Cumulative incidence and risk factors for the development of hepatocellular carcinoma in patients with chronic hepatitis B who achieved sustained disappearance of viremia by nucleos(t)ide analog treatment

Aim

Nucleos(t)ide analog (NA) therapy has been reported to reduce the risk of hepatocellular carcinoma (HCC). However, some patients who achieve hepatitis B virus (HBV)‐DNA disappearance from serum by NA develop HCC. In this study, we investigated the cumulative incidence and risk factors for HCC in patients with chronic hepatitis B (CHB) who achieved sustained disappearance of viremia by NA treatment.

Methods

A total of 133 CHB patients (median age, 51 years; 79 men [59%]; 28 with cirrhosis [21%]) who received NA therapy and achieved HBV‐DNA disappearance from serum were analyzed retrospectively. We evaluated the cumulative incidence of HCC and risk factors associated with HCC based on data collected at the time of HBV‐DNA disappearance.

Results

Thirteen patients developed HCC during the follow‐up period. The 1‐, 3‐, and 5‐year cumulative incidence of HCC was 0.0%, 7.8%, and 11.1%, respectively. In multivariate analysis, advanced age (hazard ratio [HR], 4.601; 95% confidence interval [CI], 1.220–17.351; P = 0.024), liver cirrhosis (HR, 5.563; 95% CI, 1.438–21.519; P = 0.013), and higher HBV core‐related antigen (HBcrAg) levels (HR, 13.532; 95% CI, 1.683–108.815; P = 0.014) at the time of HBV‐DNA disappearance were significantly associated with the development of HCC.

Conclusion

Our findings indicate the importance of continuous HCC surveillance especially in patients with advanced age, cirrhosis, and/or higher serum levels of HBcrAg, even if they achieve HBV‐DNA disappearance.     

Comparison of overall survival between antiviral‐induced viral suppression and inactive phase chronic hepatitis B patients

Nucleot(s)ide analogues (NAs) reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. However, the risk of HCC is reportedly higher for NA‐treated patients than for patients in the inactive CHB phase. This study aimed to compare the long‐term outcomes of CHB patients with NA‐induced viral suppression and those of patients with inactive CHB. This retrospective study involved 1118 consecutive CHB patients whose HBV DNA level was continuously <2000 IU/mL during follow‐up with/without antiviral agents. The patients were classified into inactive CHB (n = 373) or NA groups (n = 745). The primary endpoint was overall survival. Secondary endpoints included development of HCC and other liver‐related events. The median duration of follow‐up was 41.0 (interquartile range = 26.5‐55.0) months. The difference in overall survival between the NA group vs. the inactive CHB group was not significant (hazard ratio [HR] = 0.78; 95% confidence interval [CI] = 0.33‐1.85; P = .57). The NA group showed a significantly higher risk of HCC (HR = 3.44; 95% CI = 1.82‐6.52; P < .01), but comparable risk for non‐HCC liver‐related events (HR = 1.02; 95% CI = 0.66‐1.59; P = .93), compared with the inactive CHB group. Among patients with cirrhosis, the NA group showed a significantly lower risk of death (HR = 0.31; 95% CI = 0.097‐0.998; P = .05) and non‐HCC liver‐related events (HR = 0.51; 95% CI = 0.31‐0.83; P < .01), but a slightly higher risk of HCC (HR = 2.39; 95% CI = 0.85‐6.75; P = .09), compared to the inactive CHB group. The overall survival of untreated patients with inactive CHB and of CHB patients achieving viral suppression with NA was comparable. However, NA treatment of cirrhotic patients was significantly associated with longer overall survival and lower risk of liver‐related events.     

Delayed viral suppression during antiviral therapy is associated with increased hepatocellular carcinoma rates in HBeAg‐positive high viral load chronic hepatitis B

