Cardiovascular risk of tenofovir disoproxil fumarate or tenofovir alafenamide in patients with chronic hepatitis B: More questions than an answer

Pin-Nan Cheng,Ming-Lung Yu 대한간학회 2024 Clinical and Molecular Hepatology(대한간학회지) Vol.30 No.2

Real-World Effectiveness and Safety of SOF/LDV for Pa-tients with Chronic Hepatitis C in Taiwan

( Ching-chu Lo ),( Pin-nan Cheng ),( Chi-yi Chen ),( Chung-feng Huang ),( Hsing-tao Kuo ),( Kuo-chih Tseng ),( Yi-hsiang Huang ),( Chi-ming Tai ),( Cheng-yuan Peng ),( Ming-jong Bair ),( Chien-hung Ch 대한간학회 2021 춘·추계 학술대회 (KASL) Vol.2021 No.1

Race Does Not Affect the Performance of Noninvasive Tests for the Discrimination of Advanced Fibrosis due to Non-Alcoholic Steatohepatitis(NASH)

( Won Young Tak ),( Vincent Wai-sun Wong ),( George Boon Bee Goh ),( Pin-nan Cheng ),( Eric J. Lawitz ),( Zobair M. Younossi ),( Raj Vuppalanchi ),( Natalie H. Bzowej ),( Ziad Younes ),( Naim Alkhouri 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Background: Routinely available noninvasive tests of fibrosis (NITs) can be used to identify patients with advanced fibrosis due to NASH, but their performance may vary by race. Our aim was to evaluate the effect of patient race on the diagnostic performance of NITs using data from the global phase 3 STELLAR studies of selonsertib. Methods: The STELLAR studies (NCT03053050 and NCT03053063) enrolled patients with bridging fibrosis (F3) or compensated cirrhosis (F4) due to NASH (NAFLD Activity Score [NAS] ≥3). Baseline liver biopsies were centrally read using the NASH Clinical Research Network classification and NITs, including the NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness by transient elastography (LS by TE) were measured. The performance of these tests to discriminate advanced (F3-F4) fibrosis by self-reported patient race was evaluated using areas under the receiver operating characteristics curves (AUROCs) with 5-fold cross-validation repeated 100x. Results for White and Asian patients are presented; data for other races (5% of patients screened) are excluded. Results: Among 3202 patients screened for the STELLAR studies with evaluable liver histology, 24% were Asian and 71% were White. The median age was 58 years in both groups; 47% of Asians and 57% of Whites were female (p<0.0001). The prevalence of F3-F4 fibrosis was 67% in Asians and 72% in Whites (p=0.01). AUROCs for each of the NITS for the discrimination of advanced fibrosis were similar between Asian and White patients (Table). In general, literature-based thresholds for the NITs had similar sensitivity and specificity among the specific racial subgroups. Conclusion: In these large, global phase 3 trials, the diagnostic performance of routinely available NITs for the discrimination of advanced fibrosis due to NASH was acceptable and similar between Asian and White patients.

Sofosbuvir/Ledipasvir in the Treatment of Chronic Hepatitis C - A Subgroup Analysis from A Nationwide Real-World HCV Registry Program (TACR) in Taiwan

