Changes in the epidemiology and distribution of the hepatitis C virus genotypes in North-Eastern Spain over the last 35 years / Cambios en la epidemiología y distribución de los genotipos del virus de la hepatitis C en el nordeste de España durante los últimos 35 años

Background: Genotypic distribution and epidemiology of HCV infection in Western Europe countries has changed over the last decades. Aim: To establish the local genotypic profile and characterize the associated demographic variables. Material and method: All the genotyping from 1988 to 2015 were considered. Associated demographic variables were included in logistic regression models. Genotyping was carried out with updated commercial kits. Results: Genotype 1b was the most prevalent (42.4%) followed by 1a (22.5%), 3 (18.6%), 4 (10.6%) and 2 (4.6%). The prevalence of 1a was higher in males, in patients younger than 45 and in intravenous drug users (IDU). 1b was more frequent in older than 45, with transfusion-associated and parenteral/nosocomial infections and in immigrants from Eastern Europe. Genotype 2 was highly prevalent in the postransfusional route (54.9%). Genotype 3 prevalence was high in males, in patients younger than 45, in IDU (69.3%) and in Asian and Eastern European immigrants. Genotype 4 was high in males, in patients younger than 45, and in IDU (63.5%). 1a, 3, 4 were the most prevalent genotypes in HIV-coinfected patients. There was a significant decline in genotype 1b and an increase in genotypes 3 and 4 over time. Conclusions: There has been a decline of genotype 1b, associated with transfusion or parenteral/nosocomial infections, and increases in the prevalence of genotypes 1a, 3 and 4 associated with male gender and IDU, now the most prevalent infection route. Immigration contributed with genotype 2 infections from Africa and genotype 1b and 3 infections from Eastern Europe and Asia (AU)

Antecedentes: La distribución genotípica y la epidemiología de la infección por el VHC en los países de Europa Occidental ha variado en las últimas décadas. Objetivo: Establecer el perfil genotípico local y distinguir las variables demográficas asociadas. Material y método: Se han tenido en cuenta todas las genotipificaciones desde 1988 a 2015. Las variables demográficas asociadas se incluyeron en modelos de regresión logística. La genotipificación se realizó con kits comerciales actualizados. Resultados: El genotipo 1b fue el más prevalente (42,4%), seguido por 1a (22,5%), 3 (18,6%), 4 (10,6%) y 2 (4,6%). La prevalencia de 1a fue mayor en varones, en pacientes menores de 45 años y en consumidores de drogas por vía intravenosa (CDVI). El genotipo 1b fue más frecuente en pacientes mayores de 45 años, con infecciones relacionadas con la transfusión y de tipo parenteral/nosocomial, y en inmigrantes de Europa Oriental. El genotipo 2 fue muy prevalente en la vía postransfusional (54,9%). La prevalencia del genotipo 3 fue elevada en varones, en pacientes menores de 45 años, en CDVI (69,3%) y en inmigrantes asiáticos y de Europa Oriental. El genotipo 4 fue elevado en varones, en pacientes menores de 45 años y en CDVI (63,5%). Los genotipos 1a, 3 y 4 fueron los más prevalentes en pacientes coinfectados con el VIH. Hubo una disminución considerable del genotipo 1b y un aumento en los genotipos 3 y 4 en el tiempo. Conclusiones: Se ha producido una disminución del genotipo 1b, relacionado con transfusiones o infecciones parenterales/nosocomiales, y un aumento en la prevalencia de los genotipos 1a, 3 y 4, relacionados con el sexo masculino y los CDVI, que actualmente son la vía de infección más prevalente. La inmigración contribuyó con infecciones del genotipo 2 de África e infecciones de los genotipos 1b y 3 de Europa Oriental y Asia (AU)

Changes in the epidemiology and distribution of the hepatitis C virus genotypes in North-Eastern Spain over the last 35 years.

