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LDL particle size and antioxidant HDL function improve after sustained virological response in patients with chronic HCV.
Vargas, JI, Rivera, K, Arrese, M, Benitez, C, Barrera, F, Hugo, M, Arab, JP, Pino, K, Barrera, A, Lopez-Lastra, M, et al
Annals of hepatology. 2022;(1):100555
Abstract
HCV infection is associated with an increased incidence of cardiovascular (CV) events. Mechanisms underlying this association remain unknown. In our study, twenty HCV patients (median age 60.5 years, 65% male and 80% with cirrhosis) were evaluated prior, during and after direct-acting antiviral treatment. Ninety percent of patients achieved sustained virological response (SVR). Significant changes were observed in LDL particle size index, measured by LDL-C/apoB ratio, which increased after treatment (p = 0.023). In addition, HDL antioxidant capacity improved gradually from 34.4% at baseline to 42.4% at 4 weeks (p = 0.011), 65.9% at end of treatment EOT (p = 0.002) and remained elevated at 12-week (p = 0.001) after EOT compared to baseline values. Our findings suggest that a shift to a less atherogenic lipid profile may be a possible mechanism associated with CV risk reduction in patients with HCV infection achieving SVR.
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Secondary substitutions in the hemagglutinin and neuraminidase genes associated with neuraminidase inhibitor resistance are rare in the Influenza Resistance Information Study (IRIS).
Roosenhoff, R, Schutten, M, Reed, V, Clinch, B, van der Linden, A, Fouchier, RAM, Fraaij, PLA
Antiviral research. 2021;:105060
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Amino acid substitutions in influenza virus neuraminidase (NA) that cause resistance to neuraminidase inhibitors (NAI) generally result in virus attenuation. However, influenza viruses may acquire secondary substitutions in the NA and hemagglutinin (HA) proteins that can restore viral fitness. To assess to which extent this happens, the emergence of NAI resistance substitutions and secondary - potentially compensatory - substitutions was quantified in influenza viruses of immunocompetent individuals included in the Influenza Resistance Information Study (IRIS; NCT00884117). Known resistance substitutions were detected by mutation specific RT-PCR in viruses of 57 of 1803 (3.2%) oseltamivir-treated individuals, including 39 individuals infected with A/H1N1pdm09 [H275Y] virus and 18 with A/H3N2 [R292K] virus. A total of fifteen and ten other amino acid substitutions were acquired in HA and NA respectively, of A/H1N1pdm09, A/H3N2 and influenza B viruses upon treatment with oseltamivir but none of these was associated with resistance to oseltamivir. All cultured viruses with the known resistance substitutions H275Y or R292K showed reduced susceptibility to oseltamivir in the NA-star assay. Upon next-generation sequencing, the vast majority of NAI resistant A/H1N1pdm09 and A/H3N2 viruses had no resistance-associated secondary substitutions at high frequency. Only in two A/H1N1pdm09 [H275Y] viruses, the potentially compensatory secondary substitutions HA-D52N and NA-R152K were detected. We conclude that the emergence of secondary substitutions that may restore viral fitness upon the emergence of known influenza virus NAI resistance substitutions was a rare event in this immunocompetent population.
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Corrected QT interval in hospitalized patients with coronavirus disease 2019: Focus on drugs therapy.
