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1.
Mikrobiyol Bul ; 54(1): 110-119, 2020 Jan.
Artigo em Turco | MEDLINE | ID: mdl-32050882

RESUMO

Anti-HCV and HCV RNA tests are used in laboratory diagnosis of hepatitis C virus (HCV) infections. False positive results are frequently observed in anti-HCV tests used as screening tests in societies with low prevalence of HCV. The HCV RNA test, which is a confirmatory test, is not performed in every laboratory because it is a high-cost and high-tech test, which can lead to delay in the diagnosis and treatment of patients. In this study, it was aimed to obtain an optimal anti-HCV S/CO value in our laboratory for demonstrating true antibody positivity and viremia in patients by analyzing the relationship between anti-HCV, alanine aminotransferase (ALT) and HCV RNA using retrospective data. Between July 2014 and July 2017, 754.190 anti-HCV tests were performed. Patients aged 18 years or older who were reactive with anti-HCV and those with simultaneous HCV RNA and ALT prompts were included in the study. The second generation CMIA (Abbott, USA) method was used for anti-HCV detection. For quantitative HCV RNA analysis, viral nucleic acid extraction was performed with the QIAsymphony SP/AS (Qiagen, Germany) using the QIAsymphony DSP Virus/Pathogen Midi Kit; and PCR was performed by Rotor-Gene Q (Qiagen, Germany) using Artus HCV QS-RGQ kit. ARCHITECT c and AEROSET systems (Abbott, USA) were used for ALT measurement. HCV genotype determination (622 cases) was performed using GenoSen's HCV Genotyping 1/2/3/4 RG qualitative real time PCR kit (Corbett Research, Australia) and GEN-C 2.0 Reverse Hybridization Strip Assay (NLM Diagnostics, Italy) kit at different periods covered by our study. The optimal threshold value for the relationship between anti-HCV, ALT and HCV RNA was selected based on ROC analysis. Statistical significance was accepted as p<0.05. Of the anti-HCV test results, 10.679 were found to be reactive. 1754 data of 1290 cases with anti-HCV reactivity who were simultaneously tested for HCV RNA and ALT in the same serum were evaluated. Of these, 742 (42%) were found to be HCV RNA positive and 1012 (58%) were found to be HCV RNA negative. ALT and anti-HCV levels of those who were positive for HCV RNA were significantly higher than those with negative HCV RNA (p= 0.001). The threshold point for anti-HCV S/CO according to HCV RNA was found to be 7.13 (sensitivity of 97.4%, specificity of 50.3%, positive predictive value 58.9%, negative predictive value 96.4%), and the cut-off point for ALT was found to be 27.5 IU/L (sensitivity of 77.6%, specificity of 80.8%). For HCV RNA positivity, the area under the ROC curve for anti-HCV and ALT was significantly higher than 0.5 (p= 0.001). No statistically significant difference was found between HCV genotypes in terms of ALT and anti-HCV levels. By using our new threshold in the laboratory workflow, the need to verify with HCV RNA can be reduced, especially in some patients who have been screened for antiHCV for screening purposes. Anti-HCV values below 7.13 S/CO, considering the high negative predictive value of this threshold; a false positive result in a patient presenting for screening can be predicted without waiting for the HCV RNA result. In anti-HCV reactivities determined above 7.13, the possibility of absence of viremia should be considered due to the low positive predictive value.


Assuntos
Hepacivirus , Hepatite C , Viremia , Adolescente , Adulto , Técnicas e Procedimentos Diagnósticos/normas , Alemanha , Hepacivirus/genética , Hepatite C/diagnóstico , Anticorpos Anti-Hepatite C/metabolismo , Humanos , RNA Viral/genética , Estudos Retrospectivos , Viremia/diagnóstico
2.
Int J Infect Dis ; 92: 184-188, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978574

