Differences in background characteristics of patients with chronic hepatitis C who achieved sustained virologic response with interferon-free versus interferon-based therapy and the risk of developing hepatocellular carcinoma after eradication of hepatiti

We compared the background characteristics of patients with chronic hepatitis C who achieved eradication of hepatitis C virus (HCV), that is sustained virologic response (SVR), with interferon (IFN)-based versus IFN-free antiviral therapy in Japan. In addition, we used a previously reported risk assessment model to compare the incidence of hepatocellular carcinoma (HCC) after SVR by treatment type. Pretreatment characteristics of 1533 patients who achieved SVR with IFN-based therapy and 1086 patients with IFN-free therapy from five institutions across Japan were compared. The risk of HCC after SVR was assessed based on pretreatment characteristics, and the incidence of HCC after SVR was estimated in both groups. Age and serum alpha-fetoprotein levels were higher, platelet count was lower, and liver fibrosis was more advanced in patients who achieved SVR with IFN-free therapy compared with IFN-based therapy. The incidence of HCC after SVR in the IFN-free group was estimated to be more than twofold higher than in the IFN-based therapy group (7.29% vs. 3.09%, and 6.23% vs. 3.01% when excluding patients who have underwent curative treatment for HCC). There are large differences in pretreatment characteristics between patients who achieved SVR with IFN-based and IFN-free therapies in Japan, which are associated with differential risk of HCC after SVR. These differences can influence the incidence of HCC after SVR and should be taken into consideration when comparing IFN-based and IFN-free therapies in terms of hepatocarcinogenesis suppression with HCV eradication.

Toyoda H ，Tada T ，Takaguchi K ，Senoh T ，Shimada N ，Hiraoka A ，Michitaka K ，Ishikawa T ，Kumada T ... -  《-》

Viral eradication reduces all-cause mortality in patients with chronic hepatitis C virus infection: a propensity score analysis.

Eradication of hepatitis C virus (HCV) by interferon (IFN)-based therapy has been reported to reduce all-cause mortality rates in patients with chronic HCV infection. However, the impact of HCV eradication on non-liver-related mortality including the causes of death has not been sufficiently investigated in patients with chronic HCV infection. We enrolled 2743 patients with chronic HCV infection. Causes of death, incidence of hepatocellular carcinoma (HCC), and all-cause mortality including non-liver-related diseases, were analysed. Of these 2743 patients, 587 achieved sustained virological response (SVR) (eradication of HCV) by IFN-based therapy (IFN-SVR), 475 did not (without HCV eradication) (IFN-non-SVR), or 1681 did not receive IFN-based therapy (non-IFN patients) (Cohort 1); of these, 309 were selected from IFN-SVR and non-IFN groups using propensity score matching (Cohort 2).The median follow-up duration was 11.4 years. In Cohort 1 patients, mortality rates from non-liver-related diseases were 71.0% (22/31) in IFN-SVR patients, 34.9% (37/106) in IFN-non-SVR patients and 50.0% (248/496) in non-IFN patients respectively. In Cohort 2 patients, mortality rates from non-liver-related diseases were 72.2% (13/18) in IFN-SVR patients and 46.8% (29/62) in non-IFN patients respectively. The eradication of HCV reduced all-cause mortality (hazard ratio (HR), 0.265; 95% confidence interval (CI), 0.058-0.380) including non-liver-related mortality (HR, 0.439; 95% CI, 0.231-0.834) and the incidence of HCC (HR, 0.275; 95% CI, 0.156-0.448). Eradication of HCV reduced not only liver-related mortality but also non-liver-related mortality in patients with chronic HCV.

Tada T ，Kumada T ，Toyoda H ，Kiriyama S ，Tanikawa M ，Hisanaga Y ，Kanamori A ，Kitabatake S ，Yama T ，Tanaka J ... -  《-》

Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada.

