HBV Treatment Research Articles

Association between Human Leukocyte Antigen-DQ Polymorphisms and Treatment Response in Chronic Hepatitis B Egyptian Population: A Prospective Study

Background & Aims: Several studies, in different populations, have focused on the role of HLA-DQ gene polymorphism in the pathogenesis of HBV infection. However, these findings are still controversial. This study aimed to determine HLA-DQ polymorphism in Chronic HBV patients and its impact on the response to antiviral therapy. Methods: This study was carried out on a total number of 188 participants, they were subdivided as follows: Group I (patients’ group): included 97 patients with chronic hepatitis B viral infection that was further subdivided according to response to treatment into responder and non-responder subgroups, Group II (Control group): included 91 normal healthy subjects who were matched to the patient group by sex and age. PCR (Polymerase Chain Reaction) testing, for HBV-DNA, was done for all participants enrolled in the study to measure the viral virus load before and after treatment. HLA- DQ polymorphism allelic discrimination assay was assayed using the Real-time equipment. Results: In a general analysis for the SNP rs7453920, the overall genotypes frequencies were 37% for A/A, 60.6% for A/G, and 37% for G/G. The G alleles of HLA-DQ rs7453920 were significantly increased in chronic HBV infection patients. A total of 77 (79.4%) patients were responders. Among this group, 72.7% were male, and the average age was 38.59 ±9.15 years. On evaluation of the association between polymorphisms in HLA-DQ gene and treatment response, the results indicated that response to treatment declined when patients were carrying the more unfavorable rs 7453920 GG with a response rate of 64%. Patients carrying the mutant allele AG, or the wild type allele AA were more likely to achieve a higher rate of response (84.8% and 83.3%, respectively). Conclusion: The presence of HLA-DQB2 rs 7453920-G serves as a risk factor for chronic HBV infection and treatment failure in the Egyptian population.

Efficacy and safety of Tenofovir Disoproxil Fumarate in Patients with Chronic Hepatitis B with High Baseline Viral Load

Background: Chronic hepatitis B virus infection is an important cause of morbidity and mortality. Tenofovir disoproxil fumarate was licensed for the treatment of hepatitis B virus infection. So, the current study aimed to Evaluate efficacy and outcome of Tenofovir Disoproxil Fumarate in patients with Chronic Hepatitis B with High Baseline Viral Load. Patients and methods:One hundred Chronic HBV patients attend Outpatient Clinic of HBV treatment unit, Qena fever hospital, Qena, Egyptwere enrolled in this study and treated with Tenofovir Disoproxil Fumarate (300mg/day) for 24 weeks. Patients categorized into two groups: Group A: included 50 chronic HBV patients with Low Viral load < 1 million/ml and Group B: included 50 chronic HBV patients with High Viral load ≥ 1 million/ml.virological and biochemical response, as well as safety outcomes were assessed after 24 weeks of treatment. Results:The mean age of patients was 38.4 years and 33.9 years in Group A and Group B respectively. Number of males was 32 (64%) and 36 (72%) in Group A and Group B respectively. HBeAg was positive in 20 % and 36 % in Group A and Group B respectively. The rates of complete virological suppression were 88% in group A and 72% in group B. All patients achevied normalization of ALT. No severe adverse events were reported during the present study. No elevations in creatinine level were detected. Conclusion: Tenofovir Disoproxil Fumarate is an efficacious, safe and well-tolerated treatment in an Egyptian patient.

Abstract A036: Active patient and stakeholder engagement was critical to the success of a comparative trial to reduce liver cancer disparities for underserved Asian Americans with HBV