RESUMO

BACKGROUND: There are scant data regarding hepatitis C (HCV) virologic response to directly acting antiviral agents (DAAs) in chronic hepatitis B (HBV) and HCV coinfected persons. HCV treatment response in those with spontaneously cleared HBV infection is unknown. METHODS: All HCV infected persons treated with a DAA regimen in ERCHIVES were identified and categorized into HBV/HCV-coinfected (HBsAg, HBV DNA or both positive), HCV-monoinfected, and resolved HBV (isolated HBcAb+). SVR rates were determined and compared for all groups. Logistic regression model was used to determine factors associated with SVR. RESULTS: Among 115 HCV/HBV-coinfected, 38,570 HCV-monoinfected persons, and 13,096 persons with resolved HBV, 31.6% of HCV/HBV-coinfected, 24.6% of HCV-monoinfected and 26.4% with resolved HBV had cirrhosis at baseline. SVR was achieved in 90.4% of HCV/HBV-coinfected, 83.4% of HCV-monoinfected and 84.5% of those with resolved HBV infection (P = 0.04 HCV/HBV vs. HCV monoinfected). In a logistic regression model, those with HCV/HBV were more likely to achieve SVR compared with HCV monoinfected (OR 2.25, 95% CI 1.17, 4.31). For HCV/HBV coinfected, the SVR rates dropped numerically with increasing severity of liver fibrosis (P-value non-significant). Factors associated with a lower likelihood of attaining SVR included cirrhosis at baseline (OR 0.85, 95% CI 0.80, 0.92), diabetes (OR 0.93, 95% CI 0.87, 0.99) and higher pre-treatment HCV RNA (OR 0.86, 95% CI 0.84, 0.87). CONCLUSION: HBV/HCV-coinfected persons have higher overall SVR rates with newer DAA regimens. Though not statistically significant, the virologic response is graded, with decreasing SVR rates with increasing degree of liver fibrosis as determined by the FIB-4 scores.


Assuntos
Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Hepatite B Crônica/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Feminino , Hepacivirus/genética , Hepatite B Crônica/complicações , Hepatite C Crônica/complicações , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade
3.
Arch Virol ; 165(3): 583-592, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31927635

RESUMO

Interferon lambda was discovered in recent years to be an antiviral agent, and research on different aspects of this antiviral factor in viral infection and investigations of its effectiveness are also progressing. The immunological effects of interferon lambda on different cell populations is not precisely known, which may be due to its use of a heterodimeric receptor consisting of IL-10R2 and IFN-λR1, which are not broadly expressed in all types of cells. In the present study, signaling by interferon lambda and its effect on the expression of hepatitis C virus (HCV) proteins were measured, and the expression pattern of some antiviral proteins and IL-10 levels were investigated in peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 50 patients with chronic genotype 1a HCV infection and 10 healthy individuals as controls. The PBMCs were treated with various doses of interferon lambda at different times of cultivation. Real-time PCR was used for relative quantification of Mxa, PKR, OAS, ISG15 and HCV core mRNAs. Expression of the NS5A protein was measured by flow cytometry, and IL-10 production was assessed by ELISA. A significant increase in the expression of mRNA encoding antiviral proteins and a decrease in the expression of mRNAs encoding the HCV core protein were observed when cells were treated with interferon lambda in an intermittent manner. The expression of HCV NS5A protein and interleukin 10 levels were also lower than in the control group. It was shown that the maximum antiviral effect of interferon lambda in PBMCs is dependent on the dose and treatment time.


Assuntos
Hepatite C Crônica/imunologia , Interferons/farmacologia , Interleucinas/farmacologia , Leucócitos Mononucleares/imunologia , Proteínas do Core Viral/biossíntese , Proteínas não Estruturais Virais/biossíntese , Adulto , Antivirais/farmacologia , Linhagem Celular , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/imunologia , Interferon-alfa/farmacologia , Interferons/imunologia , Interleucina-10/biossíntese , Interleucinas/imunologia , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , RNA Mensageiro/biossíntese , RNA Viral/biossíntese , Proteínas do Core Viral/genética
4.
BMC Infect Dis ; 20(1): 30, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924172