Ding, J, Liu, W, Guan, H, Feng, Y, Bao, Y, Li, H, Wang, X, Zhou, Z, Chen, Z
Medicine. 2021;(28):e26538
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Corrected QT (QTc) interval prolongation has been associated with poor patient prognosis. In this study, we assessed the effects of different drugs and cardiac injury on QTc interval prolongation in patients with coronavirus disease 2019 (COVID-19).The study cohort consisted of 395 confirmed COVID-19 cases from the Wuhan Union Hospital West Campus. All hospitalized patients were treated with chloroquine/hydroxychloroquine (CQ/HCQ), lopinavir/ritonavir (LPV/r), quinolones, interferon, Arbidol, or Qingfei Paidu decoction (QPD) and received at least 1 electrocardiogram after drug administration.Fifty one (12.9%) patients exhibited QTc prolongation (QTc ≥ 470 ms). QTc interval prolongation was associated with COVID-19 severity and mortality (both P < .001). Administration of CQ/HCQ (odds ratio [OR], 2.759; 95% confidence interval [CI], 1.318-5.775; P = .007), LPV/r (OR, 2.342; 95% CI, 1.152-4.760; P = .019), and quinolones (OR, 2.268; 95% CI, 1.171-4.392; P = .015) increased the risk of QTc prolongation. In contrast, the administration of Arbidol, interferon, or QPD did not increase the risk of QTc prolongation. Notably, patients treated with QPD had a shorter QTc duration than those without QPD treatment (412.10 [384.39-433.77] vs 420.86 [388.19-459.58]; P = .042). The QTc interval was positively correlated with the levels of cardiac biomarkers (creatine kinase-MB fraction [rho = 0.14, P = .016], high-sensitivity troponin I [rho = .22, P < .001], and B-type natriuretic peptide [rho = 0.27, P < .001]).In conclusion, QTc prolongation was associated with COVID-19 severity and mortality. The risk of QTc prolongation was higher in patients receiving CQ/HCQ, LPV/r, and quinolones. QPD had less significant effects on QTc prolongation than other antiviral agents.
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Changes in Liver Stiffness and Noninvasive Fibrosis Scores in Egyptian Adolescents Successfully Treated with Ledipasvir-Sofosbuvir for Chronic Hepatitis C Virus Infection.
Fahmy, DM, Shokeir, M, El Zeiny, SM, Jonas, MM, Abdallah, A
The Journal of pediatrics. 2021;:110-116
Abstract
OBJECTIVE To assess changes in noninvasive liver fibrosis measurements after chronic hepatitis C eradication by direct-acting antivirals in Egyptian adolescents. STUDY DESIGN Liver stiffness measurement (LSM), by vibration-controlled transient elastography and noninvasive fibrosis scores (Firbosis-4, aspartate aminotransferase-platelet ratio index), was obtained before and 12 months after eradication with ledipasvir-sofosbuvir. The primary outcome was a more than 30% decrease in LSM with resulting fibrosis stage regression for initial fibrosis of F2 or higher and nonprogression of F0-F1, using the Ishak score (F0-F6). The secondary outcome was change in noninvasive fibrosis scores after treatment. RESULTS Analyzing 85 patients, the median baseline LSM was 5.8 (IQR, 4.2-6.5) and at follow-up 5.1 kPa (IQR, 4-6 kPa) (P = .045); 62 (73%) met the primary outcome, 16 patients (19%) experienced regression, and 46 (54%) nonprogression of LSM. Of 18 with initial fibrosis of F2 0r higher, 13 regressed to F0-F1 and 2 from F6 to F5, 1 unchanged at F3, and 1 increased to F3 and 1 to F4. Among 67 patients with a baseline fibrosis of F0-F1, 62 were unchanged and 5 increased-4 to F2 and 1 to F3. Although 23 (27%) had a more than 30% LSM increase, only 7 (8%), with associated comorbidities (4 β-thalassemia, 3 hepatic steatosis), had increased fibrosis stage. The median baseline FIB-4 and aspartate aminotransferase-platelet ratio index scores were 0.34 (IQR, 0.22-0.47) and 0.35 (0.24-0.57), and at follow-up 0.3 (IQR, 0.22-0.34) and 0.2 (0.18-2.8) (P < .001, <.001), respectively. CONCLUSIONS Chronic hepatitis C eradication by direct-acting antiviral agents in Egyptian adolescents was associated with nonprogression or regression of liver fibrosis, by noninvasive fibrosis measurements, at 12 months after treatment in the majority of cases.
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Virus Elimination by Direct-Acting Antiviral Agents Impacts Glucose Homeostasis in Chronic Hepatitis C Patients.
