Management of Antiviral Resistance

( Henry Lik Yuen Chan ) 대한간학회 2007 Clinical and Molecular Hepatology(대한간학회지) Vol.13 No.5(S)

No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B

( Won Young Tak ),( Henry Lik-yuen Chan ),( Patrick Marcellin ),( Calvin Q. Pan ),( Andrea L Cathcart ),( Neeru Bhardwaj ),( Yang Liu ),( Stephanie Cox ),( Bandita Parhy ),( Eric Zhou ),( John F Flahe 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Presented herein are the post Week 48 through Week 96 resistance analyses for Phase 3 studies evaluating tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF). Methods: Patients were randomized 2:1. HBV pol/RT population or deep sequencing was conducted for patients with viremia at Week 96 or at early discontinuation post Week 48. Deep sequencing was conducted for patients with HBV DNA >159 IU/mL and sequence changes at the consensus sequence level are reported. Phenotypic analysis was performed for Virologic breakthrough (VB) patients who were adherent to study drug, patients with conserved site substitutions, or for polymorphic substitutions emergent in >1 patient. Results: TAF and TDF were treated in 866 and 432 patients, respectively. A similar percentage of patients in the arms qualified for sequence analysis. In the TAF arm, 87 (10.5%) patients qualified: 31 had no sequence change from baseline, 15 were unable to sequence (UTS), 32 had polymorphic site substitutions, and 9 had conserved site substitutions. In the TDF arm, 45 (10.9%) patients qualified: 26 had no sequence change, 6 were UTS, 11 had polymorphic site substitutions, and 2 had conserved site substitutions. Each detected conserved site substitution other than rtA181T was observed in one patient. The rtA181T substitution in 2 patients, 1 from each arm, was not associated with increasing plasma HBV DNA levels. At Week 96, a small percentage of patients experienced VB, and VB was often associated with nonadherence. 27 patients qualified for phenotypic analysis and no patient isolates tested showed a reduction in susceptibility to TAF or tenofovir, respectively. Conclusions: The proportion of patients analyzed and the HBV sequence changes observed were similar between patients in the TAF and TDF arms. Most substitutions occurred at polymorphic positions and no substitutions associated with resistance to TAF were detected through 96 weeks of treatment.

Impact of Treatment with Tenofovir Alafenamide (TAF) or Tenofovir Disoproxil Fumarate (TDF) on Hepatocellular Carcinoma (HCC) Incidence in Patients with Chronic Hepatitis B (CHB)

( Young-Suk Lim ),( Henry Lik Yuen Chan ),( Wai-Kay Seto ),( Qing Ning ),( Kosh Agarwal ),( Harry L. A. Janssen ),( Calvin Q. Pan ),( Wan Long Chuang ),( Namiki Izumi ),( Scott K Fung ),( Dr Shalimar 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Potent antiviral treatment can reduce HCC incidence in CHB patients. TAF has shown antiviral efficacy similar to TDF, with higher rates of ALT normalization and no resistance in Phase 3 studies. We evaluated the impact of TAF or TDF on HCC in the ongoing Phase 3 studies. Methods: HBeAg-positive (n=1039) and -negative (n=593) patients with HBV DNA≥20,000 IU/mL and ALT >60 U/L (males) or >38 U/L (females) were recruited from 190 sites in 20 countries and randomized (2:1) to TAF or TDF. HCC was assessed at 6-monthly intervals by hepatic ultrasonography introduced after Week 96 and throughout by local standards of care. The standardized incidence ratio (SIR) for HCC was calculated for observed cases relative to predicted risk using the REACH-B model. Results: Through 5 years of follow-up, HCC occurred in 21 patients (1.0% [11/1,093] with TAF, 1.9% [10/539] with TDF). Median (Q1, Q3) time to HCC onset was 104 (55, 191) weeks. At baseline, relative to those without HCC, patients with HCC were more likely to be older (median age 53 vs 39y; P<0.001), male (90% vs 65%; P=0.014), and cirrhotic (FibroTest ³0.75; 33% vs 9%; P<0.001). The overall SIR was significantly reduced with TAF or TDF (SIR 0.42, 95% CI 0.27-0.64). HCC incidence was significantly reduced in noncirrhotic patients (SIR 0.37, 95% CI 0.22 to 0.63), and in patients receiving TAF (SIR 0.35, 95% CI 0.19-0.62). Lack of ALT normalization at Week 24 (HR 6.90; P=0.011), cirrhosis (HR 4.18; P=0.006), baseline HBsAg level (HR 0.53; P=0.006), and baseline hypertension (HR 5.55; P<0.001) were significant predictors of HCC development by multivariable analysis. Conclusions: In CHB patients receiving TAF or TDF, the incidence of HCC was reduced comparing with expected HCC incidence from REACH-B model. In patients treated with TAF, a significant reduction in SIR was seen, whereas those treated with TDF showed a trend toward a reduction.

