PARK2 polymorphisms predict disease progression in patients infected with hepatitis C virus.

 Background. The protein encoded by PARK2 gene is a component of the ubiquitin-proteasome system that mediates targeting of proteins for the degradation pathway. Genetic variations at PARK2 gene were linked to various diseases including leprosy, typhoid and cancer. The present study investigated the association of single nucleotide polymorphisms (SNPs) in the PARK2 gene with the development of hepatitis C virus (HCV) infection and its progression to severe liver diseases. MATERIAL AND METHODS: A total of 800 subjects, including 400 normal healthy subjects and 400 HCV-infected patients, were analyzed in this study. The patients were classified as chronic HCV patients (group I), patients with cirrhosis (group II) and patients with hepatocellular carcinoma (HCC) in the context of cirrhosis (group III). DNA was extracted and was genotyped for the SNPs rs10945859, rs2803085, rs2276201 and rs1931223. RESULTS: Among these SNPs, CT genotype of rs10945859 was found to have a significant association towards the clinical progression of chronic HCV infection to cirrhosis alone (OR = 1.850; 95% C. I. 1.115-3.069; p = 0.016) or cirrhosis and HCC (OR = 1.768; 95% C. I. 1.090-2.867; p value = 0.020). CONCLUSION: SNP rs10945859 in the PARK2 gene could prove useful in predicting the clinical outcome in HCV-infected patients.

Genetic variability of the core protein in hepatitis C virus genotype 4 in Saudi Arabian patients and its implication on pegylated interferon and ribavirin therapy.

BACKGROUND: Hepatitis C virus (HCV) shows a remarkable genetic diversity, contributing to its high persistence and varied susceptibilities to antiviral treatment. Previous studies have reported that the substitution of amino acids in the HCV subgenotype 1b core protein in infected patients is associated with a poor response to pegylated interferon and ribavirin (PEG-IFN/RBV) combined therapy. OBJECTIVES: Because the role of the core protein in HCV genotype 4 infections is unclear, we aimed in this study to compare the full-length core protein sequences of HCV genotype 4 between Saudi patients who responded (SVR) and did not respond (non-SVR) to PEG-IFN/RBV therapy. STUDY DESIGN: Direct sequencing of the full-length core protein and bioinformatics sequence analysis were utilized. RESULTS: Our data revealed that there is a significant association between core protein mutations, particularly at position 70 (Arg70Gln), and treatment outcome in HCV subgenotype 4d patients. However, HCV subgenotype 4a showed no significant association between core protein mutations and treatment outcome. In addition, amino acid residue at position 91 was well-conserved among studied patients where Cys91 is the dominant amino acid residue. CONCLUSIONS: These findings provide a new insight into HCV genotype 4 among affected Saudi population where the knowledge of HCV core gene polymorphisms is inadequate.

Genetic variation in interleukin 28B and correlation with chronic hepatitis B virus infection in Saudi Arabian patients.

BACKGROUND & AIMS: Several genome-wide association studies have shown that genetic variations in the chromosomal region containing interleukin-28B (IL28B) gene are associated with response to treatment in hepatitis C virus (HCV) infection. This study was conducted to examine the role of genetic variations in IL28B on disease progression in Saudi Arabian patients chronically infected with hepatitis B virus (HBV). METHODS: The study included 1128 subjects divided into four categories; 304 clearance subjects, 518 inactive carriers, 212 active carriers and 94 cirrhosis/HCC. RESULTS: Three single nucleotide polymorphisms (SNPs), rs12979860 (OR=1.307; 95% CI 1.046-1.634, χ2=5.57 and P=0.0183), rs12980275 (OR=0.642; CI 0.517-0.798, χ2=16.17 and P=0.0001) and rs8105790 (OR=0.746; CI 0.592-0.941, χ2=6.12 and P=0.0133), were found to be strongly associated with HBV clearance. The frequency of the G allele of rs12980275 and the C allele of rs8105790 were found to be more in clearance group than in patients and could contribute to protection against the disease. On the other hand, only rs12979860 showed significant difference in distribution when inactive group was compared to other groups (OR=1.285; CI 1.030-1.603, χ2=4.95, P=0.0261). No significant association was evident for any of the variants when active carriers were compared to cirrhosis/HCC patients. Haplotype analysis showed that a combination of A-T-T-G of rs12980275, rs8105790, rs8099917, and rs7248668, respectively, was associated with clearance of the virus (frequency=67.5% and P=0.015). CONCLUSION: genetic variations in IL28B gene region may influence the clearance of HBV infection.

Variations in DEPDC5 gene and its association with chronic hepatitis C virus infection in Saudi Arabia.

