Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

Foster, G.R.; Coppola, C.; Derbala, M.; Ferenci, P.; Orlandini, A.; Reddy, K.R.; Tallarico, L.; Shiffman, M.L.; Ahlers, S.; Bakalos, G.; Hassanein, T.; Basho, J.; Shabanaj, G.; Harxhi, A.; Debzi, N.; Afredj, N.; Guessab, N.; Mahindad, N.; Mahiou, H.; Aissaoui, M.; Al Qameesh, J.; Al Ghandoor, Z.; Assene, C.; Bastens, B.; Brixko, C.; Cool, M.; De Galocsy, C.; Delwaide, J.; George, C.; Laukens, P.; Lefebvre, V.; Mulkay, J.-.; Nevens, F.; Servais, B.; Van Vlierberghe, H.; Horsmans, Y.; Henrion, J.; Sprengers, D.; Michielsen, P.; Bourgeois, S.; Lasser, L.; Langlet, P.; Robaeys, G.; Martinet, J.-.; Warzee, P.; Hoste, P.; Reynaert, H.; Juriens, I.; Decaestecker, J.; Van Der Meersch, F.; Janssens, F.; Ahmetagic, S.; Verhaz, A.; Bevanda, M.; Calkic, L.; Ibrahimpasic, N.; Mesihovic, R.; Mello, C.E.; Ruiz, F.J.; Junior, E.M.; Ferraz, M.L.; Silva, G.; Mendes, C.; Lyra, A.; Silva, M.H.; Gomide, G.; Fernandes, J.C.; Pereira, P.; Correa, M.C.; Teixeira, R.; Yousry, A.; Hanno, A.; Gabr, M.; Omar, A.; Esmat, G.; Karatapanis, S.; Nikolopoulou, V.; Giannoulis, G.; Manolakopoulos, S.; Elefsiniotis, I.; Drakoulis, C.; Dimitroulopoulos, D.; Kanatakis, S.; Ketikoglou, I.; Mimidis, K.; Evgenidis, N.; Akriviades, E.; Vafiadi-Zoubouli, I.; Tsianos, E.; Mela, M.; Orfanou, E.; Mousoulis, G.; Karagiannis, I.; Manesis, E.; Varga, M.; Nemesanszky, E.; Fried, K.; Schuller, J.; Szalay, F.; Lengyel, G.; Tornai, I.; Banyai, T.; Lesch, M.; Nagy, I.; Gervain, J.; Tusnadi, A.; Schneider, F.; Szentgyorgyi, L.; Hunyady, B.; Vincze, A.; Tolvaj, G.; Varkonyi, I.; Makkai, E.; Enyedi, J.; Racz, I.; Hausinger, P.; Vaczi, Z.; Patai, A.; Ozsvar, Z.; Lakner, L.; Ribiczey, P.; Bhalla, A.; Somani, S.; Luaia, R.; Rao, P.; Philip, M.; Lawate, P.; Nagral, A.; Sood, A.; Parikh, S.; Merat, S.; Nassiri-Toosi, M.; Alavian, S.