The treatment option in chronic hepatitis B (CHB) patients with persistent low‐level viremia despite entecavir or tenofovir monotherapy is unclear. This study investigated the development of hepatocellular carcinoma (HCC) or cirrhosis in hepatitis B e antigen (HBeAg)‐positive high viral load CHB patients, according to the time needed to achieve complete viral suppression. A total of 325 HBeAg‐positive CHB patients with high viral load who were recently started on antiviral therapy with entecavir or tenofovir were included. The enrolled patients were divided into 2 groups with 4 separate criteria based on the time needed to achieve complete viral suppression: within 1, 2, 3 or 4 years of therapy initiation. The outcomes were development of HCC and cirrhosis. The cumulative incidence of HCC was significantly higher in patients failing complete viral suppression within 1 year (hazard ratio (HR), 4.54; 95% confidence interval (CI), 1.03‐19.93; P = .045) or 2 years (HR, 3.38; 95% CI, 1.24‐9.23; P = .018), than patients who achieved complete viral suppression within 1 or 2 years, respectively. Cumulative incidence of cirrhosis was also significantly higher in patients failing suppression within 1 year (HR, 1.95; 95% CI, 1.04‐3.66; P = .037) or 2 years (HR, 2.44; 95% CI, 1.41‐4.22; P = .001). When the time for achieving viral suppression exceeded 2 years, the cumulative incidence of HCC or cirrhosis was not different regardless of viral suppression. Complete hepatitis B virus suppression within 2 years of antiviral therapy initiation is associated with risk reduction in HCC or cirrhosis development.     

肝移植术后原发性肝癌复发与乙型肝炎病毒再感染的关系

目的 探讨肝移植术后原发性肝癌复发与HBV再感染的关系.方法 对2004年1月-2008年12月在中山大学附属第三医院因乙型肝炎相关性终末期肝病行肝移植手术并长期随访的340例患者回顾性分析.患者被列入肝移植等待名单后给予核苷(酸)类似物抗病毒治疗,术中和术后均给予核苷(酸)类似物联合低剂量乙型肝炎免疫球蛋白进行预防.术后定期随访并监测患者HBV再感染的发生率及生存率,用多因素COX回归分析筛选出影响术后HBV再感染的危险因素.计量资料用t检验、计数资料用x2检验进行统计学处理.用Kaplan-Meier方法进行生存率分析,对HBV再感染危险因素用COX多因素回归分析,对HBV再感染与原发性肝癌复发的时间进行Spearman线性相关分析.结果 340例患者术后发生HBV再感染33例,术后1、3、5年再感染率分别为7%、10%、13%.HBV再感染的时间为1～21个月,中位数为5个月.原发病为原发性肝癌(风险比为2.98;95%可信区间为1.08～8.25,P＜0.05)、术前HBV DNA载量＞5log10拷贝/ml(风险比为3.99;95%可信区间为1.85～8.62,P＜0.01)是发生HBV再感染的危险因素.原发性肝癌复发者HBV再感染发生率高于未复发者,分别为27.9%和8.7%(风险比为4.58; 95%可信区间为1.88～11.12;P＜0.01).12例患者肝移植术后发生HBV再感染和原发性肝癌复发,两者的复发时间具有相关性(r=0.583,P＜0.05).结论肝移植术后原发性肝癌复发是HBV再感染的危险因素.

Abstract：

Objective To investigate the relationship between hepatocellular carcinoma (HCC)recurrence and hepatitis B virus (HBV) recurrence. Method The clinical data of 340 patients underwent liver transplantation due to HBV related end-stage liver disease and received long-term follow up in our hospital from Jan 2004 to Dec 2008 were retrospectively analyzed. All patients received nucleoside analogues therapy formally before entering into the waiting list and nucleoside analogues combined low-dose HBIG therapy during and after transplantation. Patients were regularly followed up at the outpatient, monitoring the HBV recurrence and survival. Multivariate Cox regression analysis was used to evaluate the risk factors for hepatitis recurrence. Result 33 patients suffered from HBV recurrence post transplantation.The 1-, 3- and 5- year recurrence rates were 7.0%, 10% and 13% respectively. The median HBV recurrence time was 5 months (1-21 months). COX regression analysis revealed that risk factors for HBV recurrence were HCC (HR = 2.98; 95% CI 1.08-8.25; P＜0.05) and pre-transplantation HBV-DNA load over 5 log10 copies/ml (HR = 3.99; 95% CI 1.85-8.62; P＜0.01). Further stratified analysis showed that patients who suffered from carcinoma recurrence had a higher incidence of HBV recurrence than those who did not, which were 27.9% and 8.7% (HR =- 4.58;95% CI 1.88-11.12; P＜0.01) respectively. 12 patients suffered from both HCC and HBV recurrence. Spearman correlation analysis demonstrated a strong correlation between HBV and HCC recurrence times (r= 0.583, P＜0.05). Conclusion Post transplantation HCC recurrence is a risk factor for HBV recurrence.     

