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AIM: Ropeginterferon alfa-2b is a novel mono-pegylated proline-interferon. Its biweekly dosing schema has demonstrated tolerability and clinical efficacy for treating chronic hepatitis in previous clinical studies. This trial evaluates the pharmacokinetics of 400 µg ropeginterferon alfa-2b in patients with chronic hepatitis C virus (HCV) and provides the data to support the clinical utility of ropeginterferon alfa-2b at 400 µg. METHODS: Seventeen patients with chronic HCV genotype 2 were enrolled to receive a single injection of 400 µg ropeginterferon alfa-2b plus 14-day treatment of ribavirin. Pharmacokinetics, safety, and HCV RNA reduction/clearance were assessed. RESULTS: Tmax was 154.003 h and T1/2 was 114.273 h. The Cmax was 29.823 ng mL-1. AUClast was 9364.292 h∗ng mL-1 and AUCinf was 11084.317 h∗ng mL-1. All adverse events were mild or moderate, and there were no serious adverse events. A 1000-fold reduction in the geometric mean of HCV RNA was observed 14 d after the single injection of ropeginterferon alfa-2b. Two patients achieved clearance of HCV RNA, and the other five patients had HCV RNA levels lower than 200 IU mL-1. CONCLUSION: Ropeginterferon alfa-2b at 400 µg led to PK exposures associated with safety and notable clinical activity in patients with chronic HCV. This study suggests that ropeginterferon alfa-2b at 400 µg is an acceptable dosing regimen for treating chronic HCV and also provides supporting data for the clinical use of ropeginterferon alfa-2b at a higher starting dose for other indications.
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Hepatitis C Crónica , Polietilenglicoles , Humanos , Antivirales/uso terapéutico , Quimioterapia Combinada , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Resultado del Tratamiento , ARN ViralRESUMEN
The hepatitis C virus genotype 2 (HCV2) is endemic in Western and Central Africa. The HCV2 evolutionary origins remain uncertain due to the paucity of available genomes from African settings. In this study, we investigated the molecular epidemiology of HCV infections in rural Guinea, Western Africa, during 2004 and 2014. Broadly reactive nested reverse transcription polymerase chain reaction (RT-PCR)-based screening of sera from 1,571 asymptomatic adults resulted in the detection of 25 (1.5 per cent; 95 per cent confidence interval 0.9-2.3) positive samples, with a median viral load of 2.54E + 05 IU/ml (interquartile range 6.72E + 05). HCV-infected persons had a median age of 47 years, and 62.5 per cent were male and 37.5 per cent were female. The full polyprotein-encoding genes were retrieved by a combination of high throughput and Sanger sequencing from 17 samples showing sufficiently high viral loads. Phylogenetic analysis and sequence distances ≥13 per cent averaged over the polyprotein genes compared to other HCV2 subtypes revealed nine previously unknown HCV2 subtypes. The time to the most recent common ancestor of the Guinean HCV2 strains inferred in a Bayesian framework was 493 years (95 per cent Highest posterior density (HPD) 453-532). Most of the Guinean strains clustered poorly by location on both the level of sampling sites within Guinea and the level of countries in the phylogenetic reconstructions. Ancestral state reconstruction provided decisive support (Bayes factor > 100) for an origin of HCV2 in Western Africa. Phylogeographic reconstructions in a Bayesian framework pointed to a radial diffusion of HCV2 from Western African regions encompassing today's countries like Ghana, Guinea Bissau, or Burkina Faso, to Central and Northern African regions that took place from the 16th century onwards. The spread of HCV2 coincided in time and space with the main historic slave trade and commerce routes, supported by Bayesian tip-association significance testing (P = 0.01). Our study confirms the evolutionary origins of HCV2 in Western Africa and provides a potential link between historic human movements and HCV2 dispersion.
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BACKGROUND: Hepatitis C virus (HCV) genotype 6 mainly distributes in Southeast Asia and South China. Because of the low prevalence in developed countries, optimal treatment for HCV genotype 6 in real-world setting remains to be determined. We aimed to evaluate the effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) and glecaprevir/pibrentasvir (GLE/PIB) for patients with HCV genotype 6 infection in Taiwan. METHODS: A total of 286 patients with chronic hepatitis C (CHC) genotype 6, 161 receiving 12-week SOF/VEL and 125 receiving 8-week GLE/PIB, were enrolled. All patients were followed up for 12 weeks after treatment completion. Demographic information, HCV viral load (VL), profiles of lipid and sugar, and adverse events were recorded and reviewed. RESULTS: Sustained virological response (SVR) rates of SOF/VEL and GLE/PIB evaluated by intention-to-treat analysis were 99.38% and 100%, respectively. SVR achieved 100%, regardless of cirrhosis or viral load (cutoff: 6 MIU/mL), of both regimens by per-protocol analysis. Skin itching was the most common adverse event, with an overall incidence of 6.64% which was more prevalent in GLE/PIB (12.0%) than SOF/VEL (2.48%). A significant decrease in the estimated glomerular filtration rate was observed in patients receiving SOF/VEL but not in those receiving GLE/PIB at the time of SVR. No patient discontinued treatment due to adverse event. CONCLUSION: The high SVR and excellent safety of SOF/VEL and GLE/PIB in real-world setting reveals that the two DAA regimens are favorable options for treatment of HCV genotype 6 in Taiwan and Asia.
