaging results. Progression to cirrhosis occurred more frequently in patients with non-SVR than those with SVR (12 of 110 patients [10.9 %] vs. 5 of 271 patients [1.8 %], P \ 0.001). Annual rate of progression to cirrhosis was also significantly higher in non-SVR group (4.16 event/ year) compared with SVR group (1.62 event/year). In Kaplan–Meier graph, the cumulative incidence of progression to cirrhosis was higher in patients with SVR than those without (Fig. 2a, log-rank test, P \ 0.001). During the follow-up, HCC developed in 12 patients at the median of 46.7 months (range 9–84 months) after the end of antiviral treatment. The patients with non-SVR had a significantly higher incidence of HCC (9 of 163 [5.5 %] patients vs. 3 of 300 [1.0 %] patients, P = 0.005), and annual incidence of HCC development of non-SVR group (3.12 event/year) was significantly higher than those of SVR group (0.97 event/year). The cumulative incidence of HCC occurrence was also higher in patients with SVR than those without (Fig. 2b, log-rank test, P = 0.017). In patients who already had cirrhosis at baseline, cirrhosis-related complications developed in six patients during follow-up. Two patients had variceal bleeding and ascites developed in four patients. The incidence of
cirrhosis-related complications as well as those of HCC occurrence was not significantly different between patients with SVR and those without (Table 3). Table 4 presents the characteristics of 12 HCC patients. Six patients had no evidence of cirrhosis at the time of enrollment, and progression to cirrhosis occurred in 2 of 6 patients until HCC development. Among 6 HCC patients with cirrhosis at baseline, one patient belonged to SVR group and other 5 patients to non-SVR group.
Discussion HCV infection is one of the major causes of chronic liver diseases and usually progresses over time, eventually to cirrhosis resulting in increased risk of HCC. The rate of progression to advanced fibrosis is highly variable among patients; however, at least 5–20 % of CHC patients deteriorate to cirrhosis over two decades, and HCV infection is associated with higher disease-related morbidity and mortality. We analyzed data of 463 CHC patients who received standard antiviral therapy using PEG-IFN and ribavirin. The overall SVR rates were 64.8 % by intention-to-treat analysis, and patients with HCV genotype 2 or 3 had higher
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Dig Dis Sci Table 3 Comparison of clinical outcome between patients with and without SVR
Whole population (n = 463)
SVR
Non-SVR
300
163
P value
Median follow-up period (month)
37.0 (18.0–94.0)
34.6 (16.0–100.0)
0.515
HCC occurrence
3 (1.0)
9 (5.5)
0.005
271
110
Patients without cirrhosis at baseline (n = 381) Median follow-up period (month)
35.2 (18.0–94.0)
33.2 (16.0–95.0)
Progression to cirrhosis, n (%)
5 (1.8)
12 (10.9)
29
53
Patients with cirrhosis at baseline (n = 82)
0.204 \0.001
Median follow-up period (month)
38.9 (23.2–70.5)
39.4 (17.5–100.0)
0.196
Cirrhosis-related complication, n (%)
1 (3.4)
5 (9.4)
0.303
Development of ascites
1 (3.4)
3 (5.6)
Development of variceal bleeding Development of HEP
0 0
2 (3.8) 0
HCC occurrence
1 (3.4)
5 (9.4)
0.303
HCC hepatocellular carcinoma, HEP hepatic encephalopathy, SVR sustained virological response
SVR rates after antiviral therapy compared with genotype 1. The clinical factors associated with SVR were non-cirrhosis, age younger than 40 years, HCV genotype (genotype 2 or 3), low HCV RNA level (\800,000 IU/mL), and low body weight, which were consistent with the results of previous studies [5, 6]. In our study, SVR rates were found to be higher than in previous studies from Western countries [5–7]. This might be explained by two reasons. First, the difference of host genetic factors which would have affected the difference of SVR rates between Western and Korean patients. The previous studies also reported higher SVR rate in Korean patients compared with Western population [15, 16]. Recently, single nucleotide polymorphisms near the interleukin (IL) 28B gene was reported to be associated with resistance to HCV infection and treatment response and could be a good predictor of SVR [17, 18]. A better efficacy of antiviral therapy in Koreans than
Fig. 2 The cumulative incidences of progression to cirrhosis (a) and HCC occurrence (b) between patients with SVR and non-SVR. HCC hepatocellular carcinoma, SVR sustained virological response