( Ming-Lung Yu ),( Chi-Yi Chen ),( Kuo-Chih Tseng ),( Ching-Chu Lo ),( Pin-Nan Cheng ),( Cheng-Yuan Peng ),( Ming-Jong Bair ),( Chih-Lang Lin ),( Chi-Ming Tai ),( Chi-Chieh Yang ),( Chih-Wen Lin ),( C 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: TASL HCV Registry (TACR) is a nationwide registry program organized and supervised by Taiwan Association for the Study of the Liver (TASL), which aims to setup the database and biobank of patients with chronic hepatitis C (CHC) in Taiwan. The present study aimed to evaluate the treatment outcome of sofosbuvir (SOF)/ledipasvir (LDV) in Taiwanese CHC patients in TACR. Methods: By May 2020, 19 tertiary hospitals, 23 community hospitals and one primary care clinic join the TACR program. The baseline characteristics, prior liver and non-liver related medical history, DAA regimens, laboratory results, treatment course and outcome were recorded. The primary objective was sustained virological response, defined as undetectable HCV RNA 3 months after end-of-treatment (SVR12). Results: A total of 4742 SOF/LDV+ ribavirin treated CHC patients with available SVR12 data from 39 sites were enrolled in the current analysis. The mean age was 61.3 years, and female accounted for 54.8% of the population. The dominant viral genotypes were GT1b (52.6%) and GT2 (35.6%). 1354 (28.6%) patients had liver cirrhosis, including 156 (3.3%) with liver decompensation, 552 (11.6%) had preexisting hepatocellular carcinoma (HCC) before DAAs treatment and 413 (8.7%) had hepatitis B virus dual infections. The overall SVR12 rate was 98.5%, with 98.5%, 98.2%, 99.7% and 98.6% in treatment- naïve non-cirrhotics, treatment-naïve cirrhotics, treatment- experienced non-cirrhotics and treatment-experienced cirrhotics patients, respectively. While patients were stratified by HCV genotype, the SVR12 was 98.5%, 98.4% and 98.5% among those with GT1, GT2 and GT6 infection, respectively. The strongest factor independent associated with treatment failure was DAA adherence < 60% (odds ratio [OR]/95% confidence intervals [CI]: 125.4/25.7-612.4, P<0.0001), followed by active HCC (OR/CI: 6.20/2.57-14.97, P<0.0001), HIV co-infection (OR/CI: 3.01/1.14-7.92, P=0.026), and male gender (OR/ CI: 1.85/1.09-3.13, P=0.023). The eGFR decreased significantly at the end of treatment (EOT) (89.3 ml/min/1.73㎡ vs. 93.2 ml/min/1.73㎡, P< 0.001) and remained stable 3 months after EOT (89.3 ml/min/1.73㎡). However, the decreased eGFR was observed only in patients whose baseline eGFR > 90 ml/ min/1.73㎡. Instead, patients with chronic kidney diseases whose pretreatment eGFR < 60 ml/min/1.73㎡ had improved eGFR after SOF/LDV. Conclusions: SOF/LDV is highly effective in treating CHC patients in real-world setting of Taiwan. The satisfactory result could be explicitly generalized to patients with different viral genotypes and liver disease severities.

Tenofovir Alafenamide for Chronic Hepatitis B Patients with Advanced Fibrosis and Partial Virologic Responses to Oral Nucleos(T)Ide Analogues- Interim Report

( Ming-lung Yu ),( Ming-lun Yeh ),( Chi-yi Chen ),( Pin-nan Cheng ),( Ming-jong Bair ),( Jyh-jou Chen ),( Ching-chu Lo ),( Chi-ming Tai ),( Ching-yang Tsai ),( Kuo-chih Tseng ),( Chien-hung Chen ),( C 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Insufficient data regarding the treatment strategy for partial response to nucleot(s)ide analogue (NUC) raised the aim of investigating tenofovir alafenamide (TAF) switching for chronic hepatitis B (CHB) patients with advanced fibrosis and partial response to other NUCs. Methods: CHB patients with advanced fibrosis (stage 3 or 4) and under NUC (except TAF) therapy with detectable hepatitis B virus (HBV) DNA for >52 weeks are enrolled to TAF 25 mg/day for 96 weeks. The objectives are viral suppression, alanine aminotransferase (ALT) normalization and safety. Results: From Feb. 2019, 34 patients, including 21 (61.8%) with entecavir, 10 (29.4%) TDF and 3 (8.8%) lamivudine or adefovir, were enrolled (15 [44.1%] male, median 53 years). The fibroscan demonstrated a mean of 10.5 kPa (7 [20.6%] cirrhotic). Sixteen (47.1%) patients were HBV e antigen positive, seven (20.6%) had YMDD mutation. The median HBV DNA level declined from 68.5 IU/mL at enrollment to 27.0 IU/mL at 4^th week, and undetectable at 12^th, 24^th, 36^th week, respectively, after TAF switching, with undetectable HBV DNA in 14/34 (41.2%), 17/33 (51.5%), 15/25 (60.0%), and 9/15 (60.0%) patients and rate of ALT normalization (≤40 U/L) of 85.3%, 85.3%, 84.8%, 92.0%, and 80.0%, respectively, after TAF switching. (figure 1) Two patients experienced transient virological breakthrough and another one developed at the final time follow up. Serum creatinine and eGFR levels were stable after TAF switching (figure 1). Two patients early terminated including one at 12^th week due to personal reason, and another one accidently died at 20^th week due to acute heart attack. Others suffered only mild degrees of adverse events which were considered unrelated to treatment. Conclusions: The preliminary results demonstrated the TAF switching is effective and safe in viral suppression for CHB patients with advanced fibrosis and partial virologic responses to other NUCs.

