Faculty Bibliography

Objective: To investigate the effect of antiviral therapy on the progression of liver cirrhosis and related predictive factors through a retrospective analysis of patients with compensated hepatitis C cirrhosis. Methods: The patients with compensated hepatitis C cirrhosis who were treated in our hospital from 2004 to 2015 were divided into sustained virologic response (SVR) group, non-SVR (NSVR) group, and untreated group. The baseline features of patients with or without liver cirrhosis were compared to identify the predictive factors for the progression of liver cirrhosis. The changes in platelet count, spleen sizes, Model for End-Stage Liver Disease (MELD) score, Sequential Organ Failure Assessment (SOFA) score, and Child-Turotte-Pugh (CTP) score were analyzed, and the incidence rate of liver cancer was compared between groups. A one-way analysis of variance, the Kruskal-wallis H test, the two-independent-sample t test, the chi-square test, and a multivariate logistic regression analysis were used for data analysis based on data type. Results: A total of 89 patients with compensated liver cirrhosis were enrolled, among whom 42 received the antiviral treatment with interferon and ribavirin (30 were treated with pegylated interferon-α and 12 were treated with ordinary interferon) and 47 did not receive any antiviral therapy. Among the patients who received the antiviral treatment with interferon and ribavirin, 20 achieved SVR and 22 did not achieve SVR. Compared with baseline values, platelet count in the SVR group and the NSVR group was increased by (44.93 ± 32.66)×10(9)/L and (9.73 ± 28.83)×10(9)/L, respectively, and platelet count in the untreated group was reduced by (19.76 ± 54.5)×10(9)/L; the three groups had a significant change in platelet count (F = 14.731, P < 0.001). Spleen size was reduced by 0.91 ± 1.09 cm in the SVR group and increased by 0.20±0.84 cm and 1.11 ± 1.69 cm in the NSVR group and the untreated group, respectively; the three groups had a significant change in spleen size (F = 14.943, P < 0.001). The three groups had no significant changes in MELD, SOFA, and CTP scores (P > 0.05). One patient (5.00%) in the SVR group, 5 (22.73%) in the NSVR group, and 6 (12.77%) in the untreated group progressed to liver cancer (χ (2) = 13.787, P = 0.001). The univariate analysis showed that SVR, HCV RNA, total bilirubin, and albumin were predictive factors for disease progression, and the multiple logistic regression analysis demonstrated that SVR and total bilirubin were predictive factors for disease progression. Conclusion: Interferon combined with ribavirin has a marked clinical effect in the treatment of compensated hepatitis C cirrhosis with good short- and long-term efficacy.

Chronic hepatitis B virus (HBV) remains a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Because chronic hepatitis B infection is rarely eradicated, preventing mother-to-child transmission (MTCT) is the most effective strategy to eliminate HBV globally. Although immunoprophylaxis strategy is widely available and effective for infants born to mothers with chronic hepatitis B infection, postnatal immunoprophylaxis fails in approximately 5-10 % of infants, and this failure rate goes up to 30 % in infants born to highly viremic mothers. Mothers with HBV DNA levels above 200,000 IU/mL should be managed aggressively with antiviral therapy because viral load is the strongest independent risk factor for immunoprophylaxis failure. Emerging data suggest that initiation of antiviral therapy in late pregnancy in highly viremic mothers can prevent immunoprophylaxis failure in their infants. Reducing viral load to target levels below 200,000 IU/mL at delivery is a practical approach to control MTCT. This review focuses on viral factors in mothers associated with MTCT.

BACKGROUND: Precore or/and basal core promoter (PC/BCP) mutations are frequently detected in hepatitis B e antigen (HBeAg)-negative patients, but little is known about their clinical significance in HBeAg-positive patients. AIM: To characterize and report the clinical features of treatment-naive chronic hepatitis B patients who are HBeAg positive and harbor PC and/or BCP mutations. PATIENTS AND METHODS: Consecutive treatment-naive patients with chronic hepatitis B between 2004 and 2014 were enrolled. Clinical characteristics were compared based on the stratification of HBeAg status and the presence of PC/BCP mutations. In addition, subset analysis in HBeAg-positive cohort was performed to compare clinical features of patients with and without PC/BCP mutations RESULTS:: Of the 267 patients enrolled from 3 centers, 177 were HBeAg positive and 90 HBeAg negative. When compared with HBeAg-negative patients, HBeAg-positive patients were significantly younger in mean age (37.93 vs. 44.40; P<0.001), had higher levels of median ALT (51 vs. 30.5 U/mL; P<0.001), higher levels of mean HBV DNA (7.50+/-1.48 vs. 5.10+/-1.44 log10 copies/mL; P<0.001), and lower frequency of detectable PC/BCP mutations (60.45% vs. 93.33%; P<0.001), but had significantly higher frequency of BCP when mutations were detected (37.85% vs. 22.22%; P=0.013). Among HBeAg-positive patients, when compared with patients with wild type, those with PC/BCP mutations were significantly older (30.63 vs. 42.71; P<0.001), had higher median ALT levels (29.5 vs. 73 U/mL; P<0.001), but there was no significant association with mean HBV DNA levels (7.96 vs. 7.20 log10 copies/mL; P=0.865) or HBV genotype (P=1.000). In the multivariate analysis, only age and ALT were independently associated with PC/BCP mutations in HBeAg-positive patients, but there was no association with HBV genotype or DNA. CONCLUSIONS: PC/BCP mutants were frequent (up to 60%) in treatment-naive HBeAg-positive patients and were associated with distinct clinical characteristics when compared with patients with wild type or HBeAg negative. Future large studies are needed to substantiate the long-term clinical outcomes when PC/BCP mutations are detected in HBeAg-positive patients as it may impact the natural history or treatment response in such patients.

