Sex and ethnic disparities in hepatitis B evaluation and treatment across the world.

BACKGROUND & AIMS: Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. METHODS: This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. RESULTS: We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001). CONCLUSIONS: Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. IMPACT AND IMPLICATIONS: Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.

Sulfonyl thiourea derivatives from 2-aminodiarylpyrimidines: In vitro and in silico evaluation as potential carbonic anhydrase I, II, IX, and XII inhibitors.

A series of synthesized sulfonyl thiourea derivatives (7a-o) of substituted 2-amino-4,6-diarylpyrimidines (4a-o) exhibited the remarkable inhibitory activity against some the human carbonic anhydrases (hCAs), including hCA I, II, IX, and XII isoforms. The inhibitory efficacy of synthesized sulfonyl thiourea derivatives were experimentally validated by in vitro enzymatic assays. 7a (KI = 46.14 nM), 7j (KI = 48.92 nM), and 7m (KI = 62.59 nM) (for isoform hCA I); 7f (KI = 42.72 nM), 7i (KI = 40.98 nM), and 7j (KI = 33.40 nM) (for isoform hCA II); 7j (KI = 228.5 nM), 7m (KI = 195.4 nM), and 7n (KI = 210.1 nM) (for isoform hCA IX); 7l (KI = 116.9 nM), 7m (KI = 118.8 nM), and 7n (KI = 147.2 nM) (for isoform hCA XII) in comparison with KI values of 452.1, 327.3, 437.2, and 338.9 nM, respectively, of the standard drug AAZ. These compounds also had significantly more potent inhibitory action against cytosolic isoform hCA I and tumor-associated isoforms hCA IX and hCA XII. Furthermore, the potential inhibitory compounds were subjected to in silico screening for molecular docking and molecular dynamics simulations. The results of in vitro and in silico studies revealed that compounds 7a, 7j, and 7m were the most promising derivatives in this series due to their significant effects on studied hCA I, II, IX, and XII isoforms, respectively. The results showed that the sulfonyl thiourea moiety was accommodated deeply in the active site and interacted with the zinc ion in the receptors.

Real-world treatment outcome with protease inhibitor direct-acting antiviral in advanced hepatitis C cirrhosis: a REAL-C study.

INTRODUCTION: Current guidelines discourage the use of direct-acting antiviral (DAA) containing protease-inhibitor (PI) in advanced HCV cirrhosis. We aimed to compare the real-world tolerability of PI vs. non-PI DAA regimens in this population. METHODS: We identified advanced cirrhosis patients treated with DAA from the REAL-C registry. The primary outcome was significant worsening or improvement in CPT or MELD scores following DAA treatment. RESULTS: From the REAL-C registry of 15,837 patients, we included 1077 advanced HCV cirrhosis patients from 27 sites. 42% received PI-based DAA. Compared to non-PI group, the PI group was older, had higher MELD and higher percentage with kidney disease. Inverse probability of treatment weighting (IPTW; matching on age, sex, history of clinical decompensation, MELD, platelet, albumin, Asia site, Asian ethnicity, hypertension, hemoglobin, genotype, liver cancer, ribavirin) was used to balance the two groups. In the IPTW-matched cohorts, the PI and non-PI groups had similar SVR12 (92.9% vs. 90.7%, p = 0.30), similar percentages of significant worsening in CTP or MELD scores at posttreatment week 12 and 24 (23.9% vs. 13.1%, p = 0.07 and 16.5% vs. 14.6%, p = 0.77), and similar frequency of new HCC, decompensating event, and death by posttreatment week 24. In multivariable analysis, PI-based DAA was not associated with significant worsening (adjusted odds ratio = 0.82, 95% CI 0.38-1.77). CONCLUSION: Tolerability and treatment outcomes were not significantly different in advanced HCV cirrhosis treated with PI-based (vs. non-PI) DAA up to CTP-B or MELD score of 15. Safety of PI-based DAA in those with CTP-C or MELD beyond 15 awaits further data.

Substitution of the CD81 Binding Site and ß-Sandwich Area in E2 of HCV in Cambodia.