BACKGROUND: Genotypic distribution and epidemiology of HCV infection in Western Europe countries has changed over the last decades. AIM: To establish the local genotypic profile and characterize the associated demographic variables. MATERIAL AND METHOD: All the genotyping from 1988 to 2015 were considered. Associated demographic variables were included in logistic regression models. Genotyping was carried out with updated commercial kits. RESULTS: Genotype 1b was the most prevalent (42.4%) followed by 1a (22.5%), 3 (18.6%), 4 (10.6%) and 2 (4.6%). The prevalence of 1a was higher in males, in patients younger than 45 and in intravenous drug users (IDU). 1b was more frequent in older than 45, with transfusion-associated and parenteral/nosocomial infections and in immigrants from Eastern Europe. Genotype 2 was highly prevalent in the postransfusional route (54.9%). Genotype 3 prevalence was high in males, in patients younger than 45, in IDU (69.3%) and in Asian and Eastern European immigrants. Genotype 4 was high in males, in patients younger than 45, and in IDU (63.5%). 1a, 3, 4 were the most prevalent genotypes in HIV-coinfected patients. There was a significant decline in genotype 1b and an increase in genotypes 3 and 4 over time. CONCLUSIONS: There has been a decline of genotype 1b, associated with transfusion or parenteral/nosocomial infections, and increases in the prevalence of genotypes 1a, 3 and 4 associated with male gender and IDU, now the most prevalent infection route. Immigration contributed with genotype 2 infections from Africa and genotype 1b and 3 infections from Eastern Europe and Asia.

High efficacy of Sofosbuvir plus Simeprevir in a large cohort of Spanish cirrhotic patients infected with genotypes 1 and 4.

BACKGROUND AND AIMS: Hepatitis C (HCV) therapy with Sofosbuvir (SOF)/Simeprevir (SMV) in clinical trials and real-world clinical practice, showed high rates of sustained virological response (SVR) in non-cirrhotic genotype (GT)-1 and GT-4 patients. These results were slightly lower in cirrhotic patients. We investigated real-life effectiveness and safety of SOF/SMV with or without ribavirin (RBV) in a large cohort of cirrhotic patients. METHODS: This collaborative multicentre study included data from 968 patients with cirrhosis infected with HCV-GT1 or 4, treated with SOF/SMV±RBV in 30 centres across Spain between January-2014 and December-2015. Demographic, clinical, virological and safety data were analysed. RESULTS: Overall SVR was 92.3%; the majority of patients were treated with RBV (62%) for 12 weeks (92.4%). No significant differences in SVR were observed between genotypes (GT1a:94.3%; GT1b:91.7%; GT4:91.1%). Those patients with more advanced liver disease (Child B/C, MELD≥10) or portal hypertension (platelet count≤100×109 /L, transient elastography≥21 Kpa) showed significantly lower SVR rates (84.4%-91.9%) than patients with less advanced liver disease (93.8%-95.9%, P<.01 in all cases). In the multivariate analysis, the use of RBV, female gender, baseline albumin≥35 g/L, MELD<10 and lack of exposure to a triple therapy regimen were independent predictors of SVR (P<.05). Serious adverse events (SAEs) and SAE-associated discontinuation events occurred in 5.9% and 2.6%. CONCLUSIONS: In this large cohort of cirrhotic patients managed in the real-world setting in Spain, SOF/SMV±RBV yielded to excellent SVR rates, especially in patients with compensated liver cirrhosis. In addition, this combination showed to be safe, with low rates of SAEs and early discontinuations.

Predictive variables of sustained virological response after early discontinuation of triple therapy with telaprevir for genotype-1 HCV infection / Variables pronósticas de respuesta virológica sostenida tras la interrupción precoz del tratamiento triple con telaprevir de la infección por genotipo 1 del virus de la hepatitis C

