A Systematic Review of the Extrahepatic Manifestations of Hepatitis C Infection in East Asia

( Zobair M. Younossi ),( Linda Henry ),( Janus Ong ),( Atsushi Tanaka ),( Yuichiro Eguchi ),( Masashi Mizokami ),( Young-suk Lim ),( Yock Young Dan ),( Ming-lung Yu ),( Maria Stepanova ),( Sooji Lee ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Chronic hepatitis C (CHC) infection causes a systemic infection with hepatic and extrahepatic manifestation (EHMs). Although the prevalence of EHMs in Western countries is well described, the same is not well known in East Asian countries. We performed a systematic review to quantify the prevalence of selected EHMs among CHC patients in East Asia. Methods: PubMed, Medline, and Japan databases searched (1990-Dec 2016) with “hepatitis c virus” “chronic hepatitis C”, “extrahepatic manifestations”, and respective EHM’s. Data were collected and reviewed by two per PRISMA guidelines. EHMs were by ICD-9 codes or clinically: depression:BDI-2 score>19, chronic kidney disease (CKD): eGFR of < 60 mL/ min/1.73 m2 per MDRD, diabetes (DM):fasting blood glucose level > 126 mg/dL. Pooled prevalence determined by random effects models. Results: 75 articles were identified. After applying inclusion and exclusion criteria, 23 articles remained (Japan=6; China=3, Korea= 4, Taiwan=9, Asia=1) with a total of 468,656 subjects (n= 51,160 CHC and n= 417,496 non-HCV controls). HCV patient age ranged from 44-70 (mean age 55), 50% were male (range 0%-67%), and over 80% of diagnosis was established through positive HCV anti-body. CHC subjects had higher risk of lymphoma (n=2) 4.6% vs. 2.3%, OR=1.79 (1.47-2.19), P<0.0001; DM (n=11) 16.7% vs. 9.4%, OR=1.84 (1.52-2.21), P<0.0001; SS (n=2) 9.6% vs. 3.5%, OR=9.80 (1.25-76.56), P=0.0295; LP (n=5) 8.2% vs. 4.2%, OR=2.45 (1.36-4.41), P=0.0027; depression (n=1) 51.6% vs. 27.7%, OR=2.77 (1.25-6.15), P=0.0121; CKD (n=5) 3.8% vs. 1.7%, OR=2.00 (1.09-3.70), P=0.026; RA (n=2) 0.9% vs. 0.3%, OR=2.41 (1.54-3.76), P=0.0001; CVA (n=2) 25.3% vs. 19.3%, hazard ratio 1.38 (1.24-1.53), P<0.05; IHD (n=1) 25.3% vs 11.6%, OR=1.76 (1.04-2.96), P=0. 0.034. Additionally, the prevalence of MC (symptomatic and asymptomatic; n=1) in CHC was 46.9% in CHC vs. 1.9% in general population with a risk ratio of 24.7 (17.2-32.2). Conclusions: Our review found that CHC in East Asia is associated with increased risk for EHMs.

Economic Gains Related to Hepatocellular Carcinoma and Decompensated Cirrhosis Reduction in Japan is expected from Treatment of Chronic Hepatitis C

