Nucleos Ide Analogue Treatment Research Articles

Relationship between Phenotypic Changes of Dendritic Cell Subsets and the Onset of Plateau Phase during Intermittent Interferon Therapy in Patients with CHB*

ObjectiveThis study aimed to evaluate whether the onset of the plateau phase of slow hepatitis B surface antigen decline in patients with chronic hepatitis B treated with intermittent interferon therapy is related to the frequency of dendritic cell subsets and expression of the costimulatory molecules CD40, CD80, CD83, and CD86. MethodThis was a cross-sectional study in which patients were divided into a natural history group (namely NH group), a long-term oral nucleoside analogs treatment group (namely NA group), and a plateau-arriving group (namely P group). The percentage of plasmacytoid dendritic cell and myeloid dendritic cell subsets in peripheral blood lymphocytes and monocytes and the mean fluorescence intensity of their surface costimulatory molecules were detected using a flow cytometer. ResultsIn total, 143 patients were enrolled (NH group, n = 49; NA group, n = 47; P group, n = 47). The results demonstrated that CD141/CD1c double negative myeloid dendritic cell (DNmDC)/lymphocytes and monocytes (%) in P group (0.041 [0.024, 0.069]) was significantly lower than that in NH group (0.270 [0.135, 0.407]) and NA group (0.273 [0.150, 0.443]), and CD86 mean fluorescence intensity of DNmDCs in P group (1832.0 [1484.0, 2793.0]) was significantly lower than that in NH group (4316.0 [2958.0, 5169.0]) and NA group (3299.0 [2534.0, 4371.0]), Adjusted P all < 0.001. ConclusionReduced DNmDCs and impaired maturation may be associated with the onset of the plateau phase during intermittent interferon therapy in patients with chronic hepatitis B.

Don't rash it! The clinical significance of positive Varicella zoster virus PCR in cerebrospinal fluid of patients with neurological symptoms

BackgroundVaricella zoster virus (VZV) is among the leading pathogens causing meningitis and encephalitis. While VZV-PCR-positive CSF is considered a gold-standard for diagnosis, it is not-uncommon to detect VZV-DNA in CSF of patients with other acute or chronic illness. Our goal was to determine the clinical relevance of VZV-PCR-positive CSF when investigating patients with neurological symptoms. MethodsIn this retrospective cohort from the largest hospital in Israel, we collected demographic, clinical and laboratory data of patients with VZV-PCR-positive CSF, analyzing the significance of various parameters. ResultsDuring a 5-years study, 125 patient-unique VZV-PCR-positive CSFs were recorded, in which only 9 alternative diagnoses were noted. The commonest symptoms were headache (N = 104, 83 %) and rash (N = 96, 76 %). PCR-cycle-threshold (Ct), a surrogate of viral burden, did not significantly vary across the clinical manifestations; however, patients with rash and Ct<35 were prone to develop stroke in the following year (N = 6, 7 %). Empiric nucleoside-analogue treatment was not associated with a better outcome compared to treatment administered upon a positive-PCR result. DiscussionOur findings suggest that in patients with neurological symptoms, detection of VZV-DNA in CSF renders VZV the probable culprit. Nevertheless, a systematic evaluation of treatment and follow-up algorithms of patients with suspected or proved VZV meningitis and encephalitis is needed. The benefits of a prompt treatment should be weighed against the potential complications of nucleoside-analogue. Conversely, the propensity for stroke in patients with higher viral-burden, necessitates further studies assessing VZV causal role, directing additional workup, treatment and monitoring policy.

Dynamic evaluation of liver fibrosis to assess hepatocellular carcinoma risk in patients with chronic hepatitis B receiving nucleoside analogs treatment.