-.; Zali, M.R.; Daryani, N.E.; Drenaggi, D.; Attili, A.F.; Bandiera, F.; Bassi, P.; Bellati, G.; Bellantani, S.; Brunetto, M.; Bruno, S.; Castelli, F.; Castellacci, R.; Cattelan, A.M.; Colombo, M.; Craxi, A.; D'Angelo, S.; Colombo, S.; Demelia, L.; Di Perri, G.; Di Giacomo, A.; Ferrari, C.; Francisci, D.; Casinelli, K.; Ganga, R.; Costa, C.; Mangia, A.; Russo, F.P.; Matarazzo, F.; Mazzella, G.; Mazzeo, M.; Memoli, M.; Montalbano, M.; Montalto, G.; Pieri, A.; Passariello, N.; Picciotto, A.; Pietrangelo, A.; Pirisi, M.; Quirino, T.; Raimondo, G.; Rapaccini, G.L.; Rizzardini, G.; Rizzetto, M.; Russello, M.; Sabusco, G.; Santantonio, T.; Soardo, G.; Amedea, A.; Verucchi, G.; Vinelli, F.; Zignego, A.L.; Zuin, M.; Ascione, A.; Vinci, M.; Pigozzi, M.G.; Tundo, P.; Saracco, G.M.; Amoroso, P.; Andreoni, M.; Colletta, C.; Erne, E.; Megna, A.S.; Biglino, A.; Chiriaco, P.; Foti, G.; Spinzi, G.; D'Amico, E.; Paik, S.W.; Ahn, S.-.; Lee, Y.N.; Kim, Y.; Yang, J.; Han, S.Y.; Varghese, R.; Al Gharabally, A.; Askar, H.; Sharara, A.; Yaghi, C.; Abou Rached, A.; Houmani, Z.; Zaarour, F.; Dohaibi, A.; Ivanovski, L.; Joksimovic, N.; Abbas, Z.; Memon, S.; Mohsin, A.; Masood, S.; Hashmi, Z.; Halota, W.; Deron, Z.; Mazur, W.; Flisiak, R.; Lipczynski, A.; Musialik, J.; Piekarska, A.; Augustyniak, K.; Baka-Cwierz, B.; Simon, K.; Gietka, A.; Berak, H.; Sieklucki, J.; Radowska, D.; Szlauer, B.; Piekos, T.; Olszok, I.; Jablkowski, M.; Orszulak, G.; Warakomska, I.; Aleixo, M.J.; Valente, C.; Macedo, G.; Sarmento-Castro, R.; Roxo, F.; Faria, T.; Mansinho, K.; Velez, J.; Ramos, J.P.; Guerreiro, H.; Alberto, S.; Monteverde, C.; Serejo, F.; Peixe, P.; Malhado, J.; Curescu, M.; Streinu-Cercel, A.; Caruntu, F.; Livia, H.; Preotescu, L.; Arama, V.; Ancuta, I.; Gheorghe, L.; Stanciu, C.; Trifan, A.; Acalovschi, M.; Andreica, V.; Pascu, O.; Lencu, M.; Sporea, I.; Olteanu, D.; Ionita-Radu, F.; Fierbinteanu-Braticevici, C.; Motoc, A.; Silaghi, R.; Musat, M.; Coman, F.; Stan, M.; Cijevschi, C.; Miftode, E.; Delic, D.; Jesic, R.; Nozic, D.; Svorcan, P.; Fabri, M.; Konstantinovic, L.; Pelemis, M.; Jankovic, G.; Todorovic, Z.; Nagorni, A.; Kupcova, V.; Skladany, L.; Szantova, M.; Krkoska, D.; Jarcuska, P.; Schreter, I.; Oltman, M.; Bocakova, J.; Bunganic, I.; Holoman, J.; Giguere, A.; Abdou, A.M.S.

