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BACKGROUND & AIMS: Sub-Saharan African (SSA) ethnicity has been associated with a higher risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis B in cross-sectional studies. However, the incidence of HCC and performance of HCC risk scores in this population are unknown. METHODS: We conducted an international multicenter retrospective cohort study of all consecutive HBV-monoinfected individuals of SSA or Afro-Surinamese (AS) ethnicity managed at sites in the Netherlands, the United Kingdom and Spain. We assessed the 5- and 10-year cumulative incidences of HCC in the overall study population, among different clinically relevant subgroups and across (m)PAGE-B subgroups. Next, we explored the different risk factors for HCC. RESULTS: During a median follow-up of 8 years, we analyzed 1,473 individuals of whom 34 developed HCC. The 5- and 10-year cumulative incidences of HCC were 1% and 2.4%. The 10-year cumulative incidence of HCC was 0.7% among individuals without advanced fibrosis at baseline, compared to 12.1% among individuals with advanced fibrosis (p <0.001). Higher age (adjusted hazard ratio [aHR] 1.05), lower platelet count (aHR 0.98), lower albumin level (aHR 0.90) and higher HBV DNA log10 (aHR 1.21) were significantly associated with HCC development. The 10-year cumulative incidence of HCC was 0.5% among individuals with a low PAGE-B score, compared to 2.9% in the intermediate- and 15.9% in the high-risk groups (p <0.001). CONCLUSIONS: In this unique international multicenter cohort of SSA and AS individuals with chronic hepatitis B, we observed 5- and 10-year cumulative HCC risks of 1% and 2.4%, respectively. The risk of HCC was negligible for individuals without advanced fibrosis at baseline, and among individuals with low baseline (m)PAGE-B scores. These findings can be used to guide HCC surveillance strategies. IMPACT AND IMPLICATIONS: Sub-Saharan African ethnicity has been associated with a higher risk of hepatocellular carcinoma among individuals with chronic hepatitis B. In this international multicenter cohort study of sub-Saharan African and Afro-Surinamese individuals living with chronic hepatitis B in Europe, we observed 5- and 10-year cumulative incidences of hepatocellular carcinoma of 1% and 2.4%, respectively. The risk was negligible among individuals without advanced fibrosis and a low baseline (m)PAGE-B score. These findings can be used to guide HCC surveillance strategies in this population.
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Carcinoma Hepatocelular , Hepatitis B Crónica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/tratamiento farmacológico , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/epidemiología , Hepatitis B Crónica/tratamiento farmacológico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/tratamiento farmacológico , Estudios de Cohortes , Estudios Retrospectivos , Estudios Transversales , Antivirales/uso terapéutico , Factores de Riesgo , Europa (Continente) , Fibrosis , África del Sur del Sahara/epidemiología , Virus de la Hepatitis B/genéticaRESUMEN
BACKGROUND: Dietary supplementation with branched-chain amino acids (BCAA) is often used in cirrhotic patients to improve nutritional status. We wanted to explore the evidence for BCAA supplementation in chronic liver disease. METHODS: We searched MEDLINE and EMBASE for studies with BCAA supplementation with the presence of a disease-control group (placebo or no intervention) using search terms 'liver cirrhosis', 'hepatocellular carcinoma', 'branched chain amino acids' and relevant synonyms. Risk of bias was assessed using ROBINS-I and RoB 2.0 tools. Meta-analyses were performed with a random-effects model. Results were reported following EQUATOR guidelines. RESULTS: Of 3378 studies screened by title and abstract, 54 were included (34 randomized controlled trials, 5 prospective case-control studies, 13 retrospective case-control studies: in total 2308 patients BCAA supplementation, 2876 disease-controls). Risk of bias was high/serious for almost all studies. According to meta-analyses, long-term (at least 6 months) BCAA supplementation in cirrhotic patients significantly improved event-free survival (p = .008; RR .61 95% CI .42-.88) and tended to improve overall survival (p = .05; RR .58 95% CI .34-1.00). Two retrospective studies suggested the beneficial effects during sorafenib for hepatocellular carcinoma. Available studies reported no beneficial effects or contradictory results of BCAA after other specific therapeutic interventions (resection or radiological interventions for hepatocellular carcinoma, liver transplantation, paracentesis or variceal ligation). No convincing beneficial effects of BCAA supplementation on liver function, nutritional status or quality of life were found. No study reported serious side effects of BCAA. CONCLUSIONS: Prophylactic BCAA supplementation appears safe and might improve survival in cirrhotic patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Aminoácidos de Cadena Ramificada/uso terapéutico , Aminoácidos de Cadena Ramificada/efectos adversos , Suplementos Dietéticos , Cirrosis Hepática/inducido químicamente , Calidad de Vida , Estudios RetrospectivosRESUMEN
