The Safety and Tolerability of SOF/VEL/VOX for 8/12 Weeks in >1,000 Patients Treated in the POLARIS Studies: An Integrated Analysis

( Michael Manns ),( Edward J. Gane ),( Bernard E. Willems ),( Stuart K. Roberts ),( Steven Flamm ),( Marc Bourlière ),( Tarik Asselah ),( Laurent Alric ),( Sunjin Hwang ),( Robert H. Hyland ),( Luisa 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: The once-daily fixed-dose combination tablet of sofosbuvir/ velpatasvir/voxilaprevir (SOF/VEL/VOX) was evaluated for the treatment of genotype 1-6 HCV patients with and without compensated cirrhosis. Treatment was for 12 weeks for DAA-experienced patients (POLARIS-1 and POLARIS-4) and for 8 weeks for DAA-naive patients (POLARIS-2 and POLARIS-3). This analysis describes the safety of these 4 Phase 3 studies. Methods: Treatment-emergent adverse events (AEs) and laboratory abnormalities were assessed in patients who received SOF/VEL/VOX or placebo for 12 weeks(POLARIS-1), SOF/VEL/VOX or SOF/VEL for 12 weeks(POLARIS-4), or SOF/VEL/VOX for 8 weeks or SOF/VEL for 12 weeks(POLARIS-2 and POLARIS-3). SAEs and deaths were followed until post-treatment Week 24. Results: 1056 patients were treated with SOF/VEL/VOX for 8 (n=611) or 12 (n=445) weeks, 700 received SOF/VEL for 12 weeks, and 152 received placebo. 38% had compensated cirrhosis, 28% had a BMI ≥30 kg/m2, 36% were female, and 12% were ≥65 years old. Two deaths were reported, one illicit drug overdose and one attributed to hypertension, neither were related to treatment. SAEs and discontinuations were more frequent in the placebo group and occurred with similar frequency in the other groups; none were related to study treatment. Headache, fatigue, nausea, and diarrhea were the most common AEs. Mild diarrhea and nausea occurred more frequently in the SOF/VEL/VOX groups. Overall, 5.1 - 6.6% of patients who received SOF/VEL/VOX or SOF/VEL had Grade 3 or 4 laboratory abnormalities. Among patients receiving VOX, one patient each had a Grade 3 elevation in ALT and bilirubin. Conclusions: SOF/VEL/VOX for 8 or 12 weeks in the POLARIS studies was well tolerated with a low frequency of Grade 3 or 4 AEs, SAEs, and AEs leading to discontinuation. The frequency of AEs in the SOF/VEL/VOX groups was similar to SOF/VEL and placebo groups, with higher rates of mild diarrhea and nausea compared to SOF/VEL.

All-oral Dual Therapy with Daclatasvir and Asunaprevir in Patients with HCV Genotype 1B Infection

Michael Manns,Stanislas Pol,Ira M. Jacobson,Patrick Marcellin,Stuart C. Gordon,Cheng-Yuan Peng,Ting-Tsung Chang,Gregory T. Everson,Jeong Heo,Guido Gerken,Boris Yoffe,William J. Towner,Marc Bourliere,S 한국간담췌외과학회 2014 한국간담췌외과학회 학술대회지 Vol.2014 No.4

Resistance Analyses for Ledipasvir/Sofosbuvir Containing Regimens in HCV-infected Patients Who Have Advanced Liver Disease or Are Post Liver Transplant

