RESUMEN

OBJECTIVE: Direct-acting antiviral (DAA) drugs have resulted in high rates of virological cure in chronic hepatitis C (CHC)-infected patients. We used noninvasive tests to assess fibrosis in subjects who had been cured with DAA. METHODS: Retrospective data collection (2014-2019) from the medical record of CHC patients at the hepatology clinic was performed. Subjects co-infected with HIV and hepatitis B, post-liver transplant, and lost to follow-up were excluded. We evaluated fibrosis at baseline and 1 year after completing therapy using vibration-controlled transient elastography (VCTE), fibrosis-4 (FIB-4), and aspartate aminotransferase-toplatelet ratio index (APRI) scores. RESULTS: With 210 medical records reviewed, 41 were included. The mean age was 62.8 years; 61% were men. Significant fibrosis regression was observed 1-year post-treatment using 3 noninvasive methods: VCTE, APRI, and FIB-4 score. Prior to treatment, 46% of the patients had advanced fibrosis compared to 25% 1 year after treatment. The VCTE scores of 4 subjects (with body mass indices [BMIs] > 30) indicated a worsening of fibrosis. We did not find a statistically significant association between BMI and VCTE, FIB-4, or APRI score. CONCLUSION: In most CHC patients, DAA therapy leads to liver fibrosis regression. Obesity may play an important role in the worsening of hepatic fibrosis or the absence of fibrosis regression.

Asunto(s)

Antivirales , Diagnóstico por Imagen de Elasticidad , Hepatitis C Crónica , Cirrosis Hepática , Humanos , Persona de Mediana Edad , Masculino , Estudios Retrospectivos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Antivirales/administración & dosificación , Femenino , Diagnóstico por Imagen de Elasticidad/métodos , Anciano , Puerto Rico , Aspartato Aminotransferasas/sangre , Estudios de Cohortes

RESUMEN

Chronic viral infections caused by the human immunodeficiency virus (HIV), hepatitis C (HCV), and hepatitis B (HBV) are common among patients with end-stage renal disease (ESKD). These infections were once considered contraindications to kidney transplantation due to potential risks associated with long-term immunosuppression. Improved management and antiviral therapies have changed the prognosis and survival of this group of patients, along with an increased experience in transplanting people with these viral infections. We report the first successful kidney transplant in an ESKD patient on hemodialysis with a history of concomitant HIV, HCV and HBV infection in Mexico.

Asunto(s)

Infecciones por VIH , Fallo Renal Crónico , Trasplante de Riñón , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Fallo Renal Crónico/cirugía , Fallo Renal Crónico/complicaciones , Masculino , Hepatitis B/complicaciones , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , México , Persona de Mediana Edad , Adulto , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Resultado del Tratamiento , Diálisis Renal

RESUMEN

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) have immature morphology, relatively weak phagocytic activity, as well as some immunosuppressive functions. The capacity of MDSCs to inhibit T-cell-mediated immunological responses is their most notable functional characteristic. Down-regulating antitumor immune surveillance is one way that the expansion and activation of MDSCs contribute significantly to the occurrence and progression of tumors. Increased levels of MDSCs in patients with chronic hepatitis C virus (HCV) infection could suppress T-cell responses, promoting viral escape and hepatitis progression. This may make HCV-infected individuals more vulnerable to severe infections, hepatic and extra-hepatic tumors, and a diminished capacity to react to immunization. It is still unknown if effective HCV eradication with directly acting antivirals (DAAs) can restore immune functions and immune surveillance capacity. OBJECTIVE: The purpose of this study was to observe the frequency of M-MDSCs (CD33+, CD11b+, and HLA-DR) in patients with a previous history of HCV, 2-3 years after virus eradication using DAA therapy. METHODS: This study was conducted on 110 subjects: fifty-five subjects without liver cirrhosis who were treated with HCV using DAAs and attained SVR for a period of 2-3 years and 55 age- and gender-matched healthy controls. The study was conducted during the period from January to July 2022. Patients were recruited from the National Viral Hepatitis Treatment Unit, Alexandria University Hepatology outpatient clinic, and the Alexandria University Tropical Medicine outpatient clinic. The frequencies of MDSCs (CD33+CD11b + HLA-DR-) by flow cytometry were assessed. RESULTS: Even after the virus had been eradicated for longer than two years, MDSC levels in HCV-treated individuals were found to be considerably higher. In the HCV-treated group, the median number of MDSCs was 5, with an interquartile range (IQR) of 3.79-7.69. In contrast, the median for the control group was 3.1, with an IQR of 1.4-3.2 (P˂0.001). CONCLUSION: Successful DAA therapy leads to slow and partial immunological reconstitution, as demonstrated by the failure to attain normal levels of MDSC's 2 years after successful HCV eradication despite the normalization of laboratory parameters as well as the absence of liver fibrosis. The clinical implications of these findings should be thoroughly studied.

