Faculty Bibliography

Background: Pre-core and/or basal core promoter mutations are frequently detected in HBeAg(-) CHB patients, but little is known about the clinical significance of their presence in HBeAg(+) patients. Methods We performed a 2 center cross-sectional study on treatment-naive CHB patients. Clinical characteristics were compared between HBeAg(+) and HBeAg(-) cohorts with mutation analysis. In addition, patients with and without PC/BCP mutations in HBeAg (+) cohort were compared. Results We enrolled 267 consecutive patients with obtainable mutation analysis in 2 centers. Of 177 HBeAg(+) patients, 6(3.39%) were genotype A, 65(36.72%) genotype B, 104(58.76%) genotype C, 1(0.57%) genotype B/C, and 1(0.57%) genotype C/D. Of 90 HBeAg(-) patients, 1(1.11%) were genotype A, 50(55.56%) genotype B, 37(41.11%) genotype C and 2(2.22%) genotype D. When compared to HBeAg(-) patients, HBeAg(+) patients were significantly younger in mean age (37.93 vs. 44.40; P<0.001), had higher levels of mean ALT (108.93+/-169.50 vs 59.41+/-90.29 U/mL; P0.001), higher levels of mean HBV DNA (7.50+/-1.48 vs 5.10+/-1.44 log₁₀ copies/mL; P0.001) and lower frequency of detectable PC/ BCP mutations (60.45% vs. 93.33%; P< 0.001), but had significantly higher percentage of cases with BCP when mutations were detected (37.85%, vs. 22.22%; P = 0.013). Among HBeAg(+) patients, 61% (107/177) had detectable PC/BCP and their clinical features are shown on Table 1. When compared to those with wild type, HBeAg(+) patients with PC/ BCP were significantly older in mean age, had higher mean ALT levels and lower mean HBV DNA levels. Conclusions In treatment-naive HBeAg(+) patients, up to 60% had PC/BCP mutants. These patients presented with distinct clinical characteristics when compared to HBeAg(+) cases with wild type or HBeAg(-) patients. Further studies are needed to substantiate the clinical significance of PC/BCP in HBeAg(+) patients as it may impact the natural history or treatment response in such patients. (Table Presented)

Background Treatment with sofosbuvir (SOF)-based regimens for HCV infection has resulted in sustained virologic response (SVR) rates of approximately 90% in pivotal trials, in which Asian patients were underrepresented. This study aims to assess the efficacy and safety of SOF-based therapy in the Asian-American patients. Methods Asian patients with HCV genotype 1-6 mono-infection, who received SOF-based therapy for 12 or 24 weeks, were retrospectively enrolled from multiple centers throughout the United States. The primary endpoint was SVR 12. Secondary endpoints were the safety and tolerability of SOF-based treatment regimens. Results Among the 80 patients enrolled, 45 were treated with SOF+ribavirin (RBV), 15 with SOF+simprevir (SIM), 10 with SOF+RBV+peginterferon, 8 with ledipasvir+SOF and 2 with SIM+SOF+RBV. Patient baseline values are shown in Table 1. By week 4, a rapid decrease in HCV RNA levels to <20 IU/mL was observed in 85% (68/80) of patients. SVR12 was achieved in 98.3% (60/61) patients who have reached the SVR12 assessment point. One genotype 4 patient, who was non-cirrhotic and treatment naive, experienced relapse after completing a 12 week SOF+RBV therapy. ALT normalization occurred in 91% (39/43) patients who had abnormal ALT at the baseline. At the time of abstract submission, 11 patients remain on therapy and 8 are <12-week post treatment follow-up; all were included in the safety analysis. No viral breakthrough occurred during therapy. Regimens were generally well tolerated with <15% patients reporting insomnia, nausea, rash, dyspnea and epigastric discomfort, however, fatigue was reported by 31.3% of patients. Of 57 patients on a RBV containing regimen, 6 required dose reduction and 2 discontinued RBV due to severe fatigue. Conclusions SOF-based therapies for Asian Americans with HCV were well tolerated. Their SVR12 rates were similar to the SVR12 rates of non-Asians in pivotal trials. No safety concerns were identified in this real life cohort. (Table Presented)