Despite good hepatitis B virus (HBV) inhibition by nucleoside analogs (NAs), cases of hepatocellular carcinoma (HCC) still occur. This study proposed a non-invasive predictive model to assess HCC risk in patients with chronic hepatitis B (CHB) receiving NAs treatment. Data were obtained from a hospital-based retrospective cohort registered on the Platform of Medical Data Science Academy of Chongqing Medical University, from 2013 to 2019. A total of 501 patients under NAs treatment had their FIB-4 index updated semiannually by recalculation based on laboratory values. Patients were divided into three groups based on FIB-4 index values: < 1.45, 1.45-3.25, and ≥ 3.25. Subsequently, HCC incidence was reassessed every six months using Kaplan-Meier curves based on the updated FIB-4 index. The median follow-up time of CHB patients after receiving NAs treatment was 2.5 years. HCC incidences with FIB-4 index < 1.45, 1.45-3.25, and ≥ 3.25 were 1.18%, 1.32%, and 9.09%, respectively. Dynamic assessment showed that the percentage of patients with FIB-4 index < 1.45 significantly increased semiannually (P < 0.001), and of patients with FIB-4 index ≥ 3.25 significantly decreased (P < 0.001). HCC incidence was the highest among patients with FIB-4 index ≥ 3.25. The FIB-4 index effectively predicted HCC incidence, and its dynamic assessment could be used for regular surveillance to implement early intervention and reduce HCC risk.

FIB‑4 index and serum α‑fetoprotein are useful predictors of hepatocellular carcinoma occurrence in hepatitis B patients with nucleos(t)ide analogs therapy.

Current antiviral therapies cannot achieve eradication of hepatitis B virus (HBV) and can reduce but not eliminate the risk of hepatocellular carcinoma (HCC) in patients with chronic HBV infection. The present study aimed to identify the risk factors for HCC development by analyzing nucleoside analogue (NA)-treated patients as a retrospective cohort using fibrosis-4 index (FIB-4 index) as a non-invasive fibrosis marker. A total of 260 patients with HBV receiving NAs without a history of HCC between January 2001 and January 2021 were included in the present study. The incidence of HCC in patients with HBV during NA therapy and the factors contributing to HCC occurrence were identified using clinical characteristics and blood test results. Among the 260 patients, 40 patients (15.4%) developed HCC. Univariate and multivariate analysis showed that age [hazard ratio (HR), 1.03; P=0.045], male sex (HR, 3.14; P<0.01) and FIB-4 index at 6 months after NA treatment <1.95 (HR, 4.35; P<0.01) correlated with the incidence of HCC. The cumulative incidence of HCC in patients with FIB-4 index at 6 months after NA treatment >1.95 was significantly higher compared with that in patients with FIB-4 index ≤1.95 (P<0.01). Multivariate analysis in patients in which serum α-fetoprotein (AFP) level at 6 months after NA treatment was measured showed that FIB-4 index >1.95 (HR, 8.27; P=0.014) and serum AFP level >4 ng/ml (HR, 4.26; P=0.033) contributed to HCC occurrence. FIB-4 index at 6 months after NA treatment and serum AFP levels at 6 months after NA treatment were predictors for the development of HCC in patients with HBV during NA treatment. Further study of hepatocarcinogenesis during NA with a longer follow-up period and larger numbers of participants is required.

Discontinuing Hepatitis Activity Reduced Hepatocellular Carcinoma Recurrence after Primary Curative Therapy

Hepatocellular carcinoma (HCC) tends to recur after curative treatment. This study aimed to identify the clinical factors associated with HCC recurrence after initial curative therapy. We retrospectively included patients with early stage HCC Barcelona Clinic Liver Cancer (BCLC) stages 0 and A who received curative surgical resection or local ablation at three different Chang Gung Memorial Hospitals in Taiwan (527 patients from Linkou, 150 patients from Keelung, and 127 patients from Chiayi) from 2000 to 2009. Pretreatment clinical data were subjected to univariate and multivariate logistic analyses to identify the risk factors for HCC recurrence within five years after the primary curative treatment. Recurrence and survival rates were assessed using Kaplan-Meier curves and log-rank tests. Patients with a history of nucleoside analog or peg-interferon treatment for hepatitis B or hepatitis C infection had lower HCC recurrence rates than did those without such treatment. By contrast, alcohol drinking habits (p = 0.0049, hazard ratio (HR): 1.508, 95%CI: 1.133-2.009), a platelet count of < 14 × 104/μL (p = 0.003, HR: 1.533, 95%CI: 1.155-2.035), and a serum alanine aminotransferase level > 40 U/L (p = 0.0450, HR: 1.305, 95%CI: 1.006-1.694) were independent risk factors for HCC recurrence. The five-year HCC recurrence rates did not differ between patients who received either local radiofrequency ablation or surgical resection at BCLC stages 0 and A. Factors contributing to persistent hepatitis activity and advanced fibrosis precipitate tumor recurrence. Active intervention to discontinue liver injury or hepatitis could reduce HCC recurrence.

