Treatment of Hepatitis C with Direct-Acting Antivirals does not Induce Significant Arrhythmias

Abstract Background Chronic Hepatitis C (CHC) therapy with direct-acting antivirals (DAAs) has high efficacy and safety, but some cases of bradyarrhythmias have been described. Objective To evaluate heart rhythm disorders during DAA treatments. Methods Forty-eight patients with CHC (mean 61 years of age; 56% males; 73% HCV genotype 1) were evaluated before and during treatment with DAAs, analyzed by a resting 12-lead ECG [PR, QRS, and QT corrected (QTc) intervals measured] and a 24-h-Holter system, to evaluate the heart rate (HR) and the occurrence of arrhythmias. The Student's t-test or the Wilcoxon-Mann-Whitney test for continuous, independent variables were performed with a statistically significant p-value < 0.05. Results The electrocardiographic parameters before and during treatment were: PR interval (147.2 ± 15.6 vs 144.9 ± 15.6 ms; p = 0.21), QTc interval (427 ± 22.3 vs 421.7 ± 25.3 ms; p = 0.24), minimum HR (52.7 ± 8.4 vs 53.2 ± 8.5 bpm; p = 0.49), median HR (74.2 ± 10.4 vs 75.2 ± 9 bpm; p = 0.83), and maximum HR (117.4 ± 16.8 vs 117.9 ± 16.3 bpm; p = 0.25). These parameters proved to be similar among 11 beta-blockers or 22 ribavirin users. During treatment, the 21 cirrhotic patients presented significantly lower median HRs (72.1 ± 9.0 vs 77.9 ± 8.2 bpm; p = 0.02) and maximum HRs (108.9 ± 15.2 vs. 125.1 ± 13.2 bpm, p < 0.0001) through a 24-h-Holter monitoring than the patients without cirrhosis. No clinically relevant arrhythmias were detected. Conclusion DAAs do not significantly influence heart rate or induce significant cardiac arrhythmias in patients with CHC.

Tratamiento actual de la hepatitis C en Colombia / Current treatment for hepatitis C in Colombia

La infección por el virus de hepatitis C (VHC) es una epidemia global que afecta a 71 millones de personas. El diagnóstico inicial se hace mediante la detección de anticuerpos contra el VHC, que luego requiere una prueba confirmatoria molecular, debido a que la determinación de anticuerpos no diferencia los individuos que tienen una infección activa, de aquellos con una infección resuelta y sin viremia. El objetivo del tratamiento de la infección crónica por VHC es curar la enfermedad, lo que se determina cuando se logra una respuesta viral sostenida; es decir, cuando no se detecta carga viral 12 semanas o más después de terminada la terapia. Para un tratamiento óptimo de la infección y alcanzar la curación, se recomienda evaluar previamente de manera no invasiva el estadio de fibrosis, y garantizar la adherencia durante todo el tiempo de tratamiento. En la presente revisión se incluyen las recomendaciones para el tratamiento de la infección crónica por VHC, según el genotipo viral, basadas en los medicamentos disponibles en nuestro medio y en los que próximamente estarán llegando al país.

Abstract Infection with hepatitis C virus (HCV) is a global epidemic that affects 71 million people. Initial diagnosis is made by detecting antibodies against HCV, which then requires a confirmatory molecular assay in order to discriminate individuals who have an active infection from those with a resolved infection and without active viremia. The goal of treating chronic HCV infection is to cure the disease, which is determined when a sustained virological response is achieved; that is, when viral load is not detected 12 weeks or more after completing treatment. For an optimal treatment of the infection and to achieve a cure, it is recommended to previously and non-invasively evaluate the fibrosis stage, and to guarantee adherence throughout the treatment period. This review includes some guidelines for the treatment of chronic HCV infection, according to the viral genotype, and based on the drugs available and soon to be available in our country.

