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2. SAT-341 Discovery of a pan-genotypic hepatitis E virus replication inhibitor

Author

Zhang, Xin, primary, Klöhn, Mara, additional, Ouwerkerk-Mahadevan, Sivi, additional, Jagst, Michelle, additional, Vereyken, Liesbeth, additional, Verboven, Peter, additional, Todt, Daniel, additional, Jonckers, Tim H.M., additional, Coelmont, Lotte, additional, Fletcher, Helen, additional, Samby, Kirandeep, additional, Koul, Anil, additional, Neyts, Johan, additional, Steinmann, Eike, additional, and Kaptein, Suzanne J.F., additional

Published
2024
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5. Daclatasvir plus simeprevir with or without ribavirin for the treatment of chronic hepatitis C virus genotype 1 infection

Author

Zeuzem, Stefan, Hézode, Christophe, Bronowicki, Jean-Pierre, Loustaud-Ratti, Veronique, Gea, Francisco, Buti, Maria, Olveira, Antonio, Banyai, Tivadar, Al-Assi, M. Tarek, Petersen, Joerg, Thabut, Dominique, Gadano, Adrian, Pruitt, Ronald, Makara, Mihály, Bourlière, Marc, Pol, Stanislas, Beumont-Mauviel, Maria, Ouwerkerk-Mahadevan, Sivi, Picchio, Gaston, Bifano, Marc, M<ce:sup loc='post">c</ce:sup>Phee, Fiona, Boparai, Navdeep, Cheung, Kin, Hughes, Eric A., and Noviello, Stephanie

Published
2016
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9. Simeprevir versus telaprevir with peginterferon and ribavirin in previous null or partial responders with chronic hepatitis C virus genotype 1 infection (ATTAIN): a randomised, double-blind, non-inferiority phase 3 trial

Author

Reddy, K Rajender, Zeuzem, Stefan, Zoulim, Fabien, Weiland, Ola, Horban, Andrzej, Stanciu, Carol, Villamil, Federico Guillermo, Andreone, Pietro, George, Jacob, Dammers, Elisabeth, Fu, Min, Kurland, Darryl, Lenz, Oliver, Ouwerkerk-Mahadevan, Sivi, Verbinnen, Thierry, Scott, Jane, and Jessner, Wolfgang

Published
2015
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10. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study

Author

Lawitz, Eric, Sulkowski, Mark S, Ghalib, Reem, Rodriguez-Torres, Maribel, Younossi, Zobair M, Corregidor, Ana, DeJesus, Edwin, Pearlman, Brian, Rabinovitz, Mordechai, Gitlin, Norman, Lim, Joseph K, Pockros, Paul J, Scott, John D, Fevery, Bart, Lambrecht, Tom, Ouwerkerk-Mahadevan, Sivi, Callewaert, Katleen, Symonds, William T, Picchio, Gaston, Lindsay, Karen L, Beumont, Maria, and Jacobson, Ira M

Published
2014
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11. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial

Author

Manns, Michael, Marcellin, Patrick, Poordad, Fred, de Araujo, Evaldo Stanislau Affonso, Buti, Maria, Horsmans, Yves, Janczewska, Ewa, Villamil, Federico, Scott, Jane, Peeters, Monika, Lenz, Oliver, Ouwerkerk-Mahadevan, Sivi, De La Rosa, Guy, Kalmeijer, Ronald, Sinha, Rekha, and Beumont-Mauviel, Maria

Published
2014
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12. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial

Author

Jacobson, Ira M, Dore, Gregory J, Foster, Graham R, Fried, Michael W, Radu, Monica, Rafalsky, Vladimir V, Moroz, Larysa, Craxi, Antonio, Peeters, Monika, Lenz, Oliver, Ouwerkerk-Mahadevan, Sivi, De La Rosa, Guy, Kalmeijer, Ronald, Scott, Jane, Sinha, Rekha, and Beumont-Mauviel, Maria