RESUMO

BACKGROUND: Georgia has one of the highest HCV prevalence in the world and launched the world's first national HCV elimination programs in 2015. Georgia set the ambitious target of diagnosing 90% of people living with HCV, treating 95% of those diagnosed and curing 95% of treated patients by 2020. We report outcomes of Sofosbuvir (SOF) based treatment regimens in patients with chronic HCV infection in Georgia. METHODS: Patients with cirrhosis, advanced liver fibrosis and severe extrahepatic manifestations were enrolled in the treatment program. Initial treatment consisted of SOF plus ribavirin (RBV) with or without pegylated interferon (INF). Sustained virologic response (SVR) was defined as undetectable HCV RNA at least 12 weeks after the end of treatment. SVR were calculated using both per-protocol and modified intent-to-treat (mITT) analysis. Results for patients who completed treatment through 31 October 2018 were analyzed. RESULTS: Of the 7342 patients who initiated treatment with SOF-based regimens, 5079 patients were tested for SVR. Total SVR rate was 82.1% in per-protocol analysis and 74.5% in mITT analysis. The lowest response rate was observed among genotype 1 patients (69.5%), intermediate response rate was achieved in genotype 2 patients (81.4%), while the highest response rate was among genotype 3 patients (91.8%). Overall, SOF/RBV regimens achieved lower response rates than IFN/SOF/RBV regimen (72.1% vs 91.3%, P < 0.0001). In multivariate analysis being infected with HCV genotype 2 (RR =1.10, CI [1.05-1.15]) and genotype 3 (RR = 1.14, CI [1.11-1.18]) were associated with higher SVR. Patients with cirrhosis (RR = 0.95, CI [0.93-0.98]), receiving treatment regimens of SOF/RBV 12 weeks, SOF/RBV 20 weeks, SOF/RBV 24 weeks and SOF/RBV 48 weeks (RR = 0.85, CI [0.81-0.91]; RR = 0.86, CI [0.82-0.92]; RR = 0.88, CI [0.85-0.91] and RR = 0.92, CI [0.87-0.98], respectively) were less likely to achieve SVR. CONCLUSIONS: Georgia's real world experience resulted in high overall response rates given that most patients had severe liver damage. Our results provide clear evidence that SOF plus IFN and RBV for 12 weeks can be considered a treatment option for eligible patients with all three HCV genotypes. With introduction of next generation DAAs, significantly improved response rates are expected, paving the way for Georgia to achieve HCV elimination goals.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Interferons/uso terapêutico , Programas Nacionais de Saúde , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Adolescente , Adulto , Quimioterapia Combinada , Feminino , Seguimentos , Genótipo , República da Geórgia/epidemiologia , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/virologia , Perda de Seguimento , Masculino , Pessoa de Meia-Idade , RNA Viral/genética , Resposta Viral Sustentada , Adulto Jovem
5.
Arch Virol ; 165(1): 127-135, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31741097

RESUMO

In clinical virome research, whole-genome/transcriptome amplification is required when starting material is limited. An improved method, named "template-dependent multiple displacement amplification" (tdMDA), has recently been developed in our lab (Wang et al. in BioTechniques 63:21-25. https://doi.org/10.2144/000114566, 2017). In combination with Illumina sequencing and bioinformatics pipelines, its application in virome sequencing was explored using a serum sample from a patient with chronic hepatitis C virus (HCV) infection. In comparison to an amplification-free procedure, virome sequencing via tdMDA showed a 9.47-fold enrichment for HCV-mapped reads and, accordingly, an increase in HCV genome coverage from 28.5% to 70.1%. Eight serum samples from acute patients liver failure (ALF) with or without known etiology were then used for virome sequencing with an average depth at 94,913x. Both similarity-based (mapping, NCBI BLASTn, BLASTp, and profile hidden Markov model analysis) and similarity-independent methods (machine-learning algorithms) identified viruses from multiple families, including Herpesviridae, Picornaviridae, Myoviridae, and Anelloviridae. However, their commensal nature and cross-detection ruled out an etiological interpretation. Together with a lack of detection of novel viruses in a comprehensive analysis at a resolution of single reads, these data indicate that viral agents might be rare in ALF cases with indeterminate etiology.


Assuntos
Biologia Computacional/métodos , Hepatite C Crônica/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Falência Hepática Aguda/virologia , Soro/virologia , Anelloviridae/isolamento & purificação , Anelloviridae/fisiologia , Perfilação da Expressão Gênica/métodos , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/sangue , Herpesviridae/isolamento & purificação , Herpesviridae/fisiologia , Humanos , Falência Hepática Aguda/sangue , Myoviridae/isolamento & purificação , Myoviridae/fisiologia , Picornaviridae/isolamento & purificação , Picornaviridae/fisiologia , Especificidade da Espécie , Simbiose , Sequenciamento Completo do Genoma/métodos
6.
Arch Virol ; 165(2): 331-343, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31832864

RESUMO

The most characteristic feature of the hepatitis C virus (HCV) genome in patients with chronic hepatitis C is its remarkable variability and diversity. To better understand this feature, we performed genetic analysis of HCV replicons recovered from two human hepatoma HuH-7-derived cell lines after 1, 3, 5, 7, and 9 years in culture: The cell lines 50-1 and sO harbored HCV 1B-1 and O strain-derived HCV replicons established in 2002 and 2003, respectively. The results revealed that genetic variations in both replicons accumulated in a time-dependent manner at a constant rate despite the maintenance of moderate diversity (less than 1.8% difference) between the clones and that the mutation rate in the 50-1 and sO replicons was 2.5 and 2.9 × 10-3 base substitutions/site/year, respectively. We found that the genetic distance of both replicons increased from 7.9% to 10.5% after 9 years in culture. In addition, we observed that the guanine + cytosine (GC) content of both replicon RNAs increased in a time-dependent manner, as observed in our previous studies. Finally, we demonstrated that the high sensitivity of both replicons to direct-acting antivirals was maintained even after 9 years in culture. Our results suggest that long-term cultured HCV replicon-harboring cells are a useful model for understanding the variability and diversity of the HCV genome and the drug sensitivity of HCV in patients with chronic hepatitis C.