( Michael Charlton ),( Michael Manns ),( Hadas Dvory-sobol ),( Evguenia Svarovskaia ),( Brian Doehle ),( Sarah Arterburn ),( Chohee Yun ),( Diana M. Brainard ),( John G. Mchutchison ),( Michael Miller 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Ledipasvir/sofosbuvir (LDV/SOF) with ribavirin (RBV) demonstrated high SVR rates in patients with chronic hepatitis C (HCV) genotype (GT) 1 or 4 infection who have decompensated cirrhosis or who have undergone liver transplantation. Here we evaluated the effect of baseline HCV NS5A and NS5B resistance-associated variants (RAVs) on treatment outcome and characterized the viral resistance in all virologic failures. Methods: Deep sequencing with a 1% assay cut-off was performed for NS5A and NS5B at baseline for all the patients and at the time of virologic failure for those who relapsed. Results: Out of 625, 622, and 619 samples were analyzed for baseline NS5A and NS5B respectively. Table 1 summarizes SVR12 rates by treatment duration and the presence or absence of baseline NS5A RAVs. NS5B RAVs at baseline were uncommon, occurring in 4.8% (28/586) GT1 patients and 3.2% (1/31) GT 4 patients. Of these 29 patients, only one GT1 patient with CPT C cirrhosis who had L159F at baseline and was treated for 24 weeks with LDV/SOF+RBV did not achieve SVR12. NS5A RAVs at positions 24, 28, 30, 31, 58, and 93 were enriched or emerged in 20/22 (91%) GT1 and 1/3 GT4 infected patients with virologic failure. The NS5B NI RAV E237G emerged in 3 GT1a patients and 1 GT4d patient at the time of relapse (4/23, 17%). Conclusions: The presence of baseline NS5A or NS5B RAVs did not impact the treatment outcome to 12 or 24 weeks of LDV/SOF+RBV in GT1 or GT4 HCV patients with liver ransplantation without decompensated liver disease, or 24 weeks of LDV/SOF+RBV in patients with decompensated cirrhosis. Lower SVR rates were observed among the limited number of patients with decompensated cirrhosis and baseline NS5A RAVs who received 12 weeks of LDV/SOF+RBV treatment.

SOF/VEL/VOX for 12 Weeks is a Safe and Effective Salvage Regimen for NS5A Inhibitor-experienced Patients with Genotype 1-6 HCV Infection

( Eric Lawitz ),( Michael Manns ),( Marc Bourliere ),( Sooji Lee ),( Nelson Cheinquer ),( Luisa Stamm ),( Robert H. Hyland ),( Liyun Ni ),( Hadas Dvory-sobol ),( Diana Brainard ),( Mani Subramanian ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: The pangenotypic fixed-dose combination (FDC) of sofosbuvir (SOF), a HCV NS5B inhibitor, velpatasvir (VEL), a HCV NS5A inhibitor, and voxilaprevir (VOX), a HCV NS3/4A protease inhibitor, is an salvage regimen for direct acting antiviral (DAA)-experienced patients based on the safety and efficacy demonstrated in Phase 2 and Phase 3 trials in this population. Methods: This was a retrospective analysis of data from 454 NS5A inhibitor-experienced patients treated with SOF/VEL FDC+VOX or SOF/VEL/VOX FDC in the Phase 2 and Phase 3 trials. Efficacy was assessed by SVR12 and relapse rates. Safety was assessed by treatment-emergent adverse events (AEs) and laboratory abnormalities. Results: Of 454 NS5A inhibitor-experienced patients treated, 77% were male, 41% had compensated cirrhosis, 86% had NS5A and NS3 baseline resistance-associated substitutions (RASs), 74% had genotype 1 HCV infection. Most patients (53%) had previously been exposed to NS5A inhibitor+NS5B inhibitor, with 39% exposed to NS5A inhibitor+NS3/4A protease inhibitor±NS5B inhibitor and 8% exposed to NS5A inhibitor±another DAA. Overall, the SVR12 rate was 97% with a relapse rate of 2%. The SVR12 rate in patients with compensated cirrhosis was 95% and in patients with baseline RASs was 97%. The SVR12 rates by prior regimen were: NS5A inhibitor+NS5B inhibitor 95%; NS5A inhibitor+NS3/4A protease inhibitor±NS5B inhibitor 99%; and NS5A inhibitor±another DAA 100%. Treatment-emergent RASs were uncommon, present in 3 of 10 patients who relapsed. Only 1 patient (0.2%) discontinued treatment due to an AE. No serious adverse events attributed to study medication were reported. Conclusions: Results in over 450 NS5A inhibitor-experienced patients enrolled in Phase 2 or Phase 3 trials demonstrate that the 3-DAA combination of SOF, VEL and VOX for 12 weeks is a safe, well tolerated and effective treatment for patients who previously failed an NS5A inhibitor-containing regimen, irrespective of the other drugs in the prior treatment.

