Verification of the risk score of hepatocellular carcinoma in patients with hepatitis B virus-associated liver cirrhosis / 中华消化杂志

Objective:To evaluate the accuracy and practicability of hepatocellular carcinoma prediction score (PAGE-B) and modified hepatocellular carcinoma prediction score (mPAGE-B) in predicting the development of hepatocellular carcinoma in patients with hepatitis B virus (HBV)-associated liver cirrhosis and received nucleos(t)ide analogue (NA) treatment.Methods:From June 2009 to December 2014, at Department of Hepatology, the First Affiliated Hospital of Fujian Medical University, the clinical data of 707 patients with HBV-associated liver cirrhosis and received NA treatment were retrospectively collected, and the patients were followed up. The risk factors of development of hepatocellular carcinoma were analyzed. PAGE-B (including platelet count, age, gender), mPAGE-B (including platelet count, age, gender and albumin), Child-Turcotte-Pugh (CTP) score and aspartate aminotransferase to platelet ratio index (APRI) were compared in area under receiver operator characteristic curve (AUROC) for predicting the occurrence of hepatocellular carcinoma within 5 years. Risk stratification analysis was carried out for mPAGE-B and PAGE-B. Multivariate Cox regression analysis, receiver operator characteristic curve, Mann-Whitney U test and Kaplan-Meier method were used for statistical analysis. Results:The age of 707 patients was (46.7±12.2) years old, including 567 males (80.2%) and 140 females (19.8%). The positive rate of hepatitis B e antigen was 56.4% (399/707). The scores of PAGE-B, mPAGE-B, CTP and APRI were 15.90±4.24, 12.39±3.58, 6.88±2.15 and 1.80 (0.85, 3.79), respectively. The overall follow up time was (38.14±20.97) months and the incidence of hepatocellular carcinoma was 8.1% (57/707). The results of multivariate Cox regression analysis showed that advanced age, low platelet count and quantitative reduction of HBV DNA were independent risk factors of development of hepatocellular carcinoma (Wald=20.44, 5.64 and 9.25; HR(95% confidence interval (95% CI) 1.056(1.031 to 1.081), 0.994(0.989 to 0.999) and 0.769(0.649 to 0.911); P<0.001, =0.018 and 0.002). The AUROCs (95% CI) of PAGE-B, mPAGE-B, CTP score and APRI for predicting the occurrence of hepatocellular carcinoma within 5 years were 0.708 (0.639 to 0.778), 0.724 (0.657 to 0.778), 0.576 (0.500 to 0.652) and 0.516 (0.443 to 0.589), respectively. There were no statistically significant differences in AUROCs for predicting the occurrence of hepatocellular carcinoma within 5 years between mPAGE-B and PAGE-B, between APRI and CTP score (both P>0.05). The AUROC for predicting the occurrence of hepatocellular carcinoma within 5 years of CTP score was less than those of PAGE-B and mPAGE-B, and the differences were statistically significant ( Z=3.00 and 3.79; P=0.003, <0.001). The AUROC for predicting the occurrence of hepatocellular carcinoma within 5 years of APRI was less than those of PAGE-B and mPAGE-B, and the differences were statistically significant ( Z=4.75 and 5.46, both P<0.001). There were 51 cases (7.2%), 394 cases (55.7%) and 262 cases (37.1%) in the low-risk (<10) group, medium-risk (10 to 17) group and high-risk (>17) group as assessed by PAGE-B. The incidence of hepatocellular carcinoma was 0(0/51), 4.8% (19/394) and 14.5% (38/262), respectively the annual average incidence of hepatocellular carcinoma was 0, 1.6% and 5.5%, respectively, the 5-year cumulative incidence of hepatocellular carcinoma was 0, 7.3% and 31.3%, respectively. The 5-year cumulative incidence of hepatocellular carcinoma of high-risk group was higher than those of medium-risk group and low-risk group (log-rank test=19.27, P<0.001). There were 97 cases (13.7%), 246 cases (34.8%) and 364 cases (51.5%) in the low-risk group (<9), medium-risk group (9 to 12) and high-risk group (>12) as assessed by mPAGE-B. The incidence of hepatocellular carcinoma was 2.1% (2/97), 3.7% (9/246) and 12.6%(46/364), the annual average incidence of hepatocellular carcinoma was 0.6%, 1.1% and 4.7%, respectively, the 5-year cumulative incidence of hepatocellular carcinoma was 2.4%, 5.1% and 26.7%, respectively. The 5-year cumulative incidence of hepatocellular carcinoma of high-risk group was higher than those of medium-risk group and low-risk group (log-rank test value=18.64, P<0.001). Conclusions:Both PAGE-B and mPAGE-B can predict the occurrence of hepatocellular carcinoma within 5 years in patients with HBV-associated liver cirrhosis treated with antiviral therapy, identify liver cirrhotic patients at high risk of development of hepatocellular carcinoma and guide clinicans to use more efficient screening strategies.