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Hepatitis C Crónica , Hepatitis C , Ácidos Aminoisobutíricos , Antivirales/efectos adversos , Bencimidazoles , Benzopiranos , Carbamatos , Ciclopropanos , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Lípidos , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas , Sofosbuvir/efectos adversos , Azúcares/uso terapéutico , Sulfonamidas , Resultado del TratamientoRESUMEN
Context and objective. The steady increase in the number of chronic hemodialysis patients in sub-Saharan Africa (SSA) calls for improved management of those patients. The present study aimed to determine the frequency of hepatitis C virus (HCV) infection, the prevalent genotypes, and the risk factors associated with HCV in hemodialysis patients in Kinshasa (DR Congo). Methods. A cross-sectional study was conducted from February to June 2018 in all hemodialysis centers in Kinshasa. Blood samples were collected from 127 chronic hemodialysis patients and tested for the presence of antibodies against HCV. The HCV genotype was identified by real-time polymerase chain reaction (RT- PCR). Results. Twenty-two (17.3 %) patients were positive for anti-HCV antibodies, ranging from 0 % to 52.9 % in different centers. Genotype 4 was detected in 18/22 (81.8 %), followed by genotype 2 in 2/22 (9.1%), and both genotypes 2 and 4 in one patient (4.5%). One patient had an undetermined genotype (4.5 %). Having received at least 4 transfusions [7,21 (1,09- 10,61); p=0.040)], not being under EPO treatment [5,81(1,47-12,96); p=0.012)], being on hemodialysis for at least 14 months [3,63(1,60-5,05); p=0.035)]and being dialyzed in an overloaded center [2,06(0,83-5,86); p=0.073)] were associated with a greater risk of HCV infection. Conclusion. This high HCV prevalence (17.3 %) represents a substantial health burden in HD patients from Kinshasa, DR Congo. It is largely driven by the number of blood transfusions, the duration time in hemodialysis. Observations from the present study underscore the need of reducing the number of blood transfusions in people on dialysis through the administration of erythropoietin, given the unaffordable cost of HCV therapy for most individuals in DR Congo.
Contexte et Objectifs. Le nombre des patients hémodialisés en Afrique subsaharienne en constante augmentation ; justifiant de ce fait une meilleure prise en charge de ces patients. La présente étude détermine la prévalence de l'infection par le virus de l'hépatite C en en determinant les génotypes ainsi que les facteurs y associés dans ce groupe de patients. Méthodes. 127 patients hémodialisés chroniques ont subis des tests sérologiques à la recherche des anticorps anti-VHC dans plusieurs centres de Kinshasa de février à juin 2018. Le génotype viral a été déterminé par la RT-PCR. Résultats. La fréquence des anticorps anti-VHC a varié de 0 à 52,9 % dans ce groupe. Les génotypes le plus fréquents ont été le 4 (18/22) et le 2 (2/22) ; étant sumultanément rétrouvé chez un patient, et indéterminé chez un autre sujet. Avoir reçu au moins 4 transfusions [7,21 (1,09-10,61; p=0.040)], ne pas être sous EPO [5,81(1,47-12,96); p=0.012)], être en hémodialyse depuis au moins 14 mois [3,63(1,60- 5,05); p=0.035)] et être dialysé dans un centre surchargé [2,06 (0,83-5,86); p=0.073)] étaient associés à un risque plus élevé d'infection par le VHC. Conclusion. Ses principaux déterminants sont : le nombre des transfusions sanguines et la durée d'HD ; d'où la nécessité de réduire les transfusions sanguines chez les sujets dialysés par l'administration d'EPO, étant donné le coût prohibitif du traitement contre le VHC dans notre contexte
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Humanos , Masculino , Femenino , Factores Epidemiológicos , Hepacivirus , Genotipo , Prevalencia , Diálisis RenalRESUMEN
The objective of this study was to compare Reverse Hybridisation Assay with conventional sequencing for determination of Hepatitis C Virus Genotype and Subtypes. Anti-HCV antibody was determined followed by HCV RNA extraction which was used for (1) viral load determination (2) qualitative real-time PCR RHA for genotyping and (3) conventional sequencing. Compared to conventional sequencing, accuracy of RHA results was 96.55% for determination of genotype (κ = 0.93) and 89.66% for subtype (κ = 0.85). Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of the qualitative PCR were 82.29%, 100%, 44.44% and 100% respectively with an accuracy of 86.84%. RHA is a less time consuming and cheaper method for determination of HCV genotype and subtype yet results must be interpreted with caution and quality control monitoring should be strictly followed to ensure validity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13337-021-00729-9.
