First-wave protease inhibitors for hepatitis C genotype 1 treatment: a real-life experience in Brazilian patients

Abstract INTRODUCTION: Licensed for chronic hepatitis C treatment in 2011, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), which have high sustained viral responses (SVR), ushered a new era characterized by the development of direct-action drugs against the hepatitis C virus (HCV). The aim of this study was to analyze the effectiveness and safety of BOC and TVR administered with pegylated interferon and ribavirin and to share the experience of a Brazilian reference center. METHODS: A retrospective descriptive study was conducted in patients with HCV genotype 1 infection who started treatment between July 2013 and December 2015. Data were collected using a computerized system. RESULTS: A total of 115 subjects were included, of which 58 (50.4 %) had liver cirrhosis and 103 (89.6 %) used TVR. The overall SVR rate was 61.7 % (62.1 % for TVR and 58.3 % for BOC). The presence of cirrhosis was associated with a lower SVR rate, whereas patients who relapsed after prior therapy had a greater chance of showing SVR than did non-responders. The incidence of adverse drug reactions (ADRs) was high. Almost all patients (~100 %) presented with hematologic events. Furthermore, treatment had to be discontinued in 15 subjects (13 %) due to severe ADRs. CONCLUSIONS: In conclusion, the SVR rates in our study were lower than those reported in pre-marketing studies but were comparable to real-life data. ADRs, particularly hematological ADRs, were more common compared to those in previous studies and resulted in a high rate of treatment discontinuity.

Effectiveness and safety of first-generation protease inhibitors in real-world patients with hepatitis C virus genotype 1 infection in Brazil: a multicenter study

OBJECTIVE: To evaluate the effectiveness and safety of first-generation protease inhibitors for the treatment of genotype 1 hepatitis C virus-infected patients at Brazilian reference centers. METHODS: This multicenter cross-sectional study included hepatitis C virus genotype 1 monoinfected patients treated with Peg-interferon, ribavirin, and either boceprevir (n=158) or telaprevir (n=557) between July 2013 and April 2014 at 15 reference centers in Brazil. Demographic, clinical, virological, and adverse events data were collected during treatment and follow-up. RESULTS: Of the 715 patients, 59% had cirrhosis and 67.1% were treatment-experienced. Based on intention-to-treat analysis, the overall sustained viral response was 56.6%, with similar effectiveness in both groups (51.9% for boceprevir and 58% for telaprevir, p=0.190). Serious adverse events occurred in 44.2% of patients, and six deaths (0.8%) were recorded. Cirrhotic patients had lower sustained viral response rates than non-cirrhotic patients (46.9% vs. 70.6%, p<0.001) and a higher incidence of serious adverse events (50.7% vs. 34.8%, p<0.001). Multivariate analysis revealed that sustained viral response was associated with the absence of cirrhosis, viral recurrence after previous treatment, pretreatment platelet count greater than 100,000/mm3, and achievement of a rapid viral response. Female gender, age>65 years, diagnosis of cirrhosis, and abnormal hemoglobin levels/platelet counts prior to treatment were associated with serious adverse events. CONCLUSION: Although serious adverse events rates were higher in this infected population, sustained viral response rates were similar to those reported for other patient cohorts.

Predictors of early treatment discontinuation and severe anemia in a Brazilian cohort of hepatitis C patients treated with first-generation protease inhibitors

The aim of this study was to determine risk factors for adverse events (AE)-related treatment discontinuation and severe anemia among patients with chronic hepatitis C virus (HCV) genotype 1 infection, treated with first-generation protease inhibitor (PI)-based therapy. We included all patients who initiated treatment with PI-based therapy at a Brazilian university hospital between November 2013 and December 2014. We prospectively collected data from medical records using standardized questionnaires and used Epi Info 6.0 for analysis. Severe anemia was defined as hemoglobin ≤8.5 mg/dL. We included 203 patients: 132 treated with telaprevir (TVR) and 71 treated with boceprevir (BOC). AE-related treatment discontinuation rate was 19.2% and anemia was the main reason (38.5%). Risk factors for treatment discontinuation were higher comorbidity index (OR=1.85, CI=1.05-3.25) for BOC, and higher bilirubin count (OR=1.02, CI=1.01-1.04) and lower BMI (OR=0.98, CI=0.96-0.99) for TVR. Severe anemia occurred in 35 (17.2%) patients. Risk factors for this outcome were lower estimated glomerular filtration rate (eGFR; OR=0.95, CI=0.91-0.98) for patients treated with TVR, and higher comorbidity index (OR=2.21, CI=1.04-4.67) and ribavirin dosage (OR=0.84, CI=0.72-0.99) for those treated with BOC. Fifty-five (57.3%) patients treated with TVR and 15 (27.3%) patients treated with BOC achieved sustained virological response (SVR). Among patients who received TVR and interrupted treatment due to AE (n=19), only 26.3% (n=5) achieved SVR (P=0.003). Higher number of comorbidities, lower eGFR and advanced liver disease are associated with severe anemia and early treatment cessation, which may compromise SVR achievement.

