PCDH20 functions as a tumour‐suppressor gene through antagonizing the Wnt/β‐catenin signalling pathway in hepatocellular carcinoma

Several members of protocadherins have been found involved in human carcinogenesis, but little is known about PCDH20 in HCC. Here in this study, using quantitative real‐time RT‐PCR assay, we demonstrated the downregulation of PCDH20 expression in 6 of 7 HCC cell lines tested. Similarly, PCDH20 expression in primary HCC tissues was also significantly downregulated in comparison with that in either disease‐free normal liver tissues or the adjacent nontumour liver tissues (P < 0.001, respectively). Among HCC tumour tissues studied, about 48% (51/107) of them showed reduced PCDH20 mRNA level. Further statistic analysis revealed that the reduced PCDH20 mRNA level in tumour tissues was much more common in younger patients group (aged <50 years) than that in older group (≥50 years) (60% vs 33%, P = 0.0303). Loss of heterozygosity (LOH) and promoter hypermethylation analysis revealed that deletion and/or aberrant epigenetic modulation of PCDH20 gene account for its downregulation, at least in a fraction of tumour specimens. Moreover, ectopic expression of PCDH20 in HCC cells significantly suppressed cell proliferation, clonogenicity, migration and tumour formation. Notably, we proved for the first time that, via activating GSK‐3β, PCDH20 could inhibit Wnt/β‐catenin signalling pathway. Furthermore, our data suggest that PCDH20 may conduct its Wnt/β‐catenin signalling antagonizing function through suppressing Akt and Erk activities and promoting GSK‐3β signalling activities. However, the detailed mechanism remained undiscovered. In conclusion, our data here strongly suggested that PCDH20 may act as a candidate tumour suppressor in HCC.     

The impact of viral hepatitis‐related hepatocellular carcinoma to post‐transplant outcomes

Hepatocellular carcinoma (HCC) is the most common complication of HCV infection leading to liver transplantation. We evaluated the impact of aetiology of liver disease on patient and graft survival following liver transplantation for HCC. From the Scientific Registry of Transplant Recipients (2002–2011), all adults who underwent liver transplantation for HCC were retrospectively included. Aetiology of liver disease was grouped into HCV, HBV, HCV–HBV co‐infection and nonviral liver disease. Of 8,733 liver transplant recipients with HCC, 5507 had HCV, 631 had HBV, 163 were co‐infected, and 2432 had nonviral causes of liver disease. In follow‐up (48 ± 32 months), 8.2% had graft failure and 29.5% died. The mean rates of graft failure were 9.5%, 4.7%, 6.1% and 6.4% in HCV, HBV, HCV–HBV co‐infection and nonviral liver disease, respectively (P < 0.0001). Post‐transplant mortality rate in patients with HBV was 20.2%, HCV 31.0%, HCV–HBV 28.5% and nonviral 28.5% (P < 0.0001). This difference was significant starting one year post‐transplant and became even more prominent later in follow‐up. Five‐year post‐transplant survival was 64.7% in HCV, 77.7% in HBV, 71.0% in HCV–HBV and 69.1% in nonviral HCC (P < 0.0001). A diagnosis of HCV in patients with HCC was also independently associated with an increased risk of both graft failure (adjusted hazard ratio = 1.84 (1.46–2.33), P < 0.0001) and mortality (1.35 (1.21–1.50), P < 0.0001) in multivariate analysis. Patients with HCV‐related HCC are at higher risk of adverse post‐transplant outcomes. These patients should be considered for preemptive interferon‐free antiviral therapy prior to or immediately following liver transplantation.     