BACKGROUND: High dose unilobar radioembolization (also termed 'radiation lobectomy')-the transarterial unilobar infusion of radioactive microspheres as a means of controlling tumour growth while concomitantly inducing future liver remnant hypertrophy-has recently gained interest as induction strategy for surgical resection. Prospective studies on the safety and efficacy of the unilobar radioembolization-surgery treatment algorithm are lacking. The RALLY study aims to assess the safety and toxicity profile of holmium-166 unilobar radioembolization in patients with hepatocellular carcinoma ineligible for surgery due to insufficiency of the future liver remnant. METHODS: The RALLY study is a multicenter, interventional, non-randomized, open-label, non-comparative safety study. Patients with hepatocellular carcinoma who are considered ineligible for surgery due to insufficiency of the future liver remnant (< 2.7%/min/m2 on hepatobiliary iminodiacetic acid scan will be included. A classical 3 + 3 dose escalation model will be used, enrolling three to six patients in each cohort. The primary objective is to determine the maximum tolerated treated non-tumourous liver-absorbed dose (cohorts of 50, 60, 70 and 80 Gy). Secondary objectives are to evaluate dose-response relationships, to establish the safety and feasibility of surgical resection following unilobar radioembolization, to assess quality of life, and to generate a biobank. DISCUSSION: This will be the first clinical study to assess the unilobar radioembolization-surgery treatment algorithm and may serve as a stepping stone towards its implementation in routine clinical practice. TRIAL REGISTRATION: Netherlands Trial Register NL8902 , registered on 2020-09-15.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/radioterapia , Microesferas , Estudios Prospectivos , Calidad de Vida , Neoplasias Hepáticas/radioterapia , Hepatomegalia , Estudios Multicéntricos como AsuntoRESUMEN
Hepatitis E virus infection can cause chronic hepatitis in immunocompromised patients with significant chance of progressive fibrosis and possibly cirrhosis. The aim of this systematic review was to summarize the efficacy and safety of the various treatment options for chronic hepatitis E. We performed a systematic literature search. The primary outcome measure was a sustained virological response (SVR). Secondary end points were rapid virological response (RVR), relapse rates, side effects and adverse events. Forty-four articles were included with a total of 582 patients. Reduction of immunosuppressive medication induced viral clearance in 55/174 (32%) of the patients. Meta-analysis of 395 patients showed a pooled SVR rate of 78% (95-CI 72%-84%) after ribavirin treatment. Twenty-five per cent of the patients obtained a RVR, whereas a relapse occurred in 18% of the patients. Anaemia during treatment led to dose reduction, use of erythropoietin and/or blood transfusion in 37% of the patients. A second treatment attempt with ribavirin led to a SVR in 39/51 (76%) of the patients. Pegylated interferon-alpha was administered to 13 patients and SVR was obtained in 85%. Two patients (15%) suffered from acute transplant rejection during treatment with interferon. In conclusion, reduction of immunosuppressive medication and treatment with ribavirin is safe, generally well tolerated and induced viral clearance in 32% and 78% of patients, respectively. Therefore, ribavirin should be considered as first treatment step for chronic hepatitis E. Treatment with pegylated interferon-alpha increases the risk of transplant rejection and should therefore be administered with great caution.
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Virus de la Hepatitis E , Hepatitis E , Antivirales/efectos adversos , Quimioterapia Combinada , Hepacivirus , Hepatitis E/tratamiento farmacológico , Humanos , Interferón-alfa , Polietilenglicoles , Proteínas Recombinantes , Ribavirina/efectos adversos , Resultado del TratamientoRESUMEN
The aim of this study was to define the therapeutic range for ribavirin (RBV) in transplant recipients with chronic hepatitis E virus (HEV) infection. In this retrospective multicentre cohort study, data of adult transplant recipients with chronic HEV infection, who had been treated with RBV monotherapy between 01-3-2008 and 01-08-2018, were included. ROC curve analyses were performed, and the half-maximal effective RBV concentration was calculated to determine a representative therapeutic range. In 96 patients, RBV monotherapy for a median of three months resulted in a sustained virologic response in 63.5% of the patients, while 88.5% of the patients developed anaemia. RBV plasma concentrations at steady state were significantly higher in clinical responders compared with clinical non-responders: median 1.96 (IQR 1.81-2.70) versus 0.49 (IQR 0.45-0.73) mg/L, P = .0004. RBV caused a dose-dependent haemoglobin reduction with higher RBV plasma concentrations resulting in more haemoglobin reduction. The therapeutic range for RBV for chronic HEV infection in transplant recipients ranges between 1.8 and 2.3 mg/L.
