ABSTRACT
Hepatitis C virus (HCV) infection remains a global health problem. Previously, the prevalence of NS5A resistance-associated substitutions (RASs) to elbasvir, a new direct-acting antiviral (DAA) against the NS5A viral protein was assessed by our group before its introduction into clinical use in Spain. However, the origin, epidemic history, transmission dynamics, diversity and baseline RASs to NS5A direct-acting agents of HCV-GT1a in Spain remain unknown. A nationwide cross-sectional survey of individuals chronically-infected with HCV-G1a and DAAs-naïve was performed. HCV population sequencing, phylogenetic analysis and Bayesian methods were used. GT1a clade II was more prevalent than clade I (82.3% vs. 17.7%; P < 0.001) and older (estimated origin in 1912 vs. 1952). Clade II epidemic is currently declining whereas clade I epidemic has reached equilibrium. A total of 58 single RASs were identified, which account for the moderate level (10%) of baseline resistance observed. When considering the regional data, marked differences were observed, with thirteen regions showing an intermediate level (5-15%) and one a high level (20%) of resistance. Current HCV-GT1a epidemic in Spain is driven by clade I which seem to have different dissemination routes relative to clade II. A moderate level of baseline RASs to NS5A-DAAs with marked differences among regions was observed. Close surveillance of response to treatment with DAAs will be important.
Subject(s)
Antiviral Agents/therapeutic use , Drug Resistance, Viral , Hepacivirus/drug effects , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Viral Nonstructural Proteins/metabolism , Antiviral Agents/pharmacology , Bayes Theorem , Female , Geography , Hepacivirus/genetics , Hepatitis C/transmission , Hepatitis C/virology , Humans , Male , Middle Aged , Phylogeny , Polymorphism, Genetic , Protein Domains , Spain , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/geneticsABSTRACT
BACKGROUND: Hepatitis C virus (HCV) infection predisposes patients to other infectious diseases, such as sepsis. We aimed to analyze epidemiological trends of sepsis-related admissions, deaths, and costs in hospital admissions with chronic hepatitis C who had a hospital admission in Spain. METHODS: We performed a retrospective study of all hospitalizations involving chronic hepatitis C in the Spanish Minimum Basic Data Set (MBDS) between 2000 and 2015. This period was divided into four calendar periods (2000-2004, 2005-2007, 2008-2011, and 2012-2015). RESULTS: We selected 868,523 hospital admissions of patients with chronic hepatitis C over 16 years in the Spanish MBDS. Among them, we found 70,976 (8.17%) hospital admissions of patients who developed sepsis, of which 13,915 (19.61%) died during admission. We found an upward trend, from 2000-2003 to 2012-2015, in the rate of sepsis-related admission (from 6.18% to 10.64%; p < 0.001), the risk of sepsis-related admission (from 1.31 to 1.55; p < 0.001), and the sepsis-related cost per hospital admission (from 7198 to above 9497; p < 0.001). However, we found a downward trend during the same study period in the sepsis case-fatality rate (from 21.99% to 18.16%; p < 0.001), the risk of sepsis-related death (from 0.81 to 0.56; p < 0.001), and the length of hospital stay (LOHS) (from 16.9 to 13.9; p < 0.001). Moreover, the rate of bacterial Gram-positive and candidiasis infections decreased, while Gram-negative microorganisms increased from 2000-2003 to 2012-2015. CONCLUSIONS: Sepsis, in chronic hepatitis C patients admitted to the hospital, has increased the period 2000-2015 and has been an increasing burden for the Spanish public health system. However, there has also been a significant reduction in lethality and LOHS during the study period. In addition, the most prevalent specific microorganisms have also changed in this period.