Liver cirrhosis stages and the incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving antiviral therapy

Objectives: Long-term antiviral therapy decreases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB), however, it cannot eliminate the risk. We investigated the incidence of HCC at different stages of liver cirrhosis (LC) and identified clinical predictors for HCC development during antiviral therapy.

Methods: The data from 356 treatment-naïve patients aged 40 to 69 years without a history of HCC who had received entecavir for ≥6 months were collected retrospectively. The incidence of HCC was evaluated in patients with CHB only, with LC without varices (stage 1), with varices (stage 2), and with ascites (stage 3).

Results: The median follow-up period was 3.6 years. In total, 45 patients (12.6%) developed HCC. The annual incidence rates of HCC in patients with CHB only or LC in stages 1, 2, and 3 were 0.4%, 2.6%, 9.8%, and 6.7%, respectively. In multivariate analyzes, LC at stage 2 (hazard ratio [HR] 17.16, 95% confidence interval [C.I.] 3.93–75.01, p?<?.001), alcohol consumption (HR 3.84, 95% C.I. 1.99–7.39, p?<?.001), and older age (HR 1.06, 95% C.I. 1.01–1.11, p?=?.010) were significantly associated with HCC development. The risk decreased in those who stopped drinking after 2 years of abstinence (p?=?.0314).

Conclusions: LC with significant portal hypertension (varices or ascites), alcohol consumption, and older age at the time of starting antiviral therapy are independent predictors for future HCC development.     

Hepatic steatosis in chronic hepatitis C is a significant risk factor for developing hepatocellular carcinoma independent of age,sex, obesity,fibrosis stage and response to interferon therapy

Aim: Hepatic steatosis is linked to development of hepatocellular carcinoma (HCC) in non‐viral liver disease such as non‐alcoholic steatohepatitis. The present study aimed to assess whether hepatic steatosis is associated with the development of HCC in chronic hepatitis C. Methods: We studied a retrospective cohort of 1279 patients with chronic hepatitis C who received interferon (IFN) therapy between 1994 and 2005 at a single regional hospital in Japan. Of these patients, 393 had a sustained virological response (SVR) and 886 had non‐SVR to IFN therapy. After IFN therapy, these patients were screened for development of HCC every 6 months. The average period of observation was 4.5 years. Results: HCC developed in 68 patients. The annual incidence of HCC was 2.73% for patients with a steatosis grade of 10% or greater and 0.69% for patients with a steatosis grade of 0–9%. On multivariate analysis, higher grade of steatosis was a significant risk factor for HCC independent of older age, male sex, higher body mass index (BMI), advanced fibrosis stage and non‐SVR to IFN therapy. The adjusted risk ratio of hepatic steatosis was 3.04 (confidence interval 1.82–5.06, P < 0.0001), which was higher than that of older age (1.09), male sex (2.12), non‐SVR to IFN (2.43) and higher BMI (1.69). Conclusion: Hepatic steatosis is a significant risk factor for development of HCC in chronic hepatitis C independent of other known risk factors, which suggest the possibility that amelioration of hepatic steatosis may prevent hepatocarcinogenesis.     