The high genetic variability of hepatitis C virus (HCV) is the main obstacle to developing a vaccine. E2 has attracted attention for vaccine development because targeting this protein could potentially overcome issues related to the genetic diversity of HCV. In this study, we analyzed HCV genes in the general population of Cambodia and investigated the E2 locus as a candidate for vaccine development. HCV sero-epidemiological surveys were conducted between the period 2010 and 2014, with an HCV RNA-positive rate of 1.3% (11/868). Follow-up blood samples were collected from four anti-HCV- and HCV RNA- positive patients (genotype 1b: 2 cases, 6e: 1 case, 6r: 1 case) after 4.12 years. Analysis of HCV full-length nucleotide sequences in paired specimens revealed that the mutation rates of HCV genotypes 1b and 6e/6r were 1.61-2.03 × 10-3 and 2.52-2.74 × 10-3 substitutions/site/year, respectively. Non-synonymous substitutions were detected in HVR1, the front layer of the CD81 binding site, and the ß-sandwich, but not in the N-terminal region or adjacent to the CD81 binding site. Therefore, we conclude that the CD81 binding site is a promising locus for HCV vaccine development.

Effects of positive end-expiratory pressure on intraoperative core temperature in patients undergoing posterior spine surgery: prospective randomised trial.

Objective Positive end-expiratory pressure (PEEP) causes carotid baroreceptor unloading, which leads to thermoregulatory peripheral vasoconstriction. However, the effects of PEEP on intraoperative thermoregulation in the prone position remain unknown. Methods Thirty-seven patients undergoing spine surgery in the prone position were assigned at random to receive either 10 cmH2O PEEP (Group P) or no PEEP (Group Z). The primary endpoint was core temperature 180 minutes after intubation. Secondary endpoints were delta core temperature (difference in core temperature between 180 minutes and immediately after tracheal intubation), incidence of intraoperative hypothermia (core temperature of <36°C), and peripheral vasoconstriction-related data. Results The median [interquartile range] core temperature 180 minutes after intubation was 36.1°C [35.9°C-36.2°C] and 36.0°C [35.9°C-36.4°C] in Groups Z and P, respectively. The delta core temperature and incidences of intraoperative hypothermia and peripheral vasoconstriction were not significantly different between the two groups. The peripheral vasoconstriction threshold (36.2°C±0.5°C vs. 36.7°C±0.6°C) was lower and the onset of peripheral vasoconstriction (66 [60-129] vs. 38 [28-70] minutes) was slower in Group Z than in Group P. Conclusions Intraoperative PEEP did not reduce the core temperature decrease in the prone position, although it resulted in an earlier onset and higher threshold of peripheral vasoconstriction.

Open Label Study of 8 vs. 12 Weeks of Ledipasvir/Sofosbuvir in Genotype 6 Treatment Naïve or Experienced Patients.

OBJECTIVES: Hepatitis C genotype 6 (HCV-GT6) is one of the most prevalent genotypes in Southeast Asia. Ledipasvir and sofosbuvir fixed-dose combination (LDV/SOF FDC) for 12 weeks has been shown to be effective for multiple HCV genotypes including treatment-naïve HCV-6. Our goal was to examine treatment outcomes in a diverse HCV-6 population. METHODS: We prospectively enrolled 60 HCV-GT6 patients at four US centers. Treatment -naïve without cirrhosis patients received open-labeled LDV/SOF FDC orally once a day for 8 weeks; All cirrhotic and/or treatment-experienced patients received LDV/SOF FDC for 12 weeks. The primary outcome was sustained virological response 12 weeks after therapy (SVR12). Secondary outcomes were adverse events (AEs) and/or serious adverse events (SAEs). All patients gave written consent. RESULTS: Overall mean age was 58±10 and 58% were male. All patients were Asian and foreign born. The 8-week group included 20 patients (33.3%) and the 12-week included 40 patients (66.7%). There were 2 (5%) patients with decompensation, 3 with liver cancer (7.5%), and 14 with prior treatment (35%) in the 12-week group. SVR12 was 95.0% for the 8-week group (19/20) and 95.0% for the 12-week group (38/40). AEs included fatigue (5%), insomnia (3.3%), headache (1.7%), and nausea (1.7%); however, all patients completed the intended treatment duration. There were two treatment-unrelated SAEs. CONCLUSIONS: LDV/SOF FDC for 8 or 12 weeks was safe and effective for patients without cirrhosis or prior treatment failure as well as for patients with cirrhosis and/or prior treatment failure, respectively.

Clustering infection of hepatitis B virus genotype B4 among residents in Vietnam, and its genomic characters both intra- and extra-family.