Influence of hepatitis B virus reactivation on the recurrence of HBV‐related hepatocellular carcinoma after curative resection in patients with low viral load

It is unclear whether the reactivation of hepatitis B virus (HBV) influences the prognosis of hepatocellular carcinoma (HCC) after resection in patients with chronic hepatitis B. The aim of this study was to identify the influence of HBV reactivation on the recurrence of hepatitis B‐related HCC after curative resection in patients with low viral load (HBV DNA <2000 IU/mL). We retrospectively analysed a total of 130 patients who underwent curative resection for HBV‐related early stage HCC (single nodule; <5 cm/two or three nodules; <3 cm) with pre‐operative HBV DNA levels <2000 IU/mL with serial HBV DNA tests. The predictive factors including HBV reactivation for the recurrence of HBV‐related HCC after curative resection were investigated. Fifty‐three patients (41%) had HBV reactivation after resection among 130 patients. HBV reactivation was observed in 22 of 53 patients with undetectable baseline HBV DNA and in 31 of 77 patients with detectable baseline HBV DNA. Cumulative recurrence rates after resection at 1, 2 and 3 years were 17.0%, 23.3% and 31.4%, respectively. The multivariable analysis demonstrated that the risk factors for the recurrence were the presence of microvascular invasion (hazard ratio (HR) 2.62, P = 0.003), multinodularity (HR 4.61, P = 0.005), HBV reactivation after resection (HR 2.03, P = 0.032) and HBeAg positivity (HR 2.06, P = 0.044). HBV reactivation after curative resection is associated with the recurrence of HBV‐related HCC in patients with low viral load.     

Predictors associated with treatment initiation and switch in a real‐world chronic hepatitis B population from five European countries

In Europe, healthcare systems differ between countries and different factors may influence Chronic hepatitis B (CHB) treatment choices in different counties. This analysis from a prospective, longitudinal, non‐interventional study in five EU countries aimed to explore determinants associated with treatment initiation or switch in patients with CHB. A total of 1267 adult patients with compensated CHB in Germany, France, Poland, Romania and Turkey were prospectively followed for up to 2 years (March 2008–December 2010). Determinants of treatment initiation or switch were analysed using multivariate Cox proportional hazards regression. Median time since CHB diagnosis was 2.6 (0–37.7) years. Among 646 treatment‐naïve patients, the probability of treatment initiation during follow‐up was higher: in Germany (P = 0.0006), Poland (P < 0.0001) and Romania (P = 0.0004) compared with Turkey; in patients with alanine transaminase (ALT) 1–2 × upper limit of normal (ULN) (P = 0.0580) or >2 × ULN (P = 0.0523) compared with ALT ≤1 × ULN; and in patients with hepatitis B virus (HBV) DNA ≥2000 IU/mL (P < 0.0001) compared with HBV DNA <2000 IU/mL or undetectable. Among 567 treated patients, 87 switched treatment during follow‐up. The probability of treatment switch was higher: in France (P = 0.0029), Germany (P = 0.0078) and Poland (P = 0.0329) compared with Turkey; and in patients with HBV DNA <2000 (P < 0.0001) or ≥2000 IU/mL (P < 0.0001), compared with undetectable. Viral load and ALT level were identified as the major drivers of treatment initiation. HBV DNA level was also a significant determinant of treatment switch. Results were statistically different across EU countries.     

Serum microRNA‐124 is a novel biomarker for liver necroinflammation in patients with chronic hepatitis B virus infection

Patients with chronic hepatitis B virus (HBV) infection and normal or mildly increased transaminases may have sustained significant liver damage, as verified by liver biopsy. However, no suitable noninvasive method exists for identifying liver necroinflammation in such patients. We aimed to investigate the power of microRNA‐124 as a novel biomarker for liver necroinflammation. A total of 131 recruited patients with chronic HBV infection underwent liver biopsy for grading of necroinflammation (G) and staging of fibrosis (S). Thirty healthy individuals were included as controls (HCs). Serum microRNA‐124 and microRNA‐122 levels were measured using qRT‐PCR. Forty‐five patients from the study population receiving entecavir therapy were monitored for changes in serum microRNA‐124 levels in association with improved liver histology. The capacity of serum microRNA‐124 levels in discriminating the grade of liver necroinflammation was compared with alanine aminotransferase (ALT) with liver biopsy validation. Serum microRNA‐124 levels were significantly higher in patients with chronic HBV infection than in HCs (P < 0.0001). Patients with considerable liver necroinflammation (G ≥ 2) had significantly higher serum miRNA‐124 levels than those without or with mild necroinflammation (P < 0.0001). After 48 weeks of antiviral therapy, serum microRNA‐124 levels considerably declined in 45 patients (P < 0.0001), which were associated with histological improvement. In patients with normal ALT and a serum HBV DNA load >10⁴ copies/mL, receiver operating characteristic (ROC) curve of serum microRNA‐124 levels yielded an area under ROC curve (AUC) of 0.840, with 58.3% sensitivity and 91.7% specificity in discriminating between moderate‐to‐severe liver necroinflammation (G ≥ 2).     