Predictive factors for hepatocellular carcinoma in type 1 autoimmune hepatitis

OBJECTIVE:  Hepatocellular carcinoma (HCC) is an uncommon but serious occurrence in autoimmune hepatitis. Our objective was to determine predictors for this neoplasm to improve screening strategies.
METHODS:  Two hundred twenty-seven patients underwent hepatic ultrasonography and serum alpha fetoprotein determinations at 6–12-month intervals.
RESULTS:  Nine patients developed HCC (4%), and each had cirrhosis ≥73 months prior to the malignancy (mean, 110 ± 7 months). By univariate Cox analysis, features at accession associated with a higher risk of HCC were: male gender (Hazard Ratio [HR] 7.0, 95% Confidence Interval [CI] 1.87–26.1, P = 0.004), history of blood transfusion (HR 5.6, 95% CI 1.51–21.1, P = 0.01), thrombocytopenia (HR 7.3, 95% CI 1.89–28.3, P = 0.004), ascites (HR 23.8, 95% CI 4.65–121.8, P = 0.0001), esophageal varices (HR 7.9, 95% CI 1.96–31.8, P = 0.004), and any sign of portal hypertension (HR 19.1, 95% CI 3.91–93.3, P = 0.0003). Features after accession associated with a higher risk of malignancy were: treatment for ≥3 yr (HR 7.6, 95% CI 1.25–18.2, P = 0.02), worsening laboratory tests during corticosteroid therapy (HR 7.6, 95% CI 1.81–32.1, P = 0.006), and cirrhosis for ≥10 yr (HR 8.4, 95% CI 1.69–41.9, P = 0.009).
CONCLUSIONS:  Male gender, features of portal hypertension, history of blood transfusions, immunosuppressive treatment for ≥3 yr, treatment failure, and cirrhosis of ≥10 yr duration identify patients at risk for HCC. These risk factors should focus screening in autoimmune hepatitis.     

Monitoring Occurrence of Liver-Related Events and Survival by Transient Elastography in Patients With Nonalcoholic Fatty Liver Disease and Compensated Advanced Chronic Liver Disease

Background & AimsPatients with advanced fibrosis related to nonalcoholic fatty liver disease (NAFLD) are at risk of developing hepatic and extrahepatic complications. We investigated whether, in a large cohort of patients with NAFLD and compensated advanced chronic liver disease, baseline liver stiffness measurements (LSMs) and their changes can be used to identify patients at risk for liver-related and extrahepatic events.MethodsWe performed a retrospective analysis of consecutive patients with NAFLD (n = 1039) with a histologic diagnosis of F3–F4 fibrosis and/or LSMs>10 kPa, followed for at least 6 months, from medical centers in 6 countries. LSMs were made by FibroScan using the M or XL probe and recorded at baseline and within 1 year from the last follow-up examination. Differences between follow up and baseline LSMs were categorized as: improvement (reduction of more than 20%), stable (reduction of 20% to an increase of 20%), impairment (an increase of 20% or more). We recorded hepatic events (such as liver decompensation, ascites, encephalopathy, variceal bleeding, jaundice, or hepatocellular carcinoma [HCC]) and overall and liver-related mortality during a median follow-up time of 35 months (interquartile range, 19–63 months).ResultsBased on Cox regression analysis, baseline LSM was independently associated with occurrence of hepatic decompensation (hazard ratio [HR], 1.03; 95% CI, 1.02–1.04; P < .001), HCC (HR, 1.03; 95% CI, 1.00–1.04; P = .003), and liver-related death (HR, 1.02; 95% CI, 1.02–1.03; P = .005). In 533 patients with available LSMs during the follow-up period, change in LSM was independently associated with hepatic decompensation (HR, 1.56; 95% CI, 1.05–2.51; P = .04), HCC (HR, 1.72; 95% CI, 1.01–3.02; P = .04), overall mortality (HR, 1.73; 95% CI, 1.11–2.69; P = .01), and liver-related mortality (HR, 1.96; 95% CI, 1.10–3.38; P = .02).ConclusionsIn patients with NAFLD and compensated advanced chronic liver disease, baseline LSM and change in LSM are associated with risk of liver-related events and mortality.     

Frequency and clinical outcomes of flares related to nucleos(t)ide analogue therapy in patients with chronic hepatitis B

Summary. Flares in chronic hepatitis B are often detrimental but sometimes lead to sustained immune control and disease remission. The aim of this study was to estimate the frequency of hepatitis flares which occur during and/or after cessation of nucleos(t)ide analogue (NA) therapy, and to assess their outcomes. In a single centre cohort study we investigated 227 patients who received a total of 351 NA treatment courses. NA therapy was discontinued after 149 treatment courses. In total, 27 flares were observed during 9779 on‐treatment patient‐months. The frequency was estimated as 3.2 per 100 person‐years (95% CI 2.2–4.7). Lamivudine (LAM)‐treated patients demonstrated the highest frequency (4.9/100 person‐years, 95% CI 3.2–7.4). Twenty (74%) of 27 on‐therapy flares were associated with development of genotypic resistance, which all occurred during LAM therapy. NA withdrawal flares occurred after a median post‐treatment follow‐up of 3.5 months in 17 (11%) of 149 treatment discontinuations. No flares were observed in patients who switched to another antiviral agent (n = 51). None of the on‐therapy and withdrawal flares related to NA therapy were associated with sustained disease remission, and seven flares resulted in decompensated liver disease. In this study, flares related to NA therapy never led to immune control and sustained disease remission, and sometimes resulted in decompensated liver disease.     

