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1.
J Viral Hepat ; 26(9): 1040-1049, 2019 09.
Article in English | MEDLINE | ID: mdl-30972912

ABSTRACT

In a multicentre, genome-wide association study to identify host genetic factors associated with treatment response in adult chronic hepatitis B patients, genotype data were obtained by microarray analysis from 1669 patients who received peginterferon alfa-2a for ≥ 24 weeks with/without a nucleos(t)ide analog. Treatment response was assessed at least 24 weeks post-treatment, using serological and/or virological endpoints. Thirty-six single-marker analyses and a gene-by-gene analysis were conducted. No single nucleotide polymorphisms (SNPs) achieved genome-wide significance (P < 5 × 10-8 ) in single-marker analyses, but suggestive associations (P < 1 × 10-5 ) were identified for 116 SNPs. In gene-by-gene analyses, one gene, FCER1A (rs7549785), reached genome-wide significance (P = 2.65 × 10-8 ) in East Asian patients for hepatitis B surface antigen (HBsAg) clearance, with a moderate effect size (odds ratio = 4.74). Eleven of 44 carriers (25%) of the A allele at rs7549785 achieved HBsAg clearance compared with 69/1051 (7%) noncarriers. FCER1A encodes the alpha subunit of the immunoglobulin E receptor. In a post hoc analysis of a homogenous patient subset, the strongest intragenic association was for rs7712322 (POLR3G, P = 7.21 × 10-7 ). POLR3G encodes the G subunit of the polymerase (RNA) III enzyme, involved in sensing and limiting infection by intracellular bacteria and DNA viruses, and as a DNA sensor in innate immune responses. FCER1A (rs7549785) and possibly POLR3G (rs7712322) are shown to be associated with peginterferon alfa-2a response in adult patients with chronic hepatitis B. Independent confirmation of these findings is warranted (clinicaltrials.gov number NCT01855997).


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis B Surface Antigens/immunology , Hepatitis B, Chronic/ethnology , Hepatitis B, Chronic/genetics , Interferon-alpha/therapeutic use , Polyethylene Glycols/therapeutic use , Receptors, IgE/genetics , Adult , Alleles , Asian People , Drug Therapy, Combination , Female , Genetic Variation , Genome-Wide Association Study , Hepatitis B, Chronic/drug therapy , Humans , Male , Microarray Analysis , Middle Aged , Polymorphism, Single Nucleotide , RNA Polymerase III/genetics , Receptors, IgE/immunology , Recombinant Proteins/therapeutic use
2.
Liver Int ; 38(5): 842-850, 2018 05.
Article in English | MEDLINE | ID: mdl-28963781

ABSTRACT

BACKGROUND & AIMS: Chronic hepatitis D (delta) is a major global health burden. Clinical and virological characteristics of patients with hepatitis D virus (HDV) infection and treatment approaches in different regions world-wide are poorly defined. METHODS: The Hepatitis Delta International Network (HDIN) registry was established in 2011 with centres in Europe, Asia, North- and South America. Here, we report on clinical/ virological characteristics of the first 1576 patients with ongoing or past HDV infection included in the database until October 2016 and performed a retrospective outcome analysis. The primary aim was to investigate if the region of origin was associated with HDV replication and clinical outcome. RESULTS: The majority of patients was male (n = 979, 62%) and the mean age was 36.7 years (range 1-79, with 9% of patients younger than 20 years). Most patients were HBeAg-negative (77%) and HDV-RNA positive (85%). Cirrhosis was reported in 48.7% of cases which included 13% of patients with previous or ongoing liver decompensation. Hepatocellular carcinoma (HCC) developed in 30 patients (2.5%) and 44 (3.6%) underwent liver transplantation. Regions of origin were independently associated with clinical endpoints and detectability of HDV RNA. Antiviral therapy was administered to 356 patients with different treatment uptakes in different regions. Of these, 264 patients were treated with interferon-a and 92 were treated with HBV-Nucs only. CONCLUSIONS: The HDIN registry confirms the severity of hepatitis delta but also highlights the heterogeneity of patient characteristics and clinical outcomes in different regions. There is an urgent need for novel treatment options for HDV infection.


Subject(s)
Antiviral Agents/administration & dosage , Carcinoma, Hepatocellular/epidemiology , Hepatitis D/epidemiology , Hepatitis Delta Virus/genetics , Liver Neoplasms/epidemiology , Adolescent , Adult , Aged , Carcinoma, Hepatocellular/surgery , Child , Child, Preschool , Cross-Sectional Studies , Female , Genetic Heterogeneity , Hepatitis B Surface Antigens/blood , Hepatitis D/complications , Hepatitis D/drug therapy , Humans , Infant , Internationality , Liver/pathology , Liver Cirrhosis/epidemiology , Liver Neoplasms/surgery , Liver Transplantation , Logistic Models , Male , Middle Aged , Registries , Retrospective Studies , Young Adult
3.
J Hepatol ; 64(1): 19-28, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26321288

