Hepatitis B surface antigen loss and sustained viral suppression in Asian chronic hepatitis B patients: A community-based real-world study.

Community-based real-world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re-emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti-HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re-emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg-positive and HBeAg-negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti-HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on-treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re-emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community-based real-world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti-HBs, nearly all patients achieved sustained undetectable virus.

Community-based real-world treatment outcomes of sofosbuvir/ledipasvir in Asians with chronic hepatitis C virus genotype 6 in the United States.

Sofosbuvir/ledipasvir (SOF/LDV) is the first all-oral ribavirin-free treatment approved for chronic hepatitis C virus (HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real-world outcomes of this regimen are lacking. We aim to evaluate real-world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment (EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/LDV (52.3% male, mean age 66.3 years [SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community-based real-world cohort of Asian chronic HCV genotype 6 patients treated with all-oral SOF/LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations.

Intimate partner violence education for medical students in the USA, Vietnam and China.

OBJECTIVES: While intimate partner violence (IPV) is a global concern for women's health, there are few comparative studies of IPV training in medical schools. The aim of this study was to investigate medical students' knowledge of, and training in, IPV in the USA, Vietnam and China. STUDY DESIGN: Cross-national, cross-sectional study. METHODS: US (n = 60), Vietnamese (n = 232) and Chinese (n = 174) medical students participated in a cross-sectional self-administered survey that included demographic characteristics; opinions, training and knowledge regarding IPV against women; and personal experience with IPV victims. RESULTS: Attitudes, knowledge and training about IPV among medical students varied between the three countries. US participants reported higher levels of knowledge of IPV, were more likely to believe that IPV was a serious problem, and were more likely to consider IPV to be a healthcare problem compared with Vietnamese and Chinese participants. Chinese participants, in particular, did not appear to appreciate the importance of addressing IPV. Differences were found between the Vietnamese and Chinese students. CONCLUSIONS: While most medical schools in the USA include IPV training within their core medical curricula, education throughout medical school seems to be necessary to improve medical education regarding treatment of patients with a history of IPV. Vietnamese and Chinese medical schools should consider including IPV education in the training of their future physicians to improve the health of women who have experienced IPV. Practical opportunities for medical students to interact with women who have experienced IPV are essential to develop effective IPV education.

Ethnic differences in incidence of hepatitis B surface antigen seroclearance in a real-life multicenter clinical cohort of 4737 patients with chronic hepatitis B infection.

BACKGROUND: Hepatitis B surface antigen (HBsAg) positivity is associated with increased risk for cirrhosis and hepatocellular carcinoma (HCC). HBsAg seroclearance is thought to be rare in general, but cohort data from US patients are limited. AIM: To determine the incidence of HBsAg seroclearance in a real-life US cohort. METHODS: In total, 4737 patients with chronic hepatitis B from five primary care, gastroenterology and multispecialty centres, and a university medical centre were retrospectively enrolled between 2001 and 2014 with data obtained by manual review of individual patient medical records. Seroclearance was determined by loss of HBsAg seropositivity. Persistent HBsAg was confirmed by direct serology or by proxy with positive hepatitis B e-antigen (HBeAg) or HBV DNA levels. RESULTS: HBsAg seroclearance occurred in 52 patients over 16 844 person-years (0.31% annually, 1.2% overall). Median follow-up was 32 months, and mean age 45 ± 14 years. Incidence of HBsAg seroclearance was higher in non-Asians, age >45, males, and those with baseline HBV DNA ≤10 000 IU/mL. On multivariate Cox proportional modelling, non-Asian ethnicity (HR 2.8), male sex (HR 2.1), baseline HBVDNA ≤10 000 (HR 2.0) and age >45 (HR 1.8) were significant independent predictors of seroclearance. CONCLUSION: HBsAg seroclearance rates were lower than previously described in this real-life cohort of patients with chronic hepatitis B, especially among Asian, female and younger patients.

Tenofovir is superior to entecavir for achieving complete viral suppression in HBeAg-positive chronic hepatitis B patients with high HBV DNA.