Background: Data on TDF use during pregnancy for preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) are scarce. Methods: Hepatitis B E antigen (HBeAg)-positive mothers with HBV DNA levels >200,000 IU/mL were randomized 1:1 to receive either TDF from gestation week 30-32 to postpartum week 4 or no treatment, and were followed-up until postpartum week 28. All infants received immunoprophylaxis. The primary measurement was the MTCT rate, while endpoints included TDF safety, maternal HBV DNA reduction at delivery, and HBeAg or hepatitis B s antigen loss/seroconversion at postpartum week 28. Results: Among the 200 mothers enrolled in 5 regions of the country, 180 completed the study. At postpartum week 28, the MTCT rate was significantly lower in infants from TDF-treated mothers when compared to those from non-treated mothers, both on per-protocol analysis (0% vs. 6.82%, P = 0.013) and intention-to-treat analysis (5.16% vs. 18.0%, P = 0.007). The safety profile was similar between groups, with no difference in birth defect rates (2.11% with TDF exposure vs. 1.14% without exposure, P = 1.00). HBV DNA levels decreased to <200,000 IU/mL in 68% (66/97) of TDFtreated mothers before delivery compared to 2.0% (2/100) of non-treated mothers (P < 0.001). The HBV serologic outcome did not differ between groups. Conclusions: TDF therapy in late pregnancy for highly viremic mothers effectively reduced MTCT. The treatment was well tolerated, and no safety concerns were identified. TDF therapy should be strongly considered for mothers whose HBV DNA levels exceeded 200,000 IU/mL and started at gestation week 30-32. (Table Presented)

The clinical course for chronic hepatitis B (CHB) patients with normal ALT and with or without minimal histologic activity remains unclear. We assessed frequency, amplitude, disease activities, and associated factors of ALT and/or AST flares in this subpopulation. Forty-seven consecutive treatment naive Asian patients with CHB were enrolled from two liver clinics between December 2003 and January 2013, who had normal baseline ALT by routine clinical biochemical testing performed 6 weeks before or after the liver biopsy. We defined a flare as elevation of ALT/AST above the upper limit of normal of ALT/AST. The mean follow-up was 37.6 (CI = 12, 88) months, and the mean age at entry into the study was 43.3 (CI = 19, 65); 22/47 (46.8%) were males; 15/45 (33.3%), HBeAg+; 68.1% had stage 0-1 fibrosis; 63.8% had grade 0-1 inflammation. During follow-up, 13/47 (27.7%) cases developed ALT flare at least once in a mean of 13.5 (CI = 2, 43) months after liver biopsy; ALT flare was not associated with baseline ALT level, fibrosis stage, inflammation grade, hepatitis B virus (HBV) DNA load, HBeAg status, HBV genotype, HBV precore and basal core promoter mutations. 11/13 (84/6%) of ALT flares resolved during follow-up. 13/13 (100%) of ALT flares met AASLD treatment criteria, but only 6/13 (46.2%) were on HBV treatment. Serum ALT and/or AST flares occur frequently in CHB carriers who initially presented with normal ALT during pretreatment period. Thus, regular follow-up is warranted despite status of ALT/AST. No clinical factors were found to be associated with ALT flares.

Entecavir (ETV) is a first-line antiviral therapy for treating chronic hepatitis B (CHB); however, some patients have suboptimal response to ETV. Currently, there are limited data on how to approach these patients. Therefore, our aim was to compare the effectiveness of two alternate therapies - tenofovir (TDF) monotherapy and combination therapy of ETV+T

