Faculty Bibliography

Although gut dysbiosis appears in 20%-75% of cirrhotic patients, there are limited data on microbiota profiles in viral hepatitis cirrhotics and its role in progression to cirrhosis. Further understanding on the relationship between gut dysbiosis and cirrhosis presents a unique opportunity in not only predicting the development of cirrhosis but also discovering new therapies. Recent advances have been made on identifying unique microbiota in viral hepatitis cirrhotics and adopting the microbiota index to predict cirrhosis. Therapeutic intervention with microbiome-modulating has been explored. Cirrhosis from viral infection has unique bacterial or fungal profiles, which include increased numbers of Prevotella, Streptococcus, Staphylococcaceae, and Enterococcus, as well as decreased Ruminococcus and Clostridium. In addition, the gut microbiota can stimulate liver immunity, effectively helping hepatitis virus clearance. In clinical settings, CDR, GDI, Basidiomycota/Ascomycota, specific POD, and so forth are efficient microbiota indexes to diagnose or prognosticate cirrhosis from viral hepatitis. FMT, probiotics, and prebiotics can restore microbial diversity in cirrhotic patients with viral hepatitis, decrease ammonia serum or endotoxemia levels, prevent complications, reduce rehospitalization rate, and improve prognosis. Cirrhotics from viral hepatitis had unique bacterial or fungal profiles, associated with specific metabolic, immune, and endocrinological statuses. Such profiles are modifiable with medical treatment. The role of gut archaea and virome, implementation of FMT, microbiota metabolites as adjuvant immunotherapy, and microbiota indexes for prognostication deserve attention.

Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In 2 clinical trials, 1298 HBeAg-positive and HBeAg-negative patients with CHB were randomized 2:1 and treated with TAF (n=866) or TDF (n=432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (pol/RT) were assessed using INNO-LiPA Multi DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ≥69IU/mL) by HBV pol/RT sequencing at week 96 or at discontinuation. In vitro phenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to study drug. At baseline, the majority of patients harbored virus with wild type pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF 11.1%, TDF 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF: 2.8%, TDF: 3.2%) that was often associated with drug nonadherence (TAF: 30%, TDF: 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96 with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibility in vitro. After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA <69 IU/mL) was similar across treatment groups and no substitutions associated with resistance to TAF or TDF were detected.

Background: TAF provides similar efficacy to tenofovir disoproxil fumarate (TDF) but with an improved safety profile particularly for renal injury and bone loss. Here, we evaluate clinical characteristics for patients switching to TAF during the first year of availability in US. Methods: TRIO has developed a national HBV network consisting of 7 academic and 4 community-based centers serving 17 US States to understand real-world HBV treatment. This study started Nov 2016 and is planning to enroll 1000 patients. HBV data is obtained retrospectively from patient records and then followed for 2 years through an electronic registry. To assess early TAF adoption, data are presented for 320 patients who switched nucleos(t)ide (NUC) therapy Nov 2016 to Oct 2017 or who did not switch but were followed during the same period. Results: Treatment for 320 patients at enrollment: 227 (71%) TDF, 72 (23%) entecavir (ETV), 12 (4%) TDF + emtricitabine (FTC), 10/375 (3%) lamivudine (3TC), and 2/375 (1%) adefovir dipivoxil (ADV). Of 320, 156 (49%) switched NUCs to: 144/156 (92%) TAF, 5/156 (3%) TDF, 3/156 (2%) 3TC, 2/156 (1%) ETV + TDF, 1/156 (1%) ETV, and 1/156 (1%) 3TC + TDF. Physician-provided reasons for switching to TAF included: 83/144 (58%) safety concerns or side effects, 46/144 (32%) physician preference, and 7/144 (5%) lack of efficacy. TAF switchers previously received: 131/144 (91%) TDF, 8/144 (6%) ETV, 4/144 (3%) TDF + FTC, and 1/144 (1%) ADV. TAF switchers did not significantly differ from the non-switchers for demographics, select comorbidities, HBeAg status, HBV DNA, nor degree of fibrosis [TABLE]. In the non-switch group, 7/164 (4.3%) patients had eGFR <60 ml/min vs 12/122 (9.8%) for TAF switchers; however, these results were not significantly different. Within the TAF switch group, from the time of enrollment to the date of switch, 52/122 (43%) patients had a 14% mean eGFR reduction. Bone density scans were available for 102/320 (32%) patients. A Z score of-1 or less indicating bone disease was recorded for 62, of which 40/62 (65%) switched to TAF. Conclusion: In the first year after TAF approval, almost 50% of study patients switched to TAF, predominantly for safety concerns or physician preference. For some who switched, renal (43%) and bone changes (65% of those tested) were shown. Many patients who did not switch had similar bone and renal findings. Further follow up will evaluate prospective criteria for switch strategies. (Figure Presented)