BACKGROUND: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the two first-line anti-viral therapies for chronic hepatitis B (CHB); however, there are limited studies directly comparing their effectiveness. AIM: To compare the effectiveness of ETV and TDF in nucleos(t)ide-naïve CHB patients with high hepatitis B virus (HBV) DNA levels, defined as serum HBV DNA greater than 6 log10  IU/mL. METHODS: We performed a retrospective multicentre cohort study of adult CHB patients who were seen between 2009 and 2012 at four Northern California community gastroenterology and hepatology clinics. RESULTS: We identified 59 consecutive patients treated with TDF and 216 patients treated with ETV. Pre-treatment characteristics were similar between the two groups. Among HBeAg-negative patients, there was no significant difference in viral suppression rates between ETV and TDF (P = 0.72). In contrast, among HBeAg-positive patients, those treated with TDF achieved viral suppression significantly more rapidly than those treated with ETV (P < 0.0001); the Kaplan-Meier estimated probability of complete suppression was 18% vs. 11% at 6 months, 51% vs. 28% at 12 months and 72% vs. 39% at 18 months respectively. Multivariate Cox proportional hazards analysis indicated that treatment with TDF compared to ETV was a significant predictor of viral suppression, but only for HBeAg-positive patients (HR = 2.59; 95% CI 1.58-4.22; P < 0.001). CONCLUSION: Tenofovir is significantly more effective than entecavir for achieving complete viral suppression in HBeAg-positive, nucleos(t)ide-naïve chronic hepatitis B patients with HBV DNA greater than 6 log10  IU/mL.

Precore and basal core promoter mutations in Asian American patients with hepatitis B e antigen-positive chronic hepatitis B.

BACKGROUND: Prior studies have shown that precore mutations abolish and basal core promoter (BCP) mutations down-regulate hepatitis B e antigen (HBeAg) production. Thus, the presence of precore and BCP mutations in HBeAg-positive patients indicates an infection with a mixed viral population of wild-type and precore and/or BCP mutant hepatitis B virus (HBV). To date, there has been limited study of the prevalence and clinical significance of precore and BCP mutations in patients with HBeAg-positive chronic hepatitis B. AIM: To determine the prevalence, predictors and clinical characteristics of mixed wild-type and precore/BCP HBV infection, through a cross-sectional study, in a US cohort of patients with chronic hepatitis B. METHODS: We conducted a retrospective study of 828 chronic hepatitis B patients with HBV genotype and mutation panel testing seen at three US gastroenterology and liver clinics from June 2005 to September 2009. RESULTS: A majority of our patients (92.3%) were either Vietnamese or Chinese American. In the HBeAg-positive cohort, 17% of patients had precore mutations only, 28% had BCP mutations only and 5% had both BCP and precore mutations. On multivariate analyses, HBV genotype C, increasing age, lower HBV DNA level and an ALT quotient >2 were independent predictors for the presence of precore and/or BCP mutations. CONCLUSIONS: The current distinction and management recommendations for HBeAg-positive vs. HBeAg-negative patients with chronic hepatitis B should be reassessed. Additional biomarkers and treatment endpoints should be studied for their usefulness in predicting continued viral suppression after treatment discontinuation.

The efficacy of entecavir therapy in chronic hepatitis B patients with suboptimal response to adevofir.

BACKGROUND: An increasing number of patients with chronic hepatitis B (CHB) have experienced treatment failure to adefovir (ADV) and their management poses a growing challenge. Very limited data are available on the efficacy of entecavir (ETV) in patients previously treated with ADV. AIM: To examine the effect of ETV monotherapy on HBV DNA and ALT levels in CHB patients previously treated with ADV, but switched to ETV due to suboptimal response. METHODS: Study candidates were enrolled from five community gastroenterology clinics in the U.S. Each completed at least 12 months of ETV treatment after being previously treated with ADV and experiencing suboptimal response. Primary and secondary outcome measurements were complete viral suppression (CVS, HBV DNA <100 IU/mL) and biochemical response (BR, ALT < 40 U/L), respectively. RESULTS: A total of 60 patients were included in this analysis. Twelve were lamivudine (LAM)-experienced and none were LAM-resistant. At time of switch to ETV, no patients had experienced CVS. The CVS rate was 68% after 12 months of ETV therapy. The BR rate was 67% at switch to ETV and 80% after 12 months. There was no significant difference in response rates between LAM-experienced and naïve patients. Among the eight patients with ADV resistance, each achieved CVS after 12 months of ETV therapy and seven achieved BR. CONCLUSIONS: In patients with suboptimal response to adefovir, complete viral suppression and biochemical response can be achieved in the majority by 12 months after switching to entecavir, including patients with prior exposure to lamivudine and those with adefovir resistance.

