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1.
Braz. j. biol ; 83: e244977, 2023. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1285621

RESUMO

Abstract Hepatitis C virus (HCV) is the serious global public health burden of liver disease. Approximately 170 million people in the world are infected with (HCV). In Pakistan, where the disease has high occurrence rate. The present study envisages an up-to-date prevalence of HCV and genotypic distribution in the general population of Mardan District, Khyber Pakhtunkhwa (KP), Pakistan. The blood samples from 6,538 individuals including 3,263 males and 3,275 females were analyzed for hepatitis C surface antigen by Immuno-chromatographic test (ICT), Enzyme-linked immunosorbent assay (ELISA), and reverse transcription-polymerase chain reaction (PCR). It was found that 396 (12.13%) out of 3263 individuals contained antibodies in their blood against HCV, while among the different age groups, the highest incidences of HCV antibodies were found in the 31-40 age group (11.01%). The ICT positive samples were further screened by nested PCR to determine the existence of active HCV-RNA. It was identified that 7.11% (3263) of the total population (6538) tested was positive, among which the 461 (14.07%) females possessed antibodies in their blood against HCV. Our data showed total HCV infection in the investigated population was 5.78%. Higher percentage of HCV prevalence was detected in males than females in the age group 31-40 and 41-50. To compare the prevalence of HCV genotypes age-wise in male and female genotype 3a was found most prevalent genotype followed by 1a, 2a and 3b, respectively.


Resumo O vírus da hepatite C (HCV) é o grave problema de saúde pública das doenças hepáticas. Aproximadamente 170 milhões de pessoas no mundo estão infectadas com HCV; no Paquistão, a doença tem alto índice de ocorrência. O presente estudo prevê uma prevalência atualizada do HCV e distribuição genotípica na população geral do distrito de Mardan, Khyber Pakhtunkhwa (KP), Paquistão. As amostras de sangue de 6.538 indivíduos, incluindo 3.263 homens e 3.275 mulheres, foram analisadas para o antígeno de superfície da hepatite C por teste imunocromatográfico (ICT), ensaio imunoenzimático (ELISA) e reação em cadeia da polimerase de transcrição reversa (PCR). Verificou-se que 396 (12,13%) de 3.263 indivíduos continham anticorpos no sangue contra o HCV, enquanto entre as diferentes faixas etárias as maiores incidências de anticorpos anti-HCV foram encontradas na faixa etária de 31 a 40 anos (11,01%). As amostras positivas para ICT foram posteriormente rastreadas por nested PCR para determinar a existência de HCV-RNA ativo. Identificou-se que 7,11% (3.263) do total da população (6.538) testada foram positivos, dentre os quais 461 (14,07%) mulheres possuíam anticorpos no sangue contra o HCV. Nossos dados mostraram que a infecção total pelo HCV na população investigada foi de 5,78%. Maior porcentagem de prevalência de HCV foi detectada em homens do que em mulheres nas faixas etárias de 31-40 e 41-50. Para comparar a prevalência de genótipos de HCV com relação à idade no genótipo masculino e feminino 3a foi encontrado o genótipo mais prevalente seguido por 1a, 2a e 3b, respectivamente.


Assuntos
Humanos , Masculino , Feminino , Hepatite C/epidemiologia , Hepacivirus/genética , Paquistão/epidemiologia , Prevalência , Genótipo
3.
Lancet Gastroenterol Hepatol ; 7(12): 1112-1127, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36370741