Evidence is limited on hepatocellular carcinoma (HCC) risk after sustained virological response (SVR) to interferon-based treatment of hepatitis C virus (HCV) infection. We evaluated the effect of SVR on the risk of HCC and estimated its incidence in post-SVR HCV patients from a large population-based Canadian cohort. The British Columbia Hepatitis Testers Cohort includes individuals tested for HCV between 1990-2013 linked with data on their medical visits, hospitalizations, cancers, prescription drugs and mortality. Patients receiving interferon-based HCV treatments were followed from the end of treatment to HCC diagnosis, death or December 31, 2012. We examined HCC risk among those who did and did not achieve SVR using multivariable proportional hazard models with the Fine and Gray modification for competing risks. Of 8147 individuals who received HCV treatment and were eligible for analysis, 4663 (57%) achieved SVR and 3484 (43%) did not. Each group was followed for a median of 5.6years (range: 0.5-12.9) for an HCC incidence rate of 1.1/1000 person-years (PY) among the SVR and 7.2/1000 PY among the no SVR group. The HCC incidence rate was higher among those with cirrhosis (SVR: 6.4, no SVR: 21.0/1000 PY). In the multivariable model, SVR was associated with a lower HCC risk (subdistribution hazard ratio [SHR]=0.20, 95% CI: 0.13-0.3), while cirrhosis (SHR=2.61, 95% CI: 1.68-4.04), age ⩾50years, being male and genotype 3 infection were associated with a higher HCC risk. Among those who achieved SVR, cirrhosis, age ⩾50years and being male were associated with a higher HCC risk. SVR after interferon-based treatment substantially reduces but does not eliminate HCC risk, which is markedly higher among those with cirrhosis and age ⩾50years at treatment initiation. Treatment of patients at an advanced fibrosis stage with new highly effective drugs will warrant continued surveillance for HCC post-SVR. We assessed the effect of successful hepatitis C treatment with older interferon-based treatment on the occurrence of liver cancer (hepatocellular carcinoma) and found that successful treatment prevents liver cancer. However, more people with cirrhosis and older age continued to develop liver cancer after successful treatment. Thus, treatment with new drugs among those with cirrhosis will require continued monitoring for liver cancer.

Janjua NZ ，Chong M ，Kuo M ，Woods R ，Wong J ，Yoshida EM ，Sherman M ，Butt ZA ，Samji H ，Cook D ，Yu A ，Alvarez M ，Tyndall M ，Krajden M ... -  《-》

Post-treatment levels of α-fetoprotein predict incidence of hepatocellular carcinoma after interferon therapy.

In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pretreatment factors are known to affect HCC incidence, less is known about post-treatment factors-many change during the course of interferon therapy. We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsy specimens were collected before treatment; all patients received Peg-IFN plus ribavirin for 48 to 72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings. HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in nonresponders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 level and older age; among those without SVRs, risk factors included higher AFP24 level, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (≥10 ng/mL, 10-5 ng/mL, and then <5 ng/mL) was a better predictor of HCC incidence than pretreatment level of AFP among patients with and without SVRs. In patients with chronic HCV infection, levels of α-fetoprotein decrease during interferon therapy. High post-treatment levels of α-fetoprotein predict HCC, regardless of whether patients achieve an SVR. University Hospital Medical Information Network Clinical Trials Registry: C000000196, C000000197.

Oze T ，Hiramatsu N ，Yakushijin T ，Miyazaki M ，Yamada A ，Oshita M ，Hagiwara H ，Mita E ，Ito T ，Fukui H ，Inui Y ，Hijioka T ，Inada M ，Katayama K ，Tamura S ，Yoshihara H ，Inoue A ，Imai Y ，Hayashi E ，Kato M ，Miyagi T ，Yoshida Y ，Tatsumi T ，Kasahara A ，Hamasaki T ，Hayashi N ，Takehara T ，Osaka Liver Forum ... -  《-》

Risk factors of hepatocellular carcinoma development in non-cirrhotic patients with sustained virologic response for chronic hepatitis C virus infection.

Hepatocellular carcinoma (HCC) can develop in patients with chronic hepatitis C after they have achieved a sustained virologic response (SVR) to antiviral therapy, that is eradication of hepatitis C virus (HCV). Thus, surveillance for HCC remains necessary after SVR. We investigated factors that are predictive of HCC in HCV-infected patients who achieved SVR. The incidence and risk factors for HCC were evaluated in 522 patients who achieved SVR with interferon-based antiviral therapy for HCV. Patients maintained regular follow-up every 6 months for HCC surveillance. The FIB-4 index and aspartate aminotransferase to platelet count ratio index were calculated based on laboratory data at the time that SVR was documented (SVR24). Patients continued follow-up visits for 1.0-22.9 years (median, 7.2 years) after SVR. HCC developed in 18 patients. The incidence of HCC was 1.2% at 5 years and 4.3% at 10 years. The use of peginterferon or ribavirin for treatment and a history of antiviral therapy prior to the course when SVR was achieved were not associated with the incidence of HCC after SVR. The presence of diabetes mellitus (risk ratio 2.08; P = 0.0451) and FIB-4 index calculated at the time of SVR24 (risk ratio 1.73; P = 0.0198) were associated with a higher likelihood of HCC after SVR by multivariate analysis. Patients with diabetes mellitus and patients with the elevation of FIB-4 index at SVR24 are at higher risk of HCC after SVR. Surveillance for HCC should be continued in this patient subpopulation.

Toyoda H ，Kumada T ，Tada T ，Kiriyama S ，Tanikawa M ，Hisanaga Y ，Kanamori A ，Kitabatake S ，Ito T ... -  《-》