Published
2014
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28. JNJ-4178 (AL-335, Odalasvir, and Simeprevir) for 6 or 8 Weeks in Hepatitis C Virus-Infected Patients Without Cirrhosis: OMEGA-1

Author

Zeuzem, Stefan, Bourgeois, Stefan, Greenbloom, Susan, Buti, Maria, Aghemo, Alessio, Lampertico, Pietro, Janczewska, Ewa, Lim, Seng Gee, Moreno, Christophe, Buggisch, Peter, Tam, Edward, Corbett, Chris, Willems, Wouter, Vijgen, Leen, Fevery, Bart, Ouwerkerk-Mahadevan, Sivi, Ackaert, Oliver, Beumont, Maria, Kalmeijer, Ronald, Sinha, Rekha, Biermer, Michael, Zeuzem, Stefan, Bourgeois, Stefan, Greenbloom, Susan, Buti, Maria, Aghemo, Alessio, Lampertico, Pietro, Janczewska, Ewa, Lim, Seng Gee, Moreno, Christophe, Buggisch, Peter, Tam, Edward, Corbett, Chris, Willems, Wouter, Vijgen, Leen, Fevery, Bart, Ouwerkerk-Mahadevan, Sivi, Ackaert, Oliver, Beumont, Maria, Kalmeijer, Ronald, Sinha, Rekha, and Biermer, Michael

Abstract

The combination of three direct-acting antiviral agents (AL-335, odalasvir, and simeprevir: JNJ-4178 regimen) for 6 or 8 weeks demonstrated good efficacy and safety in a phase IIa study in chronic hepatitis C virus (HCV) genotype (GT)-1-infected patients without cirrhosis and has now been evaluated in a larger phase IIb study, OMEGA-1. This multicenter, randomized, open-label study (NCT02765490) enrolled treatment-naïve and interferon (±ribavirin) treatment-experienced patients with HCV GT1, 2, 4, 5, or 6 infection. Patients with HCV GT3 infection and/or liver cirrhosis were excluded. Patients received AL-335 800 mg, odalasvir 25 mg, and simeprevir 75 mg once daily for 6 or 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). In total, 365 patients (GT1a, 29.3%; GT1b, 42.5%; GT2, 12.3%; GT4, 14.2%; GT5, 1.4%; GT6, 0%) were randomized to receive 6 weeks (n = 183) or 8 weeks (n = 182) of treatment. SVR12 rates after 6 weeks (98.9%) or 8 weeks (97.8%) of treatment were noninferior to a historical control (98%). Viral relapse occurred in 5 patients (1.4%; 4 with HCV GT2c; 1 with GT1a). With the exception of 4 patients in the 8-week group, including 3 patients with missing data at the SVR24 timepoint, all patients who achieved SVR12 also achieved SVR24. One GT1a-infected patient experienced late viral relapse after achieving SVR18. Most adverse events (AEs) were mild with no treatment-related serious AEs. All randomized patients completed treatment. Conclusion: In HCV-infected patients, 6 and 8 weeks of treatment with JNJ-4178 resulted in SVR12 rates of 98.9% and 97.8%, respectively, and was well tolerated., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2019

29. Telaprevir combination therapy in HCV/HIV co‐infected patients (INSIGHT study): sustained virologic response at 12 weeks final analysis

Author

Montes, Marisa, Nelson, Mark, Girard, Pierre Marie, Sasadeusz, Joe, Horban, Andrzej, Grinsztejn, Beatriz, Zakharova, Natalia, Rivero, Antonio, Lathouwers, Erkki, Janssen, Katrien, Ouwerkerk?Mahadevan, Sivi, and Witek, James

Subjects
Interferon -- Patient outcomes, Ribavirin -- Patient outcomes, Drug therapy, Combination -- Methods -- Patient outcomes, Hepatitis C -- Diagnosis -- Drug therapy, HIV infection -- Diagnosis -- Drug therapy, Health
Abstract