No Impact of RASs on the Efficacy of SOF/VEL/VOX for 12 weeks in DAA-Experienced Patients: Integrated Analysis of the POLARIS-1/POLARIS-4 Studies

( Christoph Sarrazin ),( Curtis L. Cooper ),( Michael P. Manns ),( Rajender Reddy ),( Kris Kowdley ),( Sooji Lee ),( Hadas Dvory-Sobol ),( Evguenia Svarovskia ),( Ross Martin ),( Gregory Camus ),( Bri 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: The pangenotypic combination of sofosbuvir (SOF) /velpatasvir (VEL)/voxilaprevir(VOX), inhibit distinct HCV targets, the NS5B polymerase, the NS5A protein, and NS3/4A protease, respectively. In Phase 3 studies, SOF/VEL/VOX administered for 12weeks demonstrated a 96% SVR12 rate in NS5A inhibitor-experienced patients in POLARIS-1, and a 97% SVR12 rate in DAA-experienced patient who had not previously received an NS5A inhibitor in POLARIS-4. Here, we evaluate the effect of baseline resistance associated substitutions (RASs) on treatment outcome and the emergence of RASs in patients who experienced virologic failure. Methods: NS3, NS5A, and NS5B deep sequencing was performed at baseline for all patients and at the time of virologic failure. NS3 and NS5A class RASs as well as VOX or VEL-specific RASs that confer >2.5-fold changes in EC50 were evaluated. Results: In POLARIS-1, 79% of NS5A inhibitor-experienced patients (205/260) had baseline NS3 and/or NS5A class RASs. Of these, 75% (196/260) had baseline NS5A RASs, the most common RASs. The SVR12 rates were similar in subjects with or without NS3 and/or NS5A class RASs, and with or without VOX or VEL-specific RASs(Table 1). RASs at NS5A position Y93 were present in 25% of patients, of whom 63(95%) achieved SVR12; all patients with ≥2 NS5A RASs achieved SVR12 (n=77). 95%(18/19) of patients with NS5B nucleoside inhibitor(NI) RASs achieved SVR12; 2 patients had S282T at baseline and achieved SVR12. In POLARIS-4, the overall prevalence of baseline NS3 and/or NS5A class RASs was 47%(83/178) and all achieved SVR12. All patients with. Conclusions: Baseline RASs had no impact on response in DAA-experienced patients following treatment with SOF/VEL/VOX for 12 weeks. Viral relapse was not associated with emergence of viral resistance.

HCV, Alcoholic : PE-134 ; Hemoglobin decline during peginterferon Alfa-2B (PEG-2B)/ribavirin (RBV) treatment in real-Life is associated with favorable SVR rates in difficult-to-treat patients with HCV genotype 1 (G1) infection