BACKGROUND: Pivotal phase studies of telaprevir (TLV) and boceprevir (BOV) showed 10-56% rates of early treatment interruption. However, there have been no reports on the sustained virological response (SVR) rates of these patients. AIM: To assess the SVR rate in a large cohort of patients who discontinued triple therapy with TLV or BOV for reasons other than stopping rules and to identify variables predicting SVR. MATERIAL AND METHOD: A survey was sent to 15 hospitals in Catalonia asking them to report all TLV/BOV treatments finished by 31 May 2014. Demographic, clinical, laboratory, liver fibrosis and therapeutic data were recorded for treatments with early discontinuation. Logistic regression analysis, ROC curves and prognostic assessment of the variables identified were calculated. RESULTS: Twelve hospitals responded to the survey, representing 467 treatments and 121 (21.2%) early discontinuations, 76 (62.8%) due to stopping rules and 45 (37.2%) for other reasons. Early discontinuation was more frequent with BOV [38.2% (50/131) versus 21.1% (71/336) p < 0.005], mainly due to stopping rules [78% (39/50) versus 52.1% (37/71); p = 0.004]. SVR was achieved in 21/121 patients (17.4%), 19/71 (26.8%) treated with TLV and 2/50 (4.0%) treated with BOV. In patients discontinuing treatment for reasons other than stopping rules, SVR was achieved in 19/37 (55.9%) treated with TLV and in 2/11 (18.2%) treated with BOV. The SVR rate in patients treated with TLV who discontinued due to a severe adverse event was 61.5% (16/26). A logistic regression analysis was performed only with triple therapy with TLV and early discontinuation. The predictive variables of SVR were undetectable HCV-RNA at treatment week 4 and treatment length longer than 11 weeks. Treatment duration longer than 11 weeks showed the best accuracy (0.794), with a positive predictive value of 0.928. CONCLUSIONS: Early discontinuation of TLV-based triple therapy due to reasons other than stopping rules still have a significant SVR rate (55.9%). Undetectable HVC-RNA at week 4 of treatment and treatment duration longer than 11 weeks are predictive of SVR in this subset of patients

ANTECEDENTES: Los estudios de registro de telaprevir (TLV) y boceprevir (BOV) han mostrado tasas de interrupción precoz del tratamiento del 10-56%, pero no se ha comunicado la respuesta virológica sostenida (RVS) de estos pacientes. OBJETIVOS: Analizar la RVS, y los factores predictivos de esta, en una cohorte extensa de pacientes que pararon precozmente el tratamiento triple con TLV/BOV por causas diferentes a reglas de parada. MATERIAL Y MÉTODO: Se envió a 15 de hospitales de Cataluña un cuestionario relativo a los tratamientos con TLV/BOV finalizados antes del 31 de mayo de 2014, incluyendo información clínica, analítica, elastométrica y terapéutica de aquellos interrumpidos precozmente. Se realizaron análisis de regresión logística, curvas ROC y estimaciones pronósticas de las variables identificadas. RESULTADOS: Contestaron la encuesta 12 hospitales, sumando un total de 467 tratamientos con 121 (21,2%) interrupciones precoces del mismo, 76 (62,8%) por reglas de parada y 45 (37,2%) por otras causas. Hubo más paradas precoces en los tratamientos con BOV (38,2% [50/131] versus 21,1% [71/336]; p < 0,005), principalmente debidas a reglas de parada (78% [39/50] versus 52,1% [37/71]; p = 0,004). Alcanzaron RVS 21/121 pacientes (17,4%), 19/71 (26,8%) tratados con TLV y 2/50 (4,0%) tratados con BOV. En los pacientes que pararon el tratamiento por causas distintas a reglas de parada se alcanzó la RVS en 19/37 (55,9%) tratados con TLV y en 2/11 (18,2%) tratados con BOV. Los pacientes tratados con TLV que pararon el tratamiento por efecto adverso grave tuvieron una tasa de RVS del 61,5% (16/26). El análisis de regresión logística se hizo solo con los tratamientos triples con TLV parados precozmente. Las variables predictivas de RVS fueron el ARN-VHC indetectable en semana 4 y la duración del tratamiento mayor de 11 semanas. El mejor valor pronóstico (0,794) lo tuvo la duración total del tratamiento mayor de 11 semanas, con un VPP de 0,928. CONCLUSIONES: Los pacientes que paran precozmente el tratamiento triple con TLV por causas diferentes a reglas de parada conservan una tasa de RVS relevante (55,9%) en esta cohorte. El ARN-VHC indetectable en semana 4 y la duración del tratamiento mayor de 11 semanas son predictivas de RVS de este subgrupo de pacientes

Predictive variables of sustained virological response after early discontinuation of triple therapy with telaprevir for genotype-1 HCV infection.