Gender disparity in hepatocellular carcinoma recurrence after curative hepatectomy

Introduction and objectivesWhether there is gender disparity in the recurrence of hepatocellular carcinoma (HCC) has been not fully addressed. This study aimed to investigate the impact of gender on HCC recurrence following curative hepatectomy.Patients and methodsThis retrospective cohort study included 1087 patients with HCC (917 males, 170 females) who underwent curative hepatectomy. Cox regression models were constructed to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the risk parameters associated with HCC recurrence. In the sensitivity analysis, subgroup analysis, and propensity score matching (PSM) analysis were used. Logistic regression models were used to assess the odds ratio (OR) and 95% CI of the risk parameters related to early and late recurrence.ResultsMale patients showed significantly higher risk for HCC recurrence than females, in both multivariate Cox regression analysis (HR [95% CI] = 1.480 [1.084–2.020], P = 0.014) and PSM analysis (HR [95% CI] = 1.589 [1.093–2.312], P = 0.015). Higher risk of HCC recurrence was again found in males in the subgroup analysis, but the effect of male versus female gender on HCC recurrence did not depend on any selected subgroups (all P for interaction > 0.05). Gender was an independent risk factor for early recurrence (OR [95% CI] = 1.864 [1.215–2.936], P = 0.006), but not for late recurrence.ConclusionsThere is gender disparity in the recurrence of patients with HCC after curative hepatectomy: males had a higher risk for HCC recurrence than females.     

Reduced risk of hepatocellular carcinoma after interferon therapy in aged patients with chronic hepatitis C is limited to sustained virological responders

Summary. This study was undertaken to investigate the effect of interferon (IFN) monotherapy on the risk of hepatocellular carcinoma (HCC) in aged‐patients with chronic hepatitis C. Seven hundred and twenty‐five patients with histologically proven chronic hepatitis C were enrolled in this retrospective cohort study; 531 received IFN monotherapy for 6 months between 1992 and 1995, and 157 were collected as a historical control. The effect of IFN therapy on the development of HCC was compared between the patients with chronic hepatitis C under 60 years old (non‐aged group, n = 531) and those 60 and over (aged group, n = 194). A stepwise Cox proportional‐hazards regression analysis in the non‐aged group revealed that IFN therapy (risk ratio 0.52, 95% CI 0.33–0.81, P = 0.004), older age (P = 0.001), and higher histological stage (P < 0.001) were independent factors associated with the development of HCC. In the aged‐group, only higher histological stage (P = 0.002) and male gender (P = 0.011), but not IFN therapy (risk ratio 0.77, 95% CI 0.42–1.40, P = 0.386), were identified as independent risk factors for HCC, although HCC was significantly reduced when sustained virological response (SVR) was obtained (risk ratio 0.23, 95% CI 0.08–0.64, P = 0.005). In conclusion, inhibitory effect of IFN on development of HCC in the patients with chronic hepatitis C aged 60 and over was limited to the patients achieving SVR when treated with 6 months‐IFN monotherapy.     

The suppressive effect of nucleos(t)ide analogue treatment on the incidence of hepatocellular carcinoma in chronic hepatitis B patients

The development of nucleos(t)ide analogues (NA) has influenced hepatitis B virus management. However, the annual incidence rate during NA treatment has been reported to be 0.3–1.2% in non‐cirrhosis cases and 1.8–6.0% in cirrhosis cases, indicating that the suppressive effect of NA treatment on hepatocellular carcinoma (HCC) would be insufficient. Past studies, including one randomized control trial that compared lamivudine treatment with placebo, have revealed that NA treatment could suppress the incidence of HCC in patients with advanced fibrosis. However, it remains unknown whether NA treatment can suppress the incidence of HCC in chronic hepatitis patients without advanced fibrosis. The HCC incidence in patients treated with entecavir was similar to that of those treated with lamivudine, although entecavir exhibits a stronger viral suppression than lamivudine. The following risk factors related to the incidence of HCC during NA treatment have been identified: older age, male gender, pre‐existing cirrhosis, a family clustering of hepatitis B virus, lower platelet counts, and higher hepatitis B core‐related antigens as baseline factors and higher alpha fetoprotein levels as an on‐treatment factor. Conversely, the loss of the hepatitis B surface antigen (HBsAg) by interferon or NA was correlated with a lower HCC incidence rate. Because interferon treatment has much more effects on reducing HBsAg levels compared with NA treatment, a combination treatment with NA and pegylated interferon can bring additional reduction of HBsAg levels compared with NA monotherapy. Further study is needed to clarify this.     

