Changes in Markers of Liver Function in HCV 1b Patients with Compensated Cirrhosis Treated with Ombitasvir/Paritaprevir/ Ritonavir plus Dasabuvir with Ribavirin

( Jeong Heo ),( Yan Luo ),( Wan-long Chuang ),( Jidong Jia ),( Kwang-hyub Han ),( Ming-lung Yu ),( Hong Tang ),( Young-suk Lim ),( Cheng-yuan Peng ),( Min Xu ),( Maorong Wang ),( Bo Fu ),( Niloufar Mo 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Patients chronically infected with HCV are at risk of developing extrahepatic manifestations of HCV as well as progressing to compensated or decompensated cirrhosis and HCC. Although current treatments have high rates of SVR, relatively little is known about possible regression of liver fibrosis after achieving an SVR. The ONYX-II trial examined the efficacy and safety of ombitasvir/paritaprevir/ritonavir plus dasabuvir + ribavirin (RBV) in Asian patients with HCV genotype 1b infection and compensated cirrhosis. Here we report changes in key markers of liver fibrosis and function. Methods: Patients with chronic HCV GT1b infection and compensated cirrhosis were enrolled in China, South Korea and Taiwan and received 12 weeks of OBV/PTV/r (25 mg/150 mg/100 mg once daily) and DSV (250 mg twice daily) with weight-based RBV. The primary objective of ONYX-II was to assess efficacy (SVR12) and safety of the regimen. Changes in markers of liver fibrosis and function between baseline (BL) and post-treatment week (PTW) 12 are presented. Results: Overall, 104 patients were enrolled and treated in ONYX-II. All patients (104/104, 100%) achieved SVR12. BL and PTW12 data for FibroTest score, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, albumin, platelet count and alpha fetoprotein (AFP) are shown in Table 1. All selected parameters showed numerical improvements between BL and PTW12. Mean ALT and AST levels returned to within normal range and FibroTest scores demonstrated a numerical improvement, suggesting improvement in liver status. The complete set of data between BL and PTW12 will be presented for these parameters and other liver composite parameters at the conference. Conclusions: Measurement of key liver function markers during the ONYX-II trial showed a numerical improvement within 12 weeks of completion of treatment in HCV GT1b-infected patients with compensated cirrhosis. Further follow-up of these patients will determine the long-term durability of these changes.

Impact of Hepatoprotective Medications on the Safety and Efficacy of OBV/PTV/r plus DSV ± Ribavirin in HCV GT1b-infected Asian Patients

( Wan-long Chuang ),( Yan Luo ),( Jeong Heo ),( Gui-qing Wang ),( Ming-lung Yu ),( Yoon Jun Kim ),( Qing Xie ),( Cheng-yuan Peng ),( Mingxiang Zhang ),( Yan Huang ),( Wenjing Lu ),( Linda M. Fredrick 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Hepatoprotective medications (HPMs) are commonly used in patients with chronic liver disease, especially across Asia. The phase 3 ONYX-I and ONYX-II studies evaluated the safety and efficacy of the 3-DAA regimen of ombitasvir and paritaprevir/ritonavir (OBV/PTV/r) plus dasabuvir (DSV) ± ribavirin (RBV) in an exclusively HCV GT1b-infected Asian population. This post-hoc analysis evaluated the impact of HPM use in patients treated with OBV/PTV/r + DSV ± RBV in these studies. Methods: ONYX-I and ONYX-II enrolled patients in China, South Korea and Taiwan. SVR12, treatment-emergent adverse events (AEs), and alanine transaminase (ALT) normalization, as well as mean changes in ALT over time were assessed in patients using vs not using HPMs. HPM use defined as all medications administered during any treatment period. Results: Overall, 11% (36/325) of non-cirrhotic and 57% (59/104) of cirrhotic patients were receiving HPMs, with ursodeoxycholic acid being the most commonly used in both non-cirrhotic (5.2% [17/325]) and cirrhotic (14.4% [15/104]) patients. SVR12 rates were high (99.7- 100%) in both non-cirrhotic and cirrhotic patients irrespective of HPM use. The regimen was generally well tolerated, with low rates of SAEs and AEs leading to treatment discontinuation (Table). Of patients with ALT above normal at baseline (BL), 100% vs 95% of non-cirrhotic and 98% vs 89% of cirrhotic patients using or not using HPMs, respectively, had normal ALT values at end of treatment (EOT). Mean ALT levels during treatment declined rapidly and similarly with and without HPM use; mean changes from BL to EOT were -38.8 and -37.0 U/L, respectively, in non-cirrhotic and -54.2 and -66.6 U/L, respectively, in cirrhotic patients. Conclusions: OBV/PTV/r + DSV ± RBV achieved high SVR12 and was generally well tolerated regardless of HPM use. HPM use had no impact on the safety profile of OBV/PTV/r + DSV therapy in Asian HCV infected subjects.