Background: Cumulative resistance analyses were performed through Week 144 for 2 Phase 3 studies (GSUS-320-0108, GS-US-320-0110) evaluating tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B in HBeAg+ or HBeAgtreatment-naive or treatment-experienced adults. Methods: Patients were randomized 2:1 and stratified by HBV DNA level and treatment status to receive TAF or TDF double-blind (

Background: Few studies have evaluated the treatment landscape of chronic HBV in the US, where estimates range from 850,000 to 2.2 million people living with HBV. TRIO analytics has developed a national HBV network consisting of 7 academic and 4 community-based centers serving 17 States in the US, with the goal of understanding the realworld treatment of HBV in US clinical practice. We report here the demographic and clinical characteristics of this large cohort at enrollment. Methods: This is an observational, retrospective and prospective study of HBV patients which started in Nov 2016 and is planning to enroll 1000 patients and follow them for up to 2 years. At enrollment HBV data are retrospectively obtained from patient records through an electronic registry which collects patient demographics, treatment experience, disease characteristics, comorbidities, and lab measures. Results: 884 patients have been enrolled and data are available for this analysis on 601 patients. Select characteristics are shown in the TABLE. The majority were Asian and 8% were African or African-American. Mean age was 51 years and over 75% were HBeAg negative. Any evidence of fibrosis (measured by Fib-4 > 1.45) was 29% and cirrhosis (Fib-4 > 3.25) was 5%. At enrollment 540 patients (90%) were on treatment: 363/540 (67%) tenofovir disoproxil fumarate (TDF), 129/540 (24%) entecavir (ETV), 24/540 (4%) TDF + emtricitabine (FTC), 12/540 (2%) lamivudine (3TC), 9/540 (2%) initiated tenofovir alafenamide (TAF), and 3/540 (1%) adefovir dipivoxil (ADV). Overall 32 of 540 (6%) treated patients had viral loads >=2000 IU/ml at entry. Providerreported reasons for non-treatment of 61 patients were: 51/61 (84%) lack of clinical indication (HBeAg-/Ab+, normal liver function, and/or undetected viral load), 5/61 (8%) patient refusal, and 5/61 (8%) reason unspecified. Comorbidities of interest for risk of renal disease included hypertension (25%), diabetes (12%), and overall 51% had evidence of eGFR < 90 ml/min which was more common in treated patients. Conclusion: The HBV population in this US cohort is older, HBeAg negative, predominantly non-advanced liver disease and with significant co-morbidities. Current treatment is dominated by TDF and ETV with a high level of virological suppression. Full enrollment and prospective data over 2 years is ongoing. (Table Presented)