Efficacy and Safety of 12 Weeks of Daclatasvir, Asunaprevir Plus Ribavirin for the Treatment of HCV Genotype 1b Infection without Baseline NS5A Resistance-Associated Variants (DARING)-Interim Report

( Ming-lung Yu ),( Chao-hung Hung ),( Yi-hsiang Huang ),( Cheng-yuan Peng ),( Chun-yen Lin ),( Pin-nan Cheng ),( Rong-nan Chien ),( Shih-jer Hsu ),( Chen-hua Liu ),( Jee-fu Huang ),( Chung-feng Huang 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: The current study aims to elucidate the treatment efficacy (defined as undetectable HCV RNA throughout 12 weeks of post-treatment follow-up, SVR12) and safety DCV/ASV plus ribavirin for 12 weeks in HCV-1b patients without NS5A RAS. Methods: This is a single-arm, open-label phase 2 study. Seventy directly acting antivirals (DAA)-naïve HCV-1b patients without L31/Y93 RAS are planned to receive daclatasvir (60 mg/ day) and asunaprevir (100 mg twice daily) plus weight-based ribavirin (1000-1200 mg/day) for 12 weeks. After treatment they were followed up for 12 weeks. Results: As of 31 Oct 2017, 58 eligible patients are allocated to treatment, with a mean age of 59.3 years and female predominance (67.2%, 39/58). The mean HCV RNA was 5.87+0.77 log10 IU/mL; 23 patients (39.7 %) had significant hepatic fibrosis (>F2). In the modified intention-to-treat analysis, the rate of undetectable HCV at week 1, week 2, week 4, week 8 and endof- treatment was 25 % (14/56), 84.8 % (39/46), 100 % (46/46), 100 % (38/38) and 100 % (27/27), respectively. Undetectable HCV RNA were observed in all of the patients with HCV RNA assessable 4 weeks (SVR4, 18/18) and 12 weeks (SVR12, 12/12) post treatment. None of the 18 patients who completed the 12-week treatment experienced relapse during post-treatment follow-up. The most common adverse event was fatigue (78.3 %), followed by pruritus (65.2 %) and dizziness (52.2 %), of which were considered as ribavirin related. None of the participating subjects withdrew treatment or follow-up throughout the trial peroid. Three serious adverse events were reported which included urosepsis, appendicitis and left ureteral stone. All were unrelated to the investigating drugs. Conclusions: 12 weeks of DCV/ASV plus ribavirin was highly effective and safe in HCV-1b patients without NS5A RAS in the interim analysis. The satisfactory results would be anticipated in the full patient set.

Safety and Efficacy of Elbasvir/Grazoprevir in Asian Participants with Hepatitis C Virus Genotypes 1 and 4 Infection