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Virus de la Hepatitis E , Hepatitis E , Adulto , Antivirales/uso terapéutico , Estudios de Cohortes , Quimioterapia Combinada , Hepatitis E/tratamiento farmacológico , Humanos , Estudios Retrospectivos , Ribavirina/uso terapéutico , Receptores de TrasplantesRESUMEN
Background & Aims: High-dose unilobar radioembolization, or 'radiation lobectomy' (RL), is an induction therapy that achieves contralateral future liver remnant hypertrophy while simultaneously irradiating the tumor. As such, it may prevent further growth, but it is unknown whether RL affects intrahepatic lymphatics, a major route via which liver tumors disseminate. Methods: This was a case-control study conducted at University Medical Center Utrecht. The study compared lymph vessels in livers that had undergone RL (cases) with those in livers that had not undergone RL (controls). Histological samples were acquired from patients diagnosed with hepatocellular carcinoma (HCC) or colorectal liver metastases (CRLM) between 2017 and 2022. Lymph vessel morphology was analyzed by two researchers using podoplanin, a protein that is expressed in lymphatic endothelium. In vivo liver lymph drainage of radioembolized livers was assessed using intraoperative liver lymphangiography (ILL): during liver surgery, patent blue dye was injected into the liver parenchyma, followed by inspection for staining of perihepatic lymph structures. ILL results were compared to a previously published cohort. Results: Immunohistochemical analysis on post-RL tumor tissues from ten patients with CRLM and nine patients with HCC revealed aberrant morphology of irradiated liver lymphatics when compared to controls (n = 3 per group). Irradiated lymphatics were tortuous (p <0.05), thickened (p <0.05) and discontinuous (p <0.05). Moreover, post-RL lymphatics had larger lumens (1.5-1.7x, p <0.0001), indicating lymph stasis. ILL revealed diminished lymphatic drainage to perihepatic lymph nodes and vessels in irradiated livers when compared to non-radioembolized controls (p = 1.0x10-4). Conclusions: Radioembolization impairs peritumoral lymph vessel function. Further research is needed to evaluate if radioembolization impairs tumor dissemination via this route. Impact and implications: Unilobar radioembolization can serve as an alternative to portal venous embolization for patients who are considered unresectable due to an insufficient future liver remnant. This research suggests that radioembolization impairs the function of peritumoral liver lymph vessels, potentially hindering dissemination via this route. These findings provide support for considering unilobar radioembolization over standard portal venous embolization.
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PURPOSE: Hepatic Arteriography and C-Arm CT-Guided Ablation of liver tumors (HepACAGA) is a novel technique, combining hepatic-arterial contrast injection with C-arm CT-guided navigation. This study compared the outcomes of the HepACAGA technique with patients treated with conventional ultrasound (US) and/or CT-guided ablation. MATERIALS AND METHODS: In this retrospective cohort study, all consecutive patients with hepatocellular carcinoma (HCC) or colorectal liver metastases (CRLM) treated with conventional US-/CT-guided ablation between 1 January 2015, and 31 December 2020, and patients treated with HepACAGA between 1 January 2021, and 31 October 2023, were included. The primary outcome was local tumor recurrence-free survival (LTRFS). Secondary outcomes included the local tumor recurrence (LTR) rate and complication rate. RESULTS: 68 patients (120 tumors) were included in the HepACAGA cohort and 53 patients (78 tumors) were included in the conventional cohort. In both cohorts, HCC was the predominant tumor type (63% and 73%, respectively). In the HepACAGA cohort, all patients received microwave ablation. Radiofrequency ablation was the main ablation technique in the conventional group (78%). LTRFS was significantly longer for patients treated with the HepACAGA technique (p = 0.015). Both LTR and the complication rate were significantly lower in the HepACAGA cohort compared to the conventional cohort (LTR 5% vs. 26%, respectively; p < 0.001) (complication rate 4% vs. 15%, respectively; p = 0.041). CONCLUSIONS: In this study, the HepACAGA technique was safer and more effective than conventional ablation for HCC and CRLM, resulting in lower rates of local tumor recurrence, longer local tumor recurrence-free survival and fewer procedure-related complications.