( Zobair M. Younossi ),( Atsushi Tanaka ),( Yuichiro Eguchi ),( Linda Henry ),( Rachel Beckerman ),( Masashi Mizokami ),( Sooji Lee ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Japanese chronic hepatitis C (CHC) patients are at greater risk for hepatocellular carcinoma (HCC). Highly effective oral Direct Acting Antiviral (DAA) regimens for CHC can lead to high SVR rates that reduce CHC complications and costs. This study estimated the economic benefit of CHC cure by reducing HCC and decompensated cirrhosis (DCC) in Japan. Methods: A hypothetical cohort of 10,000 HCV GT1b Japanese patients with a mean age of 70 was modeled with a hybrid decision tree and Markov model capturing the natural history of HCV infection over a lifetime horizon. It was assumed that 15% of the cohort had cirrhosis and 20% were treatment-experienced. Treatment compared approved all-oral DAAs vs. no treatment (NT) with efficacy based on randomized controlled trials. Transition rates and costs were obtained from Japan-specific data. DCC, HCC and quality-adjusted life years (QALYs) were projected. QALYs were monetized using a willingness to pay (WTP) threshold which varied from ¥4 to ¥6 million. The incremental savings associated with treatment were calculated by adding the projected cost of complications avoided to the monetized gains in QALYs. Results: DAA treatment avoided 1583 cases of HCC and 1162 cases of DCC, saving ¥618,076 and ¥251,329 per treated patient; respectively. Treatment leads to avoidance of 2745 cases of CHC complications and associated savings of ¥869,405 per treated patient. Additionally, DAA treatment lead to an additional 1.59 QALYs gained per patient treated. The indirect economic gains associated with treatment-related QALY improvements were estimated to be ¥6,360,000, ¥7,950,000 and ¥9,540,000 per patient at WTP thresholds of ¥4 million, ¥5 million and ¥6 million. Total economic savings of HCV GT1 treatment with DAAs (vs. NT) was ¥7,229,405, ¥8,819,405and ¥10,409,405 at these different WTP thresholds. Conclusions: Treatment of HCV GT1b with all Oral DAAs in Japan can lead to significant savings related to avoidance of HCC and DCC.

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.

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.

Impact of Treatment Duration and Addition of Ribavirin on Real-World Effectiveness of Elbasvir/Grazoprevir: Retrospective Analyses from the Trio Network

( Eungeol Sim ),( Chizoba Nwankwo ),( Bruce Bacon ),( Michael P. Curry ),( Douglas T. Dieterich ),( Steven L. Flamm ),( Kris V. Kowdley ),( Scott Milligan ),( Naoky C. Tsai ),( Zobair M. Younossi ),( 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Lengthening treatment with elbasvir/grazoprevir (EBR/ GZR) to 16 weeks and/or adding ribavirin (RBV) is recommended for select patients with HCV GT1 infection. However, realworld data (J Hepatol 2017;66:S295) suggest that utilization of this regimen is low. This study examined the use of 12- and 16- week EBR/GZR ±RBV regimens in different patient subgroups. Methods: Data were collected from providers and specialty pharmacies through Trio Health’s disease management program. Patients (n=442) with HCV GT1 infection who initiated EBR/GZR therapy between Jan 28, 2016 (FDA approval) to Dec 31, 2016 were included. Results: 401 (91%) patients received EBR/GZR for 12 weeks, 12 (3%) received EBR/GZR+RBV for 12 weeks, 11 (2%) received EBR/GZR for 16 weeks, and 18 (4%) received EBR/GZR+RBV for 16 weeks. Possible baseline NS5A resistance was identified in 13/285 patients with GT1a infection: 3 (23%) received EBR/ GZR for 12 weeks, 1 (8%) received EBR/GZR+RBV for 12 weeks, 2 (15%) received EBR/GZR for 16 weeks, and 7 (54%) received EBR/GZR+RBV for 16 weeks. Across all patients, the +RBV subgroup had a higher proportion of treatment-experienced patients (43%, 13/30) than the -RBV group (17%, 69/412); and the 16-week subgroup had a higher proportion of GT1A subtype (93%, 27/29) than the 12-week group (62%, 258/413). Other characteristics including gender, age, baseline viral load, and cirrhosis were similar between regimens and between groups defined by RBV addition or therapy duration. SVR12 results at time of abstract submission were available for 262/442 patients. Overall per protocol (PP) SVR12 was 97% (253/262). Across GT1 subgroups (defined by subtype, prior treatment experience, and fibrosis) that received EBR/GZR for 12 weeks without RBV, the PP SVR12 was ≥94% (TABLE). Conclusions: In real-world practice, EBR/GZR was highly effective, with the majority of patients treated for 12 weeks without RBV. Full SVR12 data will be presented at the conference.

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.