Peginterferon plus ribavirin and sustained virological response rate in HCV-related advanced fibrosis: a real life study

Background: Tolerance and response to antiviral HCV treatment is poor in advanced fibrosis. The aim of this study was to assess SVR rate and its predictive factors in HCV advanced fibrosis patients treated in real life with full dose PEG-IFN plus RBV and to evaluate the adverse events related to treatment. Methods: A multicentric, retrospective study was conducted at six university hospitals. METAVIR F3 and F4 HCV monoinfected patients who were treated with PEG-IFN and RBV had their data analyzed. A stepwise logistic regression analysis was performed to identify the variables independently related to SVR. Adverse events were recorded during treatment. Results: 308 patients were included, 75% genotype 1 and 23% genotype 3. METAVIR F3 was present in 39% and F4 in 61% of patients. The median Child Pugh score for F4 patients was 5 (5–9). The global SVR rate was 34%, 11% were relapsers and 55% were nonresponders. SVR rates were similar between patients treated with PEG-IFN alfa 2a or alfa 2b (p = 0.24). SVR rates according to Child–Pugh score were 26% (Child A) and 18% (Child B). The independent factors related to SVR in F4 patients were genotype 3, RVR and fewer Child Pugh score points. Treatment interruption occurred in 31% patients and death occurred in 1.9%, all with liver cirrhosis. Conclusion: Treatment of HCV in patients with advanced fibrosis should not be postponed. However, a very careful evaluation of cirrhotic patients must be performed before treatment is indicated and careful monitoring is required during treatment. .

Custo-efetividade da inclusão dos respondedores virológicos lentos no tratamento da hepatite C na presença da coinfecção com o HIV / Cost-effectiveness of hepatitis C treatment in slow virologic responders coinfected with HIV / Coste-efectividad del tratamiento de la hepatitis C en coinfectados con el VIH con respuesta virológica lenta

Evidências recentes demonstram que respondedores virológicos lentos podem se beneficiar com a extensão do tratamento antiviral. O estudo investigou a adoção desse protocolo diante da coinfecção VHC/HIV. O objetivo foi estudar a relação de custo/efetividade da terapêutica com peguinterferon associado à ribavirina em portadores do genótipo 1 do VHC coinfectados com o HIV, comparando-se a inclusão ou não de respondedores virológicos lentos. Simulou-se por meio de um modelo de Markov a progressão da doença hepática em uma coorte hipotética de mil homens, maiores de 40 anos, considerandose a perspectiva do Sistema Único de Saúde (SUS) e horizonte temporal de 30 anos. A extensão do tratamento para respondedores lentos resultou em uma razão incremental de custo efetividade de R$ 44.171/QALY, valor abaixo do limiar de aceitabilidade proposto pela Organização Mundial da Saúde. A análise de sensibilidade não modificou os resultados alcançados. A inclusão de indivíduos coinfectados VHC/HIV respondedores virológicos lentos no protocolo de tratamento apresenta-se como uma estratégia custo-efetiva para o SUS.

Recent evidence has demonstrated that slow responders may benefit from antiviral treatment in HCV/HIV coinfection. This study aimed to evaluate the cost-effectiveness of HCV treatment in individuals with genotype 1 coinfected with HIV, with peg-interferon in combination with ribavirin, compared to the inclusion (versus non-inclusion) of slow responders. A Markov model was developed that simulated the progression of liver disease in a hypothetical cohort of one thousand men over 40 years of age, considering the Brazilian Unified National Health System (SUS) perspective and a 30-year timeline. The extension of treatment to slow responders provided a 60% increase in the number of individuals who eliminated HCV and an incremental cost-effectiveness ratio of 44,171 BRL/QALY, below the acceptability threshold proposed by World Health Organization. Sensitivity analysis did not alter the results. The inclusion of HCV/ HIV-coinfected slow virologic responders in the treatment protocol is shown to be a cost-effective strategy for the SUS.

