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Background: Immunity and clinical protection induced by mRNA vaccines against SARS-CoV-2 have been shown to decline overtime. To gather information on the immunity profile deemed sufficient in protecting against hospitalization, we tested IgG levels, interferon-gamma (IFN-γ) secretion, and neutralizing antibodies 180 days (d180) after the second shot of BNT162b vaccine, in HW. Methods: A total of 392 subjects were enrolled. All received BioNTech/Pfizer from February 2020 to April 2021. The vaccine-specific humoral response was quantitatively determined by testing for IgG anti-S1 domain of SARS-CoV-spike protein. Live virus microneutralization (MN) was evaluated by an assay performing incubation of serial 2-fold dilution of human serum samples, starting from 1:10 to 1:5120, with an equal volume of Wuhan strain and Delta VOC viral solution and assessing the presence/absence of a cytopathic effect. SARS-CoV-2-spike protein-specific T-cell response was determined by a commercial IFN-γ release assay. Results: In 352 individuals, at d180, IgG levels decreased substantially but no results below the assay's positivity threshold were observed. Overall, 22 naive (8.1%) had values above the highest threshold. Among COVID-naive, the impact of age, which was observed at earlier stages, disappeared at d180, while it remained significant for 81 who had experienced a previous infection. Following the predictive model of protection by Khoury, we transformed the neutralizing titers in IU/ml and used a 54 IU/ml threshold to identify subjects with 50% protective immunity. Overall, live virus MN showed almost all subjects with previous exposure to SARS-CoV-2 neutralized the virus as compared to 33% of naive double-dosed subjects (p < 0.0001). All previously exposed subjects had strong IFN-γ secretion (>200 mIU/ml); among 271 naive, 7 (2.58%) and 17 (6.27%) subjects did not show borderline or strong secretion, respectively. Conclusions: In naive subjects, low IgG titers are relatively long-lasting. Only a third of naive subjects maintain neutralizing responses. After specific stimulation, a very limited number of naive were unable to produce IFN-γ. The results attained in the small group of subjects with breakthrough infection suggest that simultaneous neutralizing antibody titers <20, binding antibody levels/ml <200, and IFN-γ <1,000 mIU/ml in subjects older than 58 may identify at-risk groups.
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Vacunas contra la COVID-19 , COVID-19 , Anticuerpos Neutralizantes/farmacología , Anticuerpos Antivirales , COVID-19/prevención & control , Personal de Salud , Humanos , Inmunidad Humoral , Inmunoglobulina G , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/farmacologíaRESUMEN
Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQß1Leu26 (p valueMeta = 1.24 × 10-14) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQß1Pro55 (p valueMeta = 8.23 × 10-11) located in the peptide binding region was positively associated, independently of HLA-DQß1Leu26. These two amino acids are not in linkage disequilibrium (r2 < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1∗03:01, and HLA-DRB1∗01:01. Additionally, HCV persistence classical alleles tagged by HLA-DQß1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC50 nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10-38). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQß1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection.
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Cadenas beta de HLA-DQ/genética , Hepacivirus/patogenicidad , Hepatitis C/genética , Interacciones Huésped-Patógeno/genética , Polimorfismo de Nucleótido Simple , Enfermedad Aguda , Alelos , Sustitución de Aminoácidos , Población Negra , Femenino , Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Cadenas beta de HLA-DQ/inmunología , Hepacivirus/crecimiento & desarrollo , Hepacivirus/inmunología , Hepatitis C/etnología , Hepatitis C/inmunología , Hepatitis C/virología , Interacciones Huésped-Patógeno/inmunología , Humanos , Leucina/inmunología , Leucina/metabolismo , Masculino , Prolina/inmunología , Prolina/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Remisión Espontánea , Población BlancaRESUMEN
BACKGROUND: Rates of Hepatitis C virus (HCV) testing and diagnosis are variable among people who use drugs (PWUD). In Puglia in 2018, of 871 subjects screened, 38% had HCV antibodies (HCVAb). Despite sustained virologic response at week 12 Sustained virologic response (SVR12) rates >95%, addiction centers in Italy are not allowed to prescribe direct-acting antivirals (DAA). AIM: To increase testing and linkage to care a dedicated program including "ad hoc" transportation and fast-track access to care was offered to PWUD from Puglia. METHODS: Over 12 months, 1,470 individuals seen at 15 Services for Dependence (SERDs) underwent screening. For HCVAb positive, a fast-track evaluation was offered at our Hepatology Unit. Patients were subsequently taken to their pharmacists to receive the prescribed DAA regimen. Treatment and adherence were supervised by SERDs physicians, SVR12 assessed at our unit. The scalability of the process was based on both, number of patients screened in our region in 2018, and number of PWUD diagnosed and treated at our center during 2018-2019. RESULTS: Of 1,470 individuals screened, 634 (43.1%) tested HCVAb positive. Overall, 231 were RNA positive, 54% of whom on opioid agonist therapy (OAT) and 32% with cirrhosis. Median interval between RNA assessment and treatment start was 22 days (0-300). Patients received 12-week sofosbuvir/velpatasvir regimen without Ribavirin; in 220 patients who completed treatment, SVR12 was 98.6%. Among GT3, SVR12 was 98%. No re-infection was observed. Improvements in screening, and linkage to care were registered. CONCLUSIONS: A PWUD-tailored service led to HCV care cascade improvement and high SVR12 rates. Despite history of drug addiction, social instability and logistic barriers, micro-elimination programs providing dedicated care are key drivers of success.