Introduction: We report the SVR12 final analysis of a phase 3 study of telaprevir in combination with peginterferon (P)/ribavirin (R) in HCV‐genotype 1, treatment‐naïve and ‐experienced patients with HCV/HIV co‐infection (INSIGHT). Materials and Methods: Patients receiving stable, suppressive HIV antiretroviral (ARV) therapy, containing atazanavir/ritonavir, efavirenz, darunavir/ritonavir, raltegravir, etravirine or rilpivirine, received telaprevir 750 mg q8h (1125 mg q8h if on efavirenz) plus P (180 µg once‐weekly) and R (800 mg/day) for 12 weeks, followed by an additional 12 weeks (non‐cirrhotic HCV treatment‐naïve and relapse patients with extended rapid viral response [eRVR]) or 36 weeks (all others) of PR alone. Analysis was performed when all patients had completed the follow‐up visit of 12 weeks after last planned dose. Results: One hundred sixty‐two patients were enrolled and treated (65 efavirenz, 59 atazanavir/ritonavir, 17 darunavir/ritonavir, 17 raltegravir, 4 etravirine). Mean age was 45 years, 78% were male, 92% were Caucasian; mean CD4 count was 687 cells/mm[sup.3]. Sixty four patients (40%) were HCV treatment‐naïve and 98 (60%) were treatment experienced (29 relapsers, 18 partial responders and 51 null responders). 64% were subtype 1a. 30% had bridging fibrosis (17%) or cirrhosis (13%). 19% of patients discontinued telaprevir, including 9% due to an adverse event (AE), 8% reaching a virologic endpoint and 2% for other reasons (non compliance or not defined). Treatment responses are shown in Table 1. There were no HIV RNA breakthroughs. Most frequently reported (≥20% patients) AEs were pruritus 43%; fatigue 27%; rash 34%, anorectal events 30% and influenza‐like illness (25%). Anemia was reported in 15% of patients; grade ≥3 haemoglobin decrease occurred in 2.5% of patients. 6% of patients experienced serious AEs. Conclusions: In this phase 3 study of HIV‐infected, HCV treatment‐naïve and ‐experienced patients, 49% achieved eRVR and 57% reached SVR12. In patients with an eRVR, SVR12 rates were >80%, irrespective of prior treatment history., Table 1: HCV RNA viral responses (Snapshot) Undetectable HCV RNA*, n (%) Treatment naïve (N=64) Prior relapser (N=29) Prior partial responder (N=18) Prior null responder (N=51) Overall (N=162) Response by [...]

Published
2014
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31. Clinical impact of pharmacokinetic interactions between the HCV protease inhibitor simeprevir and frequently used concomitant medications

Author

Marra, Fiona, primary, Höner zu Siederdissen, Christoph, additional, Khoo, Saye, additional, Back, David, additional, Schlag, Michael, additional, Ouwerkerk-Mahadevan, Sivi, additional, Bicer, Ceyhun, additional, Lonjon-Domanec, Isabelle, additional, Jessner, Wolfgang, additional, Beumont-Mauviel, Maria, additional, Kalmeijer, Ronald, additional, and Cornberg, Markus, additional

Published
2018
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32. Pharmacokinetic Interactions between Simeprevir and Ledipasvir in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients without Cirrhosis Treated with a Simeprevir-Sofosbuvir-Ledipasvir Regimen

Author

Bourgeois, Stefan, primary, Horsmans, Yves, additional, Nevens, Frederik, additional, van Vlierberghe, Hans, additional, Moreno, Christophe, additional, Beumont, Maria, additional, Vijgen, Leen, additional, van Eygen, Veerle, additional, Luo, Donghan, additional, Hillewaert, Vera, additional, Van Remoortere, Pieter, additional, van de Logt, Jolanda, additional, and Ouwerkerk-Mahadevan, Sivi, additional

