April Wong

Hepatitis due to Reactivation of Hepatitis B Virus in Endemic Areas Among Patients With Hepatitis C Treated With Direct-acting Antiviral Agents

&NA; Hepatitis due to reactivation of hepatitis B virus (HBV) has been reported in patients treated with direct‐acting antiviral (DAA) agents for chronic hepatitis C virus infection. We performed an observational study to determine the incidence of and factors associated with hepatitis in 327 patients receiving pan‐oral DAA agents for HCV infections in areas endemic for HBV in China. Ten patients were positive for hepatitis B surface antigen (HBsAg), and 124 patients had occult HBV infection. HBV reactivation was determined by measuring HBV DNA and HBsAg status in serial serum samples collected every 2 weeks during DAA treatment and then every 4 weeks after treatment until week 12. In the total study population, 10 patients (3.1%) had hepatitis; 3 cases were associated with HBV reactivation (1 case not in the icteric phase, 1 case in the icteric phase, and 1 case with liver failure) and 7 from other causes. Testing positive for HBsAg before DAA treatment was a strong risk factor for developing hepatitis during treatment (hazard ratio, 15.0; P < .001).

96 weeks combination of adefovir dipivoxil plus emtricitabine vs. adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B

BACKGROUND/AIMS In order to prevent the occurrence of drug-resistant mutants associated with treatment for chronic hepatitis B virus (HBV) infection, combination therapy is being developed. To determine the efficacy of adefovir dipivoxil (ADV) plus emtricitabine (FTC) combination therapy in chronic HBV infection. METHODS Thirty treatment-nai ve, HBeAg-positive patients were randomized to combination ADV plus FTC (n=14) or ADV plus placebo monotherapy (n=16) for 96 weeks. HBV DNA was measured by polymerase chain reaction. Treatment was stopped in those with HBeAg seroconversion. RESULTS The median decrease in HBV DNA at week 96 was higher in the combination group (-5.30 vs. -3.98 log(10)copies/ml, p=0.05). More patients in the combination group had normalization of alanine aminotransaminase and HBV DNA<300 copies/ml at week 96 when compared with the monotherapy group [11 of the 14 patients (78.6%) vs. 6 of the 16 patients (37.5%), p=0.03]. However, HBeAg seroconversion at week 96 was similar in the 2 groups [2/14 (14.3%) vs. 4/16 (25.0%), p=NS]. No ADV or FTC resistance was detected at week 96. In those with HBeAg seroconversion, 50.0% had post-treatment relapse. CONCLUSIONS Combination ADV plus FTC resulted in more potent suppression of HBV DNA over 96 weeks of therapy.

Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study.

BACKGROUND To shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor-NS5B nucleotide analogue. METHODS In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNA <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. The primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858. FINDINGS Between April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and simeprevir; and two [33%] of six patients receiving sofosbuvir, daclatasvir, and asunaprevir) and headache (one [17%] patient in each group). No patients experienced any serious adverse events. INTERPRETATION In this proof-of-concept study, all patients with chronic HCV without cirrhosis who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received 3 weeks of treatment were cured, with excellent tolerability. By shortening the duration of therapy from the currently recommended 12 weeks to 3 weeks, we could drastically reduce the cost of therapy and the rate of adverse events. Further large-scale studies should be done to confirm our findings. FUNDING Center for AIDS Research, National Institutes of Health, US Department of Energy, National Center for Research Resources and the Office of Research Infrastructure Programs, Cheng Si-Yuan (China-International) Hepatitis Research Foundation, and Humanity and Health Medical Group.

Cloning and regulation of expression of the Na+–Cl––taurine transporter in gill cells of freshwater Japanese eels

SUMMARY Our previous studies have demonstrated the hypertonic-induced expression of osmotic stress transcription factor and the regulatory volume increase (RVI) response in gill cells isolated from freshwater eels. In this study, we aimed to clone one of the organic osmolyte transporters, the Na+–Cl––taurine transporter (TauT), and to characterize its expression in anisosmotic conditions, using both in vivo and in vitro approaches. A cDNA clone encoding TauT was isolated from gill tissues of Japanese eels, Anguilla japonica. The deduced amino acid sequence shows 88–90% identity to other reported piscine TauT sequences. Our data indicated that TauT mRNA was detectable in both freshwater and seawater fish gills. The expression level of TauT mRNA increased in gills of seawater-acclimating fish. A high abundance of TauT protein was found to be localized in seawater gill chloride cells. Using primary gill cell culture, expression of the gene was induced when the ambient osmolarity was raised from 320 to 500 mosmol l–1. Hypertonic treatment of the culture caused an increase of F-actin distribution in the cell periphery. Treatment of the cells with colchicine or cytochalasin D significantly reduced TauT transcript level following hypertonic exposure. The inhibition of myosin light chain (MLC) kinase by ML-7 had a significant additive effect on hypertonic-induced TauT expression. Collectively, the data of this study reveal, for the first time, the regulation of TauT expression in gill cells of euryhaline fish. We have demonstrated the involvement of ionic strength, the cytoskeleton and MLC kinase in the regulation of TauT expression. The results shed light on the osmosensing and hyperosmotic adaption in fish gills.

