A phase 2, open-label, randomized, multiple-dose study evaluating Inarigivir in treatment-naïve patients with chronic hepatitis B.

BACKGROUND/AIMS: Novel agents acting against hepatitis B virus (HBV) are needed to improve HBsAg seroclearance or termed as 'functional cure'. Inarigivir (retinoic acid-inducible gene I agonist) has immunomodulatory and direct antiviral actions against HBV. We aimed to determine the safety and efficacy of Inarigivir for the treatment of HBV infection. PATIENTS/METHODS: 80 treatment-naïve patients were randomized in 4 ascending dose cohorts to receive 12 weeks of Inarigivir 25, 50, 100, 200 mg or placebo in a ratio of 4:1. All patients were then given tenofovir for another 12 weeks. RESULTS: Least squares (LS) mean reductions in HBV DNA from baseline increased with higher doses of Inarigivir (0.6116 in 25 mg and 1.5774 in 200 mg groups vs. 0.0352 in placebo group) (95% CI 0.9518-0.2011 and 1.921-1.1634 respectively). LS mean changes in HBV RNA and HBsAg from baseline ranged from -0.3856 to -0.5794 versus -0.1474 and -0.0956 to -0.1818 versus +0.0026 in Inarigivir-treated versus placebo groups respectively. During the tenofovir-treated period, LS mean reductions in HBsAg in the Inarigivir-treated groups ranged from 0.1709 to 0.3529 versus 0.1984 in the placebo group. Inarigivir-treated groups showed mean reductions in ALT from baseline between 23.3 and 33.8 versus 0.7 U/L in the placebo group. Treatment-emergent adverse events related to Inarigivir and placebo occurred in 4.7% and 6.3% patients respectively. CONCLUSIONS: Twelve-week Inarigivir up to 200 mg dose was associated with a reduction of HBV DNA, HBV RNA and antigen levels. A trend for greater HBsAg reduction was observed in Inarigivir pre-treated patients after switching to tenofovir.

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV. METHODS: HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24. RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury. CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile. CLINICAL TRIAL NUMBER: NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.

Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs. METHODS: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS: Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. CLINICAL TRIALS NUMBER: NCT03576066. LAY SUMMARY: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection.

BACKGROUND & AIMS: Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. METHODS: Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). RESULTS: Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy. CONCLUSIONS: Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.

Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids.

UNLABELLED: In nonalcoholic fatty liver disease, hepatic gene expression and fatty acid (FA) composition have been reported independently, but a comprehensive gene expression profiling in relation to FA composition is lacking. The aim was to assess this relationship. In a cross-sectional study, hepatic gene expression (Illumina Microarray) was first compared among 20 patients with simple steatosis (SS), 19 with nonalcoholic steatohepatitis (NASH), and 24 healthy controls. The FA composition in hepatic total lipids was compared between SS and NASH, and associations between gene expression and FAs were examined. Gene expression differed mainly between healthy controls and patients (SS and NASH), including genes related to unsaturated FA metabolism. Twenty-two genes were differentially expressed between NASH and SS; most of them correlated with disease severity and related more to cancer progression than to lipid metabolism. Biologically active long-chain polyunsaturated FAs (PUFAs; eicosapentaenoic acid + docosahexaenoic acid, arachidonic acid) in hepatic total lipids were lower in NASH than in SS. This may be related to overexpression of FADS1, FADS2, and PNPLA3. The degree and direction of correlations between PUFAs and gene expression were different among SS and NASH, which may suggest that low PUFA content in NASH modulates gene expression in a different way compared with SS or, alternatively, that gene expression influences PUFA content differently depending on disease severity (SS versus NASH). CONCLUSION: Well-defined subjects with either healthy liver, SS, or NASH showed distinct hepatic gene expression profiles including genes involved in unsaturated FA metabolism. In patients with NASH, hepatic PUFAs were lower and associations with gene expression were different compared to SS.

Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection.