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Antivirales/uso terapéutico , Consumidores de Drogas , Accesibilidad a los Servicios de Salud/organización & administración , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Tamizaje Masivo , Adulto , Anciano , Femenino , Anticuerpos Antihepatitis/sangre , Humanos , Italia , Masculino , Persona de Mediana Edad , Respuesta Virológica Sostenida , Adulto JovenRESUMEN
PURPOSE: Clinical significance and durability of serological response after mRNA COVID-19 vaccines is under investigation. Data on early virological response are limited. To iden-tify potential predictors of antibody durability, circulating antibody levels were longitudinally ex-plored in healthcare workers included in a follow-up program for SARS-CoV-2 infection. Meth-ods: Subjects meeting the inclusion criteria signed an informed consent. Serum samples were col-lected at baseline, before the first BNT162b2 vaccine, at days 7, 21, 31, 90, and 180 days after the first dose. Serological evaluation was performed by QuantiVac Euroimmune anti-S1 antibody as-say. Only subjects followed-up until day 90 are here considered. RESULTS: Of 340 taken into consid-eration, 265 subjects were naive, and 75 COVID-19 experienced. The former showed a progres-sive increase in their antibody levels before day 90 decline, while the latter showed antibody levels reaching a plateau at day 7 and slightly declining at day 90. All showed antibody levels higher than the assay cut-off at day 31 and 90. Among naive, 108 had an early response whose predic-tors were younger age and female gender (OR 0.94, 95% CI 0.91-0.96, p < 0.0001; and OR 2.58, 95% CI 1.48-4.51, p = 0.0009). Naive subjects experienced a day 30/90 decline in antibody levels, whereas experienced did not. Early response was an independent predictor of higher day 30/90 antibody levels decline (OR = 2.05, 95% CI 1.04-4.02; p = 0.037). CONCLUSIONS: Our results suggest that in healthcare workers early response might be inversely associated with antibody levels 90 days after BNT162b2 vaccine.
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Hepatitis C virus (HCV) elimination by 2030, using direct-acting antiviral treatments, has been promoted by the World Health Organization. This achievement is not attainable, however, particularly after the 2020 pandemic of the coronavirus disease 2019. Consequently, the more realistic objective of eliminating HCV from population segments for which targeted strategies of prevention and treatment are easily attained has been promoted in Europe, as a valid alternative. The underlying idea is that micro-elimination will ultimately lead to macro-elimination. The micro-elimination strategy may target different specific populations and at-risk groups. Different settings, including prisons and hospitals, have also been identified as micro-elimination scenarios. In addition, dedicated micro-elimination strategies have been designed that are tailored at the geographical level according to HCV epidemiology and individual country's income. The main elements of a valid and successful micro-elimination project are reliable epidemiological data and active involvement of all the stakeholders. Community involvement represents another essential component for a successful program.
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COVID-19 , Hepatitis C Crónica , Hepatitis C , Antivirales/uso terapéutico , Europa (Continente) , Hepacivirus , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Hepatitis C/epidemiología , Hepatitis C Crónica/tratamiento farmacológico , Humanos , SARS-CoV-2RESUMEN
BACKGROUND: Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. METHODS: To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. RESULTS: A male-specific region near the adenosine diphosphate-ribosylation factor-like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98â ×â 10-07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR,â 1.4; P =â 2.46â ×â 10-06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. CONCLUSIONS: These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.
