Summary
Background
High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg ...levels in predicting HCC in HBeAg‐positive CHB patients remains unknown.
Method
HBeAg‐positive CHB participants from the REVEAL‐HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group‐based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg‐positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p‐value less than 0.05 was considered statistically significant.
Results
A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non‐stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow‐up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj 95% CI = 4.11 2.26–7.48), genotype C (HRadj 95% CI = 4.39 1.96–9.81) and the non‐stationary group (HRadj 95% CI = 3.50 1.49–8.21) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj 95% CI = 32.75 5.41–198.42).
Conclusion
Patients with persistently high HBsAg levels during HBeAg‐seropositive stage represent a unique population with low risk of HCC development.
Persistent high HBsAg levels during HBeAg‐seropositive stage predicts lower risk of hepatocellular carcinoma in chronic hepatitis B patients
LINKED CONTENT
This article is linked to Hu et al papers. To view these articles, visit https://doi.org/10.1111/apt.16752 and https://doi.org/10.1111/apt.16833
Summary
Background
Hepatitis B surface antigen (HBsAg) seroclearance is the most important milestone indicating favourable clinical outcomes in patients with chronic hepatitis B (CHB). However, it is ...difficult to achieve due to the impaired HBV‐specific immunity, such as programmed cell death 1 (PD‐1)‐associated T cell exhaustion. We assessed soluble PD‐1 (sPD‐1) as a novel seromarker for predicting spontaneous HBsAg loss.
Methods
Serial serum levels of sPD‐1 were evaluated in 1046 untreated hepatitis B e antigen (HBeAg)‐seronegative individuals who had achieved undetectable serum HBV DNA. Multiple regression analyses were applied to assess associations among baseline and subsequent sPD‐1 levels, HBsAg decline during follow‐up, and spontaneous HBsAg seroclearance.
Results
A total of 390 individuals achieved spontaneous HBsAg seroclearance during 6464.4 person‐years of follow‐up. Baseline sPD‐1 levels were inversely associated with baseline HBsAg levels (qHBsAg) as well as a greater decline in qHBsAg during follow‐up. Incidence rates of HBsAg seroclearance were 11.5, 61.7, 96.7 and 151.0 per 1000 person‐years for sPD‐1 levels of ≥4000, 536‐3999, 125‐535 and <125 pg/mL, respectively (Ptrend < 0.0001). Compared with baseline sPD‐1 levels ≥4000 pg/mL, the rate ratio (95% CI) of HBsAg seroclearance was 2.1 (1.1‐3.9), 3.0 (1.6‐5.5) and 5.1 (2.8‐9.5), for baseline sPD‐1 levels of 536‐3999, 125‐535 and <125 pg/mL, respectively, after adjustment for sex, age and serum alanine aminotransferase and HBsAg levels.
Conclusion
sPD‐1 level is a novel marker which independently predicts spontaneous HBsAg seroclearance of HBeAg‐negative inactive CHB patients with undetectable HBV DNA. (word count: 234, <250).
Serum soluble programmed cell death 1 levels inversely predict spontaneous functional cure in inactive carriers with chronic hepatitis B.
Previous studies have shown that gabapentin or pregabalin use is associated with cognitive decline. Herein, we aimed to evaluate the association between gabapentin or pregabalin use and the risk of ...dementia.
In this retrospective, population-based matched cohort study, all research data were collected from the 2005 Longitudinal Health Insurance Database, which contains data of 2 million people randomly selected from the National Health Insurance Research Database of Taiwan in 2005. The study extracted data from 1 January 2000, to 31 December 2017. Adult patients taking gabapentin or pregabalin were included in the exposure group, and patients not using gabapentin or pregabalin matched to exposure subjects in a 1:5 ratio by propensity scores composed of age, sex and index date were included in the non-exposure group.
A total of 206,802 patients were enrolled in the study. Of them, 34,467 gabapentin- or pregabalin-exposure and 172,335 non-exposure patients were used for analysis. The mean follow-up day (±standard deviation) after the index date was 1724.76 (±1282.32) and 1881.45 (±1303.69) in the exposure and non-exposure groups, respectively; the incidence rates of dementia were 980.60 and 605.48 per 100,000 person-years, respectively. The multivariate-adjusted hazard ratio of risk of dementia for gabapentin or pregabalin exposure versus the matched non-exposed group was 1.45 (95% confidence interval CI, 1.36-1.55). The risk of dementia increased with higher cumulative defined daily doses during the follow-up period. Moreover, the stratification analysis revealed that the risk of dementia associated with gabapentin or pregabalin exposure was significant in all age subgroups; however, it was higher in younger patients (age <50) than in the older patients (hazard ratio, 3.16; 95% CI, 2.23-4.47).