BACKGROUND: Pivotal phase studies of telaprevir (TLV) and boceprevir (BOV) showed 10-56% rates of early treatment interruption. However, there have been no reports on the sustained virological response (SVR) rates of these patients. AIM: To assess the SVR rate in a large cohort of patients who discontinued triple therapy with TLV or BOV for reasons other than stopping rules and to identify variables predicting SVR. MATERIAL AND METHOD: A survey was sent to 15 hospitals in Catalonia asking them to report all TLV/BOV treatments finished by 31 May 2014. Demographic, clinical, laboratory, liver fibrosis and therapeutic data were recorded for treatments with early discontinuation. Logistic regression analysis, ROC curves and prognostic assessment of the variables identified were calculated. RESULTS: Twelve hospitals responded to the survey, representing 467 treatments and 121 (21.2%) early discontinuations, 76 (62.8%) due to stopping rules and 45 (37.2%) for other reasons. Early discontinuation was more frequent with BOV [38.2% (50/131) versus 21.1% (71/336) p<0.005], mainly due to stopping rules [78% (39/50) versus 52.1% (37/71); p=0.004]. SVR was achieved in 21/121 patients (17.4%), 19/71 (26.8%) treated with TLV and 2/50 (4.0%) treated with BOV. In patients discontinuing treatment for reasons other than stopping rules, SVR was achieved in 19/37 (55.9%) treated with TLV and in 2/11 (18.2%) treated with BOV. The SVR rate in patients treated with TLV who discontinued due to a severe adverse event was 61.5% (16/26). A logistic regression analysis was performed only with triple therapy with TLV and early discontinuation. The predictive variables of SVR were undetectable HCV-RNA at treatment week 4 and treatment length longer than 11 weeks. Treatment duration longer than 11 weeks showed the best accuracy (0.794), with a positive predictive value of 0.928. CONCLUSIONS: Early discontinuation of TLV-based triple therapy due to reasons other than stopping rules still have a significant SVR rate (55.9%). Undetectable HVC-RNA at week 4 of treatment and treatment duration longer than 11 weeks are predictive of SVR in this subset of patients.

High efficacy and safety of triple therapy in HCV genotype 1 and moderate fibrosis: a multicenter study of clinical practice in Spain.

BACKGROUND AND RATIONAL: Telaprevir-based therapy (TBT) has been extensively evaluated in clinical trials. So we designed a study to compare the efficacy and safety of TBT between patients with moderate fibrosis and those suffering from advanced fibrosis in clinical practice. A multicenter observational and ambispective study was conducted. It included 582 patients with chronic hepatitis C genotype 1, 214 with fibrosis F2, and 368 with F3/F4 (F3: 148; F4: 220). RESULTS: The mean patient age was 55 years, 67% male. Type of prior response was 22% naïve, 57% relapsers, and 21% partial/null responders, 69% had high viral load (> 800,000 IU/mL). HCV genotypes were 1a (19%), 1b (69%), and 1 (12%), respectively. Sixty-five percent were non-CC IL28B genotype. Week-12 sustained virologic response (SVR12) was significantly higher among F2-naïve patients (78%) compared with F3/F4-naïve patients (60%; p = 0.039) and among F2 non-responders (67%) compared with F3/F4 non-responders (42%; p = 0.014). SVR12 among relapsers was remarkably high in both groups (F2:89% vs. F3/F4:78%). Severe anemia and thrombocytopenia were more frequent among patients with F3/F4 than those with F2 (p < 0.01). Overall, 132 patients (22%) discontinued treatment: 58 due to adverse effects, 42 due to the stopping-rule, and 32 due to breakthrough. Premature discontinuation was more frequent among patients with F3/F4 (p = 0.028), especially due to breakthrough (p < 0.001). CONCLUSIONS: This multicenter study demonstrates high efficacy and an acceptable safety profile with regard to TBT in F2-patients in clinical practice.

La interrupción precoz del tratamiento triple con telaprevir de la hepatitis crónica C por efecto adverso grave no presupone necesariamente el fracaso del tratamiento / Early interruption of triple therapy with telaprevir in chronic hepatitis C due to severe adverse effects does not necessarily lead to treatment failure

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