Asunto(s)

Antivirales , Hepatitis C Crónica , Células Supresoras de Origen Mieloide , Humanos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Antivirales/uso terapéutico , Femenino , Masculino , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/inmunología , Persona de Mediana Edad , Estudios de Casos y Controles , Adulto , Anciano , Citometría de Flujo

RESUMEN

Objective: The aim of this study was to evaluate the glycated hemoglobin (HbA1c) levels before and after sustained virologic response (SVR) and investigate the baseline characteristics associated with improved glycemic control in patients with chronic hepatitis C (CHC) achieving SVR after directacting antivirals (DAA) therapy. Materials and methods: Consecutive adult patients with CHC who achieved SVR after DAA treatment between January 2016 and December 2017 at Hospital de Clínicas de Porto Alegre (RS, Brazil) were prospectively included. Levels of HbA1c were measured up to 24 weeks before DAA therapy and 12 weeks after SVR. Exclusion criteria were decompensated cirrhosis, HIV and/or hepatitis B virus, liver disease of other etiologies, and/or modification of prediabetes/ type 2 diabetes mellitus (PDM/T2DM) management. The primary outcome was a comparison of HbA1c levels before and after SVR. Secondary outcomes were the baseline variables associated with improved glycemic control. Results: The study included 207 patients with a mean age of 60.6±10.7 years, of whom 51.7% were women, 56% had cirrhosis, 37.7% had HCV genotype 3, and 54.5% had baseline T2DM or PDM. The median HbA1c level reduced significantly after SVR (5.5%, interquartile range [IQR] 4.9%-6.3%) compared with baseline (5.7%, IQR 5.3%-6.7%; p = 0.01). The baseline characteristics associated with improved HbA1c after SVR were cirrhosis, genotype 3, and age ≤ 60 years. Conclusion: Among patients with CHC, SVR after DAA was associated with HbA1c reduction, particularly in those with cirrhosis, genotype 3, and age ≤ 60 years.

Asunto(s)

Antivirales , Glucemia , Hemoglobina Glucada , Hepatitis C Crónica , Respuesta Virológica Sostenida , Humanos , Femenino , Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/sangre , Masculino , Persona de Mediana Edad , Hemoglobina Glucada/análisis , Glucemia/análisis , Glucemia/efectos de los fármacos , Anciano , Estudios Prospectivos , Resultado del Tratamiento , Hepacivirus/genética , Hepacivirus/efectos de los fármacos , Brasil , Adulto , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre

RESUMEN

OBJECTIVES: The primary objective was to evaluate Liver-Related Events (LREs), including hepatic decompensation (ascites, hemorrhagic varices and encephalopathy) and Hepatocellular Carcinoma (HCC), as well as changes in liver stiffness during the follow-up period among patients who achieved a Sustained Virological Response (SVR) after treatment for chronic Hepatitis C Virus (HCV) infection. METHODS: A total of 218 patients with HCV were treated, and those who achieved an SVR were followed up for 3-years. Transient Elastography (TE) using FibroScan® was performed at various time points: before treatment, at the end of treatment, at 6-months post-treatment, at 1-year post-treatment, at 2-years post-treatment, and at 3-years post-treatment. RESULTS: At 6-months post-treatment, a Liver Stiffness Measurement (LSM) cutoff of > 19 KPa was identified, leading to a 14.5-fold increase in the hazard of negative outcomes, including decompensation and/or HCC. The analysis of relative changes in liver stiffness between pre-treatment and 6-months posttreatment revealed that a reduction in LSM of -10 % was associated with a -12 % decrease in the hazard of decompensation and/or HCC, with this trend continuing as the LSM reduction reached -40 %, resulting in a -41 % hazard of decompensation and/or HCC. Conversely, an increase in the relative change during this period, such as an LSM increase of +10 %, led to a + 14 % increase in the hazard of decompensation. In cases where this relative change in LSM was +50 %, the hazard of decompensation increased to +92. CONCLUSION: Transient elastography using FibroScan® can be a good tool for monitoring HCV patients with SVR after treatment to predict LREs in the long term.