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In the TMC435-C101 study, 6 patients infected with hepatitis C virus genotype 1 were treated with the protease inhibitor TMC435 (200 mg once daily) as monotherapy for 5 days. Approximately 1.5 years later, 5 of these patients were re-treated with TMC435 (200 mg once daily) plus pegylated interferon alfa-2a and ribavirin (PegIFNα-2a and RBV) for 4 weeks, followed by PegIFNα-2a and RBV until week 48 (in the Optimal Protease inhibitor Enhancement of Response to therApy [OPERA-1] study). TMC435-resistant variants, which emerged in all 5 patients during the TMC435-C101 study, were no longer detected at the beginning of the OPERA-1 study based on virus population sequencing. During the OPERA-1 study, 3 patients had a sustained virologic response; deep sequencing indicated low-level persistence of resistant variants in the remaining 2 patients, which might have affected their response to re-treatment.
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Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , ARN Viral/sangre , Sulfonamidas/uso terapéutico , Antivirales/uso terapéutico , Farmacorresistencia Viral , Quimioterapia Combinada , Genotipo , Hepatitis C/sangre , Hepatitis C/virología , Humanos , Interferón-alfa/uso terapéutico , Masculino , Mutación , Polietilenglicoles/uso terapéutico , ARN Viral/efectos de los fármacos , Proteínas Recombinantes/uso terapéutico , Ribavirina/uso terapéutico , Simeprevir , Carga ViralRESUMEN
PURPOSE: We present a technique that combines Hepatic Arteriography with C-arm CT-Guided Ablation (HepACAGA) to improve tumor visualization, navigation and margin confirmation for percutaneous ablation of liver tumors. MATERIALS AND METHODS: All consecutive patients scheduled for HepACAGA between April 20th, 2021, and November 2nd, 2021, were included in this retrospective, cohort study. HepACAGA was performed in an angiography-suite under general anesthesia. The hepatic artery was catheterized for selective contrast injection. C-arm CT and guidance software were then used to visualize the tumor and the microwave antenna was inserted during apnea. Pre- and post-ablation C-arm CTs were performed and ablation margins assessed. Technical success, antenna placement deviation, number of repositions, tumor recurrence, and safety were evaluated. Technical success was defined as a tumor that was ablated according to the HepACAGA technique. RESULTS: A total of 21 patients (28 tumors) were included. The main tumor type was colorectal cancer liver metastases (11/21, 52%), followed by hepatocellular carcinoma (7/21, 33%), neuroendocrine tumor metastases (1/21, 5%), and other tumor types (2/21, 10%). The technical success rate was 93% (26/28 tumors) with two small hypovascular lesions unable to be identified. A single microwave antenna was used in all patients. The median antenna placement deviation was 1 mm (range 0-6 mm). At a median follow-up time of 16 months (range 5-22 months), there was no tumor recurrence in any patient. Safety analysis showed a complication rate of 5% grade 2 and 5% grade 3. CONCLUSION: HepACAGA was demonstrated to be a safe and effective percutaneous ablation technique, without any local tumor recurrence in this study.
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PURPOSE: Trans-arterial radioembolization is a well-studied tumoricidal treatment for liver malignancies; however, consensus and evidence regarding periprocedural prophylactic medication (PPM) are lacking. METHODS: A single-center retrospective analysis from 2014 to 2020 was performed in patients treated with 90Y-glass microspheres for neuroendocrine or colorectal liver metastases. Inclusion criteria were the availability of at least 3 months of clinical, biochemical, and imaging follow-up and post-treatment 90Y-PET/CT imaging for the determination of the whole non-tumorous liver absorbed dose (Dh). Logistic regression models were used to investigate if variables (among which are P/UDCA and Dh) were associated with either clinical toxicity, biochemical toxicity, or hepatotoxicity. Additionally, a structured literature search was performed in November 2022 to identify all publications related to PPM use in radioembolization treatments. RESULTS: Fifty-one patients received P/UDCA as post-treatment medication, while 19 did not. No correlation was found between toxicity and P/UDCA use. Dh was associated with biochemical toxicity (p = 0.05). A literature review resulted in eight relevant articles, including a total of 534 patients, in which no consistent advice regarding PPM was provided. CONCLUSION: In this single-center, retrospective review, P/UDCA use did not reduce liver toxicity in patients with metastatic liver disease. The whole non-tumorous liver-absorbed dose was the only significant factor for hepatotoxicity. No standardized international guidelines or supporting evidence exist for PPM in radioembolization.