Hepatitis B virus DNA in patients with hepatitis B‐related liver cirrhosis with or without hepatocellular carcinomas: a matched case‐control study

OBJECTIVE: The relationship between serum viremia and the development of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)‐related cirrhosis remains unclear. We aimed at calculating odds ratios (OR) for the presence of HCC over a range of HBV DNA levels in these patients. METHODS: Patients were identified retrospectively and 155 pairs of matched, treatment‐naive HBV‐related cirrhotic patients with and without HCC were recruited. Their serum HBV DNA levels were measured at HCC diagnosis, or at the equivalent age in non‐HCC patients, and correlations between the presence of HCC and different DNA levels were calculated using conditional logistic regression. RESULTS: The median HBV DNA level was significantly higher in HCC patients than in non‐HCC patients (5.15 vs 4.83 log₁₀ copies/mL, P = 0.024). The overall OR for HCC in patients with HBV DNA ≥ 3 log₁₀ copies/mL was 2.13, compared with patients with levels <3 log₁₀ copies/mL. Compared with patients with <3 log₁₀ copies/mL, the OR for HCC were 2.39 and 2.61 for patients with 4 to <5 and 5 to <6 log₁₀ copies/mL, respectively, while the OR for DNA levels of ≥6 log₁₀ copies/mL were not significantly different. CONCLUSION: In HBV‐related cirrhosis, a detectable serum HBV DNA was associated with the presence of HCC, but the likelihood of having HCC did not successively increase with increasing serum HBV DNA levels: patients with serum HBV DNA levels between 4 and <6 log₁₀ copies/mL were most likely to present with HCC.     

Meta‐analysis: Association between hepatitis B virus preS mutation and hepatocellular carcinoma risk

Previous observational studies suggested that hepatitis B virus (HBV) preS mutation plays an important role in the existence of HBV‐related hepatocellular carcinoma (HCC). However, the results are still debatable. With an increasing number of studies about this topic, this study employed a meta‐analysis to identify the association between HBV preS mutation and HCC risk. We searched for eligible studies from PubMed, ProQuest, CINAHL, ScienceDirect and Springer databases to assess the association between HBV mutation and HCC risk. This meta‐analysis was conducted using RevMan 5.3 to provide pooled estimate for odds ratio (ORs) with 95% confidence intervals (95% CIs). Twenty‐one clinical studies were included in this meta‐analysis study which consisted of 1738 participants with HBV‐related HCC and 3740 HBsAg‐positive patients without HCC. All studies used samples of Asian population. PreS deletion was the most common mutation found in all studies. We found that ORs of HBV overall preS deletion was associated with HCC (OR = 3.28; 95% CI = 2.32‐4.65; P < .00001; random‐effects model). Each preS1 and preS2 deletion was associated with increased risk of HCC, with OR 2.42 (95% CI = 1.25‐4.68, P = .008) and 3.36 (95% CI = 2.04‐5.55, P < .00001), respectively. PreS2 start codon mutation was also significantly associated with HCC risk (OR = 2.47; 95% CI: 1.15‐5.27; P = .02; random‐effect model). The result of this meta‐analysis suggested that HBV preS deletion (all, preS1 and preS2) and preS2 start codon mutation might contribute to the increased risk of HBV‐related HCC.     

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.     

