Switching to Tenofovir versus Continuing Entecavir in Chronic Hepatitis B Patients with Partial Virologic Response During Entecavir Therapy: STEEP Study

( Hyung Joon Yim ),( In Hee Kim ),( Sang Jun Suh ),( Young Kul Jung ),( Ji Hoon Kim ),( Yeon Seok Seo ),( Jong Eun Yeon ),( Chang Wook Kim ),( So Young Kwon ),( Sang Hoon Park ),( Myung Seok Lee ),( S 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Entecavir has been widely used for treatment-naive chronichepatitis B patients. However, about 20% of patients show partialvirologic response (PVR) after 2 year of entecavir therapy [Yoon, etal, 2011〕. If the HBV DNA continued to be detected, underlying liverdisease may progress, and the risk of hepatocellular carcinoma canbe increased. Therefore, switching to more potent antiviral therapymay be needed.In this study, we compared the efficacy of switching to tenofovirwith continuing entecavir in patients who shows PVR to entecavir.Methods: This is an investigator initiated open label randomized controlledtrial (NCT01711567). Primary end point was a virologic responserate 12 months (VR, HBV DNA < 20 IU/mL).We included chronic hepatitis B patients receiving entecavir 0.5 mgmore than 12 months with detectable HBV DNA over 60 IU/mL, butno resistance to entecavir.Results: A total of 45 patients were enrolled. Twenty two patientswere randomized to tenofovir and 23 patients to entecavir arm.Baseline characteristics were not significantly different between thegroups.After 12 month of treatment, VR rate were significantly higher intenofovir group compared with entecavir group by per protocol analysis(55% vs 20%, P = 0.022) as well as intention-to-treat analysis(50% vs 17.4%, P= 0.020). At month 12, the mean HBV DNA levelwas lower (1.54 vs. 2.01 log IU/mL, P = 0.011) and the degree ofHBV DNA reduction was greater (-1.13 vs. -0.67 log IU/mL, P = 0.024)in tenofovir group than entecavir group, respectively. Proportion ofpatients with normal ALT and HBeAg loss/seroconversion rate werenot different between the groups.Conclusions: In chronic hepatitis B patients with PVR to entecavir, switchingto tenofovir would be a better strategy to achieve optimal response.

Original Article : Performance evaluation of the HepB Typer-Entecavir kit for detection of entecavir resistance mutations in chronic hepatitis B

( Sang Hoon Ahn ),( Ji Yong Chun ),( Soo Kyung Shin ),( Jun Yong Park ),( Wang Don Yoo ),( Sun Pyo Hong ),( Soo Ok Kim ),( Kwang Hyub Han ) 대한간학회 2013 Clinical and Molecular Hepatology(대한간학회지) Vol.19 No.4

Background/Aims: Molecular diagnostic methods have enabled the rapid diagnosis of drug-resistant mutations in hepatitis B virus (HBV) and have reduced both unnecessary therapeutic interventions and medical costs. In this study we evaluated the analytical and clinical performances of the HepB Typer-Entecavir kit (GeneMatrix, Korea) in detecting entecavir-resistance-associated mutations. Methods: The HepB Typer-Entecavir kit was evaluated for its limit of detection, interference, cross-reactivity, and precision using HBV reference standards made by diluting high-titer viral stocks in HBV-negative human serum. The performance of the HepB Typer-Entecavir kit for detecting mutations related to entecavir resistance was compared with direct sequencing for 396 clinical samples from 108 patients. Results: Using the reference standards, the detection limit of the HepB Typer-Entecavir kit was found to be as low as 500 copies/mL. No cross-reactivity was observed, and elevated levels of various interfering substances did not adversely affect its analytical performance. The precision test conducted by repetitive analysis of 2,400 replicates with reference standards at various concentrations showed 99.9% agreement (2398/2400). The overall concordance rate between the HepB Typer-Entecavir kit and direct sequencing assays in 396 clinical samples was 99.5%. Conclusions: The HepB Typer-Entecavir kit showed high reliability and precision, and comparable sensitivity and specificity for detecting mutant virus populations in reference and clinical samples in comparison with direct sequencing. Therefore, this assay would be clinically useful in the diagnosis of entecavir-resistance-associated mutations in chronic hepatitis B.

