RESUMO
Hepatitis B (HBV) and delta (HDV) viruses are endemic in the Amazon region, but vaccine coverage against HBV is still limited. People who use illicit drugs (PWUDs) represent a high-risk group due to common risk behavior and socioeconomic factors that facilitate the acquisition and transmission of pathogens. The present study assessed the presence of HBV and HBV-HDV co-infection, identified viral sub-genotypes, and verified the occurrence of mutations in coding regions for HBsAg and part of the polymerase in HBV-infected PWUDs in municipalities of the Brazilian states of Amapá and Pará, in the Amazon region. In total, 1074 PWUDs provided blood samples and personal data in 30 municipalities of the Brazilian Amazon. HBV and HDV were detected by enzyme-linked immunosorbent assay and polymerase chain reaction. Viral genotypes were identified by nucleotide sequencing followed by phylogenetic analysis, whereas viral mutations were analyzed by specialized software. High rates of serological (32.2%) and molecular (7.2%) markers for HBV were detected, including cases of occult HBV infection (2.5%). Sub-genotypes A1, A2, D4, and F2a were most frequently found. Escape mutations due to vaccine and antiviral resistance were identified. Among PWUDs with HBV DNA, serological (19.5%) and molecular (11.7%) HDV markers were detected, such as HDV genotypes 1 and 3. These are worrying findings, presenting clear implications for urgent prevention and treatment needs for the carriers of these viruses.
Assuntos
Hepatite B/genética , Hepatite D/genética , Transtornos Relacionados ao Uso de Substâncias/virologia , Adulto , Brasil/epidemiologia , Coinfecção , Estudos Transversais , DNA Viral/genética , Usuários de Drogas , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Genótipo , Hepatite B/diagnóstico , Antígenos de Superfície da Hepatite B/análise , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Hepatite D/diagnóstico , Vírus Delta da Hepatite/genética , Vírus Delta da Hepatite/patogenicidade , Humanos , Drogas Ilícitas , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular/métodos , Filogenia , RNA Viral/genética , Análise de Sequência de DNA/métodosRESUMO
The treatment for hepatitis Delta virus (HDV) still consists of Pegylated interferon (PEG-IFN) combined with inhibitors of Hepatitis B virus (HBV) replication. In some patients may be occur a virological response, which means a negative HDV RNA 6 months after stopping treatment. In this study it was conducted an in vitro approach with the aim to mimic possible immunological events that are observed in patients responding to PEG-IFN therapy. Jurkat cells (human T lymphocyte cell line) were employed alone or co-cultured with THP-1 (human monocytic cell line) and stimulated with controls and HBV Surface Antigen (HBsAg), Small-Delta Antigen (SHDAg), and HBsAg + SHDAg combined. Twenty-four hours stimulation with SHDAg and/or HBSAg led to a toxic profile in a co-culture condition and cell supernatants were collected for cytokines quantification. PEG-IFN was added and cells were incubated for additional 24 h. Co-cultured cells incubated with the association (SHDAg + PEG-IFN) significantly produced levels of IFN-γ, IL-2 and IL-12. On the other hand, the HBsAg alone was able to inhibit the production of IFN-γ, suggesting that this antigen may hinder the treatment exclusively with PEG-IFN.
Assuntos
Antivirais/farmacologia , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Hepatite D/tratamento farmacológico , Vírus Delta da Hepatite/imunologia , Interferons/farmacologia , Polietilenoglicóis/farmacologia , Técnicas de Cocultura , Antígenos de Superfície da Hepatite B/farmacologia , Hepatite D/imunologia , Hepatite D/metabolismo , Hepatite D/virologia , Vírus Delta da Hepatite/patogenicidade , Antígenos da Hepatite delta/farmacologia , Interações Hospedeiro-Patógeno , Humanos , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-2/metabolismo , Células Jurkat , Transdução de Sinais , Células THP-1RESUMO
Hepatitis D virus (HDV) genotype III is endemic in the western Amazon basin and is considered to cause the most severe form of chronic viral hepatitis. Recently, noninvasive fibrosis scores to determine the stage of liver fibrosis have been evaluated in individuals positive for HDV genotype I, but their utility in HDV genotype III-positive patients is unknown. In this retrospective study conducted in an outpatient viral hepatitis referral clinic in the Brazilian Amazon region, the aspartate aminotransferase (AST) to Aspartate aminotransferase to Platelet Ratio Index (APRI) and Fibrosis Index for Liver Fibrosis (FIB-4) values were calculated and compared with histological fibrosis stages. Among the 50 patients analyzed, the median age at liver biopsy was 35.6 years, 66% were male, and all had compensated liver disease. Histological staging revealed fibrosis stages 0, 1, 2, 3, and 4 in four (8%), eight (16%), 11 (22), 11 (22%), and 16 (32%) patients, respectively. The area under the receiver operating curve (AUROC) of AST-to-alanine aminotransferase (ALT) ratio, APRI, and FIB-4 for detection of significant fibrosis (F ≥ 2) was 0.550 (P = 0.601), 0.853 (P < 0.001), and 0.853 (P < 0.0001), respectively. Lower AUROC values were obtained for cirrhosis: the AST-to-ALT ratio was 0.640 (P = 0.114), APRI was 0.671 (P = 0.053), and FIB-4 was 0.701 (P = 0.023). The optimal cutoff value for significant fibrosis for APRI was 0.708 (sensitivity 84% and specificity 92%) and for FIB-4 was 1.36 (sensitivity 76% and specificity 92%). Aspartate aminotransferase to Platelet Ratio Index and FIB-4 were less useful to predict cirrhosis. In contrast to recent reports from Europe and North America, both APRI and FIB-4 may identify significant fibrosis in HDV-III-infected patients from northwestern Brazil.
