Faculty Bibliography

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:Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed drugs and can cause drug-induced liver injury. Although patients with drug-induced liver injury from NSAIDs often recover spontaneously, 3% of them required hospitalization and those with persistent cholestasis present a diagnostic challenge. Recently, a few cases of children with persistent jaundice reported have been linked to the vanishing bile duct syndrome. However, data on adult patients is limited. CASE PRESENTATION/METHODS:We report herein a case of an adult patient who had persistent cholestasis with hyperlipidemia from the VBDS after ibuprofen use. We described a female patient with severe jaundice after taking ibuprofen, although she had no history of liver disease before. The drug-induced liver injury from ibuprofen was identified by clinical features and liver biopsy, which included the Roussel Uclaf Causality Assessment Method scores of 6 and pathological features of cholestasis with stage four drug-induced injury as well as loss of bile duct structures. The clinical course was featuring with persistently high levels of bilirubin associated with hyperlipidemia over the period of one month, although the laboratory abnormalities were slightly improved spontaneously after the cessation of ibuprofen. Her autoantibodies markers including AMA-M2 ASMA, RO-52, LKM, SLA, and anti-glycoprotein-210 were negative. The second liver biopsy was performed on day 213 due to persistent hyperbilirubinemia. Pathological findings were consistent with the diagnosis of vanishing bile duct syndrome. CONCLUSIONS:A rare case of ibuprofen-associated vanishing bile duct syndrome in an adult female patient is presented. Clinicians need to be aware of vanishing bile duct syndrome as a serious consequence of ibuprofen use in adult patients, although ibuprofen is considered to be among the safest NSAIDs.

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.

Plasmacytoid dendritic cells (pDCs) are crucial for control of chronic hepatitis B (CHB) virus infection. In this study, we evaluated the frequencies of pDCs and expression of functional molecules on pDCs in patients treated with PEG-IFN-α-2a or entecavir (ETV) and investigated changes during treatment. The mean fluorescence intensity of CD86 (CD86MFI) on the surface of pDCs and frequencies of pDCs and CD86⁺ pDCs in peripheral blood were measured. Compared with baseline, CD86⁺ pDC% and CD86MFI increased obviously after PEG-IFN-α-2a treatment for 12 and 24 weeks. For patients treated with ETV, only pDC% increased observably after treatment weeks 12 and 24 (P < 0.001) compared with baseline. Hepatitis B surface antigen (HBsAg) decline was significantly associated with elevated CD86⁺ pDC% (r = 0.348, P = 0.015) during PEG-IFN-α-2a treatment. In the HBsAg response group, CD86⁺ pDC% and CD86MFI (P < 0.001) increased observably after PEG-IFN-α-2a therapy, whereas only CD86MFI had a statistically significant difference after therapy compared with baseline (12 weeks versus 0 weeks, P = 0.022; 24 weeks versus 0 weeks, P = 0.015) in the HBsAg nonresponse group. CD86⁺ pDC% between the 2 groups had statistically significant differences at baseline (P = 0.001) and at the treatment time points of 12 and 24 weeks (P < 0.001), respectively. For patients receiving ETV therapy, pDC% increased observably, but CD86⁺ pDC% decreased significantly (P < 0.001) in the HBV DNA nonresponse group during early treatment with ETV. In CHB patients, HBsAg response in PEG-IFN-α-2a therapy correlated with the increase of CD86⁺ pDC% and HBV DNA nonresponse in ETV treatment correlated with the decrease of CD86⁺ pDC%.

