Virus DNA Levels Research Articles

287O - Development and validation of a risk model integrating plasma Epstein-Barr virus DNA (EBV DNA) level and TNM stage for stratification of nasopharyngeal cancer (NPC) to adjuvant therapy

BackgroundClinical guidelines for treatment decision in NPC are mainly based on the anatomical classification by UICC TNM staging. The concentration of plasma EBV DNA measured after radiotherapy (RT) or chemoradiation (CRT) is highly prognostic and independent of UICC stage, which may be useful in risk stratification of NPC patients to adjuvant therapy. MethodsFor model development, we used the prospective multi-center 0502 EBV DNA screening cohort (recruitment period 2006 - 2015; n = 745). Eligible patients had histologically confirmed NPC of stage II-IVB (UICC 7th Edition) and post-RT EBV DNA measured in plasma, no loco-regional disease or distant metastasis after RT/CRT and received no adjuvant therapy. Primary endpoint was overall survival (OS). We used recursive-partitioning analysis (RPA) to classify patients into groups of low-, intermediate- and high-risk of death. For internal validation, we pooled independent patient cohorts from previous published biomarker studies (1997-2006; n = 340). For external validation, we used external cohort of NPC patients treated at Sun Yat-sen University Cancer Center (2009 - 2012; n = 837) using SYSU EBV DNA test. ResultsRPA classified NPC patients based on the post-RT plasma EBV DNA level and UICC stage into three distinct prognostic groups (Table). RPA low risk group shared similar 5-yr OS (89.4%; 95% CI = 86.4-92.5%) as UICC stage II (88.5%; 84.0-93.1%) but included 2.3x number of patients that could be potentially spared of adjuvant therapy toxicity. The overall C-index of OS was 0.7118 for RPA risk group, compared to 0.6042 for TNM stage and 0.6747 for EBV DNA (both p < 0.01). RPA risk group has improved hazard discrimination and calibration than either TNM stage or plasma EBV DNA level. The result was validated in both internal and external cohorts.Table287OTablePatient No. (%)5-yr OSHR (95% C.I.)PUICC TNM stage (7th Ed)1) Stage II209 (28.1)88.5-2) Stage III368 (49.4)81.01.50 (0.99-2.25)0.0543) Stage IVAB168 (22.6)69.43.01 (1.97-4.59)<0.0001Post-RT plasma EBV DNA (copies/ml)1) 0573 (76.9)87.3-2) 1-4974 (9.9)83.21.32 (0.76-2.27)0.32593) 50-49959 (7.9)50.53.85 (2.55-5.81)<0.00014) > =50039 (5.2)28.311.59 (7.60-17.67)<0.0001RPA risk group1) Low risk EBV DNA 0 and stage II/III 1-49 and stage II483 (64.8)89.4-2) Intermediate risk EBV DNA 0 and stage IVAB 1-49 and stage III/IVAB 50-499 and stage II176 (23.6)78.52.40 (1.65-3.50)<0.00013) High risk EBV DNA 50-499 and stage III/IVAB >500 and any stage86 (11.5)37.28.54 (5.93-12.29)<0.0001 ConclusionsIncorporation of post-RT plasma EBV DNA level into UICC TNM stage improved risk stratification of NPC patients to adjuvant therapy. Clinical trial identificationIdentifier: NCT00370890. Legal entity responsible for the studyComprehensive Cancer Trials Unit, Department of Clinical Oncology, The Chinese University of Hong Kong. FundingHas not received any funding. DisclosureE.P. Hui: Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Speaker Bureau / Expert testimony: Merck Serono; Research grant / Funding (institution): Pfizer. W.K.J. Lam: Shareholder / Stockholder / Stock options: Grail. K.C.A. Chan: Advisory / Consultancy, Shareholder / Stockholder / Stock options: Grail; Leadership role, Shareholder / Stockholder / Stock options: Take2; Leadership role, Shareholder / Stockholder / Stock options: DRA. Y.M.D. Lo: Advisory / Consultancy, Leadership role, Shareholder / Stockholder / Stock options: Grail; Leadership role, Shareholder / Stockholder / Stock options: Take2 Health; Leadership role, Shareholder / Stockholder / Stock options: DRA. A.T.C. Chan: Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck Sharp & Dohme. All other authors have declared no conflicts of interest.