BACKGROUND & AIMS: Tenofovir alafenamide, a phosphonate prodrug of tenofovir with greater plasma stability than tenofovir disoproxil fumarate, provides efficient delivery of active drug to hepatocytes at reduced systemic tenofovir exposures. METHODS: Non-cirrhotic, treatment-naïve subjects with chronic hepatitis B were randomized (1:1:1:1:1) to receive tenofovir alafenamide 8, 25, 40, or 120 mg, or tenofovir disoproxil fumarate 300 mg for 28 days and assessed for safety, antiviral response, and pharmacokinetics, followed-up by off-treatment for 4 weeks. RESULTS: 51 subjects were randomized and all completed study treatment. Groups were generally well matched (67% male, 57% Asian, 53% HBeAg-negative, mean HBV DNA approximately 6.0 log10 IU/ml) with HBV genotypes reflective of the population. No subject experienced an adverse event that was serious or severe (grade 3/4). Across the tenofovir alafenamide groups, similar mean changes in serum HBV DNA were found at Week 4 (-2.81, -2.55, -2.19, and -2.76 log10 IU/ml for the 8, 25, 40, and 120 mg groups, respectively) which were also comparable to the control (-2.68 log10 IU/ml for tenofovir disoproxil fumarate 300 mg). Kinetics of viral decline were also similar among groups. Tenofovir alafenamide pharmacokinetics were linear and proportional to the dose; doses⩽25 mg were associated with ⩾92% reductions in mean tenofovir area under the curve relative to tenofovir disoproxil fumarate 300 mg. CONCLUSIONS: Tenofovir alafenamide was safe and well tolerated; declines in HBV DNA were similar to tenofovir disoproxil fumarate at all doses evaluated. Tenofovir alafenamide 25 mg has been selected for further hepatitis B clinical development.

No resistance to tenofovir disoproxil fumarate through 96 weeks of treatment in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND & AIMS: A recent study compared the efficacy of tenofovir disoproxil fumarate (TDF) vs the combination of emtricitabine and TDF (FTC/TDF) in patients with lamivudine-resistant chronic hepatitis B who were treated for as long as 96 weeks. We report findings from resistance analyses conducted for this study. METHODS: Two hundred eighty patients with chronic hepatitis B virus (HBV) infection and lamivudine resistance (confirmed by INNO-LiPA Multi-DR) were randomly assigned (1:1) to groups treated with TDF or FTC/TDF. The HBV reverse transcriptase domain from the polymerase gene from all patients was sequenced at baseline and from 18 viremic patients at week 96 or early discontinuation. RESULTS: At screening for the efficacy study, 99% of patients were found to have lamivudine resistance. Prior exposure to entecavir or entecavir resistance was observed in 12% of patients, and 22% of patients had been previously exposed to adefovir; 1.8% were resistant to adefovir. Only 18 patients (6.4%) qualified for sequence analysis, including 1 patient who experienced virologic breakthrough and 17 with persistent viremia. Six of these patients did not have any sequence changes from baseline in HBV reverse transcriptase (33%), and sequence analysis could not be performed for 5 patients (28%). In 2 patients who qualified for phenotypic analysis (1 given TDF and 1 given FTC/TDF), no resistance to TDF was observed. Neither previous treatment exposure nor resistance to entecavir or adefovir affected viral kinetics. However, the mean baseline level of HBV DNA was significantly higher in viremic patients than in patients with viral suppression by week 96 (7.28 log10 IU/mL vs 5.62 log10 IU/mL; P = .0003). CONCLUSIONS: No resistance to TDF was detected through 96 weeks of treatment in patients with lamivudine-resistant chronic hepatitis B. Prior treatment or resistance to entecavir or adefovir did not affect viral kinetics through 96 weeks. No additional benefit was observed with the addition of emtricitabine vs TDF monotherapy. ClinicalTrial.gov number: NCT00737568.

Intestinal microbiota in patients with nonalcoholic fatty liver disease.