Enrichment in selected genotypes,basal core and precore mutations of hepatitis B virus in patients with hepatocellular carcinoma in Cameroon

Worldwide, the development of hepatocellular carcinoma (HCC) is known to be influenced by several hepatitis B viral factors. However, the effect of hepatitis B virus (HBV) genotypes and a landscape of nucleotide changes affecting the precore (PC) and basal core promoter (BCP) during infection leading to HCC remain largely unknown in the Central Africa region. Thus, we performed a case‐control study on patients with HBV‐related HCC and matched controls without HCC but with chronic HBV infection. Genotypes and mutation spectrums were evaluated using a hemi‐nested amplification and sequencing analysis focused on the BCP and PC regions. We identified the co‐circulation of HBV quasi‐subgenotype A3 (QS‐A3) and genotype E in both groups. Interestingly, HBV‐QS‐A3 was significantly more prevalent in patients with HCC (80.0%) than in controls (31.9%, P = 4.5 E‐7, OR = 11.5, 95% CI: 3.8‐38.5). HBV mutation spectra and nucleotide changes were significantly more polymorphic in patients with HCC. Remarkably, HCC patients infected with HBV‐QS‐A3 were significantly more mutated compared to patients infected with genotype E (P < 0.0001). In addition, G:C>T:A transversions, generally associated with aflatoxin B1 exposure in tropical regions, were significantly more prevalent in HCC patients infected either with HBV‐QS‐A3 or HBV genotype E (P = 2.2 E‐05) when compared to controls. In conclusion, our results indicate that patients infected with HBV‐QS‐A3 are at increased risk to develop HCC. In addition, viral genomes isolated for patients with tumour are more heavily altered than those found in controls. Preferential targeting of these patients for antiviral treatment is of paramount importance to reduce future HCC incidence in Cameroon.     

Role of CYP27B1+2838 promoter polymorphism in the treatment of chronic hepatitis B HBeAg negative with PEG‐interferon

In HBV‐infected patients, the vitamin D deficiency has been related to chronic liver diseases, progression of hepatic fibrosis and poor response to the treatment. The CYP27B1 gene, which encodes the 1‐α‐hidroxylase and involved in the 1,25‐dihydroxyvitamin D synthesis, was recently associated to type‐1 diabetes, autoimmune disorders and treatment response in HCV. Then, we aimed to investigate the role of CYP27B1 polymorphisms in HBV treatment with PEG‐IFN. We retrospectively enrolled 190 patients with chronic hepatitis B HBeAg negative treated for 48 weeks with PEG‐IFN α‐2a. We examined the role of rs4646536 CYP27B1 SNP (CYP27B1+2838) according to virological and serological response. Our results showed that the TT genotype of CYP27B1+2838 was significantly prevalent in patients with end‐of‐therapy virological response (37.6%) vs CT/CC (9.4%) (P < 0.001). Virological relapse was prevalent in patients with CT/CC genotype (12.6%) vs TT genotype (2.1%) (P < 0.001). TT genotype was also related to HBsAg loss (P = 0.004) and anti‐HBs appearance (P = 0.002). In the multivariate analysis, the TT genotype resulted to be a good positive predictor of sustained virological response (OR = 5.632, IC = 1.938–16.368, P = 0.001) and serological response (OR = 6.161, IC = 1.856–20.457, P = 0.003). The CYP27B1+2838 polymorphism may be useful as pretreatment factor to selection of patients with higher probability of response to therapy.     

Precore G1896A mutation is associated with reduced rates of HBsAg seroclearance in treated HIV hepatitis B virus co‐infected patients from Western Africa