Predictive validation of qualitative fibrosis staging in patients with chronic hepatitis B on antiviral therapy

The fibrosis in chronic hepatitis shows dynamic changes during antiviral therapy (AVT). We investigated whether P-I-R (progressive vs. indeterminate vs. regressive) staging is predictive of hepatocellular carcinoma (HCC) recurrence in patients with chronic hepatitis B (CHB) taking AVT who underwent resection. Patients with CHB-related HCC who underwent curative resection between 2004 and 2017 and had received ≥2 years AVT at the time of resection were eligible. Two pathologists performed P-I-R staging. In total, 104 patients with CHB-related HCC were enrolled. The mean age of the study population was 56.3 years. The mean duration of AVT at the time of resection was 62.6 months. During the follow-up period (mean, 45.5 months), 20 (19.2%) and 14 (13.5%) patients developed early and late recurrence of HCC, respectively. The cumulative incidence of late recurrence was significantly lower in patients with regressive patterns than in those with indeterminate and progressive patterns according to P-I-R staging (P = 0.015, log-rank test), although the cumulative incidence of overall recurrence according to P-I-R staging was similar. Hepatitis B virus DNA levels (hazard ratio [HR] = 3.200, P = 0.020) and the regressive P-I-R staging pattern (HR = 0.127, P = 0.047) independently predicted the risk of late recurrence. One-time assessment of the P-I-R staging at the time of curative resection in patients with CHB-related HCC receiving AVT independently predicted late HCC recurrence. Therefore, qualitative fibrosis assessment by P-I-R staging might be useful in predicting the outcomes of patients with CHB undergoing AVT.

Prognostic value of Epstein-Barr virus DNA level for nasopharyngeal carcinoma: a meta-analysis of 8128 cases.

Plasma levels of Epstein-Barr virus (EBV) DNA have been employed to predict survival outcomes of patients with nasopharyngeal carcinoma (NPC). However, the prognostic value of subsequent EBV DNA levels (mid or post treatment) for NPC is needed to identify by a large cohort of patients. We performed a meta-analysis of studies including data from 8128 patients to evaluate the prognostic value of EBV DNA in NPC patients. We searched PubMed, Web of Science, and the Cochrane library for prospective and retrospective studies. Hazard ratios (HRs) and confidence intervals (CIs) were extracted from the studies or calculated and pooled to assess the association between EBV DNA levels pre-treatment (pre-DNA), mid-treatment (mid-DNA), and post-treatment (post-DNA) on clinical outcomes. A total of 22 studies with 8128 patients was included for analysis. Pre-DNA levels predicted overall survival, progression-free survival, distant metastasis-free survival, and local-regional failure survival with HRs (95% CIs) of 2.70 (2.06, 3.54), 2.70 (2.12, 3.44), 3.49 (2.35, 5.17), and 2.00 (1.45, 2.76), respectively, and the corresponding HRs for post-DNA levels were 4.86 (3.30, 7.17), 6.29 (3.41, 11.60), 5.68 (2.71,11.93), respectively. Mid-DNA levels predicted overall survival and progression-free survival with an HR (95% CI) of 3.02 (1.54, 5.29) and 3.15 (2.05, 4.83). Subgroup analysis showed that the HR of post-DNA wasn't influenced by different detection time of post-DNA (P = 0.22, I2 = 33.2%). The EBV DNA levels have a significant prognostic impact in patients with NPC. The effect of post-treatment EBV DNA level dominated that of pre-DNA and mid-DNA levels.

Resident memory T cells are a cellular reservoir for HIV in the cervical mucosa

HIV viral reservoirs are established very early during infection. Resident memory T cells (TRM) are present in tissues such as the lower female genital tract, but the contribution of this subset of cells to the pathogenesis and persistence of HIV remains unclear. Here, we show that cervical CD4+TRM display a unique repertoire of clusters of differentiation, with enrichment of several molecules associated with HIV infection susceptibility, longevity and self-renewing capacities. These protein profiles are enriched in a fraction of CD4+TRM expressing CD32. Cervical explant models show that CD4+TRM preferentially support HIV infection and harbor more viral DNA and protein than non-TRM. Importantly, cervical tissue from ART-suppressed HIV+ women contain high levels of viral DNA and RNA, being the TRM fraction the principal contributor. These results recognize the lower female genital tract as an HIV sanctuary and identify CD4+TRM as primary targets of HIV infection and viral persistence. Thus, strategies towards an HIV cure will need to consider TRM phenotypes, which are widely distributed in tissues.

STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production

γ-interferon-inducible protein-16 (IFI16), a key DNA sensor, triggers downstream STING-dependent type I interferon (IFN-I) production and antiviral immunity. However, it is still unclear how to negatively regulate IFI16 to avoid excessive IFN-I production and autoimmunity. Here, we find that STING directly interacts with IFI16 and facilitates IFI16 degradation via the ubiquitin-proteasome pathway by recruiting the E3 ligase TRIM21. The 1-pyrin region of IFI16 is responsible for the IFI16-STING interaction, and the first three lysines in the N-terminal region of IFI16 are the key sites that lead to STING-mediated IFI16 ubiquitination and degradation. Compared to wild-type IFI16, a higher level of viral DNA triggered IFN-β and antiviral IFN-stimulated gene expression, and thus less HSV-1 infection, was observed in the cells transfected with IFI16-K3/4/6R, an IFI16 mutant that is resistant to degradation. STING-mediated negative feedback regulation of IFI16 restricts IFN-I overproduction during antiviral immunity to avoid autoimmune diseases.

1033 Quality Metrics Adherence Assessment for Patients With Chronic Hepatitis B Virus Seen in Gastroenterology Clinics

INTRODUCTION: The American Association for the Study of Liver Disease (AASLD) guidelines for hepatitis B management have progressed over time. However, adherence to quality metrics for chronic hepatitis B (CHB) care needs to be evaluated, especially in settings where liver specific clinics are not part of the system. Our study aims to evaluate the adherence to quality of care metrics in CHB patients in a predominately African American patient population general Gastroenterology clinic in an academic medical center. METHODS: We performed a cohort chart review on 92 patients with ICD 9 or 10 codes for CHB. Patients co-infected with HIV were excluded from analysis as they were treated by Infectious Disease clinics. We identified 45 patients following up with our Gastroenterology clinic for CHB with a visit between 2017 and 2018. We gathered demographic data. Adherence metrics were collected including HAV vaccination, treatment guideline relevant metrics, timely measurement of alanine aminotransferase (ALT), Aspartate Aminotransferase (AST), platelets and hepatitis B virus DNA level check to monitor for treatment response HBV status. Hepatocellular carcinoma screening measure. RESULTS: Our patient population was 65% African American,17% Asian,13% Caucasian and 5% other races. All treated patients had &gt;2000 in HBV DNA levels and high ALT prior to treatment, whereas untreated patients had low HBV DNA and normal ALT with the exception of 1 patient under consideration for treatment. Hepatocellular cancer screening adherence was significantly high in both treated (80%) and untreated (84%) patients with 6 monthly imaging studies. Both treated and untreated patient had relatively high compliance (68%) with HAV vaccination. All the patients had ALT, AST and platelets so that APRI score could be checked every 6 months to provide an indirect assessment of fibrosis. Timely evaluation of fibrosis specific assessments has not been completed in most of the cases, and there was no consensus with respect to the preferred method for assessing fibrosis. CONCLUSION: Our finding reflects satisfactory adherence with AASLD guidelines particularly in areas of treatment indications, regular laboratory check, hepatocellular carcinoma screening and compliance with HAV vaccination. However, fibrosis evaluation was suboptimal according to guidelines. Given the access to Fibroscan in our practice, once yearly assessment is being recommended for our patients. Supported in part by an Investigator Initiated Grant from Gilead Sciences.

1024 A Retrospective Analysis of Hepatitis-B Reactivation in Hepatitis-C Patients Treated With Direct-Acting Antivirals Therapy

INTRODUCTION: Hepatitis B virus/hepatitis C virus (HBV/HCV) co-infection has a prevalence of 5%-10% in patients with chronic HCV patients. Direct-acting antiviral agent (DAA) have replaced Interferon (IFN)-based treatment for HCV infection given the increased HCV sustained virological response (SVR). However, the Food and Drug Administration (FDA) has issued warnings about HBV reactivation (HBV-R) in chronic HCV patients treated with DAA. We aimed to assess the HBV reactivation rate in our chronic HCV patient population treated with DAA (Ledipasvir / Sofosbuvir). METHODS: We conducted a retrospective study involving HCV patients treated with DAA at our outpatient hepatology clinic located in Erie county medical center. The goal as discussed above was to find the HBV reactivation which was defined as reverse seroconversion of HBsAg-negative patients at baseline becoming HBsAg-positive post DAA therapy with a DNA level &gt;0 IU/mL. Patient characteristics and laboratory results at baseline and at the end of follow-up were retrospectively analyzed from electronic medical records. A chart review was completed for a total of 260 patients fulfilling the inclusion criteria. The mean age of the study population was 56.5 years. Inclusion criteria: 1-DAA therapy for HCV with confirmed SVR. 2-HBsAg-negative/HbcAb+. 3-HBV/HCV coinfection. Exclusion criteria: 1- Coinfection of HAV/HDV/HEV. 2- Decompensated cirrhosis with CPT class B/C. 3- Active HBV coinfection. 4- Undergoing immunosuppressive therapy or chemotherapy. RESULTS: Post-treatment serum samples of 260 patients were analyzed. Of these, 19.60% (51/260) of the total population was positive for HbcAb. Out of these 51 patients, 13 post-DAA treatment patients were checked for hepatitis-B DNA level to rule out the concern for reactivation. None of the patients showed any elevation in Hepatitis-B virus DNA level, i.e. undetectable. Also, no seroconversion to HbsAg+ was noticed in our population post-DAA therapy. Further detailed results will be presented in the poster during meeting. CONCLUSION: To conclude, we found no hepatitis-B virus reactivation or seroconversion to HBsAg positive state in our cohort. Our study supports the latest literature that although it has been observed in the past, HBV reactivation in exposed patients with HbcAb without positive HbsAg is very rare.