RESUMO

BACKGROUND: To achieve WHO targets for the elimination of hepatitis C virus (HCV) as a public threat, an increased uptake of HCV treatment among people who inject drugs (PWID) is urgently needed. Optimal HCV co-located treatment models for PWID have not yet been identified. We aimed to compare two patient-centred models of HCV care in PWID with active drug use. METHODS: We did a pragmatic randomised controlled trial at eight US cities in eight opioid treatment programmes and 15 community health centres. PWID actively injecting within 90 days of study entry were randomly assigned (1:1) to either patient navigation or modified directly observed therapy (mDOT) using computer-generated variable block sizes of 2-6 stratified by city, clinical settings, and cirrhosis status. The randomisation code was concealed, in a centralised REDCap database platform, from all investigators and research staff except for an authorised data manager at the data coordinating centre. All participants received a fixed-dose combination tablet (sofosbuvir 400 mg plus velpatasvir 100 mg) orally once daily for 12 weeks. The primary outcome was sustained virological response (SVR; determined by chart review between 70 days and 365 days after end of treatment and if unavailable, by study blood draws), and secondary outcomes were treatment initiation, adherence (measured by electronic blister packs), and treatment completion. Analyses were conducted within the modified intention-to-treat (mITT; all who initiated treatment), intention-to-treat (all who were randomised), and per-protocol populations. This trial is registered with ClinicalTrials.gov, NCT02824640. FINDINGS: Between Sept 15, 2016, and Aug 14, 2018, 1891 individuals were screened and 1136 were excluded (213 declined to participate and 923 did not meet the eligibility criteria). We randomly assigned 755 participants to patient navigation (n=379) or mDOT (n=376). In the mITT sample of participants who were randomised and initiated treatment (n=623), 226 (74% [95% CI 69-79]) of 306 participants in the mDOT group and 236 (76% [69-79]) of 317 in the patient navigation group had an SVR, with no significant difference between the groups (adjusted odds ratio [AOR] 0·97 [95% CI 0·66-1·42]; p=0·35). In the ITT sample (n=755), 226 (60% [95% CI 55-65]) of 376 participants in the mDOT group and 236 (62% [57-67]) of 379 in the patient navigation group had an SVR (AOR 0·92 [0·68-1·25]; p=0·61) and in the per-protocol sample (n=501), 226 (91% [87-94]) of 248 participants in the mDOT group and 235 (93% [89-96]) of 253 in the patient navigation group had an SVR (AOR 0·79 [0·41-1·55]; p=0·44). 306 (81%) of 376 participants in the mDOT group and 317 (84%) of 379 participants in the patient navigation group initiated treatment (AOR 0·86 [0·58-1·26]; p=0·44) and, among those, 251 (82%) participants in the mDOT group and 264 (83%) participants in the patient navigation group completed treatment (AOR 0·90 [0·58-1·39]; p=0·63). Mean daily adherence was higher in the mDOT group (78% [95% CI 75-81]) versus the patient navigation group (73% [70-77]), with a difference of 4·7% ([1·9-7·4]; p=0·0010). 421 serious adverse events were reported (217 in the mDOT group and 204 in the patient navigation group), with the most common being hospital admission (176 in the mDOT group vs 161 in the patient navigation group). INTERPRETATION: In this trial of active PWID, both models resulted in high SVR. Although adherence was significantly higher in the mDOT group versus the patient navigation group, there was no significant difference in SVR between the groups. Increases in adherence and treatment completion were associated with an increased likelihood of SVR. These results suggest that active PWID can reach high SVRs in diverse settings with either mDOT or patient navigation support. FUNDING: Patient-Centered Outcomes Research Institute, Gilead Sciences, Quest Diagnostics, Monogram Biosciences, and OraSure Technologies.


Assuntos
Usuários de Drogas , Hepatite C , Abuso de Substâncias por Via Intravenosa , Humanos , Abuso de Substâncias por Via Intravenosa/complicações , Abuso de Substâncias por Via Intravenosa/tratamento farmacológico , Antivirais/efeitos adversos , Sofosbuvir/uso terapêutico , Hepatite C/tratamento farmacológico , Hepatite C/complicações , Hepacivirus
4.
J Int Med Res ; 50(11): 3000605221131136, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36345172

RESUMO

Cryoglobulinaemia can manifest as fatigue, purpura, and joint pain, and can involve the kidneys and peripheral nervous system. Type II and mixed cryoglobulinemia cases are usually associated with hepatitis C virus infection and autoimmune diseases, and most cases reported outside China have been related to hepatitis C virus. The pathological manifestation of cryoglobulinaemia glomerulonephritis is always membranous proliferative glomerulonephritis or membranous nephropathy; other pathological types are rare. This current case report describes a female patient with hepatitis B virus (HBV)-associated cryoglobulinaemic glomerulonephritis. The patient had hepatitis B complicated with purpura, abnormal urinalysis and renal function. She was positive for rheumatoid factor and had decreased complement, and her blood cryoglobulin level was positive. The pathological findings were consistent with late-stage capillary proliferative glomerulonephritis, which improved after steroid, immunosuppressant and anti-HBV treatment.


Assuntos
Crioglobulinemia , Glomerulonefrite Membranosa , Glomerulonefrite , Hepatite B , Hepatite C , Humanos , Feminino , Crioglobulinemia/complicações , Vírus da Hepatite B , Hepacivirus , Glomerulonefrite/complicações , Glomerulonefrite/tratamento farmacológico , Hepatite B/complicações
5.
BMC Cancer ; 22(1): 1153, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36348292