Published
2017
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33. Efficacy, safety, and pharmacokinetics of simeprevir, daclatasvir, and ribavirin in patients with recurrent hepatitis C virus genotype 1b infection after orthotopic liver transplantation: The Phase II SATURN study

Author

Forns, Xavier, primary, Berenguer, Marina, additional, Herzer, Kerstin, additional, Sterneck, Martina, additional, Donato, Maria Francesca, additional, Andreone, Pietro, additional, Fagiuoli, Stefano, additional, Cieciura, Tomasz, additional, Durlik, Magdalena, additional, Calleja, Jose Luis, additional, Mariño, Zoe, additional, Shukla, Umesh, additional, Verbinnen, Thierry, additional, Lenz, Oliver, additional, Ouwerkerk-Mahadevan, Sivi, additional, Peeters, Monika, additional, Janssen, Katrien, additional, Kalmeijer, Ronald, additional, and Jessner, Wolfgang, additional

Published
2017
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34. Pharmacokinetic interactions between simeprevir and ledipasvir in treatment-naive hepatitis C virus genotype 1-infected patients without cirrhosis treated with a simeprevir-sofosbuvir-ledipasvir regimen

Author

Bourgeois, Stefan, Hillewaert, Vera, Van Remoortere, Pieter, Van De Logt, Jolanda, Ouwerkerk-Mahadevan, Sivi, Horsmans, Y., Nevens, Frederik, Van Vlierberghe, Hans, Moreno, Christophe, Beumont, Maria, Vijgen, Leen, Van Eygen, Veerle, Luo, Donghan, Bourgeois, Stefan, Hillewaert, Vera, Van Remoortere, Pieter, Van De Logt, Jolanda, Ouwerkerk-Mahadevan, Sivi, Horsmans, Y., Nevens, Frederik, Van Vlierberghe, Hans, Moreno, Christophe, Beumont, Maria, Vijgen, Leen, Van Eygen, Veerle, and Luo, Donghan

Abstract

Interactions between simeprevir (hepatitis C virus [HCV] NS3/4A protease inhibitor) and ledipasvir (HCV NS5A replication complex inhibitor) were investigated in treatment-naive HCV genotype 1-infected patients without cirrhosis, treated with simeprevir-sofosbuvir-ledipasvir in a two-panel, phase 2, open-label study. Patients had stable background treatment with sofosbuvir (400 mg once daily [QD]). In panel 1 (n 20), the effect of ledipasvir (90 mg QD) on simeprevir (150 mg QD) was studied. Patients received simeprevir and sofosbuvir from days 1 to 14; steady-state pharmacokinetics (PK) of simeprevir was assessed (day 14). On day 15, ledipasvir was added and steady-state PK of simeprevir in the combination was evaluated (day 28). In panel 2 (n 20), the effect of simeprevir on ledipasvir was investigated. From days 1 to 14, patients received ledipasvir and sofosbuvir and steady-state PK of ledipasvir was assessed (day 14). On day 15, simeprevir was added and a full PK profile was obtained (day 28). The least-squares mean maximum plasma concentration and area under the concentration-time curve (90% confidence interval) increased 2.3-fold (2.0- to 2.8-fold) and 3.1-fold (2.4- to 3.8-fold) for simeprevir, respectively (panel 1), and 1.6-fold (1.4- to 1.9-fold) and 1.7-fold (1.6- to 2.0-fold) for ledipasvir, respectively (panel 2), in the presence versus the absence of the other drug. All patients achieved sustained virologic responses 12 weeks after treatment end. Adverse events, mainly grade 1/2, occurred in 80% of patients; the most common was photosensitivity (45%). Due to the magnitude of interaction and the limited amount of safety data available, the use of this treatment combination is not recommended. (This study has been registered at ClinicalTrials.gov under registration no. NCT02421211.), SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2017