Prognostic value of plasma level of superoxide dismutase in HBV-related acute-on-chronic liver failure

BackgroundHepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is the most prevalent type of ACLF in China. The mortality rate of HBV-ACLF has decreased in recent years due to advances in treatment therapies; however, it is still above 50%. Many cases of HBV-ACLF are caused by HBV reactivation due to discontinuation of nucleoside analog treatment. The present study focused on plasma levels of superoxide dismutase (SOD) in HBV-ACLF patients and investigated whether the plasma level of SOD is a useful biomarker in assessing disease severity and predicting outcomes of HBV-ACLF patients, including patients treated with Entecavir (ETV) and patients who were withdrawn from ETV treatment.MethodsPlasma samples and clinical data from 200 HBV-ACLF patients and from age- and sex-matched cirrhotic and healthy controls were collected and analyzed. Plasma levels of SOD were measured using an ELISA commercial kit.ResultsAmong the HBV-ACLF patients, in the ETV withdrawal group, the mortality rate was higher than in the ETV group (69.95% vs 46.71%, P < 0.05). Moreover, HBV-DNA and SOD plasma levels were higher in the ETV withdrawal group than in the ETV group (Log10(HBV-DNA): 6.49 ± 0.24 vs 4.79 ± 0.14, P < 0.01; SOD: 463.1 ± 27.61 U/mL vs 397.2 ± 10.97 U/mL, P < 0.05). The mortality and liver transplantation rates were significantly higher in HBV-ACLF patients with plasma levels of SOD > 428 U/mL than in patients with plasma SOD levels ≤ 428 U/mL.ConclusionsReactivation of HBV and elevated oxidative stress caused by discontinuation of ETV treatment are crucial factors in the pathogenesis of HBV-ACLF. Plasma level of SOD may serve as a useful biomarker in estimating disease severity and predicting outcomes of HBV-ACLF patients who stop ETV treatment.

The relationship between serum exosome HBV-miR-3 and current virological markers and its dynamics in chronic hepatitis B patients on antiviral treatment.

BackgroundHepatitis B virus (HBV) can encode microRNA-HBV-miR-3, which can be detected in both HBV-infected cell lines and peripheral blood exosomes of chronic hepatitis B (CHB) patients. This study was conducted to further evaluate its relationship with the current viral markers and their dynamics during antiviral therapy.MethodsWe used Stem-loop real time quantitative PCR (RT-qPCR) to quantify HBV-miR-3 in the serum exosomes of CHB patients by extracting exosomes using the Supbio exosome separation kit and designing primers and Taqman probes specific for HBV-miR-3. We conducted a cross-sectional study and two cohort studies. In the cross-sectional study, 48 treatment-naive (TN) CHB patients were enrolled. In the nucleoside analogues (NAs) cohort study, 20 hepatitis B e antigen (HBeAg) negative CHB patients with negative HBV DNA on NA therapy were followed up for 96 weeks. In the NAs + pegylated interferon (Peg-IFN) cohort study, 40 patients with hepatitis B surface antigen (HBsAg) <1,500 IU/mL, negative HBV DNA, and HBeAg after NAs treatment were enrolled and were switched to Peg-IFN therapy for 48 weeks. HBV-miR-3 titers and other viral markers were detected at different time points.ResultsHBV-miR-3 only existed in CHB patients with a concentration of 6.41±3.55 log10 copies/mL. HBV-miR-3 was positively correlated with HBV DNA, pregenomic RNA (pgRNA), and HBsAg. In the NAs cohort, HBsAg, pgRNA, and HBV-miR-3 levels showed little fluctuation during the 96 weeks of NA treatment (P>0.05). In the NAs + PEG-IFN cohort, HBsAg, pgRNA, and HBV-miR-3 levels declined significantly during the 48 weeks of sequential therapy (P<0.05).ConclusionsHBV-miR-3 was positively correlated with HBV DNA, pgRNA, and particularly HBsAg in TN CHB patients. Peg-IFN following NA therapy had a positive impact on HBsAg, pgRNA, and HBV-miR-3 decrease.