Effects of interferon therapy on development of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis: A meta-analysis of randomized controlled trials

Aim: The role of interferon (IFN) therapy on prevention of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)‐related cirrhosis remains controversial. This meta‐analysis aimed to determine whether IFN therapy reduced the incidence of HCC in HCV‐related cirrhotic patients. Methods: We performed a meta‐analysis including eight randomized controlled trials (RCT) (a total of 1505 patients) to assess the effect of IFN therapy on prevention of HCC in patients with HCV‐related cirrhosis. The pooled odds ratios (OR) were calculated using a random or fixed effects model. Results: Our results showed that IFN therapy significantly decreased the overall HCC incidence in HCV‐related cirrhotic patients (OR, 0.29; 95% confidence interval [CI], 0.10–0.80; P = 0.02). HCC risk in patients who failed to achieve sustained virological response (SVR) in the initial IFN‐based treatment was also reduced by maintenance IFN therapy (OR, 0.54; 95% CI, 0.32–0.90; P = 0.02). Subgroup analysis indicated that IFN therapy decreased HCC incidence in HCV‐related cirrhotic patients during long‐term follow up (>48 months) evidently (OR, 0.25; 95% CI, 0.09–0.67; P = 0.006). However, subgroup analysis of four RCT with short‐term follow up (≤48 months) did not demonstrate the significant difference in HCC incidence between IFN‐treated cirrhotic patients and controls (OR, 0.78; 95% CI, 0.39–1.55; P = 0.48). Conclusion: The present study suggested that IFN therapy could efficiently reduce HCC development in patients with HCV‐related cirrhosis; this effect was more evident in the subgroup of patients with long‐term follow up (>48 months). Patients who received maintenance IFN therapy had a lower risk of HCC than controls.     

Immune inflammation indicators and ALBI score to predict liver cancer in HCV-patients treated with direct-acting antivirals

BackgroundUnexpectedly high occurrence or recurrence rate of hepatocellular carcinoma (HCC) has been observed in patients with chronic hepatitis C receiving direct-acting antivirals (DAAs) therapy.AimsWe evaluated the predictive value of albumin-bilirubin (ALBI) score and immune-inflammation indicators to identify the risk of occurrence or recurrence of HCC in patients treated with DAAs in a real life setting.MethodsIn this retrospective cohort study, we analysed data from 514 patients with cirrhosis who were prospectively enrolled for treatment with DAAs. We assessed baseline neutrophil to lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet to lymphocyte ratio (PLR), aspartate aminotransferase-lymphocyte ratio (ALRI) index and ALBI score.ResultsIn patients with no history of HCC (N = 416), increased AST, bilirubin, ALRI, and ALBI score, and decreased albumin and platelets were significantly associated with an increased risk of HCC development, at univariate analysis. At multivariate analysis, increase in ALBI grade (p = 0.038, HR: 2.35, 95% CI: 1.05–5.25) and decrease in platelets (p = 0.048, HR: 0.92, 95% CI: 0.85–1.0) were independently associated with HCC development. In patients with previous HCC (N = 98), adjusting for the time from HCC treatment, increased ALRI (p = 0.008, HR: 1.05, 95% CI: 1.01–1.09) was significantly associated with a risk of recurrence.ConclusionALBI score, platelet count and ALRI are promising, easy to perform and inexpensive tools for identifying patients with higher risk of HCC after treatment with DAAs.     

Post-challenge hyperglycemia is a significant risk factor for the development of hepatocellular carcinoma in patients with chronic hepatitis C

Background

Several epidemiological studies have reported that diabetes mellitus is a risk factor for hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-positive patients. However, it is unclear whether or not post-challenge hyperglycemia is a risk factor. The purpose of this study was to determine the association between post-challenge hyperglycemia and hepatocarcinogenesis in HCV-positive patients.