Abstract Background: Asian Americans are a liver cancer disparity population and a chronic hepatitis B (CHB) disparity population. Seventy-five percent of hepatocellular carcinoma cases are developed from CHB. Moreover, in the past decades, patient and stakeholder engagement has been an emerging infrastructure in the research process. This study aims to examine the influences of patient and stakeholder engagement, an emerging infrastructure in the research process, on reducing liver cancer disparities among underserved Asian Americans with CHB. Method: A 3-year fieldwork was conducted in a broader HBV project to observe the influences of patient and stakeholder engagement. Twenty-five patient partners/caregivers, physicians, and community advocate stakeholders were engaged through numerous regular in-person meetings and teleconferences in project conceptualization, study design, patients recruitment and retention strategies, intervention components development (message and materials review/feedback, education content review/feedback), outcome measurement assessment tools, and quality control. Moreover, the engagement experiences from patients and stakeholders were examined using the Bell-Elkins questionnaire with 25 survey forms. Results: the survey indicated that there is a unanimous agreement of partnership engagement in shared mission, goals and values, and measurable outcomes (e.g., community-campus partnership, collective decisions, effective communication, resource shared, addressed weakness, and mutual trust and respect) addressed for the study. All of the 25 patient and stakeholders agreed that the partnership shared the same goals and values, the members had mutual trust and respect and they shared varied resources. A majority of them (84%-92%) believed that the partnership had effective communication, it was a true community-clinical-academic partnership, the decisions were collectively made, and it addressed its weaknesses. The fieldwork observation showed that the patient and stakeholder engagement can improve the study quality by enhancing intervention content, offering practical suggestions, promoting recruitment and increasing the retention rate. Furthermore, the adoption of the patient-centered strategy in the HBV project has resulted in significant benefits for patients, as patients can better manage their health when they are informed and supported. Full engagement empowered target populations to make lifestyle modifications, enhance patients’ HBV monitoring and treatment, and thus reducing the risk of developing liver cancer. Conclusion: the active involvement of patient and stakeholders can significantly empower the investigators and reduce the HBV patient’s liver cancer disparities among Asian Americans. In the future studies, the patient and stakeholders should be involve actively in the different stages of the project to improve the project quality, reduce cancer disparities, and improve the public health. Citation Format: Wenyue Lu, Yin Tan, Michelle Naidoo, Aliyah Saber, Ming-Chin Yeh, Grace X Ma. Active patient and stakeholder engagement was critical to the success of a comparative trial to reduce liver cancer disparities for underserved Asian Americans with HBV [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A036.

Prevalence of Hepatitis B and C Virus Infection among Pregnant Women in Sharkia Governorate, Egypt

Background and study aim: Viral infections is the cause of liver inflammation, cirrhosis and even liver hepatocellular carcinoma (HCC). Despite the availability of HBV vaccine and antiviral treatment for HBV and HCV both remain a major health problem. The aim of this study To determine the seroprevalence of HBV and HCV infection among pregnant women in Sharkia governorate, Egypt. Subject and Methods: : is a cross-sectional study, It involved 563pregnant women attending the antenatal care clinic, all women are subjected to full history taking, clinical examination, laboratory investigations, detection of HBsAb, HCV antibodies by rapid one-step test then by ELISA if positive, PCR was done. Results: In this study, 10 cases had anti-HCV positive with ELISA, 8 cases were positive by PCR while one case was positive for HBs Ag by ELISA, no co-infected pregnant women were detected. the prevalence rate of HBV&HCV was 0.17%, 1.7 % respectively. Conclusion: All pregnant women should be routinely screened during an early antenatal visit for HCV Antibodies and HBsAg. Cases with HCV antibodies positivity should be subjected to PCR for HCV RNA.

Abstract B002: Improving knowledge and identifying barriers to screening for hepatitis B and hepatocellular carcinoma in trainees