Assuntos
Variação Genética/genética , Hepacivirus/genética , Replicação Viral/genética , Carcinoma Hepatocelular/virologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Genes Reporter/genética , Genoma Viral/genética , Genótipo , Hepatite C Crônica/virologia , Humanos , Neoplasias Hepáticas/virologia , RNA Viral/genética , Replicon/genética
7.
Gene ; 730: 144289, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-31846709

RESUMO

Interferon lambda proteins activate the JAK-STAT signalling pathway, resulting in upregulation of genes with antiviral effects. The interferon lambda family was initially thought to be redundant to the interferon alpha family, which signals through the same pathway, except for the more limited expression of the IFNLR1 receptor. However, recent studies show that interferon lambdas uniquely protect tissue barriers against a wide range of important viral infections. The interferon lambda 4 gene (IFNL4) was discovered in 2013. The IFNL4 protein is determined by the IFNL4-ΔG/TT (rs368234815) variant. The ancestral IFNL4-ΔG allele generates IFNL4, whereas IFNL4-TT causes pre-mature termination of the protein. Surprisingly, although interferons are generally antiviral proteins, the genotypes that generate the IFNL4 protein are strongly linked to impaired clearance of hepatitis C virus (HCV). IFNL4 genotype has also been linked to variation within the HCV genome, as well as risk of hepatic fibrosis, certain cancers and some infectious diseases. There has been very strong evolutionary selection against the ancestral IFNL4-ΔG allele, which is the major form in African populations, but the minor allele in Europeans and Asians. The reason for this selection and the biological mechanisms underlying observed phenotypic associations remain to be explained.


Assuntos
Interleucinas/genética , Interleucinas/metabolismo , Alelos , Grupos de Populações Continentais/genética , Evolução Molecular , Frequência do Gene/genética , Variação Genética/genética , Genótipo , Hepacivirus/genética , Hepatite/genética , Humanos , Interleucinas/fisiologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
8.
Arq Gastroenterol ; 56(4): 344-350, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800733

RESUMO

BACKGROUND: Hepatitis B and C virus (HBV and HCV) are the two most common infections among human immunodeficiency virus (HIV)-infected patients. OBJECTIVE: To identify the frequency of HIV subtypes and HCV genotypes in HIV-coinfected patients. METHODS: A cross-sectional and retrospective study was carried out into two reference centers in Southern Brazil between January 1, 2002 and June 30, 2016. The Abbott Real Time HCV Genotype II system was used for routine diagnostics to determine the HCV genotype based on dual-target real-time PCR. Proviral HIV-1 RNA was extracted from serum samples and fragments of the pol gene were generated by PCR. The HIV-1 PT and RT gene sequences were submitted to Maximum Likelihood Phylogenetic analysis by collecting reference sequences from the HIV-1 group M subtype of the Los Alamos database. RESULTS: During the study period, 3340 patients with HIV were diagnosed at both referral centers, of which 4.97% (166/3340) had HBV and/or HCV coinfection. Seroprevalence of HIV-HBV, HIV-HCV and HIV-HBV-HCV was 37.4%, 58.4%, and 4.2%, respectively. HIV-HCV-coinfected patients had a lower median nadir CD4+ T-cell count when compared to HIV-HBV-coinfected patients (P=0.01). Among those coinfected with HCV, HCV-1 (HCV-1) and HCV-3 (HCV-3) genotypes were the most prevalent, being detected in 73.8% and 21.4%, respectively. Among the HCV-1 coinfected patients, 79.3% and 20.1% had subtypes 1a and 1b, respectively. HIV subtype B was the most prevalent in HIV-coinfected patients. There was no significant difference regarding nadir CD4+ T-cell count and HIV viral load when compared to coinfected with HCV-1 with HCV-3, as well as those co-infected with HCV-1a with HCV-1b. CONCLUSION: In the present study, a higher frequency of subtype B of HIV and HCV-1 were found in HIV-coinfected patients. Further larger-scale and long-term studies are needed to better understand the effect of HCV genotypes in HIV-infected patients.


