In Silico Screening of Aptamers Configuration against Hepatitis B Surface Antigen

A new role for an old marker, HBsAg

Hepatitis B Surface Antigen Loss: Too Little, Too Late and the Challenge for the Future

Identifying Hepatitis B Carriers at Low Risk for Hepatocellular Carcinoma

In recent years, short peptide self-assembled materials, prepared under the control of the thermolysin catalyst, have been investigated extensively and shown to acquire various morphologies and fun...

CLINICAL CURE OF A CHRONIC HEPATITIS B PATIENT WITH NORMAL SERUM ALANINE AMINOTRANSFERASE TREATED WITH PEGYLATED INTERFERON ALFA-2A: A CASE REPORT.

Data on kidney transplantation (KTx) from hepatitis B surface antigen (HBsAg)-positive (HBsAg+) donors to HBsAg-negative (HBsAg-) recipients [D(HBsAg+)/R(HBsAg-)] are limited. We aimed to report the outcomes of D(HBsAg+)/R(HBsAg-) KTx in recipients with or without hepatitis B surface antibody (HBsAb). Eighty-three D(HBsAg+)/R(HBsAg-) living KTx cases were retrospectively identified. The 384 cases of KTx from hepatitis B core antibody-positive (HBcAb+) living donors to HBcAb-negative (HBcAb-) recipients [D(HBcAb+)/R(HBcAb-)] were used as the control group. The primary endpoint was posttransplant HBsAg status change from negative to postive (-- →+). Before KTx, 24 donors (28.9%) in the D(HBsAg+)/R(HBsAg-) group were hepatitis B virus (HBV) DNA positive, and 20 recipients were HBsAb-. All 83 D(HBsAg+)/R(HBsAg-) recipients received HBV prophylaxis, while no D(HBcAb+)/R(HBcAb-) recipients received prophylaxis. After a median follow-up of 36 months (range, 6-106) and 36 months (range, 4-107) for the D(HBsAg+)/R(HBsAg-) and D(HBcAb+)/R(HBcAb-) groups, respectively, 2 of 83 (2.41%) D(HBsAg+)/R(HBsAg-) recipients and 1 of 384 (0.26%) D(HBcAb+)/R(HBcAb-) became HBsAg+, accompanied by HBV DNA-positive (P = .083). The 3 recipients with HBsAg-→+ were exclusively HBsAb-/HBcAb- before KTx. Recipient deaths were more frequent in the D(HBsAg+)/R(HBsAg-) group (6.02% vs 1.04%, P = .011), while liver and graft function, rejection, infection, and graft loss were not significantly different. In univariate analyses, pretransplant HBsAb-/HBcAb- combination in the D(HBsAg+)/R(HBsAg-) recipients carried a significantly higher risk of HBsAg-→+, HBV DNA-→+, and death. Living D(HBsAg+)/R(HBsAg-) KTx in HBsAb+ recipients provides excellent graft and patient survivals without HBV transmission. HBV transmission risks should be more balanced with respect to benefits of D(HBsAg+)/R(HBsAg-) KTx in HBsAb-/HBcAb- candidates.