RESUMO

BACKGROUND: The approved dose of nivolumab is 3 mg/kg or a flat dose of 240 mg for indications. There is no dose-response relationship for nivolumab; therefore, a low-dose regimen may be an option to reduce financial toxicity. This study was designed to investigate the efficacy and safety of low-dose nivolumab in the management of hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed patients with HCC who received 20 or 100 mg of nivolumab intravenously every 2 weeks. The objective response rate was determined in accordance with the Response Evaluation Criteria in Solid Tumors criteria version 1.1. The Cox regression model and Kaplan-Meier method were used to analyze hazard factors, progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. RESULTS: In total, 78 patients were enrolled, including 49 with hepatitis B virus (HBV) and 23 with hepatitis C virus (HCV). All patients were staged as Barcelona Clinic Liver Cancer stage C, and 20 patients were classified as having Child-Pugh classification B (7). Nivolumab 20 mg was an independent prognostic factor for better PFS, and albumin-bilirubin grade 1 was the independent prognostic factor for superior OS in the multivariate analyses. Patients with better HBV (HBV DNA < 500 IU/ml) and HCV (HCV RNA undetectable) controls had superior OS. All AEs were grade 1-2 in severity, and all patients tolerated nivolumab without treatment interruption or dose adjustment. Additionally, 31 patients underwent subsequent therapy after nivolumab treatment. CONCLUSION: Low-dose nivolumab may be effective with manageable toxicity and can be an alternative option to reduce financial toxicity in patients with advanced HCC who cannot afford the high cost of immune checkpoint inhibitors in real-world practice.


Assuntos
Carcinoma Hepatocelular , Hepatite C , Neoplasias Hepáticas , Humanos , Nivolumabe/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/induzido quimicamente , Estudos Retrospectivos , Vírus da Hepatite B , Hepatite C/tratamento farmacológico , Hepacivirus
6.
J Ayub Med Coll Abbottabad ; 34(3): 447-451, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36377154

RESUMO

BACKGROUND: Pakistan has the highest prevalence of Β-Thalassemia major in children and Chronic Hepatitis C (HCV) infection is a common transfusion transmitted infection. After the emergence of new generations of Antiviral drugs labelled as Direct Acting Antivirals (DAAs), substantial eradication of HCV has been reported as 90-95% with fewer side effects as compared to older regimen of Peginterferon with or without Ribavirin. The main objective of this study was to assess the Rapid virological response (RVR) at 4th week, End of treatment response (ETR) at 12th week and sustained viral response (SVR) at 24th week achieved by using direct acting antiviral and to assess their safety. Methods: Retrospective descriptive study was conducted from July 2018 to July 2020 at National Institute of Child Health. All ß-thalassemia major paediatric patients with HCV infection and age between 3-14 years were included. Demographic data, liver function test, HCV PCR, and response of antiviral therapy was recorded and analyzed. Safety was determined by adverse effects reported in records and efficacy was documented by clearance of HCV-RNA to see ETR and SVR. RESULTS: Total 21 patients were treated. Mean age was 7.67±3yr and 12 (57%) were male. Mean weight was 19.3±3.2kg. RVR and ETR was achieved in all (100%) and SVR was achieved in 20/21 (95%) patients. Headache in 2(9.5%) and generalized body ache was found in 1 (4.25%) patient. Conclusion: Combined Sofosbuvir and Daclatasvir were found to be effective and safe for treating HCV in Thalassaemia Major Children.


Assuntos
Hepatite C Crônica , Hepatite C , Talassemia beta , Humanos , Criança , Masculino , Pré-Escolar , Adolescente , Feminino , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Antivirais/efeitos adversos , Talassemia beta/tratamento farmacológico , Estudos Retrospectivos , Hepacivirus/genética , Quimioterapia Combinada , Ribavirina/uso terapêutico , Hepatite C/tratamento farmacológico , Resultado do Tratamento , Genótipo
7.
J Ayub Med Coll Abbottabad ; 34(3): 474-477, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36377159

RESUMO

BACKGROUND: Hepatitis C is associated with a wide range of health repercussions. Pakistan is one of the highly prevalent countries of Hepatitis C Virus (HCV) infection. The availability of cost-effective, robust, and reliable screening and diagnostic tests for hepatitis C is important to address the disease burden. Standardization of screening and diagnostic assays in clinical laboratories is crucial for achieving big goals. Objectives of this study are to correlate the results of two different HCV antibody (HCV Ab) assays and to examine the correlation of HCV core antigen (HCV c Ag) results with HCV PCR for HCV infection diagnosis. METHODS: This descriptive cross-sectional study was carried out from November to December 2020 at Dow University of Health Sciences. Total number of 40 HCV Ab samples were analysed by both chemiluminescence (CMIA) and electrochemiluminescence (ECLIA) immunoassays. Tests for HCV RNA PCR and HCV c Ag were performed on all samples. Results of screening and diagnostic assays were correlated and agreements were examined. Statistical analysis for agreement was carried out by using R software version 3.6.3 through AC1 Gwetz Statistic. The study was approved by the institutional ethical review committee. RESULTS: An agreement of 0.73 and 0.95 was found between two different HCV Ab immunoassays and HCV c Ag and HCV PCR, respectively. CONCLUSIONS: We found a good correlation between CMIA and ECLIA for HCV Ab. An excellent correlation was found between HCV c Ag and HCV PCR. Based on our study findings, HCV c Ag is a candidate test for the diagnosis of active HCV infection.