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Hepatitis C , Factores Sexuales , Femenino , Estudio de Asociación del Genoma Completo , Hepacivirus/genética , Hepatitis C/genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Proteínas Ribosómicas/genética , Septinas/genética , Carga ViralRESUMEN
Liver injury has been reported in coronavirus disease 2019 (COVID-19) cases but the impact of pre-existing liver damage and related etiology have not been completely elucidated. Our research interests include the potential reciprocal influence of COVID-19 and pre-existing liver damage related to hepatitis C virus (HCV) infection, in particular. To this end, we have evaluated three cohorts of patients admitted at three Italian hospitals during the coronavirus pandemic; these included 332 patients with COVID-19 and 1527 patients with HCV who were from established real-world antiviral treatment study cohorts (sofosbuvir/velpatasvir), with either liver disease (various severities; n = 1319) or cirrhosis (n = 208). Among the COVID-19 patients, 10 had cirrhosis (3%), including 7 of metabolic origin and 3 of viral origin. Mortality among the COVID-19 patients was 27.1%, with 70% of those with cirrhosis of metabolic etiology having died. Cirrhosis, older age, low white blood cell count and lymphocyte count being identified as risk predictors of death [odds ratio (OR) = 13.7, 95% confidence interval (CI): 2.59-83.01, P = 0.006; OR = 1.05, 95%CI: 1.03-1.08, P = 0.0001; OR = 1.09, 95%CI: 1.36-1.16, P = 0.001; OR = 0.61, 95%CI: 0.39-0.93, P = 0.023, respectively]. In the two cohorts of HCV patients, COVID-19 diagnosis was made in 0.07% of those with liver disease and 1% of those with cirrhosis. Thus, the prevalence of HCV antibodies among COVID-19-infected patients was comparable to that currently reported for the general population in Italy. Amongst the COVID-19 patients, pre-existing metabolic cirrhosis appears to be associated with higher mortality, while HCV antibodies may be suggestive of "protection" against COVID-19.
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The aim of this review is to outline emerging biomarkers that can serve as early diagnostic tools to identify patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) and, among them, the subgroup of best candidates for clinical trials on emerging compounds. Regarding possible predictors of NAFLD, a number of studies evaluated a combination of serum biomarkers either available in routine practice (or investigational) or proprietary and expensive. So far, magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) appears to be the most accurate for fatty liver diagnosis. In clinical practice, the main question is how to diagnose NASH early. There are new promising biomarkers that can help in diagnosing early stages of NASH, yet they include variables not routinely tested. In the setting of NASH, most studies confirm that, in spite of several well-known limitations, transient elastography or point shear wave elastography can help in enriching the pool of patients that should be screened for investigational treatments. Newer multiomics biomarkers including those focusing on microbiota can be useful but require methods to be standardized and implemented. To date, one biomarker alone is not able to non- or minimally invasively identify patients with NASH and mild to moderate fibrosis.
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Biomarcadores/sangre , Imagen por Resonancia Magnética/métodos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , HumanosRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0215783.].
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Besides seven major hepatitis C virus (HCV) genotypes (GT), a number of intergenotypic recombinant strains have been described. These so-called chimeras combine genetic characteristics of different HCV genotypes. However, correct genotype classification is important, as choice and duration of direct-acting antiviral (DAA) treatment is mainly based on the viral genotype. Therefore, misclassification of chimeras might lead to suboptimal treatment of patients infected with these strains. For example, 2k/1b chimeras are typically described as HCV genotype 2 strains by commercially available hybridization assays, but real-time PCR-based tests recognizing another HCV region might be more suitable for correct chimera detection. In this study, the analytic capacity of the hybridization-assay Versant HCV Genotype 2.0 (LiPA 2.0) and the real-time PCR-based-assays cobas HCV GT and Abbott RealTime HCV Genotype II were tested in a selected cohort of 230 patients infected with HCV genotype 1 (n = 53) and 2 (n = 177) and 48 patients infected with HCV 2/1 chimeric strains. While the Versant HCV Genotype 2.0 (LiPA 2.0) assay failed to identify chimeras in all of the patients (48/48, 100%), cobas HCV GT and Abbott HCV Genotype II assays identified chimeras correctly in 90% (43/48) and 65% (31/48) of the cases, respectively. In conclusion, while the hybridization-based Versant HCV Genotype 2.0 (LiPA 2.0) assay seems to be unsuitable for detection of HCV 2/1 chimeras, use of the real-time PCR-based assays cobas HCV GT and Abbott RealTime HCV Genotype II led to a higher rate of chimera detection.
