AIM To determine the number of mutations in the NS5 A region of the hepatitis C virus(HCV) and its relationship to the response to antiviral therapy in patients with chronic hepatitis C genotype 1 who are non-responde...AIM To determine the number of mutations in the NS5 A region of the hepatitis C virus(HCV) and its relationship to the response to antiviral therapy in patients with chronic hepatitis C genotype 1 who are non-responders to two or more treatments. METHODS Sequences within HCV NS5 A [PKR binding domain(PKRBD) and the interferon-sensitivity-determining region(ISDR)] were analysed via direct sequencing in a selected cohort of 72 patients, with a total of 201 treatments [interferon-alpha(IFN-α), n = 49; IFN-α + ribavirin(RBV), n = 75; pegylated(peg) IFN-α + RBV, n = 47; first-generation direct-acting antivirals(DAAs), n = 13; and second-generation DAAs, n = 17]. Of these, 48/201 achieved a sustained virological response(SVR) and 153/201 achieved no virological response(NVR).RESULTS For both regions, treatments resulting in SVR were associated with more baseline mutations than were treatments resulting in NVR(SVR vs NVR; PKRBD: 5.82 ± 3 vs 4.86 ± 2 mutations, P = 0.045; ISDR: 2.65 ± 2 vs 1.51 ± 1.7 mutations, P = 0.005). A decrease or no change in the number of mutations over time between treatments in the PKRBD or ISDR, as shown by sequencing, was associated with patients who usually failed to respond to treatment(PKRBD, P = 0.02; ISDR, P = 0.001). Moreover, patients showing a post-treatment baseline viral load > 600000 IU/m L and increased ISDR mutations with respect to the previous treatment were 9.21 times more likely to achieve SVR(P = 0.001). CONCLUSION The obtained results show that among patients who have shown no response to two or more antiviral treatments, the likelihood of achieving SVR increases with the genetic variability in the ISDR region(≥ 2 mutations or number of substitutions from the HCV-J and HCV-1 prototype), especially when the viral load is greater than 600000 IU/m L.展开更多
AIM: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 stu...AIM: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-na?ve(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(m ITT) 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 m ITT there were no significant differences between BOC and TVR. In the multivariate analysis by m ITT,the significant SVR factors were relapsers,IL28 B 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). CONCLUSION: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.展开更多
基金Supported by“Consejería de Salud de la Junta de Andalucía”,No.PI0137/07“Instituto de Salud CarlosⅢ”,No.FISIntrasalud PI010/717
文摘AIM To determine the number of mutations in the NS5 A region of the hepatitis C virus(HCV) and its relationship to the response to antiviral therapy in patients with chronic hepatitis C genotype 1 who are non-responders to two or more treatments. METHODS Sequences within HCV NS5 A [PKR binding domain(PKRBD) and the interferon-sensitivity-determining region(ISDR)] were analysed via direct sequencing in a selected cohort of 72 patients, with a total of 201 treatments [interferon-alpha(IFN-α), n = 49; IFN-α + ribavirin(RBV), n = 75; pegylated(peg) IFN-α + RBV, n = 47; first-generation direct-acting antivirals(DAAs), n = 13; and second-generation DAAs, n = 17]. Of these, 48/201 achieved a sustained virological response(SVR) and 153/201 achieved no virological response(NVR).RESULTS For both regions, treatments resulting in SVR were associated with more baseline mutations than were treatments resulting in NVR(SVR vs NVR; PKRBD: 5.82 ± 3 vs 4.86 ± 2 mutations, P = 0.045; ISDR: 2.65 ± 2 vs 1.51 ± 1.7 mutations, P = 0.005). A decrease or no change in the number of mutations over time between treatments in the PKRBD or ISDR, as shown by sequencing, was associated with patients who usually failed to respond to treatment(PKRBD, P = 0.02; ISDR, P = 0.001). Moreover, patients showing a post-treatment baseline viral load > 600000 IU/m L and increased ISDR mutations with respect to the previous treatment were 9.21 times more likely to achieve SVR(P = 0.001). CONCLUSION The obtained results show that among patients who have shown no response to two or more antiviral treatments, the likelihood of achieving SVR increases with the genetic variability in the ISDR region(≥ 2 mutations or number of substitutions from the HCV-J and HCV-1 prototype), especially when the viral load is greater than 600000 IU/m L.
文摘AIM: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-na?ve(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(m ITT) 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 m ITT there were no significant differences between BOC and TVR. In the multivariate analysis by m ITT,the significant SVR factors were relapsers,IL28 B 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). CONCLUSION: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.