Risk Factors for Kaposi's Sarcoma-Associated Herpesvirus DNA in Blood and in Saliva in Rural Uganda.

Detectable Kaposi's sarcoma-associated herpesvirus (KSHV) DNA in blood and increased antibody titres may indicate KSHV reactivation, while the transmission of KSHV occurs via viral shedding in saliva. We investigated the risk factors for KSHV DNA detection by real-time polymerase chain reaction in blood and by viral shedding in saliva, in 878 people aged 3 to 89 years of both sexes in a rural Ugandan population cohort. Helminths were detected using microscopy and the presence of malaria parasitaemia was identified using rapid diagnostic tests. Regression modelling was used for a statistical analysis. The KSHV viral load in blood did not correlate with the viral load in saliva, suggesting separate immunological controls within each compartment. The proportions of individuals with a detectable virus in blood were 23% among children aged 3-5 years and 22% among those 6-12 years, thereafter reducing with increasing age. The proportions of individuals with a detectable virus in saliva increased from 30% in children aged 3-5 years to 45% in those aged 6-12 years, and decreased subsequently with increasing age. Overall, 29% of males shed in saliva, compared to 19% of females (P = .008). Together, these data suggest that young males may be responsible for much of the onward transmission of KSHV. Individuals with a current malaria infection had higher levels of viral DNA in their blood (P = .031), compared to uninfected individuals. This suggests that malaria may lead to KSHV reactivation, thereby increasing the transmission and pathogenicity of the virus.

Occult hepatitis B infection among blood donors from Yaoundé, Cameroon.

In Cameroon, the prevention of hepatitis B virus (HBV) transmission by blood transfusion is still only based on hepatitis B surface antigen (HBsAg) screening. However, occult HBV infection (OBI) characterised by the absence of detectable HBsAg and low level of viral DNA remains a potential threat for blood safety. The prevalence of OBI was investigated in blood donors from Yaoundé to provide evidence-based recommendations to improve HBV blood safety. Blood donations from August 1st, 2016 to March 31st, 2017 were routinely screened for HBV, human immunodeficiency virus (HIV), and hepatitis C virus (HCV) infections (Murex HBsAg Version 3, Murex HIV Ag/Ab Combination, and Murex HCV Ag/Ab Combination [DiaSorin]). Additional HBV investigations were performed, including hepatitis B core antibody ([HBc] Monolisa Anti-HBc PLUS; BIO-RAD) and HBV DNA tested in minipools of two samples using the quantitative Cobas Taqman HBV assay (Roche; LoQ: 6 IU/mL) and HBV DNA genotyping by sequencing. Of 1,162 donations analysed, 91 (7.8%) were reactive for HBsAg. All of them were also anti-HBc positive. Among the 1,071 HBsAg negative samples, 522 (48.7%) were reactive for anti-HBc. Six (0.56% of all donations) samples fulfilled the consensus definition of OBI and showed low HBV DNA loads (all <6 IU/mL). Following nested polymerase chain reaction amplifications, HBV DNA sequences were obtained for 4 of these samples (1 nearly whole genome [3123 nt], 2 Pre-S/S regions [1,356 nt], and 1 S region [445 nt]). Phylogenetic analysis identified genotype E in all samples. Around 1 in 100 Cameroonian blood donors screened who resulted HBsAg negative and anti-HBc positive carried occult HBV infection. HBsAg alone for screening prospective donors is not sufficient to eliminate the risk of HBV transfusion transmission in Cameroon, and because anti-HBc screening does not seem to be feasible without compromising blood supply, implementation of HBV nucleic acid testing could be considered when possible.

HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact.

Human T-cell leukemia virus-1 (HTLV-1) is a neglected and incurable retrovirus estimated to infect 5 to 10 million worldwide. Specific indigenous Australian populations report infection rates of more than 40%, suggesting a potential evolution of the virus with global implications. HTLV-1 causes adult T-cell leukemia/lymphoma (ATLL), and a neurological disease named HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Even though HTLV-1 transmission primarily occurs from cell-to-cell, there is still a gap of knowledge regarding the mechanisms of viral spread and disease progression. We have recently shown that Extracellular Vesicles (EVs) ubiquitously produced by cells may be used by HTLV-1 to transport viral proteins and RNA, and elicit adverse effects on recipient uninfected cells. The viral proteins Tax and HBZ are involved in disease progression and impairment of autophagy in infected cells. Here, we show that activation of HTLV-1 via ionizing radiation (IR) causes a significant increase of intracellular Tax, but not EV-associated Tax. Also, lower density EVs from HTLV-1-infected cells, separated by an Iodixanol density gradient, are positive for gp61+++/Tax+++/HBZ+ proteins (HTLV-1 EVs). We found that HTLV-1 EVs are not infectious when tested in multiple cell lines. However, these EVs promote cell-to-cell contact of uninfected cells, a phenotype which was enhanced with IR, potentially promoting viral spread. We treated humanized NOG mice with HTLV-1 EVs prior to infection and observed an increase in viral RNA synthesis in mice compared to control (EVs from uninfected cells). Proviral DNA levels were also quantified in blood, lung, spleen, liver, and brain post-treatment with HTLV-1 EVs, and we observed a consistent increase in viral DNA levels across all tissues, especially the brain. Finally, we show direct implications of EVs in viral spread and disease progression and suggest a two-step model of infection including the release of EVs from donor cells and recruitment of recipient cells as well as an increase in recipient cell-to-cell contact promoting viral spread.

Combining pretreatment plasma Epstein‐Barr virus DNA level and cervical node necrosis improves prognostic stratification in patients with nasopharyngeal carcinoma: A cohort study

This study aimed to evaluate the prognostic value of combining pretreatment Epstein‐Barr virus (EBV) DNA level and cervical node necrosis (CNN) for patients with nasopharyngeal carcinoma (NPC) receiving intensity‐modulated radiotherapy (IMRT). A total of 607 incident nonmetastatic NPC patients treated with IMRT ± chemotherapy were reviewed. Patients were divided into four groups based on EBV DNA level and CNN status. The primary endpoint was progression‐free survival (PFS). Kaplan‐Meier curves with log‐rank test were applied to compare survival outcomes and the Cox proportional model was used to identify independent prognostic factors. Pretreatment EBV DNA level and CNN status were independent prognostic factors. Patients in the low‐level EBV DNA group or non‐CNN group had significantly better 5‐year PFS. Multivariate analyses demonstrated that CNN was an independent prognostic factor for overall survival (OS) (HR = 1.927, 95% CI: 1.129‐3.290, P = .016), PFS (HR = 1.492, 95% CI: 1.005‐2.214, P = .047), distant metastasis‐free survival (DMFS) (HR = 1.661, 95% CI: 1.044‐2.644, P = .032), but not locoregional relapse‐free survival. EBV DNA levels correlated significantly with CNN with a correlation coefficient of .324 (P < .001). Compared with low‐level EBV DNA and non‐CNN grouping, high‐level EBV DNA and CNN grouping had poor PFS. The combined classification was an independent prognostic factor for OS (P < .001), PFS (P = .001), and DMFS (P = .018). Pretreatment plasma EBV DNA level and CNN status both closely correlated with prognosis of NPC patients in the IMRT era. Combined EBV DNA level and CNN status improves risk stratification and prognostic value.