Assuntos
Antígenos da Hepatite C , Hepatite C , Humanos , Estudos Transversais , Anticorpos Anti-Hepatite C , Hepacivirus/genética , Hepatite C/diagnóstico , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , RNA Viral
8.
Harm Reduct J ; 19(1): 121, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36320005

RESUMO

BACKGROUND: The incidence of HIV among persons who inject drugs (PWID) in the USA has been increasing since 2014, signaling the need to identify effective ways to engage PWID in HIV prevention services, namely pre-exposure prophylaxis (PrEP). Yet, the uptake of PrEP in this population is minimal compared to other populations at risk of HIV acquisition. In this work, we sought to explore knowledge, attitudes, and perspectives of PrEP acceptability among PWID. METHODS: In the context of a pilot study to explore the acceptability of pharmacy-based hepatitis C virus (HCV) treatment, we conducted semi-structured interviews (n = 24) and focus groups (n = 4, 16 participants) with people who were living with HCV and reported active injection drug use (≤ 90 days since last use). Participants were asked open-ended questions about their familiarity with and motivation to use PrEP. As part of a sub-analysis focused on PrEP, qualitative data were analyzed using a Rapid Assessment Process, where three coders used structured templates to summarize qualitative data and iteratively reviewed coded templates to identify themes. Participants also completed short quantitative questionnaires regarding drug use history and attitudes toward health concerns. RESULTS: Forty-seven percent of participants expressed having little or no concern regarding HIV acquisition. Targeted analyses focused on HIV prevention identified three themes, which help characterize behavioral determinants of nonadoption. First, knowledge of PrEP was limited among PWID and influenced by infrequent open community discussions around HIV risk. Second, PWID perceived sexual behaviors-but not injection drug use-as a motivator for HIV risk prevention. Finally, PWID identified many individual and environmental barriers that hinder PrEP uptake. CONCLUSION: Among PWID, PrEP is rarely discussed and concerns about the feasibility of using daily PrEP are common. Taken with the prevalent perception that drug use is not a high risk for HIV acquisition, our findings point to opportunities for public health work to target PrEP education to PWID and to leverage other successful interventions for PWID as an opportunity to provide PrEP to this vulnerable population.


Assuntos
Fármacos Anti-HIV , Usuários de Drogas , Infecções por HIV , Hepatite C , Profilaxia Pré-Exposição , Abuso de Substâncias por Via Intravenosa , Humanos , Abuso de Substâncias por Via Intravenosa/epidemiologia , Fármacos Anti-HIV/uso terapêutico , Hepacivirus , Projetos Piloto , Infecções por HIV/prevenção & controle , Hepatite C/tratamento farmacológico
9.
Sci Rep ; 12(1): 19257, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357472

RESUMO

Innovative testing approaches and care pathways are required to meet HIV, hepatitis B (HBV) and hepatitis C (HCV) elimination goals. Routine testing for blood-borne viruses (BBVs) within emergency departments (EDs) is suggested by the European Centre for Disease Prevention and Control but there is a paucity of supporting evidence. We evaluated the introduction of routine BBV testing in EDs at a large teaching hospital in northern England. In October 2018, we modified the electronic laboratory ordering system to reflex opt-out HIV, HBV and HCV testing for all ED attendees aged 16-65 years who had a routine blood test for urea and electrolytes (U&Es). Linkage to care (LTC) was attempted for newly diagnosed patients, those never referred and those who had previously disengaged from care. The project operated for 18 months, here we present evaluation of the initial nine months (2 October 2018-1 July 2019). We analysed testing uptake, BBV seropositivity, LTC and treatment initiation within six months post-diagnosis. Over 9 months, 17,026/28,178 (60.4%) ED attendees who had U&Es performed were tested for ≥ 1 BBV. 299 active BBV infections were identified: 70 HIV Ab/Ag-positive (0.4% seroprevalence), 73 HBsAg-positive (0.4%) and 156 HCV RNA-positive (1.0%). Only 24.3% (17/70) HIV Ab/Ag-positive individuals required LTC, compared to 94.9% (148/156) HCV RNA-positive and 53.4% (39/73) HBsAg-positive individuals. LTC was successful in 94.1% (16/17) HIV Ab/Ag-positive and 69.3% (27/39) HBsAg-positive individuals. However, at 6 months LTC was just 39.2% (58/148) for HCV RNA-positive individuals, with 64% (37/58) of these commencing treatment. Universal opt-out ED BBV testing proved feasible and effective in identifying active BBV infections, especially among marginalised populations with reduced healthcare access. Our integrated approach achieved good LTC rates although further service development is necessary, particularly for HCV RNA-positive people who inject drugs.