BACKGROUND: Variations at DEPDC5 gene have been recently reported as genetic markers associated with hepatocellular carcinoma (HCC) progression in chronic HCV-infected patients. This study was conducted to assess the association of DEPDC5 variants with advanced liver cirrhosis and HCC development among chronic HCV-infected patients in Saudi Arabian population. METHODS: Six-hundred and one HCV-infected patients were genotyped for DEPDC5 polymorphisms (rs1012068 and rs5998152), in comparison with 592 non-infected healthy control subjects. The allelic frequency and genotype distribution of both DEPDC5 polymorphisms were determined followed by haplotype frequency estimation and multiple logistic regression analysis. RESULTS: The frequency of the risk alleles of both rs1012068 and rs5998152 was shown to be more in healthy control subjects than in patients (p = 0.0001, OR = 0.704, CI = 0.591-0.839; p = 0.002, OR = 0.761, CI = 0. 0.639-0.907, respectively). Also, our results revealed that GT for SNP rs1012068 (OR =1.715; 95% CI 1.132-2.597; p = 0.0104) and CT for SNP rs5998152 (OR = 1.932; 95% CI 1.276-2.925; p = 0.0017) showed significant association with development of cirrhosis compared with the GG and CC genotypes, respectively. The data also revealed that subjects with the T allele of both SNPs appeared to have a lower susceptibility to HCV-related cirrhosis/HCC than those with the G allele of rs1012068 (p = 0.038, OR = 1.353, 95 % CI 1.017-1.800) and C allele of rs5998152 (p = 0.043, OR = 1.342, 95 % CI 1.010-1.784). Haplotype analysis showed that a combination of T-T alleles of rs1012068 and rs5998152 was significantly associated with liver cirrhosis (frequency = 71.3% and p = 0.027) and with cirrhosis/HCC (frequency = 71.4% and P = 0.045). Also, multiple logistic regression analysis showed that rs5998152 (OR = 2.844, 95% CI 1.333-6.069 and p = 0.007), rs1012068 (OR = 2.793, 95% CI 1.316-5.928 and p = 0.010), age (OR = 1.029, 95% CI 1.001-1.057 and p = 0.041) and HCV genotypes (OR = 0.247, 95% CI 0.097-0.630 and p = 0.003) were independently associated with chronicity of HCV infection. CONCLUSION: Genetic variations in DEPDC5 gene region may influence HCV-associated liver cirrhosis and/or HCC development.

Genetic variation at -1878 (rs2596542) in MICA gene region is associated with chronic hepatitis B virus infection in Saudi Arabian patients.

MHC class I polypeptide-related chain A (MICA), mapping to 6p21.33, belongs to the non-classical class I family and its expression is induced by several stress factors including viral infection. A recent genome-wide association study has identified a single nucleotide polymorphism (SNP) of MICA, rs2596542 to be significantly associated with hepatitis C-induced hepatocellular carcinoma (HCC) in a Japanese population. Therefore, this study aims to investigate whether the SNP rs2596542 plays any role in hepatitis B virus (HBV) sero-clearance or in the development of complications associated with chronic HBV such as cirrhosis and/or HCC. TaqMan genotyping assay was used to identify the association of the SNP among 584 normal healthy controls and 777 HBV-infected patients. The patient group was further categorized into inactive carriers (Group I), active carriers (Group II), cirrhosis (Group III) and cirrhosis-HCC (Group IV). Variation at this SNP was found to be significantly more frequent in control subjects than in patients (OR = 0.852; 95% C.I. = 0.730-0.994; p = 0.0415). Also, the SNP was found to have a highly significant association when the inactive carriers were compared to the rest of the patients (OR = 1.308; 95% C.I. = 1.058-1.617; p = 0.0130). The TT genotype was found to occur more frequently among active HBV carriers (groups II, III and IV) when compared to inactive HBV carriers, thus suggesting that the rs2596542-T may be recessively associated with an active HBV infection. However, no significant association was observed in the case of HBV-related cirrhosis or HCC. These findings indicate that the MICA rs2596542 has a significant role in HBV infection.

Association between IL-37 gene polymorphisms and risk of HBV-related liver disease in a Saudi Arabian population.