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BACKGROUND: Hepatitis C virus genotype 3a (HCV G3a) is highly prevalent in Pakistan. Due to the elevated cost of available Food and Drug Administration-approved drugs against HCV, medicinal natural products of potent antiviral activity should be screened for the cost-effective treatment of the disease. Furthermore, from natural products, active compounds against vital HCV proteins like non-structural protein 3 (NS3) protease could be identified to prevent viral proliferation in the host. AIM: To develop cost-effective HCV genotype 3a NS3 protease inhibitors from citrus fruit extracts. METHODS: Full-length NS3 without co-factor non-structural protein 4A (NS4A) and codon optimized NS3 protease in fusion with NS4A were expressed in Escherichia coli. The expressed protein was purified by metal ion affinity chromatography and gel filtration. Citrus fruit extracts were screened using fluorescence resonance energy transfer (FRET) assay against the protease and polyphenols were identified as potential inhibitors using electrospray ionization-mass spectrometry (MS)/MS technique. Among different polyphenols, highly potent compounds were screened using molecular modeling approaches and consequently the most active compound was further evaluated against HCV NS4A-NS3 protease domain using FRET assay. RESULTS: NS4A fused with NS3 protease domain gene was overexpressed and the purified protein yield was high in comparison to the lower yield of the full-length NS3 protein. Furthermore, in enzyme kinetic studies, NS4A fused with NS3 protease proved to be functionally active compared to full-length NS3. So it was concluded that co-factor NS4A fusion is essential for the purification of functionally active protease. FRET assay was developed and validated by the half maximal inhibitory concentration (IC50) values of commercially available inhibitors. Screening of citrus fruit extracts against the native purified fused NS4A-NS3 protease domain showed that the grapefruit mesocarp extract exhibits the highest percentage inhibition 91% of protease activity. Among the compounds identified by LCMS analysis, hesperidin showed strong binding affinity with the protease catalytic triad having S-score value of -10.98. CONCLUSION: Fused NS4A-NS3 protease is functionally more active, which is effectively inhibited by hesperidin from the grapefruit mesocarp extract with an IC50 value of 23.32 µmol/L.
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PURPOSE: Current direct-acting antiviral agents for treatment of hepatitis C virus genotype 4a (HCV-4a) have been reported to cause adverse effects, and therefore less toxic antivirals are needed. This study investigated the role of curcumin chitosan (CuCs) nanocomposite as a potential anti-HCV-4a agent in human hepatoma cells Huh7. METHODS: Docking of curcumin and CuCs nanocomposite and binding energy calculations were carried out. Chitosan nanoparticles (CsNPs) and CuCs nanocomposite were prepared with an ionic gelation method and characterized with TEM, zeta size and potential, and HPLC to calculate encapsulation efficiency. Cytotoxicity studies were performed on Huh7 cells using MTT assay and confirmed with cellular and molecular assays. Anti-HCV-4a activity was determined using real-time PCR and Western blot. RESULTS: The strength of binding interactions between protein ligand complexes gave scores with NS3 protease, NS5A polymerase, and NS5B polymerase of -124.91, -159.02, and -129.16, for curcumin respectively, and -68.51, -54.52, and -157.63 for CuCs nanocomposite, respectively. CuCs nanocomposite was prepared at sizes 29-39.5 nm and charges of 33 mV. HPLC detected 4% of curcumin encapsulated into CsNPs. IC50 was 8 µg/mL for curcumin and 25 µg/mL for the nanocomposite on Huh7 but was 25.8 µg/mL and 34 µg/mL on WISH cells. CsNPs had no cytotoxic effect on tested cell lines. Apoptotic genes' expression revealed the caspase-dependent pathway mechanism. CsNPs and CuCs nanocomposite demonstrated 100% inhibition of viral entry and replication, which was confirmed with HCV core protein expression. CONCLUSION: CuCs nanocomposite inhibited HCV-4a entry and replication compared to curcumin alone, suggesting its potential role as an effective therapeutic agent.