Asunto(s)

Antivirales , Carcinoma Hepatocelular , Diagnóstico por Imagen de Elasticidad , Hepatitis C Crónica , Cirrosis Hepática , Neoplasias Hepáticas , Respuesta Virológica Sostenida , Humanos , Diagnóstico por Imagen de Elasticidad/métodos , Masculino , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/virología , Femenino , Persona de Mediana Edad , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/diagnóstico por imagen , Antivirales/uso terapéutico , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/virología , Estudios de Seguimiento , Factores de Tiempo , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/virología , Resultado del Tratamiento , Adulto , Anciano , Valor Predictivo de las Pruebas

RESUMEN

BACKGROUND: Results of studies evaluating the effect of viral eradication following direct-acting antiviral (DDA) therapy on skeletal muscle mass of patients with chronic hepatitis C (CHC) are scarce. AIM: To assess the components of sarcopenia (low muscle mass, low muscle strength and low physical performance) in a cohort of CHC individuals before and after DAA therapy. METHODS: We performed a longitudinal study of patients with CHC who underwent body composition assessment before (T0), and at 12 (T1) and 48 (T2) weeks after DDA therapy. Bioelectrical Impedance Analysis was used to assess skeletal mass muscle (SM) and phase angle (PhA). SM index (SMI) was calculated by dividing the SM by squared height. Muscle function was evaluated by hand grip strength (HGS) and timed up-and-go (TUG) test. Mixed-effects linear regression models were fitted to SMI, HGS and physical performance and were used to test the effect of HCV eradication by DAA. RESULTS: 62 outpatients (mean age, 58.6 ± 10.8 years; 58% with compensated cirrhosis) were included. Significant decreases in liver fibrosis markers and an increase of 0.20 and 0.22 kg/m2 in the SMI were observed at T1 and T2. Following DAA therapy, an increase of one unit of PhA was associated with a reduction of 0.38 min in TUG. CONCLUSION: HCV eradication with DAA therapy was associated with a dynamic reduction of non-invasive markers of liver fibrosis and increased muscle mass in 62 patients with CHC who had an undetectable HCV load at 12 weeks after completion of antiviral treatment.

Asunto(s)

Antivirales , Composición Corporal , Hepatitis C Crónica , Músculo Esquelético , Sarcopenia , Humanos , Hepatitis C Crónica/tratamiento farmacológico , Antivirales/uso terapéutico , Masculino , Persona de Mediana Edad , Femenino , Estudios Longitudinales , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Anciano , Sarcopenia/tratamiento farmacológico , Composición Corporal/efectos de los fármacos , Fuerza de la Mano , Fuerza Muscular/efectos de los fármacos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/virología

RESUMEN

Hepatitis C virus (HCV) infection is a significant cause of morbidity and mortality among hematopoietic stem cell transplant (HCT) recipients. In Brazil, its occurrence in HCT recipients remains undetermined. We now report on HCV prevalence in HCT recipients and its clinical consequences. The medical records of all HCT recipients seen at Hospital das Clinicas, Sao Paulo University Medical School, from January 2010 to January 2020 were reviewed to determine HCV serostatus. A retrospective analysis of medical charts was undertaken on all seropositive cases to determine HCV genotype, presence of liver fibrosis, co-infections with other viruses, previous treatments, and clinical evolution of liver pathology after HCT. Of the 1,293 HCT recipients included in the study, seven (0.54%) were HCV antibody-positive and five (0.39%) were also viremic for HCV-RNA. Four of these individuals had moderate to severe liver fibrosis (METAVIR F2/F3) and one was cirrhotic. Two of the viremic patients developed acute liver dysfunction following transplantation. All patients had their acute episode of liver dysfunction resolved with no further complications. Four of the viremic patients were treated for HCV infection with direct acting agents (DAA). Information regarding HCV treatment was lacking for one of the viremic HCV patients due to loss of follow up. Sustained anti-virologic responses were observed in three cases after the use of DAA. The detection of HCV in hematological adults undergoing HCT and its successful treatment with DAA highlight the necessity of testing for HCV both prior to and following transplantation.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Hepatitis C Crónica , Hepatitis C , Humanos , Adulto , Hepacivirus/genética , Estudios Retrospectivos , Prevalencia , Antivirales/uso terapéutico , Brasil/epidemiología , Hepatitis C/complicaciones , Hepatitis C/epidemiología , Cirrosis Hepática/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hepatitis C Crónica/tratamiento farmacológico