Interleukin-37 (IL-37) has recently been recognized as a strong anti-inflammatory cytokine having anti-tumor activity against hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-infected patients. HCC is a typical inflammation-related cancer, and genetic variations within the IL-37 gene may be associated with the risk of HBV infection. Identification of the allelic patterns that genetically have a high disease risk is essential for the development of preventive diagnostics for HBV-mediated liver disease pathogenesis. In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within the IL-37 gene and disease sequelae associated with HBV infection. We genotyped ten IL-37 SNPs in 1274 patients infected with HBV and 599 healthy controls from a Saudi Arabian population. Among the selected SNPs, two SNPs (rs2723175 and rs2708973) were strongly associated with HBV infection, and six SNPs (rs2723176, rs2723175, rs2723186, rs364030, rs28947200, rs4392270) were associated with HBV clearance, comparing healthy controls and HBV infected-patients respectively. A suggestive association of rs4849133 was identified with active HBV surface antigen (HBsAg) carrier and HBV-related liver disease progression. In conclusion, our findings suggest that variations at the IL-37 gene may be useful as genetic predictive risk factors for HBV infection and HBV-mediated liver disease progression in the Saudi Arabian population.

The Correlation Between Hepatitis B Virus Precore/Core Mutations and the Progression of Severe Liver Disease.

Viral mutations acquired during the course of chronic hepatitis B virus (HBV) infection are known to be associated with the progression and severity of HBV-related liver disease. This study of HBV-infected Saudi Arabian patients aimed to identify amino acid substitutions within the precore/core (preC/C) region of HBV, and investigate their impact on disease progression toward hepatocellular carcinoma (HCC). Patients were categorized according to the severity of their disease, and were divided into the following groups: inactive HBV carriers, active HBV carriers, liver cirrhosis patients, and HCC patients. Two precore mutations, W28* and G29D, and six core mutations, F24Y, E64D, E77Q, A80I/T/V, L116I, and E180A were significantly associated with the development of cirrhosis and HCC. Six of the seven significant core mutations that were identified in this study were located within immuno-active epitopes; E77Q, A80I/T/V, and L116I were located within B-cell epitopes, and F24Y, E64D, and V91S/T were located within T-cell epitopes. Multivariate risk analysis confirmed that the core mutations A80V and L116I were both independent predictors of HBV-associated liver disease progression. In conclusion, our data show that mutations within the preC/C region, particularly within the immuno-active epitopes, may contribute to the severity of liver disease in patients with chronic hepatitis. Furthermore, we have identified several distinct preC/C mutations within the study population that affect the clinical manifestation and progression of HBV-related disease. The specific identity of HBV mutations that are associated with severe disease varies between different ethnic populations, and so the specific preC/C mutations identified here will be useful for predicting clinical outcomes and identifying the HBV-infected patients within the Saudi population that are at high risk of developing HCC.

Gastrosplenic fistula in Hodgkin's lymphoma treated successfully by laparoscopic surgery and chemotherapy.

A gastrosplenic fistula is a rare complication of a gastric or splenic lesion. We report a case of Hodgkin's lymphoma nodular sclerosis involving the spleen that was complicated by spontaneous gastrosplenic fistula. The fistula was closed laparoscopically, and the patient underwent partial gastrectomy and gastric wall repair, followed by successful chemotherapy. This is also the first reported case in published literature where closure of gastrosplenic fistula and partial gastrectomy was carried out laparoscopically. We recommend that extensive open surgical procedures including total gastrectomy, splenectomy, and pancreatectomy may be avoided in the management of gastrosplenic fistula, and the patient could be managed by less radical, simple laparoscopic fistulectomy, with partial gastric resection. If the fistula is caused by a malignant process, the surgical repair should be followed by definitive treatment with chemotherapy and radiotherapy.

Juvenile hemochromatosis and hepatocellular carcinoma in a patient with a novel mutation in the HJV gene.

Juvenile hemochromatosis is a rare but the most severe form of hereditary hemochromatosis which develops due to mutations in the HJV or HAMP genes. It presents in the early adulthood mainly as cardiomyopathy, hypogonadism and liver fibrosis. Unlike hereditary hemochromatosis due to HFE mutation, hepatocellular carcinoma is not known to be associated with juvenile hemochromatosis. Here, we report a patient of Arab ancestry who presented with severe cardiomyopathy. Sequence analysis of the HJV gene followed by homozygosity mapping, identified a previously undescribed homozygous missense variation in exon 3 (c.497A > G; p.H166R) in both the proband and his clinically asymptomatic brother. The former, later developed hepatocellular carcinoma. To the best of our knowledge, neither the mutation identified in our patient, nor a case of juvenile hemochromatosis with hepatocellular carcinoma has been reported before.

The epidemic dynamics of hepatitis C virus subtypes 4a and 4d in Saudi Arabia.