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Técnicas de Genotipaje/métodos , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Genotipo , Humanos , Hibridación de Ácido Nucleico , ARN Viral/sangre , ARN Viral/genética , Juego de Reactivos para Diagnóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Sensibilidad y Especificidad , Análisis de Secuencia de ADN , Proteínas Virales/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: The pangenotypic single tablet regimen of NS5B inhibitor sofobuvir (SOF) and NS5A inhibitor velpatasvir (VEL) is advised for 12 weeks in HCV-infected patients including those with compensated cirrhosis. Addition of ribavirin (RBV) may be considered in genotype 3 (GT3) with compensated and is recommended in decompensated cirrhosis. Real-life results with SOF/VEL are limited. To evaluate efficacy and safety in a large real-world-cohort including patients with different GTs and various fibrosis stages. DESIGN: In total, 1429 patients were treated with SOF/VEL 400/100 mg for 12 weeks in the Puglia registry between June 2017 and May 2018. 1319 (92.3%) reached week 12 post-treatment (SVR12) at the moment. Only 41 received RBV. Diagnosis of cirrhosis was based on transient elastography and/or APRI or FIB-4 scores. Sensitivity analysis in the population including all patients except non virological failure was conducted. Primary efficacy endpoint was the percentage of patients with SVR12. RESULTS: Patients' mean age was 63.8 years, 42.3% had GT1. The majority were naïve and 735 (55.5%) F0/F2. Of the remaining 587, 282 had cirrhosis. SVR12 was 98.5%, 98.0% in GT1, 99.4% in GT2, 97.1% in GT3, 100% in GT4. Overall, SVR12 by sensitivity analysis was 99.4%; 99.7% among F0-F1. Among 218 PWID, SVR12 was 94.5%. Discontinuation rates were 3.7% among PWID and 0.7% among non-PWID (p = 0.004). CONCLUSIONS: SOF/VEL treatment of chronic HCV infection reaches very high cure rates in a variety of patients; including those with F0/F1 and PWID.
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Carbamatos/uso terapéutico , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Cirrosis Hepática/complicaciones , Sofosbuvir/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carbamatos/efectos adversos , Interacciones Farmacológicas , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Seguridad , Sofosbuvir/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND & AIMS: One strategy to treat chronic hepatitis B virus (HBV) infection could be to increase the functions of virus-specific T cells. We performed a multicenter phase 2 study to evaluate the safety and efficacy of GS-4774, a yeast-based therapeutic vaccine engineered to express HBV antigens, given with tenofovir disoproxil fumarate (TDF) to untreated patients with chronic HBV infection. METHODS: We performed an open-label study at 34 sites in Canada, Italy, New Zealand, Romania, South Korea, and United States from July 2014 to August 2016. Adults who were positive for HB surface antigen (HBsAg) > 6 months and levels of HBV DNA ≥2000 IU/mL who had not received antiviral treatment for HBV within 3 months of screening were randomly assigned (1:2:2:2) to groups given oral TDF 300 mg daily alone (n = 27; controls) or with 2, 10, or 40 yeast units GS-4774 (n = 168), administered subcutaneously every 4 weeks until week 20 for a total of 6 doses. Blood samples were collected and analyzed and patients received regular physical examinations. Efficacy was measured by decrease in HBsAg from baseline to week 24. Specific responses to HBV (production of interferon gamma [IFNG], tumor necrosis factor [TNF], interleukin 2 [IL2], and degranulation) were measured in T cells derived from 12 HBeAg-negative patients with genotype D infections, after overnight or 10 days of stimulation of peripheral blood mononuclear cells with peptides from the entire HBV proteome. T-regulatory cells were analyzed for frequency and phenotype. Data from studies of immune cells were compared with data on reductions in HBsAg, HBV DNA, and alanine aminotransferase in blood samples from patients. RESULTS: GS-4774 was safe and well tolerated but did not produce significant decreases in levels of HBsAg. Production of IFNG, TNF, and IL2 increased significantly at weeks 24 and 48, compared with baseline, in HBV-specific CD8+ T cells from patients given GS-4774 but not from controls. GS-4774 had greater effects on CD8+ than CD4+ T cells, which were not affected at all or very weakly by TDF with or without GS-4774. GS-4774 did not affect responses of T cells to other viruses tested. HBV core peptides induced the greatest production of IFNG by T cells following overnight stimulation, whereas HBV envelope antigens did not induce a response. Following 10 days of stimulation, production of IFNG and TNF increased with time of exposure to GS-4774; the greatest levels of responses were to HBV envelope antigens followed by core and polymerase peptides. We observed a correlation in patients given GS-4774 between increased T-cell functions and reductions in numbers of T-regulatory cells. CONCLUSIONS: In a phase 2 study of patients with chronic HBV infection given TDF with or without GS-4774, we found that vaccination can increase production of IFNG, TNF, and IL2 by CD8+ T cells exposed to antigenic peptides, with little effect on CD4+ T cells. Although GS-4774 did not reduce levels of HBsAg in patients, its strong immune stimulatory effect on CD8+ T cells might be used in combination with other antiviral agents to boost the antivirus immune response. Clinicaltrials.gov no: NCT02174276.