Assuntos
Infecções por HIV , Hepatite B , Hepatite C , Humanos , Antígenos de Superfície da Hepatite B , Estudos Soroepidemiológicos , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Hepatite C/diagnóstico , Hepatite C/epidemiologia , Hepatite B/diagnóstico , Hepatite B/epidemiologia , Hepacivirus , Serviço Hospitalar de Emergência , Resultado do Tratamento , Reino Unido , RNA
10.
Biomolecules ; 12(11)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36358979

RESUMO

While host miRNA usually plays an antiviral role, the relentless tides of viral evolution have carved out a mechanism to recruit host miRNA as a viral protector. By complementing miR-122 at the 5' end of the genome, the hepatitis C virus (HCV) gene can form a complex with Argonaute 2 (Ago2) protein to protect the 5' end of HCV RNA from exonucleolytic attacks. Experiments showed that the disruption of the stem-loop 1(SL1) structure and the 9th nucleotide (T9) of HCV site 1 RNA could enhance the affinity of the Ago2 protein to the HCV site 1 RNA (target RNA). However, the underlying mechanism of how the conformation and dynamics of the Ago2: miRNA: target RNA complex is affected by the SL1 and T9 remains unclear. To address this, we performed large-scale molecular dynamics simulations on the AGO2-miRNA complex binding with the WT target, T9-abasic target and SL1-disruption target, respectively. The results revealed that the T9 and SL1 structures could induce the departing motion of the PAZ, PIWI and N domains, propping up the mouth of the central groove which accommodates the target RNA, causing the instability of the target RNA and disrupting the Ago2 binding. The coordinated motion among the PAZ, PIWI and N domains were also weakened by the T9 and SL1 structures. Moreover, we proposed a new model wherein the Ago2 protein could adopt a more constraint conformation with the proximity and more correlated motions of the PAZ, N and PIWI domains to protect the target RNA from dissociation. These findings reveal the mechanism of the Ago2-miRNA complex's protective effect on the HCV genome at the atomic level, which will offer guidance for the design of drugs to confront the protection effect and engineering of Ago2 as a gene-regulation tool.


Assuntos
Hepatite C , MicroRNAs , Humanos , Hepacivirus/genética , RNA Viral/genética , RNA Viral/metabolismo , Regiões 5' não Traduzidas , Hepatite C/prevenção & controle , MicroRNAs/genética , MicroRNAs/metabolismo
11.
Viruses ; 14(11)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36366415

RESUMO

BACKGROUND: The benefits of hepatitis C virus (HCV)eradication for hepatocellular carcinoma (HCC) patients in Barcelona Clinic Liver Cancer (BCLC) stage B/C remain uncertain. METHODS: In this hospital-based cohort study, all HCV-infected patients with BCLC stage B/C HCC during the period January 2017 to March 2021 were retrospectively screened, with 97 patients who had completed direct-acting antiviral (DAA) therapy being enrolled for final analysis. RESULTS: In total, the sustained virological response (SVR) rate was 90.7%. In logistic regression analysis, progressive disease (PD) to prior tumor treatments was significantly associated with SVR failure (odds ratio 5.59, 95% CI 1.30-24.06, p = 0.021). Furthermore, the overall survival (OS) rate was significantly higher in the SVR group than that in the non-SVR group (1-year OS: 87.5% vs. 57.1%, p = 0.001). SVR was found to be an independent factor related to OS (hazard ratio 8.42, 95% CI 2.93-24.19, p = 0.001). However, even upon achieving SVR, the OS rates in BCLC stage C or Child-Pugh stage B patients remained poor. CONCLUSIONS: In BCLC stage B/C HCC, DAA could achieve a high SVR rate except in those patients with PD to prior HCC treatments. SVR was related to improvements in OS; therefore, DAA therapy should be encouraged for patients diagnosed without a short life expectancy.


Assuntos
Carcinoma Hepatocelular , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Hepacivirus/genética , Antivirais , Neoplasias Hepáticas/diagnóstico , Estudos Retrospectivos , Estudos de Coortes , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C/complicações , Hepatite C/tratamento farmacológico
12.
Viruses ; 14(11)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36366588

RESUMO

Infectious diseases are a major contributor to human suffering and the associated socioeconomic burden worldwide. A better understanding of human pathogen-host interactions is a prerequisite for the development of treatment strategies aimed at combatting human pathogen-induced diseases. Model systems that faithfully recapitulate the pathogen-host interactions in humans are critical to gain meaningful insight. Unfortunately, such model systems are not yet available for a number of pathogens. The strict tropism of the hepatitis B (HBV) and C (HCV) viruses for the human liver has made it difficult to study their virus-host interactions during the natural history of these infections. In this case, surplus liver biopsy tissue donated by patients provides an opportunity to obtain a snapshot of the phenomenological and molecular aspects of the human liver of chronically HCV or HBV-infected patients. In this review, we will briefly summarize our own efforts over the years to advance our knowledge of the virus-host interactions during the natural history of chronic HCV and HBV infection.


