Effectiveness and safety of first-generation protease inhibitors in clinical practice: Hepatitis C virus patients with advanced fibrosis.
OBJECTIVE
To evaluates the effectiveness and safety of the first generation, NS3/4A protease inhibitors (PIs) in clinical practice against chronic C virus, especially in patients with advanced fibrosis.


METHODS
Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1, treatment-naïve (TN) or treatment-experienced (TE), who underwent triple therapy with the first generation NS3/4A protease inhibitors, boceprevir (BOC) and telaprevir (TVR), in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up.


RESULTS
One thousand and fifty seven patients were included, 405 (38%) were treated with BOC and 652 (62%) with TVR. Of this total, 30% (n = 319) were TN and the remaining were TE: 28% (n = 298) relapsers, 12% (n = 123) partial responders (PR), 25% (n = 260) null-responders (NR) and for 5% (n = 57) with prior response unknown. The rate of sustained virologic response (SVR) by intention-to-treatment (ITT) was greater in those treated with TVR (65%) than in those treated with BOC (52%) (P < 0.0001), whereas by modified intention-to-treatment (mITT) no were found significant differences. By degree of fibrosis, 56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients, both TN and TE. In the analysis by groups, the TN patients treated with TVR by ITT showed a higher SVR (P = 0.005). However, by mITT there were no significant differences between BOC and TVR. In the multivariate analysis by mITT, the significant SVR factors were relapsers, IL28B CC and non-F4; the type of treatment (BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients, treated with BOC (46%) or with TVR (45%). 28% of the patients interrupted the treatment, mainly by non-viral response (51%): this outcome was more frequent in the TE than in the TN patients (57% vs 40%, P = 0.01). With respect to severe haematological disorders, neutropaenia was more likely to affect the patients treated with BOC (33% vs 20%, P ≤ 0.0001), and thrombocytopaenia and anaemia, the F4 patients (P = 0.000, P = 0.025, respectively).


CONCLUSIONS
In a real clinical practice setting with a high proportion of patients with advanced fibrosis, effectiveness of first-generation PIs was high except for NR patients, with similar SVR rates being achieved by BOC and TVR.
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Javier
J
Salmerón
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Carmen
C
Vinaixa
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Rubén
R
Berenguer
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Juan Manuel
JM
Pascasio
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Juan José
JJ
Sánchez Ruano
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Miguel Ángel
MÁ
Serra
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Ana
A
Gila
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Moisés
M
Diago
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Manuel
M
Romero-Gómez
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
José María
JM
Navarro
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Milagros
M
Testillano
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Conrado
C
Fernández
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Dolores
D
Espinosa
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Isabel
I
Carmona
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
José Antonio
JA
Pons
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Francisco
F
Jorquera
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Francisco Javier
FJ
Rodriguez
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Ramón
R
Pérez
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
José Luis
JL
Montero
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Rafael
R
Granados
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Miguel
M
Fernández
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Ana Belén
AB
Martín
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Paloma
P
Muñoz de Rueda
Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Rosa
R
Quiles
D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D057194:Intention to Treat Analysis; D047908:Intracellular Signaling Peptides and Proteins; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D012008:Recurrence; D012042:Registries; D013030:Spain; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D015415:Biomarkers; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011480:Protease Inhibitors; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus
Advanced fibrosis; Boceprevir; First-generation protease inhibitors; Hepatitis C; Telaprevir