RESUMEN

Direct-acting antivirals are the gold-standard treatment for chronic HCV infections, but few studies have investigated their use on kidney and liver transplant recipients. We conducted a real-world study to evaluate the rates of sustained virological response with direct-acting antivirals in kidney and liver transplant recipients. Moreover, it also aimed to evaluate direct-acting antivirals (DAAs) interference with immunosuppressant levels and to describe the frequency of adverse events. As part of this retrospective observational cohort, we included adult patients that had undergone a kidney transplant (KT) or liver transplant (LT) at our center, had a chronic HCV infection, and were treated with DAAs from June 2016 to December 2021. A total of 165 patients were included in the analysis, divided in 108 KT and 57 LT recipients. HCV genotype 1 was more frequent in KT (58.4%), and genotype 3 was more prevalent in LT (57.9%) patients. Sustained virological response was achieved in 89.6% of patients. Adverse effects were reported by 36% of patients. There were significant interactions with immunosuppressants requiring dose adjustments. A total of three episodes of rejection were reported in KT recipients. In conclusion, DAA treatment resulted in high rates of SVR and was well tolerated in both kidney and liver transplant patients. Adverse events were frequent but not severe in most patients, with low treatment drop-out rates. Interactions with immunosuppressants need monitoring since dose adjustments may be required. Reporting real-life experiences is important to help build evidence for patient management in non-controlled environments.

Asunto(s)

Hepatitis C Crónica , Hepatitis C , Trasplante de Hígado , Adulto , Humanos , Antivirales/efectos adversos , Hepacivirus/genética , Estudios Retrospectivos , Brasil , Hepatitis C Crónica/tratamiento farmacológico , Inmunosupresores/efectos adversos , Riñón , Resultado del Tratamiento

RESUMEN

Hepatitis C virus (HCV) infection is a worldwide public health problem associated with significant morbidity and mortality. In the context of liver transplantation, the demand for organs continues to exceed the supply, prompting the consideration of using organs from HCV-positive donors in HCV-negative recipients. The introduction of direct-acting antivirals (DAAs), which have demonstrated great efficacy in eradicating the virus, has made transplantation of organs from donors with HCV infection possible. The present article provides a brief review of the current evidence on the use of organs from HCV-infected patients.

Asunto(s)

Hepatitis C Crónica , Hepatitis C , Trasplante de Hígado , Humanos , Hepacivirus , Antivirales/uso terapéutico , México , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/cirugía , Hepatitis C/tratamiento farmacológico

RESUMEN

BACKGROUND: Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals achieves a sustained virologic response rate higher than 95%. However, virologic failure remains a clinical challenge, and data on retreatment are limited, especially in special populations such as liver transplant (LT) recipients. OBJECTIVES: This study evaluated the sofosbuvir plus glecaprevir-pibrentasvir (GLE/PIB) regimen in LT recipients who had failed to a nonstructural protein 5A (NS5A) inhibitor-based regimen. MATERIAL AND METHODS: Retrospective study of 111 liver transplant recipients between January 2018 and December 2020; 18 patients presented with HCV recurrent infection after LT, out of whom three had a history of at least one NS5A inhibitor-based regimen. Salvage therapy with sofosbuvir plus GLE/PIB was started for 12 weeks; baseline characteristics and outcomes were recorded. RESULTS: All three patients (100%) achieved an undetectable HCV viral load 12 weeks after treatment completion. No serious adverse events were observed. CONCLUSION: In our series, sofosbuvir plus GLE/PIB for 12 weeks is an effective and safe salvage therapy after LT in patients previously treated with NS5A inhibitors.