Plenary Session l : A 96-week Randomized Trial of Switching to Entecavir in Chronic Hepatitis B Patients with a Complete Virologic Response to Lamivudine

( Jeong Heo ),( Sang Hoon Ahn ),( Jun Yong Park ),( Hyun Young Woo ),( Heon Ju Lee ),( Won Young Tak ),( Soon Ho Um ),( Ki Tae Yoon Soo ),( Young Park ),( Yeon Seok Seo ),( Chang Wook Kim ),( Kwang Hy 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Backgrounds: Entecavir has a higher potent antiviral efficacy and a lower drug resistance rate than Lamivudine in nucleoside- naive chronic hepatitis B (CHB) patients. The switch from Lamivudine to Entecavir in patients who have undetectable hepatitis B virus DNA (HBV DNA < 60 IU/mL) may lead to more prolonged viral suppression to undetectable level by PCR method, compared to patients with continuous Lamivudine treatment. This prospective, 96 week study investigated the antiviral efficacy, safety and tolerability of switching to Entecavir versus maintaining Lamivudine in CHB patients with virologic response to Lamivudine. Methods: A total of 73 HBeAg-positive patients, with serum HBV DNA < 60 IU/mL after at least 6 months Lamivudine monotherapy were randomized 1:1 into either switching to Entecavir 0.5 mg/day, or continuing with Lamivudine 100 mg/ day. Results: Mean duration of prior Lamivudine treatment (n=35) was 25.7 months in the Lamivudine-maintained, and 27.4 months in the Entecavir-switch patients. At 96 weeks of followup, 20/35 (57.1%) patients in the Lamivudine arm had persistently undetectable HBV DNA, compared with 37/38 (97.4%) patients in the Entecavir arm (P <0.001). Out of total 16 patients with HBV DNA rebound, 8/15 in the Lamivudine arm had HBV DNA of more than 1,000 IU/mL during rebound, while none in Entecavir arm. Genotypic resistance to assigned intervention emerged in 28.6% (10/35) of Lamivudine-maintained patients, and in 0% (0/38) of Entecavir-switched patients during 96 weeks (P <0.001). Seventeen Entecavir-switched (45.9%) and seven Lamivudine-maintained (21.2%) patients achieved HBeAg loss (P =0.043), and nine Entecavir (24.3%) and five Lamivudine (15.2%) patients achieved HBeAg seroconversion.

Telbivudine versus Entecavir in Entecavir-Treated Patients with Undetectable Hepatitis B Virus DNA: Randomized Trial

( Jihyun An ),( Young-suk Lim ),( Gi-ae Kim ),( Hyung Don Kim ),( Seong-bong Han ),( Danbi Lee ),( Ju Hyun Shim ),( Han Chu Lee ),( Yung Sang Lee ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Recent study suggested that telbivudine (LdT) may have similar efficacy in reducing Hepatitis B surface antigen (HBsAg) titer compared with pegylated interferon. We aimed to investigate whether telbivudine could further decrease HBsAg titer in the patients who maintained undetectable serum hepatitis B virus (HBV) DNA after initial entecavir (entecavir) treatment. Methods: In this open-label, single-center study, patients were randomly assigned 1:1 to switch to telbivudine (n=47) or continue with entecavir (n=50). HBV DNA, HBsAg titer, and liver biochemistry were performed at weeks 0, 12, 24, and 48. Mutational analysis was checked at the time of HBV DNA relapse. Results: Median baseline HBsAg levels were comparable between LdT and entecavir groups (3.43 vs. 3.40 log10IU/mL, P=0.427). At 48 weeks of follow-up, median HBsAg titer was not significantly different between LdT and entecavir arm (3.37 vs. 3.39 log10 IU/mL, P=0.653). The decline in mean HBsAg over 48 weeks was also similar (-0.03 ± 0.14 vs. -0.05 ± 0.11 log10IU/mL, P=0.568). Viral breakthrough (VBT), mostly along with genotypic resistance, was significantly more frequent in LdT group compared with those with entecavir (19.1% vs. 0%, P=0.001 for VBT, and 14.9% vs. 0%, P=0.005 for emergence of antiviral resistance). One patient developed myopathy on LdT treatment and recovered after discontinuation of drug. Conclusions: Sequential therapy using entecavir followed by LdT did not show additional benefit on reducing HBsAg titer compared with entecavir continuation. Switching to LdT was associated with higher rate of VBT and resistance development during 48 weeks.

