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 of first-wave protease inhibitors in hepatitis C virus genotype 1 infection: a multicenter study in Brazil

Abstract INTRODUCTION: In 2013, combination therapy using peginterferon, ribavirin, and boceprevir or telaprevir was introduced to treat hepatitis C virus genotype 1 infection in Brazil. The effectiveness of this therapy in four Brazilian regions was evaluated. METHODS: Clinical and virological data were obtained from patients of public health institutions in five cities, including sustained virological response (SVR) and side effects. Patients with advanced fibrosis (F3/4), moderate fibrosis (F2) for > 3 years, or extra-hepatic manifestations were treated according to Ministry of Health protocol. Treatment effectiveness was verified by using bivariate and multivariate analysis; p-values of < 0.05 were considered significant. RESULTS: Of 275 patients (64.7% men; average age, 57 years old), most (61.8%) were treatment-experienced; 53.9% had subgenotype 1a infection, 85.1% had advanced fibrosis, and 85.5% were treated with telaprevir. SVR was observed in 54.2%. Rapid virological response (RVR) was observed in 54.6% of patients (data available for 251 patients). Overall, 87.5% reported side effects and 42.5% did not complete treatment. Skin rash, severe infection, and death occurred in 17.8%, 2.5%, and death in 1.4% of cases, respectively. SVR was associated with treatment completion, RVR, and anemia. CONCLUSIONS: The effectiveness of hepatitis C virus triple therapy was lower than that reported in phase III clinical trials, possibly owing to the prioritized treatment of patients with advanced liver fibrosis. The high frequency of side effects and treatment interruptions observed supported the decision of the Brazilian authorities to suspend its use when safer and more effective drugs became available in 2015.

Regional Differences in the Safety of Telaprevir-Based Triple Therapy for Chronic Hepatitis C in Japan: / 医薬品情報学

Objective:The objectives were to assess regional differences in the safety outcomes of telaprevir-based triple therapy(T/PR) in Japan and evaluate a suitable generalized linear mixed model for estimating regional differences.Design and Methods:This study targeted individuals infected with genotype 1 chronic hepatitis C virus registered in a nationwide Japanese interferon database from December 2009 to August 2015. The rate of dropout from treatmentattributable to adverse events was calculated in every prefecture where ≥ 20 cases were reported. We constructed the following four models and evaluated the best-fit model based on Akaike information criterion (AIC) and Bayesian information criterion (BIC):1)prefecture as a fixed-effect,2)prefecture and identified confounding factors as fixed-effects,3)prefecture as a random-effect,and 4)prefecture as a random-effect and identified confounding factors as fixed-effects.Results:A total of 25,989 individuals from 38 prefectures were registered during the study period;among them,1,591 from18 prefectures were included as the study population. The dropout rate ranged from 7.0 to 23.1%among 17 prefectures.The model considering prefecture as a random-effect and confounding factors as fixed-effects showed the best-fit for the databased on both the AIC (1,108.06)and BIC (1,113.41).Conclusion:It is difficult to determine if regional differences exist in the safety outcomes of T/PR in Japan because of the limited number of cases. However, the model using prefecture as a random-effect and other confounding factors as fixed-effects would be suitable for estimating parameters that reflect the influence of the prefecture. Further studies using the model would help inform chronic hepatitis C treatment.

Comparison of simeprevir versus telaprevir plus pegylated interferon alfa and ribavirin in patients with hepatitis C virus genotype 1 infection——a meta-analysis / 中华传染病杂志