UNLABELLED: Despite evidence that the intestinal microbiota (IM) is involved in the pathogenesis of obesity, the IM composition of patients with nonalcoholic fatty liver disease (NAFLD) has not been well characterized. This prospective, cross-sectional study was aimed at identifying differences in IM between adults with biopsy-proven NAFLD (simple steatosis [SS] or nonalcoholic steatohepatitis [NASH]) and living liver donors as healthy controls (HC). Fifty subjects were included: 11 SS, 22 NASH, and 17 HC. One stool sample was collected from each participant. Quantitative real-time polymerase chain reaction was used to measure total bacterial counts, Bacteroides/Prevotella (herein referred to as Bacteroidetes), Clostridium leptum, C. coccoides, bifidobacteria, Escherichia coli and Archaea in stool. Clinical and laboratory data, food records, and activity logs were collected. Patients with NASH had a lower percentage of Bacteroidetes (Bacteroidetes to total bacteria counts) compared to both SS and HC (P = 0.006) and higher fecal C. coccoides compared to those with SS (P = 0.04). There were no differences in the remaining microorganisms. As body mass index (BMI) and dietary fat intake differed between the groups (P < 0.05), we performed linear regression adjusting for these variables. The difference in C. coccoides was no longer significant after adjusting for BMI and fat intake. However, there continued to be a significant association between the presence of NASH and lower percentage Bacteroidetes even after adjusting for these variables (P = 0.002; 95% confidence interval = -0.06 to -0.02). CONCLUSION: There is an inverse and diet-/BMI-independent association between the presence of NASH and percentage Bacteroidetes in the stool, suggesting that the IM may play a role in the development of NAFLD.

Atherosclerotic cardiovascular disease risk profile of patients with chronic hepatitis B treated with tenofovir alafenamide or tenofovir disoproxil fumarate for 96 weeks.

BACKGROUND: Patients with chronic hepatitis B (CHB) who switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) show changes in lipid profiles. AIM: To evaluate how these changes affect cardiovascular risk. METHODS: This pooled analysis, based on two large prospective studies, evaluated fasting lipid profiles of patients with CHB who were treated with TAF 25 mg/day or TDF 300 mg/day for 96 weeks. Patients who fulfilled the American College of Cardiology criteria (age 40-79 years, high-density lipoprotein [HDL] 20-100 mg/dL, total cholesterol [TC] 130-320 mg/dL and systolic blood pressure 90-200 mmHg) required to assess 10-year atherosclerotic cardiovascular disease (ASCVD) risk with baseline lipid data and at least one post-baseline measurement were included in the ASCVD-risk population. The 10-year ASCVD risk was calculated for patients in this population, and changes from baseline to Week 96 were assessed using intermediate- (≥7.5%) and high-risk (≥20%) cut-offs. RESULTS: Among 1632 patients, 620 (38%) met the criteria for the ASCVD-risk population. At Week 96, fasting levels of all lipids, except TC:HDL ratio, were lower with TDF than TAF. No significant increase was observed in overall ASCVD risk or in any ASCVD-risk categories during the 96-week treatment period compared with baseline. A similar proportion of patients in the TAF and TDF treatment groups (1.3% and 2.3%, respectively; p = 0.34) reported cardiovascular events. CONCLUSION: Despite on-treatment differences in lipid profiles with TAF and TDF, predicted cardiovascular risk and clinical events were similar for both groups after 96 weeks.

Characterization of hepatitis B virus genotypes and quantitative hepatitis B surface antigen titres in North American tertiary referral liver centres.

BACKGROUND & AIMS: Hepatitis B virus (HBV) genotype and quantitative hepatitis B surface antigen (qHBsAg) have been related to clinical outcome. In this nationwide cross-sectional study, we aimed to investigate the epidemiology and clinical significance of HBV genotype and qHBsAg in patients with chronic hepatitis B (CHB). METHODS: Six hundred and thirty patients with CHB were seen in four urban tertiary referral centres in Canada. HBV genotype was determined by line probe assay (INNO-LIPA) and HBV DNA quantified by commercial PCR (Roche TaqMan, sensitivity <55 IU/ml or AMPLICOR, sensitivity <60 IU/ml). Titres of qHBsAg were determined by an in-house assay based on the WHO standard (calibration range 0.24-62.5 IU/ml). RESULTS: In 630 patients (57% male, 69% Asian, median age 42 years), 21% were hepatitis B e antigen positive and the median alanine aminotransferase was 29 U/L. The HBV genotype distribution was A (16%), B (29%), C (31%), D (16%), E (6%). HBV genotype was strongly associated with ethnicity, but neither genotype nor qHBsAg correlated with the degree of fibrosis. In the treatment-naïve patients, the baseline qHBsAg levels correlated with HBV DNA (r = 0.2517, P < 0.0008). The median qHBsAg levels were lowest in patients with genotype B (P < 0.0001), but no significant correlation was noted with all other HBV genotypes. CONCLUSIONS: In this large North American HBV epidemiological study, genotypes B and C were the most common; however, all genotypes (A-E) were observed with varied distribution nationwide. Baseline qHBsAg significantly correlated with HBV DNA and with HBV genotype B, but not with liver fibrosis.