Patients treated with gabapentin or pregabalin had an increased risk of dementia. Therefore, these drugs should be used with caution, particularly in susceptible individuals.
Soluble programmed death-1 (sPD-1) is a novel immune markers and possibly predictive of chronic hepatitis B (CHB) outcome. However, results were inconsistent by different ELISA kits. This study aims ...to compare the characteristics and correlations with other markers for sPD-1 measured by MyBioSource (MB) and R&D (RD) kits.
A total of 254 untreated CHB patients from three sites were assayed with sPD-1 by MB and RD kits at the same time. Spearman's correlations between the kits, and those with viral markers and ALT levels were calculated. Multivariate linear regression analysis was applied for independent factors associated with the sPD-1 levels.
There's no correlation between sPD-1 level using MB and RD assays. sPD-1 by MB correlated profoundly with HBsAg (r = 0.8311, P < 0.0001), HBV DNA (r = 0.3896, P < 0.0001), and ALT levels (r = 0.1604, P = 0.0105) while an opposite trend by RD kit (r = - 0.0644, P = 0.3109; r = 0.2554, P < 0.0001; r = 0.4417, P < 0.0001, respectively for the 3 markers). In the multivariate linear regression analysis, HBsAg and ALT levels was the major factor associated with sPD-1 levels by MB and RD, respectively.
The characteristics and correlations with host/viral markers of sPD-1 by the two kits are different and leading to different associations on clinical outcomes of CHB.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diversity in the human leukocyte antigen (HLA) genes might be associated with disease outcomes - the heterozygote advantage hypothesis. We tested this hypothesis in relation to hepatitis B virus ...(HBV)-associated hepatocellular carcinoma (HCC).
We utilized DNA from >10,000 Taiwanese individuals with current or past HBV infection to examine the association between HLA diversity and critical natural history steps in the progression from HBV infection to HCC. Individuals were classified as homozygotes at a given locus when imputed to carry the same 4-digit allele for the two HLA alleles at that locus.
Increase in number of homozygous HLA class II loci was associated with an increased risk of chronic HBV infection (Ptrend=1.18×10 -7). Among chronic HBV carriers, increase in number of homozygous HLA class II loci was also associated with an increased risk of HBV-associated HCC (Ptrend=0.031). For individual HLA loci, HLA-DQB1 homozygosity was significantly associated with HCC risk (adjusted hazard ratio=1.40, 95% confidence interval=1.06-1.84). We also found that zygosity affects risk of HCC through its ability to affect viral control.
Homozygosity at HLA class II loci, particularly HLA-DQB1, is associated with a higher risk of HBV-associated HCC.
Chronic hepatitis B (CHB) infection is rarely eradicated by current antiviral nucleos(t)ide analogues. We found that alpha2,6-biantennary sialoglycans of HBV surface antigen (HBsAg) bound human ...SIGLEC-3 (CD33) by IP and ELISA, and the binding affinity between SIGLEC-3 and alpha2,6-biantennary sialoglycans was determined by biolayer interferometry (equilibrium dissociation constant KD: 1.95 * 10.sup.-10 + or - 0.21 * 10.sup.-10 M). Moreover, HBV activated SIGLEC-3 on myeloid cells and induced immunosuppression by stimulating immunoreceptor tyrosine-based inhibitory motif phosphorylation and SHP-1/-2 recruitment via alpha2,6-biantennary sialoglycans on HBsAg. An antagonistic anti-SIGLEC-3 mAb reversed this effect and enhanced cytokine production in response to TLR-7 agonist GS-9620 in PBMCs from CHB patients. Moreover, anti-SIGLEC-3 mAb alone was able to upregulate the expression of molecules involved in antigen presentation, such as CD80, CD86, CD40, MHC-I, MHC-II, and PD-L1 in CD14.sup.+ cells. Furthermore, SIGLEC-3 SNP rs12459419 C, which expressed a higher amount of SIGLEC-3, was associated with increased risk of hepatocellular carcinoma (HCC) in CHB patients (HR: 1.256, 95% CI: 1.027-1.535, P = 0.0266). Thus, blockade of SIGLEC-3 is a promising strategy to reactivate host immunity to HBV and lower the incidence of HCC in the CHB patient population.
Background and aims
In chronic hepatitis B virus (HBV) infection, earlier seroclearance of hepatitis B e antigen (HBeAg) is associated with more favorable outcomes. Soluble programmed cell death 1 ...(sPD-1) has been implicated in higher viral load and hepatocellular carcinoma. We investigated the association between sPD-1 levels and spontaneous HBeAg seroclearance.