Predictors of HBeAg seroconversion after long-term nucleos(t)ide analogues treatment for chronic hepatitis B: a multicenter study in real clinical setting

ABSTRACT Aims: To evaluate the HBeAg seroconversion rate in real clinical setting and explore its predictors in long-term nucleos(t)ide analogues (NAs) treatment for chronic hepatitis B (CHB). Methods: 251 patients were recruited from January 2001 to September 2009 in four hospitals in Hebei province, China, for this retrospective study. Clinical and laboratory data before and after treatment with lamivudine (LAM, 100 mg daily), adefovir (ADV, 10 mg daily), telbivudine (LDT, 600 mg daily), entecavir (ETV, 0.5 mg daily), and LAM/ADV combination were compared among three groups according to treatment outcomes: synchronous HBeAg loss and HBeAg seroconversion, anti-HBe development after treatment, and no anti-HBe. Adherence was also evaluated. Results: In real clinical setting, cumulative HBeAg seroconversion rates were 14.3%, 32.7%, 43.0%, 46.9%, and 50.5% after 1, 2, 3, 5, and 8 years, respectively. 45 patients (17.9%) were non-adherent. Adherence (p < 0.001, Hazard Ratio (HR) = 2.203), elevated alanine aminotransferase (ALT) levels (p < 0.001, HR = 2.049), and non-vertical transmission (p = 0.006, HR = 1.656) were predictors of HBeAg seroconversion. Conclusion: Adherence, elevated ALT, and non-vertical transmission are predictors of HBeAg seroconversion in CHB patients treated with NAs.

Combination Therapy for Chronic Hepatitis B: Current Updates and Perspectives

Nucleos(t)ide analogues (NUCs) and interferon have been used for several decades to treat chronic hepatitis B; however, the therapeutic response remains unsatisfactory. Although NUC therapy exhibits potent on-treatment viral suppression, frequent off-therapy virological relapses suggest an indefinite treatment course. Interferon modulates the innate and adaptive antiviral immune responses and thus increases the chance of viral eradication. Interferon therapy has the advantage of a finite duration, absence of drug resistance, and durable posttreatment responses. Therefore, the combination of NUCs and interferon can theoretically facilitate a synergistic therapeutic effect. This paper summarizes the current strategies of various combination therapies into three categories: the simultaneous “dual” strategy, sequential combination “add-on” strategy, and “switch” strategy. Generally, dual therapy exhibits greater on-treatment and off-therapy viral suppression and lower drug resistance compared with NUC monotherapy. Compared with interferon monotherapy, dual therapy has greater on-treatment viral suppression but shows no difference in off-therapy sustained virological responses. Specific add-on or switch strategies provide promising on-treatment efficacy in select patients. Pretreatment or on-treatment quantitative hepatitis B surface antigen and e antigen are predictive for the treatment efficacy of combination therapy. The optimal schedule of combination regimens and individualized therapy remain to be comprehensively evaluated.

Combination Therapy for Chronic Hepatitis B: Current Updates and Perspectives

Nucleos(t)ide analogues (NUCs) and interferon have been used for several decades to treat chronic hepatitis B; however, the therapeutic response remains unsatisfactory. Although NUC therapy exhibits potent on-treatment viral suppression, frequent off-therapy virological relapses suggest an indefinite treatment course. Interferon modulates the innate and adaptive antiviral immune responses and thus increases the chance of viral eradication. Interferon therapy has the advantage of a finite duration, absence of drug resistance, and durable posttreatment responses. Therefore, the combination of NUCs and interferon can theoretically facilitate a synergistic therapeutic effect. This paper summarizes the current strategies of various combination therapies into three categories: the simultaneous “dual” strategy, sequential combination “add-on” strategy, and “switch” strategy. Generally, dual therapy exhibits greater on-treatment and off-therapy viral suppression and lower drug resistance compared with NUC monotherapy. Compared with interferon monotherapy, dual therapy has greater on-treatment viral suppression but shows no difference in off-therapy sustained virological responses. Specific add-on or switch strategies provide promising on-treatment efficacy in select patients. Pretreatment or on-treatment quantitative hepatitis B surface antigen and e antigen are predictive for the treatment efficacy of combination therapy. The optimal schedule of combination regimens and individualized therapy remain to be comprehensively evaluated.

Is alanine aminotransferase flare-up in nucleos(t)ide analogue treatment of chronic hepatitis B a promising, rather than a devastating, sign?

No abstract available.

Long-term virological outcome in chronic hepatitis B patients with a partial virological response to entecavir