Assuntos
Infecções por HIV/complicações , Hepacivirus/genética , Hepatite C/virologia , Adulto , Brasil , Coinfecção , Estudos Transversais , Feminino , Genótipo , Hepatite C/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Carga Viral
9.
BMC Infect Dis ; 19(1): 1019, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791253

RESUMO

BACKGROUND: Chronic hepatitis C is a major public health burden. With new interferon-free direct-acting agents (showing sustained viral response rates of more than 98%), elimination of HCV seems feasible for the first time. However, as HCV infection often remains undiagnosed, screening is crucial for improving health outcomes of HCV-patients. Our aim was to assess the long-term cost-effectiveness of a nationwide screening strategy in Germany. METHODS: We used a Markov cohort model to simulate disease progression and examine long-term population outcomes, HCV associated costs and cost-effectiveness of HCV screening. The model divides the total population into three subpopulations: general population (GEP), people who inject drugs (PWID) and HIV-infected men who have sex with men (MSM), with total infection numbers being highest in GEP, but new infections occurring only in PWIDs and MSM. The model compares four alternative screening strategies (no/basic/advanced/total screening) differing in participation and treatment rates. RESULTS: Total number of HCV-infected patients declined from 275,000 in 2015 to between 125,000 (no screening) and 14,000 (total screening) in 2040. Similarly, lost quality adjusted life years (QALYs) were 320,000 QALYs lower, while costs were 2.4 billion EUR higher in total screening compared to no screening. While incremental cost-effectiveness ratio (ICER) increased sharply in GEP and MSM with more comprehensive strategies (30,000 EUR per QALY for total vs. advanced screening), ICER decreased in PWIDs (30 EUR per QALY for total vs. advanced screening). CONCLUSIONS: Screening is key to have an efficient decline of the HCV-infected population in Germany. Recommendation for an overall population screening is to screen the total PWID subpopulation, and to apply less comprehensive advanced screening for MSM and GEP.


Assuntos
Erradicação de Doenças , Hepatite C/prevenção & controle , Programas de Rastreamento/economia , Programas de Rastreamento/métodos , Adulto , Antivirais/economia , Antivirais/uso terapêutico , Estudos de Coortes , Análise Custo-Benefício , Testes Diagnósticos de Rotina/economia , Testes Diagnósticos de Rotina/estatística & dados numéricos , Erradicação de Doenças/economia , Erradicação de Doenças/métodos , Erradicação de Doenças/estatística & dados numéricos , Usuários de Drogas/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Infecções por HIV/diagnóstico , Infecções por HIV/economia , Infecções por HIV/epidemiologia , Custos de Cuidados de Saúde , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C/diagnóstico , Hepatite C/economia , Hepatite C/epidemiologia , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/economia , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/prevenção & controle , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Masculino , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Vigilância da População/métodos , Anos de Vida Ajustados por Qualidade de Vida , Minorias Sexuais e de Gênero/estatística & dados numéricos
11.
Medicine (Baltimore) ; 98(51): e18334, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860986

RESUMO

The aim of this study was to evaluate the effectiveness of hospital-based hepatitis C epidemic surveillance initiated by China's CDC STD/AIDS (National Center for AIDS/STD Control and Prevention of Chinese Center for Disease Control and Prevention) Prevention and Control Center in 2017.A total of 104,666 anti-hepatitis C virus (HCV) and 633 HCV-RNA detection records in our hospital from 2014 to 2017 were used to analyze the anti-HCV and HCV-RNA detection rates and positive rates in patients before and after implementation of epidemic surveillance.We found that the estimated HCV positive rate was 0.395% in all patients, and this rate increased to 0.533% after the pilot research. The positive rates of anti-HCV were significantly enhanced, although certain differences were observed among different departments. Significant increase of positive rate of HCV-RNA was only found in the inpatients from nonsurgical departments. Eighty-one cases were diagnosed after this pilot research, exceeding the 70 total cases in the previous 3 years. Most cases were diagnosed by nonsurgical departments; the upward trend of the cases diagnosed by surgical departments cannot be ignored.Our study indicates expanding anti-HCV and HCV-RNA detection in the target populations in hospitals is a useful strategy for finding more occult HCV infection. In addition, our results provide useful pilot data of the seroepidemiology of Hepatitis C for the special populations in hospitals, which will provide valuable information for public health research.


Assuntos
Hepatite C/diagnóstico , Hepatite C/epidemiologia , Vigilância da População , Anticorpos/sangue , China/epidemiologia , Hepacivirus/genética , Hepacivirus/imunologia , Humanos , Imunoglobulina G/imunologia , Pacientes Internados , Pacientes Ambulatoriais , Projetos Piloto , RNA Viral/sangue , Estudos Soroepidemiológicos
12.
BMC Infect Dis ; 19(1): 943, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31703669