Effects of Antiviral Nucleoside Analogues on the Maintenance of the Mitochondrial Genome

The outbreak of the COVID‐19 pandemic prompted the search for effective antivirals. Remdesivir (Gilead Sciences) was the first nucleoside analogue approved by the FDA for COVID‐19 treatment, and currently the FDA considers authorization for the use of another analogue, molnupiravir (Merck). Mitochondrial toxicity, resulting from the interference with mitochondrial DNA (mtDNA) replication, is the most common side effect of nucleoside analogues treatment. In addition, defects to the mtDNA synthesis may give rise to heritable mutations, which may be carried undetected for generations before populating mitochondria to the level that onsets a mitochondrial disease. Therefore, nucleoside analogues need to be thoroughly investigated for their impact on the maintenance and integrity of the mitochondrial genome.We recently assessed the effect of remdesivir on the maintenance of the mitochondrial genome. We observed that in in vitro DNA synthesis assays, its triphosphate metabolite may impede the synthetic activity of the mitochondrial replicative polymerase, Pol γ, when in excess over nucleotides. Prompted by this finding, we tested the effect of the nucleoside metabolite of remdesivir on the maintenance and integrity of the mitochondrial genome in proliferating fibroblasts. However, we found no evidence for deleterious effects on the integrity of the mitochondrial genome.We are currently performing an analogical assessment of the effects of molnupiravir on the integrity of the mitochondrial genome. Thus far, we have observed that, unlike remdesivir, molnupiravir is cytotoxic for proliferating fibroblasts and results in a decrease in mtDNA copy number. We are currently testing the impact of molnupiravir on the activity of Pol γ in vitro, and its potential to elicit mutations in the mitochondrial genome in vivo.

Soluble programmed cell death-1 predicts hepatocellular carcinoma development during nucleoside analogue treatment

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

Natural Products: Review for Their Effects of Anti-HBV.

Hepatitis B is a global infectious disease, seriously endangering human health. Currently, there are mainly interferons and nucleoside analogues treatment of hepatitis B in the clinic, which have certain therapeutic effects on hepatitis B, but their side effects and drug resistance are increasingly prominent. Therefore, it is urgently needed to discover and develop new anti-HBV drugs, especially natural products, which have novel, high efficiency, and low toxicity anti-HBV compounds with novel antiviral mechanisms. In this manuscript, the natural products (polysaccharides and 165 compounds) with the activity of antihepatitis B virus are discussed according to their chemical classes, including 14 phenylpropanoids, 8 flavonoids,12 xanthones, 13 anthroquinones, 47 terpenoids, 6 alkaloids, 15 enediynes, 11 aromatics, 18 phenylalanine dipeptides compounds, and 13 others. In addition, the anti-HBV mechanism and targets of natural product were also discussed. The aim of this review is to report new discoveries about anti-HBV natural products and to provide reference for researchers.

Nucleoside (Acid) Analogues Treatment in Patients With Normal ALT and Positive HBVDNA.

Nucleoside (Acid) Analogues Treatment in Patients With Normal ALT and Positive HBVDNA.

Impact of AAV2 and Hepatitis B Virus Integration Into Genome on Development of Hepatocellular Carcinoma in Patients with Prior Hepatitis B Virus Infection.