Long-term real-world entecavir therapy in treatment-naive hepatitis B patients: base-line hepatitis B virus DNA and hepatitis B surface antigen levels predict virologic response

( Ju-yeon Cho ),( Won Sohn ),( Dong-hyun Sinn ),( Geum-youn Gwak ),( Yong-han Paik ),( Moon Seok Choi ),( Kwang Cheol Koh ),( Seung Woon Paik ),( Byung Chul Yoo ),( Joon Hyeok Lee ) 대한내과학회 2017 The Korean Journal of Internal Medicine Vol.32 No.4

Background/Aims: Entecavir is a potent nucleoside analogue with high efficacy and barrier for resistance. We aimed to investigate the long-term efficacy and viral resistance rate of entecavir and explore the factors associated with virologic response, including quantitative hepatitis B surface antigen (qHBsAg) levels. Methods: One thousand and nine treatment-naive chronic hepatitis B (CHB) patients were evaluated for cumulative rates of virologic response, biochemical response, and entecavir mutations. The role of baseline qHBsAg for virologic response was assessed in 271 patients with qHBsAg prior to entecavir treatment. Results: The median duration of entecavir treatment was 26.5 months. The cumulative rate of virologic response at years 1, 3, and 5 were 79.0%, 95.6%, and 99.4%, respectively. The cumulative rate of entecavir resistance was 1.0% and 2.1% in years 3 and 5. Multivariate analysis identified baseline hepatitis B e antigen (HBeAg) negative status (p < 0.001) and lower hepatitis B virus (HBV) DNA (p < 0.001) as predictors of virologic response. Lower qHBsAg was an independent predictor of virologic response in patients with baseline qHBsAg. There were no serious adverse events during treatment. Conclusions: Long-term entecavir treatment of nucleos(t)ide-naive CHB patients was associated with an excellent virologic response and a low rate of entecavir-resistant mutations at 5 years. Baseline HBV DNA load, qHBsAg levels, and HBeAg status were predictors of virologic response during entecavir treatment.

Performance evaluation of the HepB Typer-Entecavir kit for detection of entecavir resistance mutations in chronic hepatitis B

안상훈,천지용,신수경,박준용,유왕돈,홍선표,김수옥,한광협 대한간학회 2013 Clinical and Molecular Hepatology(대한간학회지) Vol.19 No.4

Background/Aims: Molecular diagnostic methods have enabled the rapid diagnosis of drug-resistant mutations in hepatitis B virus (HBV) and have reduced both unnecessary therapeutic interventions and medical costs. In this study we evaluated the analytical and clinical performances of the HepB Typer-Entecavir kit (GeneMatrix, Korea) in detecting entecavir-resistance-associated mutations. Methods: The HepB Typer-Entecavir kit was evaluated for its limit of detection, interference, cross-reactivity, and precision using HBV reference standards made by diluting high-titer viral stocks in HBV-negative human serum. The performance of the HepB Typer-Entecavir kit for detecting mutations related to entecavir resistance was compared with direct sequencing for 396 clinical samples from 108 patients. Results: Using the reference standards, the detection limit of the HepB Typer-Entecavir kit was found to be as low as 500 copies/mL. No cross-reactivity was observed, and elevated levels of various interfering substances did not adversely affect its analytical performance. The precision test conducted by repetitive analysis of 2,400 replicates with reference standards at various concentrations showed 99.9% agreement (2398/2400). The overall concordance rate between the HepB Typer-Entecavir kit and direct sequencing assays in 396 clinical samples was 99.5%. Conclusions: The HepB Typer-Entecavir kit showed high reliability and precision, and comparable sensitivity and specificity for detecting mutant virus populations in reference and clinical samples in comparison with direct sequencing. Therefore, this assay would be clinically useful in the diagnosis of entecavir-resistance-associated mutations in chronic hepatitis B. (Clin Mol Hepatol 2013;19:399-408)

Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Patients Receiving Entecavir or Tenofovir Treatment Showing Maintained Virological Response

( Ji Eun Na ),( Dong Hyun Sinn ),( Jeong-hoon Lee ),( Wonseok Kang ),( Geum-youn Gwak ),( Young-han Paik ),( Moon Seok Choi ),( Joon Hyeok Lee ),( Kwang Cheol Koh ),( Seung Woon Paik ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Observational studies suggested tenofovir may have favorable efficacy for the prevention of (HCC) development compared to entecavir. However, mechanism of both drugs is suppression of hepatitis B virus (HBV) replication and whether class effect exist despite same mechanism of action remains controversial, and data from randomized controlled trial are lacking. As a results, whether change in therapy is required for those who shows good virological response to entecavir treatment in order to further reduce HCC risk remains unknown. Methods: A retrospective cohort of 1,336 treatment-naïve chronic HBV mono-infected adults patients without malignancy or organ transplantation at baseline who started entecavir or tenofovir treatment between June 2012 to December 2015, and showed maintained virological response during follow-up were analyzed. Primary outcome was comparison of entecavir and tenofovir on incident HCC during follow-up. Results: During a median 4.4 years of follow-up (range: 1.0- 7.4 years) after achieving virological response, 99 patients developed HCC. The 5-years cumulative HCC incidence rate was 7.3% and 6.3% for entecavir and tenofovir group, with similar risk of HCC between two groups (adjusted hazard ratio: 0.82; 95% confidence interval 0.52 to 1.28; P=0.39). The risk of HCC was similar in in propensity score-matched cohort (entecavir = 570; tenfovir =570; hazard ratio 1.02; 95% confidence interval 0.68 to 1.52; P=0.94). In subgroup analysis, HCC risk was similar between two drugs in both patients with and without cirrhosis. Conclusions: In patients who showed good virological response, we observed no difference in the risk of HCC between two drugs. This observation suggest class effect may not exist and imply entecavir is equally effective as tenofovir for the prevention of HCC among those with good virological response.

HBV : No Additional Resistance Mutations after Up to 2 Years of Entecavir Plus Adefovir Combination Therapy in Multiple Drug-refractory Chronic Hepatitis B Patients

( Young Suk Lim ),( Ji Young Lee ),( Han Chu Lee ),( Yung Sang Lee ),( Dong Jin Suh ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Background: Previous studies showed that entecavir plus adefovir combination resulted in a higher rate of virological response (VR) compared with lamivudine plus adefovir in multiple drug-refractory chronic hepatitis B (CHB) patients. Methods: This extension study enrolled 89 of 90 patients who completed a 52-week randomized trial comparing treatment with entecavir plus adefovir (EA) to lamivudine plus adefovir (LA). At the baseline of the original study, all patients had lamivudine- resistant hepatitis B virus (HBV) and serum HBV DNA >2000 IU/mL despite prior lamivudine plus adefovir therapy. Forty-five patients initially randomized to entecavir plus adefovir (EA-EA) and the other 44 patients randomized to lamivudine plus adefovir (LA-EA) received entecavir plus adefovir for an additional 52 weeks. Results: The proportion of patients with VR (serum HBV DNA <60 IU/mL) gradually increased in both groups, and was comparable at week 104 (42.2% in the EA-EA group and 34.1% in the LA-EA group, P=0.51). The mean reduction in serum HBV DNA from baseline was similar in the two groups (-2.8 log10 IU/mL and -2.8 log10 IU/mL, respectively, P=0.87). At week 104, the number of patients who retained the baseline mutations to adefovir or entecavir has decreased from 8 to 2 in the EA-EA group and 15 to 6 in the LA-EA group (P=0.27). No patient developed additional resistance mutations to adefovir or entecavir. Both study groups had favorable safety profiles. Conclusions: Multiple drug-refractory CHB patients achieved a progressive VR during up to 104 weeks of entecavir plus adefovir treatment without the emergence of additional resistance mutations.