Background and Aims Data on kidney transplantation (KTx) from hepatitis B surface antigen (HBsAg)+ donors to HBsAg- recipients [D(HBsAg+)/R(HBsAg-)] are limited. We aimed to report the outcomes of D(HBsAg+)/R(HBsAg-) KTx in recipients with or without hepatitis B surface antibody (HBsAb). Method Eighty-three D(HBsAg+)/R(HBsAg-) living KTx cases were retrospectively identified. The 384 cases of KTx from hepatitis B core antibody (HBcAb)+ living donors to HBcAb- recipients [D(HBcAb+)/R(HBcAb-)] were used as the control group. Primary endpoint was post-transplant HBsAg -→+. Results Before KTx, 24 donors (28.9%) in the D(HBsAg+)/R(HBsAg-) group were hepatitis B virus (HBV) DNA+, and 20 recipients were HBsAb-. All eighty-three D(HBsAg+)/R(HBsAg-) recipients received HBV prophylaxis, while no D(HBcAb+)/R(HBcAb-) recipients received prophylaxis. After a median follow-up of 36 months (range 6-106) and 36 months (range 4-107) for the D(HBsAg+)/R(HBsAg-) and D(HBcAb+)/R(HBcAb-) groups, respectively, 2/83 (2.41%) D(HBsAg+)/R(HBsAg-) recipients and 1/384 (0.26%) D(HBcAb+)/R(HBcAb-) became HBsAg+, accompanied with HBV DNA+ (P=0.083). The three recipients with HBsAg-→+ were exclusively HBsAb-/HBcAb- before KTx. Recipient deaths were more frequent in the D(HBsAg+)/R(HBsAg-) group (6.02% vs. 1.04%, P=0.011), while liver and graft function, rejection, infection, and graft loss were not significantly different. In univariate analyses, pre-transplant HBsAb-/HBcAb- combination in the D(HBsAg+)/R(HBsAg-) recipients carried a significantly higher risk of HBsAg-→+, HBV DNA-→+, and death. Conclusion Living D(HBsAg+)/R(HBsAg-) KTx in HBsAb+ recipients provides excellent graft and patient survivals without HBV transmission. HBV transmission risks should be more balanced with respect to benefits of D(HBsAg+)/R(HBsAg-) KTx in HBsAb-/HBcAb- candidates.

Pharmacophore-based virtual screening for identifying β5 subunit inhibitor of 20S proteasome

Objective To investigate the predictive value of on-treatment hepatitis B surface antigens (HBsAg) levels for HBsAg loss/seroconversion in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients treated with pegylated interferon (peg-IFN)-α-2a. Methods HBeAg-negative CHB naive patients were collected from 2008 May to 2011 August in Beijing Ditan Hospital affiliated to Capital Medical University. Eligible patients had been HBsAg-positive, HBeAg-negative and with detectable hepatitis B virus (HBV) DNA for>6 months, had elevated alanine aminotransferase for>3 months, had no other liver diseases, and had been treated with peg-IFN-α-2a>3 months or had finished the treatment. All the enrolled patients were administered with peg-IFN-α-2a 180 μg/week. Serum HBV DNA, HBsAg, and anti-HBs levels were measured at baseline and every 3 months during peg-IFN-α-2a treatment. The primary efficacy of response to the treatment was HBsAg loss. Comparison between groups was conducted by chi-square test. The absolute levels of HBsAg and the decline rate of HBsAg at week 12 and week 24 were assessed using receiver operating characteristic (ROC) curve for predicting HBsAg loss at week 96 and week 120. Results A total of 81 patients were included into the data analysis. According to on-treatment HBsAg decline, patients were divided into completed response group (12 cases, 14.8%), partial response group (20 cases, 24.7%), and poor response group (49 cases, 60.5%). On week 12 of treatment, mean HBsAg decline levels in completed response and partial response groups were 0.62(0.06, 0.91) lg IU/mL and 0.19(–0.01, 0.48) lg IU/mL, respectively, which was not statistical different (Z=1.581, P=0.209). Adjusting for differences of baseline factors (calculation of the mean decline of HBsAg), completed response group and partial response group had much more pronounced decline than poor response group 0.00(–0.01, 0.14) lg IU/mL, χ2=9.00, P<0.01]. On week 24, difference of HBsAg decline among the 3 groups was statistically significant (χ2=27.72, P<0.01). The predictive ability of HBsAg cut-off level at week 24 was better than week 12 for HBsAg loss at either 96 or 120 weeks, and the differences of the area under the ROC curve were both significantly different (χ2=3.880, P=0.049 and χ2=4.412, P=0.036, respectively). Conclusion Dynamics of HBsAg level in early treatment of peg-IFN-α-2a can predict the therapeutic effect of patients with HBeAg-negative CHB. Key words: Hepatitis B, chronic; Hepatitis B surface antigens; Peg interferon α-2a; HBsAg seroconversion

Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B: Perspectives and challenges

BackgroundFor chronic hepatitis B (CHB) patients without willingness to extend the routine duration of interferon (IFN) therapy, it is important to identify patients who will benefit from treatment cessation. Hepatitis B surface antigen (HBsAg) quantification is recommended for management of IFN therapy. At present, the understanding on end-of-treatment (EOT) HBsAg level predicting post-treatment response to IFN is still finite.MethodsA total of 2451 non-cirrhosis, HBsAg-postive patients treated with IFN-based therapy during the period from December 2010 to December 2017 at Nanfang Hospital were enrolled in this study. Serum HBsAg levels at EOT were measured to evaluate the associations between EOT HBsAg levels (Group 1, HBsAg > 0.05 and ≤ 10 IU/mL; Group 2, HBsAg > 10 and ≤ 200 IU/mL; Group 3, HBsAg > 200 IU/mL) with post-treatment HBsAg loss. Chi-squared, t-test,,Kaplan-Meier analysis, Cox regression analysis, and Multivariate Logistic regression analysis were used to analyse and evaluate differences between the there groups.ResultsThe cumulative HBsAg loss rates 5 years after treatment in Group 1–3 were 30.4% (17/56), 9.8%(4/41) and 0%(0/153) (p < 0.001). An EOT HBsAg level of > 10 IU/mL showed relatively high negative predictive value (NPV) of up to 97.9% for HBsAg loss. Low baseline HBsAg level < 25,000 IU/mL, on-treatment HBsAg decline > 1 log10IU/mL at week 24 and EOT HBsAg level ≤ 10 IU/mL were found significantly associated with HBsAg loss. A total of 6 patients have achieved HBsAg loss at EOT and 17 patients with EOT HBsAg level ≤ 10 IU/mL have achieved post-treatment HBsAg loss. Baseline characteristics, dynamic changes of on-treatment HBsAg and duration of IFN therapy were balanced across patients with EOT or post-treatment HBsAg loss.ConclusionEOT HBsAg level can serve as a monitoring indicator for IFN therapy. EOT HBsAg level ≤ 10 IU/mL was found to lead to high rate of post-treatment HBsAg loss. For patients without willingness to extend IFN treatment, off-treatment follow-up could be considered when HBsAg level decreased to ≤10 IU/mL.

BackgroundThe efficacy of entecavir (ETV) add-on peg-interferon therapy compared with ETV monotherapy in treatment-naïve hepatitis B virus (HBV) patients remains controversial. We investigated whether adding peg-interferon to ongoing ETV treatment leads to a better curative effect or not.MethodsAll patients have been recruited between August 2013 and January 2015 from the Shanghai Public Health Clinical Center and Zhongshan Hospital (China). Eligible HBV patients (n = 144) were randomly divided (1:1) to receive either ETV monotherapy (n = 70) or peg-interferon add-on therapy from week 26 to 52 (n = 74). Patients were followed-up for at least 2 years. Indexes including hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) seroconversion rate, sustained virologic response, transient elastography value, and histological scores were evaluated every 3 months until the end of the study. The rate of patients with HBsAg loss was defined as the primary endpoint criteria.ResultsAt week 26, no patient achieved HBsAg seroconversion in either group. At week 52, one patient in the monotherapy group was HBsAg-negative but there was none in the combination therapy group. The monotherapy group showed significantly better liver function recovery results than the combination therapy group. At week 78, one patient in the combination group had HBsAg seroconverted. At week 104, only three patients in the combination therapy group were HBsAg-negative compared with one patient in monotherapy. The mean alanine aminotransferase and aspartate aminotransferase levels and transient elastography values decreased significantly compared with baseline. Both groups showed a favorable decrease in alpha-fetoprotein (monotherapy: 4.5 [2.8, 7.1] vs. 2.2 [1.8, 3.1] ng/mL, P < 0.001; combination therapy: 5.7 [3.0, 18.8] vs. 3.2 [2.0, 4.3] ng/mL, P < 0.001) and an improved result of liver biopsy examination scores. The combination group showed a better improvement in histology compared with the monotherapy group (mean transient elastography value 6.6 [4.9, 9.8] vs. 7.8 [5.4, 11.1] kPa, P = 0.028). But there was no significant difference in HBsAg conversion rate (1.8% [1/56] vs. 4.1% [3/73], P = 0.809) and HBeAg conversion rate (12.5% [7/56] vs. 11.0% [8/73], P = 0.787), as well as HBV-DNA, sustained virologic response (93.2% vs. 98.5%, P = 0.150) between the two groups.ConclusionsBoth therapies supported liver function recovery and histology improvement. Combination therapy did not show better anti-viral efficacy in HBsAg or HBeAg seroconversion compared with monotherapy. However, combination therapy played a more positive role in reversing hepatic fibrosis compared with monotherapy.Trial registrationClinicalTrials.gov: NCT02849132; https://clinicaltrials.gov/ct2/show/NCT02849132