Abstract Background: Hepatitis B (HBV), a leading cause of hepatocellular carcinoma (HCC) worldwide, disproportionately affects minorities in the United States. Undiagnosed HBV infection precludes HCC screening and contributes to late-stage presentation and decreased survival. Previously, we reported low HBV screening rates in persons from endemic countries. Barriers to screening include lack of insurance, limited diffusion of guidelines, and provider uncertainty. We aimed to assess knowledge about HBV and HCC screening and to explore barriers to HCC screening among trainees from three unique institutions. Methods: We administered a survey to trainees from the University of Miami/Jackson Memorial Hospitals, Palmetto General Hospital, and Mount Sinai Medical Center. We used univariate, bivariate, and Pearson's chi-squared analyses to assess knowledge and barriers using clinical vignettes. Results: There were 183 respondents born in 36 countries. Median age was 31 years. The sample was 35% Hispanic, 29% White, 18% Asian, 9% Black, 7% other, 2% multiracial and 52% male. Training department was Internal Medicine, 71%, Family Medicine, 11%, Infectious Diseases (ID), 6%, or Gastroenterology (GI), 7%. The perceived burden of HBV was low; 2/3 stated HBV affects &amp;lt;5% of the patient population, 59% correctly estimated national HBV prevalence and 25% correctly estimated global prevalence. In vignettes with behavioral risk factors (e.g., intravenous drug use), trainees correctly advised screening, 63-96%. However, when birthplace was the only risk factor, correct responses ranged from 33-53%. Overall, 48% chose an incorrect combination of HBV screening tests. Respondents from HBV-endemic countries were no more likely to screen for HBV. Knowledge of HBV treatment indications was poor. More fellows (ID/GI) correctly recommended treatment than residents, p &amp;lt;0.01. Barriers to HBV screening were lack of education among health care workers, limited expertise in screening of immigrants, and limited patient education. Barriers to treatment were cost, knowledge about HBV regimens, and provider comfort. Respondents were more likely to recommend HCC screening in cirrhotic patients vs. noncirrhotic HBV patients, even when indicated. Only 43% of participants recognized that HCC screening is unnecessary in patients with acute HBV and 53% either recommended HCC screening or indicated uncertainty in noncirrhotic patients with resolved HBV infection. Respondents indicated they would screen for HCC if strong evidence suggested a mortality benefit or if recommended by a national organization. Key barriers to screening were uncertainty or lack of awareness about HCC guidelines and patient financial barriers. Conclusions: In a diverse sample of trainees, knowledge of HBV and HCC screening recommendations is suboptimal. Efforts to broadly disseminate guidelines through targeted educational interventions are needed as responses confirm that HCC screening indications, especially in HBV, are not universally known. Citation Format: Patricia D. Jones, Mahmoud Mahfouz, Harry Nguyen, Jonathan Tu, Carlos R. Diaz, Shweta Anjan, Stefanie Brown, Kassandra Bosire, Paul M. Martin, Olveen Carrasquillo. Improving knowledge and identifying barriers to screening for hepatitis B and hepatocellular carcinoma in trainees [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B002.

PIN8 HEPATITIS B TREATMENT PATTERNS IN US CLINICAL CARE FOLLOWING TENOFOVIR ALAFENAMIDE (TAF) APPROVAL

Here, we describe changes in HBV treatment in the 24 months after TAF approval as observed in a US network of 10 HBV-care centers. Data were retrospectively obtained from patient records through an electronic registry at enrollment (Nov 2016) with further collection at each patient visit. Of 1037 enrolled patients, 725 patients with 24-month follow up were included in this study. 7% (50/725) patients were untreated at enrollment and throughout the observation period (Nov 2016 to Dec 2018). Reasons for non-treatment: 82% (41/50) low HBV DNA, 54% (27/50) normal liver function, 8% (4/50) patient decision, 6% (3/50) HBeAg negative, 2% (1/50) does not meet guidelines, and 2% (1/50) unspecified. In Jan 2017 (end of enrollment), 58% (418/725) patients received tenofovir disoproxil fumarate (TDF), 23% (168/725) entecavir (ETV), and 2% (14/725) TAF. In Dec 2018 (end of the observation period), 30% (218/725) received TDF, 21% (152/725) ETV, and 35% (254/725) TAF. 37% (271/725) patients switched therapies for reasons of safety/side effects (58%, 156/271), physician preference (25%, 69/271), efficacy (8%, 23/271), or insurance/cost (6%, 17/271). Most switches were to TAF (91%, 246/271) from TDF (88%, 217/246). Rate of switching differed by site of care; compared to community practices, academic sites had a lower switch rate (26% [114/441] vs 55% [157/284]). Treatment switches in both academic (81%, 92/114) and community (98%, 154/157) sites were mainly to TAF, but the therapies prior to TAF were more varied in the academic sites. In this study, 7% of patients were untreated while 37% received >1 regimen during the observation window. Reasons for non-treatment were mainly low HBV DNA and normal liver function. For the population receiving treatment, initial regimens were mostly TDF and ETV. Switches away from initial therapy was mainly due to safety/side effects concerns and were predominately to TAF.

A long-acting 3TC ProTide nanoformulation suppresses HBV replication in humanized mice

Nowadays, there is a strong request for the treatment of chronic HBV-infection with direct acting antivirals. Furthermore, prevalent human immunodeficiency virus (HIV-1) and hepatitis B (HBV) co-infections highlight an immediate need for dual long-acting and easily administered antivirals. To this end, we modified lamivudine (3TC), a nucleoside analog inhibitor of both viruses, into a lipophilic monophosphorylated prodrug (M23TC). Prior work demonstrated that nanoformulation of M23TC (NM23TC) enhanced drug stability, controlled dissolution and improved access to sites of viral replication. The present study evaluated the efficacy of a NM23TC in HBV-infected chimeric liver humanized mice. Levels of HBV DNA and HBsAg in plasma were monitored up to 8 weeks posttreatment. A single intramuscular dose of 75 mg/kg 3TC equivalents of nanoformulated NM23TC provided sustained drug levels and suppressed HBV replication in humanized mice for 4 weeks. The results support further development of this long-acting 3TC nanoformulation for HBV treatment and prevention.