Objective To compare the efficacy and safety of simeprevir-based (SMV) or telaprevir-based (TVR) triple therapy [SMV + Pegylated interferon alfa (PegIFNα) and ribavirin (RBV) versus TVR + PegIFNαand RBV] in patients with hepatitis C virus (HCV) genotype 1 infection .Methods A systematic literature searching was conducted in multiple online databases to identify relevant studies .The sustained virologic response rate at 12 (SVR12) and 24 weeks (SVR24) after end of the treatment were used as the efficacy endpoints .The rate of treatment related adverse events (AEs) ,discontinuation due to AEs and overall treatment discontinuation were used as safety endpoints . Patients were divided into multiple subgroups according to the previous treatment history to further compare the efficacy of the two treatment regimen .Statistical analyses were performed using the RevMan 5 .3 software .The Jajad score scale and the Newcastle-Ottawa scale were employed to evaluate the quality of included studies .Results A total of 5 clinical studies including 1666 HCV genotype 1 patients were included in this study .The pooled results showed that SVR12 rates in SMV group and TVR group were 67 .6％ and 68 .3％ , respectively .There was no significant difference in overall SVR12 rate between SMV and TVR groups (OR=0 .95 ,95％ CI:0 .76 -1 .18 , P=0 .65) .There was no significant heterogeneity among studies (P=0 .84 ,I2 = 0％ ) .For SVR24 rate ,the average SVR24 rate in SMV group was 78％ ,which was lower than that in TVR group of 84％ .However ,there was no significant difference in overall SVR24 rate between SMV and TVR groups (OR=0 .71 ,95％ CI:0 .42-1 .20 ,P=0 .20) .Meanwhile ,there was no significant heterogeneity among studies (P= 0 .69 ,I2 = 0％ ) .The subgroup analysis also showed that there was no significant difference in efficacy between SMV and TVR-based triple therapy for treatment-native patients ,prior partial response ,relapse ,and prior null response patients (all P>0 .05) .However , the pooled analysis indicated that both SMV-based and TVR-based triple therapies were most effective for the treatment-naive patients(SMV :85 .7％ ,TVR :85 .6％ ) .For the safety endpoints ,the incidence rate of anemia was significant lower in SMV group compared to TVR group (OR=0 .30 ,P<0 .001) .For the rate of overall treatment discontinuation ,there was no statistically significant difference between SMV and TVR group (OR=0 .48 ,P=0 .12) .Conclusions This meta-analysis suggests that the efficacy of SMV-based triple therapy is non-inferior to TVR-based triple therapy .However ,the SMV-based triple therapy is more tolerable and has a lower incident rate of anemia and discontinuation due to AEs compared to TVR-based triple therapy .

Aproximación para establecer y evaluar la relevancia clínica de las interacciones medicamentosas en el tratamiento de pacientes infectados con virus de hepatitis C genotipo 1: Revisión estructurada / A Structured Review of Approaches for Establishing and Evaluating Clinical Relevance of Drug Interactions in Patients with Hepatitis C Virus Genotype 1

Objetivo: establecer y evaluarla relevancia clínica de interacciones medicamentosas en el tratamiento de pacientes con hepatitis C genotipo 1. Método: se realizó una búsqueda en PubMed/MedLine de artículos publicados en inglés y en español, desde el diciembre de 2004 a diciembre de 2014, utilizando los términos Mesh: Hepatitis C AND drug interactions OR herb-drug interactions OR food-drug interactions, de estudios realizados en humanos. Además, la búsqueda se complementó con la revisión, en el mismo período, sobre interacciones de antiretrovirales y hepatitis C en humanos, utilizando los términos Mesh: (Anti-retroviral agents AND Hepatitis C AND drug interactions OR herb-drug interactions OR food-drug interactions). La relevancia clínica de las interacciones medicamentosas se definió y evaluó con base a la probabilidad de ocurrencia y la gravedad de la interacción. Resultados: se identificaron 228 artículos, de los que se pudo acceder al texto completo en 212. De estos, 62 aportaban interacciones, lo que permitió identificar 128 parejas de IM, de las cuales 120 (93,7%) fueron farmacocinéticas y 8 (6,3%) farmacodinámicas. Por su parte, de estas 128 parejas, 2 (1,6%) fueron valoradas de nivel 1: 110 (53,7%) de nivel 2; 16 (7,8%) de nivel 3; y 0 (0%) de nivel 4. Además, se identificaron 78 parejas agrupadas como interacciones con evidencia de ausencia de relevancia clínica. Conclusiones: más del 90% de las interacciones medicamentosas de relevancia clínica son farmacocinéticas asociadas a cambios del metabolismo hepático, el telaprevir fue el medicamento con mayor número de interacciones.

Objective: Our objective was to establish and evaluate the clinical relevance of drug interactions in the treatment of patients with hepatitis C genotype 1. Method: We searched for articles published in English and Spanish from December 2004 to December 2014 in PubMed/MedLine. We used the following Medical Subject Headings (MESH): Hepatitis C and drug interactions OR herb-drug interactions OR food-drug interactions studies performed in humans. We conducted an additional complementary search for articles published in the same period about interactions of anti-retroviral and hepatitis C in humans using the following MESH: (Anti-retroviral agents AND Hepatitis C and drug interactions OR herb-drug interactions OR food -drug interactions). The clinical relevance of drug interactions was defined and evaluated based on the probability of occurrence and severity of interaction. Results: We identified 228 articles. Of these, it was possible to read the full text of 212. Of these, 62 contributed interactions which allowed us to identify 128 pairs of drug interactions, of which 120 (93.7%) were pharmacokinetic and 8 (6.3%) pharmacodynamic. Of these 128 pairs, two (1.6%) were rated Level 1: 110 (53.7%) were Level 2, 16 (7.8%) were Level 3, and 0 (0%) were Level 4. In addition, 78 pairs were identified that were grouped as interactions with evidence of absence of clinical significance. Conclusions: More than 90% of clinically relevant drug interactions are pharmacokinetic interactions associated with hepatic metabolism. Telaprevir has the greatest number of interactions.

