Yuko Nagaoki, Michio Imamura, Hiroshi Aikata, Kana Daijo, Yuji Teraoka, Fumi Honda, Yuki Nakamura, Masahiro Hatooka, Reona Morio, Kei Morio, Hiromi Kan, Hatsue Fujino, Tomoki Kobayashi, Kazuaki Chayama
Published: August 10, 2017
https://doi.org/10.1371/journal.pone.0182710
Abstract
The risk of hepatocellular carcinoma (HCC) development is reduced following viral elimination by interferon therapy in chronic hepatitis C patients. However, the risk in patients treated with interferon-free direct-acting antivirals (DAAs) is unknown. We evaluated chronic hepatitis C patients who achieved viral eradication by pegylated-interferon plus ribavirin (PEG-IFN/RBV, n = 244) or daclatasvir plus asunaprevir (DCV/ASV, n = 154) therapy. None of the patients had prior history of HCC or antiviral therapy. The median observation period after the end of treatment for the PEG-IFN/RBV and DCV/ASV groups were 96 (range 10–196) and 23 (range 4–78) months, respectively. During the observation period, HCC developed in 13 (5.3%) and 7 (4.5%) patients in the PEG-IFN/RBV and DCV/ASV groups, respectively. The cumulative HCC development rate after 1-, 3- and 5-years (0.4%, 3% and 5% for the PEG-IFN/RBV group and 0.6%, 9% and 9% for the DAA group, respectively) were similar between the two groups. Propensity score matching analysis also showed no significant difference in HCC development rates between the two groups. Serum AFP levels decreased to similar levels between PEG-IFN/RBV and DCV/ASV groups following the achievement of viral eradication. The risk for HCC development following viral eradication by IFN-free DAA therapy may be similar to that in IFN-based therapy.
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This study examined the cumulative incidence of HCC development after HCV eradication by PEG-IFN/RBV or DCV/ASV treatment. During the follow-up period, HCC developed in 13 out of 244 (5.3%) of the PEG-IFN/RBV group and 7 out of 154 (4.5%) of the DCV/ASV group, and the cumulative HCC development rate tended to be high in DCV/ASV groups (P = 0.053). To overcome bias due to the different distributions of covariates among patients treated with PEG-IFN/RBV or DCV/ASV, one-to-one matches were created using propensity score analysis. The cumulative HCC development rate after 1-, 3- and 5-years were 1.5%, 10% and 19% for the PEG-IFN/RBV group and 1.5%, 10% and 12% for the DCV/ASV group, respectively. Propensity score matching analysis also showed similar rates of HCC development in the two groups. Based on the results of this analysis, one can argue that the risk of HCC development after HCV eradication achieved by DCV/ASV is similar to that of IFN therapy. In the present study, HCC development risk was similar between the PEG-IFN/RBV and the DCV/ASV groups in both patients with and without advanced liver fibrosis. In contrast, Conti, et al. reported that virus eradication by DAAs treatment did not reduce occurrence of HCC development in HCV-infected cirrhosis patients [29]. Further analysis is needed to clarify the relationship between HCC development risk after HCV eradication by DAAs treatment and liver fibrosis.
A recent study showed a high rate and unexpected pattern of HCC recurrence after HCV eradication by IFN-free DAA therapy in patients with HCV-related HCC [30]. Although the mechanism underlying this unexpected early HCC recurrence is unknown, it is possible that HCV eradication by DAA therapy could enhance HCC development or recurrence in patients who have elevated risk for HCC. However, the present study showed no evidence for an increase in HCC development following achievement of HCV eradication by DAA therapy.
The present study has several limitations. First, the observation period was relatively short in the DCV/ASV group; the median observation period was only 23 months in this group compared with 96 months in the PEG-IFN/RBV group. Furthermore, only 7 patients developed HCC in DCV/ASV group. This short observation period and the small number of patients who developed HCC might underlie the lack of significance between the two groups.
Second, patients who were treated with PEG-IFN/RBV and those treated with DCV/ASV differ with respect to many host and viral factors that potentially affect HCC development. Although propensity score analysis showed a similar HCC development risk between the two groups, the propensity score matching may not completely compensate for these differences among the patient populations. Large-scale, long-term follow-up studies that include patients treated with other DAA regimens, such as sofosbuvir plus ledipasvir, ombitasvir/paritaprevir/ritonavir, and elbasvir plus grazoprevir, should be performed.
Previous studies have shown that advanced liver fibrosis, male gender, older age, high AFP levels, greater alcohol intake, complications from diabetes mellitus, and obesity were risk factors for HCC development after HCV eradication by IFN treatment [17,18, 31–34]. The present study showed that male gender and AFP levels ≥10 ng/mL were associated with HCC development after HCV eradication by DCV/ASV therapy; however, no factor was identified for independent risk for HCC development. The small number of patients who developed HCC might be associated with the absence of independent factors. AFP is a surrogate marker for risk of HCC development. Previous reports showed that AFP levels after the completion of IFN treatment were useful predictors for HCC development in chronic hepatitis C patients who achieved viral eradication [10, 34]. In the present study, serum AFP levels decreased to similar levels following achievement of SVR both in the PEG-IFN/RBV and the DCV/ASV groups, suggesting the possibility of reduced potential for HCC development. Future analysis to identify predictors for HCC development after HCV eradication to examine whether AFP levels could be a surrogate marker for HCC development in patients who achieved SVR by IFN-free DAA therapy using a larger number of patients is needed.