Prevalence of hepatitis B virus DNA polymerase mutations in treatment-naïve patients with chronic hepatitis B.

BACKGROUND: One of the most important factors in treatment failure using nucleos(t)ide analogues in chronic hepatitis B is anti-viral resistance. Primary drug resistance refers to amino acid changes in the hepatitis B virus polymerase/reverse transcriptase (rt) that result in reduced susceptibility to anti-viral agents. Pre-existing drug resistance mutations may occur in untreated patients and may affect their treatment outcomes. AIM: To determine the prevalence of hepatitis B DNA polymerase mutations in treatment-naïve patients. METHODS: We used a direct PCR sequencing test to detect DNA polymerase mutations in 472 consecutive treatment-naïve patients at two community gastroenterology clinics in Northern California. RESULTS: A majority of patients were Asians (>95%), had either genotype B or C (95%) and had no evidence of cirrhosis or liver cancer (94%). Mean age was 45 +/- 13 and mean hepatitis B virus DNA was 5.3 +/- 1.8 log(10) IU/mL. Most patients did not have any detectable mutations (82.4%). Some (16.7%) had mutations of unknown clinical significance (rtV207M/L/I) and only 4 patients had rtA181A/S, rtA194S or M250I. CONCLUSIONS: No rtM204V/I or rtN236T mutations were observed in our study. Less than 1% of our patients had mutations that can be associated with primary resistance to existing anti-viral therapies for hepatitis B virus.

Heterogeneity of NH+4 transport in mouse inner medullary collecting duct cells.

Previous studies from our laboratory have demonstrated that NH+4 substitutes for K+ on the Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) in rat terminal inner medullary collecting duct cells (tIMCD). To examine other NH+4 transport pathways, a transgenic mouse cell line, mIMCD-3, was employed. 86Rb+ was used as a K+ congener to explore NH+4/Rb+ (K+) competition on the extracellular K+ binding site of the Na(+)-K(+)-2Cl- cotransporter and the Na(+)-K(+)-ATPase. Addition of K+ or NH+4 reduced both bumetanide- and ouabain-sensitive Rb+ uptake. This reduction in Rb+ uptake with NH+4 addition was not due to intracellular pH-mediated changes in transporter activity. K+ and NH+4 are competitive inhibitors on both transporters. On the Na(+)-K(+)-2Cl- cotransporter, the Michaelis constant (Km) for K+ was 4.6 +/- 0.5 mM with an inhibitory constant (Ki) for NH+4 of 2.8 mM. In contrast, on the Na(+)-K(+)-ATPase, the apparent affinity for K+ was greater than for NH+4. To test Na(+)-K(+)-2Cl- cotransport-mediated NH+4 flux, bumetanide-sensitive NH+4/Rb+ exchange was measured. Bumetanide-sensitive Rb+ efflux was greater with extracellular K+ or NH+4 present relative to efflux with extracellular N-methyl-D-glucamine. This demonstrates both K+/Rb+ and NH+4/Rb+ countertransport by the Na(+)-K(+)-2Cl- cotransporter. In conclusion, NH+4 is transported in a bumetanide-sensitive Na(+)-NH+4-Cl- mode, and both NH+4 and Rb+ (K+) are competitive inhibitors for the extracellular K+ binding site. However, the kinetics of Na(+)-K(+)-2Cl(-)-mediated NH+4 transport differ from other K+ transport-mediated NH+4 pathways, such as the Na(+)-K(+)-ATPase.