Vietnam has a high rate of hepatitis B virus (HBV) infection and a high mortality rate from hepatocellular carcinoma. We performed a detailed genetic analysis of 48 residents and four families from Binh Thuan Province, a southern coastal area of Vietnam. The route of infection and genomic characteristics related to hepatocellular carcinoma (HCC) were studied in HBV spread among carriers that we detected in our previous hepatitis survey. The HBV genotype was B4 in 91.7% and C1 in 8.3% of the cases. The intra-family's HBV sequence homology was high at 96.8-99.4%. However, it was also high at 99.4-99.8% among residents of the same age and sex as family members. In addition, full genome analysis was performed in 21 cases. The core region of all 20 isolates with genotype B4 was a recombinant of genotype C, and pre-S deletion was found in 20% of cases. The promoter mutation G1613A was found in 13.6% of cases, and a 24 bp insertion from nt1673 in the X region was found in 6.3% of cases. The phylogenetic tree and homology analysis of the HBV full genome suggested the probability and its possibility of horizontal transmission not only within families nor vertical transmission but within cohorts of the same generation in the population. Moreover, the HBV genotype B4 isolates were found not only to be recombinants of genotype C, which results in a high cancer risk, but also to have other risk of HCC, pre-S deletions, the G1613A mutation, and X region insertions corresponding to the promoter. These genomic characters were suggested to be one of the factors to explain the high HCC mortality rate in Vietnam.

Lower Observed Hepatocellular Carcinoma Incidence in Chronic Hepatitis B Patients Treated With Entecavir: Results of the ENUMERATE Study.

OBJECTIVES: Data from the United States are lacking regarding the impact of entecavir (ETV) on the risk of hepatocellular carcinoma (HCC). Our aim is to determine whether treatment with ETV is associated with a reduced HCC risk by calculating the expected HCC incidence based on the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model and comparing it with the observed HCC incidence. METHODS: The incidence of HCC in US patients treated with ETV between 2005 and 2013 in a retrospective cohort was obtained. The predicted HCC incidence was calculated using the REACH-B model. The standardized incidence ratios (SIRs) were calculated as a ratio of observed over predicted HCC cases. RESULTS: Of 841 patients, 646 (65% male, 84% Asian, median age 47 years, 36% hepatitis B e antigen positive, 9.4% with cirrhosis) met the inclusion criteria. Over a median follow-up of 4 years, 17 (2.6%) cases of HCC were diagnosed, including 8 out of 61 (13.1%) patients with cirrhosis and 9 out of 585 (1.5%) without cirrhosis. Compared with those without HCC, the 17 patients with HCC were older at 53 years vs. 47 years and more likely to have cirrhosis at 47.1% vs. 8.4%. Among patients without cirrhosis, the observed HCC incidence was significantly lower than predicted by the fourth year (SIR, 0.37; 95% confidence interval: 0.166-0.82). A sensitivity analysis that comprised all patients, including those with cirrhosis, showed that at the maximum follow-up time of 8.2 years, a significantly lower than predicted HCC incidence was noted with an SIR of 0.56 (95% confidence interval: 0.35-0.905). CONCLUSIONS: Based on the REACH-B model, long-term ETV therapy was associated with a lower than predicted HCC incidence. However, the risk of HCC persisted, and careful HCC surveillance remains warranted despite the anti-viral treatment.

Epidemiology of Hepatitis B and C Virus Infections and Liver Cancer in Vietnam.

Vietnam has been a highly endemic country of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections with high hepatitis B surface antigen (HBsAg) rate (8.8-19.0%) and high anti-HCV rate (1.0-3.3%) among general population. High mortality rates of liver cancer were also estimated from 14.8 to 23.7 per 100,000. Recently, the coverage of universal HB vaccination for infants has not been high as expected while there have been no other national programs against HBV and HCV infections yet. The burden of HBV and HCV-related diseases is predicted to remain a significant health problem in next decade. HOW TO CITE THIS ARTICLE: Do SH. Epidemiology of Hepatitis B and C Virus Infections and Liver Cancer in Vietnam. Euroasian J Hepato-Gastroenterol 2015;5(1):49-51.

High prevalences of hepatitis B and C virus infections among adults living in Binh Thuan province, Vietnam.