BACKGROUND & AIMS/OBJECTIVE:Tenofovir alafenamide (TAF) is a new prodrug of tenofovir developed to treat patients with chronic hepatitis B virus (HBV) infection at a lower dose than tenofovir disoproxil fumarate (TDF) through more efficient delivery of tenofovir to hepatocytes. In 48-week results from two ongoing, double-blind, randomized phase III trials, TAF was non-inferior to TDF in efficacy with improved renal and bone safety. We report 96-week outcomes for both trials. METHODS:In two international trials, patients with chronic HBV infection were randomized 2:1 to receive 25 mg TAF or 300 mg TDF in a double-blinded fashion. One study enrolled HBeAg-positive patients and the other HBeAg-negative patients. We assessed efficacy in each study, and safety in the pooled population. RESULTS:At week 96, the differences in the rates of viral suppression were similar in HBeAg-positive patients receiving TAF and TDF (73% vs. 75%, respectively, adjusted difference -2.2% (95% CI -8.3 to 3.9%; p = 0.47), and in HBeAg-negative patients receiving TAF and TDF (90% vs. 91%, respectively, adjusted difference -0.6% (95% CI -7.0 to 5.8%; p = 0.84). In both studies the proportions of patients with alanine aminotransferase above the upper limit of normal at baseline, who had normal alanine aminotransferase at week 96 of treatment, were significantly higher in patients receiving TAF than in those receiving TDF. In the pooled safety population, patients receiving TAF had significantly smaller decreases in bone mineral density than those receiving TDF in the hip (mean % change -0.33% vs. -2.51%; p <0.001) and lumbar spine (mean % change -0.75% vs. -2.57%; p <0.001), as well as a significantly smaller median change in estimated glomerular filtration rate by Cockcroft-Gault method (-1.2 vs. -4.8 mg/dl; p <0.001). CONCLUSION/CONCLUSIONS:In patients with HBV infection, TAF remained as effective as TDF, with continued improved renal and bone safety, two years after the initiation of treatment. Clinicaltrials.gov number: NCT01940471 and NCT01940341. LAY SUMMARY/UNASSIGNED:At week 96 of two ongoing studies comparing the efficacy and safety of tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B patients, TAF continues to be as effective as TDF with continued improved renal and bone safety. Registration: Clinicaltrials.gov number: NCT01940471 and NCT01940341.

Background: TAF, a novel prodrug of tenofovir, has demonstrated efficacy noninferior to that of TDF at Week 48 in patients with chronic HBV (CHB) with significantly reduced bone and renal effects. Here we evaluated the efficacy and safety of TAF vs TDF in the subset of patients of Chinese ethnicity enrolled in two overseas studies. Method: In 2 Phase 3 studies, HBeAg-negative (Study 108) and HBeAg-positive (Study 110) CHB patients were randomized 2:1 to TAF 25 mg QD or TDF 300 mg QD and treated for 96 weeks. In this analysis, the efficacy (HBV DNA\29 IU/mL, biochemical and serological responses) and safety, including assessment of bone and renal parameters, were evaluated in the subset of Asian patients enrolled in sites outside of China who self-identified to be of Chinese ethnicity. Result: Of 1298 patients randomized and treated, 471 (36%) were of Chinese ethnicity; 156 (TAF 97; TDF 59) and 315 (TAF 207; TDF 108) patients were HBeAg-negative and HBeAg-positive, respectively. For the TAF and TDF groups within each study, baseline characteristics of the study populations were generally similar. Key efficacy results at Weeks 48 and 96 are presented in the Table. In both HBeAg-negative and HBeAg-positive patients of Chinese ethnicity, the antiviral efficacy of TAF was similar to that of TDF and results were comparable to those in the overall overseas population. Numerically higher percentages of patients treated with TAF achieved normalization of serum ALT values and anti-HBe seroconversion at Weeks 48 and 96. The safety of TAF and TDF, including changes in renal and bone parameters were similar to results previously reported in the overall overseas population. Conclusion: In CHB patients of Chinese ethnicity, TAF 25 mg showed similar antiviral efficacy to TDF 300 mg, with less change in bone and renal parameters. Results in this subgroup were comparable to those in the overall population. [Table Presented]

BACKGROUND:Hepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide. AIM/OBJECTIVE:To generate recommendations for the management of Asian Americans infected with HBV. METHODS:These guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women. RESULTS:, basal core promoter (BCP) mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive life-long anti-viral therapy. Indications for treatment include pregnant women with high viraemia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg positive patients with risk factors, life-long surveillance for HCC with alpha-fetoprotein (AFP) testing and abdominal ultrasound examination at 6-month intervals is required. In CHB patients receiving HCC treatments, repeat imaging with contrast CT scan or MRI at 3-month intervals is strongly recommended. These guidelines have been assigned to a Class (reflecting benefit vs. risk) and a Level (assessing strength or certainty) of evidence. CONCLUSIONS:Application of the recommendations made based on a review of the relevant literature and the opinion of a panel of Asian American physicians with expertise in HBV treatment will inform physicians and improve patient outcomes.