( Wei Lai ),( Hiromitsu Kumada ),( Ponni Perumalswami ),( Tawesak Tanwandee ),( Wendy Cheng ),( Jeong Heo ),( Pin Nan Cheng ),( Peggy Hwang ),( Sheng Mei Mu ),( Xu Min Zhao ),( Michael Robertson ),( B 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Clinical experience with direct-acting antiviral treatments for hepatitis C virus (HCV) infection is emerging in the Asia-Pacific region. We conducted an integrated analysis of the safety and efficacy of elbasvir (EBR)/grazoprevir (GZR) in self-identified Asian participants who were enrolled in 11 EBR/GZR phase 2/3 studies. Methods: All participants received EBR/GZR 50 mg/100 mg alone for 12 weeks or in combination with ribavirin (RBV) for 16 weeks. The primary endpoint of all studies was sustained virologic response (HCV RNA < 15 IU/mL) 12 weeks after end of therapy (SVR12). Results: A total of 780 Asian participants with HCV GT1 or 4 infection were included (GT1b, n=715; GT1non-b, n=63; GT4, n=2). Most participants were enrolled from Japan (n=366, 46.9%), mainland China (n=146, 18.7%), Taiwan (n=109, 14.0%) and South Korea (n=90, 11.5%). Overall, 12.4% of participants had cirrhosis, and 20.4% were treatment-experienced. SVR12 was achieved by 756/780 (96.9%, 95% CI 95.5-98.0) of all Asian participants, including 748/772 (96.9%, 95% CI 95.4- 98.0) who received EBR/GZR for 12 weeks and 8/8 (100%, 95% CI 63.1-100.0) who received EBR/GZR + RBV for 16 weeks. The frequency of safety events among Asian participants was: any adverse event (AE), 58.1% (453/780), drug-related AEs, 23.6% (184/780), serious AEs, 2.6% (20/780), and discontinuation due to an AE, 0.9% (7/780). Fifteen participants (1.9%) had elevated ALT/AST levels that met the criteria for an event of clinical interest (ALT/AST >3× baseline and >100 U/L), 3 of whom discontinued treatment. The efficacy and safety profile of EBR/GZR was comparable to that observed among non-Asians. Conclusions: The combination of EBR/GZR was safe and highly effective in this large population of Asian participants with primarily HCV GT1b infection. Late transaminase elevations were reported in approximately 2% of participants, which is consistent with the safety profile of EBR/GZR in non-Asians.

Efficacy and Safety of Elbasvir/Grazoprevir in Treatment- Naive Subjects with Chronic HCV GT 1, GT 4 and GT 6 Infection (C-CORAL): A Phase III Randomized Multinational Clinical Trial

( Do Young Kim ),( Lai Wei ),( Konstantin Zhdanov ),( Eduard Burnevich ),( I-Shyan Sheen ),( Jeong Heo ),( Van Kinh Nguyen ),( Tawesak Tanwandee ),( Pin-Nan Cheng ),( Won Young Tak ),( Svetlana Kizhlo 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Hepatitis C virus (HCV) contributes significantly to the overall liver disease burden in the Asia Pacific region and Russia where the seroprevalence rates vary from 1-5% and genotype (GT) 1b accounts for about half of infections. The efficacy and safety of the fixed-dose combination of elbasvir (EBR) 50 mg and grazoprevir (GZR) 100 mg has been demonstrated in a broad population of HCV-infected subjects and supports evaluation in this region where clinical experience with direct-acting antivirals is limited. EBR/GZR is approved in the United States for treatment of HCV GT1 and 4 infection. Methods: C-CORAL is a double-blind placebo-controlled, Phase 3 trial that randomized treatment-naive HCV GT1, 4 or 6 infected subjects in a 3:1 ratio to an immediate treatment group (ITG; 12 wks of EBR/GZR) or deferred treatment group (DTG; 12 wks of placebo, followed by 12 wks of EBR/GZR). Subjects were enrolled in an ex-China cohort that included subjects from Korea, Taiwan, Vietnam, Thailand, Australia, and Russia; and a second cohort enrolled subjects from China. The primary endpoints include the % of patients in the ITG who achieved SVR12 and a comparison of the safety and tolerability of EBR/GZR in the ITG vs placebo in the DTG. We will present the efficacy results of the ITG and safety results of the ITG and DTG in both cohorts. Results: To date, data from the ex-China cohort are available. In this cohort, a total of 250 subjects were enrolled in the ITG and 86 in the DTG. Mean age (±SD) was 50 ±12 years, 57% were females, 59% were Asian, 74% were GT1b, and 19% were cirrhotic. SVR12 in the ITG was 92.8% (table). Eighteen subjects in the ITG did not achieve SVR12: 11 were relapses, 6 were on-treatment failures (all GT6) and 1 GT1b subject withdrew consent. The incidence of adverse events (AEs) was generally comparable between the ITG vs the DTG including drug-related AEs (21.2% vs 19.8%) and serious AEs (0.8% vs 1.2%; none considered drug-related). During treatment with EBR/GZR or placebo 2/250 (0.8%) subjects in the ITG and 11/86 (12.8%) subjects in the DTG had an ALT value >5x ULN and greater than baseline. One subject in the ITG withdrew after meeting a trial specific discontinuation criterion for elevated ALT, which was not considered drug related. Updated safety and efficacy data will be presented for the ITG for both the ex-China and China study cohorts. Conclusions: A 12-week regimen of EBR/GZR is effective and well-tolerated in GT1 and GT4-infected, treatment-naive patients in the Asia Pacific/Russia region.