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Antivirales/farmacología , Curcumina/farmacología , Hepacivirus/efectos de los fármacos , Nanopartículas/química , Antivirales/química , Línea Celular , Quitosano/química , Curcumina/administración & dosificación , Curcumina/química , Genotipo , Hepacivirus/genética , Hepacivirus/patogenicidad , Humanos , Neoplasias Hepáticas/virología , Nanopartículas/uso terapéutico , Proteínas del Núcleo Viral/metabolismo , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo , Internalización del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Egypt is one of the highest prevalence rates of hepatitis C virus (HCV) infection worldwide. HCV is among major reasons for chronic liver diseases. MicroRNA (miRNAs), small noncoding regulatory molecules play a key role in the pathogenesis of liver. Circulating miRNAs represent potential noninvasive biomarkers for diagnosis and monitoring patients with liver diseases progression. To investigate the potential role of circulating miRNAs for surveillance of liver disease progression, we assessed the expression of 20 liver-related miRNAs in sera of 47 chronic hepatitis C Egyptian patients compared with 25 controls using quantitative reverse-transcription polymerase chain reaction assay. The sensitivity and specificity were evaluated using receiver operating characteristic (ROC) curve. The correlations between their levels and the clinicopathological features were assessed. Fourteen miRNAs showed upregulation and six miRNAs showed downregulation. ROC curve analyses revealed that the explored miRNAs could serve as valuable biomarkers for chronic hepatitis with an area under the curve ranged from 0.708 (95% confidence interval [95% CI], 0.587 to 0.829; P = 0.004) for miR-199 up to 0.974 (95% CI, 0.943 to 1.00; P < 0.001) for miR-23b. The expression level of miR-21 demonstrated significant correlation with age, liver enzymes, ALT/AST, and α-fetoprotein level. AST level was directly correlated with miR-122, while an inversely correlated with miR-23b. Fibrosis and steatosis stages possessed positive correlation with miR-199 expression and negative correlation with miR-27a and miR-93. In conclusion, miR-23b and miR-106 might be a useful biomarker for chronic hepatitis C (CHC). MiR-27a, miR-93, and miR-199 might have a potential role in the progression of liver diseases. Unravel the role of these miRNAs in CHC patients might lead to precise prognosis and management.
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Biomarcadores/sangre , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/patología , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/patología , MicroARNs/sangre , Técnicas de Diagnóstico Molecular/métodos , Adulto , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Progresión de la Enfermedad , Egipto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: The efficacy of direct-acting antivirals (DAAs) depends on the hepatitis C virus (HCV) genotype 4 (GT4) subtype which are used in the treatment of HCV. We aimed to retrospectively investigate the baseline prevalence of HCV NS5A and NS5B polymorphisms and their impact on virological outcome in GT4-infected patients treated with various DAA regimens. PATIENTS AND METHODS: Available plasma samples from HCV GT4-infected patients treated with different DAA regimens were analyzed at baseline and after treatment failure, where applicable. Sanger sequencing of patient-derived NS5A and NS5B regions was performed on all available samples, while ultradeep pyrosequencing (UDPS) of NS5A and NS5B regions was performed only on samples from treatment failures at different time points. RESULTS: Sustained virological response (SVR) was achieved by 96% (48/50) of patients. Of 16 patients with baseline NS5A sequence, polymorphisms at amino acid positions associated with drug resistance were detected only at position 58: P58 (69.2%) and T58 (30.8%). Of 21 patients with baseline NS5B sequence, N142S was detected only in the two treatment failures, both with GT4d were treated with sofosbuvir (SOF)-based regimens, suggesting a potential involvement in SOF efficacy. Two patients (patient 1 [Pt1] and patient 2 [Pt2]) relapsed. In Pt1, NS5A-T56I and NS5A-Y93H/S emerged. In Pt2, NS5A-L28F emerged and a novel NS5B resistance-associated substitution (RAS), L204F, representing 1.5% of the viral population at baseline, enriched to 71% and 91.6% during and after treatment failure, respectively. UDPS of NS5B from Pt2 indicated a mixed infection of approximately 1:5, GT1a:GT4d, at baseline and GT4d during failure. Phylogenetic analysis of NS5A sequences indicated no clustering of HCV strains from patients achieving SVR vs patients who relapsed. The mean genetic distance in NS5A sequences was 5.8%, while a lower genetic distance (3.1%) was observed in NS5B sequences. CONCLUSION: Results from these analyses confirm the importance of UDPS in the analysis of viral quasispecies variability and the identification of novel RASs potentially associated with DAA treatment failure in HCV GT4-infected patients.