The E3 Ubiquitin Ligase TRIM21 Promotes HBV DNA Polymerase Degradation.

The tripartite motif (TRIM) protein family is an E3 ubiquitin ligase family. Recent reports have indicated that some TRIM proteins have antiviral functions, especially against retroviruses. However, most studies mainly focus on the relationship between TRIM21 and interferon or other antiviral effectors. The effect of TRIM21 on virus-encoded proteins remains unclear. In this study, we screened candidate interacting proteins of HBV DNA polymerase (Pol) by FLAG affinity purification and mass spectrometry assay and identified TRIM21 as its regulator. We used a coimmunoprecipitation (co-IP) assay to demonstrate that TRIM21 interacted with the TP domain of HBV DNA Pol. In addition, TRIM21 promoted the ubiquitination and degradation of HBV DNA Pol using its RING domain, which has E3 ubiquitin ligase activity. Lys260 and Lys283 of HBV DNA Pol were identified as targets for ubiquitination mediated by TRIM21. Finally, we uncovered that TRIM21 degrades HBV DNA Pol to restrict HBV DNA replication, and its SPRY domain is critical for this activity. Taken together, our results indicate that TRIM21 suppresses HBV DNA replication mainly by promoting the ubiquitination of HBV DNA Pol, which may provide a new potential target for the treatment of HBV.

A same day 'test and treat' model for chronic HCV and HBV infection: Results from two community-based pilot studies in Egypt.

Prompt access to confirmatory viral load testing and staging of liver disease are key barriers in uptake of treatment for chronic hepatitis B and C infection. Our objective was to establish the feasibility of a same day 'test and treat' model in two distinct community-based settings in Egypt through use of key point-of-care(POC) portable tools for HCV and HBV viral load assessment and staging of liver disease followed by treatment initiation. Community sites were a village in northern Egypt (site 1) and a government office in Cairo (site 2). The following model was adopted: community awareness raising in the week before project initiation; site assessment to ensure optimal placement and calibration of equipment and clinical care set-up; transfer of key portable laboratory instruments to the sites (four cartridge GeneXpert, FibroScan and abdominal ultrasound); screening using rapid diagnostic tests for HCV-Ab and HBsAg, with immediate venous or finger-stick blood sampling for HCV-RNA and HBV-DNA assay, FibroScan staging of liver disease and ultrasound screening for liver cancer. At site 1, 475 individuals were screened over a single day, 125 were positive for HCV-Ab and 4 for HBsAg, 43 of 56 new HCV diagnoses were HCV RNA positive, and 3 of 4 HBsAgpositive were HBV DNA positive, 40 initiated HCV treatment, and one HBVtreatment. At site 2, 3188 individuals were screened over 3days, 157 were positive for HCV-Ab, and 27 for HBsAg; 38 of 76 new HCV diagnoses were HCV RNA positive, and 15 of 18 HBsAgpositivewere HBV-DNA positive. Across both sites, 78 patients were counselled and initiated on treatment for HCV and 12 for HBV within 3 and 4hours, respectively, of initial positive rapid diagnostic test result. We have shown the feasibility of a same day 'test and treat' model for chronic HCV and HBV infection in two community-based settings in Egypt that achieved high levels of linkage to care and initial treatment.

Pegylation and Cell Based Bioassay of Human Interferon-α2b Along its Docking Studies and Effect on Plasma Half-Life.