The relatedness between viral variants sampled at different locations through time can provide information pertinent to public health that cannot readily be obtained through standard surveillance methods. Here, we use virus genetic data to identify the transmission dynamics that drive the hepatitis C virus subtypes 4a (HCV4a) and 4d (HCV4d) epidemics in Saudi Arabia. We use a comprehensive dataset of newly generated and publicly available sequence data to infer the HCV4a and HCV4d evolutionary histories in a Bayesian statistical framework. We also introduce a novel analytical method for an objective assessment of the migration intensity between locations. We find that international host mobility patterns dominate over within country spread in shaping the Saudi Arabia HCV4a epidemic, while this may be different for the HCV4d epidemic. This indicates that the subtypes 4a and 4d burden can be most effectively reduced by combining the prioritized screening and treatment of Egyptian immigrants with domestic prevention campaigns. Our results highlight that the joint investigation of evolutionary and epidemiological processes can provide valuable public health information, even in the absence of extensive metadata information.

Hepatitis B virus (HBV) X gene mutations and their association with liver disease progression in HBV-infected patients.

Hepatitis B virus (HBV) is one of the most widespread human pathogens causing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). This study investigated the clinical impact of single and combinational mutations in HBx gene on the pathogenesis of HCC during progressive stages of liver disease. The patients were categorized into inactive HBV carriers, active carriers, cirrhosis and HCC groups based on disease severity. Male sex, age > 50 years, and high serum alanine aminotransferase level were associated with risk of progressive liver disease. I127T, V131I, and F132Y/I/R mutations showed a significant increasing trend associated with the disease progression to HCC. H94Y and K130M mutations were also significantly associated with severe liver disease. One double mutation (K130M+V131I) and two triple mutations (I127T+K130M+V131L and K130M+V131I+F132Y) were observed, with significant rising prevalence through progressive clinical phases of liver disease to HCC. Several single and combinational mutations in HBx correlating with severity and progressive clinical phases of HBV infection were identified. The mutational combinations may have a synergistic effect in accelerating the progression to HCC. These specific patterns of HBx mutations can be useful in predicting the clinical outcome of HBV-infected patients and may serve as early markers of high risk of developing HCC.

Pharmacokinetics-Based Adjusted Versus Standard Dose of Ribavirin Does Not Improve Virologic Response Rates in Chronic Hepatitis C Genotype 4 Patients: A Randomized Controlled Trial.

Optimal doses of Ribavirin (RBV) for hepatitis C virus (HCV) treatment are not known. To assess the safety and efficacy of PegIFNalfa-2a in combination with an adjusted (ADJ) RBV dose based on early pharmacokinetics versus a fixed standard (STD) dose of RBV in chronic HCV genotype (GT) 4-naive patients in a randomized trial. One hundred eighty-one patients were randomized. The baseline variables were similar in both arms and females were 50.3% of the patients, 76.5% had minimal-moderate fibrosis (F0-2). Sustained virologic response (SVR) was achieved in 99 (54.7%) subjects. SVR was seen in 50/90 (55.6%) of ADJ dose of RBV and 49/91 (53.9%) of STD dose subjects. Prematurely withdrawal or discontinuation of treatment prematurely in the ADJ RBV arm occurred in 11/90 patients (12.2%) compared with 6/91 subjects (6.6%) in the STD arm (P = 0.214). Similarly, virologic relapse was seen in 14/90 (15.6%) patients of the ADJ arm and 12/91 (13.2%) of the STD arm. Anemia grade 3-4 was seen in 36.7% in ADJ versus 17.6% in STD arm (P = 0.003). Occurrence of rapid virologic response and absences of F4 fibrosis predicted SVR in a univariate analysis. However, age, gender, weight, presence of diabetes, baseline alanine aminotransferase, and vitamin D levels were not significantly different in patients achieving SVR. ADJ higher doses of RBV based on its early pharmacokinetics-based RBV do not improve SVR rates in HCV GT4 treated in combination with peg-IFN alpha-2-a versus STD therapy. Patients on ADJ higher doses of RBV experienced higher rates of anemia and require more erythropoietin without increasing SVR.

Clinical, endoscopic, and radiologic features of three subtypes of achalasia, classified using high-resolution manometry.