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Purpose: The hepatitis C virus (HCV) has seven main genotypes and multiple subtypes. The distribution of HCV genotypes varies across geographical regions worldwide. Updated estimates of HCV genotype distributions have a critical importance for developing strategies to manage or eliminate HCV infection. The aim of this study was to determine the distribution of HCV genotypes in patients with HCV admitted to a university hospital in Istanbul, Turkey. Materials and Methods: A total of 412 HCV RNA positive patients with 46.6% of males and 53.4% of females between January 2013 and September 2016 were included in the study. Genotyping of HCV of the study population was performed by a commercial reverse hybridisation line probe-based assay. Results: Genotype 1 (82.5%) was dominant genotype, followed by genotype 3 (10.7%), genotype 2 (4.6%) and genotype 4 (2.2%). Among patients with genotype 1, subtype 1a, 1b and undetermined subtype were 6.3%, 38.8% and 37.4%, respectively. It was observed that genotype proportion was dependent on gender and age of the patients. Genotype 1 and genotype 2 were more prevalent in females, whereas genotypes 3 and 4 were more prevalent in males. Genotype 1 in the older patients and genotype 3 in the younger patients were more prevalent. Conclusion: The majority of patients with HCV infection had genotype 1 (82.5%), followed by genotype 3, 2 and 4. Monitoring the change in HCV genotype distribution is critical for the development of effective strategies for HCV elimination.
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Hepacivirus/genética , Hepatitis C Crónica/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Genotipo , Hepatitis C Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/genética , Turquía , Adulto JovenRESUMEN
BACKGROUND: Fast hepatitis C virus (HCV) replication is one of the reasons for frequent changes in viral genome. OBJECTIVES: The objective of this study was to evaluate the frequency and type of mutation in NS3/4 protease in patients with HCV genotype 1b and to determine the effect of the mutation on viral load, fibrosis stage, alanine aminotransferase (ALT) activity, and alpha-fetoprotein (AFP) level. MATERIAL AND METHODS: The study included 46 treatment-naïve patients, infected with HCV genotype 1b. Mutations were analyzed after isolating HCV RNA, and then evaluating the compliance of the amino acid sequence, using 3500 Genetic Analyzer (Applied Biosystems, Foster City, USA). RNA fragment from nucleotide 1-181 encoding NS3/4 protease was subjected to analysis. RESULTS: Mutations were demonstrated in 65% of subjects. Changes in the protease region affecting resistance to treatment (T54, Q80, V158, M175, D186) were detected in 10.8% of patients. Substitution mutation at T72 was found most frequently - in 49.9% of cases. In 13% of patients, mutation at G86 was demonstrated, including G86P in 5 patients and G86S in 1 patient. In the group of patients with T72 mutation, viral load was significantly higher (1.3 × 106 IU/mL vs 1.0 × 105 IU/mL; p = 0.01), AFP level was higher and fibrosis level was lower (1.26 vs 2.17; p = 0.008) compared to the patients without the mutation. Cryoglobulinemia was observed in 74% of patients with mutation at position T72. CONCLUSIONS: Natural mutations of the region coding for NS3/4 protease are found frequently in patients infected with genotype 1b, but they may cause resistance to antiviral agents only in 11% of patients. Changes were most frequently found at position T72. Mutations at position T72 are correlated with the cryoglobulinemia occurrence. This is a substitution mutation, accompanied by a high viral load, high ALT activity and AFP level, which may point to a more unfavorable influence of such a modified virus, compared to wild-type virus, onto pathological processes in the liver.
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Hepacivirus/genética , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/genética , Proteínas no Estructurales Virales/genética , Secuencia de Aminoácidos , Antivirales/uso terapéutico , Crioglobulinemia/virología , Farmacorresistencia Viral/genética , Genotipo , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Mutación , Péptido Hidrolasas , Carga ViralRESUMEN
INTRODUCTION: One of the most common blood-borne transfusion-transmitted diseases is hepatitis C. Patients with a history of multiple blood transfusions are significantly at a greater risk of infection by contaminated blood and blood products. Beta thalassemia major is one such condition where repeated blood transfusions are required for patient management. MATERIALS AND METHODS: The present study was conducted to investigate the serological prevalence of hepatitis C virus (HCV), its viremia, and genotype distribution with clinical parameters among multitransfused thalassemic individuals. In this study, a total of 300 patients were screened to detect anti-HCV antibody in serum, along with liver function parameters and genotyping. RESULTS: Seventy-five (25%) patients were found to be HCV positive by enzyme-linked immunosorbent assay (ELISA). Among them, 49 (65%) were HCV RNA positive having a significant viral load in their blood and rest 26 (35%) were below detection level, which signify auto clearance of the virus in those patients. According to our study, HCV genotype 3 was the major circulating strain (92.59%) followed by genotype 1. Liver enzymes, such as alanine aminotransferase, aspartate aminotransferase, and total bilirubin, were significantly elevated among HCV seroreactive individuals. CONCLUSIONS: This study clearly indicates that the incidence of transfusion-transmitted hepatitis C is high in thalassemia patients, but actual scenario of HCV viremia can only be found by HCV RNA qualitative and quantitative detection method and not by ELISA, is a major concern for this high-risk group of population.