ABSTRACT

BACKGROUND & AIMS: Telaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin (OBV/PTV/r+DSV±RBV) and TPV+PegIFN/RBV. METHODS: Treatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r+DSV+weight-based RBV, OBV/PTV/r+DSV (treatment-naïve, GT1b-infected patients only), or 12weeks of TPV+PegIFN+weight-based RBV and 12-36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies. RESULTS: Three hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r+DSV+RBV, OBV/PTV/r+DSV, and TPV+PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. Rates of discontinuation due to adverse events (0-1% and 8-11%, respectively, p<0.05) and rates of hemoglobin decline to <10g/dl (0-4% and 34-47%, respectively, p<0.05) were lower for OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. CONCLUSIONS: Among non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97-99% with 12week, multi-targeted OBV/PTV/r+DSV±RBV regimens and 66-82% with 24-48 total weeks of TPV+PegIFN/RBV. OBV/PTV/r+DSV±RBV was associated with a generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.


Subject(s)
Anilides/administration & dosage , Antiviral Agents/administration & dosage , Carbamates/administration & dosage , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Macrocyclic Compounds/administration & dosage , Sulfonamides/administration & dosage , Uracil/analogs & derivatives , 2-Naphthylamine , Adult , Aged , Anilides/adverse effects , Carbamates/adverse effects , Cyclopropanes , Drug Therapy, Combination , Female , Genotype , Hepacivirus/classification , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Lactams, Macrocyclic , Macrocyclic Compounds/adverse effects , Male , Middle Aged , Polyethylene Glycols/administration & dosage , Proline/analogs & derivatives , Recombinant Proteins/administration & dosage , Sulfonamides/adverse effects , Uracil/administration & dosage , Uracil/adverse effects , Valine
4.
J Gastrointestin Liver Dis ; 24(4): 413-21, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26697566

ABSTRACT

BACKGROUND: Hepatitis delta virus (HDV) infection is associated with accelerated progression of fibrosis, early occurrence of hepatic decompensation and an increased risk for hepatocellular carcinoma. Epidemiological data on hepatitis delta virus (HDV) in Romania are still lacking. AIM: To assess the prevalence, virological, clinical and epidemiological features of HDV infection in Romanian patients. METHODS: We conducted a multicenter study in 10 centers. Data on sociodemographic characteristics and potential risk factors were collected through a questionnaire. Virological markers of HBV and HDV infection, biochemical and clinical features of liver disease were evaluated. RESULTS: The study population comprised 2,761 HBsAg(+) patients with a mean age of 43.8+/-13.8 years, out of whom 5.2% were HBeAg(+) and 55.7% were males. Liver cirrhosis was detected in 17.9% of patients, while 80.4% had chronic hepatitis. The prevalence of IgG anti-HDV(+) patients was 23.1%, out of whom 16.4% were HDV RNA positive. The highest prevalence of HDV infection was encountered in patients aged 50-59 years (28.9%) and patients aged >/= 60 (24.8%) (p=0.0001). Seroprevalence of HDV was significantly higher in AgHBs(+) cirrhotics vs. noncirrhotics (43.4% vs 19.0%, p=0.0001). Risk factors for HDV infection were: occupational hazard, no HCV chronic infection, lack of anti-HBV vaccination, presence of blood transfusions, any previous surgery, frequent hospitalization or endoscopies, tattoos, body piercing, use of glass syringes, number of female sexual partners. CONCLUSIONS: HBsAg(+) population in Romania is characterized by a high prevalence of HBeAg(-) HBV infection as well as HDV co-infection. A cohort phenomenon for HDV prevalence is also observed similar to that of HCV/HBV monoinfections.


Subject(s)
Coinfection , Hepatitis B, Chronic/epidemiology , Hepatitis D/epidemiology , Adolescent , Adult , Biomarkers/blood , Female , Hepatitis B Surface Antigens/blood , Hepatitis B e Antigens/blood , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/transmission , Hepatitis B, Chronic/virology , Hepatitis D/diagnosis , Hepatitis D/transmission , Hepatitis D/virology , Hepatitis Delta Virus/isolation & purification , Humans , Liver Cirrhosis/diagnosis , Liver Cirrhosis/epidemiology , Liver Cirrhosis/virology , Male , Middle Aged , Prevalence , Risk Factors , Romania/epidemiology , Seroepidemiologic Studies , Young Adult
5.
Roum Arch Microbiol Immunol ; 74(1-2): 18-25, 2015.
Article in English | MEDLINE | ID: mdl-26727850

ABSTRACT

Chronic hepatitis B is widespread and represents an important cause of morbidity and mortality due to the evolution to cirrhosis and hepatocellular carcinoma. This study was designed to improve the national laboratory surveillance of hepatitis B virus (HBV) infection, focusing on genomic analysis of isolates from Romanian patients. Sera from ten patients with HBV were collected and analyzed. Phylogenetic analysis was conducted on a DNA fragment spanning almost the entire genome. The occurrence of mutations was assessed for each open reading frame in the viral genome. Phylogenetic analysis revealed five isolates belonging to genotype A (subgenotype A2) and other five clustering with genotype D strains (subgenotype D1). Two patients treated with lamivudine were found to carry isolates harboring rtM204V lamivudine resistance mutation. An HBV isolate displaying a lamivudine complex resistance pattern, rtM204I in conjunction with rtL180M and rtA200V, was found in a lamivudine naïve patient. All samples harbored sA105P substitution, usually found in HBIg therapy escape isolates. Three of the studied strains were simultaneously displaying T1753, T1762 and A1764 mutations which in vitro induce enhanced genome replication and reduction of HBeAg expression. The sequence obtained from a patient with decompensated liver cirrhosis presents a novel type of insertion consisting of nine nucleotides between positions 260 and 261 in the X gene. Despite the small number of samples, our findings suggest the need to determine the drug resistance pattern for each patient before taking a therapeutic decision and also highlight the necessity of knowing the real level of drug resistance among HBV strains circulating in Romania.