Cloning and regulation of expression of theNa+–Cl––taurine transporter in gillcells of freshwater Japanese eels

SUMMARY Our previous studies have demonstrated the hypertonic-induced expression of osmotic stress transcription factor and the regulatory volume increase (RVI) response in gill cells isolated from freshwater eels. In this study, we aimed to clone one of the organic osmolyte transporters, the Na+–Cl––taurine transporter (TauT), and to characterize its expression in anisosmotic conditions, using both in vivo and in vitro approaches. A cDNA clone encoding TauT was isolated from gill tissues of Japanese eels, Anguilla japonica. The deduced amino acid sequence shows 88–90% identity to other reported piscine TauT sequences. Our data indicated that TauT mRNA was detectable in both freshwater and seawater fish gills. The expression level of TauT mRNA increased in gills of seawater-acclimating fish. A high abundance of TauT protein was found to be localized in seawater gill chloride cells. Using primary gill cell culture, expression of the gene was induced when the ambient osmolarity was raised from 320 to 500 mosmol l–1. Hypertonic treatment of the culture caused an increase of F-actin distribution in the cell periphery. Treatment of the cells with colchicine or cytochalasin D significantly reduced TauT transcript level following hypertonic exposure. The inhibition of myosin light chain (MLC) kinase by ML-7 had a significant additive effect on hypertonic-induced TauT expression. Collectively, the data of this study reveal, for the first time, the regulation of TauT expression in gill cells of euryhaline fish. We have demonstrated the involvement of ionic strength, the cytoskeleton and MLC kinase in the regulation of TauT expression. The results shed light on the osmosensing and hyperosmotic adaption in fish gills.

Will Sofosbuvir/Ledipasvir (Harvoni) Be Cost-Effective and Affordable for Chinese Patients Infected with Hepatitis C Virus? An Economic Analysis Using Real-World Data

Background Little is known on the cost-effectiveness of novel regimens for hepatitis C virus (HCV) compared with standard-of-care with pegylated interferon (pegIFN) and ribavirin (RBV) therapy in developing countries. We evaluated cost-effectiveness of sofosbuvir/ledipasvir for 12 weeks compared with a 48-week pegIFN-RBV regimen in Chinese patients with genotype 1b HCV infection by economic regions. Methods A decision analytic Markov model was developed to estimate quality-adjusted-life-years, lifetime cost of HCV infection and incremental cost-effectiveness ratios (ICERs). SVR rates and direct medical costs were obtained from real-world data. Parameter uncertainty was assessed by one-way and probabilistic sensitivity analyses. Threshold analysis was conducted to estimate the price which can make the regimen cost-effective and affordable. Results Sofosbuvir/ledipasvir was cost-effective in treatment-experienced patients with an ICER of US

The cloning and the regulation of Na+-Cl--taurine transporter expression in gill cells of freshwater Japanese eels.

21,612. It varied by economic regions. The probability of cost-effectiveness was 18% and 47% for treatment-naive and experienced patients, and it ranged from 15% in treatment-naïve patients in Central-China to 64% in treatment-experienced patients in Eastern-China. The price of 12-week sofosbuvir/ledipasvir treatment needs to be reduced by at least 81% to US

Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: a systematic review and meta-analysis

18,185 to make the regimen cost-effective in all patients at WTP of one time GDP per capita. The price has to be US

567 RELATIONSHIP BETWEEN HBV CCCDNA AND HBsAg LEVELS IS ASSOCIATED WITH HBeAg STATUSES OF CHRONIC HEPATITIS B PATIENTS

105 to make the regimen affordable in average patients in China. Conclusion Sofosbuvir/ledipasvir regimen is not cost-effective in most Chinese patients with genotype 1b HCV infection. The results vary by economic regions. Drug price of sofosbuvir/ledipasvir needs to be substantially reduced when entering the market in China to ensure the widest accessibility.

No increase in the occurrence rate of hepatocellular carcinoma in Chinese treated by direct-acting antivirals compared to Interferon after eradication of hepatitis c virus: a long-term follow-up

SUMMARY Our previous studies have demonstrated the hypertonic-induced expression of osmotic stress transcription factor and the regulatory volume increase (RVI) response in gill cells isolated from freshwater eels. In this study, we aimed to clone one of the organic osmolyte transporters, the Na+–Cl––taurine transporter (TauT), and to characterize its expression in anisosmotic conditions, using both in vivo and in vitro approaches. A cDNA clone encoding TauT was isolated from gill tissues of Japanese eels, Anguilla japonica. The deduced amino acid sequence shows 88–90% identity to other reported piscine TauT sequences. Our data indicated that TauT mRNA was detectable in both freshwater and seawater fish gills. The expression level of TauT mRNA increased in gills of seawater-acclimating fish. A high abundance of TauT protein was found to be localized in seawater gill chloride cells. Using primary gill cell culture, expression of the gene was induced when the ambient osmolarity was raised from 320 to 500 mosmol l–1. Hypertonic treatment of the culture caused an increase of F-actin distribution in the cell periphery. Treatment of the cells with colchicine or cytochalasin D significantly reduced TauT transcript level following hypertonic exposure. The inhibition of myosin light chain (MLC) kinase by ML-7 had a significant additive effect on hypertonic-induced TauT expression. Collectively, the data of this study reveal, for the first time, the regulation of TauT expression in gill cells of euryhaline fish. We have demonstrated the involvement of ionic strength, the cytoskeleton and MLC kinase in the regulation of TauT expression. The results shed light on the osmosensing and hyperosmotic adaption in fish gills.