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BACKGROUND: Impaired nutritional status is a risk factor for unfavorable outcome in cirrhosis. METHODS: In this prospective cohort study in hepatocellular carcinoma patients referred for tumor-specific therapy, nutritional status was assessed before and 3 months post-treatment using 4 complementary tools: hand-grip strength (HGS), Liver Frailty Index (LFI), Patient-Generated Subjective Global Assessment (PG-SGA) and skeletal muscle index (L3-SMI). Uni- and multivariable analyses were performed using Kaplan Meier curves and Cox's regression analyses with correction for Barcelona Clinic Liver Cancer (BCLC) stage, alpha-fetoprotein and age. RESULTS: 56 patients were evaluated at baseline and 38 patients 3 months post-treatment. Baseline BCLC stage was 0 in 14%, A in 27%, B in 36%, C in 21%, and D in 2%. HGS, LFI, PG-SGA and L3-SMI were impaired in 13%, 95%, 21% and 71% respectively. Of all patients, 52% died after (median, range) 373 (32-962) days. Of the nutritional assessment tools, only HGS was independently associated with complication-free survival (HR 0.304, 95%CI 0.10-0.88: p = 0.028) and, approaching significance, with overall survival (HR 0.323, 95%CI 0.103-1.008: p = 0.052). Tumor-specific therapy was administered in 50 patients (20% radiofrequency / microwave ablation, 4% resection, 74% transarterial radio- or chemoembolization, 2% sorafenib). Three months post-treatment, complete response occurred in 44%, partial response in 20%, stable disease in 20% and progressive disease in 16%. Child-Pugh scores deteriorated and such deterioration was independently associated with reduced overall and complication-free survival. CONCLUSIONS: reduced baseline HGS and deteriorated post-treatment Child-Pugh score are associated with reduced overall and complication-free survival in HCC.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica/efectos adversos , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/terapia , Estadificación de Neoplasias , Estado Nutricional , Estudios Prospectivos , Estudios Retrospectivos , Sorafenib/uso terapéutico , Resultado del Tratamiento , alfa-Fetoproteínas/uso terapéuticoRESUMEN
UNLABELLED: Narlaprevir (SCH 900518) is a potent inhibitor of the hepatitis C virus (HCV) nonstructural protein 3 serine protease that is primarily metabolized by the cytochrome P450-3A4 system. In order to explore the use of ritonavir-based pharmacokinetic enhancement of an HCV protease inhibitor, this study investigated the safety, tolerability, pharmacokinetics, and antiviral activity of narlaprevir (with or without ritonavir) administered as monotherapy and as combination therapy with pegylated interferon-α-2b (PEG-IFN-α-2b) to HCV genotype 1-infected patients. This was a randomized, placebo-controlled, two-period, blinded study in 40 HCV genotype 1-infected patients (naïve and treatment-experienced). In period 1, narlaprevir was administered for 7 days as 800 mg three times daily without ritonavir or 400 mg twice daily with 200 mg ritonavir twice daily. In period 2, after a 4-week washout, the same dose and regimen of narlaprevir was administered in combination with PEG-IFN-α-2b for 14 days. Upon completion of period 2, all patients initiated PEG-IFN-α-2b and ribavirin treatment. A rapid and persistent decline in plasma HCV-RNA was observed in both treatment-experienced and treatment-naïve patients during period 1, with a mean viral load decline of at least 4 log10 in all treatment groups. A high percentage of both treatment-experienced (50%) and treatment-naïve (≥ 60%) patients had undetectable HCV-RNA (< 25 IU/mL) after period 2. Standard of care resulted in sustained virological response (SVR) rates of 38% and 81% in treatment-experienced and treatment-naïve patients, respectively. Narlaprevir (with or without ritonavir) alone or in combination with PEG-IFN-α-2b was safe and well tolerated. CONCLUSION: Narlaprevir administration resulted in a robust HCV-RNA decline and high SVR rates when followed by standard of care in both treatment-experienced and treatment-naïve HCV genotype 1-infected patients.