Methods

A total of 203 HCV-RNA-positive subjects (108 males, mean age 54.3?±?10.8?years; 95 females, mean age 56.6?±?10.3?years; genotype 1b/2a/2b/3a: 152/38/12/1) who underwent liver biopsy and a 75-g oral glucose tolerance test, and who were treated with interferon (IFN) were enrolled in this study. None of the subjects had been treated with antidiabetic drugs. The subjects underwent ultrasonography and/or computed tomography every 6?months after the end of the IFN therapy.

Results

Thirteen patients, including one patient who achieved a sustained viral response (SVR) with IFN, developed HCC. On multivariate analysis, male sex, age >65?years, excessive alcohol consumption, non-SVR, liver steatosis area >5% in liver specimens, and 120-min post-challenge hyperglycemia were risk factors for the development of HCC. After matching subjects for sex, age, alcohol intake, and response to the IFN therapy, advanced fibrosis stages [hazard ratio (HR) 2.8], liver steatosis (HR 5.4), and 120-min post-challenge hyperglycemia (HR 4.9) were significant risk factors for the development of HCC. Furthermore, after matching for the fibrosis stage, liver steatosis (HR 5.7) and 120-min post-challenge hyperglycemia (HR 6.9) remained as significant factors for HCC development.

Conclusion

Post-challenge hyperglycemia is an independent risk factor for HCC in HCV-positive patients.     

Prediction of long‐term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE‐B score

An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment‐naïve CHB patients at one tertiary care centre were scored by a single hepato‐pathologist. Laboratory values at liver biopsy were used to calculate the PAGE‐B, REACH‐B, GAG‐HCC, CU‐HCC and FIB‐4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow‐up of 10.1 (IQR 5.7‐15.9) years. The PAGE‐B score predicted any clinical event (C‐statistic.86, 95% CI: 0.80‐0.92), HCC development (C‐statistic .91) and reduced transplant‐free survival (C‐statistic .83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C‐statistics (95% CI) of the REACH‐B, GAG‐HCC, CU‐HCC and FIB‐4 scores for any event were .70 (0.59‐0.81), .82 (0.75‐0.89), .73 (0.63‐0.84) and.79 (0.69‐0.89), respectively. The PAGE‐B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C‐statistic .87, 95% CI: 0.82‐0.93). The PAGE‐B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15 years of follow‐up. Additional liver histological characteristics did not appear to provide a clinically significant improvement.     

Factors Associated with Progression to Hepatocellular Carcinoma and to Death from Liver Complications in Patients with HBsAg-Positive Cirrhosis

Background and Aims Hepatitis B viral markers and liver tests were used as predictors for development of hepatocellular carcinoma and progression to end-stage liver disease in 128 cirrhosis patients with hepatitis B. Results During a median follow-up of 63.5 months, 28 patients (21.9%) developed HCC and 36 (28.1%) died from non-HCC liver deaths. By multivariate analysis, independent predictors of HCC development and their hazard ratios were high alfa-fetoprotein (HR2.83, 95% CI 1.60–5.00, P = 0.0003), negative HBeAg (HR2.33, 95% CI 1.04–5.29, P = 0.04), and low alanine aminotransferase value (HR1.42, 95% CI 1.08–1.89, P = 0.02). Independent predictors of non-HCC liver deaths were HBeAg positivity (HR3.39, 95% CI 1.16–9.93, P = 0.02), decrease albumin (HR1.61, 95% CI 0.99–2.63, P = 0.05), decrease platelet count (HR2.54, 95% CI 1.03–6.25, P = 0.04), high ALT value (HR1.22, 95% CI 1.03–1.43, P = 0.02), and onset of encephalopathy (HR3.34, 95% CI 1.21–9.27, P = 0.02). Concusions HBeAg negativity, elevated AFP, and low ALT values predicted HCC development, while HBeAg positivity, abnormal liver tests, and low platelet counts identified patients with non-HCC liver deaths.     