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in Caucasians would be attributed to favorable IL 28B polymorphisms [19–21]. Second, dose reduction rates of our cohort was lower than those of previous studies, as our study was conducted more recently than previous ones, and the patients were recruited from a single center instead of multiple centers [22–24]. It could be suggested that the standard antiviral therapy might be applied more consistently with close contact and monitoring by an experienced medical team, consequently resulting in higher patient compliance without dose reduction in our study. The most important finding in the present study is that SVR was related to a reduced risk of disease progression from hepatitis C. Patients who had achieved SVR had significantly lower risk of progression to cirrhosis from non-cirrhotic state compared with patients with non-SVR. Furthermore, SVR was also significantly associated with decreasing development of HCC. Recently, several studies
Dig Dis Sci Table 4 Characteristics of patients who developed HCC after antiviral treatment Case
Age
Sex
Treatment response
Liver activity
Cirrhotic change until HCC
Duration to HCC (month)
AFP (ng/ml)
Alcohol
1
45
M
Non-response
Cirrhosis
56
13.7
No
2
56
M
Relapse
Cirrhosis
3
58
M
SVR
No cirrhosis
No
9
11.1
Yes
73
1.8
4
58
M
Non-response
No cirrhosis
Cirrhosis
63
6.2
No Yes
5
59
M
Non-response
No cirrhosis
No
13
10.0
No
6
60
F
Relapse
Cirrhosis
45
6.43
No
7 8
60 63
M M
Relapse SVR
Cirrhosis Cirrhosis
9 34
6.9 5.44
Yes No
9
65
F
Non-response
No cirrhosis
No
84
9.6
No
10
66
M
SVR
No cirrhosis
No
18
7.4
No
11
66
M
Non-response
No cirrhosis
Cirrhosis
73
11.7
Yes
12
67
M
Relapse
Cirrhosis
49
5.28
Yes
AFP alpha-fetoprotein, HCC hepatocellular carcinoma, SVR sustained virological response
evaluated risk factors associated with hepatitis C-related HCC development. In a Japanese study analyzing data of 1,028 patients who received PEG-IFN plus ribavirin therapy, non-SVR was selected as independent risk factors associated with HCC development together with older age, male gender, advanced fibrosis, severe steatosis, lower serum albumin, and higher post-IFN treatment ALT or AFP levels [25]. In another study from Japan, moderate to advanced fibrosis stage, advanced age, alcohol history, AFP elevation were identified as risk factors associated with HCC development [26]. Consistent with previous studies, our data suggested that SVR is a good surrogate marker against HCC development. However, it is also notable that potential risk of developing HCC might still exist even if CHC patient achieved SVR after antiviral therapy. For instance, Yamashita et al. [26] analyzed a cohort of 562 patients achieving SVR after IFN therapy and reported that HCC was detected in 26 % of patients more than 10 years after completing IFN therapy. Interestingly, 42 % of those patients were in early fibrosis stage such as F2. In our study, among 12 patients who developed HCC, there were 3 patients with SVR and two of them had no evidence of cirrhosis until HCC diagnosis. However, because the assessment of fibrosis stage in these 3 patients was made based on clinical criteria, there is a possibility that histological cirrhosis might already exist at the time of HCC occurrence. Additionally, it would be also important to find risk factor of HCC occurrence or progression to cirrhosis in patients who achieved SVR. Unfortunately, our study failed to provide confirmative result regarding these, as HCC or progression to cirrhosis occurred in only a small number of patients. When comparing SVR patients with HCC occurrence than those without, there was no
significant difference of clinical variables between two groups. Although SVR patients with progression to cirrhosis had higher baseline AST and ALT levels than those without (all P \ 0.05), these results need to be interpreted carefully and warrant more studies. Given that mortality of patients with liver disease is determined primarily by complications associated with cirrhosis or HCC, eradication of HCV with successful antiviral therapy may prevent disease progression and HCC development, eventually lowering disease-related mortality in CHC patients. In fact, a recent study in Japan reported that SVR with successful antiviral therapy reduced the risk ratio for overall mortality and disease-related mortality of CHC patients [27]. Regarding the role of SVR in CHC patients, it was reported that patients with SVR had no development of HCC and decompensated liver disease in a cohort of CHC patients who had received combination therapy of IFN alfa and ribavirin at a single center [28]. In that study, 138 CHC patients were followed for a median of 41 months and HCC and decompensated liver disease were not observed in 57 patients with SVR while occurring in 5 of 81 (6.2 %) patients with non-SVR. However, the study included patients who underwent conventional IFN-based therapy, not PEG-IFN, and the results had no statistical significance. Our study showed that SVR with PEG-IFN and ribavirin treatment could reduce the risk of progression to cirrhosis from non-cirrhosis and could potentially lower the development of HCC development. Hence, the current study clearly shows the clinical benefits of successful antiviral therapy using a standard regimen for hepatitis C. Ultimately, it would be possible to reduce the morbidity and mortality of CHC patients by achieving SVR with antiviral therapy. Although all CHC patients may be subject to