Previous studies showed that IL28B and DEPDC5 genotypes were strongly associated with IFN treatment response and HCC development in chronic hepatitis C patients, respectively [21–23]. However, the present study showed that IL28B and DEPDC5 genotypes were not independent risk factors for HCC after HCV eradication. Recent genome-wide association study identified the association between the SNP rs17047200 in the TLL1 locus and HCC development after HCV eradication in patients treated with IFN-based treatments [35]. Future analysis is expected to identify SNPs associated with HCC development after HCV eradication, particularly in patients treated with DAAs.
In conclusion, we demonstrated that the risk of HCC development in patients infected with HCV genotype 1 after achieving viral eradication with DAA therapy is similar to that for PEG-IFN/RBV therapy.
This study examined the cumulative incidence of HCC development after HCV eradication by PEG-IFN/RBV or DCV/ASV treatment. During the follow-up period, HCC developed in 13 out of 244 (5.3%) of the PEG-IFN/RBV group and 7 out of 154 (4.5%) of the DCV/ASV group, and the cumulative HCC development rate tended to be high in DCV/ASV groups (P = 0.053). To overcome bias due to the different distributions of covariates among patients treated with PEG-IFN/RBV or DCV/ASV, one-to-one matches were created using propensity score analysis. The cumulative HCC development rate after 1-, 3- and 5-years were 1.5%, 10% and 19% for the PEG-IFN/RBV group and 1.5%, 10% and 12% for the DCV/ASV group, respectively. Propensity score matching analysis also showed similar rates of HCC development in the two groups. Based on the results of this analysis, one can argue that the risk of HCC development after HCV eradication achieved by DCV/ASV is similar to that of IFN therapy. In the present study, HCC development risk was similar between the PEG-IFN/RBV and the DCV/ASV groups in both patients with and without advanced liver fibrosis. In contrast, Conti, et al. reported that virus eradication by DAAs treatment did not reduce occurrence of HCC development in HCV-infected cirrhosis patients [29]. Further analysis is needed to clarify the relationship between HCC development risk after HCV eradication by DAAs treatment and liver fibrosis.
A recent study showed a high rate and unexpected pattern of HCC recurrence after HCV eradication by IFN-free DAA therapy in patients with HCV-related HCC [30]. Although the mechanism underlying this unexpected early HCC recurrence is unknown, it is possible that HCV eradication by DAA therapy could enhance HCC development or recurrence in patients who have elevated risk for HCC. However, the present study showed no evidence for an increase in HCC development following achievement of HCV eradication by DAA therapy.
The present study has several limitations. First, the observation period was relatively short in the DCV/ASV group; the median observation period was only 23 months in this group compared with 96 months in the PEG-IFN/RBV group. Furthermore, only 7 patients developed HCC in DCV/ASV group. This short observation period and the small number of patients who developed HCC might underlie the lack of significance between the two groups.
Second, patients who were treated with PEG-IFN/RBV and those treated with DCV/ASV differ with respect to many host and viral factors that potentially affect HCC development. Although propensity score analysis showed a similar HCC development risk between the two groups, the propensity score matching may not completely compensate for these differences among the patient populations. Large-scale, long-term follow-up studies that include patients treated with other DAA regimens, such as sofosbuvir plus ledipasvir, ombitasvir/paritaprevir/ritonavir, and elbasvir plus grazoprevir, should be performed.
Previous studies have shown that advanced liver fibrosis, male gender, older age, high AFP levels, greater alcohol intake, complications from diabetes mellitus, and obesity were risk factors for HCC development after HCV eradication by IFN treatment [17,18, 31–34]. The present study showed that male gender and AFP levels ≥10 ng/mL were associated with HCC development after HCV eradication by DCV/ASV therapy; however, no factor was identified for independent risk for HCC development. The small number of patients who developed HCC might be associated with the absence of independent factors. AFP is a surrogate marker for risk of HCC development. Previous reports showed that AFP levels after the completion of IFN treatment were useful predictors for HCC development in chronic hepatitis C patients who achieved viral eradication [10, 34]. In the present study, serum AFP levels decreased to similar levels following achievement of SVR both in the PEG-IFN/RBV and the DCV/ASV groups, suggesting the possibility of reduced potential for HCC development. Future analysis to identify predictors for HCC development after HCV eradication to examine whether AFP levels could be a surrogate marker for HCC development in patients who achieved SVR by IFN-free DAA therapy using a larger number of patients is needed.
Previous studies showed that IL28B and DEPDC5 genotypes were strongly associated with IFN treatment response and HCC development in chronic hepatitis C patients, respectively [21–23]. However, the present study showed that IL28B and DEPDC5 genotypes were not independent risk factors for HCC after HCV eradication. Recent genome-wide association study identified the association between the SNP rs17047200 in the TLL1 locus and HCC development after HCV eradication in patients treated with IFN-based treatments [35]. Future analysis is expected to identify SNPs associated with HCC development after HCV eradication, particularly in patients treated with DAAs.
In conclusion, we demonstrated that the risk of HCC development in patients infected with HCV genotype 1 after achieving viral eradication with DAA therapy is similar to that for PEG-IFN/RBV therapy.
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