Association between the IL28B rs12979860 POLYMORPHISM and therapy response in patients infected with genotype 1 of hepatitis c virus in central Brazil

Single nucleotide polymorphisms (SNPs) upstream of the IL28B gene have been associated with the spontaneous clearance of hepatitis C virus (HCV) and with a sustained virological response (SVR) to HCV infection treatment. This study aimed to investigate the association between IL28B SNP rs12979860 and SVR in patients with hepatitis C in Central Brazil. A total of 101 HCV genotype 1 mono-infected chronic patients treated with pegylated interferon and ribavirin (PEG-IFN/RBV) were studied in the City of Goiânia, Central Brazil. Analysis of rs12979860 showed that the most prevalent genotype was CT (57.4%), followed by CC (23.8%) and TT (18.8%). An overall SVR rate of 28.7% (95% CI: 20.4-38.7) was found in the study population. In a multivariate analysis, only IL28B rs12979860 CC genotype (OR: 3.77; 95% CI: 1.13-12.60; p = 0.031) was associated with SVR. These findings show that IL28B SNP rs12979860 is a strong predictor of SVR in the PEG-IFN/RBV treatment in patients infected with genotype 1 of HCV in Central Brazil

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.

Treatment of hepatitis C virus genotype 3 infection with direct-acting antiviral agents

Hepatitis C virus (HCV) genotype 3 is responsible for 30.1% of chronic hepatitis C infection cases worldwide. In the era of direct-acting antivirals, these patients have become one of the most challenging to treat, due to fewer effective drug options, higher risk of developing cirrhosis and hepatocellular carcinoma and lower sustained virological response (SVR) rates. Currently there are 4 recommended drugs for the treatment of HCV genotype 3: pegylated interferon (PegIFN), sofosbuvir (SOF), daclatasvir (DCV) and ribavirin (RBV). Treatment with PegIFN, SOF and RBV for 12 weeks has an overall SVR rate of 83–100%, without significant differences among cirrhotic and non-cirrhotic patients. However, this therapeutic regimen has several contraindications and can cause significant adverse events, which can reduce adherence and impair SVR rates. SOF plus RBV for 24 weeks is another treatment option, with SVR rates of 82–96% among patients without cirrhosis and 62–92% among those with cirrhosis. Finally, SOF plus DCV provides 94–97% SVR rates in non-cirrhotic patients, but 59–69% in those with cirrhosis. The addition of RBV to the regimen of SOF plus DCV increases the SVR rates in cirrhotic patients above 80%, and extending treatment to 24 weeks raises SVR to 90%. The ideal duration of therapy is still under investigation. For cirrhotic patients, the optimal duration, or even the best regimen, is still uncertain. Further studies are necessary to clarify the best regimen to treat HCV genotype 3 infection.

Chronic Hepatitis C treatment for genotype 2 or 3 in Brazil: cost effectiveness analysis of peginterferon plus ribavirin as first choice treatment

Brazilian Guidelines to HCV treatment (2007) recommended that the first choice treatment for patients with chronic hepatitis C (CHC) and genotype 2 or 3 is interferon alpha (IFN) plus ribavirin (RBV) for 24 weeks. The aim of this study is compare the cost and effectiveness to Hepatitis C treatment in patients with genotype 2 or 3 of peginterferon alpha (PEG) as the first choice of treatment within PEG for those that do not respond to IFN. The target population is CHC patients with genotype 2 or 3 in Brazil. The interventions are: PEG-SEC (first IFN plus RBV for 24 weeks, after, for non-responders and relapsers subsequently PEG plus RBV for 48 weeks); PEG-FIRST24 (PEG+RBV for 24 weeks). The type of the study is cost-effectiveness analysis. The data sources are: Effectiveness data from meta-analysis conducted on the Brazilian population. Treatment cost from Brazilian micro costing study is converted into USD (2010). The perspective is the Public Health System. The outcome measurements are Sustained Viral Response (SVR) and costs. PEG-FIRST24 (SVR: 87.8%, costs: USD 8,338.27) was more effective and more costly than PEG-SEC (SVR: 79.2%, costs: USD 5,852.99). The sensitivity analyses are: When SVR rates with IFN was less than 30% PEG-FIRST is dominant. On the other hand, when SVR with IFN was more then 75% PEG-SEC is dominant (SVR=88.2% and costs USD $ 3,753.00). PEG-SEC is also dominant when SVR to PEG24 weeks was less than 54%. In the Brazilian context, PEG-FIRST is more effective and more expensive than PEG-SEC. PEG-SEC could be dominant when rates of IFN therapy are higher than 75% or rates of PEG24 therapy are lower than 54%.