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ANTECEDENTES: El tratamiento del virus de la hepatitis C (VHC) crónica con antivirales de acción directa logra tasas de respuesta virológica sostenida superiores a 95 %. Sin embargo, el manejo del fracaso virológico sigue siendo un desafío clínico y la evidencia sobre el retratamiento es limitada, especialmente en poblaciones como los receptores de trasplante hepático (TH). OBJETIVO: Este estudio evaluó el régimen de sofosbuvir más glecaprevir/pibrentasvir (GLE/PIB) en receptores de TH en quienes falló el régimen basado en inhibidores de la proteína no estructural 5A (NS5A). MATERIAL Y MÉTODOS: Estudio retrospectivo de 111 pacientes trasplantados entre enero de 2018 y diciembre de 2020; 18 pacientes presentaron infección recurrente por VHC posterior al TH, tres de ellos tuvieron antecedentes de al menos un régimen basado en inhibidores de NS5A. Se inició terapia de rescate con sofosbuvir más GLE/PIB durante 12 semanas posterior al TH; se registraron las características basales de los pacientes y sus desenlaces. RESULTADOS: En los tres pacientes se logró obtener una carga viral indetectable de VHC a las 12 semanas de finalizar el tratamiento. No se observaron eventos adversos graves. CONCLUSIÓN: En nuestra serie, sofosbuvir más GLE/PIB durante 12 semanas demostró ser una terapia de rescate efectiva y segura posterior al TH en pacientes previamente tratados con inhibidores de NS5A.

Asunto(s)

Hepatitis C Crónica , Hepatitis C , Trasplante de Hígado , Humanos , Sofosbuvir/uso terapéutico , Terapia Recuperativa , Hepatitis C Crónica/tratamiento farmacológico , Antivirales/uso terapéutico , Estudios Retrospectivos

Asunto(s)

Hepatitis C Crónica , Hepatitis C , Humanos , Hepatitis C/tratamiento farmacológico , Hepacivirus , Riñón , Antivirales/efectos adversos , Hepatitis C Crónica/tratamiento farmacológico

RESUMEN

BACKGROUND: Several HCV patients in Brazil were lost to follow-up (LTFU) in the last two decades before achievement of sustained virological response (SVR). Strategies to recall those diagnosed but untreated patients have been used elsewhere with different success rates. AIM: To identify and retrieve LTFU patients in order to offer them the treatment with the current highly effective direct acting antiviral agents (DAAs). METHODS: Registries ofall HCV patients from three large reference centers in Brazil were retrospectively reviewed to identify those with no registry of SVR. Reasons for non-achievement of SVR were elicited in HCV-RNA + patients. All patients who were not treated or cured were contacted to offer the therapy with DAAs. RESULTS: 10,289 HCV patients (50% males, mean age 52 ± 11 years) were identified. Only 4,293 (41.7%) had been successfully treated previously. From the remaining 5,996 most were LTFU (59%), were not treated for other reasons (14.7%) or were non-responders (26.3%). After revision of the charts 3,559 were considered eligible to be retrieved. The callback success of phone calls was 18%, 13% to cellphone messages (SMS or WhatsApp) and 7% to regular mail. Five-hundred sixty patients had been already treatedor were on treatment and 234 were reported to be dead or transplanted. Finally, 201 had made an appointment and initiated antiviral treatment. CONCLUSION: Even considering the low callback rate, retrieval of LTFU patients was shown to be an important strategy forhepatitis C micro-elimination in Brazil.

Asunto(s)

Hepatitis C Crónica , Hepatitis C , Masculino , Humanos , Adulto , Persona de Mediana Edad , Femenino , Antivirales/uso terapéutico , Brasil/epidemiología , Hepatitis C Crónica/tratamiento farmacológico , Estudios Retrospectivos , Perdida de Seguimiento , Hepatitis C/tratamiento farmacológico , Hepatitis C/epidemiología , Hepacivirus/genética

RESUMEN

Infections caused by the Hepatitis C virus (HCV) affect around 70 million people worldwide, leading to serious liver problems, such as fibrosis, steatosis, and cirrhosis, in addition to progressing to hepatocellular carcinoma and becoming globally the main cause of liver disease. Despite great therapeutic advances in obtaining pan-genotypic direct-acting antivirals (DAAs), around 5-10% of affected individuals are unable to eliminate the virus by their own immune system's activity. Still, there are no licensed vaccines so far. In this context, the orchestrated process of virus entry into host cells is a crucial step in the life cycle and the infectivity capability of most viruses. In recent years, the entry of viruses has become one of the main druggable targets used for designing effective antiviral molecules. This goal has come to be widely studied to develop pharmacotherapeutic strategies against HCV, combined or not with DAAs in multitarget approaches. Among the inhibitors found in the literature, ITX 5061 corresponds to the most effective one, with EC50 and CC50 values of 0.25 nM and >10 µM (SI: 10,000), respectively. This SRBI antagonist completed the phase I trial, constituting a promising compound against HCV. Interestingly, chlorcyclizine (an antihistamine drug) showed action both in E1 apolipoproteins (EC50 and CC50 values of 0.0331 and 25.1 µM, respectively), as well as in NPC1L1 (IC50 and CC50 values of 2.3 nM and > 15 µM, respectively). Thus, this review will discuss promising inhibitors targeting HCV entry, discussing their SAR analyzes, recent contributions, and advances in this field.