Assuntos
Vírus da Hepatite B/patogenicidade , Hepatite B/diagnóstico , Hepatite D/diagnóstico , Vírus Delta da Hepatite/patogenicidade , Cirrose Hepática/diagnóstico , Adulto , Alanina Transaminase/metabolismo , Área Sob a Curva , Aspartato Aminotransferases/metabolismo , Biomarcadores/análise , Plaquetas/patologia , Plaquetas/virologia , Brasil , Doença Crônica , Coinfecção , Feminino , Hepatite B/enzimologia , Hepatite B/patologia , Hepatite B/virologia , Hepatite D/enzimologia , Hepatite D/patologia , Hepatite D/virologia , Humanos , Cirrose Hepática/enzimologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Contagem de Plaquetas , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: The study aimed to evaluate the prevalence and predictor factors for compensated advanced chronic liver disease (c-ACLD) in patients with hepatitis Delta virus (HDV) infection. METHODS: This cross-sectional study included consecutive HDV-infected patients defined by positive anti-HDV. Patients with hepatitis C coinfection, liver transplantation or presence of conditions that limit liver (LSM) or spleen stiffness measurement (SSM) were excluded. Blood tests, abdominal ultrasound, SSM and LSM by transient elastography (FibroScan®) were performed at the same day. Alcohol consumption was quantified using the AUDIT score and c-ACLD was defined by LSM ≥ 15 kPa performed by an experimented operator blinded for clinical and laboratory data. RESULTS: 101 patients were eligible and few patients were excluded due to negative anti-HDV (n = 7), hepatitis C coinfection (n = 2), liver transplantation (n = 10) and limitation for LSM or SSM (n = 5). Therefore, 77 patients [61% male, age = 43 (IQR,36-52) years] were included. The prevalence of c-ACLD was 57% (n = 44/77). Patients with c-ACLD had a higher rate of detectable HBV viral load (p = 0.039), higher levels of transaminases, GGT, alkaline phosphatases, total bilirubin and INR (p<0.001 for all), as well as lower platelet count and albumin levels (p>0.001 for both) compared to those without c-ACLD. Patients with c-ACLD had higher SSM [65.2 (IQR,33.8-75.0) vs 21.8 (16.5-32.0) kPa; p<0.001] and higher splenic volume [475 (IQR,311-746) vs 154 (112-283) cm3; p<0.001] compared to those without. Detectable HBV viral load (>10 UI/ml), alkaline phosphatase (per IU/L) and GGT levels (per IU/L) were independently associated with c-ACLD in all multivariate models. Splenic volume [per cm3,OR = 1.01 (95%CI,1.01-1.02);p = 0.002], SSM [per kPa, OR = 1.04 (1.01-1.07);p = 0.012] and splenomegaly [yes vs no,OR = 28.45 (4.42-182.95);p<0.001] were independently associated with c-ACLD. CONCLUSIONS: The prevalence of c-ACLD was high in patients with chronic HDV infection in western Amazon basin. HBV viral load, liver enzymes and splenic features can be used to predict severe liver disease in HDV-infected patients.
Assuntos
Hepatite D Crônica/epidemiologia , Hepatite D Crônica/virologia , Hepatopatias/virologia , Adulto , Coinfecção/epidemiologia , Coinfecção/virologia , Estudos Transversais , Feminino , Hepacivirus/patogenicidade , Anticorpos Anti-Hepatite/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/virologia , Hepatite C/epidemiologia , Hepatite C/virologia , Vírus Delta da Hepatite/patogenicidade , Humanos , Fígado/virologia , Testes de Função Hepática/métodos , Masculino , Pessoa de Meia-Idade , Prevalência , Carga Viral/métodosRESUMO
UNLABELLED: The hepatitis delta virus (HDV) is a hepatotropic subvirus that is dependent on the hepatitis B virus (HBV) and supplies the viral envelope containing the surface antigen of hepatitis B. Viral genetic diversity is related to the geographical origin of the isolates, and there are at least eight genotypes that are referred to as HDV-1 through HDV-8. HDV-3 is responsible for epidemics of severe and fulminant hepatitis, which are common in northeastern South America. HDV-3 is prevalent in the Brazilian Amazon and is associated with the increased aggressiveness of HDV infections. Although isolated, the characteristics of the clinical presentation of HDV-1 in the Amazon region have not yet been clearly reported. OBJECTIVE: This study aims to assess the genotypic and clinical characteristics of individuals with the HDV-1 genotype in the western Amazon region. METHODS: The HDV was genotyped by nested PCR-RFLP and sequencing from serum samples of 56 patients with HBV/HDV infection. The genotypes were correlated with the clinical characteristics presented by patients with HBV/HDV infection. RESULTS: A prevalence of 92.3% for the HDV-3 genotype (n = 48) and 7.6% (n = 4) for the HDV-1 genotype was observed. CONCLUSION: To date, this is the most extensive clinical study of HDV-1 genotype infections in the nonindigenous population of Western Amazonia.