La evidencia reciente ha demostrado que los individuos con respuesta virológica lenta pueden beneficiarse de una extensión del tratamiento antiviral. El estudio investigó la adopción de este protocolo antes de la coinfección por VHC/HIV. El objetivo fue estudiar la relación coste-efectividad de la terapia con peginterferon asociado con ribavirina en pacientes con genotipo 1 del VHC, coinfectados por el HIV respondedores virológicos lentos. Se simula mediante un modelo de Markov la progresión de la enfermedad hepática en una cohorte hipotética de un millar de hombres, más de 40, teniendo en cuenta la perspectiva del Sistema Único de Salud (SUS) y un horizonte temporal de 30 años. El grado de tratamiento a los respondedores lentos dio lugar a un incremento de coste-efectividad de R$ 44.171/QALY, por debajo del umbral de aceptabilidad propuesto por la Organización Mundial de la Salud. El análisis de sensibilidad no modificó los resultados. La inclusión de los individuos coinfectados y con respuesta virológica lenta en el protocolo de tratamiento se presenta como una estrategia económica para el SUS.

Response to treatment in Brazilian patients with chronic hepatitis C is associated with a single-nucleotide polymorphism near the interleukin-28B gene

A single-nucleotide polymorphism (SNP) upstream of interleukin (IL)28B was recently identified as an important predictor of the outcome of chronic hepatitis C patients treated with pegylated interferon plus ribavirin (PEG-IFN/RBV). The aim of this study was to investigate the association between the IL28B gene polymorphism (rs12979860) and virological response in chronic hepatitis C patients. Brazilian patients (n = 263) who were infected with hepatitis C virus (HCV) genotype 1 and were receiving PEG-IFN/RBV were genotyped. Early virological response (EVR) (12 weeks), end-of-treatment response (EOTR) (48 weeks), sustained virological response (SVR) (72 weeks) and relapse were evaluated using conventional and quantitative polymerase chain reaction (PCR) assays. The frequency of the C allele in the population was 39%. Overall, 43% of patients experienced SVR. The IL28B CC genotype was significantly associated with higher treatment response rates and a lower relapse rate compared to the other genotypes [84% vs. 58% EVR, 92% vs. 63% EOTR, 76% vs. 38% SVR and 17% vs. 40% relapse rate in CC vs. other genotypes (CT and TT), respectively]. Thus, the IL28B genotype appears to be a strong predictor of SVR following PEG-IFN/RBV therapy in treatment-naïve Brazilian patients infected with HCV genotype 1. This study, together with similar research examining other SNPs, should help to define adequate protocols for the treatment of patients infected with HCV genotype 1, especially those with a poor prognosis.

Therapeutic effectiveness of biosimilar standard interferon versus pegylated interferon for chronic hepatitis C genotypes 2 or 3

BACKGROUND: Pegylated interferon (Peg-IFN) and standard interferon (IFN) play a significant role in the treatment of hepatitis C virus (HCV) infection. Biosimilar standard IFN is widely available in Brazil for the treatment of HCV infection genotypes 2 or 3, but its efficacy compared to Peg-IFN is unknown. OBJECTIVE: To compare the sustained virological response (SVR) rates following treatment with biosimilar standard IFN plus ribavirin (RBV) versus Peg-IFN plus RBV in patients with HCV genotypes 2 or 3 infection. METHODS: A retrospective cohort study was conducted in patients with HCV genotypes 2 or 3 infection treated with biosimilar standard IFN plus RBV or with Peg-IFN plus RBV. SVR rates of the two treatments were compared. RESULTS: From January 2005 to December 2010, 172 patients with a mean age of 44 +/- 9.3 years were included. There were eight (4.7%) patients with HCV genotype 2 infections. One hundred fourteen (66.3%) were treated with biosimilar standard IFN plus RBV, whist 58 (33.7%) patients were treated with Peg-IFN plus RBV. Between the two groups, there were no significant differences regarding age, gender, glucose level, platelet count, hepatic necroinflammatory grade, and hepatic fibrosis stage. Overall, 59.3% (102/172) patients had SVR. In patients treated with Peg-IFN plus RBV, 79.3% (46/58) had SVR compared to 49.1% (56/114) among those treated with biosimilar standard IFN plus RBV (p = 0.0001). CONCLUSION: In patients with HCV genotypes 2 or 3 infection, a higher SVR was observed in patients receiving Peg-IFN plus RBV related to patients treated with biosimilar standard IFN plus RBV.