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Antivirales/uso terapéutico , Vacunas contra Hepatitis B/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Tenofovir/uso terapéutico , Adolescente , Adulto , Anciano , Linfocitos T CD8-positivos/inmunología , ADN Viral , Quimioterapia Combinada , Femenino , Antígenos del Núcleo de la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Humanos , Tolerancia Inmunológica/inmunología , Interferón gamma/inmunología , Interleucina-2/inmunología , Masculino , Persona de Mediana Edad , Transactivadores/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Carga Viral , Proteínas Reguladoras y Accesorias Virales , Adulto JovenRESUMEN
In clinical trials, a sofosbuvir/velpatasvir (SOF/VEL) pangenotypic single-tablet regimen was associated with high sustained virological response (SVR) rates at 12 weeks (SVR12) after the end of treatment, regardless of genotype and fibrosis stage. No real-life data on genotype 3 (GT3) cirrhotic patients with portal hypertension are available. The aim of this study was to assess the effectiveness of SOF/VEL in GT3 cirrhotics with portal hypertension. Patients with GT3 and advanced cirrhosis were treated for 12 weeks with SOF/VEL without ribavirin at five different centers in Italy from June 2017 to August 2018 and their SVR12 was assessed. Of the 227 GT3 cirrhotics evaluated, 205 met the inclusion criteria and 111 had transient elastography results ≥20 KPa. SVR12 was 97.6% (95% CI 94.4-98.9), rates were 99.1% (95% CI 95.7-99.8) in patients with ≥20 KPa and 95.8% (95% CI 89.5-98.3) in those with <20 KPa (p = 0.18). Analyzed by presence of esophageal varices, the SVR12 rates were 98.4% (95% CI 91.4-99.7) and 97.1% (95% CI 92.9-98.9) in patients without and with varices, respectively (p = 1.0). In real life, SOF/VEL GT3 cirrhotic patients with evidence of portal hypertension can achieve SVR12 levels comparable to those of patients without portal hypertension. These SVR12 rates are similar to what is reported in compensated cirrhosis treated within clinical trials.
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Carbamatos/uso terapéutico , Hepacivirus/genética , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Hipertensión Portal/tratamiento farmacológico , Hipertensión Portal/virología , Cirrosis Hepática/tratamiento farmacológico , Ribavirina/uso terapéutico , Sofosbuvir/uso terapéutico , Respuesta Virológica Sostenida , Adulto , Anciano , Estudios de Cohortes , Comorbilidad , Femenino , Humanos , Hipertensión Portal/complicaciones , Cirrosis Hepática/complicaciones , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry. METHODS: We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed. RESULTS: In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10-50) and the MHC locus 6p21.32 (P = 1.15 × 10-21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10-07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants. CONCLUSIONS: In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.