Maximal standard uptake values of 18F-fluoro-2-deoxy-D-glucose positron emission tomography compared with Epstein-Barr virus DNA as prognostic indicators in de novo metastatic nasopharyngeal carcinoma patients

BackgroundThis study aimed to evaluate the prognostic value of maximal standard uptake values (SUVmax) of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) comparing with Epstein-Barr virus (EBV) DNA levels in de novo metastatic nasopharyngeal carcinoma (NPC) patients.MethodsFrom December 2006 to December 2016, 253 de novo metastatic NPC patients assessed by PET/ computed tomography were involved in current study. SUVmax-T, SUVmax-N, and SUVmax-M referred to the SUVmax at the primary tumor, cervical lymph nodes, and metastatic lesions respectively. Overall survival (OS) was the primary endpoint.ResultPatients who died during the follow-up had significantly higher SUVmax-N, SUVmax-M, and EBV DNA level than those in the patients who were alive. SUVmax-N and SUVmax-M were positively correlated with EBV DNA level. The cut-off values of SUVmax-T, SUVmax-N, SUVmax-M, and EBV DNA were 17.0, 12.7, and 6.9, and 13,800 copies/mL respectively, which were determined by receiver operating characteristic (ROC) curve analysis. Patients with elevated SUVmax-N, SUVmax-M, and EBV DNA levels had a lower 3-year OS rate. In multivariate analysis, the independent prognostic factors of OS included EBV DNA, metastatic site, and locoregional radiotherapy application, while SUVmax was not an independent prognostic factor.ConclusionIn de novo metastatic NPC patients, higher SUVmax-N and SUVmax-M were associated with worse prognosis. However, the predictive ability of SUVmax-N and SUVmax-M was poorer than that of EBV DNA.

A randomized, double-blind, double-dummy, controlled, multicenter study of Qingzhong (tenofovir disoproxil fumarate) versus Viread for the treatment of chronic hepatitis B: First-stage results at week 48.

Background:Tenofovir disoproxil fumarate (TDF) has been widely recommended as a first-line antiviral agent to treat chronic hepatitis B (CHB). Qingzhong and Viread, formulations of TDF commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd and GlaxoSmithKline, respectively, have both been approved by the State Food and Drug Administration, China. This study analyzed the efficacy and safety of these 2 TDF agents in Chinese patients with CHB.Methods:In this multicenter, randomized, double-blind, double-dummy, noninferiority phase 3 clinical trial (ClinicalTrials.gov identifier: NCT02287857), 330 Chinese patients with CHB [hepatitis B envelope antigen-positive (HBeAg) (+): 232] were randomly assigned to receive Qingzhong (group A: 161 patients) or Viread (group B: 169 patients) 300 mg once daily for 48 weeks. Subsequently, all patients were administered Qingzhong 300 mg once daily from week 49 to week 240. The primary end point was the degree of decline of plasma hepatitis B virus (HBV) DNA levels at week 48 and the secondary endpoints were viral suppression, normalization of alanine aminotransferase (ALT) levels, hepatitis B surface antigen (HBsAg)/HBeAg loss or seroconversion, and virological breakthrough.Results:Among patients with CHB who were HBeAg (+), the mean HBV DNA titer decreased similarly between the groups at week 48. The percentages of patients who achieved undetectable HBV DNA were similar between the groups (85.11% and 82.35% in groups A and B, respectively) and similar losses of HBeAg and HBeAg seroconversion rates were achieved. Moreover, for patients with CHB who were HBeAg (−), reductions in HBV DNA were similar. Among all patients with CHB, the rates of normalization of ALT and the loss of HBsAg were similar. The overall incidence of adverse events was comparable between the groups.Conclusion:In conclusion, the 48-week administration of Qingzhong showed noninferior efficacy and safety profiles compared to Viread in Chinese patients with CHB.

Hepatitis B virus DNA levels and overall survival in hepatitis B-related hepatocellular carcinoma patients with low-level viremia.

Clinical course of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients presenting with low-level viremia (LLV) is unclear. A total of 565 HBV-related HCC patients with LLV (detectable but HBV DNA≤2000IU/mL) at the time of HCC diagnosis were analyzed. Based on patterns of HBV DNA levels during follow-up, patients were categorized into three groups: maintained virologic remission (MVR), LLV, and flare. Overall survival was compared between those three groups. During a median 4.5years of follow-up, 33% showed MVR, 39% showed LLV, and 28% experienced flare. The overall survival differed between MVR, LLV, and flare groups (5-year overall survival: 74.3%, 67.3%, and 61.7%, respectively, 0.015). The patterns of HBV DNA levels were independent factors associated with overall survival, along with age, antiviral treatment, Barcelona clinic liver cancer stage, and initial treatment modality. Flare group showed increased risk of mortality (adjusted hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.15-2.55) compared with MVR group, while the risk was statistically marginal for the LLV group (adjusted HR 1.39, 95% CI 0.95-2.04). During follow-up, 183 patients (32.4%) newly started antiviral therapy (AVT) at LLV. Flare risk was significantly lower among patients who started AVT at LLV compared with those who did not (adjusted HR 0.26, 95% CI 0.17-0.38). Among HBV-related HCC patients with LLV, flare was frequent during follow-up and was associated with poorer overall survival compared with MVR group. Prospective studies that address whether inducing MVR by early AVT improves patient outcome are warranted.