There are little data on the timing of initiating lamivudine therapy for preventing transmission of hepatitis B in highly viremic mothers. Between May 2008 and January 2015, we retrospectively enrolled mothers with HBV DNA >6 log10 copies/mL who received lamivudine during pregnancy, and we compared them to untreated mothers. The primary measurement was the vertical transmission rate. The secondary outcomes were the mothers' and infants' safety. Among 249 consecutive mothers enrolled, 66 and 94 received lamivudine during the second and third trimesters, respectively, and 89 were untreated. At delivery, maternal mean HBV DNA levels were significantly lower in mothers who received lamivudine (4.45 log10; vs 7.16 log10 copies/mL; P<.001). Lamivudine treatment was well tolerated. However, early treatment during the second trimester did not significantly increase the percentage of mothers achieving HBV DNA levels of <6 log10 copies/mL compared to those treated during the third trimester (98.5% vs 94.7%; P=.40). At the age of 28 weeks, the vertical transmission rates were significantly lower in the lamivudine-treated mothers vs in the untreated mothers (0% [0/160] vs 5.62% [5/89]; P<.001), but the rates were similar when comparing the two subgroups treated with lamivudine (0% [0/66] vs 0% [0/94], P>.05). The birth defect rates and mothers' and infants' adverse events were similar among the groups. Lamivudine treatment initiated in the second or third trimester for mothers with HBV DNA levels below 9 log10 copies/mL was equally safe and effective in preventing vertical transmission. Thus, lamivudine should be deferred until the third trimester to minimize foetal exposure and drug resistance.

Inter-tissue communication via secreted proteins has been established as a vital mechanism for proper physiologic homeostasis. We have developed a bioinformatics framework using a mouse reference population, the Hybrid Mouse Diversity Panel (HMDP), which integrates multi-tissue expression arrays and publicly available resources to identify and functionally annotate novel tissue-tissue communication. We validate this method by showing that we can identify known, as well as novel endocrine factors responsible for communication between tissues. We further show the utility of this approach by identification and mechanistic characterization of two new endocrine factors. Adipose-derived Lipocalin-5 is shown to enhance skeletal muscle mitochondrial function and liver-secreted Notum acts to promote white adipose tissue "beiging". We have explored these factors in both basal and high-fat/high-sucrose dietary perturbations and show the physiologic effects are robust and significant. We have additionally screened mouse and human datasets using this method and uncovered in vivo evidence for 7 novel inter-tissue communicatory axes. The developed methodology is generally applicable to any collection of organs, tissues, or cell types sampled from a genetically diverse population and profiled using omics platforms

AIM: Abnormal uterine bleeding (AUB) occurs in 10-30% of women of reproductive age and up to 61% of cirrhotic women. We evaluated the efficacy and safety of endometrial ablation (NovaSure therapy) for AUB in cirrhotic women. METHODS: This prospective, two-arm, observational study enrolled patients for NovaSure treatment, and they were followed for 12 months. Primary measurements were the amenorrhea rate and changes of pictorial blood loss assessment chart (PBLAC) scores at 1-month post-therapy. Key secondary end-points included the longevity of amenorrhea at 12 months, safety profile, and progression of cirrhosis. RESULTS: Among 88 women, 26 were cirrhotic and 62 were non-cirrhotic. At 1-month post-NovaSure treatment, a significant reduction of mean PBLAC scores was observed in cirrhotic patients compared to those at baseline (0.4 +/- 1.3 vs 215.2 +/- 410.9, P < 0.001), and the amenorrhea rate was 88.5%. The efficacy outcomes of the PBLAC scores and amenorrhea rate were maintained until the end of the 12-month follow-up. A significant improvement in quality of life scores was observed 1-month post-therapy compared to those at baseline (5.4 +/- 3.1 vs 20.5 +/- 5.5, P < 0.001). Patients' satisfaction rates were 100% and 92.31% at 6 and 12 months, respectively. The aforementioned outcomes were comparable with those in non-cirrhotic patients. No significant progression of cirrhosis or safety concern was reported. CONCLUSION: Cirrhotic patients on NovaSure therapy had a high rate of amenorrhea 1-month post-treatment, which maintained longevity for 12 months. The safety profile was similar to that in non-cirrhotic patients.