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Población Negra/genética , Hepacivirus/fisiología , Hepatitis C/genética , Hispánicos o Latinos/genética , Población Blanca/genética , Femenino , Estudio de Asociación del Genoma Completo , Hepatitis C/diagnóstico , Hepatitis C/etnología , Hepatitis C/virología , Interacciones Huésped-Patógeno , Humanos , Interferones , Interleucinas/genética , Complejo Mayor de Histocompatibilidad/genética , Masculino , Receptores Acoplados a Proteínas G/genética , Remisión Espontánea , Estados Unidos/epidemiología , Carga ViralRESUMEN
BACKGROUND & AIMS: The oral Toll-like receptor (TLR) 7 agonist GS-9620 has antiviral effects in woodchuck and chimpanzee models of chronic hepatitis B virus (HBV) infection. We investigated, in a clinical trial, the capacity of this agent to reconstitute protective immunity in patients with chronic HBV infection. METHODS: We performed a prospective study of 28 patients with suppression of HBV infection by nucleos(t)ide analogue therapy and who tested negative for hepatitis B e antigen at 4 medical centers in Italy. Patients were randomly assigned (1:3:3:3) to groups given placebo or different doses of GS-9620 (1, 2, and 4 mg, weekly for 12 weeks). We added data from 8 patients receiving nucleos(t)ide analogue therapy to the placebo group (controls); 13 treatment-naïve patients with chronic HBV infection and 15 subjects who spontaneously recovered from an acute HBV infection served as additional controls. Peripheral blood mononuclear cells were collected at baseline, during administration of GS-9620 or placebo, and 12 weeks afterward. Phenotype and function of natural killer (NK) and HBV-specific T cells were analyzed by flow cytometry. T cells were expanded by incubation with peptides from the entire HBV proteome and studied after overnight or 10 days culture. NK-cell inhibition of T-cell responses was measured by assessing cytokine production by T cells stimulated with peptides in the presence or absence of NK cells. RESULTS: T cells collected at baseline before addition of GS-9620, when patients were receiving only nucleos(t)ide therapy, had greater responses to HBV than T cells from treatment-naïve patients, based on cytokine production in response to HBV peptides. However, during or after administration of GS-9620, T cells produced higher levels of cytokines compared to baseline. NK-cell activation and function increased after patients were given GS-9620, but the ability of NK cells to suppress T-cell responses was lower during GS-9620 therapy than before. Changes in T-cell or NK-cell function did not correlate with levels of hepatitis B surface antigen. Serum levels of hepatitis B surface antigen did not decrease significantly compared to baseline in patients given any dose of GS-9620. CONCLUSIONS: Twelve weeks administration of GS-9620 had no significant effect on serum hepatitis B surface antigen levels, but did appear to increase T-cell and NK-cell responses and reduce the ability of NK to suppress T cells. GS-9620 might therefore be included in therapies to increase the immune response to HBV.
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Antivirales/administración & dosificación , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/tratamiento farmacológico , Células Asesinas Naturales/efectos de los fármacos , Pteridinas/administración & dosificación , Linfocitos T/efectos de los fármacos , Adulto , Femenino , Antígenos de Superficie de la Hepatitis B/sangre , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Nucleósidos/uso terapéutico , Estudios Prospectivos , Receptor Toll-Like 7/agonistasRESUMEN
BACKGROUND & AIMS: Little is known about the epidemiology and frequency of recombinant HCV genotype 2/1 strains, which may represent a challenge for direct antiviral therapy (DAA). This study aims to identify the epidemiology and phylogeny of HCV genotype 2/1 strains and encourages genotype screening, to select the DAA-regimen that achieves the optimal sustained virologic response. METHODS: Consecutive samples from HCV genotype 2 infected patients, according to commercial genotyping, from Germany, Italy and Israel were re-genotyped by Sanger-based sequencing. Virologic, epidemiological, and phylogenetic analyses including other published chimeras were performed. RESULTS: Sequence analysis of 442 supposed HCV genotype 2 isolates revealed 61 (genotype 2k/1b (n=59), 2a/1b (n=1) or 2b/1a (n=1)) chimeras. No chimeras were observed in Italy, but the frequency was 14% and 25% in Germany and Israel. Treatment of viral chimera with sofosbuvir/ribavirin led to virologic relapse in 25/27 patients (93%). Nearly all patients treated with genotype 1-based DAA-regimens initially (n=8/9), or after relapse (n=13/13), achieved a sustained virologic response. Most patients with 2k/1b chimeras (88%) were originally from eight different areas of the former Soviet Union. All known 2k/1b chimeras harbour the same recombination breakpoint and build one phylogenetic cluster, while all other chimeras have different phylogenies. CONCLUSIONS: The HCV genotype 2k/1b variant derives from one single recombination event most likely in the former Soviet Union, while other chimeras are unique and develop independently. A relatively high frequency has been observed along the migration flows, in Germany and Israel. In countries with little migration from the former Soviet Union the prevalence of 2k/1b chimeras is expected to be low. Treatment with sofosbuvir plus ribavirin is insufficient, but genotype 1-based regimens seem to be effective. Lay summary: The frequency of recombinant HCV is higher than expected. A novel recombinant variant (HCV genotype 2a/1b) was identified. Screening for recombinant viruses would contribute to increased response rates to direct antiviral therapy.