Interferon-α2b is FDA approved drug for the treatment of chronic HCV and HBV, melanoma, AIDS-related KS, carcinomas, hairy cell leukemia and chronic myelogenous leukemia. However, administration of interferon-α2b to patients takes place thrice in a week due to short in vivo circulation half-life. To extend the circulation half-life of IFN-α2b, it is conjugated with polyethylene glycol (PEG). However, PEGylation may results in reduction of its antiviral and antiproliferative activities but on the other side, it results in prolonged plasma half-life. Human interferon-α2b was PEGylated with linear 20kDa methoxypolyethlene glycol (mPEG) Propionaldehyde (IFN-Ald20K), Y-Shaped 40kDa mPEG-Propionaldehyde (IFNAld40K), linear 20-kDa mPEG-Succinimidyl Succinate (IFN-NHS20K), and Y shaped 40kDa mPEG-Succinimidyl Succinate (IFN-NHS40K). Impact of PEG size, shape and PEGylation site was studied to establish their relationship with antiprolifetaive activities and serum retention time of PEGylated IFN-α2b. RP-HPLC studies showed that larger PEGs (40kDa) increased the hydrodynamic volume and increased the serum retention time while antiproliferative activity in HepG2 cell line was decreased with increase in PEGylated interferon-α2b size. Molecular docking results also dictated the same effect that increase in PEGylated interferon-α2b size results in steric shielding of the receptor-binding site on interferon-α2b. IFN-Ald20K showed highest (45%) biological activity with serum half-life 40 hours while IFN-NHS40K showed least (7%) biological activity with serum halflife 56 hours. Thus, IFN-Ald40K with 12% residual activity and 62 hours of serum half-life proved to be a potent candidate for anticancer and antiviral effect with enhanced serum retention time.

The effect of tenofovir disoproxil fumarate on bone mineral density: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis (CRD#42017070552) to quantify the impact of oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) on bone mineral density (BMD) and the risk of osteoporosis, low bone mass and fractures, among people taking it as pre-exposure prophylaxis (PrEP), HIV treatment and HBV treatment. We searched MEDLINE and EMBASE for randomized controlled trials published from 1997-2018 reporting BMD, osteoporosis, low bone mass and/or fractures in treatment-naive patients taking compared with not taking TDF for 48 ±4 weeks. We pooled outcomes using DerSimonian random-effects models. Our search yielded 5,178 abstracts, representing 3,865 articles, with 25 meeting the inclusion criteria. TDF was associated with greater BMD decline when taken as PrEP (lumbar spine: mean difference [MD]=-0.82%, 95% CI=-1.28, -0.37%, I2=38%; total hip: MD=-0.81%, 95% CI=-1.22, -0.40%, I2=48%) and HIV treatment (lumbar spine: MD=-1.62%, 95% CI=-2.30, -0.95%, I2=93%; total hip: MD=-1.75%, 95% CI=-2.08, -1.42%, I2=83%; femoral neck: MD=-1.26%, 95% CI=-2.15, -0.38%, I2=43%) in comparison to those not taking TDF. Eight studies reported on incident osteoporosis or low bone mass, with variable results. Pooled results from five PrEP studies showed that TDF was not associated with increased fractures compared with no PrEP (RR=1.12, 95% CI=0.752, 1.74, I2=26%). TDF caused greater decreases in BMD than did comparators when used for all three indications and the magnitude of this decrease was larger for HIV treatment compared with PrEP. Fractures were not increased among PrEP patients. The clinically significant BMD decline caused by TDF and current expansion of PrEP use suggest attention to the adverse bone effects of TDF will increase in importance.

Low Level of Hepatitis B Surface Antigen Screening in a Tertiary Health Facility in Nigeria 2000-2014: Imperative for Provider Initiated Testing and Counselling for Hepatitis B Virus?

Introduction: Viral hepatitis is a major public health challenge that requires an urgent response. Reducing mortality requires major scale-up in prevention, testing and treatment access; coverage in HBV vaccination, testing and treatment is low and must accelerate massively to achieve the 2030 targets. Less than 1% of HBV-infected individuals are diagnosed in Sub-Sahara Africa, despite the availability of rapid tests with good diagnostic accuracy. Materials and Methods: This was retrospective cross sectional study conducted in Federal Teaching Hospital Gombe, in North East Nigeria. All children and adults who presented to the out-patient departments, and those that were admitted irrespective of their HIV and or Hepatitis C virus status and had Hepatitis B and/or Hepatitis B envelope antigen test were conducted between 2000 to 2015. All children and adults were tested using the Hospital standard for Hepatitis B surface antigen test strip. Results: Between 2000 and 2014, 739,456 children and adults were admitted and reviewed in the outpatient units of the Federal Teaching Hospital Gombe; there were 685,552 adults and 53,904 children. Children constituted 7.3% (53,904/739,456) of admissions and outpatient consultations. 2.8% (210/7570), 3.3% (773/23,783), 3.6% (1145/32,142), 5.2% (1694/33,043), 3.3% (986/29,216), 1.9% (661/3321), 0.1% (53/41,626), 0.2% (113/46,634), 2.6% (1418/54,423), 5.4% (3717/69,696), 3.7% (2332/62,086), 3.5% (3241/90,623), 3.2% (2881/89,398), 3.8% (2428/62,687), 2.8% (1835/63,208) of children and adults were tested for HBsAg in 2000, 2001, 20002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013 and 2014 respectively. 23,487 children and adults were tested for HBsAg with a cumulative testing rate of 3%. Overall 4465/23,487 children and adults were seropositive for HBsAg giving a cumulative prevalence of 19%. Conclusion: HBV screening in our health facility is very low. Massive scale up in awareness and HBV vaccination are required. Provider initiated testing and counseling for HBV in health facilities needs support for implementation in Health Facilities in Sub Saharan Africa.