ONYX-I: Efficacy of Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir in South Korean and Taiwanese Patients with HCV Genotype 1b Infection and without Cirrhosis

( Jeong Heo ),( Wan-Long Chuang ),( Yan Luo ),( Mong Cho ),( Chi-Jen Chu ),( Kwang-Hyub Han ),( Jia-Horng Kao ),( Seung Woon Paik ),( Chun-Yen Lin ),( Jin-Woo Lee ),( Cheng-Yuan Peng ),( Young-Suk Lim 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Background: Approximately 45-50% of Hepatitis C virus (HCV) infections in South Korea and Taiwan are genotype (GT) 1b. Previous phase 3 studies demonstrated that the direct-acting antiviral (DAA) regimen of ombitasvir (OBV), ritonavir-boosted paritaprevir (PTV/r; identified by Abbvie and Enanta) and dasabuvir (DSV) was well tolerated and achieved sustained virologic response at post-treatment week 12 (SVR12) in 99% of treatment-naive and 100% of treatment- experienced patients with HCV GT1b. ONYX-I (NCT02517515) was designed to evaluate efficacy and safety in Asian patients with HCV GT1b infection without cirrhosis. Methods: Treatment-naive and IFN-based therapy-experienced patients with HCV GT1b infection in South Korea, Taiwan, and China were randomized 1:1 to receive either OBV/PTV/r (25 mg/150 mg/100 mg once daily) and DSV (250 mg twice daily) or placebo for 12 weeks during the double-blind (DB) period. Patients in the placebo arm subsequently received OBV/PTV/r + DSV for 12 weeks during the open-label period. Patients will be followed for 48 weeks after last dose of study drugs. The primary objectives are to compare the SVR12 rates for the treatment-naive and -experienced patients to corresponding historical SVR rates of telaprevir + peg-interferon and ribavirin therapy, and assess the safety of the OBV/PTV/r + DSV regimen. Presented are results from the South Korean and Taiwanese populations. Results: In both South Korea and Taiwan, 120 patients were randomized and treated. Of South Korean patients, 45% were male, 33% were treatment-experienced and 89% had F0-F1 fibrosis. Of Taiwanese patients, 39% were male, 33% were treatment-experienced, and 87% had F0-F1 fibrosis. Safety data and SVR at post-treatment week 4 will be presented. Conclusions: The ONYX-I study is evaluating the safety and efficacy of DAA regimen, OBV/PTV/r + DSV, in Southeast Asian patients without cirrhosis infected with HCV GT1b. Resultant data may help inform treatment guidelines for HCV GT1b in this population.

Smaller Decreases in Bone Mineral Density in CHB Patients Receiving Tenofovir Alafenamide Compared with Tenofovir Disoproxil Fumarate Over 96 Weeks