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Dig Dis Sci
antiviral therapy, it might be ideal to select patients for whom antiviral therapy is the most helpful, considering cost-effectiveness and adverse events given by the standard of care. The current antiviral therapy has a limited efficacy, especially in patients with HCV genotype 1; therefore, clinicians should consider the benefits and risks of antiviral therapy before making recommendations for individual patient [1]. In this regards, it might be hopeful that recently there was a substantial progress on antiviral therapy for HCV infection due to the emergence of new drugs, directly acting antiviral agents (DAA) that are selective inhibitors of HCV protease or polymerase. The first-generation DAAs, boceprevir and telaprevir, were approved by the FDA in 2011, and several studies reported that the addition of these new agents to PEG-IFN/ribavirin therapy in HCV genotype 1 infection achieved much higher SVR rate compared with the current PEG-IFN/ribavirin regimen [29–33]. Drugs with other classes such as sofosbuvir and asunaprevir/daclatasvir have also been approved or are under clinical trials and are expected to further increase the SVR rates in the near future. The improvement in SVR with these new drugs will translate into more favorable long-term outcomes in CHC patients. We recognize that several previous studies in Western countries support our finding that SVR leads to good longterm outcomes in CHC patients by decreasing the risk of liver-related morbidity and mortality [34–37]. The latest study was a large, international, multicenter study of 530 CHC patients who were treated with IFN-based therapy in Europe and Canada [38]. SVR had a positive effect on longterm outcomes such as all-cause mortality, liver-related mortality, or liver transplantation and HCC. When 405 nonSVR patients and 125 SVR patients were followed for a median of 8.4 years (IQR: 6.4–11 0.4), SVR significantly reduced the risk of all-cause mortality (hazard ratio [HR] 0.26; 95 % CI 0.14–0.49; P \ 0.001), liver-related mortality and liver transplantation (HR 0.06; 95 % CI 0.02–0.19; P \ 0.001), and HCC (HR 0.19; 95 % CI 0.08–0.44; P \ 0.001). Lastly, it is an interesting finding in our study that 4 of 12 HCC patients had no evidence of liver cirrhosis at the time of HCC occurrence, because HCV-related HCC predominantly occurs in the setting of cirrhosis. In one patient (patient 5), HCC was resected and the histological examination showed F3 stage of background liver, and there was no clinical evidence of cirrhosis in the other three patients. The reason for this is not clearly explained, but recent meta-analysis suggested that HCV also could arise from non-cirrhotic liver [39]. New phenotypic expression of HCV followed by long-standing infection or unknown interaction of HCV protein to host cell, or enhanced hepatocarcinogenesis in non-cirrhotic liver by DM might be a possible explanation [39, 40]. However, it is also possible
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that histological cirrhosis or advanced liver fibrosis already existed without clinical evidence in these patients. We are also aware that this study has some limitations. First, histological information by liver biopsy was available only in 46 of 436 (9.9 %) patients at baseline, and the diagnosis of cirrhosis and progression to cirrhosis were performed by clinical criteria of cirrhosis in many patients. Consequently, estimation of fibrosis status before and after treatment might be inaccurate in our study. Furthermore, a subgroup analysis according to fibrosis stage was not possible. Secondly, this study is a retrospective study, which had a potential of selection bias, and the follow-up period (median 36.1 months) was not long enough. Accordingly, long-term outcomes such as all-cause mortality and liver-related mortality were not investigated. In conclusion, our study showed that successful antiviral therapy results in favorable long-term outcomes by reducing the risk of cirrhosis development and HCC occurrence in CHC patients. If patients have progressed to cirrhosis, they have a higher likelihood of mortality and morbidity than noncirrhotic patients. Therefore, anti-HCV treatment should be considered as early as possible after HCV diagnosis. Conflict of interest
None.
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