The nucleotide substitution G1896A on the precore (pc) region has been implicated in virological and serological responses during treatment in hepatitis B virus (HBV)‐infected patients. Whether this mutation affects the therapeutic course of HIV‐HBV co‐infected patients, especially from Western Africa, is unknown. In this prospective cohort study, 86 antiretroviral (ARV)‐naïve HIV‐HBV co‐infected patients from Côte d'Ivoire, initiating ARV‐treatment containing lamivudine (n = 53) or tenofovir (n = 33), had available baseline pc sequences. Association of the pcG1896A mutation with time to undetectable HBV‐DNA, hepatitis B “e” antigen (HBeAg) seroclearance (in HBeAg‐positive patients), and hepatitis B surface antigen (HBsAg) seroclearance was evaluated using Cox proportional hazards regression. At ARV‐initiation, median HBV‐DNA was 6.04 log₁₀ copies/mL (IQR = 3.70‐7.93) with 97.7% harbouring HBV genotype E. Baseline pcG1896A mutation was identified in 51 (59.3%) patients, who were more commonly HBeAg‐negative (P < .001) and had basal core promotor A1762T/G1764A mutations (P < .001). Patients were followed for a median 36 months (IQR = 24‐36). Cumulative proportion of undetectable HBV‐DNA was significantly higher in patients with baseline mutation (pcG1896A = 86.6% vs no pcG1896A = 66.9%, P = .04), but not after adjusting for baseline HBV‐DNA levels and anti‐HBV agent (P = .2). No difference in cumulative proportion of HBeAg seroclearance was observed between mutation groups (pcG1896A = 57.1% vs no pcG1896A = 54.3%, P = .7). Significantly higher cumulative proportion of HBsAg seroclearance was observed in patients without this mutation (pcG1896A = 0% vs no pcG1896A = 36.9%, P < .001), even after adjusting for baseline HBsAg quantification and anti‐HBV agent (P < .001). In conclusion, lacking the pcG1896A mutation before ARV initiation appeared to increase HBsAg seroclearance rates during treatment. The therapeutic implications of this mutation need further exploration in this setting.     

Serum hepatitis B core‐related antigen is an effective tool to categorize patients with HBeAg‐negative chronic hepatitis B

The discrimination between active chronic hepatitis B (CHB) and the clinically quiescent infection (CIB) is not always easy, as a significant portion of patients falls in a “grey” zone. Hepatitis B core‐related antigen (HBcrAg) is a now quantifiable serological marker with potential applications in diagnosis and therapy monitoring. The aim of the present study was to evaluate the HBcrAg serum levels in HBeAg‐negative HBV infection, and its ability in identifying the clinical profile, in comparison with HBsAg serum levels. HBcrAg was retrospectively assessed on serum samples from a population of treatment‐naive HBeAg‐negative patients by ChemiLuminescent Enzyme Immunoassay (CLEIA). HBsAg and HBV‐DNA data were collected. Serological data were associated to clinical profile, defined in the subsequent follow‐up of at least 1 year. In the overall population of 160 HBeAg‐negative patients, HBcrAg results weakly correlated with qHBsAg levels (Spearman r = 0.471, P < 0.0001) and correlated closely with HBV‐DNA (Spearman r = 0.746, P < 0.0001). HBcrAg levels were significantly higher in 85 CHB patients relative to 75 CIB carriers. A value of 2.5 logU/mL produced the optimal cut‐off to identify CIB patients, with diagnostic accuracy comparable to HBsAg levels. In long‐term clinical evaluation, a single measurement of HBcrAg at the established cut‐off was optimally consistent with clinical outcome. Conversely, the HBsAg cut‐off performed well in the true quiescent phase and less in more difficult‐to‐categorize patients. In conclusion, single‐point use of HBcrAg serum levels provides an accurate identification of CIB and represents a useful tool for patient classification.     

PD‐1 expression on CTL may be related to more severe liver damage in CHB patients with HBV genotype C than in those with genotype B infection