Chronic hepatitis B in pregnancy: unique challenges and opportunities.

Chronic hepatitis B (CHB) affects 350 million individuals worldwide. Perinatal transmission leads to high rates of chronic infection and complications, including cirrhosis and hepatocellular carcinoma. It is important to recognize and appropriately treat CHB in pregnancy, thereby reducing the risk of neonatal transmission and HBV-associated morbidity and mortality. Screening for CHB is recommended in all pregnant mothers as is universal vaccination of infants with hepatitis B virus (HBV) vaccine with or without hepatitis B immunoglobulin (HBIG). This has resulted in a lower incidence of HBsAg seropositivity and HCC in regions where universal infant vaccination has been endorsed. Mode of delivery and breastfeeding do not appear to affect HBV transmission rates based on available data. Overall, CHB does not increase perinatal maternal-fetal mortality. Administration of oral antiviral therapy during the third trimester to HBsAg-positive mothers with HBV DNA≥7 log IU/mL may be useful in preventing breakthrough infection. Treatment may be considered earlier in pregnancy for persistently active liver disease shown by high ALT, HBV DNA levels and/or significant hepatic fibrosis. Lamivudine, tenofovir and telbivudine are safe and effective and are the agents of choice in pregnancy. However, further clinical studies are necessary to elucidate the role of antiviral therapy in the pregnant HBV carrier.

Cancer-related gene expression is associated with disease severity and modifiable lifestyle factors in non-alcoholic fatty liver disease.

OBJECTIVE: The aim of this study was to determine whether hepatic gene expression related to hepatocellular carcinoma (HCC) is associated with disease severity and modifiable lifestyle factors in non-alcoholic fatty liver disease (NAFLD). METHODS: In a cross-sectional study, the associations between hepatic gene expression and liver histology, insulin resistance, anthropometrics, diet, and physical activity were assessed in patients with non-alcoholic steatohepatitis (NASH; n = 19) or simple steatosis (SS; n = 20). In a group of patients with NASH, we then conducted a 1-y, single-arm, pilot study using ω-3 polyunsaturated fatty acid (PUFA) supplementation to determine whether changes in hepatic PUFA content would have a modulating effect on hepatic gene expression and would affect liver histology. RESULTS: In the cross-sectional study, histological features of disease severity correlated with AKR1B10, ANXA2, PEG10, SPP1, STMN2, MT1A, and MT1B in NASH and with EEF1A2, PEG10, and SPP1 in SS. In addition, PEG10, SPP1, ANXA2, and STMN2 expression correlated positively with insulin resistance in NASH. SPP1 and UBD correlated strongly with body mass index in SS. Associations between ENPP2, AKR1B10, SPP1, UBD, and waist circumference depended on sex and diagnosis. Several genes correlated with protein, fat, or carbohydrate intake. PEG10 correlated positively with physical activity in NASH and inversely with plasma vitamin C in both groups. Despite increased erythrocyte and hepatic ω-3 PUFA, supplementation did not alter hepatic gene expression and liver histology. CONCLUSIONS: HCC-related gene expression was associated with liver histology, body mass index, waist circumference, diet, and physical activity but was not affected by ω-3 PUFA supplementation.

Epidemiologic and clinical features of chronic hepatitis B virus infection in 8 Canadian provinces: a descriptive study by the Canadian HBV Network.