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OBJECTIVES: To analyse the variation of hepatitis C virus (HCV) prevalence and genotype distribution and their determinants in people living with human immunodeficiency virus (HIV) who entered care between 1997 and 2015. METHODS: HIV-infected patients enrolled in ICONA who were tested for HCV antibodies (HCV-Ab) were included. RESULTS: Overall 3407 of 12 135 (28.1%) were HCV-Ab+; and 735 of 12 135 (6.1%) were HBsAg+. Among patients whose HCV genotype was known, the most represented were genotypes 1 and 3. The prevalence of HCV infection decreased from 49.2% (2565/5217) during 1997-2002 to 10.2% (556/5466) during 2009-2015. The frequency of genotype 1a increased from 29.0% (264/911) to 43.0% (129/300), whereas genotype 3 decreased from 38.5% (351/911) to 27.0% (81/300). Independent predictors of HCV-Ab+ status were being female (adjusted OR (AOR) 1.23, 95% CI 1.04-1.50, p = 0.01), risk category (versus injecting drug users: men who have sex with men AOR 0.01, 95% CI 0.01-0.01, p <0.001; heterosexuals AOR 0.01, 95% CI 0.01-0.01, p <0.001; other/unknown AOR 0.02, 95% CI 0.01-0.02, p <0.001), being cared for in Central Italy (versus being cared for in Northern Italy: AOR 0.85, 95% CI 0.73-0.98, p <0.001), being Italian-born (AOR 1.44, 95% CI 1.16-1.80, p = 0.001) and being enrolled in less recent calendar years (versus 1997-2002: 2009-2015 AOR 0.23, 95% CI 0.19-0.27, p <0.001; 2003-2008 AOR 0.49, 95% CI 0.41-0.61, p <0.001). CONCLUSIONS: The prevalence of HCV infection in HIV-infected patients entering into care in Italy significantly declined in more recent calendar years. After adjusting for risk factors and calendar years, HCV co-infection was more frequent in females and in those born in Italy.
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Genotipo , Infecciones por VIH/complicaciones , Hepacivirus/clasificación , Hepacivirus/genética , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/virología , Adulto , Femenino , VIH , Hepacivirus/aislamiento & purificación , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios ProspectivosRESUMEN
Interactions between simeprevir (hepatitis C virus [HCV] NS3/4A protease inhibitor) and ledipasvir (HCV NS5A replication complex inhibitor) were investigated in treatment-naive HCV genotype 1-infected patients without cirrhosis, treated with simeprevir-sofosbuvir-ledipasvir in a two-panel, phase 2, open-label study. Patients had stable background treatment with sofosbuvir (400 mg once daily [QD]). In panel 1 (n = 20), the effect of ledipasvir (90 mg QD) on simeprevir (150 mg QD) was studied. Patients received simeprevir and sofosbuvir from days 1 to 14; steady-state pharmacokinetics (PK) of simeprevir was assessed (day 14). On day 15, ledipasvir was added and steady-state PK of simeprevir in the combination was evaluated (day 28). In panel 2 (n = 20), the effect of simeprevir on ledipasvir was investigated. From days 1 to 14, patients received ledipasvir and sofosbuvir and steady-state PK of ledipasvir was assessed (day 14). On day 15, simeprevir was added and a full PK profile was obtained (day 28). The least-squares mean maximum plasma concentration and area under the concentration-time curve (90% confidence interval) increased 2.3-fold (2.0- to 2.8-fold) and 3.1-fold (2.4- to 3.8-fold) for simeprevir, respectively (panel 1), and 1.6-fold (1.4- to 1.9-fold) and 1.7-fold (1.6- to 2.0-fold) for ledipasvir, respectively (panel 2), in the presence versus the absence of the other drug. All patients achieved sustained virologic responses 12 weeks after treatment end. Adverse events, mainly grade 1/2, occurred in 80% of patients; the most common was photosensitivity (45%). Due to the magnitude of interaction and the limited amount of safety data available, the use of this treatment combination is not recommended. (This study has been registered at ClinicalTrials.gov under registration no. NCT02421211.).
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Antivirales/uso terapéutico , Bencimidazoles , Fluorenos , Hepatitis C Crónica/tratamiento farmacológico , Simeprevir , Uridina Monofosfato/análogos & derivados , Adulto , Anciano , Antivirales/farmacocinética , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Bencimidazoles/uso terapéutico , Citocromo P-450 CYP3A/genética , Interacciones Farmacológicas/fisiología , Quimioterapia Combinada , Femenino , Fluorenos/efectos adversos , Fluorenos/farmacocinética , Fluorenos/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Masculino , Persona de Mediana Edad , Trastornos por Fotosensibilidad/inducido químicamente , Simeprevir/efectos adversos , Simeprevir/farmacocinética , Simeprevir/uso terapéutico , Sofosbuvir , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/antagonistas & inhibidores , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/genética , Resultado del Tratamiento , Uridina Monofosfato/efectos adversos , Uridina Monofosfato/farmacocinética , Uridina Monofosfato/uso terapéutico , Carga Viral/efectos de los fármacosRESUMEN
AIM: To evaluate and compare the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older. METHODS: The present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin (RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment. RESULTS: Among the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response (SVR) was found between the younger (80.8%) and older (88.2%) groups. The SVR rates for patients with the interleukin 28B (IL28B) (rs8099917) TG/GG-genotypes (73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger group than in the older group (91.7% vs 66.7%, respectively, P < 0.01), but the cumulative exposure to TVR was not significantly different between the younger and older groups (91.6% vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B (OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV (> 60%) (OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger (81.1%) and older (82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes (77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR (OR = 9.677; 95%CI: 1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively. CONCLUSION: Both TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.