Custo-efetividade da Terapia Tripla para pacientes adultos portadores do genótipo 1 da hepatite C crônica / Cost effectiveness of Triple Therepy for adult patients genotype 1 chronic hepatitis C

As ações de prevenção, diagnóstico e tratamento da hepatite C crônica integram as agendas das políticas de saúde do Brasil e do mundo, pois se trata de uma doença com grande número de acometidos, com alto custo tratamento e que ocasiona graves desfechos e incapacidade, o que acaba por onerar seu custo social. Os protocolos clínicos e diretrizes terapêuticas demonstram os esforços de inúmeras entidades no combate da hepatite C, pois informam aos profissionais de saúde, pacientes e familiares e cidadãos em geral, qual seria a melhor forma, comprovada cientificamente, de se proceder frente a uma infecção desta natureza. Realizouse uma análise de custoefetividade, sob a perspectiva do SUS, das estratégias: tratamento e retratamento com a terapia dupla, tratamento com a terapia dupla e retratamento com a terapia tripla e tratamento com a terapia tripla. Através de modelo de simulação baseado em cadeias Markov foi criada uma coorte hipotética de 1000 indivíduos adultos, acima de 40 anos, de ambos os sexos, sem distinção declasse socioeconômica, com diagnóstico confirmado para hepatite C crônica, monoinfectados pelo genótipo 1 do VHC e com ausência de comorbidades. A simulação foi iniciada com todos os indivíduos portando a forma mais branda da doença, tida como a classificação histológica F0 ou F1 segundo a escala Metavir. Os resultados demonstram que as duas opções, ou seja, a terapia dupla/tripla e a terapia tripla estão abaixo do limiar de aceitabilidade para incorporação de tecnologia proposto pela OMS (2012) que é de 72.195 (R$/QALY) (IBGE, 2013; WHO, 2012). Ambas são custoefetivas, visto que o ICER da terapia dupla/tripla em relação alinha de base foi de 7.186,3 (R$/QALY) e o da terapia tripla foi de 59.053,8 (R$/QALY). Entretanto o custo incremental de terapia tripla em relação à dupla/tripla foi de 31.029 e a efetividade incremental foi de 0,52. Em geral, quando as intervenções analisadas encontramse abaixo do limiar, sugerese a adoção do esquema de maior efetividade. A terapia tripla, apesar de ter apresentado uma efetividade um pouco acima da terapia dupla/tripla, apresentou custo muito superior. Assim, como seria coerente a adoção de uma ou da outra para utilização no SUS, visto que este sistema apresenta recursos limitados, indicase a realização de um estudo de impacto orçamentário para obterse mais um dado de embasamento da decisão e assim poder apoiar o protocolo brasileiro existente ou sugerir a confecção de novo documento

The prevention, diagnosis and treatment of chronic hepatitis C integrates health policies in Brazil and worldwide. This disease affect many people, features high cost treatment and cause severe outcomes and disability, increasing social cost. We performed a costeffectiveness analysis under the perspective of SUS, with the following strategies: treatment and retreatment with dual therapy, treatment with dual therapy and retreatment with triple therapy and treatment with triple therapy. A Markov model was developed with a hypothetical cohort of 1000 adults, over 40 years, of both sexes, with confirmed diagnosis for chronic hepatitis C, monoinfected by HCV genotype 1 and absence of comorbidities.The simulation started with all individuals carrying the milder form of the disease, considered F0 or F1, according to Metavir histological classification. The results demonstrate the dual/triple therapy and triple therapy are below the acceptable threshold for embedding technology proposed by the WHO. Both are costeffective. ICER of dual/triple therapy compared with base line was 7186.3 (R$/QALY) and the triple therapy compared with dual/triple therapy was 59053.8 (R$/QALY). However, the incremental cost of triple therapy compared to dual/triple therapy was 31,029 and incremental effectiveness was 0.52. Triple therapy, despite having a little more effectiveness than the dual/triple therapy, showed much highercost. Thus, as would be consistent adopt one or the other for use in the SUS, since this system has limited resources, is better indicate the realization a budget impact analysis to have one more data information to support the decision to continue adopting the Brazilian guideline existing or suggest making another one