Assuntos
Hepatite A , Hepatite B , Hepatite C , Humanos , Interações entre Hospedeiro e Microrganismos , Vírus da Hepatite B , Fígado , Biópsia , Hepatite C/patologia , Hepacivirus
13.
Sci Rep ; 12(1): 18506, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36323770

RESUMO

SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with significant mortality and morbidity. At this time, the only FDA-approved therapeutic for COVID-19 is remdesivir, a broad-spectrum antiviral nucleoside analog. Efficacy is only moderate, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. This identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir's apparent potency > 25-fold. We report that HCV NS5A inhibitors act on the SARS-CoV-2 exonuclease proofreader, providing a possible explanation for the synergy observed with nucleoside analog remdesivir. FDA-approved Hepatitis C therapeutics Epclusa® (velpatasvir/sofosbuvir) and Zepatier® (elbasvir/grazoprevir) could be further optimized to achieve potency and pharmacokinetic properties that support clinical evaluation in combination with remdesivir.


Assuntos
COVID-19 , Hepatite C , Humanos , SARS-CoV-2 , Antivirais/uso terapêutico , Sofosbuvir/farmacologia , Nucleosídeos/farmacologia , COVID-19/tratamento farmacológico , Monofosfato de Adenosina , Alanina , Hepacivirus , Hepatite C/tratamento farmacológico , Pulmão
14.
BMC Infect Dis ; 22(1): 848, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376846

RESUMO

BACKGROUND: Hepatitis C virus (HCV) is a global public health problem, with ~ 11 million people in Africa infected. There is incomplete information on HCV in Sudan, particularly in haemodialysis patients, who have a higher prevalence compared to the general population. Thus, our objectives were to genotype and molecularly characterize HCV isolated from end-stage renal disease haemodialysis patients. METHODS: A total of 541 patients were recruited from eight haemodialysis centres in Khartoum and screened for anti-HCV. Viral loads were determined using in-house real-time PCR in seropositive patients. HCV was genotyped and subtyped using sequencing of amplicons of 5' untranslated (UTR) and non-structural protein 5B (NS5B) regions, followed by phylogenetic analysis of corresponding sequences. RESULTS: The HCV seroprevalence in the study was 17% (93/541), with HCV RNA-positive viremic rate of 7% (40/541). A low HCV load, with a mean of 2.85 × 104 IU/ml and a range of 2.95 × 103 to 4.78 × 106 IU/ml, was detected. Phylogenetic analyses showed the presence of genotypes 1, 3, 4, and 5 with subtypes 1a, 1b, 1 g, 3a, 4a, 4 l, 4 m, 4 s, and 4t. Sequences of HCV from the same haemodialysis units, clustered in similar genotypes and subtypes intimating nosocomial infection. CONCLUSION: HCV infection is highly prevalent in haemodialysis patients from Sudan, with phylogenetic analysis intimating nosocomial infection. HCV genotyping is useful to locate potential transmission chains and to enable individualized treatment using highly effective direct-acting antivirals (DAAs).


Assuntos
Infecção Hospitalar , Hepatite C Crônica , Hepatite C , Falência Renal Crônica , Humanos , Hepacivirus/genética , Genótipo , Antivirais , Estudos Soroepidemiológicos , Filogenia , Diálise Renal , Falência Renal Crônica/terapia , Infecção Hospitalar/epidemiologia , Sudão/epidemiologia
15.
Am J Gastroenterol ; 117(11): 1834-1844, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36327437

RESUMO

INTRODUCTION: There are limited data on the effect and evolution of risk factors for hepatocellular carcinoma (HCC) in patients with virologically cured hepatitis C virus (HCV) infection. METHODS: We conducted a retrospective cohort study of patients with HCV who achieved sustained virological response with direct-acting antivirals from 130 Veterans Administration hospitals during 2014-2018, followed through 2021. Cox proportional hazards models were constructed at 3 landmark times (baseline and 12 and 24 months after sustained virological response) to examine associations between demographic, clinical, and behavioral factors and HCC risk, stratified by cirrhosis status. RESULTS: Among 92,567 patients (32% cirrhosis), 3,247 cases of HCC were diagnosed during a mean follow-up of 2.5 years. In patients with cirrhosis, male sex (hazard ratios [HR]: 1.89, 1.93, and 1.99), cirrhosis duration ≥5 years (HR: 1.71, 1.79, and 1.34), varices (HR: 1.73, 1.60, and 1.56), baseline albumin (HR: 0.48, 0.47, and 0.49), and change in albumin (HR: 0.82 and 0.90) predicted HCC risk at each landmark time. HCV genotype 3, previous treatment, bilirubin, smoking, and race influenced HCC risk at baseline, but their effects attenuated over time. In patients without cirrhosis, diabetes (HR: 1.54, 1.42, and 1.47) and hypertension (HR: 1.59, 1.65, and 1.74) were associated with HCC risk at all landmark times. Changes in fibrosis-4 scores over time were associated with HCC risk both in patients with and without cirrhosis. DISCUSSION: Risk factors for HCC were different in patients with and without cirrhosis and some also evolved during follow-up. These factors can help with risk stratification and HCC surveillance decisions in patients with cured HCV.