Asunto(s)

Hepatitis C Crónica , Hepatitis C , Neoplasias Hepáticas , Humanos , Hepacivirus , Antivirales/farmacología , Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Internalización del Virus , Neoplasias Hepáticas/tratamiento farmacológico

RESUMEN

The activity of the membrane transporters organic anion-transporting polypeptide 1B1 (OATP1B1) & breast cancer resistance protein (BCRP) (rosuvastatin) and P-glycoprotein (P-gp) (fexofenadine) was evaluated in patients with chronic hepatitis C virus (HCV) infection (n = 28), genotypes 1 and 3, investigated before the treatment with direct-acting antiviral agents (Phase 1) and up to 30 days after the assessment of the virologic response (Phase 2). Participants allocated in Groups 1 (n = 15; F0/F1 and F2, mild to moderate liver fibrosis) and 2 (n = 13; F3 and F4, advanced course of liver fibrosis/cirrhosis) received in both phases fexofenadine (10 mg) and rosuvastatin (2 mg). OATP1B1 & BCRP activity (rosuvastatin area under the plasma concentration-time curve of rosuvastatin from time zero to infinity (AUC0-∞ )) was reduced in Groups 1 and 2, respectively, by 25% (ratio 0.75 (0.53-0.82), P < 0.01) and 31% (ratio 0.69 (0.46-0.85), P < 0.05) in Phase 1 compared with Phase 2. OATP1B1 & BCRP activity was reduced in Phases 1 and 2, respectively, by 49% (median ratio 1.51 (1.17-2.20), P < 0.05) and 61% (ratio 1.39 (1.16-2.02), P < 0.01) in Group 2 compared with Group 1. P-gp activity (fexofenadine AUC0-∞ ) was also reduced in Phase 1 compared with Phase 2 (ratio Phase2/Phase1 0.79 (0.66-0.96) in Group 1 and 0.81 (0.69-0.96) in Group 2) as well as in Group 2 compared with Group 1 in both Phases (ratio Group2/Group1 1.47 (1.08-2.01) in Phase 1 and 1.51 (1.10-2.07) in Phase 2). Thus, clinicians administering OATP1B1 & BCRP and P-gp substrates with low therapeutic indexes should consider the evolution of the treatment and the stage of HCV infection.

Asunto(s)

Hepatitis C Crónica , Transportadores de Anión Orgánico , Humanos , Proteínas de Transporte de Membrana/metabolismo , Rosuvastatina Cálcica , Hepatitis C Crónica/tratamiento farmacológico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Glicoproteínas de Membrana/metabolismo , Antivirales/uso terapéutico , Interacciones Farmacológicas , Proteínas de Neoplasias/metabolismo , Transportadores de Anión Orgánico/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Cirrosis Hepática/tratamiento farmacológico

RESUMEN

Although chronic hepatitis C has been effectively treated with direct-acting antivirals (DAAs), the use of conventional therapy with peg-interferon (Peg-IFN) or (predominantly) ribavirin (RBV), remains widespread. R70Q/H and L/C91M amino acid substitutions in the hepatitis C virus (HCV) core protein may modulate responses to IFN and/or RBV, and are associated with cirrhosis, hepatocellular carcinoma (HCC), insulin resistance, and liver steatosis. We evaluated the R70Q/H and L/C91M substitutions, clinical and epidemiological profiles, and risk factors of Brazilian patients chronically infected with HCV subgenotypes 1a and 1b (HCV-GT1a and HCV-GT1b) unresponsive to IFN and/or RBV therapy. Sequencing and pyrosequencing analyses and sociodemographic and clinical predictive variables were used to assess the relationship between R70Q/H and L/C91M substitutions. Leukocyte counts, ALT levels, and ALT/AST ratios were significantly reduced in treated individuals, but more of these patients had advanced fibrosis and cirrhosis. L91M was more prevalent (19.7%), occurring only in HCV-GT1b, followed by R70Q/P (11.5%) and R70P (1.4%). R70Q/P exhibited higher mean AST, ALT, and GGT values, whereas L91M showed higher mean GGT values. Pyrosequencing of the L91M position revealed mutant subpopulations in 43.75% of samples.