RESUMO

BACKGROUND: A large proportion of people who inject drugs (PWID) living with hepatitis C virus (HCV) infection have not been treated. It is unknown whether inclusion of HCV diagnostics and treatment into integrated substance use disorder treatment and care clinics will improve uptake and outcome of HCV treatment in PWID. The aim is to assess the efficacy of integrating HCV treatment to PWID and this paper will present the protocol for an ongoing trial. METHODS: INTRO-HCV is a multicentre, randomised controlled clinical trial that will compare the efficacy of integrated treatment of HCV in PWID with the current standard treatment. Integrated treatment includes testing for HCV, assessing liver fibrosis with transient elastography, counselling, treatment delivery, follow-up and evaluation provided by integrated substance use disorder treatment and care clinics. Most of these clinics for PWID provide opioid agonist therapy while some clinics provide low-threshold care without opioid agonist therapy. Standard care involves referral to further diagnostics, treatment and treatment follow-up given in a hospital outpatient clinic with equivalent medications. The differences between the delivery platforms in the two trial arms involve use of a drop-in approach rather than specific appointment times, no need for additional travelling, less blood samples taken during treatment, and treatment given from already known clinicians. The trial will recruit approximately 200 HCV infected individuals in Bergen and Stavanger, Norway. The primary outcomes are time to treatment initiation and sustained virologic response, defined as undetectable HCV RNA 12 weeks after end of treatment. Secondary outcomes are cost-effectiveness, treatment adherence, changes in quality of life, fatigue and psychological well-being, changes in drug use, infection related risk behaviour, and risk of reinfection. The target group is PWID with HCV diagnosed receiving treatment and care within clinics for PWID. DISCUSSION: This study will inform on the effects of an integrated treatment program for HCV in clinics for PWID compared to standard care aiming to increase access to treatment and improving treatment adherence. If the integrated treatment model is found to be safe and efficacious, it can be considered for further scale-up. TRIAL REGISTRATION: ClinicalTrials.gov.no. NCT03155906.


Assuntos
Antivirais/uso terapêutico , Prestação Integrada de Cuidados de Saúde/métodos , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Tratamento de Substituição de Opiáceos , Abuso de Substâncias por Via Intravenosa/tratamento farmacológico , Assistência ao Convalescente , Análise Custo-Benefício , Aconselhamento , Feminino , Hepatite C/etiologia , Humanos , Masculino , Noruega , Reação em Cadeia da Polimerase , Qualidade de Vida , Recidiva , Abuso de Substâncias por Via Intravenosa/complicações , Resposta Viral Sustentada , Cooperação e Adesão ao Tratamento
13.
BMC Infect Dis ; 19(1): 932, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690267

RESUMO

BACKGROUND: Although DAAs hold promise to significantly reduce rates of chronic HCV infections, its eradication still requires development of an effective vaccine. Prolonged T cell responses and cross neutralizing antibodies are ideal for vaccination against the infection. We aimed to design and synthesize a 6 multi epitope peptide vaccine candidate and provide evidence for production of extended cellular and neutralizing Abs in mice. METHODS: Six peptides derived from conserved epitopes in E1, E2 (n = 2),NS4B, NS5A and NS5B were designed, synthesized in a multiple antigenic peptide (MAP) form and administered w/o adjuvant to BALB/c mice as HCVp6-MAP at doses ranging from 800 ng to 16 µg. Humoral responses to structural epitopes were assayed by ELISA at different times after injection. ELISpot assay was used to evaluate IFN É£ producing CD4+/ CD8+ T- lymphocytes at extended durations i.e. > 20 weeks. Viral neutralization by mice sera was tested for genotypes 2a (JFH1) and a chimeric 2a/4a virus (ED43/JFH1) in HCVcc culture. RESULTS: HCVp6-MAP confers potent viral neutralization and specific cellular responses at > 1600 ng/ animal for at least 20 weeks. CONCLUSION: We report on a promising anti HCV vaccine for future studies on permissive hosts and in clinical trials.


Assuntos
Anticorpos Neutralizantes/sangue , Epitopos/imunologia , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/sangue , Imunidade Celular , Peptídeos/imunologia , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Genótipo , Hepacivirus/genética , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/síntese química , Vacinas de Subunidades/imunologia
14.
Chem Commun (Camb) ; 55(93): 14027-14030, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31690898

RESUMO

RNA-biased small molecules with a monoquinoxaline core target the L-shaped structure of subdomain IIa of Hepatitis C virus internal ribosome entry site (IRES) RNA in proximity to the Mg2+ binding site. The binding event leads to the destacking of RNA bases, resulting in the inhibition of IRES-mediated translation and HCV RNA replication.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Sítios Internos de Entrada Ribossomal/efeitos dos fármacos , Quinoxalinas/farmacologia , RNA Viral/efeitos dos fármacos , Antivirais/química , Hepacivirus/genética , Humanos , Sítios Internos de Entrada Ribossomal/genética , Conformação Molecular , Quinoxalinas/química , RNA Viral/genética , Replicação Viral/efeitos dos fármacos
15.
Vnitr Lek ; 65(9): 553-563, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31635466