Hepatitis B viral (HBV) DNA is frequently integrated into the genomes of hepatocellular carcinoma (HCC) in patients with chronic HBV infection (chronic HBV, hereafter), whereas the frequency of HBV integration in patients after the disappearance of HBV (prior HBV, hereafter) has yet to be determined. This study aimed to detect integration of HBV and adeno-associated virus type 2 (AAV2) into the human genome as a possible oncogenic event. Virome capture sequencing was performed, using HCC and liver samples obtained from 243 patients, including 73 with prior HBV without hepatitis C viral (HCV) infection and 81 with chronic HBV. Clonal HBV integration events were identified in 11 (15.0%) cases of prior HBV without HCV and 61 (75.3%) cases of chronic HBV (P < 0.001). Several driver genes were commonly targeted by HBV, leading to transcriptional activation of these genes; TERT [four (5.4%) vs. 15 (18.5%)], KMT2B [two (2.7%) vs. five (6.1%)], CCNE1 [zero vs. one (1.2%)], CCNA2 [zero vs. one (1.2%)]. Conversely, CCNE1 and CCNA2 were, respectively, targeted by AAV2 only in prior HBV. In liver samples, HBV genome recurrently integrated into fibrosis-related genes FN1, HS6ST3, KNG1, and ROCK1 in chronic HBV. There was not history of alcohol abuse and 3 patients with a history of nucleoside analogue treatment for HBV in 8 prior HBV with driver gene integration. Despite the seroclearance of hepatitis B surface antigen, HBV or AAV2 integration in prior HBV was not rare; therefore, such patients are at risk of developing HCC.

Longitudinal effects of Nucleos(t)ide analogue therapy in chronic hepatitis B patients and the utility of non-invasive fibrosis markers during treatment: A single-center experience for up to 17 years

BackgroundFibrosis regression has been associated with nucleoside analogue (NA) treatment in chronic hepatitis B (CHB) patients. Although non-invasive fibrosis markers have been evaluated in CHB, their utility for monitoring on-treatment histologic regression has not been evaluated. AimsTo characterize improvements in disease severity and the utility of non-invasive biomarkers in CHB NA treated patients. MethodsHistology, labs, AST-to-platelet ratio index, and Fibrosis-4 (Fib-4) from treatment-naïve CHB patients were evaluated at baseline and longitudinally. Relative change from baseline to various time points during treatment were evaluated. Correlative analysis of APRI and Fib-4 with histology was performed longitudinally. Results80 CHB patients (84% male, median age 45 (IQR 32, 54)) with histology up to 17 years (median 6(IQR 3.9, 8.0)) years were studied. Median baseline Ishak fibrosis was 3 (IQR 2, 4), histologic activity index (HAI) inflammation was 9 (IQR 7, 11), and AUROC of fibrosis markers for detecting cirrhosis (Ishak ≥ 5) was >0.64. HAI improved at a rate of 54% during year 1 and 37% in year 2, both greater than in the remaining follow-up periods. Within the first year, fibrosis improved by 35%, greater than all other time periods. Non-invasive biomarkers began to correlate with histology beyond 4 years (APRI: 4–6 years: r = 0.33, p = 0.03; ≥6 years: r = 0.41, p = 0.009; Fib-4: ≥6 years: r = 0.35, p = 0.03). ConclusionEarly dynamic changes in histology occur in CHB patients on NA followed by linear improvements. Non-invasive fibrosis biomarkers do not capture these dynamic changes and may demonstrate clinical utility beyond 4 years of treatment.

Determination of reverse transcriptase inhibitor nucleoside analogue resistance profile in pretreatment phase of patients with viral hepatitis B