This study aimed to identify natural bioactive compounds (NBCs) as potential inhibitors of the spike (S1) receptor binding domain (RBD) of the COVID-19 Omicron variant using computer simulations (in silico). NBCs with previously proven biological in vitro activity were obtained from the ZINC database and analyzed through virtual screening, molecular docking, molecular dynamics (MD), molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA), and molecular mechanics/generalized Born surface area (MM/GBSA). Remdesivir was used as a reference drug in docking and MD calculations. A total of 170,906 compounds were analyzed. Molecular docking screening revealed the top four NBCs with a high affinity with the spike (affinity energy <-7 kcal/mol) to be ZINC000045789238, ZINC000004098448, ZINC000008662732, and ZINC000003995616. In the MD analysis, the four ligands formed a complex with the highest dynamic equilibrium S1 (mean RMSD <0.3 nm), lowest fluctuation of the complex amino acid residues (RMSF <1.3), and solvent accessibility stability. However, the ZINC000045789238-spike complex (naringenin-4'-O glucuronide) was the only one that simultaneously had minus signal (-) MM/PBSA and MM/GBSA binding free energy values (-3.74 kcal/mol and −15.65 kcal/mol, respectively), indicating favorable binding. This ligand (naringenin-4'-O glucuronide) was also the one that produced the highest number of hydrogen bonds in the entire dynamic period (average = 4601 bonds per nanosecond). Six mutant amino acid residues formed these hydrogen bonds from the RBD region of S1 in the Omicron variant: Asn417, Ser494, Ser496, Arg403, Arg408, and His505. Naringenin-4'-O-glucuronide showed promising results as a potential drug candidate against COVID-19. In vitro and preclinical studies are needed to confirm these findings. Communicated by Ramaswamy H. Sarma