Cheng, CH, Chu, CY, Chen, HL, Lin, IT, Wu, CH, Lee, YK, Bair, MJ
Frontiers in endocrinology. 2021;:799382
Abstract
BACKGROUND AND AIMS Chronic hepatitis C virus (HCV) infection is associated with dysregulation of glucose homeostasis, including insulin resistance (IR) and type 2 diabetes. However, independent risk factors associated with IR in chronic HCV-infected patients have not been detailly elucidated. Previous data regarding the impact of HCV elimination by direct-acting antiviral agents (DAAs) on glucose homeostasis is insufficient and controversial. This study aimed to analyze the independent factors associated with IR and to evaluate the changes in glucose homeostasis in chronic HCV-infected patients treated with DAAs therapies. METHODS We screened 704 patients with chronic HCV infection who underwent treatment with interferon-free DAAs. Patients' baseline characteristics, biochemical and virological data were collected. The outcome measurements were their IR and β-cell function assessed by the homeostasis model assessment (HOMA) method at baseline and 12-weeks post-treatment. RESULTS High IR (HOMA-IR ≥ 2.5) was observed in 35.1% of the patients. Multivariable logistic regression analysis revealed that body mass index (BMI) >25 kg/m2, treatment experience, elevated baseline levels of alanine aminotransferase (ALT) and triglyceride, as well as Fibrosis-4 score >3.25 were independently associated with high IR. In patients who achieved sustained virological response (SVR), no significant change in mean HOMA-IR was observed from baseline to 12-weeks post-treatment (2.74 ± 2.78 to 2.54 ± 2.20, p = 0.128). We observed a significant improvement in β-cell secretion stress from 121.0 ± 110.1 to 107.6 ± 93.0 (p = 0.015). Subgroup analysis revealed that SVR was associated with a significant reduction in mean HOMA-IR in patients with baseline HOMA-IR ≥ 2.5 (5.31 ± 3.39 to 3.68 ± 2.57, p < 0.001), HCV genotype 1 (3.05 ± 3.11 to 2.62 ± 2.05, p = 0.027), and treatment experience (4.00 ± 3.37 to 3.01 ± 2.49, p = 0.039). CONCLUSIONS There were several independent factors associated with IR in patients with chronic HCV infection, including obesity, treatment experience, high serum ALT and triglyceride levels, as well as advanced hepatic fibrosis. After viral elimination by DAAs, we observed a significant reduction in mean HOMA-IR in patients with baseline high IR, HCV genotype 1, and treatment experience.
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Duration of fever and symptoms in children after treatment with baloxavir marboxil and oseltamivir during the 2018-2019 season and detection of variant influenza a viruses with polymerase acidic subunit substitutions.
Saito, R, Osada, H, Wagatsuma, K, Chon, I, Sato, I, Kawashima, T, Saito, T, Kodo, N, Ono, Y, Shimada, Y, et al
Antiviral research. 2020;:104951
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We conducted a prospective, multicenter, non-randomized observational study to assess the duration of fever and symptoms of influenza A/H1N1pdm09 and A/H3N2 infected children < 19 years old treated with either baloxavir or oseltamivir. Additionally, these symptoms were investigated in association with pre- and post-baloxavir treatment-emergent polymerase acidic unit (PA) variants as compared to non-substituted viruses. Following receipt of informed consent, baloxavir was administered to 102 influenza A patients, and oseltamivir to 52 patients during the 2018-2019 influenza season in Japan. The average age was higher in the baloxavir treatment group compared to the oseltamivir treatment group (10.6 ± 2.7 versus 6.9 ± 2.9 years old, p < 0.01). The duration of fever and symptoms in baloxavir-treated A/H1N1pdm09 and A/H3N2-infected children did not differ from those in oseltamivir-treated groups (median 22.0, 11.8, 23.0, and 21.0 h, and median 114.5, 121.0, 123.0, and 122.0 h, respectively). One (1.2%) of 83 A/H3N2 patients possessed a PA/I38T substituted virus prior to treatment. The frequency of PA variants in post-treatment samples obtained 2-11 days after beginning of baloxavir was 12.5% (4/32) for A/H1N1pdm09 and 14.1% (9/64) for A/H3N2 when the total number of cases was used as the denominator, however, were 57.1% (4/7) and 33.3% (9/27) when PCR-positive cases at the time of second sampling was used as the denominator. The most frequent PA substitution was I38T (9), with E23K (1), I38K (1), I38M (1), and PA/I38S (1) also observed. The duration of fever and overall symptoms did not differ significantly following baloxavir treatment in individuals with PA variant viruses, non-substituted virus, or in those that were PCR negative at the second sampling (median 20, 24 and 11 h, and median 121, 115 and 121 h, respectively). Rebound of viral RNA load was observed in 13.5% (2/13) of PA variants but it was not associated with recurrence of fever and symptoms. Hence, prolonged fever or symptoms were not observed in children treated with baloxavir following emergence of PA variants, however, further studies are needed to evaluate the clinical impact of PA variants.