HBV : PO-02 ; Entecavir improve liver function in patients with hepatitis B virus associated liver cirrhosis: 2 years study

( Jong Joon Lee ),( Oh Sang Kwon ),( Ju Seung Kim ),( Min Su Ha ),( Ji Won Lee ),( Jung Ho Kim ),( Young Kul Jung ),( Duck Joo Choi ),( Yun Soo Kim ),( Ju Hyun Kim ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Background: Entecavir induces biochemical and histologic improvement of the liver in patients with chronic hepatitis B. This study aimed to clarify whether entecavir improves liver function in patients with hepatitis B virus (HBV) associated liver cirrhosis during 2 years treatment. Methods: A total of 356 patients who have HBV associated cirrhosis were treated with entecavir. Among them, 89 patients who are treated for at least 2 years and had no occurrence of hepatocellualr carcinoma, were enrolled retrospectively. A diagnosis of cirrhosis was based on image and/or endoscopic findings. Laboratory findings, model for end stage liver disease (MELD) score, Child-Pugh score, and AST platelet ratio index (APRI) score were compared between the initial and after 2 years entecavir treatment. Results: The mean age was 52±9 years old and number of male patients was 53 (59.6%). The mean AST and ALT were 117± 80 IU/L and 118±88 IU/L, respectively. The number of HBeAg positivity was 39 (43.8%) and mean HBV DNA level was 6.7±1.6 log10 copies/mL. After 2 years entecavir treatment, the rate of ALT normalization was 79.8%, undetectable HBV DNA was 91% (by real-time polymerase chain reaction), and HBeAg loss in HBeAg positive-patient was 71.8%. The improvement of total bilirubin level, albumin level, INR, platelet count, MELD score, Child-Pugh score, APRI score between the two time points was from 2.2±3.5 to 1.2±0.7 mg/dL (p=0.006), 3.7±0.6 to 4.0±0.6 g/dL (p<0.001), 1.4±0.4 to 1.2±0.2 (p<0.001), 110±48 to 121±58 ×103/mm3 (p=0.016), 11.9±4.7 to 9.5±3.4 (p<0.001), 6.3±1.9 to 5.5±1.3 (p<0.001), and 3.2±2.3 to 1.0±0.9 (p<0.001), respectively. Conclusions: Entecavir improves not only liver function but also fibrosis score in patients with HBV associated liver cirrhosis for long-term treatment.

Tenofovir does not induce renal dysfunction compared to entecavir in post-liver-transplant hepatitis B virus patients

Sang Jin Kim,Jinsoo Rhu,Seo Hee Lee,Jong Man Kim,Gyu-Seong Choi,김경아,Jae-Won Joh 대한외과학회 2020 Annals of Surgical Treatment and Research(ASRT) Vol.99 No.3

Purpose: Tenofovir disoproxil fumarate is accepted as an effective and tolerable drug for treatment of HBV, similar to entecavir. However, there are some concerns about the nephrotoxicity of tenofovir. The aim of this study is to compare the renal-function change of liver recipients who received tenofovir or entecavir for HBV. Methods: Among 468 patients with HBV who underwent liver transplantation at Samsung Medical Center between January 2008 and December 2015, the patients treated with tenofovir (n = 39) or entecavir (n = 429) were reviewed retrospectively. Baseline characteristics and renal-function change after 1 month, 1 year, and 2 years were compared. Propensity-score matching was performed for 37 patients using tenofovir and 132 patients using entecavir. We also analyzed risk factors of renal dysfunction. Results: Age, preoperative creatinine, estimated glomerular filtration rate (e-GFR), and hepatic encephalopathy score showed statistical difference between the tenofovir and entecavir groups. The proportion of patients with ‘decreased renal function (e-GFR < 60 mL/min/1.73 m2)’ was higher in the tenofovir group than in the entecavir group (33.3% vs. 12.4% at postoperative one year, P < 0.005). After propensity-score matching, there was no statistical difference in preoperative characteristics. Postoperative 1-, 2-, and 3-year e-GFR and creatinine showed no statistical difference in either group. On multivariate analysis, only preoperative high e-GFR showed a protective effect on renal-function change (odds ratio, 0.97; P < 0.001), and there was no aggravating factor. Conclusion: Tenofovir disoproxil fumarate does not induce renal dysfunction in liver-transplanted patients with HBV more than does entecavir.