BACKGROUND: The novel prodrug tenofovir alafenamide delivers the nucleotide reverse transcriptase inhibitor tenofovir to target cells more efficiently at a lower dose than tenofovir disoproxil fumarate, thereby reducing systemic exposure. We compared the efficacy and safety of the two drugs in patients with HBeAg-negative chronic hepatitis B virus (HBV) infection in a non-inferiority study. METHODS: In this ongoing randomised, double-blind, phase 3, non-inferiority study in 105 centres in 17 countries, patients with HBeAg-negative chronic HBV were randomly assigned (2:1) by a computer-generated allocation sequence (block size six), stratified by plasma HBV DNA concentration and previous treatment status, to receive once-daily oral doses of tenofovir alafenamide 25 mg or tenofovir disoproxil fumarate 300 mg, each with matching placebo. Participants, investigators, and those assessing outcomes were masked to group assignment. Eligible patients were aged at least 18 years with HBeAg-negative chronic HBV infection (with plasma HBV DNA concentrations of >20 000 IU/mL), serum alanine aminotransferase concentrations of greater than 60 U/L in men or greater than 38 U/L in women and at no more than ten times the upper limit of normal, and estimated creatinine clearance of at least 50 mL/min (by the Cockcroft-Gault method). The primary efficacy endpoint was the proportion of patients who had HBV DNA less than 29 IU/mL at week 48 in those who received at least one dose of study drug; the study was powered to show non-inferiority with a 10% efficacy margin of tenofovir alafenamide compared with tenofovir disoproxil fumarate. Bone and renal safety, and key secondary safety endpoints were assessed sequentially. The study will be conducted for a total of 3 years as a double-blind comparison to assess the longer term response to treatment. This study is registered with ClinicalTrials.gov, number NCT01940341. FINDINGS: Between Sept 12, 2013, and Oct 31, 2014, 426 patients were randomly assigned (285 assigned to tenofovir alafenamide and 141 assigned to tenofovir disoproxil fumarate; one patient assigned to tenofovir disoproxil fumarate did not receive the treatment. 268 (94%) of 285 patients receiving tenofovir alafenamide had HBV DNA less than 29 IU/mL at week 48 versus 130 (93%) of 140 patients receiving tenofovir disoproxil fumarate (difference 1.8% [95% CI -3.6 to 7.2]; p=0.47), which demonstrates non-inferiority. Patients receiving tenofovir alafenamide had significantly smaller mean percentage declines in bone mineral density than those receiving tenofovir disoproxil fumarate (hip -0.29% [95% CI -0.55 to -0.03] vs -2.16% [-2.53 to -1.79], adjusted percentage difference 1.87% [95% CI 1.42 to 2.32; p<0.0001]; spine -0.88% [-1.22 to -0.54] vs -2.51% [-3.09 to -1.94], adjusted percentage difference 1.64% [95% CI 1.01 to 2.27]; p<0.0001). At week 48, mean change in serum creatinine was small in both groups (tenofovir alafenamide 0.01 mg/dL [95% CI 0.00 to 0.02] vs tenofovir disoproxil fumarate 0.02 mg/dL [0.00 to 0.04], adjusted percentage difference -0.01 mg/dL [95% CI -0.03 to 0.01]; p=0.32), but patients receiving tenofovir alafenamide had a smaller reduction in creatinine clearance (median change in estimated glomerular filtration rate -1.8 mL/min [IQR -7.8 to 6.0] vs -4.8 mL/min [-12.0 to 3.0]; p=0.004). Most adverse events were mild to moderate in severity in the two treatment groups. The most common adverse events overall were headache (tenofovir alafenamide 40 [14%] patients vs tenofovir disoproxil fumarate 14 [10%] patients), nasopharyngitis (30 [11%] vs 15 [11%]), and upper respiratory tract infection (35 [12%] vs ten [7%]). 14 (5%) patients receiving tenofovir alafenamide and nine (6%) patients receiving tenofovir disoproxil fumarate had serious adverse events, none of which was deemed by investigators to be related to study treatment; one patient in the tenofovir disoproxil fumarate group died, but this was not deemed to be related to study treatment. INTERPRETATION: In patients with HBeAg-negative chronic HBV, the efficacy of tenofovir alafenamide was non-inferior to that of tenofovir disoproxil fumarate, and had improved bone and renal effects. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING: Gilead Sciences.