RESUMEN
OBJECTIVE: The aim of this study was to determine the predictive capacity of response at treatment week (TW) 4 for the achievement of sustained virological response 12 weeks after the scheduled end of therapy date (SVR12) to treatment against hepatitis C virus (HCV) genotype 3 (GT3) infection with all-oral direct-acting antiviral (DAA) -based regimens. PATIENTS AND METHODS: From a prospective multicohort study, HCV GT3-infected patients who completed a course of currently recommended DAA-based therapy at 33 Spanish hospitals and who had reached the SVR12 evaluation time-point were selected. TW4 HCV-RNA levels were categorized as target-not-detected (TND), below the lower limit of quantification (LLOQTD) and ≥LLOQ. RESULTS: A total of 123 patients were included, 86 (70%) received sofosbuvir/ daclatasvir±ribavirin, 27 (22%) received sofosbuvir/ ledipasvir/ ribavirin and 10 (8.1%) received sofosbuvir/ ribavirin, respectively. In all, 114 (92.7%) of the 123 patients presented SVR12 in an on-treatment approach, but nine (7.3%) patients relapsed, all of them had presented cirrhosis at baseline. In those who achieved TND, LLOQTD and ≥LLOQ, SVR12 was observed in 81/83 (98%; 95% CI 91.5%-99.7%), 24/28 (85.7%; 95% CI 67.3%-96%) and 9/12 (75%; 95% CI 42.8%-94.5%), respectively; p(linear association) 0.001. Corresponding numbers for subjects with cirrhosis were: 52/54 (96.3%; 95% CI 87.3%-95.5%), 14/18 (77.8%; 95% CI 52.4%-93.6%) and 7/10 (70%; 95% CI 34.8%-93.3%); p 0.004. CONCLUSIONS: TW4-response indicates the probability of achieving SVR12 to currently used DAA-based therapy in HCV genotype 3-infected individuals with cirrhosis. This finding may be useful to tailor treatment strategy in this setting.
Asunto(s)
Antivirales/administración & dosificación , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Administración Oral , Antivirales/farmacología , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacología , Carbamatos , Femenino , Fluorenos/administración & dosificación , Fluorenos/farmacología , Genotipo , Hepacivirus/genética , Humanos , Imidazoles/administración & dosificación , Imidazoles/farmacología , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pirrolidinas , Ribavirina/administración & dosificación , Ribavirina/farmacología , Sofosbuvir/administración & dosificación , Sofosbuvir/farmacología , Respuesta Virológica Sostenida , Resultado del Tratamiento , Valina/análogos & derivadosRESUMEN
BACKGROUND AND AIM: Daclatasvir plus asunaprevir (DCV + ASV) has demonstrated potent antiviral activity in patients with hepatitis C virus (HCV) genotype 1b infection. A definite conclusion about efficacy and safety of DCV + ASV in patients with HCV genotype 1b is not available. A meta-analysis was conducted to evaluate outcomes of all-oral treatment with DCV + ASV in terms of sustained virological response at 12 (SVR12 ) and 24 (SVR24 ) weeks and adverse effects after the end of treatment. METHODS: PUBMED, MEDLINE, and EMBASE databases were searched in May 2016. The data were analyzed with Review Manager 5.3. RESULTS: Nine trials (n = 1690) met entry criteria. SVR12 was achieved by 89.9% of treatment-naïve patients, 84.7% of interferon-ineligible/intolerant patients, and 81.9% of nonresponder patients. Moreover, 89.0% of interferon-ineligible/intolerant patients and 83.1% of nonresponder patients achieved SVR24 . Baseline characteristics, including gender, race, advanced age, non-CC IL28B genotype, and cirrhosis, did not appear to impact SVR rates. However, the rate of SVR12 in all patients with viral load < 8 × 105 was higher than that of all those with viral load ≥ 8 × 105 (151/162 vs 625/753). Moreover, pre-existing nonstructural protein 5A resistance-associated variants (RAVs) were associated with virological failure during DCV + ASV therapy, resulting in the emergence of multiple RAVs. Treatment with DCV + ASV was well tolerated, with low incidences of serious adverse effects, discontinuations, and grade 3 or 4 laboratory abnormalities in all patients. CONCLUSIONS: Daclatasvir plus asunaprevir provides a highly effective and well-tolerated treatment option for patients with HCV genotype 1b. However, patients with nonstructural protein 5A RAVs at baseline should be assessed to optimize more potent direct antiviral agent therapies.