BACKGROUND/AIMS: The clinical outcome of patients with a partial virological response (PVR) to entecavir (ETV), in particular nucloes(t)ide analogue (NA)-experienced patients, has not been thoroughly investigated. The aim of the present study was to assess long-term outcomes in NA-naive and NA-experienced chronic hepatitis B patients with a PVR to ETV. METHODS: Chronic hepatitis B patients treated with ETV (0.5 mg/day) for at least 1 year were enrolled retrospectively. PVR was defined as a decrease in hepatitis B virus (HBV) DNA titer of more than 2 log10 IU/mL, yet with residual serum HBV DNA, as determined by real time-polymerase chain reaction, at week 48 of ETV therapy. RESULTS: A total of 202 patients (127 NA-naive and 75 NA-experienced, male 70.8%, antigen positive 53.2%, baseline serum HBV DNA 6.2 +/- 1.5 log10 IU/mL) were analyzed. Twenty-eight patients demonstrated a PVR. The PVR was associated with a high serum HBV DNA titer at baseline and at week 24. Virological response (< 60 IU/mL) was achieved in 46.2%, 61.5%, 77.6%, and 85% of patients with PVR at week 72, 96, 144, and 192, respectively. Resistance to antivirals developed in two NA-experienced patients. Failure of virological response (VR) in patients with PVR was associated with high levels of serum HBV DNA at week 48. CONCLUSIONS: Patients with PVR to ETV had favorable long-term virological outcomes. The low serum level of HBV DNA (< 200 IU/mL) at week 48 was associated with subsequent development of a VR in patients with PVR to ETV.

Tenofovir disoproxil fumarate monotherapy for nucleos(t)ide analogue-naive and nucleos(t)ide analogue-experienced chronic hepatitis B patients

BACKGROUND/AIMS: This study investigated the antiviral effects of tenofovir disoproxil fumarate (TDF) monotherapy in nucleos(t)ide analogue (NA)-naive and NA-experienced chronic hepatitis B (CHB) patients. METHODS: CHB patients treated with TDF monotherapy (300 mg/day) for > or =12 weeks between December 2012 and July 2014 at a single center were retrospectively enrolled. Clinical, biochemical, and virological parameters were assessed every 12 weeks. RESULTS: In total, 136 patients (median age 49 years, 96 males, 94 HBeAg positive, and 51 with liver cirrhosis) were included. Sixty-two patients were nucleos(t)ide (NA)-naive, and 74 patients had prior NA therapy (NA-exp group), and 31 patients in the NA-exp group had lamivudine (LAM)-resistance (LAM-R group). The baseline serum hepatitis B virus (HBV) DNA level was 4.9+/-2.3 log IU/mL (mean+/-SD), and was higher in the NA-naive group than in the NA-exp and LAM-R groups (5.9+/-2.0 log IU/mL vs 3.9+/-2.0 log IU/mL vs 4.2+/-1.7 log IU/mL, P<0.01). The complete virological response (CVR) rate at week 48 in the NA-naive group (71.4%) did not differ significantly from those in the NA-exp (71.3%) and LAM-R (66.1%) groups. In multivariate analysis, baseline serum HBV DNA was the only predictive factor for a CVR at week 48 (hazard ratio, 0.809; 95% confidence interval, 0.729-0.898), while the CVR rate did not differ with the NA experience. CONCLUSIONS: TDF monotherapy was effective for CHB treatment irrespective of prior NA treatment or LAM resistance. Baseline serum HBV DNA was the independent predictive factor for a CVR.

Durability after discontinuation of nucleos(t)ide therapy in chronic HBeAg negative hepatitis patients

BACKGROUND/AIMS: Relapse has been reported after stopping nucleos(t)ide (NUC) therapy in the majority of chronic HBeAg negative hepatitis patients. However, the ideal treatment duration of HBeAg negative chronic hepatitis B (CHB) is not well known. We investigated the frequency of relapse in HBeAg negative CHB patients receiving NUC therapy. METHODS: The NUC therapy was discontinued at least 3 times undetectable level of HBV DNA leave 6 months space in 45 patients. Clinical relapse was defined as HBV DNA >2,000 IU/mL and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times of upper limit of normal range. Virological relapse was defined as HBV DNA >2,000 IU/mL. RESULTS: Clinical relapse developed in 16 (35.6%) and 24 (53.3%) patients after stopping therapy at 6 months and 12 months off therapy, respectively. Virological relapse developed 22 (48.9%) and 33 (73.3%) patients at 6 months and 12 months off therapy. The factors such as age, gender, cirrhosis, baseline AST, ALT, HBV DNA levels, treatment duration, and consolidation duration were analyzed to investigate the predictive factors associated with 1 year sustained response. Of these factors, cirrhosis (86.1% in CHB, 22.2% in LC) was significantly associated with 1 year virological relapse rate. Baseline HBV DNA and total treatment duration tended to be associated with virological relapse. CONCLUSIONS: Virological relapse developed in the majority (73.3%) of HBeAg negative CHB patients and clinical relapse developed in the half (53.3%) of patients at 1 year off therapy. Cirrhosis may be associated with the low rate of virological relapse.

Current Nucleos(t)ide Analogue Therapy for Chronic Hepatitis B

Although the prevalence of chronic hepatitis B has decreased considerably in recent years due to widespread use of the hepatitis B virus (HBV) vaccine, its prevalence still remains high in adults, and this can place a significant burden on health care in areas with endemic HBV. Since the introduction of nucleos(t)ide analogues (NUCs), there has been marked improvement in the care of patients with chronic hepatitis B, resulting in increased survival. However, the emergence of drug resistance in patients treated with NUCs is a major concern. The number of multi-drug resistant patients is increasing, and many patients may not respond to the currently available drugs. In this review, we describe the current status of NUC therapy for antiviral-naive and -resistant patients.