AIM: Vietnam is one of the countries with the highest mortality from liver cancer, which is mostly attributed to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. For planning preventive strategies against these infections, we investigated prevalences of HBV and HCV infections among adults living in Binh Thuan, Vietnam. METHODS: Our study consisted of a serological survey for HBV and HCV infections and a questionnaire survey on their risk factors. The sample size was calculated based on anticipated rate of hepatitis B surface antigen (HBsAg). Subjects were randomly sampled using a multistage method. Confirmation and family-tree surveys were conducted to examine persistent HBV infection and intrafamilial HBV transmission, respectively. RESULTS: A total of 509 adults, comprised of 230 men (45.2%) and 279 women (54.8%), were enrolled. Prevalences of HBsAg, hepatitis B surface antibody and hepatitis B core antibody were 15.3%, 60.3% and 71.7%, respectively. Most HBV DNA positive sera were classified as genotype B (75.3%) and C (11.7%). Of HBsAg positive subjects, 96.7% were persistently infected and one acutely HBV infected person was identified. Family-tree surveys suggested that horizontal extrafamilial HBV transmission might have been frequent. Prevalences of anti-HCV and HCV RNA were 3.3% and 1.8%, respectively. HCV genotype 6a was prominent (55.6%). CONCLUSION: In Binh Thuan, prevalences of HBV and HCV infections are high, HBV genotype B and HCV genotype 6a are predominant, and horizontal HBV transmission may still occur. Therefore, raising the coverage of a universal HBV vaccination program may be an effective liver cancer control in Vietnam.

Diverse gene expression pattern during 5-fluorouridine-induced apoptosis.

The purpose of this study was to establish experimental conditions to produce apoptosis by the fluorinated pyrimidine 5-fluorouridine and to examine the changes in gene expression that occurred during cell death. HCT-116 colorectal carcinoma cells were exposed to 10 microM 5-fluorouridine alone or in the presence of 1 mM uridine, 30 microM thymidine or both uridine and thymidine. A time-dependent increase in the percentage of apoptotic cells and a decrease in the percentage of viable cells were observed when the cells were treated with 5-fluorouridine in the absence of uridine (p < 0.001) but not in the presence of uridine. cDNA microarray analysis was used to study the expression of 1,200 different genes during apoptosis by 5-flurouridine. The expression of 33 genes was upregulated by 5-fold or greater at 16 and 24 h of 5-fluorouridine exposure. The largest cluster of upregulated genes included a group of genes classified as growth factors, cytokines and chemokines (e.g. interleukin-3, interleukin-4, B-cell growth factor 1 and stem cell growth factor). The expression of MIC-1 increased up to 100-fold during 5-flurouridine exposure. One hundred and twenty-four genes were downregulated by 5-fold or greater following exposure to 5-fluorouridine. The downregulated genes were distributed throughout the six different classifications on the array. Our data demonstrate a diverse pattern of gene expression during the fluorouridine-induced apoptosis and suggest that mechanisms besides a global inhibition of RNA synthesis/ processing contribute to the RNA-directed cytotoxicity of fluoropyrimidines.

Keratinocyte Growth Factor-Mediated Pattern of Gene Expression in Breast Cancer Cells.

BACKGROUND: Breast cancer metastasis is associated with the motility and invasiveness of breast cancer cells. In a previous study we reported the motility enhancement effect of keratinocyte growth factor (KGF) on breast cancer cells. This study established and characterized the influence of KGF on breast cancer cell motility and determined that KGF-induced motility was observed only in estrogen receptor-positive breast cancer cells. The objective of the present study was to identify genes involved in the KGF motility response in human breast cancer cells. MATERIALS AND METHODS: Using cDNA expression assays, we compared the expression of mRNA in control and KGF-treated MCF-7 breast cancer cells. Scatter plots and cluster analysis of gene expression were used to determine KGF-mediated gene expression patterns. RESULTS: It was determined that over 100 genes were up- or down-regulated from 3-100 fold at 1h following KGF treatment. We identified up-regulated and down-regulated target genes that are associated with some aspect of tumor progression, proliferation or metastasis. CONCLUSION: Knowledge of specific genes and patterns of gene regulation associated with KGF-enhanced cell motility may provide important new information concerning the mechanisms involved in tumor metastasis. In addition, these genes and/or protein products may serve as novel therapeutic targets or biomarkers of metastatic progression. The pattern gene of expression observed in this study provides new information on the molecular signature associated with the motility and metastatic progression of breast cancer.