ABSTRACT
OBJECTIVE: Analysis the epidemiological trends of hospital admissions, intra-hospital deaths, and costs related to chronic hepatitis C (CHC) taking into account four major clinical stages [compensated cirrhosis (CC), end-stage liver disease (ESLD), hepatocellular carcinoma (HCC), and liver transplantation (LT)] in Spain. METHODS: Retrospective study in patients with chronic hepatitis C and a hospital admission in the Spanish Minimum Basic Data Set from 2000 to 2015. Outcome variables were admission, death, length of hospital stay and costs. RESULTS: A total of 868,523 hospital admissions with CHC (25.5% CC, 25.3% ESLD, 8.6% HCC, and 2.5% LT) were identified. Overall rates of admission and mortality increased from 2000-2003 to 2004-2007, but after 2008, these rates stabilized and/or decreased. An upward trend was found for hospitalization percentage in CC (from 22.3% to 30%; p < 0.001), ESLD (from 23.9% to 27.1%; p < 0.001), HCC (from 7.4% to 11%; p < 0.001), and LT (from 0.07% to 0.10%; p = 0.003). An upward trend was also found for case fatality rate, except in ESLD (p = 0.944). Gender and age influenced the evolution of hospitalization rates and mortality differently. The length of hospital stay showed a significant downward trend in all strata analyzed (p < 0.001). Cost per patient had a significant upward trend (p < 0.001), except in LT, and a decrease from 2008-2011 to 2012-2015 in CC (p = 0.025), HCC (p < 0.001), and LT (p = 0.050) was found. CONCLUSION: The initial upward trend of the disease burden in CHC has changed from 2000 to 2015 in Spain, improving in many parameters after 2004-2007, particularly in the 2012-2015 calendar period.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis C, Chronic , Hepatitis C , Liver Neoplasms , Carcinoma, Hepatocellular/epidemiology , Hepatitis C, Chronic/epidemiology , Humans , Liver Cirrhosis/epidemiology , Liver Neoplasms/epidemiology , Retrospective Studies , Spain/epidemiologyABSTRACT
Hepatitis C virus (HCV) is the primary etiologic agent of liver cirrhosis or hepatocellular carcinoma. HCV elevated infection rates are mostly due to the lack of an accurate and accessible screening and diagnosis, especially in low- and middle-income countries. Conventional HCV diagnostic algorithm consists of a serological test followed by a nucleic acid test. This sequence of tests is time consuming and not affordable for low-resource settings. Nanotechnology have introduced new promising tests for the diagnose of infectious diseases. Based on the employment of nanoparticles and other nanomaterials which lead to highly sensitive and specific nanoscale tests, most of them target pathogen genome. Implementation of nanoscale tests, which are affordable, portable and easy to use by non-specialized personal, would improve HCV diagnosis algorithm. In this review, we have summed up the current emerging nanotechnology tools, which will improve actual screening and treatment programs, and help to reach HCV elimination proposal.
Subject(s)
Hepacivirus , Hepatitis C , Hepacivirus/genetics , Hepatitis C/diagnosis , Humans , Liver Cirrhosis , Serologic Tests , Viral LoadABSTRACT
Las sustituciones asociadas a resistencia (RAS) a elbasvir, el nuevo inhibidor de la NS5A del virus de la hepatitis C (VHC), pueden presentar relevancia al limitar su eficacia y conducir al fracaso virológico en pacientes infectados por VHC genotipo 1a (GT1a) a diferencia de lo observado en GT1b y GT4. No existen datos fuera de ensayos clínicos que evalúen la prevalencia y el impacto de grazoprevir/elbasvir en pacientes infectados con GT1a en España. Se llevó a cabo un estudio transversal multicéntrico en 632 pacientes iniciales, en 13 de los cuales no se consiguió amplificar la muestra o no fue válida para alcanzar una secuencia consenso mediante secuenciación de Sanger. Finalmente, se analizaron 617 individuos infectados con VHC-GT1a atendidos en 84 hospitales distribuidos por las 17 comunidades autónomas más las 2 ciudades autónomas que conforman el territorio español. La población de VHC secuenciada se ha usado para identificar RAS a elbasvir, mientras que el patrón mutacional y la sensibilidad farmacológica se confirmaron mediante geno2pheno[HCV]. Los virus portadores de RAS a elbasvir se observaron en el 6,2% de los pacientes infectados con el VHC-G1a. Las RAS más comunes fueron Y93C/H/N y Q30E/H/R (2,4 y 2,3%, respectivamente). Solo el 3,4% de las RAS a elbasvir identificadas confirieron susceptibilidad reducida al fármaco mediante geno2pheno[HCV] que identificó exclusivamente como principales RAS a elbasvir las posiciones Q30H/R (n = 7) y Y93C/H/N (n = 8) como mutaciones simples y Q30H+Y93H (n = 4) y Q30R+Y93H (n = 2) como mutaciones dobles. En nuestra cohorte española con VHCG1a se observó una menor prevalencia de RAS a elbasvir que la reportada previamente en ensayos clínicos realizados en pacientes norteamericanos. Esta información puede ser esencial para el manejo de los pacientes infectados con G1a y guiar la implementación de grazoprevir/elbasvir en España