Assuntos
Carcinoma Hepatocelular , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Humanos , Masculino , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/diagnóstico , Hepacivirus/genética , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/diagnóstico , Antivirais/uso terapêutico , Estudos Retrospectivos , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Incidência , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Cirrose Hepática/tratamento farmacológico , Fatores de Risco , Albuminas/uso terapêutico
16.
Viruses ; 14(11)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36366561

RESUMO

BACKGROUND: New technologies and therapies allow the possibility of a single-visit test and treat model for hepatitis C virus (HCV), addressing some of the barriers to care faced by people who inject drugs. METHODS: The TEMPO Pilot Study was an interventional cohort study evaluating a single-visit test and treat intervention among people with recent injecting drug use at a one peer-led needle and syringe program (NSP) in Sydney, Australia between September 2019 and February 2021. This analysis evaluated awareness of HCV status and agreement of self-report with HCV RNA test results. The analysis also assessed acceptability of: modality of result delivery, modality of blood sampling, site of treatment, and duration of treatment. RESULTS: Among 101 participants (median age 43; 31% female), 100 had a valid HCV RNA test result and 27% (27/100) were HCV RNA detectable. Overall, 65% (65/100) were aware of their status. Among people with a positive HCV RNA result, 48% (13/27) were aware of their status. People preferred same-day HCV test results (95%, 96/101), and preferred to receive results in person (69%, 70/101). Receiving treatment at an NSP was acceptable (100%, 101/101) and 78% (79/101) were willing to discuss their health with a peer NSP worker. CONCLUSION: Half of people with current HCV infection were aware of their status. The high acceptability of simplified testing and treatment pathways delivered at NSPs indicates that this is an appropriate strategy to improve HCV awareness and treatment uptake in this population.


Assuntos
Hepatite C , Abuso de Substâncias por Via Intravenosa , Transtornos Relacionados ao Uso de Substâncias , Adulto , Feminino , Humanos , Masculino , Estudos de Coortes , Hepacivirus/genética , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Projetos Piloto , Abuso de Substâncias por Via Intravenosa/complicações , Seringas , RNA Viral
17.
J Gen Virol ; 103(11)2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36399377

RESUMO

A better understanding of the antibody response during natural infection and the effect on disease progression and reinfection is necessary for the development of a protective hepatitis C virus (HCV) vaccine. The HCV pseudoparticle (HCVpp) system enables the study of viral entry and inhibition by antibody neutralization. A robust and comparable neutralization assay is crucial for the development and evaluation of experimental vaccines.With the aim of optimizing the HCVpp-murine leukaemia virus (MLV) system, we tested the neutralization of HCVpp-harbouring E1E2 from 21 HCV isolates representing 6 different genotypes by several monoclonal antibodies (mAbs). HCVpps are generated by expressing functional envelope glycoproteins (E1E2) onto pseudoparticles derived from env-deleted MLV. Adjustments of E1E2, gag-pol and luciferase plasmid ratios resulted in increased yields for most HCVpps and recovery of one non-infectious HCVpp. We simplified and improved the protocol to achieve higher signal/noise ratios and minimized the amount of HCVpps and mAbs needed for the detection of neutralization. Using our optimized protocol, we demonstrated comparable results to previously reported data with both diluted and freeze-thawed HCVpps.In conclusion, we successfully established a simplified and reproducible HCVpp neutralization protocol for studying a wide range of HCV variants. This simplified protocol provides highly consistent results and could be easily adopted by others to evaluate precious biological material. This will contribute to a better understanding of the antibody response during natural infection and help evaluate experimental HCV vaccines.