PE-164: Impact of Ledipasvir/Sofosbuvir on the Work Productivity of Chronic Hepatitis C Patients in Asia

( Young-suk Lim ),( Henry Lik Yuen Chan ),( Yock Young Dan ),( Mei Hsuan Lee ),( Eliza Kruger ),( Seng Tan5,Zobair M. Younossi ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: To estimate the work productivity gains associated with LDV/SOF treatment for CHC in Hong Kong, Singapore, South Korea and Taiwan. Methods: The model captures anticipated impact of LDV/SOF on productivity loss over a one-year time horizon from a societal perspective for each country. A literature review was performed to identify country- specific inputs and expert advice was solicited to verify key variables. Patients enter the model post-treatment, having achieved SVR12, or not. Absenteeism and presenteeism rates were estimated based on the Work Productivity and Activity Index-Specific Health Problem (WPAI-SHP) data collected from the Phase III ION trials (US participants only) at baseline and at 12 weeks with rates assumed to remain unchanged from baseline for patients not achieving SVR. Sensitivity analyses were performed on key variables. Results: Total Work productivity loss due to not treating CHC was highest in Taiwan at US$349M ($355 per capita) given high prevalence of HCV, followed by US$146M ($358) in Korea, US$17M ($914) in Singapore and US$11M ($351) in Hong Kong. Treatment with LDV/SOF resulted in estimated productivity gains of $138 million, $58.7 million, $6.8 million and $4.5 million in Taiwan, Korea, Singapore and Hong Kong respectively. Conclusions: CHC imposes a significant indirect economic burden. Our model demonstrates that treatment of HCV GT1 patients with LDV/SOF is likely to result in significant cost savings due to an improvement in presenteeism versus no treatment across 4 Asian countries. This indirect economic gain should be considered when assessing the benefits of treating CHC.

Sofosbuvir/Velpatasvir (SOF/VEL) for 12 Weeks in Genotype 1, 2, 4, 5, 6 HCV Patients: Results of the ASTRAL-1 Study

( Mark S. Sulkowski ),( Henry Lik Yuen Chan ),( Jordan J. Feld ),( Kosh Agarwal ),( Christophe Hezode ),( Tarik Asselah ),( Peter J. Ruane ),( Norbert Gruener ),( Armand Abergel ),( Alessandra Mangia 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Background: Velpatasvir (VEL) is a pangenotypic HCV-NS5A inhibitor. This Phase 3 study evaluated treatment with a fixed dose combination of SOF/VEL for 12 weeks in patients with genotype 1, 2, 4, 5, or 6 HCV infection. Methods: Patients with genotype 1, 2, 4, or 6 chronic HCV infection were randomized 5:1 to received SOF/VEL (400 mg /100 mg daily) or placebo for 12 weeks. Patients with genotype 5 infection were enrolled to the SOF/VEL treatment group and patients with genotype 3 were evaluated in a separate study. Results: 740 patients were enrolled at 81 international sites: 60% male, 79% white, 32% treatment-experienced (TE), and 19% compensated- cirrhosis. Of the 624 patients treated with SOF/VEL, the genotype distribution was 53% GT1, 17% GT2, 19% GT4, 6% GT5 and 7 % GT6. Overall SVR12 for SOF/VEL-treated patients was 99.0% and the study met its primary efficacy endpoint. SVR12 rates by HCV genotype are presented in the table. Two of 328 patients (0.6%) with genotype-1 infection had virologic relapse. No patients with genotype 2, 4, 5, or 6, including 48 with cirrhosis, had virologic failure. Four patients did not achieve SVR12 for non-virologic reasons. AEs and laboratory abnormalities were similar in the SOF/VEL-treated patients compared with the 116 placebo-treated patients. One patient discontinued SOF/VEL treatment due to adverse-events. Conclusions: Treatment with the once daily, all-oral, single tablet regimen of SOF/VEL for 12 weeks is well tolerated and results in high SVR12 rates in treatment-naive and treatment-experienced genotype 1, 2, 4, 5, and 6 HCV-infected patients with and without cirrhosis.