( Scott Fung ),( Wan Long Chuang ),( Shuhei Nishiguchi ),( Wai Kay Seto ),( Won Young Tak ),( Elke M. Erne ),( Maciej,Jablkowski ),( Vyacheslav Morozov ),( Audrey H. Lau ),( Vithika Suri ),( John F. F 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Compared with TDF, smaller declines in bone mineral density (BMD) were demonstrated with TAF vs. TDF over 48 weeks. Presented here are bone safety results at Week 96. Methods: In two Phase 3 studies, 1301 patients were randomized (2:1) to receive TAF 25 mg QD or TDF 300 mg QD. Dual energy X-ray absorptiometry (DXA) scans were evaluated for mean percent change from baseline and by the proportion with >3% declines in hip and spine BMD. BMD changes were also assessed in the subset of patients at higher risk for bone loss (females, advanced age [≥ 50 y], Asian race, eGFR <90 mL/min). Serum markers of bone resorption (CTX) and formation (osteocalcin, bone-specific alkaline phosphatase, P1NP) were also assessed serially. Results: Patients with TAF experienced lesser declines in hip and spine BMD over 96 weeks(Table, p< 0.001). A higher proportion of subjects treated with TDF also experienced >3% declines in hip and spine BMD compared with TAF-treated patients (Table, p < 0.0001). Greater declines in BMD were seen in patients with >1 risk factor for bone loss at baseline; however, in comparison to TDF, the proportion with >3% declines in hip and spine BMD were lower in the TAF group (p<0.0001 for all) and were less impacted by the presence of multiple risk factors (Table, p< 0.005 for all). By multivariate analysis baseline predictors for >3% decline in hip or spine BMD at Week 96 were: treatment with TDF, female gender, and older age. The smaller changes in BMD seen with TAF were associated with minimal changes in markers of bone turnover compared with TDF. Conclusions: Through 96 weeks, TAF was associated with had less impact on BMD and bone parameters compared to TDF. The magnitude of these differences was most pronounced in those at higher risk for bone loss.

Improvement in Renal Parameters in CHB Patients Treated with Tenofovir Alfenamide (TAF) versus Tenofovir Disoproxil Fumarate (TDF) over 96 Weeks

( Hyung Joon Kim ),( Wan Long Chuang ),( Kosh Agarwal ),( Jae Seok Hwang ),( Florin Caruntu ),( Florence Wong ),( Hie Won Hann ),( John Flaherty ),( Audrey Lau ),( Anuj Gaggar ),( Vithika Suri ),( Shu 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: In Phase 3 studies in CHB patients the efficacy of TAF was found smaller changes in renal parameters compared with TDF treatment. This benefit was particularly evident in patients with risk factors for renal impairment.Here, we present renal safety results after 96 weeks of treatment. Methods: In Phase 3 studies (HBeAg positive patients [N=873] and HBeAg negative patients [N=425]), patients were randomized 2:1 to TAF 25 mg QD or TDF 300 mg QD, and treated for 144 weeks. Renal parameters including estimated glomerular filtration rate (eGFR) calculated by the Cockcroft-Gault method were evaluated. Chronic kidney disease (CKD) staging was categorized by the National Kidney Foundation KDOQI guidelines. Evaluated risk factors for kidney disease included older age (age ≥ 50), female gender, renal impairment (eGFR <90mL/min) and presence of comorbidities (hypertension, cardiovascular disease and diabetes). Urine markers of renal glomerular dysfunction (urine protein and albumin to creatinine ratio) and tubular dysfunction (retinol binding protein (RBP) and beta-2 microglobulin [B2M] to creatinine ratio) were serially assessed. Results: Patients treated with TAF continued to show smaller changes in serum creatinine (p=0.001) and eGFRCG (p<0.001) at 96 weeks. Similarly, median percentage changes in renal tubular markers, were also smaller in TAF-treated patients compared with TDF patients at Week 96; RBP/Cr (p<0.0001) and B2M/Cr (p<0.0001). A lower percentage of patients experienced ≥1 stage worsening in NKF CKD stage when treated with TAF compared with TDF at Week 96 overall and when evaluated by risk factors for kidney disease.Furthermore, CKD stage progression increased disproportionately in the TDF group in patients with ≥2 risk factors (Table). Conclusions: Treatment with TAF for 96 weeks continued to be associated with smaller changes in renal parameters compared with TDF treatment. The benefits of TAF are particularly evident in patients with risk factors for kidney disease.