HBV is a DNA virus and the causative agent of hepatitis B infection. Hepatitis B is a contagious disease and is still a major health problem all over the world. When the infection become chronic, it may cause serious diseases such as fibrosis, cirrhosis and/or hepatocellular carcinoma. Interferon/pegylated interferon by intravenous route and nucleoside/nucleotide (NA) analogues such as lamivudine, adefovir, entecavir, telbivudine and tenofovir given by oral route are used in the treatment. Antivirals given by oral route are mostly preferred in the treatment. However, because of the replication strategy and biological properties of HBV, mutations that cause antiviral resistance against these drugs can occur at different rates, although they can vary from drug to drug over time. It is possible that drug resistant virus may transmit from patient to healthy individuals. Therefore, there is a possibility of infection with drug-resistant HBV before treatment. Antiviral resistance mutations are divided into four categories; i) Nucleos(t)ide analog resistance (NAr)-related mutations, ii) primary drug resistance mutations, iii) secondary/compensatory mutations, iv) putative antiviral resistance mutations and pre-treatment variations. Recent studies have focused particularly on putative mutations and pre-treatment variations. The aim of this study was to better understanding of the antiviral resistance profiles of chronic hepatitis B (CHB) patients treated and untreated with NA, and help to preventunnecessary drug use, minimize the side effects and economic damages. A total of 124 patients who have received nucleoside analog (NA) drug treatments (n= 72) and patients without NA treatment (n= 52) were included in the study. Viral DNA was isolated from the plasma samples of the patients. A DNA fragment, which is 551 bp, was amplified and sequenced including the binding side of all nucleoside analogs containing the B, C and D domains located in the reverse transcriptase region in the HBV genome. Different types of mutations were detected in 13 (18.05%) of 72 treated patients and in 18 (34.61%) of 52 untreated patients (p< 0.05). Primary drug resistance mutations such as rtI169T, rtA181T/V, rtT184A/C/F/G/I/L/M/S, rtA194T, rtS202C/G/I, rtM204I/V/S, rtN236T, rt M250I/L/V and rtV173L were not detected in any of the patient samples. However, potential drug resistance mutations such as rtR164R, rtG165D/A, rtG172Q, rtS176N, rtF178V, rtA181G, rtS185N/G/C, rtV207M, rtQ215H/S, rtL231V, rtI233K, rtN238S, rtV253T, rtC256G/S and rtI266R/V were detected in untreated patient samples in B, C, D and D domains of reverse transcriptase region. Our results have suggested that the detection of pretreatment variations could be helpful for choosing the correct antiviral drug for the better treatment management.

FA-06-Maternal nucleoside analogues treatment and infant immunoprophylaxis to prevent chronic hepatitis B in children: A prospective eight-year real-world study

FA-06-Maternal nucleoside analogues treatment and infant immunoprophylaxis to prevent chronic hepatitis B in children: A prospective eight-year real-world study

Hepatitis B virus surface gene mutants in immunoprophylaxis-failed infants from Southern China.

Hepatitis B virus (HBV) vaccination was considered the most powerful tool for prevention of HBV transmission from mother to infant. In 1992, a universal HBV vaccination program for infants was launched in China. The aim of this study was to investigate the HBV surface antigen (HBsAg) variations in immunoprophylaxis-failed infants, vaccine free infant patients and adult chronic hepatitis B (CHB) patients (without nucleoside analog treatment). Immunoprophylaxis-failed infants were recruited from two centers (Guangdong and Chongqing, representing Southern China). HBV serum markers, including HBsAg, hepatitis e antigen (HBeAg), and core antigen, were detected by the enzyme-linked immunosorbent assay. HBV DNA load was detected by quantitative polymerase chain reaction. Nucleotide sequences encoding HBsAg were amplified and analyzed. Frequencies of amino acid substitutions within the second loop of "a" determinant (region with greater local hydrophilicity) in immunoprophylaxis-failed infants were clearly higher than the unvaccinated infant patients and adult CHB patients (9.6% vs 0% vs 3.8%; χ 2 = 7.454; P = 0.024). More than 50% (52.8%) aa substitutions in immunoprophylaxis-failed infants were located in B cell epitopes, while 64.6% aa substitutions in adult CHB patients were located in CTL cell epitopes. HBeAg negative patients had higher substitution frequency in CTL and Th cell epitopes, and in immunoprophylaxis-failed infant patients with substitution in major hydrophilic region region had a higher alanine aminotransferase level (68.6 ± 111.5 vs 62.1 ± 132.2; P = 0.026), and lower DNA load (7.03 ± 1.72 vs 7.82 ± 1.73; P < 0.001). In conclusion, our results observed vaccine-induced immune selection pressure in vaccine failed infants, substitutions in "a" determinant, especially the G145 substitution was still the most stable and remarkable site of vaccine escape.

Pre-S/Surface and Core Promoter/Precore Mutations in Chronic Hepatitis B Patients with Severe Acute Exacerbation.