High Therapeutic Efficiency of LDV/SOF in Asian Patients with CHC Genotype 1 Infection

( Young-suk Lim ),( Henry Lik Yuen Chan ),( Yock Young Dan ),( Mei Hsuan Lee ),( Ming-lung Yu ),( Marta Silva ),( Jorge Felix ),( Zobair M. Younossi ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Current Asian treatment practices for Chronic Hepatitis C (CHC) Genotype (GT) 1 patients use regimens containing pegylated inferferon and ribavirin (PR). As interferon-free regimens become the standard of care in most Western countries, it is necessary to understand the potential impact of an all-oral, PR-free single-tablet regimen of Ledipasvir/Sofosbuvir (LDV/SOF) on Asian CHC patients. The aim of this study was to estimate long-term health outcomes of LDV/SOF therapy in 4 Asian countries: Taiwan, South Korea, Singapore, Hong Kong. Methods: A hypothetical cohort of 10,000 adult patients/country was modeled with a hybrid decision tree and Markov state-transition model capturing the natural history of CHC and treatment implications over a lifetime. Efficacy was based on randomized controlled trials; country-specific demographics, HCV-related epidemiology and treatment data were retrieved from literature. Therapeutic efficiency was defined as the number of advanced liver disease (ALD) cases averted (decompensated cirrhosis, hepatocellular carcinoma, liver transplants, HCV-related deaths) with LDV/SOF relative to PR or no treatment (NT) in treatment-naive patients. The differing immunomodulatory and anti-tumor effects of the therapies were not modeled. Results: A 12 week regimen of LDV/SOF compared to PR/NT is estimated to substantially impact CHC disease burden by reducing the incidence of ALD (Table 1): -90.6% / -94.2% vs. PR/NT (Taiwan), -92.5% / -95.7% (South Korea), -93.3% / -96.2% (Singapore), -93.4% / -96.3% (Hong Kong). Conclusions: LDV/SOF is a highly effective treatment associated with potentially more favorable health outcomes when compared with current treatment practices or no treatment for GT1 CHC Asian patients.

Serum fibrosis index-based risk score predicts hepatocellular carcinoma in untreated patients with chronic hepatitis B

( Lilian Yan Liang ),( Hye Won Lee ),( Vincent Wai-sun Wong ),( Terry Cheuk-fung Yip ),( Yee-kit Tse ),( Vicki Wing-ki Hui ),( Grace Chung-yan Lui ),( Henry Lik-yuen Chan ),( Grace Lai-hung Wong ) 대한간학회 2021 Clinical and Molecular Hepatology(대한간학회지) Vol.27 No.3

Background/Aims: Serum fibrosis scores comprised of common laboratory tests have high utility to assess severity of liver fibrosis. We aimed to derive and validate a hepatocellular carcinoma (HCC) risk score based on serum fibrosis scores to predict HCC in treatment-naive chronic hepatitis B (CHB) patients. Methods: Fifteen thousand one hundred eighty-seven treatment-naive adult CHB patients were identified to form the training cohort in this retrospective study. Individual fibrosis score was included to construct a new HCC prediction score. The score was externally validated in an independent treatment-naive Korean CHB cohort. Results: 180/15,187 patients (1.2%) in training cohort and 47/4,286 patients (1.1%) in validation cohort developed HCC during a mean follow-up of 52 and 50 months, respectively. The newly developed HCC risk score, Liang score, is composed of gender, age, hepatitis B virus DNA, fibrosis-4 (FIB-4) index, and ranges from 0 to 22. Area under the time-dependent receiver operating characteristic curve of Liang score was 0.79 (95% confidence interval, 0.70-0.89). A cutoff value of nine provided an extremely high negative predictive value of 99.9% and high sensitivity of 90.0% at 5 years in the validation cohort. Patients with Liang score ≤9 had HCC incidence <0.2% per year in both training and validation cohorts, in whom HCC surveillance might be exempted. Conclusion: A novel HCC risk score, Liang score, based on FIB-4 index, is applicable and accurate to identify treatment-naive CHB patients with very low risk of HCC to be exempted from HCC surveillance. (Clin Mol Hepatol 2021;27:499-509)

U-shaped relationship between urea level and hepaticU-shaped relationship between urea level and hepatic decompensation in chronic liver diseases decompensation in chronic liver diseases