Nuevos antivirales frente al VHC: actualidad y perspectivas / New direct acting antiviral for hepatitis C: future perspectives

Aproximadamente 175 millones de personas están infectadas por el virus de la hepatitis C (VHC), lo que representa un 3% de la población mundial. En ausencia de tratamiento eficaz, un 25% de los pacientes desarrollan complicaciones hepáticas tras 25 años de hepatitis crónica C. Hasta hace poco, la única opción terapéutica en estos pacientes era la combinación de interferón pegilado (peg-IFN) y ribavirina (RBV). Alcanzaban la erradicación del VHC un 30-40% de los pacientes infectados con el genotipo 1 del VHC. Recientes avances han permitido desarrollar replicones y sistemas de cultivo tisulares para el VHC. Esto ha facilitado el diseño de fármacos antivirales directos (DAA) que inhiben específicamente la replicación del VHC. Los dos primeros inhibidores de la proteasa del VHC fueron aprobados en mayo de 2011. Permiten obtener tasas de curación en el 70% de los pacientes infectados con el genotipo 1 sin experiencia previa a interferón. La respuesta es menor en pacientes con fracasos previos, excepto en los recidivantes, en los que tasa de curación es del 90%...

Approximately 175 million people worldwide are chronically infected with the hepatitis C virus (HCV), representing 3% of the total world population. In the absence of successful therapy nearly 25% of these patients will develop hepatic complications within 25 years. Until recently, the only available therapeutic option for these patients was the combination of peginterferon-a plus ribavirin. Overall it allowed achievement of eradication in only 30-40% of patients infected by HCV genotype 1. The development of HCV replicons and the chance of producing infectious viral particles in culture systems have both enabled the rational design of direct-acting antivirals (DAA) that specifically inhibit HCV replication. The first two HCV protease inhibitors were marketed in May 2011. Triple therapy has increased the response rate to 70% in HCV genotype 1 carrier naïve to interferon. Although response rates are lower in prior failures, 90% sustained virological response rates are achieved in prior relapsers...

Aproximación al paciente con hepatitis C que ha fallado al tratamiento antiviral / Management of hepatitis C patient who failed to respond to antiviral treatment

The patient who fails to an interferon based treatment with or without ribavirin represents a major challenge for the clinician. In the initial evaluation a detailed history of the first course of treatment is critical, since it largely determines the likelihood of response to retreatment. In addition, the use of adequate doses of ribavirin and excellent adherence are key for a successful therapy. During re-treatment, a viral load detectable at 12 weeks at any level is considered an indication to discontinue treatment because of the low probability of achieving sustained response. There are new direct antiviral agents (protease inhibitors) that have been shown to increase response rate in patients who previously failed treatment, nevertheless, these drugs have limitations, such as high cost, activity restricted to certain genotypes, additional adverse effects and low response in previous null-responders. There is great optimism in the development of multiple new therapies with different mechanisms of action that promise to significantly increase the chances of eradicating the virus in these difficult to treat patients.

El paciente que ha fallado a un tratamiento sobre la base de interferón, con o sin ribavirina representa un desafío importante para el clínico. En su enfrentamiento inicial es clave una historia detallada del primer curso de tratamiento, ya que en gran parte determina la posibilidad de respuesta a un re-tratamiento. Por otro lado, el uso de dosis adecuadas de ribavirina y una excelente adherencia son claves en el éxito de la terapia. Durante un re-tratamiento, una carga viral a las 12 semanas detectable en cualquier nivel se considera indicación de suspender el tratamiento por la baja probabilidad de lograr respuesta sostenida. Se debe considerar que existen nuevas drogas antivirales directas (inhibidores de proteasa) que han demostrado aumentar la tasa de respuesta en pacientes que previamente han fallado al tratamiento, no obstante, estas drogas tienen limitaciones tales como alto costo, efectividad restringida a algunos genotipos, efectos adversos adicionales y baja respuesta en pacientes respondedores nulos a un tratamiento previo. Existe gran optimismo en el desarrollo de múltiples nuevas terapias con diferentes mecanismos de acción que prometen aumentar en forma significativa la posibilidad de erradicar el virus en este grupo de pacientes difícil de tratar.