Subject(s)
Hepatitis B virus/genetics , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/virology , Adult , Aged , Antiviral Agents/administration & dosage , Female , Genome, Viral , Genomics , Genotype , Hepatitis B virus/classification , Hepatitis B, Chronic/drug therapy , Humans , Male , Middle Aged , Molecular Sequence Data , Mutation , Phylogeny , Romania , Tenofovir/administration & dosage , Young Adult
6.
J Gastrointestin Liver Dis ; 23(1): 45-50, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24689096

ABSTRACT

BACKGROUND: A number of high quality randomized clinical trials examining the efficacy and safety of triple therapy in genotype-1 HCV-infected patients have been published. However, these trials included a small number of patients with advanced fibrosis, and selected a population different from that in real-world settings. AIM: To determine the efficacy of boceprevir, pegInterferon and ribavirin regimen in genotype-1 treatment-experienced HCV-infected patients with cirrhosis and bridging fibrosis in real-life setting. METHOD: 167 treatment-experienced patients (85.6% relapsers) out of which 33.5% had cirrhosis, with a mean age of 52.6 years, registered in the Romanian Name Patient Program Database were included into the study. RESULTS: 16.7% of patients had a viral load >100 IU/mL. Undetectable HCV RNA was encountered in 77.3% of patients at week 12. Multiple logistic regression analysis revealed the following independent predictors, measured at week 8, for an HCV RNA ≥100 IU/mL at week 12 of triple therapy: alanine aminotransferase values (p=0.01), hemoglobin level (p=0.04) and <2 log drop of viral load (p<0.0001). A stopping score at 8 weeks was created as the sum of these 3 parameters, with a total of 4 possible points. AUROC of this score was 0.84, with a sensitivity of 75% and a specificity of 86.2%. CONCLUSION: Triple therapy in this cohort of real-life genotype-1 HCV-infected patients with advanced fibrosis showed robust early virological response (EVR) rates. A week 8 model predicting lack of EVR was created, with good clinical utility that can be validated in prospective larger cohorts.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/virology , Proline/analogs & derivatives , Adolescent , Adult , Aged , Antiviral Agents/adverse effects , Drug Therapy, Combination , Female , Genotype , Hepacivirus/classification , Hepacivirus/genetics , Hepacivirus/isolation & purification , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/virology , Humans , Interferon alpha-2 , Interferon-alpha/adverse effects , Interferon-alpha/therapeutic use , Male , Middle Aged , Prognosis , Proline/adverse effects , Proline/therapeutic use , Prospective Studies , RNA, Viral/blood , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Ribavirin/adverse effects , Ribavirin/therapeutic use , Treatment Outcome , Viral Load , Young Adult
7.
Roum Arch Microbiol Immunol ; 68(3): 151-7, 2009.
Article in English | MEDLINE | ID: mdl-20361535

ABSTRACT

Accurate genotyping of hepatitis C virus (HCV) has clinical implications for treatment orientation and epidemiological impact in tracing the contamination sources. The aim of the study was to compare a genotyping assay by restriction fragment length polymorphism (RFLP) in the HCV 5'untranslated region (5'UTR) with sequencing in the 5'untranslated and NS5B regions. One hundred and three samples, collected between 2004 and 2006 from chronically infected patients with HCV, were tested with the 5'UTR and NS5B protocols. Of the total number of the samples tested by the 5'UTR-RFLP assay (n=103) the HCV subtype could be inferred by this method for 92 samples, by 5'UTR sequencing for 16 samples out of 23 tested (n=23) and by using the NS5B sequencing for all the samples tested (n=34). Our results showed that the HCV genotype distribution in Romania is: 1b--86.4%, 1a--10.7% and 4a--2.9%. In conclusion, RFLP screening in the 5'UTR is a convenient method for HCV genotyping and discrimination between 1b and non-1b genotypes but has a poor resolving power for subtyping and evaluation of the transmission routes. Sequencing in NS5B region is more adapted than RFLP and sequencing in 5'UTR for subtyping and epidemiological investigation.


Subject(s)
Hepacivirus/genetics , Hepatitis, Chronic/virology , 5' Untranslated Regions , Genotype , Hepacivirus/isolation & purification , Hepatitis, Chronic/blood , Humans , Phylogeny , Polymorphism, Restriction Fragment Length , RNA, Viral/chemistry , RNA, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction , Romania , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics
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