Ledipasvir/Sofosbuvir for 12 Weeks Is Safe and Effective in CHC and CHB Coinfection Patients: A Phase 3 Study in Taiwan

( Chun-Jen Liu ),( Wan-Long Chuang ),( I-Shyan Sheen ),( Horng-Yuan Wang ),( Chi-Yi Chen ),( Kuo-Chih Tseng ),( Ting-Tsung Chang ),( Benede tta Massetto ),( Jenny Yang ),( Gregory Camus ),( Fangqiu Zh 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Patients co-infected with HCV and HBV have more rapid progression and worse outcomes than mono-infected patients. Taiwan has among the highest prevalence of chronic HCV/HBV coinfection in Southeast Asia. This study evaluated the safety and efficacy of an all-oral treatment with ledipasvir(LDV)/sofosbuvir(SOF) for 12 weeks in chronic HCV and HBV coinfection. Methods: Patients with or without compensated cirrhosis chronic HCV GT1/GT2 and HBV (HBsAg+) treatment naïve were enrolled into open-label, receiving LDV 90 mg/SOF 400 mg(QD) for 12 weeks. The primary efficacy endpoint is SVR12. HBV DNA was monitored at all study visits and it will be monitored for 2 years post-treatment. Results: A total of 111 patients (68[61%] with GT1 and 43[39%] with GT2) were enrolled and treated. The majority were female(62%), treatment naive(67%), and non-cirrhotic(85%), with a mean age of 55 years and mean BMI of 24.5kg/m2. All but one was HBeAg negative. Mean baseline HBV DNA was 2.1 log10IU/mL. SVR4 was 100%(111/111). The mean change in HBV DNA ranged from -0.06 log10IU/mL at week 1 to +0.49 log10IU/mL at follow-up visit 4; HBV DNA kinetics are shown in Fig 1. 60(54%) patients had an increase in HBV DNA> 10 x BL or became HBV DNA > LLOQ. No patients had ALT ≥ 2 X baseline. No patients discontinued treatment due to adverse events (AEs). Three patients had serious AEs(optic neuritis, post procedural bleeding and duodenal ulcer bleeding; none was considered drug related). Conclusions: In chronic HCV/HBV infection patients, LDV/SOF for 12 weeks resulted in an SVR4 rate of 100%. Although most patients had an increase in HBV DNA during treatment, this was not associated with ALT elevations ≥2 X baseline, and no patients started HBV therapy to date. This all-oral, interferon-free regimen was well tolerated, supporting its potential as a treatment option for HCV/HBV co-infected patients.

Daclatasvir plus Asunaprevir in Interferon (± Ribavirin)- Ineligible/Intolerant Asian Patients with Chronic HCV Genotype-1b Infection

( Lai Wei ),( Mingxiang Zhang ),( Min Xu ),( Wan-Long Chuang ),( Wei Lu ),( Wen Xie ),( Zhansheng Jia ),( Guozhong Gong ),( Yueqi Li ),( Si Hyun Bae ),( Yong-Feng Yang ),( Qing Xie ),( Shumei Lin ),( 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: The efficacy/safety of daclatasvir (pan-genotypic NS5A inhibitor) plus asunaprevir (NS3 protease inhibitor) in interferon (± ribavirin)- ineligible/intolerant patients with chronic HCV genotype-1b infection from mainland China, Korea and Taiwan was investigated in a phase 3, open-label study. Methods: Patients received daclatasvir 60 mg (tablet) once daily plus asunaprevir 100 mg (soft capsule) twice daily for 24 weeks. The primary endpoint was sustained virologic response at post-treatment Week 24 (SVR24). Results: This study treated 159 patients from mainland China (80%), Korea (11%) and Taiwan (9%), including patients with cirrhosis (33%), IL28B non-CC genotypes (40%), and aged ≥70 years (4%). SVR24 was achieved by 91% of patients (100% concordance with SVR12) and was similarly high in all subgroups, e.g. cirrhotic patients (90%), and in patients from mainland China (91%), Korea (94%) and Taiwan (87%). SVR24 was higher in patients without baseline NS5A (L31M/Y93H) resistance-associated variants (RAVs) (n=137/139 [99%]), regardless of the presence (98%) or absence (99%) of cirrhosis, and lower in patients with baseline NS5A RAVs (n=8/19 [42%]). All serious adverse events (AEs) (n=5/159 [3.1%]), grade 4 laboratory abnormalities (n=3/159 [1.9%]) and deaths (n=1/159 [0.6%]) that occurred on-treatment were unrelated to the study drugs; two patients discontinued due to AEs. Treatment was generally well tolerated regardless of cirrhosis status. Conclusions: Daclatasvir plus asunaprevir achieved a high SVR24 rate of 91%, rising to 99% in patients without baseline NS5A RAVs, and was generally well tolerated in cirrhotic and non-cirrhotic interferon (± ribavirin)-ineligible/intolerant patients with HCV genotype-1b infection from mainland China, Korea and Taiwan.