36. Ribavirin concentration determines treatment success of first-generation DAA-based chronic HCV therapy

Author

Apotheek Klinische Farmacie, De Kanter, Clara T M M, Buti, Maria, DeMasi, Ralph, Ouwerkerk-Mahadevan, Sivi, Dofferhoff, Anton S M, Witek, James, Drenth, Joost P H, Zeuzem, Stefan, Burger, David M., Apotheek Klinische Farmacie, De Kanter, Clara T M M, Buti, Maria, DeMasi, Ralph, Ouwerkerk-Mahadevan, Sivi, Dofferhoff, Anton S M, Witek, James, Drenth, Joost P H, Zeuzem, Stefan, and Burger, David M.

Published
2016

38. Telaprevir-based therapy in patients coinfected with chronic hepatitis C virus infection and HIV: INSIGHT study

Author

Montes, Maria Luisa, primary, Nelson, Mark, additional, Girard, Pierre-Marie, additional, Sasadeusz, Joe, additional, Horban, Andrzej, additional, Grinsztejn, Beatriz, additional, Zakharova, Natalia, additional, Rivero, Antonio, additional, Durant, Jacques, additional, Ortega-Gonzalez, Enrique, additional, Lathouwers, Erkki, additional, Janssen, Katrien, additional, Ouwerkerk-Mahadevan, Sivi, additional, Witek, James, additional, and González-García, Juan, additional

Published
2015
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41. Sa2072 Simeprevir (TMC435) With Peginterferon/Ribavirin for Chronic HCV Genotype-1 Infection in Treatment-Nai;auve Patients: Results From QUEST-1, a Phase III Trial

Author

Jacobson, Ira M., primary, Dore, Gregory J., additional, Foster, Graham, additional, Fried, Michael W., additional, Radu, Monica N., additional, Rafalskiy, Vladimir V, additional, Moroz, Larysa, additional, Craxi;ag, Antonio, additional, Peeters, Monika, additional, Lenz, Oliver, additional, Ouwerkerk-Mahadevan, Sivi, additional, Kalmeijer, Ronald, additional, and Beumont-Mauviel, Maria, additional

Published
2013
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42. 869a Simeprevir (TMC435) With Peginterferon/Ribavirin for Treatment of Chronic HCV Genotype-1 Infection in Treatment-Naive Patients: Results From QUEST-2, a Phase III Trial

Author

Poordad, Fred, primary, Manns, Michael P., additional, Marcellin, Patrick, additional, de Araujo, Evaldo Stanislau Affonso, additional, Buti, Maria, additional, Horsmans, Yves, additional, Janczewska, Ewa, additional, Villamil, Federico, additional, Peeters, Monika, additional, Lenz, Oliver, additional, Ouwerkerk-Mahadevan, Sivi, additional, Kalmeijer, Ronald, additional, and Beumont-Mauviel, Maria, additional

Published
2013
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43. 869b Simeprevir (TMC435) With Peginterferon/Ribavirin for Treatment of Chronic HCV Genotype 1 Infection in Patients Who Relapsed After Previous Interferon-Based Therapy: Results From PROMISE, a Phase III Trial

Author

Lawitz, Eric, primary, Forns, Xavier, additional, Zeuzem, Stefan, additional, Gane, Edward, additional, Bronowicki, Jean-Pierre, additional, Andreone, Pietro, additional, Horban, Andrzej, additional, Brown, Ashley, additional, Peeters, Monika, additional, Lenz, Oliver, additional, Ouwerkerk-Mahadevan, Sivi, additional, Kalmeijer, Ronald, additional, and Beumont-Mauviel, Maria, additional

Published
2013
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44. Discovery of novel and selective tertiary alcohol containing inhibitors of the norepinephrine transporter