RESUMO

The treatment of chronic hepatitis C is currently based exclusively on the use of drugs from the direct-acting anti-viral class. They are substances that inhibit one of the 3 most important enzymes of the virus replication cycle. Anti-viral drugs are divided according to the target structure into 3 basic classes, further division is mainly based on the chemical structure of individual antivirals. A common feature of all the regimens is high efficiency and safety. Pangenotypic efficacy regimens are those that utilize a combination of 2 or 3 antiviral agents of different classes, and are effective for all HCV genotypes. Currently there are 3 such regimens available. Pangenotypic regimens probably represent the latest stage of development of treatment for chronic hepatitis C. The review discusses in detail the efficiency of different pangenotypic regimens in individual subgroups of patients with HCV infection. Atten-tion is primarily paid to the data bases for their use.


Assuntos
Antivirais , Hepacivirus , Hepatite C Crônica , Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Humanos
16.
Int J Infect Dis ; 89: 131-136, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31580940

RESUMO

INTRODUCTION: New efficient strategies are needed for the assessment of active hepatitis C virus (HCV) infection. The aim of this study was to evaluate the ability of HCV core antigen (HCV-cAg) as a marker of active HCV infection in newly diagnosed patients, for treatment monitoring, and for the detection of therapeutic failure. MATERIALS AND METHODS: A prospective study was conducted at a regional reference hospital in Spain. HCV-cAg and viral load (RNA-HCV) were tested in plasma or serum samples from three patient groups: new diagnosis, treatment monitoring, and treatment failure. The treatment monitoring group was tested at the beginning of treatment, at 4 weeks post-initiation, at the end of treatment, and at 12 weeks post-treatment completion. The Architect HCV core antigen assay was performed for HCV-cAg testing, and viral load was quantified with the Cobas 6800 system. RESULTS: A total of 303 samples from 124 patients were analyzed. Excellent correlation was seen between HCV-cAg and HCV-RNA (R2=0.932). The optimal cut-off value was 3fmol/l in the receiver operating characteristics curve analysis, and the area under the curve was 0.987 (95% confidence interval 0.972-1.000). HCV-cAg sensitivity and specificity were 97% and 95%, respectively. Most diverging results were observed in the treatment follow-up group. CONCLUSIONS: HCV-cAg demonstrated good sensitivity and specificity as a marker for active HCV infection, new diagnosis, detection of antiviral therapeutic failure, and treatment monitoring.


Assuntos
Hepacivirus/isolamento & purificação , Antígenos da Hepatite C/genética , Hepatite C/diagnóstico , Adulto , Antivirais/uso terapêutico , Feminino , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C/virologia , Antígenos da Hepatite C/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/genética , Curva ROC , Sensibilidade e Especificidade , Espanha/epidemiologia , Carga Viral
17.
Sensors (Basel) ; 19(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31575036

RESUMO

Hepatitis C virus (HCV) accounts for 15%-20% of cases of acute infection, and chronic HCV infection is developed in about 50%-80% of HCV patients. Unfortunately, due to the lack of proper medical care, difficulty in screening for HCV infection, and lack of awareness resulted in chronic HCV infection in 71 million people on a global scale, and about 399,000 deaths in 2016. It is crucial to recognize that the effective use of antiviral medicines can cure more than 95% of HCV infected people. The Global Health Sector Strategy (GHSS) aim is to reduce the new HCV infections and the HCV associated mortality by 90% and 65%, respectively. Therefore, the methods that are simple, yet powerful enough to detect HCV infections with high sensitivity, specificity, and a shorter window period are crucial to restrain the global burden of HCV healthcare. This article focuses on the technologies used for the detection of HCV in clinical specimens.


Assuntos
Hepacivirus/imunologia , Hepatite C/diagnóstico , Immunoblotting/métodos , Técnicas Imunoenzimáticas/métodos , Anticorpos Antivirais/análise , Antígenos Virais/análise , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Hepacivirus/genética , Hepatite C/imunologia , Humanos , Luminescência , Proteínas Virais/metabolismo
18.
BMC Infect Dis ; 19(1): 882, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640579

