Faculty Bibliography

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.

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.

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

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.

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.

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.