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Antivirales/administración & dosificación , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Imidazoles/administración & dosificación , Isoquinolinas/administración & dosificación , Sulfonamidas/administración & dosificación , Carbamatos , Bases de Datos Bibliográficas , Quimioterapia Combinada , Genotipo , Humanos , Pirrolidinas , Resultado del Tratamiento , Valina/análogos & derivados , Carga Viral , Proteínas no Estructurales ViralesRESUMEN
Hepatitis C is one of the leading causes of hepatocellular carcinoma and remains at a high prevalence in Egypt and other resource-limited countries. Several hepatitis C virus (HCV) genotypes are distributed throughout the world, with genotype 4 being most common in North and Central Africa. We developed a multiplex serological assay for the detection of the HCV specific humoral immune response, with a focus on genotype 4. For the multiplex HCV assay we used twelve antigenic regions of different HCV proteins (core, and non-structural (NS) proteins NS3, NS4, NS5A, NS5B) and validated the assay technically and clinically. In comparison to a commercially available test, our assay revealed a higher sensitivity for genotype 4, and is therefore more suited for studying immune seroconversion in samples from acutely infected Egyptian HCV patients. Furthermore, our assay discriminates acutely and chronically infected HCV patients. Of 296 well characterized HCV patient samples, 83.9% of the acute samples and 86.5% of the chronic samples could be correctly classified. In sum, this newly developed serological HCV assay has a higher sensitivity for HCV genotype 4, and can thus improve diagnostic accuracy. Through the discrimination of acutely and chronically infected HCV patients the assay may be useful in supporting clinical management of HCV patients.
RESUMEN
Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) often accelerates the course of HCV-associated liver disease. Daclatasvir (DCV) plus asunaprevir (ASV) have been shown to be highly effective for HCV-infected patients with genotype 1b. Three patients co-infected with HIV/HCV genotype 1b were enrolled in this study. Prior to initiation of HCV treatment, the variants associated with L31 and Y93 in the non-structural protein 5A (NS5A) region of the HCV genome were confirmed to be absent using a direct sequencing method. Taking into consideration the lower risk of drug-drug interaction and the need for immediate treatment, the patients received 60 mg DCV once daily plus 100 mg ASV twice daily for 24 weeks. In one patient, the alanine aminotransferase level was elevated to 228 IU/L at 24 weeks after the start of treatment, but he completed the 24-week treatment course. All three patients achieved sustained viral response, without severe complications (including HIV virological rebound). Thus, in cases where NS5A variants are confirmed to be absent and patients are antiretroviral therapy-naïve, with CD4+ over 500/µL or HIV well controlled by RAL-based cART, DCV plus ASV may represent a good treatment option for HIV and HCV genotype 1b co-infected patients.
Asunto(s)
Coinfección/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/uso terapéutico , Isoquinolinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Antivirales/uso terapéutico , Carbamatos , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinas , Valina/análogos & derivadosRESUMEN
BACKGROUND: Hepatitis C is a significant cause for end-stage liver diseases and liver transplantation which affects approximately 3% of the global populations. Despite the current several direct antiviral agents in the treatment of Hepatitis C, the standard treatment for HCV infection is accompanied by several drawbacks, such as adverse side effects, high pricing of medications and the rapid emerging rate of resistant HCV variants. OBJECTIVES: To discover potential inhibitors for HCV helicase through an optimized in silico approach. METHODS: In this study, a homology model (HCV Genotype 3 helicase) was used as the target and screened through a benzopyran-based virtual library. Multiple-seedings of AutoDock Vina and in situ minimization were to account for the non-deterministic nature of AutoDock Vina search algorithm and binding site flexibility, respectively. ADME/T and interaction analyses were also done on the top hits via FAFDRUG3 web server and Discovery Studio 4.5. RESULTS: This study involved the development of an improved flow for virtual screening via implemention of multiple-seeding screening approach and in situ minimization. With the new docking protocol, the redocked standards have shown better RMSD value in reference to their native conformations. Ten benzopyran-like compounds with satisfactory physicochemical properties were discovered to be potential inhibitors of HCV helicase. ZINC38649350 was identified as the most potential inhibitor. CONCLUSION: Ten potential HCV helicase inhibitors were discovered via a new docking optimization protocol with better docking accuracy. These findings could contribute to the discovery of novel HCV antivirals and serve as an alternative approach of in silico rational drug discovery.