Compared with Chronic hepatitis B (CHB) patients infected with genotype B, those infected with genotype C have higher hepatic histopathological activity and higher level of alanine aminotransferase (ALT). Our previous studies suggest that this phenomenon is related to lower level of HBV specific cytotoxic T lymphocyte (CTL) of patients infected with genotype C than those infected with genotype B, but its mechanism was not clear. The aim of present study was to explain the possible mechanism of lower level of HBV specific CTL and more serious liver function damage of patients infected with genotype C than those infected with genotype B through study on relationship between expression of HBV specific CTL surface programmed death receptor‐1 (PD‐1) and viral genotypes of CHB patients. A total of 100 CHB patients were studied, human leukocyte antigen (HLA)‐A2 positive, hepatitis B virus (HBV) DNA>10³ copies/ml, of which 48 cases were genotype C (48%) positive, and 52 cases were genotype B positive (52%). Expression of Peripheral blood HBV specific CTL surface PD‐1, levels of HBV specific CTL, HBV DNA, ALT and total bilirubin (TBil) of patients infected with genotype C and B were compared. Expression of HBV specific CTL surface PD‐1 of CHB patients infected with genotype C was significantly higher than that of patients infected with genotype B, t = 17.57, P < 0.001, level of HBV specific CTL was significantly lower than that of patients infected with genotype B, t = 23.64, P < 0.001, level of HBV DNA was significantly higher than that of patients infected with genotype B, t = 9.43, P < 0.001, level of ALT was significantly higher than that of patients infected with genotype B, t = 13.42, P < 0.001. Expression of peripheral blood HBV specific CTL surface PD‐1 of CHB patients infected with genotype C was significantly higher than that of patients infected with genotype B, resulting in lower level of HBV specific CTL and higher level of HBV DNA of patients infected with genotype C than those of patients infected with genotype B. So liver function damage of CHB patients infected with genotype C was more serious than those infected with genotype B.     

Overexpression of Yes‐associated protein and its association with clinicopathological features of hepatocellular carcinoma: A meta‐analysis

Background

Yes‐associated protein (YAP) overexpression is reported to be associated with risk of hepatocellular carcinoma (HCC) but current studies have not explored the relationship between YAP expression with HCC clinicopathological features.

Methods

To assess these associations, a meta‐analysis was performed which included four eligible studies including 391 HCC cases and 334 controls. There were eight eligible studies to investigate the association between YAP expression in HCC and clinicopathological features of liver cancer patients. Literature was obtained from PubMed, Embase, Wangfang and China National Knowledge Infrastructure.

Results

Analysis indicated that YAP expression in HCC was greater than in adjacent non‐tumour tissue (odds ratio [OR], 15.80, 95% confidence interval [CI], 10.53‐23.70, P<.00001; heterogeneity=.30). YAP overexpression in HCC was significantly associated with vascular invasion (OR, 2.21, 95% CI, 11.64‐2.97, P<.00001, heterogeneity=.10), less cellular differentiation (OR, 2.38, 95% CI, 1.61‐3.51, P<.00001, heterogeneity=.333), tumours larger than 5 cm (OR, 2.52, 95% CI, 1.75‐3.62, P<.00001; heterogeneity=.17) and TNM tumour stage I + II (OR, 0.44, 95% CI, 0.28‐0.75, P=.00003, heterogeneity=.12).

Conclusions

Overexpression of YAP contributes to HCC formation, and its overexpression is associated with vascular invasion, low cellular differentiation tumours larger than 5 cm and TNM tumour stage III + IV.     

HLA‐DQ polymorphisms with HBV infection: different outcomes upon infection and prognosis to lamivudine therapy

Two recent genome‐wide studies showed that the single‐nucleotide polymorphisms in the HLA‐DQ region (rs2856718 and rs9275572) were associated with chronic hepatitis B virus infection and chronic hepatitis C virus‐associated hepatocellular carcinoma in Japanese patients. We tested the effects of the two single‐nucleotide polymorphisms for all major HBV outcomes and lamivudine treatment in Han Chinese. A total of 1649 samples were enrolled, and peripheral blood samples were collected in this study. The single‐nucleotide polymorphisms in the HLA‐DQ region were genotyped using matrix‐assisted laser desorption/ionization time of flight mass spectrometry. Our study demonstrated the clear relevance of HLA‐DQ rs2856718 and rs9275572 with HBV susceptibility, natural clearance and HBV‐associated HCC. HLA‐DQ rs2856718G and rs9275572A were strongly associated with decreased risk of chronic HBV infection (odds ratio = 0.641; P = 2.64 × 10⁻⁴; odds ratio = 0.627, P = 7.22 × 10⁻⁵) and HBV natural clearance (odds ratio = 0.610; P = 4.80 × 10⁻⁴; odds ratio = 0.714, P = 0.013). Moreover, rs9275572A was also associated with development of cirrhosis and hepatocellular carcinoma (odds ratio = 0.632, P = 0.008). In addition, we showed for the first time to our knowledge that rs9275572 was a predictor for lamivudine therapy (viral response: odds ratio = 2.599, P = 4.43 × 10⁻⁴; biochemical response: odds ratio = 2.279, P = 4.23 × 10⁻⁴). Our study suggested that HLA‐DQ loci were associated with both HBV clearance and HBV‐related diseases and outcomes of lamivudine treatment in Han Chinese.     