Background: Randomized-trial data on the long-term effects on infants' physical growth and neurodevelopment of the use of tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) mothers are lacking. Methods: All 180 infants who completed the IN-US174-0174 study were offered participation in a long-term follow-up (LTFU) study.1 They were from CHB mothers who were randomly assigned (1:1 ratio) to receive usual care without antiviral therapy or to receive TDF from 30 to 32 weeks of gestation until postpartum week 4. For the LTFU study, infants were assessed at the ages of 72, 120 and 192 weeks for growth and neurodevelopment with Bayley-III measurement. Their bone mineral density (BMD) was measured at week 192. The neurodevelopmental delay was defined by cognitive and language composite scores <85 (1 SD below the mean of 100).2 These parameters were compared between the TDF-exposed and TDFunexposed groups. Results: Among 180 infants completed in the initial study, 176 (98%) participated in the LTFU study and 144 (82%) completed the LTFU. In the TDF-exposed group, the mean (+/-SD) duration of fetal exposure to TDF was 8.57+/-0.53 weeks. The gestational age, delivery mode, weight, height, and Apgar score at birth were similar in the two groups. At week 192, there was no significant difference in the pre-specified outcomes between groups including head circumference, height, BMD, cognitive, social-emotional, and adaptive behavior measurements between groups. There was no neurodevelopmental delay in the cohort. In the TDF-exposed group, children had significantly higher motorcomposite scores (146.46+/-6.39 vs 142.88+/-9.54; p=0.009) and boys had significantly lower mean body weight (18.48+/-2.35kg vs 19.84+/-3.46kg; p= 0.029). However, the boys' mean body weight in the TDF-exposed group was significantly higher than that of the national Chinese reference value of 4-year-old boys (18.48+/-2.35kg vs 16.64+/-1.89; p=0.010).3Conclusion: Among infants with fetal exposure to TDF, the physical growth, BMD, and neurodevelopment were similar to those without the exposure and within the normal range of Chinese reference values during 192-week follow-up. Our data support the safety of using TDF during the third trimester in mothers with CHB. Acknowledgment: (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01488526.) References: Pan CQ, Duan Z, Dai E, et al. Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load. N Engl J Med 2016;374:2324-34. Johnson S, Moore T, Marlow N. Using the Bayley-III to assess neurodevelopmental delay: which cut-off should be used? Pediatr Res 2014;75:670-4. Li H. [Growth standardized values and curves based on weight, length/ height and head circumference for Chinese children under 7 years of age]. Zhonghua Er Ke Za Zhi 2009;47:173-8. (Table Presented)

Background: In 2 identically-designed double-blind, randomized (2:1), Phase 3 studies, TAF has shown efficacy non-inferior to that of TDF at Weeks 48 and 96, with a superior renal and bone safety profile. Following a protocol amendment, 50% of enrolled patients had their double-blind (

Background: Mother-to-child transmission (MTCT) is responsible for the majority of chronic hepatitis B (CHB) infections worldwide. Identification and evaluation of pregnant women with CHB are key steps to reducing MTCT. We aimed to assess demographic and clinical characteristics and MTCT risk in Asian American women with CHB receiving prenatal care at two community health center sites in New York City. Methods: We performed a retrospective cross-sectional study of all women with CHB evaluated with HBV DNA during prenatal care from 2007 to 2017. Clinical and demographic data were extracted from medical records and analyzed. We measured the percentage of pregnant women not on antiviral treatment at high-risk for MTCT, defined by highly viremic levels (HBV DNA >=200,000 IU/mL), then further analyzed by HBeAg status, alanine aminotransferase (ALT) levels, age, birth region, and other demographic variables to measure association with MTCT risk using logistic regression analysis. Results: There were a total of 978 unique pregnancies in 804 HBsAg-positive women included in this study. All 804 women were born in Asia with 786 (97.8%) born in China, and 589 (73.3%) from China's Fujian province. Of 978 unique pregnancies, the women's mean (range) age and gestational age at the time of initial HBV DNA levels were 29.2 (18-55) years and 16.9 (1.0-38.4) weeks, respectively. The distribution of initial HBV DNA and ALT level during each unique pregnancy is presented in Figure 1. Of 933 unique pregnancies of women not on HBV antiviral treatment at initial evaluation, 203 (21.8%) had a HBV DNA level >=200,000 IU/mL of which 185 (91.1%) were HBeAg-positive, 15 (7.4%) were HBeAg negative, and 3 (1.5%) were unknown. HBeAg-positive status (aOR 204.2, CI 104.0-400.8, p<0.01) and elevated ALT (aOR 1.02, CI 1.01-1.03, p<0.01) were associated with increased odds for high levels of viremia. Conclusion: At two community health sites providing perinatal HBV care to primarily Asian American patients, 21.8% of pregnant women were high risk for MTCT. While HBeAg-positive status was associated with high viremia, it is a limited predictor of MTCT alone as 7.4% of high risk patients were HBeAg-negative. Full assessment of CHB pregnant women and early coordinated care is needed to offer and deliver interventions to prevent MTCT during critical windows of time including antiviral therapy for highly viremic women. (Figure Presented)