Hepatitis B Virus cccDNA in Hepatocellular Carcinoma Tissue Increases the Risk of Recurrence After Liver Transplantation

BackgroundHigh hepatitis B virus (HBV) DNA level is strongly associated with hepatocellular carcinoma (HCC) development in chronic HBV infection. The aim of this study was to investigate the association between intrahepatic HBV DNA titer and post-liver transplantation (LT) prognosis for HBV-related HCC (HBV-HCC) patients. MethodsA total of 60 patients with HBV-HCC who underwent LT were retrospectively studied. Using quantitative TaqMan fluorescent real-time polymerase chain reaction assay, HBV total DNA (tDNA) and covalently closed circular DNA (cccDNA) were both quantified in tumor tissue (TT) and adjacent non-tumor tissue (ANTT) from the explanted liver. ResultsThe loads of tDNA and cccDNA in ANTT were associated with serum HBV DNA levels. Multivariate analysis showed that the presence of vascular invasion and cccDNA in TT were independent risk factors for tumor recurrence. The group of patients with cccDNA titers ≥31ogl0 copies/μg in TT had significantly higher cumulative recurrence rates than those with <31ogl0 copies/μg group. The cccDNA titers predicted the tumor recurrence with an area under the receiver operating characteristic curve of 0.664. ConclusionsOur findings would assist the clinical implementation of a more personalized therapy for tumor recurrence control and improve the prognosis of HBV-HCC patients.

HBV DNA levels impact the prognosis of hepatocellular carcinoma patients with microvascular invasion.

To discuss the prognostic correlation between hepatitis B virus DNA (HBV DNA) level and HBV-related hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI).Data from HCC patients undergoing hepatectomy with pathological evidence of MVI were retrospectively collected and 1:1 propensity scoring matching (PSM) analysis was performed. According to the HBV DNA levels before and after surgery, the disease-free survival (DFS) and overall survival (OS) were evaluated using the Kaplan-Meier method, and the Cox proportional hazards regression was used to analyze the risk factors associated with the postoperative prognosis. After 1:1 PSM, 139 pairs of patients were enrolled in the high preoperative HBV DNA level group (H group) and low preoperative HBV DNA level group (L group), and after operation, patients with high preoperative HBV DNA levels were divided into the persistently high HBV DNA level group (P group) and the decreased HBV DNA level group (D group).According to the multivariate analysis, the HBV DNA level of 2000 IU/ml or greater before operation was significantly associated with the DFS (hazard ratio, 1.322; 95%CI, 1.016-1.721) and OS (hazard ratio, 1.390; 95%CI, 1.023-1.888). A persistent HBV DNA level of 2,000 IU/ml or greater after operation was also the independent risk factor of DFS (hazard ratio, 1.421; 95%CI, 1.018-1.984) and OS (hazard ratio, 1.545; 95%CI, 1.076-2.219).For the HBV-related HCC patients with MVI, preoperative high HBV DNA copies are prognostication of poorer prognosis, and effective antivirus treatment would significantly improve the patients' prognosis.

Risk factors for resistance development against lamivudine during long-term treatment of chronic hepatitis B virus infections.

The use of lamivudine for the treatment of chronic hepatitis B (CHB) is limited by high rates of lamivudine resistance. However, it is still in use in many regions. Factors associated with lamivudine resistance development have been studied in only a few European cohorts. The aim of our study was to assess the rate and risk factors for lamivudine resistance in a large real-life European cohort. We retrospectively analyzed patients with CHB treated in three German University centers over up to 12 years. Lamivudine resistance was defined as virologic breakthrough and presence of genotypic lamivudine resistance. The probability of resistance was estimated by Kaplan-Meier analysis and resistance predictors by Cox regression. A total of 227 patients were included into the analysis (hepatitis B envelope antigen positive or negative). Rates of lamivudine resistance by years 1-7 were 7, 26, 35, 41, 46, 53, and 55%, respectively. Interestingly, two hepatitis B envelope antigen-negative patients developed resistance during the year 12 of treatment. Independent risk factors for resistance development were hepatitis B virus DNA levels of at least 10 copies/ml before and detectable hepatitis B virus DNA by month 6 of treatment. Even after long-term response to lamivudine more than 10 years, resistance may still develop. Our findings further discourage the use of lamivudine for the treatment of CHB.