Switching from Tenofovir Disoproxil Fumarate (TDF) or Other Oral Antiviral Therapy (OAV) to Tenofovir Alafenamide (TAF) in Virally Suppressed CHB Patients with Hepatic Impairment

( Sang Hoon Ahn ),( Young-Suk Lim ),( Pietro Lampertico ),( Ho Bae ),( Wan-Long Chuang ),( Jeong Heo ),( Yi-Hsiang Huang ),( Aric Josun Hui ),( Chun-Yen Lin ),( Claire Fournier ),( Chien-Hung Chen ),( 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: TAF, a novel tenofovir (TFV) prodrug, has greater plasma stability, more targeted delivery of TFV to hepatocytes, and reduced circulating levels of TFV compared to TDF. We evaluated efficacy and safety when virally suppressed CHB (Chronic Hepatitis B) patients with hepatic impairment were switched to TAF. Methods: In this Phase 2 study (NCT03180619) CHB patients with a ChildTurcottePugh (CTP) score of ³7 and £12 at screening (or past history of CTP ³7 and any score £12 at screening) who were taking TDF and/or other OAVs for ³48 weeks, with HBV DNA <LLOQ for ³24 weeks and <20 IU/mL at screening were eligible. All patients were switched to TAF 25 mg QD and treated for 96 weeks. The co-primary endpoints were proportion with HBV DNA <20 IU/mL and graded adverse events (AEs)/lab abnormalities at Week 24. Results: 31 patients were enrolled at 18 sites in 7 countries. At baseline, 19 (61%), 9 (29%) and 3 (10%) were CTP Class A, B, or C, respectively. Median age was 57 y (19% ³65 y), 68% male, 81% Asian, 90% HBeAg-negative, median fibrotest score 0.81, and median eGFR_CG 98 mL/min; up to 48% had low BMD at hip and/or spine, and 68% had prior TDF exposure. Key efficacy/safety results at Week 24 are summarized in the Table. All patients had HBV DNA <20 IU/mL and a high proportion had normal ALT. Switching to TAF resulted in increases in hip/spine BMD, decreases in bone turnover markers, an increase in eGFR_CG with decreases in tubular markers. TAF was well tolerated with few having Grade 3 or 4 AEs (2 patients) and no discontinuations for and AE. ^aHBV DNA results are missing=failure. ^bALT normal is the proportion with ALT ≤ULN at Week 48, regardless of baseline ALT level; ^cULN 35 U/L males, 25 U/L females; ^dPatients with ALT >ULN at baseline; ^eHBeAg-positive at baseline. ^fSerum C-type collagen sequence (bone resorption marker); ^gSerum procollagen type 1 N-terminal propeptide (bone formation marker); ^hUrine retinol binding protein/creatinine (tubular marker); ⁱUrine beta-2 microglobulin/creatinine (tubular marker). BMD, bone mineral density by DXA scan; sCr, serum creatinine; PO₄, serum phosphorus; eGFR_CG, estimated creatinine clearance (Cockcroft-Gault method) Conclusions: In CHB patients with hepatic impairment switched to TAF from TDF or other OAVs, viral suppression was well maintained and improved bone and renal safety was seen at Week 24.