Asunto(s)

Carcinoma Hepatocelular , Hepatitis C Crónica , Hepatitis C , Neoplasias Hepáticas , Humanos , Antivirales , Brasil/epidemiología , Carcinoma Hepatocelular/tratamiento farmacológico , Quimioterapia Combinada , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Ribavirina/uso terapéutico

RESUMEN

BACKGROUND: Conflicting data regarding the incidence of hepatocellular carcinoma (HCC) after cure of HCV infection with direct-acting antivirals (DAAs) remains. We investigated the incidence and risk factors to HCC after treatment with DAAs followed up for five years. METHODS: A total of 1075 HCV patients ≥ 18 years were treated with DAAs from 2015 to 2019 and followed until 2022. Ultrasonography was performed before DAAs and each 6 months thereafter. RESULTS: Of the total, 51/1075 (4.7%) developed HCC in the median of 40 (IQR 25-58) months: 26/51 (51%) male, median age 60 (IQR 54-66) years, alpha-fetoprotein (AFP) 12.2 (IQR 6.1-18.8) ng/mL, 47/51 (92.1%) cirrhotic 78.7%, 8/51 (15.7%) without sustained virological response (SVR). Seventeen percent had non-characterized nodules before DAAs. Cumulative HCC incidence was 5.9% in 5 years. Overall incidence was 1.46/100 patient-years (PY) (95% CI = 1.09-1.91), being 2.31/100 PY (95% CI = 1.70-3.06), 0.45/100 PY (95% CI = 0.09-1.32) and 0.20/100 PY (95% CI 0.01-1.01) in METAVIR F4, F3 and F2, respectively, and the main risks to HCC were non-characterized nodule, cirrhosis, high AFP values and non-SVR. CONCLUSION: HCV cure reduced risk for HCC, but it still occurred particularly in cirrhotic patients. Some risk factors can be identified to predict early HCC diagnosis.

Asunto(s)

Carcinoma Hepatocelular , Hepatitis C Crónica , Hepatitis C , Neoplasias Hepáticas , Humanos , Masculino , Persona de Mediana Edad , Femenino , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/diagnóstico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Antivirales/uso terapéutico , alfa-Fetoproteínas , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/diagnóstico , Incidencia , Factores de Riesgo , Cirrosis Hepática/diagnóstico , Hepatitis C/tratamiento farmacológico

RESUMEN

INTRODUCTION AND OBJECTIVES: In clinical trials, patients with hepatitis C virus (HCV) genotype (GT)1a infection and baseline resistance-associated substitutions (RASs) at amino acid positions 28, 30, 31, or 93 receiving elbasvir/grazoprevir for 12 weeks achieved lower rates of sustained virologic response (SVR) than those without baseline RASs. SVR rates in patients with RASs were improved when elbasvir/grazoprevir treatment duration was extended from 12 to 16 weeks and administered concomitantly with ribavirin. MATERIALS AND METHODS: This was a retrospective, observational analysis using electronic health record abstraction. Patients with HCV GT1a infection and RASs at positions 28, 30, 31, or 93 who were prescribed 16 weeks of elbasvir/grazoprevir and ≥ 1 prescription for ribavirin were included. SVR was defined as HCV RNA below the lower limit of quantification ≥ 70 days after end of treatment. RESULTS: The primary analysis included patients with baseline RASs at positions 30, 31, or 93 (n = 76); a secondary analysis included patients with RASs at positions 28, 30, 31, or 93 (n = 93). SVR was achieved by 77.6% (59/76) of patients in the primary analysis and 80.6% (75/93) of those in the secondary analysis. Of the 18 (19.4%) patients in the secondary cohort who failed to achieve SVR, 8 relapsed (4 with treatment-emergent NS5A substitutions) and 10 did not have viral sequencing to distinguish relapse from reinfection. CONCLUSIONS: This analysis highlights the opportunities in leveraging real-world data to further understand treatment outcomes in smaller, discrete subgroups of patients with HCV infection who cannot be thoroughly evaluated in clinical trials.