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Antivirales/uso terapéutico , Dipéptidos/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ritonavir/uso terapéutico , Sulfonas/uso terapéutico , Adulto , Anciano , Antivirales/administración & dosificación , Ciclopropanos , Dipéptidos/administración & dosificación , Dipéptidos/farmacocinética , Esquema de Medicación , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/genética , Humanos , Pacientes Internos , Interferón alfa-2 , Leucina/análogos & derivados , Masculino , Persona de Mediana Edad , Pacientes Ambulatorios , Prolina/análogos & derivados , ARN Viral/sangre , Proteínas Recombinantes , Recurrencia , Ritonavir/administración & dosificación , Sulfonas/administración & dosificación , Sulfonas/farmacocinética , Urea , Adulto JovenRESUMEN
Hepatitis C virus (HCV) genotype 4 (HCV-4) infection is considered to be difficult to treat and has become increasingly prevalent in European countries, including The Netherlands. Using a molecular epidemiological approach, the present study investigates the genetic diversity and evolutionary origin of HCV-4 in Amsterdam, The Netherlands. Phylogenetic analysis of the NS5B sequences (668 bp) obtained from 133 patients newly diagnosed with HCV-4 infection over the period from 1999 to 2008 revealed eight distinct HCV-4 subtypes; the majority of HCV-4 isolates were of subtypes 4d (57%) and 4a (37%). Three distinct monophyletic clusters were identified, with each one having a specific epidemiological profile: (i) Egyptian immigrants infected with HCV-4a (n = 46), (ii) Dutch patients with a history of injecting drug use infected with HCV-4d (n = 44), and (iii) Dutch human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) infected with HCV-4d (n = 26). Subsequent molecular clock analyses confirmed that the emergence of HCV-4 within these three risk groups coincided with (i) the parenteral antischistosomal therapy campaigns in Egypt (1920 to 1960), (ii) the popularity of injecting drug use in The Netherlands (1960 to 1990), and (iii) the rise in high-risk sexual behavior among MSM after the introduction of highly active antiretroviral therapy (1996 onwards). Our data show that in addition to the influx of HCV-4 strains from countries where HCV-4 is endemic, the local spread of HCV-4d affecting injecting drug users and, in recent years, especially HIV-positive MSM will further increase the relative proportion of HCV-4-infected patients in The Netherlands. HCV-4-specific agents are drastically needed to improve treatment response rates and decrease the future burden of HCV-4-related disease.
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Hepacivirus/clasificación , Hepacivirus/genética , Hepatitis C/epidemiología , Epidemiología Molecular , Evolución Molecular , Variación Genética , Genotipo , Hepacivirus/aislamiento & purificación , Hepatitis C/virología , Humanos , Masculino , Datos de Secuencia Molecular , Países Bajos/epidemiología , Filogenia , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Ursodeoxycholic acid (UDCA) is used for treatment of cholestatic liver diseases and may improve long-term outcome. Although treatment with this hydrophilic bile acid is virtually without side effects, medication adherence might be suboptimal due to patient misconceptions, compromising clinical outcome. Our aim was to evaluate adherence to UDCA in relation to patient beliefs about medicine and to identify potential predictors of poor adherence. METHODS: Prospective open-label study recruiting patients in treatment with UDCA from April 2016 to March 2017. Adherence was assessed both by the Sensemedic dispenser and by patient-reported adherence, during 12 weeks. Good adherence was defined as ≥ 80% intake. Quality of life (by SF-36) and beliefs about medicine (by BMQ) were also assessed. RESULTS: A total of 75 patients were enrolled (32% primary biliary cholangitis, 31% autoimmune hepatitis, 29% primary sclerosing cholangitis and 8% other conditions). Average adherence according to the medication dispenser was 92 ± 16% (range: 17-100). Eighty-nine percent of the patients exhibited good adherence and 11% poor adherence. According to the BMQ, 42% of all patients were accepting, 50% ambivalent, 8% indifferent and 0% skeptical to UDCA treatment. Poor adherence was associated with young age (P = 0.029) and male gender (P = 0.021). CONCLUSIONS: Despite the excellent safety profile of UDCA, still a significant number of patients are poorly adherent. Young age and male sex are associated with poor adherence. Efforts should be made to identify patients with poor adherence and to improve their compliance to therapy.
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Enfermedades Autoinmunes/tratamiento farmacológico , Colagogos y Coleréticos/uso terapéutico , Colestasis/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Hepatopatías/inmunología , Cumplimiento de la Medicación/estadística & datos numéricos , Ácido Ursodesoxicólico/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/complicaciones , Colestasis/complicaciones , Femenino , Humanos , Hepatopatías/complicaciones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
Chronic hepatitis B and C affect approximately 500 million people in the world, with substantial disease burden including liver cirrhosis and hepatocellular carcinoma. For chronic hepatitis B, two treatment strategies are currently available, both with suboptimal response and significant side effects. Promising new drugs are approaching the stage of approval; however, these agents still need further development to control this disease. Based on the understanding of the hepatitis C virus life cycle, new treatment developments for chronic hepatitis C tend to succeed rapidly; therefore, it is only a matter of time before new therapies emerge. This review summarizes the most important new agents available for treatment of chronic hepatitis B and C.