Author

Cases-Thomas, Manuel J., primary, Masters, John J., additional, Walter, Magnus W., additional, Campbell, Gordon, additional, Haughton, Louise, additional, Gallagher, Peter T., additional, Dobson, David R., additional, Mancuso, Vincent, additional, Bonnier, Benjamin, additional, Giard, Thierry, additional, Defrance, Thierry, additional, Vanmarsenille, Michel, additional, Ledgard, Andrew, additional, White, Craig, additional, Ouwerkerk-Mahadevan, Sivi, additional, Brunelle, Francoise J., additional, Dezutter, Nancy A., additional, Herbots, Camy A., additional, Lienard, Joel Y., additional, Findlay, Jeremy, additional, Hayhurst, Lorna, additional, Boot, John, additional, Thompson, Linda K., additional, and Hemrick-Luecke, Susan, additional

Published
2006
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45. Ribavirin Concentration Determines Treatment success of First-Generation DAA-Based Chronic HCV Therapy

Author

De Kanter, Clara TMM, Buti, Maria, DeMasi, Ralph, Ouwerkerk-Mahadevan, Sivi, Dofferhoff, Anton SM, Witek, James, Drenth, Joost PH, Zeuzem, Stefan, and Burger, David M

Abstract

Background Monitoring ribavirin concentrations during hepatitis C treatment with dual therapy can help optimize treatment response and minimize anaemia. A defined therapeutic range for ribavirin during direct-acting antiviral-based therapies is lacking. This analysis explores whether a therapeutic range for ribavirin concentrations can be defined in patients treated with boceprevir- or telaprevir-based triple therapies.Methods Treatment-naive patients from ADVANCE, ILLUMINATE, OPTIMIZE and SPRINT-2, and treatment-experienced patients from RESPOND-2 were included. Multivariable logistic regression analyses were performed to evaluate whether ribavirin concentrations were an independent predictor of sustained virological response or anaemia. Optimal cutoff values and the percentage of patients within the proposed therapeutic range were determined, along with the associated chance of response.Results Overall, 1,502 patients were included. In both regimens, ribavirin concentrations were significantly associated with anaemia (haemoglobin level <10 g/dl) at all time points (1.75 < odds ratio [OR] <2.45) and sustained virological response was associated with ribavirin concentrations at week 8 (OR=1.43 for telaprevir and 1.78 for boceprevir). A therapeutic range for ribavirin at week 8 of 2.2–3.5 mg/l was defined for telaprevir treatment. Of the 48% of patients with a concentration within this range, 81% achieved sustained virological response and only 5.1% reported anaemia. For boceprevir treatment, the week 8 optimal range was defined as 2.2–3.6 mg/l and 50% of patients had a concentration within this range, of whom 69% achieved sustained virological response and 46% developed anaemia.Conclusions We established the therapeutic range for ribavirin in boceprevir- and telaprevir-based therapy that balances safety and efficacy.

Published
2016
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48. Inhibition of Glutathione Conjugation by Glutathione Analogues in the Perfused Rat Liver

Author

Ouwerkerk-Mahadevan, Sivi, Tirona, Rommel G., Ripping, Richard A., Ploemen, Jan H.T.M., van Bladeren, Peter J., Pang, K.Sandy, van Boom, Jacques H., and Mulder, Gerard J.

Abstract

To assess the role of GST’s (glutathione S-transferases) in the (de)toxification of their substrates, an in vivoactive inhibitor based on the structure of glutathione (GSH), γ-L-glutamyl-α-(D-2-aminoadipyl)-N-2-heptylamine monoethyl ester (Et-R-Hep), was developed. To increase its effectivity, analogues esterified with alkyl chains of varying lengths and one diesterified derivative (DiEt-R-Hep) were synthesized. The unesterified analogue, R-Hep, was also tested. Their isoenzyme selectivity was characterized using purified rat GST isoenzymes. Furthermore, the extent of inhibition of the GSH conjugation of (RS)-2-bromoisovalerylurea (BIU) was evaluated in rat liver cytosol, isolated hepatocytes, and in liver perfusions. All compounds inhibited Alpha- (1–1 and 2–2) more effectively than Mu (3–3 and 4–4) class GSTs; Pi-(5–5) and Theta (7–7) classes were minimally inhibited. The unesterified R-Hep was the most effective inhibitor towards purified isoenzymes; its Kivalue towards GST 3–3 (S-BIU as substrate) was 27 μM. The mono ethyl ester derivative, Et-R-Hep (Ki270 μM for 3–3), was the most potent inhibitor in hepatocytes and in the perfused liver: 50 μM inhibited the conjugation of (S)-BIU by 50%. Longer ester chains or diesterification did not increase the inhibitory potency; R-Hep had less inhibitory activity. In all systems, only the (S)-enantiomer of BIU, which is conjugated mainly by Alpha class GSTs, was inhibited, confirming Alpha isoenzyme selective inhibition.