The role of pre-S/surface and basal core promoter/precore (BCP/PC) mutations in chronic hepatitis B (CHB) patients with severe acute exacerbation (SAE) remains unclear. To investigate the role of pre-S/surface and BCP/PC mutations in CHB patients with SAE and mortality. A total of 114 CHB patients with spontaneous SAE [alanine aminotransferase (ALT) ≥ 400U/L] and hepatic decompensation were analyzed along with 114 patients with moderate liver inflammation (ALT: 80-400U/L without hepatic decompensation) who were matched with the SAE patients in regard to age, sex, HBeAg, and cirrhosis. Compared with patients with moderate liver inflammation, those with SAE had a higher rate of genotype B. Multivariate analysis showed that the independent factors for SAE were V14G/A and L21S in surface genes, codons 109-119 deletions in pre-S1 genes, M1V/T/I in pre-S2 genes, and C1766T/T1768A and C1913A/G mutations in BCP/PC genes. However, these gene variants or mutations were not significant predictors of mortality in patients with SAE. Of the 114 SAE patients, 17 died at week 24 of nucleoside analog treatment. Cox regression analysis showed that independent predictors for mortality at week 24 of treatment in SAE patients were higherinternational normalized ratio, the presence of ascites, and T1753C/A/G mutations. The SAE patients with T1753C/A/G mutations had a higher rate of acute-on-chronic liver failure (P = 0.006) and higher MELD score (P = 0.018) than those without T1753C/A/G mutations. The variants or mutations in pre-S/surface and BCP/PC regions might play important roles and could predict mortality in SAE patients.

How to estimate renal function in patients with liver disease: choosing the most suitable equation.

Hepatitis B virus (HBV) infection is a public health challenge, especially in China. In clinical practice, HBV infection is associated with nephropathy. Impaired renal function is frequently observed in compensated Chronic Hepatitis B (CHB) and cirrhosis (LC). Thus, renal function must be monitored to avoid nephrotoxic effects before and during nucleoside analog treatment. Investigating the predictive markers of early renal dysfunction is essential. New GFR-predicting equations, based on Pcr and/or CystC, have been recently recommended in the general population, but their performance in liver disease patients has been rarely studied. In this study, we will discuss how to detect renal dysfunction in patients with HBV infection. A total of 16 LC patients and 23 CHB patients were enrolled in this study, and we collected and compared the clinical data of the two groups. The estimated glomerular filtration rates (eGFRs) were also calculated by several equations. All patients received 99mTc-DTPA dynamic radionuclide imaging examinations to obtain mGFRs as the reference standard. To evaluate the performance of any equation in the CHB and LC groups, paired t test, Pearson's correlation, Kappa analysis and Bland-Altman plots were utilized. Moreover, all 39 subjects were divided into two groups (according to GFR > 90mL/min/1.73m2). We compared the serum and urinary markers of kidney injury between the two groups and selected the indicators of renal injury by univariate analysis. The mGFR was 72.26 ± 20.69mL/min/1.73m2 in the LC group, and 87.49 ± 25.91mL/min/1.73m2 in the CHB group. The paired t test results of eGFR and mGFR showed no difference between eGFR (estimated by the CHINAcr-cys equation) and mGFR (p > 0.05) in the compensated LC and CHB groups. The difference between mGFR and eGFR estimated by other methods was obvious (p < 0.05). Comparing the eGFRs (estimated by 5 different equations) with mGFR in the compensated LC and CHB groups, Pearson's correlation showed that only eGFR (estimated by the CHINAcr-cys equation) had a significant correlation coefficient in CHB (r = 0.678, p = 0.000) and had the highest R2 (R2 = 0.459) among all other measures. The kappa consistency test showed that eGFR from CHINAscr-cys had poor consistency with mGFR in the compensated LC group but moderate consistency in the CHB group. Bland-Altman consistency analysis showed that in the CHB group, the CHINAcr-cys and CKD-EPIcr equations presented narrower acceptable limits than did the aMDRD, c-aMDRD, and CKD-EPIcr-cys equations (62.8, 56.1 vs .85.7, 102.9, 93.6mL/min per 1.73m2). In the compensated LC group, the CHINAcr-cys and CKD-EPIcr equations presented narrower acceptable limits than did the aMDRD, c-aMDRD, and CKD-EPIcr-cys equations (83.6, 81.3 vs. 98, 113.5, 106.3mL/min per 1.73m2). Serum or urinary markers were compared with renal function (GFR > 90mL/min/1.73m2) and showed International normalized ratio (INR) (p = 0.009), creatinine (p = 0.006), urine N-acetyl-β-glucosaminidase (NAG) (p = 0.001) and serum cystatin C (CysC) (p = 0.044). The CHINAcr-cys equation may be more suitable for the estimation of GFR in Chinese patients with CHB or compensated cirrhosis. INR, creatinine, NAG, and CysC are proper biomarkers for screening renal dysfunction in Chinese patients with CHB or compensated LC.