Asunto(s)
Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Sustitución de Aminoácidos , Antivirales/uso terapéutico , Quimera/genética , Farmacorresistencia Viral/genética , Evolución Molecular , Genotipo , Alemania/epidemiología , Hepacivirus/clasificación , Hepatitis C Crónica/epidemiología , Humanos , Israel/epidemiología , Italia/epidemiología , Epidemiología Molecular , Filogenia , Polimorfismo de Nucleótido Simple , Prevalencia , Virus Reordenados/efectos de los fármacos , Virus Reordenados/genética , Recombinación Genética , Respuesta Virológica SostenidaRESUMEN
BACKGROUND & AIMS: Sofosbuvir (SOF) and weight-based ribarivin (RBV) represented until recently the standard of care in hepatitis C virus (HCV) genotype (GT)2 patients. In registration studies 12-16weeks duration were associated with a 90% sustained virological response at 12weeks (SVR12). Real life cohorts showed lower SVR12 rates. METHODS: SVR12 rates attained in an Italian real life cohort and possible benefits of a duration extended up to 20weeks was investigated in HCV GT2 patients with cirrhosis. The role of 2k/1b chimeras as potential predictor of treatment failure was also analysed. RESULTS: Overall, 291 HCV GT2 infected patients with bridging fibrosis or cirrhosis were evaluated. Median age was 68years (18-87); 163 were treatment naïve. Of 168 cirrhotic patients, 149 had Child-Pugh score A and 19 B, 50 platelets count <100,000/mm3 and 62 albumin <3.5g/dl. SVR12 were 95.53% overall, with 99.15% in non-cirrhotic patients and 93.06% in cirrhotic patients. In patients who completed treatment, SVR rates for cirrhotic patients resulted in 94.51%, and 94.94% after 16 or 20weeks respectively. Predictors of SVR were low platelet count and esophageal varices (OR 7.2; 95% CI 1.67-31.25; p=0.0022 and OR 0.1; 95% CI 0.01-0.72; p=0.0079, respectively). Anemia was mild in 12.4%, moderate in 3.4%, and severe in 2.4% of cases. Anemia was slightly more frequent among longer duration but not associated with treatment discontinuations. No 2k/1b strains or genotypes different from those at baseline were identified at relapse. CONCLUSIONS: In GT2 cirrhotic patients, SOF/RBV for 16 or 20weeks is associated with real life SVR12 rates of 95%. LAY SUMMARY: A duration of treatment of 16-20weeks was recommended for treatment of HCV GT2 patients using the combination of sofosbuvir and ribavirin. Real life experiences, where patients received 12weeks of treatment regardless of the severity of liver disease, suggested that response rates are lower than expected, in particular in patients with liver cirrhosis. A misleading genotyping of a 2k/1b strain as GT2 was also hypothesized as a further explanation for less effectiveness. We demonstrated that using the recommended extended duration in patients with more severe disease 95% of patients with severe liver disease including cirrhosis can be cured and that 2k/1b strain plays only a secondary role in specific countries like Germany. Although this combination has been recently replaced by sofosbuvir and velpatasvir fixed dose combination as the standard of care for treating HCV GT2 patients, our findings may inform physicians from countries where the new regimen is not yet available.