Serial Serum MHC Class I Chain-Related a Levels in Predicting Hepatocellular Carcinoma in Chronic Hepatitis C Patients with Curative Antiviral Treatment

( Ming Lung Yu ),( Chung-feng Huang ),( Chia-yen Dai ),( Jee-fu Huang ),( Wan-long Chuang ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: MHC class I chain-related A (MICA) genetic variants and its serum level (sMICA) were associated with hepatitis C virus (HCV) related hepatocellular carcinoma (HCC) in untreated cohorts. The dynamic changes of serial sMICA levels regarding anti-HCV treatment and consequent HCC development is elusive. Methods: Single nucleotide polymorphism rs2596542 of MICA and serial sMICA levels were tested in chronic hepatitis C (CHC) patients with sustained virological response after antiviral treatment. Forty-two patients who developed HCC and another 84 age-, sex- and cirrhosis-propensity score matched non-HCC controls were compared. Serial sMICA levels were measured at three-time points: within 6 months of pretreatment (pre-sMICA), 6 months after the end of treatment (post-sMICA) and last visit before HCC occurrence or not (last-sMICA). Results: Compared to patients without HCC occurrence, those with HCC had lower platelet counts, higher levels of post-sMICA (197.4+398.0 pg/mL vs. 57.6+89.6 pg/mL, P=0.03) and last-sMICA (320.4+508.4 pg/mL vs. 37.7+140.2 pg/mL, P<0.001). Cox regression analysis revealed that last-sMICA is the only factor predictive of HCC development (hazard ratio [HR]/ 95 % confidence intervals [CI.]: 2.27 (per 1 log pg/mL increase)/1.672-3.082, P<0.001). Patients without HCC had a significantly decreased trend of sMICA levels during follow-up (trend P=0.001). In contrast, HCC patients had an increased trend of sMICA levels (trend P=0.024). MICA rs2596542 GG genotype carriers without HCC had a significantly decreased trend of sMICA levels during follow-up (trend P<0.001). However, HCC patients who carried GG genotype had a substantially increased trend of sMICA levels (trend P=0.06). Nevertheless, both trends were not observed in A allele carriers with or without HCC development. t three-time points: within 6 months of pretreatment (pre-sMICA), 6 months after the end of treatment (post-sMICA) and last visit before HCC occurrence or not (last-sMICA). Conclusions: Serial sMICA levels could serve as a surrogate marker for HCC development in CHC patients with SVR. The clinical utility is restricted to MICA rs2596542 GG genotype carriers. CA (320.4+508.4 pg/mL vs. 37.7+140.2 pg/mL, P<0.001). Cox regression analysis revealed that last-sMICA is the only factor predictive of HCC development (hazard ratio [HR]/ 95 % confidence intervals [CI.]: 2.27 (per 1 log pg/mL increase)/1.672-3.082, P<0.001). Patients without HCC had a significantly decreased trend of sMICA levels during follow-up (trend P=0.001). In contrast, HCC patients had an increased trend of sMICA levels (trend P=0.024). MICA rs2596542 GG genotype carriers without HCC had a significantly decreased trend of sMICA levels during follow-up (trend P<0.001). However, HCC patients who carried GG genotype had a substantially increased trend of sMICA levels (trend P=0.06). Nevertheless, both trends were not observed in A allele carriers with or without HCC development. t three-time points: within 6 months of pretreatment (pre-sMICA), 6 months after the end of treatment (post-sMICA) and last visit before HCC occurrence or not (last-sMICA).

Safety and Efficacy of Switching to Tenofovir Alafenamide in Chronic Hepatitis B Patients with Hepatic Impairment: Week 48 Results

( Young-suk Lim ),( Jeong Heo ),( Chun-yen Lin ),( Ho Bae ),( Wan-long Chuang ),( Aric Josun Hui ),( Chun-yen Lin ),( Magdy Elkhashab ),( Huy Trinh ),( Susanna Tan ),( Grace Zhao ),( John F. Flaherty 대한간학회 2021 춘·추계 학술대회 (KASL) Vol.2021 No.1