AIM: To compare the efficacy and safety of tenofovir disoproxil fumarate (TDF) in Asian and non-Asian chronic hepatitis B (CHB) patients. METHODS: The efficacy and safety of the initial 48 wk of treatment with TDF was compared in a post-hoc analysis of combined data from 217 Asians and 299 non-Asians included in Studies 102 and 103 and a post-approval, open-label trial (Study 123). Patient groups were compared according to baseline hepatitis B e antigen (HBeAg) status and viral load. The main outcome measures included the proportion of patients who achieved a hepatitis B virus (HBV) DNA level < 400 copies/mL at Week 48 of treatment. Secondary measures included: HBV DNA and alanine aminotransaminase (ALT) levels over time; proportion of patients with normal ALT levels; proportion of patients with HBeAg loss/seroconversion and proportion of patients with hepatitis B surface antigen loss/seroconversion; changes in liver histology. Safety and tolerability were evaluated by the occurrence of adverse events (AEs), serious AEs, laboratory abnormalities, discontinuation of the study drug due to AEs, or death. The primary efficacy and safety analysis set included all patients who were randomly assigned to treatment and received at least one dose of study drug. RESULTS: At week 48, similar proportions of Asians and non-Asians reached HBV DNA < 400 copies/mL (96% of Asian and 97% of non-Asian patients with HBeAg-negative CHB and 83% of Asian and 79% of non-Asian patients with HBeAg-positive CHB had HBV DNA) and normal ALT (78% of Asian and 81% of non-Asian patients with HBeAg-negative CHB and 71% of Asian and 74% of non-Asian patients with HBeAg-positive CHB had normal ALT). On-treatment HBV DNA decline rates were similar between Asians and non-Asians regardless of baseline HBeAg status and viral load. HBV DNA decline during the first four weeks was 2.9 log10 copies/mL in HBeAg-negative Asians and non-Asians, and in HBeAg-positive non-Asians, and 3.1 log10 copies/mL in HBeAg-positive Asians. HBeAg loss and seroconversion was achieved in 14% of Asians vs 26% and 24%, respectively, in non-Asians. Liver histology improved in 77.2% of Asians and 71.5% of non-Asians. No resistance to TDF developed. No renal safety signals were observed. CONCLUSION: TDF demonstrated similar viral suppression, normalization of ALT, improvements in liver fibrosis, and no detectable resistance in Asian and non-Asian patients regardless of baseline HBeAg status.

Aim: The impact of tenofovir disoproxil fumarate (TDF) on lipid profile in chronic hepatitisB(CHB) patients is unknown. Data from GSUS- 174-0149, a clinical trial evaluating pegylated interferon alfa-2a (PEG) +/- TDF combination therapy in non-cirrhotic CHB patients, were analyzed for impact of antiviral treatment on fasting lipid profile. Methods: 570 subjects with fasting baseline and week 24 total cholesterol, LDL, HDL, and triglyceride were included. Regression analyses of on-treatment changes in lipid profile were examined, adjusted for baseline lipid values, age, sex, race, and BMI. Results: Comparing baseline and week 24 results, TDF monotherapy was significantly associated with reductions in total cholesterol, LDL, and HDL (-25.6 mg/dL, -16.4 mg/dL, and, -9.6 mg/dL, respectively, P<0.05) with no significant change in triglyceride or total cholesterol/HDL ratio (p-values > 0.05). Moreover, TDF + PEG x 48 weeks combination therapy was significantly associated with an even greater reductions in total cholesterol, LDL, and HDL, and a moderate triglyceride increase (-42.5 mg/dL, -29.0 mg/dL, and -18.1 mg/dL, +18.8 mg/dL, respectively, p-values<0.05) compared to baseline. The changes were also significant relative to either monotherapy. In patients, who were on (TDF + PEG) x 16 weeks then continuing on TDF, the lipid impact of PEG lessened after its discontinuation. Only minor cardiovascular events, mostly palpitations, occurred up to Week 72. Conclusion: TDF monotherapy was associated with significant improvements in total cholesterol and LDL in CHB patients. PEG + TDF x 48 weeks was associated with greater changes in lipid profile than either monotherapy

Hepatitis B remains a leading cause of cirrhosis, hepatocellular carcinoma and liver transplantation worldwide. Management of chronic hepatitis B during pregnancy is challenging. Transmission of hepatitis B to infants still occurs perinatally although immunoprophylaxis is widely available for infants born to mothers with chronic hepatitis B infection. The emerging data suggest that initiation of antiviral therapy in the beginning of the third trimester in highly viremic mothers can prevent immunoprophylaxis failure in their infants. The available drug safety data show that lamivudine, telbivudine and tenofovir are generally safe to be used during the pregnancy. In order to minimize the fetal exposure to the antiviral medication, antiviral therapy during the pregnancy should be limited to a selected group of patients with cirrhosis, high hepatitis B viral load, or prior history immunoprophylaxis failure. An elective Caesarean section may reduce the risk of perinatal transmission. For those females planning for pregnancy or in early stage of pregnancy, communication and follow-up among obstetrician, gastroenterologist, and primary care physician are important. In this article, we will review the features of hepatitis B infection before, during and after the pregnancy; the risk factors that increase mother-to-child transmission; safety data on antiviral drug use during pregnancy; and the potential role of Caesarean section in selected cases.