Published
1997
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49. Efficacy of telaprevir-based therapy in stable liver transplant patients with chronic genotype 1 hepatitis C

Author

Forns, Xavier, Samuel, Didier, Mutimer, David, Fagiuoli, Stefano, Navasa, Miguel, Kosh Agarwal, Berenguer, Marina, Colombo, Massimo, Herzer, Kerstin, Nevens, Frederik, Daems, Bjorn, Janssen, Katrien, Ouwerkerk-Mahadevan, Sivi, Kimko, Holly, Lathouwers, Erkki, Witek, James, Solingen-Ristea, Rodica, Forns, X, Samuel, D, Mutimer, D, Fagiuoli, S, Navasa, M, Agarwal, K, Berenguer, M, Colombo, M, Herzer, K, Nevens, F, Daems, B, Janssen, K, Ouwerkerk-Mahadevan, S, Kimko, H, Lathouwers, E, Witek, J, and van Solingen-Ristea, R

Subjects
Adult, Graft Rejection, Male, Genotype, Sustained Virologic Response, Medizin, Specialties of internal medicine, Hepacivirus, Antiviral Agents, Tacrolimus, Polyethylene Glycols, Telaprevir, Ribavirin, Humans, Hepatitis C infection, Liver transplant, Aged, Hepatitis C, Chronic, Middle Aged, Viral Load, Liver Transplantation, Treatment Outcome, RC581-951, Cyclosporine, RNA, Viral, Drug Therapy, Combination, Female, Interferons, Oligopeptides, Immunosuppressive Agents
Abstract

Background and rationale. The REPLACE study (NCT01571583) investigated telaprevir-based triple therapy in patients who have recurrent genotype 1 hepatitis C virus (HCV) infection following liver transplantation and are on a stable immunosuppressant regimen of tacrolimus or cyclosporin A. Patients received telaprevir 750 mg 8-hourly with pegylated interferon 180 mu g weekly and ribavirin 600 mg daily, followed by a further 36 weeks of pegylated interferon and ribavirin alone and 24 weeks of follow-up. Efficacy (sustained virological response [SVR] 12 weeks after last planned study dose), safety and tolerability of telaprevir throughout the study were assessed. Pharmacokinetics of telaprevir, tacrolimus and cyclosporin A were also examined. Results: In total, 74 patients were recruited. Overall, 72% (53/74; 95% CI: 59.9 to 81.5) of patients achieved SVR at 12 weeks following completion of treatment. Anticipated increases in plasma concentrations of tacrolimus and cyclosporin A occurred during telaprevir treatment and were successfully managed through immunosuppressant dose reduction and, for tacrolimus, reduced dosing frequency. Safety and tolerability of telaprevir-based triple therapy were generally comparable with previous data in non-transplant patients, although rates of reported anemia (55% [41/74]) were higher. Elevated plasma creatinine (46% [34/74]) was observed during REPLACE - consistent with the post-liver transplant population and the co-administered immunosuppressants. Conclusion: Telaprevir-based triple therapy in patients with recurrent genotype 1 HCV infection following liver transplantation produced high rates of SVR. Therapeutic concentrations of immunosuppressants were maintained successfully through dose modification during telaprevir treatment.