Asunto(s)
Antivirales/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Esquema de Medicación , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/clasificación , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Italia , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , ARN Viral/sangre , ARN Viral/genética , Recombinación Genética , Respuesta Virológica Sostenida , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The current standard-of-care for treatment of HCV genotype 2 (GT-2) patients is the combination of sofosbuvir (SOF) with weight-based ribavirin (RBV). Patients with HCV GT-2 infection and ribavirin contraindications require the use of SOF plus NS5A inhibitor daclatasvir (DCV) which is not reimbursed everywhere. METHODS: We conducted an open-label observational, prospective study on a subgroup of GT-2 patients either naïve or treatment experienced (TE) with contraindications to the use of RBV. Patients with cirrhosis of Child-Pugh-Turcotte (CPT) class A and B or advanced fibrosis with comorbidities were included. They were assigned to receive 12 or 24 weeks of SOF/DCV. The primary end point of the study was sustained virological response (SVR) defined as HCV RNA levels <12 IU/ml, 12 weeks post treatment. RESULTS: Out of 106 patients with GT-2 who received treatment at our unit from July 2014 to June 2015, 20 (18.8%) patients, whose treatment could not be deferred, were ribavirin intolerant; 19 received SOF/DCV combination for 12 or 24 weeks. The majority of the patients was men, 58% had cirrhosis, and 58% were TE. All treated patients achieved SVR regardless of treatment duration. The most common adverse events (AEs) were fatigue, headache and nausea. No discontinuations due to AEs were observed. Two patients had oesophageal bleeding but continued treatment and achieved SVR; one patient developed HCC 12 weeks post treatment, but remained HCV RNA undetectable. CONCLUSIONS: This study supports the use of SOF/DCV for 12 weeks in non-cirrhotics or 24 weeks in cirrhotic GT-2 patients who cannot tolerate RBV, including those with decompensated disease.
Asunto(s)
Antivirales/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/administración & dosificación , Sofosbuvir/administración & dosificación , Anciano , Antivirales/efectos adversos , Carbamatos , Esquema de Medicación , Quimioterapia Combinada , Fatiga/inducido químicamente , Femenino , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Humanos , Imidazoles/efectos adversos , Italia , Cirrosis Hepática/complicaciones , Masculino , Estudios Prospectivos , Pirrolidinas , Ribavirina , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Valina/análogos & derivados , Carga ViralRESUMEN
BACKGROUND & AIMS: Different prevalence of favourable IL28BCC genotype have been reported in studies performed in different countries around the world. Data on distribution of IL28B genotypes in healthy Italian subjects are lacking. METHODS: Studies on prospectively collected untreated chronic HCV-infected Italian patients led to conflicting results. To investigate the prevalence of IL28B genotypes in untreated HCV-infected patients and in subjects able to clear HCV, and to compare them to the prevalence registered in healthy Italian controls. To evaluate IL28B prevalence across different HCV genotypes. RESULTS: IL28BCC was observed in 30.9% of chronic HCV patients, in 71.0% of subjects able to clear HCV infection and in 41.6% of the Italian controls. The frequency of IL28BCC was higher in HCV genotype 2 and 3 than in 1 (38.3 vs. 28.2) (P = 0.02). Levels of ALT higher in IL28BCC than in non-CC were observed regardless of HCV genotypes (P = 0.0014). CONCLUSIONS: IL28BCC frequencies progressively decline from subjects with spontaneous HCV clearance to normal non-infected subjects and to chronically infected. This study suggests that patients with IL28BCC, if genotype 1, are able to clear HCV more often than if genotype 2 and 3 infected, and that CC genotype is associated with higher grade of necro-inflammation.
Asunto(s)
Variación Genética/genética , Hepatitis C/epidemiología , Hepatitis C/genética , Interleucinas/genética , Diagnóstico por Imagen de Elasticidad , Frecuencia de los Genes , Genotipo , Hepatitis C/patología , Humanos , Interferones , Italia/epidemiología , Desequilibrio de Ligamiento , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genética , Prevalencia , Estadísticas no ParamétricasRESUMEN
The uridine nucleotide analogue sofosbuvir is a selective hepatitis C virus NS5B polymerase inhibitor, active regardless of genotype. We analyzed data on efficacy and safety of sofosbuvir, either in combination with pegylated interferon alfa-2a and ribavirin, or in combination with ribavirin alone as part of an interferon free regimen in more than 1300 patients. Treatment with sofosbuvir for 12 weeks in combination with P/R, in naïve genotype 1 patients was mainly studied in Neutrino. The efficacy of sofosbuvir as part of an all-oral combination including ribavirin alone, was explored in 555 naïve, ineligible and previous treatment failure genotype 2/3 patients. Rates of Sustained Viral Response in genotype 1 and 2 were higher than 85%. For genotype 3 and 4, a European study, Valence, and a US study on patients of Egyptian origin showed that naïve patients are cured at high rates by the all-oral combination given for 24 weeks. The efficacy of sofosbuvir plus P/R for 12 weeks in previous treatment failure genotype 3 has also been demonstrated. Sofosbuvir-based combinations are safe and well tolerated without side effects directly related to the drug. A large body of evidence suggests that sofosbuvir marks a revolution in HCV treatment.