Hepatitis B and survival after renal transplant: meta‐analysis of observational studies

Recent evidence has been accumulated suggesting that HBsAg seropositive status is significantly linked to lower patient and graft survival after renal transplant even if conflicting data on this point exist. The aim of this study was to conduct a systematic review of the published medical literature concerning the impact of HBV surface antigen seropositive status on all‐cause mortality and graft loss after RT. The relative risk of all‐cause mortality and graft loss was regarded as the most reliable outcome end‐point. Study‐specific relative risks were weighted by the inverse of their variance to obtain fixed‐ and random‐effect pooled estimates for mortality and graft loss with HBsAg across the published studies. We identified ten observational studies involving 82 690 unique renal transplant recipients. The summary estimate for adjusted relative risk (aRR) of all‐cause mortality was 2.214 with a 95% confidence interval (CI) of 1.56; 3.137 (P < 0.0001); heterogeneity statistics, Ri = 0.98 (P‐value by Q‐test = 0.0001). The overall estimate for adjusted RR of all‐cause graft loss was 1.44 (95% CI, 1.26; 1.63) (P < 0.0001) and heterogeneity statistics, Ri = 0.05 (P‐value by Q‐test = 0.4). Stratified analysis changed marginally the results. Meta‐regression showed that diabetes mellitus had a detrimental role on patient survival (P = 0.02). This meta‐analysis of observational studies supports the notion that HBsAg‐positive patients after RT have an increased risk of mortality and graft loss. The mechanisms underlying the relationship between HBsAg and mortality or graft dysfunction after renal transplant are an area of avid research.     

Peg‐interferon and nucleos(t)ide analogue combination at inception of antiviral therapy improves both anti‐HBV efficacy and long‐term survival among HBV DNA‐positive hepatocellular carcinoma patients after hepatectomy/ablation

Antiviral therapy has been shown to improve the prognosis of hepatitis B virus (HBV) DNA‐positive hepatocellular carcinoma (HCC) after radical treatment, but antiviral treatments require further optimization. This study aimed to evaluate the efficacies of different antiviral strategies with HCC patients after hepatectomy/ablation. This prospective, randomized, controlled and multi‐centre trial enrolled HBV DNA‐positive primary HCC patients after hepatectomy/ablation between January 2007 and January 2009. Patients were divided into four groups: early combination (entecavir plus Peg‐interferon [IFN]α‐2a co‐administration during year 1); late combination (addition of Peg‐IFNα‐2a for 48 weeks after 1 year of entecavir); nucleos(t)ide analogue[NA] monotherapy; and non‐antiviral treatment. Primary endpoints included recurrence‐free survival and overall survival. A total of 447 patients were enrolled. The 2‐year and 8‐year recurrence‐free survival and 8‐year overall survival rates were significantly higher in the early combination group than in the other two antiviral groups (P < .05). After 48‐week treatment, more patients achieved an HBsAg reduction >1500 IU/mL and the mean HBsAg level was significantly lower in the early combination group compared with the late combination and NA monotherapy groups (P < .05). Multivariate analysis showed that early combination therapy and a reduction in HBsAg by >1500 IU/mL after 48 weeks of therapy correlated with reduced mortality and disease recurrence. Early introduction of combination antiviral treatment may represent a more effective therapeutic strategy for patients with HBV DNA‐positive HCC after hepatectomy/ablation. A reduction in HBsAg by >1500 IU/mL after 48‐week treatment is associated with reduced mortality and disease recurrence of HBV DNA‐positive HCC patients after hepatectomy/ablation.