Hydroa vacciniforme–like lymphoproliferative disorder: an EBV disease with a low risk of systemic illness in whites

AbstractPatients with classic hydroa vacciniforme–like lymphoproliferative disorder (HVLPD) typically have high levels of Epstein-Barr virus (EBV) DNA in T cells and/or natural killer (NK) cells in blood and skin lesions induced by sun exposure that are infiltrated with EBV-infected lymphocytes. HVLPD is very rare in the United States and Europe but more common in Asia and South America. The disease can progress to a systemic form that may result in fatal lymphoma. We report our 11-year experience with 16 HVLPD patients from the United States and England and found that whites were less likely to develop systemic EBV disease (1/10) than nonwhites (5/6). All (10/10) of the white patients were generally in good health at last follow-up, while two-thirds (4/6) of the nonwhite patients required hematopoietic stem cell transplantation. Nonwhite patients had later age of onset of HVLPD than white patients (median age, 8 vs 5 years) and higher levels of EBV DNA (median, 1 515 000 vs 250 000 copies/ml) and more often had low numbers of NK cells (83% vs 50% of patients) and T-cell clones in the blood (83% vs 30% of patients). RNA-sequencing analysis of an HVLPD skin lesion in a white patient compared with his normal skin showed increased expression of interferon-γ and chemokines that attract T cells and NK cells. Thus, white patients with HVLPD were less likely to have systemic disease with EBV and had a much better prognosis than nonwhite patients. This trial was registered at www.clinicaltrials.gov as #NCT00369421 and #NCT00032513.

A quantitative method for hepatitis B virus covalently closed circular DNA enables distinguishing direct acting antivirals from cytotoxic agents

Studying the biogenesis of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and developing anti-HBV agents require analytical methods to quantify viral DNA levels inside host cells. The well-accepted Southern blotting method is only semi-quantitative, while the other widely used methods (based on qPCR) have been questioned as to their fidelity for cccDNA quantification. In addition, Southern blotting and qPCR results barely reflect the number of host cells present in an analytical sample. We here developed new techniques that substantially improve cccDNA detection and quantification, including a sample pretreatment method that i) exploits high temperature and exonuclease V (an ATP-dependent, bidirectional exonuclease) digestion to effectively increase the amplification efficiency of HBV cccDNA by removing rcDNA and denaturing the cccDNA template, and ii) a method that splits cell samples and uses separate extraction technologies to facilitate “host normalization” based on host genomic DNA signals. Our study introduces new analytical techniques that should be useful for the basic biology and translational studies of HBV.

PIN100 IMPACT OF CHRONIC HEPATITIS B VIRUS INFECTION ON HEALTH-RELATED QUALITY OF LIFE: A LITERATURE REVIEW

Chronic hepatitis B (CHB) is a viral infection that can lead to fatal liver diseases such as cirrhosis and hepatocellular carcinoma. We conducted a targeted literature review to describe the impact of CHB on health-related quality of life (HRQoL). Searches were conducted in Biosis, Derwent Drug, Embase, PubMed, Medline, Clinicaltrials.gov, Google, and Google Scholar from the beginning of database inception through October 2017. Search strings contained MESH terms and key words such as "Hepatitis B, Chronic”, “Quality of Life”, and "patient reported outcome", and were limited to English and humans. 29 published studies were included. Most studies were cross-sectional. The SF-36, EQ-5D, and Chronic Liver Disease Questionnaire (CLDQ) were frequently used. The majority of the measures identified were not CHB-specific. Compared to the general population, patients with CHB reported worse HRQoL, particularly in aspects such as physical and emotional functioning, fatigue, worry, depression, and stigma. Patients with CHB reported similar or better HRQoL compared to those with other liver diseases such as hepatitis C and non-alcoholic fatty liver disease. CHB patients with impaired liver functions such as cirrhosis, hepatocellular carcinoma, and liver failure had worse scores on SF-36, EQ-5D, and CLDQ than those without impaired liver function. Declines in physical and emotional functioning in patients during peginterferon alpha-2a treatment were observed, but functioning returned to baseline levels at post-treatment follow up, while patients treated with nucleos(t)ide analogs reported improvements in physical functioning and general health status. Virologic response (i.e., reduction in hepatitis B virus DNA level) was associated with HRQoL improvements in patients who received antiviral therapy. CHB has a negative impact on HRQoL. Prospective, interventional studies evaluating the effect of currently available treatments and novel curative regimens on HRQoL in CHB are needed.