Assuntos
Hepatite B/epidemiologia , Hepatite D/epidemiologia , Vírus Delta da Hepatite/genética , Vírus Delta da Hepatite/isolamento & purificação , Animais , Brasil , Feminino , Variação Genética , Genótipo , Hepatite B/virologia , Vírus da Hepatite B/genética , Hepatite D/virologia , Vírus Delta da Hepatite/classificação , Vírus Delta da Hepatite/patogenicidade , Humanos , Masculino , Filogenia , Polimorfismo de Fragmento de Restrição , Prevalência , Análise de Sequência de DNARESUMO
Hepatitis delta is an inflammatory liver disease caused by infection with HDV. HDV is a single-stranded circular RNA pathogen with a diameter of 36 nm. HDV is classified in the genus Deltavirus and is still awaiting a final taxonomic classification up to the family level. HDV shares similarities with satellite RNA and viroids including a small circular single-stranded RNA with secondary structure that replicates through the 'double rolling circle' mechanism. The HDV RNA genome is capable of self-cleavage through a ribozyme and encodes only one structural protein, the hepatitis delta antigen (HDAg), from the antigenomic RNA. There are two forms of HDAg, a shorter (S; 22 kDa) and a longer (L; 24 kDa) form, the latter generated from an RNA editing mechanism. The S form is essential for viral genomic replication. The L form participates in the assembly and formation of HDV. For complete replication and transmission, HDV requires the hepatitis B surface antigen (HBsAg). Thus, HDV infection only occurs in HBsAg-positive individuals, either as acute coinfection in treatment-naive HBV-infected persons, or as superinfection in patients with pre-existing chronic hepatitis B (CHB). HDV is found throughout the world, but its prevalence, incidence, clinical features and epidemiological characteristics vary by geographic region. There are eight genotypes (1 to 8) distributed over different geographic areas: HDV-1 is distributed worldwide, whereas HDV-2 to 8 are seen more regionally. Levels of HDV viraemia change over the course of HDV infection, being significantly higher in patients with early chronic hepatitis than in cirrhosis. Chronic HDV infection leads to more severe liver disease than chronic HBV monoinfection with an accelerated course of fibrosis progression, an increased risk of hepatocellular carcinoma and early decompensation in the setting of established cirrhosis. Current treatments include pegylated interferon-α and liver transplantation; the latter of which can be curative. Further studies are needed to develop better treatment strategies for this challenging disease.
Assuntos
Hepatite D/terapia , Hepatite D/virologia , Vírus Delta da Hepatite/genética , Vírus Delta da Hepatite/fisiologia , Coinfecção , Genótipo , Hepatite B/complicações , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/genética , Hepatite D/diagnóstico , Vírus Delta da Hepatite/patogenicidade , Vírus Delta da Hepatite/ultraestrutura , Antígenos da Hepatite delta/química , Antígenos da Hepatite delta/genética , Antígenos da Hepatite delta/metabolismo , Humanos , Transplante de Fígado , Filogenia , RNA Viral/química , RNA Viral/genética , RNA Viral/metabolismo , Vírus Satélites/genética , Vírus Satélites/patogenicidade , Replicação ViralAssuntos
Vírus da Hepatite B/patogenicidade , Hepatite B/epidemiologia , Hepatite D/epidemiologia , Vírus Delta da Hepatite/patogenicidade , África/epidemiologia , Ásia/epidemiologia , Brasil/epidemiologia , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , DNA Viral/genética , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Hepatite D/complicações , Vírus Delta da Hepatite/genética , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Reação em Cadeia da Polimerase , Estudos Prospectivos , RNA Viral/genética , Estudos Retrospectivos , Turquia/epidemiologia , Replicação ViralRESUMO
En esta revisión se describen los virus hepatotropos actualmente conocidos, su epidemiología con referencia especial a los datos nacionales relativos a los virus A, B, C y E; su historia natural y sus aspectos clínicos más relevantes. Se enfatizan, además los diferentes marcadores virales serológicos, para el diagnóstico de infección aguda o crónica. Se incluyen también los diferentes tratamientos y las medidas de prevención (pasivas o activas) recomendadas actualmente