doi:10.1371/journal.pone.0151703

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. Results: SVR24 rates were 46.1 % (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1,2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. Conclusions: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginter-feron alfa-2a/ribavirin.

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort / G.R. Foster, C. Coppola, M. Derbala, P. Ferenci, A. Orlandini, K.R. Reddy, L. Tallarico, M.L. Shiffman, S. Ahlers, G. Bakalos, T. Hassanein, J. Basho, G. Shabanaj, A. Harxhi, N. Debzi, N. Afredj, N. Guessab, N. Mahindad, H. Mahiou, M. Aissaoui, J. Al Qameesh, Z. Al Ghandoor, C. Assene, B. Bastens, C. Brixko, M. Cool, C. De Galocsy, J. Delwaide, C. George, P. Laukens, V. Lefebvre, J.-. Mulkay, F. Nevens, B. Servais, H. Van Vlierberghe, Y. Horsmans, J. Henrion, D. Sprengers, P. Michielsen, S. Bourgeois, L. Lasser, P. Langlet, G. Robaeys, J.-. Martinet, P. Warzee, P. Hoste, H. Reynaert, I. Juriens, J. Decaestecker, F. Van Der Meersch, F. Janssens, S. Ahmetagic, A. Verhaz, M. Bevanda, L. Calkic, N. Ibrahimpasic, R. Mesihovic, C.E. Mello, F.J. Ruiz, E.M. Junior, M.L. Ferraz, G. Silva, C. Mendes, A. Lyra, M.H. Silva, G. Gomide, J.C. Fernandes, P. Pereira, M.C. Correa, R. Teixeira, A. Yousry, A. Hanno, M. Gabr, A. Omar, G. Esmat, S. Karatapanis, V. Nikolopoulou, G. Giannoulis, S. Manolakopoulos, I. Elefsiniotis, C. Drakoulis, D. Dimitroulopoulos, S. Kanatakis, I. Ketikoglou, K. Mimidis, N. Evgenidis, E. Akriviades, I. Vafiadi-Zoubouli, E. Tsianos, M. Mela, E. Orfanou, G. Mousoulis, I. Karagiannis, E. Manesis, M. Varga, E. Nemesanszky, K. Fried, J. Schuller, F. Szalay, G. Lengyel, I. Tornai, T. Banyai, M. Lesch, I. Nagy, J. Gervain, A. Tusnadi, F. Schneider, L. Szentgyorgyi, B. Hunyady, A. Vincze, G. Tolvaj, I. Varkonyi, E. Makkai, J. Enyedi, I. Racz, P. Hausinger, Z. Vaczi, A. Patai, Z. Ozsvar, L. Lakner, P. Ribiczey, A. Bhalla, S. Somani, R. Luaia, P. Rao, M. Philip, P. Lawate, A. Nagral, A. Sood, S. Parikh, S. Merat, M. Nassiri-Toosi, S.-. Alavian, M.R. Zali, N.E. Daryani, D. Drenaggi, A.F. Attili, F. Bandiera, P. Bassi, G. Bellati, S. Bellantani, M. Brunetto, S. Bruno, F. Castelli, R. Castellacci, A.M. Cattelan, M. Colombo, A. Craxi, S. D'Angelo, S. Colombo, L. Demelia, G. Di Perri, A. Di Giacomo, C. Ferrari, D. Francisci, K. Casinelli, R. Ganga, C. Costa, A. Mangia, F.P. Russo, F. Matarazzo, G. Mazzella, M. Mazzeo, M. Memoli, M. Montalbano, G. Montalto, A. Pieri, N. Passariello, A. Picciotto, A. Pietrangelo, M. Pirisi, T. Quirino, G. Raimondo, G.L. Rapaccini, G. Rizzardini, M. Rizzetto, M. Russello, G. Sabusco, T. Santantonio, G. Soardo, A. Amedea, G. Verucchi, F. Vinelli, A.L. Zignego, M. Zuin, A. Ascione, M. Vinci, M.G. Pigozzi, P. Tundo, G.M. Saracco, P. Amoroso, M. Andreoni, C. Colletta, E. Erne, A.S. Megna, A. Biglino, P. Chiriaco, G. Foti, G. Spinzi, E. D'Amico, S.W. Paik, S.-. Ahn, Y.N. Lee, Y. Kim, J. Yang, S.Y. Han, R. Varghese, A. Al Gharabally, H. Askar, A. Sharara, C. Yaghi, A. Abou Rached, Z. Houmani, F. Zaarour, A. Dohaibi, L. Ivanovski, N. Joksimovic, Z. Abbas, S. Memon, A. Mohsin, S. Masood, Z. Hashmi, W. Halota, Z. Deron, W. Mazur, R. Flisiak, A. Lipczynski, J. Musialik, A. Piekarska, K. Augustyniak, B. Baka-Cwierz, K. Simon, A. Gietka, H. Berak, J. Sieklucki, D. Radowska, B. Szlauer, T. Piekos, I. Olszok, M. Jablkowski, G. Orszulak, I. Warakomska, M.J. Aleixo, C. Valente, G. Macedo, R. Sarmento-Castro, F. Roxo, T. Faria, K. Mansinho, J. Velez, J.P. Ramos, H. Guerreiro, S. Alberto, C. Monteverde, F. Serejo, P. Peixe, J. Malhado, M. Curescu, A. Streinu-Cercel, F. Caruntu, H. Livia, L. Preotescu, V. Arama, I. Ancuta, L. Gheorghe, C. Stanciu, A. Trifan, M. Acalovschi, V. Andreica, O. Pascu, M. Lencu, I. Sporea, D. Olteanu, F. Ionita-Radu, C. Fierbinteanu-Braticevici, A. Motoc, R. Silaghi, M. Musat, F. Coman, M. Stan, C. Cijevschi, E. Miftode, D. Delic, R. Jesic, D. Nozic, P. Svorcan, M. Fabri, L. Konstantinovic, M. Pelemis, G. Jankovic, Z. Todorovic, A. Nagorni, V. Kupcova, L. Skladany, M. Szantova, D. Krkoska, P. Jarcuska, I. Schreter, M. Oltman, J. Bocakova, I. Bunganic, J. Holoman, A. Giguere, A.M.S. Abdou. - In: PLOS ONE. - ISSN 1932-6203. - 11:3(2016), pp. e0151703.1-e0151703.20. [10.1371/journal.pone.0151703]