Tenofovir does not induce renal dysfunction compared to entecavir in post-liver-transplant hepatitis B virus patients.

PurposeTenofovir disoproxil fumarate is accepted as an effective and tolerable drug for treatment of HBV, similar to entecavir. However, there are some concerns about the nephrotoxicity of tenofovir. The aim of this study is to compare the renal-function change of liver recipients who received tenofovir or entecavir for HBV.MethodsAmong 468 patients with HBV who underwent liver transplantation at Samsung Medical Center between January 2008 and December 2015, the patients treated with tenofovir (n = 39) or entecavir (n = 429) were reviewed retrospectively. Baseline characteristics and renal-function change after 1 month, 1 year, and 2 years were compared. Propensity-score matching was performed for 37 patients using tenofovir and 132 patients using entecavir. We also analyzed risk factors of renal dysfunction.ResultsAge, preoperative creatinine, estimated glomerular filtration rate (e-GFR), and hepatic encephalopathy score showed statistical difference between the tenofovir and entecavir groups. The proportion of patients with ‘decreased renal function (e-GFR < 60 mL/min/1.73 m2)’ was higher in the tenofovir group than in the entecavir group (33.3% vs. 12.4% at postoperative one year, P < 0.005). After propensity-score matching, there was no statistical difference in preoperative characteristics. Postoperative 1-, 2-, and 3-year e-GFR and creatinine showed no statistical difference in either group. On multivariate analysis, only preoperative high e-GFR showed a protective effect on renal-function change (odds ratio, 0.97; P < 0.001), and there was no aggravating factor.ConclusionTenofovir disoproxil fumarate does not induce renal dysfunction in liver-transplanted patients with HBV more than does entecavir.

Albumin-bilirubin score is associated with response to pegylated interferon and nucleos(t)ide analogues in chronic hepatitis B patients

Background and aimRecently, the role of albumin-bilirubin (ALBI) score in chronic hepatitis B (CHB) has not been well-understood. We aimed to investigate the association of ALBI score with natural history of chronic HBV infection and treatment response of CHB patients. MethodsThe ALBI score in a cohort of 849 individuals including 721 chronic HBV-infected patients naïve to anti-HBV treatment in different phases and 128 healthy controls were estimated. Additionally, the dynamic changes of ALBI score of 243 hepatitis B e antigen (HBeAg)-positive CHB patients treated with pegylated interferon-alpha (PEG-IFN-α) or nucleos(t)ide analogues (NAs) were tested for 72 weeks. ResultsALBI score differed among phases, with the highest score in HBeAg-positive CHB patients, followed by HBeAg-negative CHB patients, HBeAg-positive chronic HBV infection, and HBeAg-negative chronic HBV infection. Besides, CHB patients harbouring high baseline ALBI score exhibited a relatively stronger therapeutic response to PEG-IFN-α or NAs. Moreover, the rate of HBeAg and HBsAg loss in patients with ALBI grade 2 was persistently higher than that in patients with ALBI grade 1 throughout the course of treatment. Furthermore, ALBI score was an independent predictor of sustained response achievement. The combined use of ALBI score, HBeAg and ALT could enhance the predictive value of treatment response. ConclusionsALBI score differed significantly across the natural course of chronic HBV infection and was correlated with PEG-IFN-α and NAs treatment response in HBeAg-positive CHB patients, which suggested that ALBI score could be useful as an auxiliary clinical factor to determine the initiation of therapy and predict stronger antiviral treatment response.