ARB-1740, a RNA Interference Therapeutic for Chronic Hepatitis B Infection.

Current approved nucleoside analogue treatments for chronic hepatitis B virus (HBV) infection are effective at controlling viral titer but are not curative and have minimal impact on the production of viral proteins such as surface antigen (HBsAg), the HBV envelope protein believed to play a role in maintaining the immune tolerant state required for viral persistence. Novel agents are needed to effect HBV cure, and reduction of HBV antigenemia may potentiate activation of effective and long-lasting host immune control. ARB-1740 is a clinical stage RNA interference agent composed of three siRNAs delivered using lipid nanoparticle technology. In a number of cell and animal models of HBV, ARB-1740 caused HBV RNA reduction, leading to inhibition of multiple elements of the viral life cycle including HBsAg, HBeAg, and HBcAg viral proteins as well as replication marker HBV DNA. ARB-1740 demonstrated pan-genotypic activity in vitro and in vivo, targeting three distinct highly conserved regions of the HBV genome, and effectively inhibited replication of nucleoside analogue-resistant HBV variants. Combination of ARB-1740 with a capsid inhibitor and pegylated interferon-alpha led to greater liver HBsAg reduction which correlated with more robust induction of innate immune responses in a human chimeric mouse model of HBV. The preclinical profile of ARB-1740 demonstrates the promise of RNA interference and HBV antigen reduction in treatment strategies driving toward a cure for HBV.

Poor adherence is a contributor to viral breakthrough in patients with chronic hepatitis B.

ObjectiveThe objective of this study was to explore the risk factors of poor adherence of nucleoside analogs (NUC) treatment in chronic hepatitis B (CHB) patients and the virological changes in patients with poor adherence.Subjects and methodsA total of 205 CHB patients were enrolled. The patients’ demographic data and family history were collected. NUC adherence was calculated every 12 weeks as follows: number of NUC tablets taken by the patients was divided by the number of NUC tablets prescribed. NUC adherence > 90% was defined as good adherence of NUC treatment.ResultsNUC adherence of male patients was significantly lower than that of female patients. Adherence among patients with previous NUC treatment was poorer than that of patients without previous NUC treatment. Multivariate analysis indicated that female gender (OR =0.367, P=0.013) was the protective factor for NUC adherence in CHB patients, while pretreatment with NUC was the risk factor for NUC adherence (OR =3.209, P=0.002). A total of six patients in the good adherence group experienced virological breakthroughs while 15 of 77 patients in the poor adherence group experienced virological breakthroughs (P=0.001). Similar trends were observed in NUC resistance. Four of the 128 patients with good adherence developed NUC resistance while nine of the 77 patients with poor adherence developed resistance (P=0.015). Multivariate analysis suggested that pretreatment with NUC (OR =3.133, P=0.031), NUC drugs (OR = 3.951, P=0.010), and adherence (OR =2.749, P=0.046) were independent risk factors associated with virological breakthroughs and that NUC drugs (OR =7.083, P=0.005) and poor adherence (OR =4.951, P=0.009) were independent risk factors for NUC resistance.ConclusionMale gender and pretreatment with NUC were risk factors associated with NUC adherence. Poor NUC adherence is more likely to induce virological breakthroughs and NUC resistance. For patients with poor NUC adherence, it is necessary to give timely education to improve treatment adherence.