Objective To reveal the characteristics of S gene sequence of hepatitis B surface antigen (HBsAg) in hepatitis B virus (HBV)-infected patients with low HBsAg level. Methods From February 2016 to December 2017, 1 308 serum samples of inactive HBsAg carriers were collected from the 903rd Hospital of PLA and Hangzhou Jianggan District People′s Hospital.The cases were divided into high-level group and low-level group according to the level of serum HBsAg (10 IU/mL) expression. The HBV S gene was sequenced in patients with low-level HBsAg expression. In addition, in patients with high-level HBsAg, 100 patients were randomly selected (stratified sampling) for HBV S gene sequencing based on the matching of age and serological pattern (hepatitis B e antigen [HBeAg] negative) of low-level HBsAg group. A comparative analysis was conducted between HBV S gene sequences from inactive HBsAg carrier in low HBsAg expression group and the HBV reference S gene sequences from inactive HBsAg carrier in high HBsAg expression group.The results of normal distribution data were expressed as Mean±SD, and analyzed using t-test. The results of non-normal distribution data were expressed by M(QR), and analyzed using Mann-Whitney U test.Chi-square test or Fisher exact test was used to compare continuous variables and classification variables between the two groups. Results There were 276 serum samples from the low level group and 1 032 serum samples from the high level group, including 257 HBsAg/HBeAg/anti-HBc-positive cases, 753 HBsAg/anti-HBe/anti-HBc-positive cases, and 22 HBsAg/anti-HBc-positive cases. Successful HBV S gene sequencing was performed on 126 out of 276 patients in the low-level HBsAg group. According to the age inthe low-level HBsAg group, 100 samples with negative HBeAg in the high-level HBsAg group were randomly selected, among which 94 patients were genotyped and hemotyped. The results showed that there were statistically significant differences in HBV serological markers, HBV DNA level and HBV genotype distribution between the high level group (94 cases) and the low level group (126 cases) (all P 0.05). For genotype B, 12 single point mutations and 4 dual co-mutations were found in low level group. Among them, one single point mutation (S210R) and 3 dual co-mutations (G44E/V+ T45P/I, G44E/V+ L49P/R and N40S+ I208T) were not hot spot mutations, while 2 dual co-mutations and 2 single point mutations were found in high level group. The difference between two groups was statistical significant (χ2=7.533, P=0.006). For genotype C, 5 single point mutations (T5A, A45T, T47A/K, Q101R and I126S/T) were found in low level group and 1 single point mutation (N3S) in high level group. The difference in mutation frequency between two groups were statistical significant (χ2=47.914, P=0.000). Conclusions Significant mutations in multiple regions and at multiple sites (including co-mutations) on both sides of the MHR may be one of the causes of low HBsAg expression level in this population. Key words: Hepatitis B surface antigens; Genotype; HBV markers; HBV DNA; S gene; Mutation site

BackgroundIn order to reduce the burden on organ shortage around the world, using potential infectious donor might be an option. However, scarce evidences have been published on kidney transplantation (KTx) from hepatitis B surface antigen (HBsAg) + donors to HBsAg- recipients [D (HBsAg+)/R(HBsAg-)] without hepatitis B virus (HBV) immunity. Here, we reported the results of D(HBsAg+/HBV DNA- or +)/R(HBsAg-) living KTx recipients with or without HBV immunity.MethodsWe retrospectively identified 83 D(HBsAg+)/R(HBsAg-) living KTx recipients, and 83 hepatitis B core antibody (HBcAb) + living donors to HBcAb- recipients [D(HBcAb+)/R(HBcAb-)] were used as control group by reviewing medical archives and propensity score matching. Treatment failure (defined as any HBV serology conversion, liver injury, graft loss, or recipient death) is the primary endpoint.ResultsTwenty-four donors (28.9%) were HBV DNA+, and 20 recipients had no HBV immunity in the D(HBsAg+)/R(HBsAg-) group pre-transplantation. HBV prophylaxis was applied in all D(HBsAg+)/R(HBsAg-) recipients, while none was applied in the D(HBcAb+)/R(HBcAb-) group. We observed a significant higher treatment failure in D(HBsAg+)/R(HBsAg-) than D(HBcAb+)/R(HBcAb-) group (21.7% vs. 10.8%, P < 0.001). Interestingly, no significant difference was found between groups on HBV seroconversion, liver and graft function, rejection, infection, graft loss, or death. However, 2/20 recipients without HBV immunity in the D(HBsAg+)/R(HBsAg-) group developed HBV DNA+ or HBsAg+, while none observed in the D(HBcAb+)/R(HBcAb-) group. HBV DNA+ donor and male recipient were significant risk factors for treatment failure.ConclusionD(HBsAg+)/R(HBsAg-) should be considered for living kidney transplantation, but with extra caution on donors with HBV DNA+ and male candidates.