Interferon: tratamiento alternativo con infiltración intralesional en el carcinoma basocelular / Interferon: an alternative treatment with IL infiltration for basal cell carcinoma

Los interferones son citoquinas que tienen una importante acción antitumoral, caracterizada por tener efecto antiproliferativo, control sobre los genes implicados en el crecimiento y diferenciación celular, modulación de antígenos de superficie y una acción antiangiogénica. Se seleccionaron 8 pacientes con carcinomas basocelulares de localización cefálica, 2 eran de tipo recidiva ulcerados, 2 recidivados con compromiso óseo, 1 con CBC múltiples desarrollados sobre radiodermitis crónica, 1 recaída noduloide, 1 plano cicatrizal y otro ulcerado desarrollado sobre radiodermitis crónica, algunos de los cuales habían recibido distintos tratamientos convencionales y otros vírgenes de todo tratamiento, que presentaban dificultades terapéuticas y que nos permitió desarrollar esta experiencia de infiltraciones intralesionales con interferon a 2b. La dosis utilizada fue de 3 MUI para los CBC menores de 2 cm y 5 MUI para los de mayor tamaño, aplicados tres veces por semana, día por medio. Los resultados obtenidos comprendieron un 37,5 por ciento para la resolución completa (tres pacientes), un 37,5 por ciento para la resolución parcial (tres pacientes) y un 25 por ciento (dos pacientes) sin respuesta significativa. Por lo tanto, en el 75 por ciento de los casos se observó una acción efectiva, que en el caso de la resolución parcial permitió la curación quirúrgica con menor sacrificio de tejido. La histopatología fue negativa para los tres casos de resolución completa en la semana dieciséis. La dosis media total de interferon a 2b utilizada fue de 113,4 MUI, en un período medio de 12,4 semanas, dejando cicatrices ligeramente hipocrómicas planas, sin observarse recidivas en los tres casos de curación, durante un seguimiento de dos años. En conclusión la infiltración intralesional con INF a 2b es una alternativa terapéutica en el tratamiento de los CBC, en pacientes seleccionados, que permite desde una resolución completa a una resolución parcial, posterior a la cual se pueden implementar otras conductas terapéuticas

Interferón alfa2b en el dolor por herpes zoster. Informe preliminar / Interferon alpha2b in the pain herpes zoster. A case report

Se estudiaron 40 pacientes con herpes zoster, 22 de ellos con cuadro agudo, 18 con neuralgia postherpética, que se consideraron crónicos. Por medio de la escala visual análoga se evaluó el efecto del interferón alfa2b (INF alfa2b) en el control del dolor debido a cuadros de herpes zoster agudo y en los pacientes con neuralgia secundaria crónica severa en comparación con la evolución del tratamiento. Los pacientes con dolor agudo ingresaron con una escala visual análoga del dolor entre 10 y 2 puntos, con una media de 7.7, DS: 2.1: (p< 0.6), en la prueba de t de Student. La mejoría en los pacientes con dolor agudo fue de 6 a 0 puntos, DS: 2.7 con media de 0.27 (DS: 1.2), y en los crónicos fue de 6 a 0 puntos, con una media de 1.2 (DS: 2.4), con diferencia significativa por t de Student para comparar la escala inicial y final (p< 0.0001.) comparando la mejoría en días. En ambos grupos los agudos respondieron más rápidamente que los crónicos, con diferencias significativa (p< 0.0001). La comparación del dolor en pacientes agudos y crónicos al inicio y al final mostró una diferencia significativa (p< 0.001)

Busulfán versus busulfán-interferón como terapia de mantenimiento en leucemia mieloide crónica / Busulfan versus busulfan-interferon as maintenance therapy in chronic myeloid leukemia

Se estudiaron 30 pacientes con el fin de evaluar la eficacia terapéutica y la toxicidad del interferón alfa-2b, asociado al busulfán, en el mantenimiento de la fase crónica con leucemia mieloide crónica de novo. Los pacientes recibieron busulfán hasta alcanzar la remisión hematológica completa, y se dividieron aleatoriamente en dos grupos: uno se mantuvo con busulfán el cual se administró cuando los leucocitos superaron los 5 x 10 9/L, y otro recibió interferón alfa a dosis de 5 millones UI SC tres veces por semana, agregándose busulfán cuando los leucocitos eran superiores a 15 x 10 9/L. El promedio de la duración de la fase crónica fue mayor en el grupo de busulfán-interferón, 31 vs 16 meses (p= 0.03) pero no hubo ningún caso de remisión citogenética. El interferón fue bien tolerado: ningún enfermo se eliminó por toxicidad del medicamento

Tratamiento de niños con hepatitis B crónica con interferón alfa 2b: comunicación preliminar / Interferon alfa-2B in the treatment of children with chronic hepatitis B: preliminary comunication