Efficacy and Safety of Elbasvir/Grazoprevir in Treatment- Naive Subjects with Chronic HCV GT 1, GT 4 and GT 6 Infection (C-CORAL): A Phase III Randomized Multinational Clinical Trial

( Jeong Heo ),( Lai Wei ),( Konstantin Zhdanov ),( Eduard Burnevich ),( I-Shyan Sheen ),( Van Kinh Nguyen ),( Tawesak Tanwandee ),( Pin-Nan Cheng ),( Do Young Kim ),( Won Young Tak ),( Svetlana Kizhlo 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Hepatitis C virus (HCV) contributes significantly to the overall liver disease burden in the Asia Pacific region and Russia where the seroprevalence rates vary from 1-5% and genotype (GT) 1b accounts for about half of infections. The efficacy and safety of the fixed-dose combination of elbasvir (EBR) 50 mg and grazoprevir (GZR) 100 mg has been demonstrated in a broad population of HCV-infected subjects and supports evaluation in this region where clinical experience with direct-acting antivirals is limited. EBR/GZR is approved in the United States for treatment of HCV GT1 and 4 infection. Methods: C-CORAL is a double-blind placebo-controlled, Phase 3 trial that randomized treatment-naïve HCV GT1, 4 or 6 infected subjects in a 3:1 ratio to an immediate treatment group (ITG; 12 wks of EBR/GZR) or deferred treatment group (DTG; 12 wks of placebo, followed by 12 wks of EBR/GZR). Subjects were enrolled in an ex-China cohort that included subjects from Korea, Taiwan, Vietnam, Thailand, Australia, and Russia; and a second cohort enrolled subjects from China. The primary endpoints include the % of patients in the ITG who achieved SVR12 and a comparison of the safety and tolerability of EBR/GZR in the ITG vs placebo in the DTG. We will present the efficacy results of the ITG and safety results of the ITG and DTG in both cohorts. Results: To date, data from the ex-China cohort are available. In this cohort, a total of 250 subjects were enrolled in the ITG and 86 in the DTG. Mean age (±SD) was 50 ±12 years, 57% were females, 59% were Asian, 74% were GT1b, and 19% were cirrhotic. SVR12 in the ITG was 92.8% (table). Eighteen subjects in the ITG did not achieve SVR12: 11 were relapses, 6 were on-treatment failures (all GT6) and 1 GT1b subject withdrew consent. The incidence of adverse events (AEs) was generally comparable between the ITG vs the DTG including drug-related AEs (21.2% vs 19.8%) and serious AEs (0.8% vs 1.2%; none considered drug-related). During treatment with EBR/GZR or placebo 2/250 (0.8%) subjects in the ITG and 11/86 (12.8%) subjects in the DTG had an ALT value >5x ULN and greater than baseline. One subject in the ITG withdrew after meeting a trial specific discontinuation criterion for elevated ALT, which was not considered drug related. Updated safety and efficacy data will be presented for the ITG for both the ex-China and China study cohorts. Conclusions: A 12-week regimen of EBR/GZR is effective and well-tolerated in GT1 and GT4-infected, treatment-naïve patients in the Asia Pacific/Russia region.