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Hepatitis B Crónica/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , HumanosRESUMEN
INTRODUCTION: Pegylated interferon-based therapy for hepatitis C virus (HCV) negatively impacts nutritional state and patient-reported outcomes (PROs) such as health-related quality of life (HRQL). Clinical trials with direct-acting antivirals (DAAs) report significant PRO improvement but real-world data are still scarce. METHODS: Prospective cohort study recruiting HCV patients treated with DAAs in 2015-2016. Data at baseline, end of treatment (EOT) and 12 weeks thereafter (FU12) included: patient-reported medication adherence; SF-36; Karnofsky Performance Status; paid labour productivity; physical exercise level; nutritional state [by body mass index (BMI) and Jamar hand grip strength (HGS)] and Beliefs about Medicines Questionnaire. Potential factors predicting these PROs were evaluated with multiple regression analysis. RESULTS: A total of 68 patients were enrolled: 85% male, median age 57 years, 80% genotype 1, 40% cirrhotics, 46% haemophilia. Both cure rate and patient-reported adherence were 97%. SF-36 Physical Component Summary did not change (43.2 ± 11.9, 44.9 ± 10.3 and 44.7 ± 10.9 at baseline, EOT and FU12, p = 0.71). In contrast, SF-36 mental component summary (MCS) decreased transiently during therapy (49.2 ± 11.9, 44.6 ± 10.3 and 49.9 ± 12.6 at baseline, EOT and FU12, p < 0.01). Concomitant ribavirin-use was the only independent predictor of decreased SF-36 MCS. BMI (25.7 ± 4.5 and 25.6 ± 4.4 at baseline and EOT, p = 0.8) and Jamar HGS (39.7 ± 13.0, 37.4 ± 11.9 and 37.9 ± 13.8 at baseline, EOT and FU12, p = 0.56) did not change. CONCLUSION: Our study reveals concomitant ribavirin as the only independent predictor of transient decrease in SF-36 mental HRQL during DAA therapy. In contrast to interferon-based therapy, DAAs do not affect BMI or Jamar HGS.
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MicroRNAs regulate gene expression by binding to the 3'-untranslated region (UTR) of target messenger RNAs (mRNAs). The importance of microRNAs has been shown for several liver diseases, for example, viral hepatitis. MicroRNA-122 is highly abundant in the liver and is involved in the regulation of lipid metabolism. MicroRNA-122 is also an important host factor for the HCV and promotes HCV replication. In contrast to HCV, microRNA-122 inhibits replication of the HBV. MicroRNA-122 acts as a tumour suppressor and reduced levels of microRNA-122 are associated with hepatocellular carcinoma. MicroRNAs other than microRNA-122 have been linked to viral hepatitis, fibrosis and inflammation. In this review, we discuss function and clinical implications of microRNA-122 and other microRNAs in liver diseases, especially viral hepatitis.
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Terapia Genética , Virus de Hepatitis/genética , Hepatitis Viral Humana/genética , Hepatitis Viral Humana/terapia , MicroARNs/genética , Virus de Hepatitis/clasificación , Hepatitis Viral Humana/virología , Humanos , MicroARNs/metabolismoRESUMEN
BACKGROUND AND AIMS: MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus (HCV) and promotes HCV RNA accumulation. Decreased intra-hepatic levels of miR-122 were observed in patients with hepatocellular carcinoma, suggesting a potential role of miR-122 in the development of HCC. Miravirsen targets miR-122 and resulted in a dose dependent and prolonged decrease of HCV RNA levels in chronic hepatitis C patients. The aim of this study was to establish the sustained virological response rate to peginterferon (P) and ribavirin (R) following miravirsen dosing and to assess long-term safety in patients treated with miravirsen. METHODS: In this multicenter, retrospective follow-up study we included 36 treatment naïve patients with chronic hepatitis C genotype 1 who received five weekly subcutaneous injections with miravirsen or placebo over a 29-day period in a phase 2a study. Patients were offered PR therapy 3weeks (3mg/kg group) or 6weeks (5 or 7mg/kg group) after completion of miravirsen or placebo dosing. RESULTS: PR therapy was started in 14/36 patients of whom 12 had received miravirsen. SVR was achieved in 7/12 patients previously dosed with miravirsen. All patients dosed with 7mg/kg miravirsen who were subsequently treated with PR achieved SVR. One patient had a prolonged undetectable HCV RNA period from week 14 to week 29 after baseline without subsequent antiviral therapy and relapsed thereafter. None of the patients treated with anti-miR-122 developed HCC or other liver-related complications. CONCLUSION: No long-term safety issues were observed among 27 miravirsen-treated patients. Targeting miR-122 may be an effective and safe treatment strategy for HCV infection and should be investigated in larger clinical trials.