285. Fibrosis Progression and Clinical Outcomes in HCV/HBV Coinfected Persons in the ERCHIVES Cohort

BackgroundProgression of liver disease and clinical outcomes in HCV/HBV coinfected persons and how they differ from HCV monoinfected persons and HCV infected persons with resolved HBV infection are not well characterized. We compared incidence of cirrhosis, hepatic decompensation and overall mortality in these three groups.MethodsUsing the Electronically Retrieved Cohort of HCV-infected Veterans (ERCHIVES), we identified those with HCV infection only, HCV/HBV coinfection (HbsAg or HBV DNA or both positive) or HCV with resolved HBV (HbcAb+ in absence of HbsAg or HBV DNA positivity). We excluded those with HIV coinfection or hepatocellular carcinoma at or before baseline, and those who received any HCV or HBV treatment. Incident rates (95% CI) were determined for cirrhosis, first hepatic decompensation event and overall mortality in the three groups.ResultsWe identified 60,368 HCV monoinfected (Gp A), 151 HCV/HBV coinfected (Gp B) and 19,802 HCV infected with resolved HBV infection (Gp C). Mean age was 61.0, 60.9, and 63.0 years in the three groups and 96.5%, 96.0%, and 97.9% were males. Median baseline FIB-4 index was 2.0, 2.2, and 2.1, respectively. Incident cirrhosis (among those without cirrhosis at baseline) was increased 2- to 2.5-fold in HCV/HBV coinfected persons with baseline FIB-4 of 1.46–3.25. Hepatic decompensation and mortality were also increased several-fold in the HCV/HBV coinfected who had minimal or mild/moderate fibrosis at baseline. However, among those with cirrhosis at baseline, the difference was small among HCV/HBV coinfected and the other groups.ConclusionHCV/HBV coinfected persons with minimal or mild/moderate fibrosis at baseline have a much higher risk of developing cirrhosis, hepatic decompensation and mortality. However, once cirrhosis has is established, the difference is diminished. This underscores the need to intervene early when HCV/HBV coinfected persons still have minimal or mild/moderate fibrosis. Disclosures All authors: No reported disclosures.

Restoring, releasing or replacing adaptive immunity in chronic hepatitis B.

Multiple new therapeutic approaches are currently being developed to achieve sustained, off-treatment suppression of HBV, a persistent hepatotropic infection that kills ~2,000 people a day. A fundamental therapeutic goal is the restoration of robust HBV-specific adaptive immune responses that are able to maintain prolonged immunosurveillance of residual infection. Here, we provide insight into key components of successful T cell and B cell responses to HBV, discussing the importance of different specificities and effector functions, local intrahepatic immunity and pathogenic potential. We focus on the parallels and interactions between T cell and B cell responses, highlighting emerging areas for future investigation. We review the potential for different immunotherapies in development to restore or release endogenous adaptive immunity by direct or indirect approaches, including limitations and risks. Finally, we consider an alternative HBV treatment strategy of replacing failed endogenous immunity with infusions of highly targeted T cells or antibodies.

Synthesis, pharmacological evaluation, and mechanistic study of adefovir mixed phosphonate derivatives bearing cholic acid and l-amino acid moieties for the treatment of HBV

The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephrotoxicity. A series of adefovir mono l-amino acids, mono cholic acid-drug conjugates were designed and synthesized, and their antiviral activity and uptake in rat primary hepatocytes and Na+-dependent taurocholate co-transporting polypeptide (NTCP)-HEK293 cells were evaluated. We isolated compound 6c as the optimal molecular candidate, with the highest antiviral activity (EC50 0.42 μmol/L, SI 1063.07) and highest cellular uptake in primary hepatocytes and NTCP-HEK293 cells. In-depth mechanistic studies demonstrated that 6c exhibited a lower toxicity in HK-2 cells when compared to adefovir dipivoxil (ADV). This is because 6c cannot be transported by the human renal organic anion transporter 1 (hOAT1). Furthermore, pharmacokinetic characterization and tissue distribution of 6c indicates it has favorable druggability and pharmacokinetic properties. Further docking studies suggested compounds with ursodeoxycholic acid and l-amino acid groups are better at binding to NTCP due to their hydrophilic properties, indicating that 6c is a potential candidate as an anti-HBV therapy and therefore merits further investigation.

Proceedings of the Canadian Association for HIV Research: Canadian Foundation for Infectious Diseases Professional Development Workshop for Viral Researchers.