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Hepatitis C Virus Clearance by Direct-Acting Antivirals Agents Improves Endothelial Dysfunction and Subclinical Atherosclerosis: HEPCAR Study.
Muñoz-Hernández, R, Ampuero, J, Millán, R, Gil-Gómez, A, Rojas, Á, Macher, HC, Gallego-Durán, R, Gato, S, Montero-Vallejo, R, Rico, MC, et al
Clinical and translational gastroenterology. 2020;(8):e00203
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INTRODUCTION Hepatitis C virus (HCV) infection has been related to increased cardiovascular (CV) risk. The aim of this study was to analyze the impact of sustained virological response (SVR) on endothelial dysfunction and subclinical atherosclerosis in patients with hepatitis C virus treated with direct-acting antiviral agents. METHODS A total of 114 patients were prospectively recruited and underwent CV risk assessment including (i) endothelial dysfunction determined through laser Doppler flowmetry and (ii) subclinical atherosclerosis, elucidated by the ankle-brachial index (ABI). Atherogenic lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides); markers of oxidative stress (oxidized low-density lipoprotein antibodies [OLAbs]), soluble markers of adhesion (vascular cell adhesion molecule [VCAM], e-selectin, and soluble markers of angiogenesis; and vascular endothelial growth factor, endothelial [EMPs] and platelet [PMPs] apoptotic microparticles, and cell-free DNA [cfDNA]) were measured. All determinations were performed at baseline, 12 weeks (SVR time), and 1 year after treatment. RESULTS In patients with endothelial dysfunction, area of hyperemia improved after virus clearance (P = 0.013) and was related to significant decrease in VCAM, e-selectin (P < 0.001), and cfDNA (P = 0.017) and to increased OLAb levels (P = 0.001). In patients with subclinical atherosclerosis at baseline, a significantly improved ABI was seen after HCV clearance (P < 0.001). Levels of both EMPs and PMPs also decreased after SVR and at follow-up (P = 0.006 and P = 0.002, respectively). DISCUSSION HCV clearance improved not only liver function but also endothelial dysfunction and subclinical atherosclerosis promoted by decrease in levels of VCAM, e-selectin, cfDNA, and PMPs and EMPs.
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Palivizumab and Long-term Outcomes in Cystic Fibrosis.
Fink, AK, Graff, G, Byington, CL, Loeffler, DR, Rosenfeld, M, Saiman, L
Pediatrics. 2019;(1)
Abstract
BACKGROUND The American Academy of Pediatrics does not recommend routine use of palivizumab prophylaxis for infants with cystic fibrosis (CF) but recommends consideration in infants with clinical evidence of chronic lung disease or nutritional compromise. However, the beneficial impact of palivizumab on longer-term outcomes is uncertain. METHODS We used Cystic Fibrosis Foundation Patient Registry data to assess the association of receiving palivizumab during the first 2 years of life with longer-term outcomes, including lung function at 7 years old, time to first positive Pseudomonas respiratory culture, and pulmonary-related hospitalizations during the first 7 years of life. Eligible infants were born from 2008 to 2015 and diagnosed with CF during the first 6 months of life. Demographic and clinical confounders of association between palivizumab receipt and outcomes were explored. We created propensity scores to adjust for potential confounding by indication (ie, sicker infants were more likely to receive palivizumab). For each outcome, we performed regression analyses adjusted by propensity scores. RESULTS The sample included 4267 infants; 1588 (37%) received palivizumab. Mean percent forced expiratory volume in 1 second predicted at 7 years old was similar among those who did (98.2; 95% confidence interval: 96.9-99.5) and did not (97.3; 95% confidence interval: 96.1-98.5) received palivizumab, adjusting for propensity scores. Time to first positive Pseudomonas aeruginosa culture and annual risk of hospitalization were similar among those who did and did not receive palivizumab. CONCLUSIONS At the population level, palivizumab receipt was not associated with improved longer-term outcomes in children with CF.