Assuntos
Hepatite C , Vacinas , Animais , Camundongos , Hepacivirus , Anticorpos Neutralizantes , Anticorpos Anti-Hepatite C , Testes de Neutralização , Proteínas do Envelope Viral/genética , Hepatite C/genética , Anticorpos Monoclonais
18.
PLoS One ; 17(11): e0277987, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36399489

RESUMO

BACKGROUND: The rising prevalence of hepatitis C virus (HCV) infection and the availability of direct acting antivirals for HCV treatment has prompted a public health goal of HCV eradication. Despite the availability of treatment for HCV, treatment programs have generally excluded pregnant individuals. Our objective was to query patients and clinicians to identify barriers to including pregnant individuals in HCV treatment programs. METHODS AND FINDINGS: This qualitative investigation included obstetricians and previously/currently pregnant individuals with HCV. Participants completed interviews regarding knowledge of and attitudes towards HCV treatment and perceived barriers to treatment during pregnancy. Data were analyzed using the constant comparative method. Obstetricians (N = 18) and patients (N = 21) described concerns about equity, access, and cost. Both expressed uncertainty about safety and confirmed a need for clinician education. Obstetricians emphasized the lack of professional guidelines. Although some clinicians expressed concern about patient adherence and engagement, patients were largely desirous of treatment; both groups identified potential benefits of antenatal treatment. CONCLUSIONS: Both patients and obstetricians were generally receptive to HCV treatment in pregnancy and recognized pregnancy as an important window of opportunity for treatment. Our findings suggest the need for further research on maternal-fetal safety of HCV treatment as well as on interventions to ensure fair and appropriate access to HCV treatment for pregnant individuals.


Assuntos
Hepatite C Crônica , Hepatite C , Humanos , Estados Unidos , Feminino , Gravidez , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C/tratamento farmacológico , Hepacivirus , Cooperação do Paciente
19.
Sci Rep ; 12(1): 19925, 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36402865

RESUMO

Although the smoking rate of human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infected people was much higher than that of the general population, smoking cessation interventions have long been ineffective. We aimed to examine the estimates of prevalence, time-trend, and association of smoking among people living with HIV, HBV, or HCV. This cohort was composed of 32,115 individuals from the NHANES database (1999-2018) and they were collected in the US. The time trend analysis of smoking and quitting rates was conducted using different years of survey follow-up and different infected groups. Multivariable logistic regression analysis was used to identify the risk factors related to smoking behavior of these infected people. Compared to non-infected smokers, infected smokers were more likely to be older (aged 30-39, OR = 9.92, CI 6.07-16.21; aged 40-49,OR = 3.51, CI 2.49-4.94), males (1.99, 1.54-2.55), lower education and economic level (1.78, 1.39-2.29; 2.05, 1.59-2.65), unemployed (1.63, 1.21-2.20), suffering depression (1.35, 1.05-1.72), and drug users (7.65, 5.04-11.59). Taken together, our study showed that these complex psychosocial characteristics and unhealthy behavioral factors might be major independent risk factors for increasing smoking rate and decreasing smoking cessation rate among these infected people.


Assuntos
Infecções por HIV , Hepatite C , Humanos , Adulto , Masculino , Hepacivirus , Vírus da Hepatite B , Prevalência , Inquéritos Nutricionais , Hepatite C/epidemiologia , Hepatite C/complicações , Fumar/epidemiologia , Fumar/psicologia , Infecções por HIV/complicações
20.
Sci Rep ; 12(1): 19528, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376416

RESUMO

NOD-like receptor pyrin domain containing 3 (NLRP3) is a microbial and danger signal sensor that acts as a regulator of inflammation via activation of Caspase-1 (CASP1) and has been identified as a major contributor to human liver diseases. The present study was conducted to investigate the association between NLRP3 and the progression of hepatitis C virus (HCV)-related liver disease. Serum NLRP3 levels were analyzed in 49 patients with chronic HCV infection and 18 healthy controls and liver tissues from 34 patients were examined to assess the protein expression of NLRP3 and its activation marker CASP1 using immunohistochemical staining. The results showed that the median serum NLRP3 levels was significantly higher in HCV-infected patients compared with healthy controls (1040 pg/ml vs 695 pg/ml respectively, P < 0.001) and were positively correlated with hepatic NLRP3 and CASP1 expression (r = 0.749, P < 0.001 and r = 0.557, P = 0.001 respectively). The NLRP3 levels in serum and the liver significantly increased with worsening liver pathology and showed positive correlations with serum aminotransferases levels, HCV viremia, and albumin-bilirubin score (P < 0.05). The receiver operating characteristic curve analysis revealed a high diagnostic performance of serum NLRP3 in determining the extent of liver necroinflammation, fibrosis, and steatosis (area under the curve = 0.951, 0.971, and 0.917 respectively, P < 0.001). In conclusion, NLRP3 plays an important role in liver disease progression during HCV infection via CASP1 activation and might be a promising therapeutic target. Serum NLRP3 could be an additional biomarker for liver inflammation and fibrosis.


Assuntos
Hepacivirus , Hepatite C Crônica , Humanos , Caspase 1/metabolismo , Fibrose , Hepacivirus/metabolismo , Inflamassomos/metabolismo , Fígado/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismo , Domínio Pirina
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