Se estudiaron 9 pacientes con hepatitis crónica B, con una edad media de 7 años 9 meses, los cuales presentaban AgeHB y ADN-HVB positivos. Se incluyeron en un protocolo mediante randomización en bloque, diferenciándose en grupos. El grupo A recibió previamente prednisona y el grupo B interferón (IFN) solo. Ambos grupos recibieron IFN alfa-2b a 3 millones de unidades por metro cuadrado de superficie corporal (MU/m²SC), 3 veces por semana durante 4 meses. Al final del tratamiento se negativizarón el AgeHB y ADN-HVB en 4/5 en el grupo A. En el grupo B todos positivos en el control realizado a los 4 meses. Estos datos sugieren que el tratamiento combinado de esteroides-IFN aumenta la eficiencia del IFN en el tratamiento de niños con hepatitis B crónica

Interferon alfa en el tratamiento de la hepatitis cronica C: curso de 24 versus 48 semanas. Resultados de un estudio randomizado / Interferon alfa in the treatment of chronic hepatitis C: course of 24 versus 48 weeks. Results of a randomized trial

The aim of this trial was to investigate if a more prolonged course of interferon (IFN) is able to increase the long-term benefit in patients with chronic hepatitis C. Forty-four patients with active chronic hepatitis and antibodies to HCV were randomly assigned to receive IFN-alfa 2b 3 MU t.i.w. during 24 weeks (group I, n 23) or during 48 weeks (group II, n 21). In the evaluation of results, complete response was considered when the ALT values returned to normality during the treatment; and sustained response, when the ALT values persisted below normal range during at least 6 months post therapy. Histologic changes were compared by using the Histological Activity Index, or Knodell score. Viremia status was evaluated for the study of HCV RNA (by nested-RT-PCR). Results: There were no significant differences between boths groups before treatment, in terms of age, sex, ALT, or histologic findings (11 patients in group I, and 7 in group II had cirrhosis). Complete response was found in 9 patients (39.1 per cent) from group I; in 11 (52.4 per cent) from group II (NS). Basal histologic findings were identified as the only predictive factor of complete and sustained response, by logistic regresion analysis. Considering only noncirrhotic patients, complete response was seen in 58.3 per cent in patients from group I, 71.4 per cent in group II. Sustained response was obtained in 4 patients from group I, (17.4 per cent), 7 from group II (33.3 per cent) (NS). Post IFN liver biopsies were performed in 23 patients (12 from group I, 11 from group II). In group I patients, there were no significant changes. In group II, Knodell score was found to be significantly decreased post IFN (pre IFN, median 10, range 3-15; post IFN, median 6, range 2-14) (p<0.05). HCR RNA was absent in serum during the follow-up post IFN in 2 patients from group I, in 3 from group II. The results of this study show that a 48 weeks course of IFN has a trend to achieve a higher sustained response than the usual regime (but non significant); and it produces a decrease in the histologic activity. The best predicitve factor of positive response was the absence of cirrhosis in our study (although we did not evaluate viral factors, such as genotypes or HCV viremia levels).

Hepatitis crónica / Chronic hepatitis

Se revisa la literatura sobre esta enfermedad de etiologia diversa y de curso clínico variable, que muchas veces progresa a la cirrosis y al hepatocarcinoma. la clasificacion basada en los hallazgos histológicos de la biopsia hepática en crónica persistente y crónica activa se ha abandonado por la falta de correlación clínica, bioquímica e histológica. Una nueva clasificación establecida por el grupo de trabajo internacional sobre Nomenclatura de las Enfermedades del Higado y basada en la etiología se afirma: tres tipos de hepatitis crónica se observan con mas frecuencia: una asociada a la infección crónica con el virus de la hepatitis B, otra asociada a la infección crónica con el virus de la hepatitis C; y una tercera denominada autoinmune por estar presente autoanticuerpos que explican la patogenia. Existe un cuarto grupo asociado a la reacción producida por uso de ciertos medicamentos que originan lesiones hepáticas similares al tipo autoinmune. El diagnóstico se basa en los marcadores específicos para el virus B, el virus C y los de autoinmunidad. La asociación entre los autoanticuerpos a los microsomas del higado y del riñon con el virus C puede causar confusión diagnóstica. El tratamiento de la etiología viral B y C esta basado en el uso del interferon alfa que da respuesta sostenida en la hepatitis crónica Ben el 40 por ciento y en el menor grado en la hepatitis C. El tratamiento con corticosteroides y azatioprina a largo plazo es exitoso en la de tipo autoinmune. La suspensión del farmaco que ocasiona la hepatopatia crónica favorece la resolución del cuadro. Se debate aun el uso del transplante hepatico en ciertas formas de hepatitis crónica, sobre todo la originada por el virus B o C