Methods
Baseline serum samples from 488 HBeAg-seropositive patients in the REVEAL-HBV cohort were tested for sPD-1 levels. Among them, 329 with available follow-up serum samples were further assayed. Multivariate Cox regression analysis was used to estimate the adjusted rate ratio (aRR) and 95% confidence interval (CI) with adjustment of host and viral factors. The 66th percentile and an annual reduction of ≥ 10% were used as the cut-off point for baseline sPD-1 levels (high/low) and sPD-1 trajectory (decline/no decline), respectively.
Results
Lower baseline sPD-1 levels aRR (95% CI): 2.19 (1.47–3.27) and long-term decline in sPD-1 levels aRR (95% CI): 4.08 (2.79–5.97) were both independent predictors for HBeAg seroclearance. However, further stratification analysis by HBV genotype showed that lower baseline sPD-1 levels were significantly associated with HBeAg seroclearance only in genotype C infection aRR (95% CI): 4.47 (2.38–8.37) but not in genotype B infection. On the other hand, long-term decline in sPD-1 levels was predictive for HBeAg seroclearance regardless of HBV genotype with aRR (95% CI) of 4.62 (2.71–7.88) and 2.95 (1.68–5.17), respectively, for genotypes B and C.
Conclusion
Serum sPD-1 levels may serve as a novel immunological predictor for spontaneous HBeAg seroclearance in patients with chronic hepatitis B.
ObjectivesThis study aimed to develop a predictive model using polygenic risk score (PRS) to forecast renal outcomes for adult systemic lupus erythematosus (SLE) in a Taiwanese ...population.MethodsPatients with SLE (n=2782) and matched non-SLE controls (n=11 128) were genotyped using Genome-Wide TWB 2.0 single-nucleotide polymorphism (SNP) array. PRS models (C+T, LDpred2, Lassosum, PRSice-2, PRS-continuous shrinkage (CS)) were constructed for predicting SLE susceptibility. Logistic regression was assessed for C+T-based PRS association with renal involvement in patients with SLE.ResultsIn the training set, C+T-based SLE-PRS, only incorporating 27 SNPs, outperformed other models with area under the curve (AUC) values of 0.629, surpassing Lassosum (AUC=0.621), PRSice-2 (AUC=0.615), LDpred2 (AUC=0.609) and PRS-CS (AUC=0.602). Additionally, C+T-based SLE-PRS demonstrated consistent predictive capacity in the testing set (AUC=0.620). Individuals in the highest quartile exhibited earlier SLE onset (39.06 vs 44.22 years, p<0.01), higher Systemic Lupus Erythematosus Disease Activity Index scores (3.00 vs 2.37, p=0.04), elevated risks of renal involvement within the first year of SLE diagnosis, including WHO class III–IV lupus nephritis (OR 2.36, 95% CI 1.47 to 3.80, p<0.01), estimated glomerular filtration rate <60 mL/min/1.73m2 (OR 1.49, 95% CI 1.18 to 1.89, p<0.01) and urine protein-to-creatinine ratio >150 mg/day (OR 2.07, 95% CI 1.49 to 2.89, p<0.01), along with increased seropositivity risks, compared with those in the lowest quartile. Furthermore, among patients with SLE with onset before 50 years, the highest PRS quartile was significantly associated with more serious renal diseases within the first year of SLE diagnosis.ConclusionsPRS of SLE is associated with earlier onset, renal involvement within the first year of SLE diagnosis and seropositivity in Taiwanese patients. Integrating PRS with clinical decision-making may enhance lupus nephritis screening and early treatment to improve renal outcomes in patients with SLE.
Display omitted
Hepatitis B core-related antigen (HBcrAg) is a surrogate seromarker of intrahepatic hepatitis B virus covalently closed circular DNA quantity and activity and a predictor of ...hepatocellular carcinoma (HCC) in chronic hepatitis B patients. We assess association between HBcrAg and HCC in individuals seronegative for hepatitis B surface antigen and anti-hepatitis C virus (NBNC) in Taiwan.
A total of 129 newly developed HCC cases and 520 frequency-matched non-HCC controls were drawn from the REVEAL-NBNC cohort. Serum HBcrAg and other risk factors measured at recruitment were compared between cases and controls. Regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).
The proportion of baseline HBcrAg positivity (≥1000 U/mL) was significantly higher in HCC cases than in controls (12.4% vs 1.4%, P < .001). In multivariate analysis, HBcrAg positivity was associated with significantly higher risk of HCC (adjusted OR 95% CI: 9.3 3.3–26.4; P < .001. The HCC population attributable to HBcrAg positivity was 11.1% (95% CI: 9.7%–12.5%).
Seropositivity of HBcrAg might identify a subset of the NBNC population at higher risk of HCC in hepatitis B virus endemic areas.
PDF