Trends in mortality of liver cancer before and during the COVID-19 pandemic, 2017–2021

We studied the trends in liver cancer-related mortality before and during the COVID-19 pandemic. Quarterly age-standardized mortality and quarterly percentage change (QPC) for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) were estimated using the US national mortality database 2017–2021. Quarterly age-standardized mortality from HCC decreased steadily with an average QPC of −0.4% (95% confidence interval [CI]: −0.6% to −0.2%). A decrease in hepatitis C virus and hepatitis B virus-related HCC mortality of −2.2% (95% CI: −2.4% to −1.9%) and −1.1% (95% CI: −2.0% to −0.3%) was noted. In contrast, mortality for HCC from nonalcoholic fatty liver disease (3.0%, 95% CI: 2.0%–4.0%) and alcohol-related liver disease (1.3%, 95% CI: 0.8%–1.9%) demonstrated a linear increase. There was a linear increase in the quarterly age-standardized ICC-related mortality (0.8%, 95% CI: 0.5%–1.0%). While ICC-related mortality continued to increase, HCC-related mortality tended to decline mainly due to a decline in mortality due to viral hepatitis.     

Sustained viral response prolonged survival of patients with C-viral hepatocellular carcinoma.

BACKGROUND: We conducted this retrospective study to evaluate the position of interferon therapy in the curative treatment of hepatitis C virus-associated hepatocellular carcinoma (HCC). METHODS: We compared overall and recurrence-free survival rates between 191 patients who received interferon therapy before HCC development (15 with sustained virologic response (SVR)), 53 who received interferon therapy after HCC ablation (17 with SVR), and 399 HCC patients with Child-Pugh class A liver function who did not receive interferon (controls). RESULTS: The overall survival rate in the controls was 82.4%, 53.2%, and 28.3% at 3, 6, and 9 years, respectively, whereas that in patients who developed HCC after achieving SVR was 93.3%, 93.3%, and 93.3%; those with HCC after non-SVR, 87.8%, 56.5%, and 35.8%; SVR after HCC, 100%, 87.5%, and 59.7%; and non-SVR after HCC, 94.3%, 70.9%, and 53.2%. Cox proportional hazard regression analysis revealed that the risk of death was significantly reduced in patients with HCC after SVR and those with SVR after HCC, with a risk ratio of 0.124 (95% confidence interval (95% CI): 0.017-0.890, P = 0.0378) and 0.388 (95% CI: 0.169-0.887, P = 0.0250), respectively, compared with the controls. Improved survival was attributable mainly to sustained liver function among patients with SVR, and recurrence-free survival did not differ significantly. CONCLUSION: Interferon therapies before and after HCC development were both significantly associated with prolonged survival when SVR was achieved.     

Development of sorafenib-related side effects in patients diagnosed with advanced hepatocellular carcinoma treated with sorafenib: a systematic-review and meta-analysis of the impact on survival

?Introduction: Clinical markers to predict the benefit from sorafenib in patients diagnosed with hepatocellular carcinoma (HCC) are lacking. A meta-analysis exploring the impact of development of sorafenib-related side effects on survival was conducted.

Areas covered: Eligible studies included all clinical studies reporting on the survival/toxicity relationship in sorafenib-treated HCC patients. Data sources included Pub-Med, the Cochrane Controlled Trials Register, and Google scholar. After exclusion of ineligible studies, 16 studies were included in the analysis. Pooled hazard ratio (HR) for overall survival (OS) for patients developing diarrhoea vs. patients who did not was 0.42 (95% confidence interval (CI): 0.30–0.60; p < 0.00001); pooled HR for patients developing hypertension vs. those who did not was 0.46 (95% CI: 0.30–0.70; p = 0.0003); pooled HR for patients developing hand foot skin reaction vs. those who did not was 0.47 (95% CI: 0.35–0.62; p < 0.00001); pooled HR for OS for all types of skin toxicities was 0.51 (95% CI: 0.36–0.72; p = 0.0002); while pooled HR for OS for a combination of selected side effects (hypertension, HFS and diarrhoea) was 0.38 (95% CI: 0.30–0.48; p < 0.00001). No information was available regarding the impact of thyroid dysfunction or proteinuria.

Expert commentary: This analysis of data demonstrated that the occurrence of sorafenib-related side effects (such as diarrhoea, hypertension and skin toxicities) is associated with a better OS in sorafenib-treated HCC patients.