In March 2018, the Canadian Association for HIV Research (CAHR) and Canadian Foundation for Infectious Diseases (CFID) collaborated to conduct a workshop targeted to mid-career virology researchers. Key objectives of the workshop included 1) sharing knowledge and expertise cutting across various viral diseases, 2) developing collaborations as we anticipate the next wave of suppressive and curative treatment for HIV, HBV, CMV, and other viral diseases, and 3) providing insights, advice, and "food for thought" as participants advance to mid- and later phases of their research careers. This article reports on the key topics contemplated including scientific misinformation within the public realm, network building, interdisciplinary collaboration, mentorship, and communicating with decision makers. Given the focus on virology, the Canadian Society for Virology was invited to highlight their efforts to build a cohesive network that is impactful in facilitating viral research in Canada including advocating for appropriate levels of peer-reviewed research funding. Many key pearls of wisdom are contained within this document which are of value to all researchers aiming for success in a continually evolving, complex, and challenging Canadian research and academic environment.

PIN9 CLINICAL PRACTICE EXPERIENCE WITH TENOFOVIR ALAFENAMIDE (TAF) FOR TREATMENT OF HEPATITIS B IN THE US

Tenofovir disoproxil fumarate (TDF) is effective for treatment of Hepatitis B but may be associated with bone loss and kidney problems in susceptible individuals. Tenofovir alafenamide (TAF) is a novel pro-drug formulation with an improved safety profile for bone loss and renal injury. Here, we assess the clinical experience with TAF for Hepatitis B in the US. The TRIO HBV Registry, consisting of 1078 enrolled patients from 6 academic and 4 community-based centers serving 17 US States, was created to understand real-world HBV treatment. Data presented here are limited to 250 registry patients who initiated TAF between Nov 2016 and Apr 2018, received ≥6 months of TAF therapy, and were followed up to 18 months. Characteristics of the study population: median age 52 years, BMI 24.3 kg/m2, male (147/250, 59%), Asian ethnicity (220/250, 88%), HBeAg positive (54/250, 22%), osteopenia/osteoporosis (47/250, 19%), and FIB-4 >3.25 (17/250, 7%). Mean and median TAF duration was 13 months as of data collection. 233/250 (93%) of patients receiving TAF switched from TDF (214/233, 92%), entecavir (16/233, 7%), or other therapies (3/233, 1%). HBV DNA suppression (<2000 IU/ml) increased from 93% (233/250) patients at baseline to 99% after 6 or 12 months TAF (249/250, p=0.001). In paired comparisons, mean eGFR increased 5% from baseline 85.7 to 90.1 ml/min (p<0.001) after 6 months of TAF therapy (n=213) and 4% from baseline 86.9 to 90.5 ml/min (p=0.001) after 12 months of TAF (n=158). Normal ALT (≤29 U/L females, ≤35 U/L males) increased from 71% patients at baseline to 86% after 6 months TAF (n=219, p=0.001) and from 69% at baseline to 87% after 12 months TAF (n=147, p=0.001). In US, clinical practice experience with TAF indicates effective HBV suppression and improved renal function and ALT normalization.

Development of a Transdermal Delivery System for Tenofovir Alafenamide, a Prodrug of Tenofovir with Potent Antiviral Activity Against HIV and HBV

Tenofovir alafenamide (TAF) is an effective nucleotide reverse transcriptase inhibitor that is used in the treatment of HIV-1 and HBV. Currently, it is being investigated for HIV prophylaxis. Oral TAF regimens require daily intake, which hampers adherence and increases the possibility of viral resistance. Long-acting formulations would significantly reduce this problem. Therefore, the aim of this study was to develop a transdermal patch containing TAF and investigate its performance in vitro through human epidermis. Two types of TAF patches were manufactured. Transparent patches were prepared using acrylate adhesive (DURO-TAK 87-2516), and suspension patches were prepared using silicone (BIO-PSA 7-4301) and polyisobutylene (DURO-TAK 87-6908) adhesives. In vitro permeation studies were performed while using vertical Franz diffusion cells for seven days. An optimized silicone-based patch was characterized for its adhesive properties and tested for skin irritation. The acrylate-based patches, comprising 2% w/w TAF and a combination of chemical enhancers, showed a maximum flux of 0.60 ± 0.09 µg/cm2/h. However, the silicone-based patch comprising of 15% w/w TAF showed the highest permeation (7.24 ± 0.47 μg/cm2/h). This study demonstrates the feasibility of developing silicone-based transdermal patches that can deliver a therapeutically relevant dose of TAF for the control of HIV and HBV infections.