Asunto(s)

Hepatitis C Crónica , Hepatitis C , Humanos , Ribavirina/uso terapéutico , Hepacivirus/genética , Antivirales/efectos adversos , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Quimioterapia Combinada , Recurrencia Local de Neoplasia/inducido químicamente , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Respuesta Virológica Sostenida , ARN Viral/genética , Genotipo , Farmacorresistencia Viral/genética

RESUMEN

Objective: To compare the glucose metabolism of patients with chronic hepatitis C virus infection treated with direct-acting antivirals (DAAs) in pretreatment and sustained viral response (SVR) periods. Materials and methods: This was an intervention pre-post study of 273 patients with chronic hepatitis C virus infection treated with DAAs from March 2018 to December 2019. Glycidic metabolism was evaluated through homeostasis model assessment (HOMA) - insulin resistance (IR) and HOMA-ß indices and assessments of insulinemia and HbA1c levels. These parameters were analyzed with a T test by paired comparison of the means of the variables and Wilcoxon's test paired for the median; in the variables with an abnormal distribution, the Z score was generated for the mean in both the pretreatment and SVR periods. Statistical significance was considered at p ≤ 0.05. Results: Among 273 participants, 125 (45.8%) had prediabetes, and 50 (18.3%) had diabetes. In SVR, there was a significant increase in platelets, albumin, alkaline phosphatase, cholesterol and triglycerides and a significant decrease in aspartate aminotransferase, alanine aminotransferase, gamma GT and bilirubin. The HOMA-IR and HOMA-ß indices increased in SVR from 1.95 to 2.29 (p = 0.087) and 71.20 to 82.60 (p = 0.001), respectively. Insulinemia increased from 7.60 µU/mL to 8.90 µU/mL (p = 0.011). HbA1c decreased from 5.6 to 5.4 (p < 0.001). Among patients with prediabetes and those with diabetes, the reduction in HbA1c values was significant (p = 0.006 and p = 0.026, respectively). Conclusion: SVR significantly impacts and leads to improvement in glucose metabolism in patients with chronic liver disease induced by hepatitis C virus.

Asunto(s)

Diabetes Mellitus , Hepatitis C Crónica , Resistencia a la Insulina , Estado Prediabético , Humanos , Antivirales/uso terapéutico , Antivirales/farmacología , Hepatitis C Crónica/tratamiento farmacológico , Hepacivirus , Hemoglobina Glucada , Estado Prediabético/tratamiento farmacológico , Resistencia a la Insulina/fisiología , Diabetes Mellitus/tratamiento farmacológico , Glucosa

RESUMEN

Direct-acting antiviral (DAA) therapy for the treatment of chronic hepatitis C virus (HCV) infection is efficacious and well-tolerated in the post-liver transplant (LT) setting, prompting increased use of donors with HCV infection in patients waitlisted for LT.1,2 Although the incidence of nonviral hepatocellular carcinoma (HCC) is rising, HCV remains the most common risk factor for HCC among patients listed for LT in the United States.3 The use and outcomes of HCV-infected donors among patients with active HCV viremia waitlisted for (HCV-HCC) is lacking. Our aim was to evaluate post-LT survival among patients with HCV-HCC based on both recipient (active vs cured HCV) and donor (HCV+ vs HCV-) viremic status. Using the United Network for Organ Sharing (UNOS) registry, we analyzed all adult patients with HCV-HCC who underwent LT and had available recipient/donor HCV nucleic acid test (NAT) results from March 31, 2015 (date UNOS began reporting donor NAT) through June 30, 2021. Patients with acute liver failure, simultaneous organ transplant, previous LT, and those missing recipient and/or donor NAT results were excluded.

Asunto(s)

Carcinoma Hepatocelular , Hepatitis C Crónica , Hepatitis C , Neoplasias Hepáticas , Trasplante de Hígado , Adulto , Humanos , Estados Unidos , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/tratamiento farmacológico , Viremia/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Antivirales/uso terapéutico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Hepacivirus/genética

RESUMEN

5'-Phosphorylated nucleoside derivatives are molecules that can be found in all living organisms and viruses. Over the last century, the development of structural analogs that could disrupt the transcription and translation of genetic information culminated in the development of clinically relevant anticancer and antiviral drugs. However, clinically effective broad-spectrum antiviral compounds or treatments are lacking. This viewpoint proposes that molecules that inhibit nucleotide biosynthesis may sensitize virus-infected cells toward direct-acting antiviral nucleosides. Such potentially synergistic combinations might allow the repurposing of drugs, leading to the development of new combination therapies.

Asunto(s)

Antivirales , Hepatitis C Crónica , Humanos , Antivirales/farmacología , Antivirales/química , Nucleósidos/farmacología , Nucleósidos/química , Relación Estructura-Actividad , Hepatitis C Crónica/tratamiento farmacológico , Nucleótidos/farmacología