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

Foster G. R.;Coppola C.;Derbala M.;Ferenci P.;Orlandini A.;Reddy K. R.;L. Tallarico;Shiffman M. L.;Ahlers S.;Bakalos G.;Hassanein T.;Basho J.;Shabanaj G.;Harxhi A.;Debzi N.;Afredj N.;Guessab N.;Mahindad N.;Mahiou H.;Aissaoui M.;Al Qameesh J.;Al Ghandoor Z.;Assene C.;Bastens B.;Brixko C.;Cool M.;De Galocsy C.;Delwaide J.;George C.;Laukens P.;Lefebvre V.;Mulkay J. -P.;Nevens F.;Servais B.;Van Vlierberghe H.;Horsmans Y.;Henrion J.;Sprengers D.;Michielsen P.;Bourgeois S.;Lasser L.;Langlet P.;Robaeys G.;Martinet J. -P.;Warzee P.;Hoste P.;Reynaert H.;Juriens I.;Decaestecker J.;Van Der Meersch F.;Janssens F.;Ahmetagic S.;Verhaz A.;Bevanda M.;Calkic L.;Ibrahimpasic N.;Mesihovic R.;Mello C. E.;Ruiz F. J.;Junior E. M.;Ferraz M. L.;Silva G.;Mendes C.;Lyra A.;M.H. Silva;Gomide G.;Fernandes J. C.;P. Pereira;Correa M. C.;R. Teixeira;Yousry A.;Hanno A.;Gabr M.;Omar A.;Esmat G.;Karatapanis S.;Nikolopoulou V.;Giannoulis G.;Manolakopoulos S.;Elefsiniotis I.;Drakoulis C.;Dimitroulopoulos D.;Kanatakis S.;Ketikoglou I.;Mimidis K.;Evgenidis N.;Akriviades E.;Vafiadi-Zoubouli I.;Tsianos E.;Mela M.;Orfanou E.;Mousoulis G.;Karagiannis I.;Manesis E.;Varga M.;Nemesanszky E.;Fried K.;Schuller J.;Szalay F.;Lengyel G.;Tornai I.;Banyai T.;Lesch M.;Nagy I.;Gervain J.;Tusnadi A.;Schneider F.;Szentgyorgyi L.;Hunyady B.;Vincze A.;Tolvaj G.;Varkonyi I.;Makkai E.;Enyedi J.;Racz I.;Hausinger P.;Vaczi Z.;Patai A.;Ozsvar Z.;Lakner L.;Ribiczey P.;Bhalla A.;Somani S.;Luaia R.;Rao P.;Philip M.;Lawate P.;Nagral A.;Sood A.;Parikh S.;Merat S.;Nassiri-Toosi M.;Alavian S. -M.;Zali M. R.;Daryani N. E.;Drenaggi D.;Attili A. F.;Bandiera F.;Bassi P.;Bellati G.;Bellantani S.;Brunetto M.;Bruno S.;Castelli F.;Castellacci R.;Cattelan A. M.;Colombo M.;Craxi A.;S. D'Angelo;Colombo S.;Demelia L.;Di Perri G.;Di Giacomo A.;Ferrari C.;Francisci D.;Casinelli K.;Ganga R.;Costa C.;Mangia A.;Russo F. P.;Matarazzo F.;Mazzella G.;Mazzeo M.;Memoli M.;Montalbano M.;G. Montalto;Pieri A.;Passariello N.;Picciotto A.;Pietrangelo A.;Pirisi M.;T. Quirino;G. Raimondo;Rapaccini G. L.;Rizzardini G.;Rizzetto M.;Russello M.;Sabusco G.;Santantonio T.;Soardo G.;Amedea A.;Verucchi G.;Vinelli F.;Zignego A. L.;M. Zuin;Ascione A.;Vinci M.;Pigozzi M. G.;Tundo P.;Saracco G. M.;Amoroso