O protocolo brasileiro de tratamento da Hepatite C (2007) recomendava como primeira escolha para pacientes com hepatite C crônica e portadores de genótipo 2 ou 3 o tratamento com interferona alfa (IFN) associada à ribavirina (RBV), por 24 semanas. O objetivo deste estudo é comparar o custo e a efetividade para pacientes com hepatite C crônica e portadores do genótipo 2 ou 3 o uso de peguinterferon (PEG) como primeiro escolha com o PEG como secunda escolha para aqueles que não responderam ao tratamento com IFN. A população alvo compreende pacientes com hepatite C crônica portadores de genótipo 2 ou 3 no Brasil. As intervenções são: PEG-SEC (IFN + RBV por 24 semanas, para os não respondedores e recidivantes tratamento subsequente com PEG + RBV por 48 semanas; PEG-FIRST24 (PEG + RBV por 24 semanas). O tipo de estudo envolvido é Análise de Custo Efetividade. Os dados de efetividade são provenientes de um metanálise de estudos brasileiros e os dados de custo do tratamento de um estudo de custo do contexto brasileiro. A perspectiva é o Sistema Público de Saúde. Os desfechos avaliados foram Resposta Viral Sustentada (RVS) e Custos. PEG-FIRST24 (RVS: 87,8%, costs: USD 8.338,27) foi mais efetivo e apresentou maior custo que PEG-SEC (RVS: 79,2%, custo USD 5.852,99). A análise de sensibilidade demonstrou que PEG-SEC é dominado por PEG-FIRST24 quando RVS com IFN for menor que 30%. Por outro lado, quando RVS com IFN for maior que 75% PEG-SEC é dominante (RVS=88.2% e custo USD $ 3.753,00). PEG-SEC é também dominante quando RVS para PEG24 for menor que 54%. Conclusão: No contexto brasileiro, PEG-FIRST é mais efetivo e mais custoso que PEG-SEC. PEG-SEC poderia ser dominante quando as taxas de RVS do tratamento com IFN forem superiores a 75% ou as taxas de PEG24 forem inferiores a 54%.

Evaluation of the therapeutic response of hepatitis C in coinfected patients (HIV/HCV): a study of cases from a hospital for chronic liver diseases in the Eastern Brazilian Amazon

INTRODUCTION: The aim of this study was to evaluate the therapeutic response of hepatitis C in patients coinfected with human immunodeficiency virus (HIV-1). METHODS: A retrospective study of 20 patients coinfected with HIV-1/HCV who were treated in the outpatient liver clinic at the Sacred House of Mercy Foundation Hospital of Pará (Fundação Santa Casa de Misericórdia do Pará - FSCMPA) from April 2004 to June 2009. Patients were treated with 180µg PEG interferon-α2a in combination with ribavirin (1,000 to 1,250mg/day) for 48 weeks. The end point was the sustained virological response (SVR) rate (HCV RNA negative 24 weeks after completing treatment). RESULTS: The mean age of the patients was 40±9.5 years, of which 89% (n=17) were male, and the HCV genotypes were genotype 1 (55%, n=11/20), genotype 2 (10%, n=2/20) and genotype 3 (35%, n=7/20). The mean CD4+ lymphocyte count was 507.8, and the liver fibrosis stages were (METAVIR) F1 (25%), F2 (55%), F3 (10%) and F4 (10%). The early virological response (EVR) was 60%, the end-of-treatment virological response (EOTVR) was 45% and the SVR was 45%. CONCLUSIONS: The median HCV viral load was high, and in 85% of cases in which highly active antiretroviral therapy (HAART) was used, none of the patients with F3-F4 fibrosis responded to treatment. Of the twenty patients treated, 45% achieved SVR and 45% achieved EOTVR. Studies that include cases from a wider region are needed to better evaluate these findings.