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Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.
Carrat, F, Fontaine, H, Dorival, C, Simony, M, Diallo, A, Hezode, C, De Ledinghen, V, Larrey, D, Haour, G, Bronowicki, JP, et al
Lancet (London, England). 2019;(10179):1453-1464
Abstract
BACKGROUND Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort. METHODS We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458. FINDINGS Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0-40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07-3·71) and decompensated cirrhosis (3·83, 2·29-6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33-0·70) and hepatocellular carcinoma (0·66, 0·46-0·93), and was not associated with decompensated cirrhosis (1·14, 0·57-2·27). INTERPRETATION Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection. FUNDING INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.
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Patient-reported symptoms during and after direct-acting antiviral therapies for chronic hepatitis C: The PROP UP study.
Evon, DM, Sarkar, S, Amador, J, Lok, AS, Sterling, RK, Stewart, PW, Reeve, BB, Serper, M, Reau, N, Rajender Reddy, K, et al
Journal of hepatology. 2019;(3):486-497
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BACKGROUND & AIMS A comprehensive analysis of changes in symptoms and functioning during and after direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has not been conducted for patients treated in real-world clinical settings. Therefore, we evaluated patient-reported outcomes (PROs) in a diverse cohort of patients with HCV treated with commonly prescribed DAAs. METHODS PROP UP is a US multicenter observational study of 1,601 patients with HCV treated with DAAs in 2016-2017. PRO data were collected at baseline (T1), early on-treatment (T2), late on-treatment (T3) and 3-months post-treatment (T4). PRO mean change scores were calculated from baseline and a minimally important change (MIC) threshold was set at 5%. Regression analyses investigated patient and treatment characteristics independently associated with PRO changes on-treatment and post-treatment. RESULTS Of 1,564 patients, 55% were male, 39% non-white, 47% had cirrhosis. Sofosbuvir/ledipasvir was prescribed to 63%, sofosbuvir/velpatasvir to 21%, grazoprevir/elbasvir to 11%, and paritaprevir/ombitasvir/ritonavir + dasabuvir to 5%. During DAA therapy, mean PRO scores improved slightly in the overall cohort, but did not reach the 5% MIC threshold. Between 21-53% of patients experienced >5% improved PROs while 23-36% experienced >5% worse symptoms. Of 1,410 patients with evaluable sustained virologic response (SVR) data, 95% achieved SVR. Among those with SVR, all mean PRO scores improved, with the 5% MIC threshold met for fatigue, sleep disturbance, and functioning well-being. Regression analyses identified subgroups, defined by age 35-55, baseline mental health issues and a higher number of health comorbidities as predictors of PRO improvements. CONCLUSIONS In real-world clinical practices, we observed heterogeneous patient experiences during and after DAA treatment. Symptom improvements were more pronounced in younger patients, those with baseline mental health issues and multiple comorbidities. LAY SUMMARY Patients who received direct-acting antiviral medications for hepatitis C at several liver centers in the US did not generally experience significant changes in baseline symptoms during treatment. We observed a full range of patient experiences with some patients experiencing substantial symptom improvements, yet others experiencing less improvements and some even experiencing a worsening of symptoms. The 1,346 patients who were cured of hepatitis C experienced improvements in fatigue, sleep disturbance, and functional well-being, and trends for improved pain and depression; whereas the 64 who were not cured experienced minimal improvements. Clinicaltrial.gov: NCT02601820.