P.;M. Andreoni;Colletta C.;Erne E.;Megna A. S.;Biglino A.;Chiriaco P.;Foti G.;Spinzi G.;D'amico E.;Paik S. W.;Ahn S. -H.;Lee Y. N.;Kim Y.;Yang J.;Han S. Y.;Varghese R.;Al Gharabally A.;Askar H.;Sharara A.;Yaghi C.;Abou Rached A.;Houmani Z.;Zaarour F.;Dohaibi A.;Ivanovski L.;Joksimovic N.;Abbas Z.;Memon S.;Mohsin A.;Masood S.;Hashmi Z.;Halota W.;Deron Z.;Mazur W.;Flisiak R.;Lipczynski A.;Musialik J.;Piekarska A.;Augustyniak K.;Baka-Cwierz B.;Simon K.;Gietka A.;Berak H.;Sieklucki J.;Radowska D.;Szlauer B.;Piekos T.;Olszok I.;Jablkowski M.;Orszulak G.;Warakomska I.;Aleixo M. J.;Valente C.;Macedo G.;Sarmento-Castro R.;Roxo F.;Faria T.;Mansinho K.;Velez J.;Ramos J. P.;Guerreiro H.;Alberto S.;Monteverde C.;Serejo F.;Peixe P.;Malhado J.;Curescu M.;Streinu-Cercel A.;Caruntu F.;Livia H.;Preotescu L.;Arama V.;Ancuta I.;Gheorghe L.;Stanciu C.;Trifan A.;Acalovschi M.;Andreica V.;Pascu O.;Lencu M.;Sporea I.;Olteanu D.;Ionita-Radu F.;Fierbinteanu-Braticevici C.;Motoc A.;Silaghi R.;Musat M.;Coman F.;Stan M.;Cijevschi C.;Miftode E.;Delic D.;Jesic R.;Nozic D.;Svorcan P.;Fabri M.;Konstantinovic L.;Pelemis M.;Jankovic G.;Todorovic Z.;Nagorni A.;Kupcova V.;Skladany L.;Szantova M.;Krkoska D.;Jarcuska P.;Schreter I.;Oltman M.;Bocakova J.;Bunganic I.;Holoman J.;Giguere A.;Abdou A. M. S.

2016

Abstract

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. Results: SVR24 rates were 46.1 % (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1,2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. Conclusions: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginter-feron alfa-2a/ribavirin.

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	Parole chiave
	
			Adult; Aged; Anemia; Antiviral Agents; Asthenia; Cohort Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Host-Pathogen Interactions; Humans; Interferon-alpha; Male; Middle Aged; Neutropenia; Outcome Assessment (Health Care); Polyethylene Glycols; Proportional Hazards Models; RNA, Viral; Recombinant Proteins; Ribavirin; Withholding Treatment
		
	Settori scientifico-disciplinari dell'articolo
	
			Settore MED/09 - Medicina Interna
		
	Data di pubblicazione
	
			2016
		
	Rivista in ANCE
	
			PLOS ONE
		
	DOI
	
			https://dx.doi.org/10.1371/journal.pone.0151703
		
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