Resistance-associated substitutions (RASs) to the new HCV NS5A inhibitor elbasvir may limit its efficacy and lead to virological failure in HCV-GT1a-infected patients. There are no data outside clinical trials evaluating their prevalence and impact in grazoprevir/elbasvir in GT1a-infected patients in Spain. A multicentre cross-sectional study of 632 initial patients was conducted. In 13 of these patients, the sample could not be amplified or a consensus sequence by Sanger sequencing could not be performed. Ultimately, 617 HCV-G1a-infected individuals treated at 84 Spanish hospitals from the 17 autonomous communities plus the 2 autonomous cities of Spain were analysed. HCV population sequencing was used to identify RAS to elbasvir and the mutational pattern and drug sensitivity were confirmed by geno2pheno[HCV]. Viruses bearing RASs to elbasvir were present in 6.2% of HCV-G1a infected patients. The most common RASs were the Y93C/H/N and Q30E/H/R (2.4% and 2.3%, respectively). Only 3.4% of the identified RASs to elbasvir conferred reduced susceptibility to elbasvir by geno2pheno[HCV], which exclusively identified the positions Q30H/R (n = 7) and Y93C/H/N (n = 8) as single mutations and Q30H+Y93H (n = 4) and Q30R+Y93H (n = 2) as double mutations as the major RASs to elbasvir. A lower prevalence of RASs to elbasvir was observed in our HCV-G1a Spanish cohort than reported previously in clinical trials evaluating patients from the USA. This information may be essential to guide the implementation of grazoprevir/elbasvir in Spain and to manage G1a-infected patients
Subject(s)
Humans , Hepacivirus , Hepacivirus/genetics , Drug Resistance, Viral/genetics , Viral Nonstructural Proteins/genetics , Hepatitis C/virology , Cross-Sectional Studies , Prevalence , Genotype , SpainABSTRACT
Resistance-associated substitutions (RASs) to the new HCV NS5A inhibitor elbasvir may limit its efficacy and lead to virological failure in HCV-GT1a-infected patients. There are no data outside clinical trials evaluating their prevalence and impact in grazoprevir/elbasvir in GT1a-infected patients in Spain. A multicentre cross-sectional study of 632 initial patients was conducted. In 13 of these patients, the sample could not be amplified or a consensus sequence by Sanger sequencing could not be performed. Ultimately, 617 HCV-G1a-infected individuals treated at 84 Spanish hospitals from the 17 autonomous communities plus the 2 autonomous cities of Spain were analysed. HCV population sequencing was used to identify RAS to elbasvir and the mutational pattern and drug sensitivity were confirmed by geno2pheno[HCV]. Viruses bearing RASs to elbasvir were present in 6.2% of HCV-G1a infected patients. The most common RASs were the Y93C/H/N and Q30E/H/R (2.4% and 2.3%, respectively). Only 3.4% of the identified RASs to elbasvir conferred reduced susceptibility to elbasvir by geno2pheno[HCV], which exclusively identified the positions Q30H/R (n=7) and Y93C/H/N (n=8) as single mutations and Q30H+Y93H (n=4) and Q30R+Y93H (n=2) as double mutations as the major RASs to elbasvir. A lower prevalence of RASs to elbasvir was observed in our HCV-G1a Spanish cohort than reported previously in clinical trials evaluating patients from the USA. This information may be essential to guide the implementation of grazoprevir/elbasvir in Spain and to manage G1a-infected patients.
Subject(s)
Amino Acid Substitution , Benzofurans/therapeutic use , Drug Resistance, Viral , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Imidazoles/therapeutic use , Viral Nonstructural Proteins/genetics , Cross-Sectional Studies , Female , Genotype , Hepacivirus/drug effects , Humans , Male , Middle Aged , SpainABSTRACT
Relevant resistance-associated substitutions (RASs) to elbasvir, the new HCV NS5A inhibitor, may limit its efficacy and lead to virological failure in HCV-GT1a-infected patients. There are few data outside clinical trials evaluating their prevalence and impact of elbasvir/grazoprevir. A multicenter cross-sectional study of 617 HCV-GT1a-infected individuals attended in 84 Spanish hospitals from the 17 Autonomous Communities and two Autonomous cities was performed. HCV population sequencing was used to identify RASs to elbasvir and the mutational pattern and drug sensitivity were confirmed by geno2pheno[HCV]. Viruses bearing RASs to elbasvir were present in 6.2% of HCV-GT1a infected patients. The most common RASs were the Y93C/H/N and Q30E/H/R (2.4% and 2.3%; respectively). Only 3.4% of patients had viruses with RASs that confer reduced susceptibility to elbasvir by geno2pheno[HCV] that identified exclusively the positions Q30H/R (n = 7) and Y93C/H/N (n = 8) as single mutations and Q30H + Y93H (n = 4) and Q30R + Y93H (n = 2) as double mutations considered as RASs to elbasvir. Lower prevalence of RASs to elbasvir in our HCV-GT1a-Spanish cohort was observed than reported previously in clinical trials. This information may be essential to guiding the implementation of elbasvir/grazoprevir in Spain, expected at the beginning of 2017 and the management of GT1a-infected patients.
