Faculty Bibliography

Background: Interferon monotherapy or oral agents with add-on interferon treatment provides significantly higher rates of HBsAg loss compared to oral antiviral therapy in chronic hepatitis B (CHB) patients. We evaluate the post-treatment sustainability of HBsAg loss and clearance of viremia with interferon monotherapy versus the add-on therapy. Methods: We prospectively enrolled CHB Patients who achieved HBsAg loss and HBV DNA levels <20 IU/mL through interferon or oral agents with add-on interferon treatment within post-treatment 24 weeks. Participants were followed every 12 weeks until week 96. Primary outcomes were the percentage of patients with HBsAg seroreversion and/or viremia at week 96. Secondary measurements included clinical relapse, HBeAg seroreversion, and predictor(s) for HBsAg seroreversion or viremia. Subgroup analyses were performed and compared between the two groups (ClinicalTrials.gov ID: NCT02336399). Results: Among 420 consecutive patients enrolled, 70% were male, mean age 39.53+/-9.80, 58% HBeAg positive before treatment, and 7.79% HBeAg positive after treatment. There were 290 and 130 patients received interferon and the addon therapy, respectively (Table 1). At week 96 assessment of 376/420 (90%) patients, the cumulative rates of HBsAg seroreversion, recurrent viremia, and clinical relapses were 14.8%, 5.0%, and 0.5% respectively. When compared the two groups with on-protocol analyses, all endpoints were similar between groups; which included HBsAg seroreversion (15.5% vs 15.3%, p=0.950), viremia (6.59% vs 4.24%, p=0.367), clinical relapse (0.39% vs 0.85%, p=0.530), and HBeAg seroreversion (0% vs 0.85% p=0.314). Additionally, the intention-to-treat analyses or analyses based on the last available test results showed no difference on these endpoints between groups. The clinical outcomes were similar when compared patients who received entecavir vs. telbivudine/lamivudine/adefovir prior to the add-on therapy. The multivariance analyses showed that post-treatment HBeAg positivity was a positive predictor for recurrent viremia and HBsAg seroreversion at week 96 (OR 8.412, 95% CI: 1.430-49.493; p=0.019). Conclusion: Patients who received oral antiviral therapy with add-on interferon to achieve HBsAg loss and clearance of viremia had sustainable outcomes in 96 weeks, which were comparable with those of interferontreated patients. Our data supports adding interferon treatment to patients without HBsAg loss on antiviral therapy. (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.

INTRODUCTION/BACKGROUND:We aimed to characterize postpartum disease flares among treatment-naive mothers with chronic hepatitis B (CHB). CHB mothers were enrolled and compared with non-infected mothers in terms of postpartum alanine aminotransferase (ALT) abnormalities. METHODS:Demographic, virological, and biochemical parameters were collected up to postpartum week 16, with flares and exacerbations defined as ALT levels 5-10 and >10 times the upper limit of normal, respectively. Outcome assessments included ALT flares or exacerbation and their predictive parameters. RESULTS:IU/mL at delivery predicted ALT events (positive predictive value, 14.4%; negative predictive value, 98.2%). CONCLUSIONS:IU/mL at delivery.

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: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.

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.

There is little information on the association between baseline non-structural protein (NS) 5b resistance-associated variants (RAVs) and treatment failure in hepatitis C patients. This study examined the frequencies of natural hepatitis C virus (HCV) NS5B resistance-associated variants (RAVs) in an Asian cohort. Samples from Asian HCV patients enrolled between October 2009 and September 2014 were analyzed for NS5B RAVs within the region from amino acid 230 to 371. Serum samples were tested by PCR genotyping, with sequence alignment performed using the neighbor-joining method. NS5B was detected by Sanger sequencing followed by Geno2pheno analysis. NS5B RAVs were detected in 80.52% (1199/1489) of patients; 68.4% (1019/1489) and 79.7% (1186/1489) were associated with resistance to sofosbuvir (SOF) and dasabuvir (DSV), respectively. These RAVs were present in 95% (1004/1058) of genotype 1b patients. When genotypes 1b and 2a were compared, SOF-associated RAVs were detected at a higher frequency in genotype 1b (94.8% [1004/1058] vs. 2.9% [9/309]; chi2 = 1054.433, P < 0.001), C316H/N was more common in genotype 1b (94.7% [1002/1058] vs. 0% [0/309]; chi2 = 1096.014, P < 0.001), M289F/L/I/W/V had a higher frequency in genotype 2a (0.7% [7/309] vs. 2.3% [7/1058]; chi2 = 4.589, P = 0.032), DSV-associated RAVs were most often found in genotype 1b (95.0% [1005/1058] vs. 40.1% 124/309]; chi2 = 500.577, P < 0.001), and frequency of C316Y/H/N/W was higher in genotype 1b (94.7% [1002/1058] vs. 0% [0/309]; chi2 = 1096.014, P < 0.001). In conclusion, baseline SOF and DSV RAVs are common in Asian HCV patients and predominantly occur in genotype 1b.

BACKGROUND: TAF has shown less bone and renal effects with similar efficacy rates compared to TDF in two large multinational Phase 3 studies after 96 weeks of double-blind (

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]