BACKGROUND: Published Canadian epidemiologic data on hepatitis B virus (HBV) infection include single-centre studies or are focused on Indigenous populations. We performed a study to characterize the demographic and clinical features, liver disease status and treatment of people with chronic hepatitis B in Canada. METHODS: In this descriptive, opportunistic, cross-sectional study, available data for people known to be monoinfected with HBV were collected by the Canadian HBV Network from existing clinical databases, with support from the National Microbiology Laboratory, Public Health Agency of Canada. Data were collected in all provinces with the exception of New Brunswick and Newfoundland and Labrador. We analyzed the data using parametric and nonparametric statistical methods, with a significance level of p < 0.05. RESULTS: In the 9380 unique patient records reviewed, the median age was 48 years, and 5193 patients (55.4%) were male. Ethnicity information was available for 7858 patients, of whom 5803 (73.8%) were Asian, 916 (11.6%) were black and 914 (11.6%) were white. Most of those tested (5556/6796 [81.8%]) were negative for HBV e-antigen, and most of those with fibrosis data (3481/4260 [81.7%]) had minimal liver fibrosis, with more advanced fibrosis noted in older people (> 40 yr). Of the 980 patients with genotype data, 521 (53.2%) had genotype B or C infection. Most of the 9241 patients with known confirmed treatment status received tenofovir disoproxil fumarate (1655 [17.9%]), lamivudine (1434 [15.5%]) or entecavir (548 [5.9%]). INTERPRETATION: Based on available data, Canadian patients with chronic hepatitis B are predominantly Asian and negative for HBV e-antigen, and have genotype B or C infection. Interprovincial variations were noted in antiviral treatment regimen. This multicentre nationwide study provides data regarding patients with chronic hepatitis B and may inform future studies on the epidemiologic features of HBV infection in Canada.

Altered hepatic genes related to retinol metabolism and plasma retinol in patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), especially non-alcoholic steatohepatitis (NASH) is a chronic liver disease commonly associated with hepatic fibrosis. NASH patients have an increased risk for hepatocellular carcinoma (HCC). An altered retinol metabolism is one of the pathways involved in the process of hepatic fibrosis, and enzymes involved in retinol metabolism have been associated with HCC. We aimed to determine the association between plasma retinol levels and hepatic expression of genes related to retinol metabolism, as well as to assess the hepatic expression of transcription factors regulated by retinoic acid in patients with NAFLD. Cross-sectional study where hepatic gene expression (Illumina microarray) and plasma retinol levels (HPLC) were measured in 17 patients with simple steatosis (SS), 15 with NASH, and 22 living liver donors (LD) as controls. Plasma retinol levels were higher in SS (1.53 ± 0.44 µmol/L) and NASH (1.51 ± 0.56 µmol/L) compared to LD (1.21 ± 0.38 µmol/L; p<0.05). AKR1B10 was highly overexpressed in NASH compared to SS (+6.2-fold) and LD (+9.9-fold; p = 4.89E-11). Retinaldehyde dehydrogenase 1 family, member A2 (ALDH1A2) and retinaldehyde dehydrogenase 1 family, member A3 (ALDH1A3), key enzymes for retinoic acid synthesis, were underexpressed in SS (-1.48 and -2.3-fold, respectively) and NASH (-1.47 and -2.6-fold, respectively) versus LD. In NASH, hepatic ALDH1A2 and ALDH1A3 were underexpressed and inversely correlated with plasma retinol levels, which may reduce retinoic acid in the liver. This, in addition to changes in expression of other genes involved in retinol metabolism, suggests a role for altered retinol homeostasis in NASH.

Management of Hepatitis B Virus Infection: 2018 Guidelines from the Canadian Association for the Study of Liver Disease and Association of Medical Microbiology and Infectious Disease Canada.

Hepatitis B virus (HBV) infection is an important public health problem in Canada. In keeping with evolving evidence and understanding of HBV pathogenesis, the Canadian Association for the Study of Liver Disease periodically publishes HBV management guidelines. The goals of the 2018 guidelines are to (1) highlight the public health impact of HBV infection in Canada and the need to improve diagnosis and linkage to care, (2) recommend current best-practice guidelines for treatment of HBV, (3) summarize the key HBV laboratory diagnostic tests, and (4) review evidence on HBV management in special patient populations and include more detail on management of HBV in pediatric populations. An overview of novel HBV tests and therapies for HBV in development is provided to highlight the recent advances in HBV clinical research. The aim and scope of these guidelines are to serve as an up-to-date, comprehensive resource for Canadian health care providers in the management of HBV infection.