Asunto(s)
Antivirales/administración & dosificación , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/genética , MicroARNs/uso terapéutico , Oligonucleótidos/administración & dosificación , Adulto , Anciano , Antivirales/efectos adversos , Femenino , Estudios de Seguimiento , Hepacivirus/genética , Hepacivirus/fisiología , Hepatitis C Crónica/metabolismo , Hepatitis C Crónica/virología , Humanos , Masculino , MicroARNs/efectos adversos , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Replicación Viral/efectos de los fármacosRESUMEN
INTRODUCTION: Combination therapy with pegylated interferon alpha (Peg-interferon) and ribavirin is currently the cornerstone of antiviral therapy for chronic hepatitis C. Monotherapy with Peg-interferon still is important for the treatment of chronic hepatitis B. With the advent of new therapies, protease inhibitors for chronic hepatitis C and nucleotide inhibitors for chronic hepatitis B, there remains a need for interferon-based therapies. The side effects of Peg-interferon are a main disadvantage and represent a stumbling block for many patients to enter and continue therapy. AREAS COVERED: In this review, the authors will discuss controlled-release interferon alpha 2b (CR2b) (Locteron®, Biolex Therapeutics, Pittsboro, NC, USA), a new slow-release interferon alpha 2b preparation for the treatment of chronic viral hepatitis. Other alternative interferons will also be discussed. EXPERT OPINION: CR2b is a slow-release microsphere preparation for the administration of plant-derived recombinant human interferon alpha 2b. Compared with Peg-interferon, treatment with CR2b shows less flu-like reactions and less depression, and is at least as effective as conventional Peg-interferon-based therapy in patients with chronic hepatitis C. CR2b has the added advantage of biweekly instead of once weekly administration. CR2b appears to cause more neutropenia than Peg-interferon alpha 2b. This may be due to higher trough serum levels of CR2b at the end of a dosing interval. The bone marrow effects of CR2b closely resemble those published for the registered Peg-interferon alpha 2a. CR2b appears to have at least comparable efficacy with fewer side effects than current registered Peg-interferons.
Asunto(s)
Antivirales/farmacología , Hepatitis C Crónica/tratamiento farmacológico , Interferones/farmacología , Proteínas Recombinantes/farmacología , Antivirales/administración & dosificación , Antivirales/efectos adversos , Preparaciones de Acción Retardada , Esquema de Medicación , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Interferón-alfa/farmacología , Interferones/administración & dosificación , Interferones/efectos adversos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Polietilenglicoles/farmacología , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversosRESUMEN
BACKGROUND: Telaprevir is a selective inhibitor of the hepatitis C virus NS3·4A serine protease. Treatment with telaprevir resulted in a rapid HCV-RNA decline in chronic hepatitis C genotype 1 patients. OBJECTIVES: To report the clinical and viral course of a patient treated with telaprevir in combination with pegylated interferon-alpha-2a and ribavirin in a Phase 2 clinical trial (PROVE3). STUDY DESIGN: This previous non-responder to interferon based therapy was treated for 40 weeks with a telaprevir, pegylated interferon alpha-2a, and ribavirin regimen. Viral sequencing and phylogenetic analysis were performed before, during and after therapy. RESULTS: The patient, a 54 years old male patient, experienced a viral relapse 4 weeks post-treatment and HCV-RNA levels continued to increase 14 weeks post-treatment (150,000 IU/mL). The viral population, which was wild type at baseline, consisted of only V36A variants at both of these post-treatment timepoints. Subsequently, this patient had a transient disappearance of HCV-RNA for more than 1 year in the absence of antiviral therapy. Thereafter, HCV-RNA reappeared again with a viral population consisting of only wild type virus. Phylogenetic analysis of NS3·4A corresponded with a viral population bottleneck resulting in changes in viral quasispecies. CONCLUSION: In this case report, significant viral load reductions resulted in a genetic bottleneck leading to a reduction of variability in the hepatitis C viral population. We hypothesize that the reduction in viral heterogeneity potentially led to a reduced viral capacity to adapt to a host immune response leading to a transient loss of detectable HCV-RNA.