( G Teuber ),( S Mauss ),( D Huppe ),( E Zehnter ),( M P Manns ),( T Dahhan6 ),( U Meyer ),( T Witthoft ),( B Moller9,),( N Dikopoulos ),( J Brack ),( B Stade ),( M Bilzer ),( The Bng Hepatitis Study 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Background and Aims: Recently, it has been shown for the overall G1 population that anemia as well as the maximal hemoglobin (Hb) decline during peginterferon/RBV treatment is associated with higher SVR rates. We here investigated whether the maximal Hb decline influences SVR rates in difficult-to-treat patients undergoing Peg2b/RBV therapy for HCV G1 infection in real-life. Methods: Data of patients treated for G1 infection within the German Peg2b/RBV observational study were retrospectively analyzed. In this real-life cohort study G1 infection was treated with Peg2b 1.5 μg/kg/wk + weight-based RBV (800-1200 mg/day) for up to 48 wks at 285 sites. Subjects who discontinued for non-response or for any other reasons were included in the analysis. SVR was defined as undetectable serum HCV-RNA 24 wks after EOT response. Only one patient received erythropoietin treatment for anemia. Results: 1851 patients had baseline and at least one Hb measurement during therapy. Overall SVR rate was 42.6% (789/1851). SVR rates were only slightly higher for subjects with an absolute Hb decline >3 g/dL (44.3%, 493/1114) compared to those with maximum Hb declines <3 g/dL (40.2%, 296/737) (p=0.08). In contrast, a significant (p=0.0004) difference in SVR rates was obtained by comparing subjects with Hb declines >2 g/dL (44.6%, 673/1510) with those who experienced Hb declines <2 g/dL (34.0%, 116/341). Similar SVR rates of 46.1% (164/356) and 44.1% (509/1154) in patients with Hb declines >2 g/dL even if they did/did not become anemic (Hb<10 g/dL) strongly support Hb decline, and not anemia, as primary beneficial mechanism improving SVR. As summarized in the table, Hb declines >2 g/dl were significantly associated with higher SVR rates in difficult-to-treat patients, such as subjects elder than 50 years or subjects with high baseline viral load >600.000 IU/ml. Interestingly no beneficial effect was observed in patients with low platelet count (<150/nL), an indicator of advanced fibrosis/cirrhosis. Patients who first developed a Hb decline >2 g/dL during weeks 0-4 were likely to achieve similar SVR (41.3%, 365/883) than those who developed a Hb decline <2 g/dL (44.9%, 386/859). In contrast, a Hb decline >2 g/dL compared to <2 g/dL during weeks 0-4 was associated with a 2-3 fold higher risk of anemia in female (16.6% vs 40.5%) and male patients (7.3% vs 19.0%) when compared with a Hb decline <2 g/dL. Conclusions: Patients with HCV genotype 1 infection and in particular the subgroup of difficult-to-treat patients elder than 50 years or with HVL, achieve up to 15% higher SVR rates when they develop a Hb decline >2 g/dL during Peg2b/RBV therapy. However, patients with low platelet count <150/nL do not achieve this beneficial virologic effect.

HCV : PE-134 ; Hemoglobin decline during peginterferon Alfa-2B (PEG-2B)/ribavirin (RBV) treatment in real-life is associated with favorable SVR rates in difficult-to-treat patients with HCV genotype 1 (G1) infection

( G Teuber ),( S Mauss ),( D Huppe ),( E Zehnter ),( M P Manns ),( T Dahhan ),( U Meyer ),( T Witthoft ),( B Moller ),( N Dikopoulos ),( J Brack ),( B Stade ),( M Bilzer ),( Bng Hepatitis Study Group 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

Background and Aims: Recently, it has been shown for the overall G1 population that anemia as well as the maximal hemoglobin (Hb) decline during peginterferon/RBV treatment is associated with higher SVR rates. We here investigated whether the maximal Hb decline influences SVR rates in difficult-to-treat patients undergoing Peg2b/RBV therapy for HCV G1 infection in real-life. Methods: Data of patients treated for G1 infection within the German Peg2b/RBV observational study were retrospectively analyzed. In this real-life cohort study G1 infection was treated with Peg2b 1.5 μg/kg/wk + weight-based RBV (800-1200 mg/day) for up to 48 wks at 285 sites. Subjects who discontinued for non-response or for any other reasons were included in the analysis. SVR was defined as undetectable serum HCV-RNA 24 wks after EOT response. Only one patient received erythropoietin treatment for anemia. Results: 1851 patients had baseline and at least one Hb measurement during therapy. Overall SVR rate was 42.6% (789/1851). SVR rates were only slightly higher for subjects with an absolute Hb decline >3 g/dL (44.3%, 493/1114) compared to those with maximum Hb declines <3 g/dL (40.2%, 296/737) (p=0.08). In contrast, a significant (p=0.0004) difference in SVR rates was obtained by comparing subjects with Hb declines >2 g/dL (44.6%, 673/1510) with those who experienced Hb declines <2 g/dL (34.0%, 116/341). Similar SVR rates of 46.1% (164/356) and 44.1% (509/1154) in patients with Hb declines >2 g/dL even if they did/did not become anemic (Hb<10 g/dL) strongly support Hb decline, and not anemia, as primary beneficial mechanism improving SVR. As summarized in the table, Hb declines >2 g/dl were significantly associated with higher SVR rates in difficult-to-treat patients, such as subjects elder than 50 years or subjects with high baseline viral load >600.000 IU/ml. Interestingly no beneficial effect was observed in patients with low platelet count (<150/nL), an indicator of advanced fibrosis/cirrhosis. Patients who first developed a Hb decline >2 g/dL during weeks 0-4 were likely to achieve similar SVR (41.3%, 365/883) than those who developed a Hb decline <2 g/dL (44.9%, 386/859). In contrast, a Hb decline >2 g/dL compared to <2 g/dL during weeks 0-4 was associated with a 2-3 fold higher risk of anemia in female (16.6% vs 40.5%) and male patients (7.3% vs 19.0%) when compared with a Hb decline <2 g/dL. Conclusions: Patients with HCV genotype 1 infection and in particular the subgroup of difficult-to-treat patients elder than 50 years or with HVL, achieve up to 15% higher SVR rates when they develop a Hb decline >2 g/dL during Peg2b/RBV therapy. However, patients with low platelet count <150/nL do not achieve this beneficial virologic effect.

Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis

Plentz, Ruben Raphael,Park, Young Nyun,Lechel, André,Kim, Haeryoung,Nellessen, Friederike,Langkopf, Britta Heike Eva,Wilkens, Ludwig,Destro, Annarita,Fiamengo, Barbara,Manns, Michael Peter,Ronca Wiley Subscription Services, Inc., A Wiley Company 2007 Hepatology Vol.45 No.4

<P>Telomere shortening and inactivation of cell cycle checkpoints characterize carcinogenesis. Whether these molecular features coincide at specific stages of human hepatocarcinogenesis is unknown. The preneoplasia–carcinoma sequence of human HCC is not well defined. Small cell changes (SCC) and large cell changes (LCC) are potential precursor lesions. We analyzed hepatocellular telomere length, the prevalence of DNA damage, and the expression of p21 and p16 in biopsy specimens of patients with chronic liver disease (n = 27) that showed different precursor lesions and/or HCC: liver cirrhosis (n = 25), LCC (n = 26), SCC (n = 13), and HCC (n = 13). The study shows a decrease in telomere length in nondysplastic cirrhotic liver compared with normal liver and a further significant shortening of telomeres in LCC, SCC, and HCC. HCC had the shortest telomeres, followed by SCC and LCC. Hepatocytes showed an increased p21 labeling index (p21-LI) at the cirrhosis stage, which remained elevated in most LCC. In contrast, most SCC and HCC showed a strongly reduced p21-LI. Similarly, p16 was strongly expressed in LCC but reduced in SCC and not detectable in HCC. γH2AX-DNA-damage-foci were not detected in LCC but were present in SCC and more frequently in HCC. These data indicate that LCC and SCC represent clonal expansions of hepatocytes with shortened telomeres. Conclusion: The inactivation of cell cycle checkpoints coincides with further telomere shortening and an accumulation of DNA damage in SCC and HCC, suggesting that SCC represent more advanced precursor lesions compared with LCC. (HEPATOLOGY 2007;45:968–976.)</P>

춘계학술대회 : 총회구연 ; 인체의 다단계 간암발생과정에서 틸로미어길이 감소와 p21-checkpoint의 불활성화

( Young Nyun Park ),( Ruben Raphael Plentz ),( Hae Ryoung Kim ),( Friederike Nellessen ),( Britta Heike Eva Langkopf ),( Ludwig Wilkens ),( Annarita Destro ),( Barbara Fiamengo ),( Michael Peter Manns 대한간학회 2007 Clinical and Molecular Hepatology(대한간학회지) Vol.13 No.3(S)

心理環境의 理論的 背景에 관한 硏究

林晩澤 朝鮮大學校 建設技術硏究所 1999 建設技術硏究 Vol.19 No.1

This study aims at clarifying the theoretical background of psychological environment from the historical point of view. The psychological environment is related to not only perception but also cognition, Gestalt psychology, and environmental psychology. The environmental psychology can be defined as the study of interactions of human behavior and physical environment. The problems of the environment and human behavior have to be solved by the several kinds of approaching method not only physical approach but psychological and social phenomena.