Huapeng Lin,Grace Lai-Hung Wong,Xinrong Zhang,Terry Cheuk-Fung Yip,Ken Liu,Yee Kit Tse,Vicki Wing-Ki Hui,Jimmy Che-To Lai,Henry Lik-Yuen Chan,Vincent Wai-Sun Wong 대한간학회 2022 Clinical and Molecular Hepatology(대한간학회지) Vol.28 No.1

Background/Aims: We aimed to determine the association between blood urea level and incident cirrhosis, hepatic decompensation, and hepatocellular carcinoma in chronic liver disease (CLD) patients. Methods: The association between blood urea level and liver fibrosis/liver-related events were evaluated on continuous scale with restricted cubic spline curves based on generalized additive model or Cox proportional hazards models. Then, the above associations were evaluated by urea level within intervals. Results: Among 4,282 patients who had undergone liver stiffness measurement (LSM) by transient elastography, baseline urea level had a U-shaped association with LSM and hepatic decompensation development after a median follow-up of 5.5 years. Compared to patients with urea of 3.6–9.9 mmol/L, those with urea ≤3.5 mmol/L (adjusted hazard ratio [aHR], 4.15; 95% confidence interval [CI], 1.68–10.24) and ≥10 mmol/L (aHR, 5.22; 95% CI, 1.86–14.67) had higher risk of hepatic decompensation. Patients with urea ≤3.5 mmol/L also had higher risk of incident cirrhosis (aHR, 3.24; 95% CI, 1.50–6.98). The association between low urea level and incident cirrhosis and hepatic decompensation was consistently observed in subgroups by age, gender, albumin level, and comorbidities. The U-shaped relationship between urea level and LSM was validated in another population screening study (n=917). Likewise, urea ≤3.5 mmol/L was associated with a higher risk of incident cirrhosis in a territory-wide cohort of 12,476 patients with nonalcoholic fatty liver disease at a median follow-up of 9.9 years (aHR, 1.27; 95% CI, 1.03–1.57). Conclusions: We identified a U-shaped relationship between the urea level and liver fibrosis/incident cirrhosis/hepatic decompensation in patients with CLD.

Hepatic Decompensation in Cirrhotic Patients Receiving Antiviral Therapy for Chronic Hepatitis B

( Hye Won Lee ),( Terry Cheuk-fung Yip ),( Yee-kit Tse ),( Grace Lai-hung Wong ),( Beom Kyung Kim ),( Seung Up Kim ),( Jun Yong Park ),( Do Young Kim ),( Henry Lik-yuen Chan ),( Sang Hoon Ahn ),( Vinc 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: It is unclear if anti-hepatitis B virus (HBV) treatment can eliminate incident hepatic decompensation. Here we report the incidence and predictors of hepatic decompensation among cirrhotic patients receiving antiviral therapy for chronic hepatitis B. Methods: This is a post hoc analysis of two prospective HBV cohorts from Hong Kong and South Korea. Patients with liver stiffness measurement (LSM) ≥10 kPa and compensated liver disease at baseline were included. The primary endpoint was incident hepatic decompensation (jaundice or cirrhotic complications) with competing risk analysis. Results: 818 patients (mean age, 54.9 years; 519 male [63.4%]) were included in the final analysis. During a mean follow-up of 58.1 months, 32 (3.9%) patients developed hepatic decompensation, among whom 34% were secondary to HCC. Three (0.4%) patients experienced variceal bleeding alone, 27 (3.3%) had non-bleeding decompensation and 13 (1.6%) had more than 2 decompensating events. On multivariable analysis, baseline LSM (adjusted hazard ratio [aHR] 1.03), diabetes (aHR 3.27), platelet (aHR 0.99), and international normalized ratio (aHR 7.99) were independent predictors of hepatic decompensation. 30/506 (5.9%) patients fulfilling the Baveno VI criteria (LSM ≥20 kPa and/or platelet count <150ⅹ10⁹/L) and 2/312 (0.6%) patients not fulfilling the criteria developed hepatic decompensation (P<0.001). Conclusions: Hepatic decompensation is uncommon but not eliminated in patients receiving antiviral therapy for HBV-related cirrhosis, and only a third of decompensating events are secondary to HCC. The Baveno VI criteria, which was originally designed to detect varices needing treatment, can be effectively applied in this population to identify patients at risk of decompensation.