RESUMO

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) requires lengthy use of second-line drugs, burdened by many side effects. Hepatitis C virus (HCV) chronic infection increases risk of drug-induced liver injury (DILI) in these patients. Data on MDR-TB patients with concurrent HCV chronic infection treated at the same time with second-line antitubercular drugs and new direct-acting antivirals (DAAs) are lacking. We evaluate if treating at the same time HCV infection and pulmonary MDR-TB is feasible and effective. CASES PRESENTATION: In this study, we described two cases of patients with pulmonary MDR-TB and concurrent HCV chronic infection cured with DAAs at a Tertiary Infectious Diseases Hospital in Italy. During antitubercular treatment, both patients experienced a DILI before treating HCV infection. After DAAs liver enzymes normalized and HCV RNA was undetectable. Then antitubercular regimen was started according to the institutional protocol, drawn up following WHO MDR-TB guidelines. It was completed without further liver side effects and patients were declared cured from both HCV infection and MDR-TB. CONCLUSIONS: We suggest to consider treatment of chronic hepatitis C with DAAs as a useful intervention for reintroduction of second-line antitubercular agents in those patients who developed DILI, reducing the risk of treatment interruption when re-exposed to these drugs.


Assuntos
Antituberculosos/uso terapêutico , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Idoso , Antituberculosos/efeitos adversos , Antivirais/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Hepacivirus/genética , Humanos , Itália , Masculino , RNA Viral/sangue , Retratamento , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/virologia , Tuberculose Pulmonar/virologia
19.
BMC Infect Dis ; 19(1): 875, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640596

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease globally. Direct acting antivirals (DAAs) have proven effective in curing HCV. However, the current standard of care (SOC) in Botswana remains PEGylated interferon-α (IFN-α) with ribavirin. Several mutations have been reported to confer resistance to interferon-based treatments. Therefore, there is a need to determine HCV genotypes in Botswana, as these data will guide new treatment guidelines and understanding of HCV epidemiology in Botswana. METHODS: This was a retrospective cross-sectional pilot study utilizing plasma obtained from 55 participants from Princess Marina Hospital in Gaborone, Botswana. The partial core region of HCV was amplified, and genotypes were determined using phylogenetic analysis. RESULTS: Four genotype 5a and two genotype 4v sequences were identified. Two significant mutations - K10Q and R70Q - were observed in genotype 5a sequences and have been associated with increased risk of hepatocellular carcinoma (HCC), while R70Q confers resistance to interferon-based treatments. CONCLUSION: Genotypes 5a and 4v are circulating in Botswana. The presence of mutations in genotype 5 suggests that some patients may not respond to IFN-based regimens. The information obtained in this study, in addition to the World health organization (WHO) recommendations, can be utilized by policy makers to implement DAAs as the new SOC for HCV treatment in Botswana.


Assuntos
Hepacivirus/genética , Hepatite C/virologia , Mutação , Filogenia , Adulto , Antivirais/uso terapêutico , Botsuana , Carcinoma Hepatocelular/virologia , Estudos Transversais , Farmacorresistência Viral , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepatite C/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Retrospectivos , Ribavirina/uso terapêutico
20.
Life Sci ; 238: 116958, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628915

RESUMO

AIM: To work on Hepatitis C Virus (HCV), one of the major causes of liver cirrhosis and hepatocellular carcinoma, polymerase of genotype 4a that have no solved structures deposited in the protein data bank (PDB) yet. Understanding the dynamics and testing some novel inhibitors are also covered. MATERIALS AND METHODS: Molecular Dynamics Simulation (MDS) is performed for a period of 1 µs on comparatively modeled then validated NS5b of subtype 4a. Following MDS analysis, molecular docking is performed to test the inhibitory performance of eight novels suggested guanosine derivatives using 181 different conformations of the protein model gathered during the MDS run after the equilibration period. KEY FINDINGS: The results yield that the eight modified, at position 2', GTP derivatives (fluorine, Hydroxyl, and sulphonyl oxydanyl) have binding energies comparable to the parent molecule, GTP. Besides, the eight suggested compounds have lower binding energies (and hence better in binding) compared to sofosbuvir (a drug approved by FDA in 2013 against HCV) and ribavirin (a wide range acting antiviral drug used before against HCV). SIGNIFICANCE: Combined molecular dynamics and molecular docking are able to test the hypothesis of HCV polymerase dynamics doesn't affect the nucleotides (or nucleotide inhibitors) binding to its active site. Despite the reported highly dynamic subtype 4a of HCV; all the nucleotide inhibitors under the study are able to, tightly, bind to NS5b of genotype 4a. This behavior is reported before for the Zika virus polymerase, as well.


Assuntos
Antivirais/química , Antivirais/farmacologia , Guanosina Trifosfato/química , Hepacivirus/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas não Estruturais Virais/antagonistas & inibidores , Hepacivirus/classificação , Hepacivirus/genética , Humanos , Modelos Moleculares , Conformação Proteica , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
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