Management of drug-resistant chronic hepatitis B.

Lamivudine, adefovir, and entecavir are safe and effective orally administered inhibitors of hepatitis B virus (HBV) replication, but drug-resistant strains of HBV with point mutations in the HBV polymerase gene are being reported with prolonged treatment that can lead to viral rebound and serum alanine aminotransferase flares. Salvage treatment with antiviral agents including investigational nucleoside/nucleotide analogues is available but highlights the limitations and hazards of sequential antiviral monotherapy for chronic HBV. Studies of pegylated interferon combined with an antiviral agent or dual nucleoside/nucleotide combination therapy are awaited to minimize the incidence of drug-resistant HBV and improve long-term outcomes.

Management of hepatitis B patients with antiviral resistance.

Drug resistance is an expected consequence of antiviral therapy for chronic hepatitis B because of the high rate of hepatitis B virus (HBV) replication, the lack of proof-reading during reverse transcription of the pregenomic RNA and the low efficacy of available therapies in eliminating covalently closed circular HBV DNA. Mutations involving the YMDD motif of the catalytic domain of HBV reverse transcriptase have been reported in patients who have received lamivudine, emtricitabine and telbivudine. Drug-resistant mutations affecting other regions of HBV polymerase have also been reported, but at much lower rates in patients who have received adefovir dipivoxil or entecavir. Antiviral resistance is initially manifested as virological breakthrough infection. In most patients, this is followed by biochemical breakthrough and, in some patients, hepatitis flares and hepatic decompensation. Monitoring drug resistance may improve the management of patients with antiviral-resistant HBV and can guide the selection of salvage therapy. The optimal management of patients with antiviral-resistant HBV continues to evolve. The ideal approach is to prevent antiviral resistance through judicious use of antiviral therapy and the use of more potent antiviral agents, possibly in combination.

Drug insight: Nucleoside and nucleotide analog inhibitors for hepatitis B.

In the past decade, substantial advances have been made in the treatment of chronic hepatitis B. Approved treatments include interferon-alpha, the nucleoside analog inhibitor lamivudine, and the nucleotide analog inhibitor adefovir dipivoxil. This review provides insights into the benefits and limitations of lamivudine and adefovir dipivoxil for the treatment of chronic hepatitis B. Lamivudine and adefovir dipivoxil have similar antiviral efficacies. Lamivudine has negligible side effects but a high rate of drug resistance, whereas adefovir dipivoxil has a low rate of drug resistance but long-term use is associated with a small risk of nephrotoxicity. Several other nucleoside and nucleotide analogs are being evaluated in phase II/III clinical trials for hepatitis B.

Combined topical and oral antimicrobial therapy for the eradication of methicillin-resistant Staphylococcus aureus (MRSA) colonization in hospitalized patients.

OBJECTIVE: How to eradicate methicillin-resistant Staphylococcus aureus (MRSA) colonization in hospitalized patients is uncertain. We reviewed our experience with MRSA decolonization therapy in hospitalized patients. SETTING: An 1100-bed, university-affiliated tertiary care teaching hospital in Toronto, Ontario. DESIGN: Retrospective chart review of 207 adult inpatients with MRSA colonization hospitalized between February 1996 and March 1999. INTERVENTIONS: All patients with MRSA colonization were assessed for possible decolonization therapy with a combination of 4% chlorhexidine soap for bathing and washing, 2% mupirocin ointment applied to the anterior nares three times/day, rifampin (300 mg twice daily) and either trimethoprim/sulfamethoxazole (160 mg/800 mg twice daily) or doxycycline (100 mg twice daily). This treatment was given for seven days. RESULTS: A total of 207 hospitalized patients with MRSA colonization were identified and 103 (50%) received decolonization therapy. Patients who received decolonization therapy were less likely than untreated patients to have intravenous (P=0.004) or urinary catheters (P<0.001), or extranasal sites of colonization (P=0.001). Successful decolonization was achieved in 90% of the 43 patients who were available for at least three months of follow-up. CONCLUSIONS: Combined topical and oral antimicrobial therapy was found to be effective in eradicating MRSA colonization in selected hospitalized patients, especially those without indwelling medical devices or extranasal sites of colonization.