50. Efficacy, safety, and pharmacokinetics of simeprevir, daclatasvir, and ribavirin in patients with recurrent hepatitis C virus genotype 1b infection after orthotopic liver transplantation: The Phase II SATURN study

Author

Martina Sterneck, Zoe Mariño, Katrien Janssen, Sivi Ouwerkerk-Mahadevan, Marina Berenguer, T. Cieciura, Jose Luis Calleja, Pietro Andreone, Oliver Lenz, Xavier Forns, Magdalena Durlik, Umesh Shukla, Thierry Verbinnen, Kerstin Herzer, Stefano Fagiuoli, W. Jessner, R. Kalmeijer, Maria Francesca Donato, Monika Peeters, Forns, X, Berenguer, M, Herzer, K, Sterneck, M, Donato, M, Andreone, P, Fagiuoli, S, Cieciura, T, Durlik, M, Calleja, J, Marino, Z, Shukla, U, Verbinnen, T, Lenz, O, Ouwerkerk-Mahadevan, S, Peeters, M, Janssen, K, Kalmeijer, R, Jessner, W, Forns, Xavier, Berenguer, Marina, Herzer, Kerstin, Sterneck, Martina, Donato, Maria Francesca, Andreone, Pietro, Fagiuoli, Stefano, Cieciura, Tomasz, Durlik, Magdalena, Calleja, Jose Lui, Mariño, Zoe, Shukla, Umesh, Verbinnen, Thierry, Lenz, Oliver, Ouwerkerk-Mahadevan, Sivi, Peeters, Monika, Janssen, Katrien, Kalmeijer, Ronald, and Jessner, Wolfgang

Subjects
Graft Rejection, Male, Simeprevir, hepatitis C virus, Pyrrolidines, medicine.medical_treatment, Medizin, Hepacivirus, Liver transplantation, medicine.disease_cause, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, Medicine, hepatitis C viru, liver transplantation, Imidazoles, Valine, Middle Aged, Viral Load, Treatment Outcome, surgical procedures, operative, Infectious Diseases, 030220 oncology & carcinogenesis, Cyclosporine, RNA, Viral, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, Immunosuppressive Agents, medicine.drug, Adult, medicine.medical_specialty, Daclatasvir, Genotype, ribavirin, Hepatitis C virus, simeprevir, Antiviral Agents, Tacrolimus, 03 medical and health sciences, Internal medicine, Humans, daclatasvir, Adverse effect, Aged, Transplantation, business.industry, Ribavirin, Interferon-alpha, Hepatitis C, Chronic, chemistry, Concomitant, Immunology, Carbamates, business
Abstract

Background Recurrent hepatitis C virus (HCV) infection following liver transplantation is associated with accelerated progression to graft failure and reduced patient survival. Methods The Phase II, open-label SATURN study (NCT01938625) investigated the combination of simeprevir (SMV), daclatasvir (DCV), and ribavirin (RBV) administered for 24 weeks in 35 patients with recurrent HCV genotype (GT) 1b infection after orthotopic liver transplantation (OLT). Results High rates of both on-treatment and sustained virologic response 12 weeks after end of treatment (SVR12) were achieved in patients who were either treatment-naive or had failed post-OLT treatment with peginterferon and RBV. Overall, 91% of patients (32/35) achieved SVR12. The combination was generally well tolerated, with an adverse event profile consistent with that observed in previous clinical trials of SMV or DCV separately. Co-administration of SMV with cyclosporine resulted in significantly increased SMV plasma exposures, which was not the case with the co-administration of SMV with tacrolimus. Therefore, the concomitant use of SMV with cyclosporine is not recommended. Conclusion The interferon-free combination of SMV, DCV, and RBV administered for 24 weeks was shown to be effective and well tolerated in the treatment of post-OLT HCV GT1b-infected patients. This article is protected by copyright. All rights reserved.

Published
2017

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