BACKGROUND/AIMS: High-resolution manometry (HRM) has improved the accuracy of manometry in detecting achalasia and determining its subtypes. However, the correlation of achalasia subtypes with clinical, endoscopic, and radiologic findings has not been assessed. We aimed to evaluate and compare the clinical, endoscopic, and fluoroscopy findings associated with three subtypes of achalasia using HRM. PATIENTS AND METHODS: The retrospective clinical data, HRM, endoscopy, and radiologic findings were obtained from the medical records of untreated achalasia patients. RESULTS: From 2011 to 2013, 374 patients underwent HRM. Fifty-two patients (14%) were diagnosed with achalasia, but only 32 (8.5%) of these patients had not received treatment and were therefore included in this study. The endoscopy results were normal in 28% of the patients, and a barium swallow was inconclusive in 31% of the achalasia patients. Ten patients (31%) were classified as having type I achalasia, 17 (53%) were classified as type II, and 5 (16%) were classified as type III. Among the three subtypes, type I patients were on average the youngest and had the longest history of dysphagia, mildest chest pain, most significant weight loss, and most dilated esophagus with residual food. Chest pain was most common in type III patients, and frequently had normal fluoroscopic and endoscopic results. CONCLUSION: The clinical, radiologic, and endoscopic findings were not significantly different between patients with type I and type II untreated achalasia. Type III patients had the most severe symptoms and were the most difficult to diagnose based on varied clinical, radiologic, and endoscopic findings.

Correlation between genetic variations and serum level of interleukin 28B with virus genotypes and disease progression in chronic hepatitis C virus infection.

Recent studies have demonstrated that polymorphisms near the interleukin-28B (IL-28B) gene could predict the response to Peg-IFN-a/RBV combination therapy in HCV-infected patients. The aim of the study was to correlate the serum level of IL28B in HCV-infected patients with virus genotype/subgenotype and disease progression. IL28B serum level was detected and variations at five single nucleotide polymorphisms (SNPs) in IL28B gene region were genotyped and analyzed. The variation of IL28B genetic polymorphisms was found to be strongly associated with HCV infection when healthy control group was compared to HCV-infected patients with all P values <0.0001. Functional analysis revealed that subjects carrying rs8099917-GG genotype had higher serum level of IL28B than those with GT or TT genotypes (P = 0.04). Also, patients who were presented with cirrhosis (Cirr) only or with cirrhosis plus hepatocellular carcinoma (Cirr+HCC) had higher levels of serum IL28B when compared to chronic HCV-infected patients (P = 0.005 and 0.003, resp.). No significant association was found when serum levels of IL28B were compared to virus genotypes/subgenotypes. This study indicates that variation at SNP rs8099917 could predict the serum levels of IL28B in HCV-infected patients. Furthermore, IL28B serum level may serve as a useful marker for the development of HCV-associated sequelae.

The association of toll-like receptor 4 polymorphism with hepatitis C virus infection in Saudi Arabian patients.

Hepatitis C virus (HCV) is a single stranded RNA virus. It affects millions of people worldwide and is considered as a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. A recent study reported that TLR4 gene polymorphisms are good prognostic predictors and are associated with protection from liver fibrosis among Caucasians. This study aims to investigate the implication of genetic polymorphisms of TLR4 gene on the HCV infection in Saudi Arabian patients. Two SNPs in the TLR4 gene, rs4986790 (A/G) and rs4986791 (C/T), were genotyped in 450 HCV patients and 600 uninfected controls. The association analysis confirmed that both SNPs showed a significant difference in their distribution between HCV-infected patients and uninfected control subjects (P < 0.0001; OR = 0.404, 95% CI = 0.281-0.581) and (P < 0.0001; OR = 0.298, 95% CI = 0.201-0.443), respectively. More importantly, haplotype analysis revealed that four haplotypes, AC, GT, GC, and AT (rs4986790, rs4986791), were significantly associated with HCV infection when compared with control subjects. One haplotype AC was more prominently found when chronic HCV-infected patients were compared with cirrhosis/HCC patients (frequency = 94.7% and P = 0.04). Both TLR4 SNPs under investigation were found to be significantly implicated with HCV-infection among Saudi Arabian population.

Association between HLA variations and chronic hepatitis B virus infection in Saudi Arabian patients.

Hepatitis B virus (HBV) infection is a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. Human leukocyte antigens (HLAs) play an important role in the regulation of immune response against infectious organisms, including HBV. Recently, several genome-wide association (GWAS) studies have shown that genetic variations in HLA genes influence disease progression in HBV infection. The aim of this study was to investigate the role of HLA genetic polymorphisms and their possible role in HBV infection in Saudi Arabian patients. Variations in HLA genes were screened in 1672 subjects who were divided according to their clinical status into six categories as follows; clearance group, inactive carriers, active carriers, cirrhosis, hepatocellular carcinoma (HCC) patients and uninfected healthy controls. Three single nucleotide polymorphisms (SNPs) belonged to HLA-DQ region (rs2856718, rs7453920 and rs9275572) and two SNPs belonged to HLA-DP (rs3077 and rs9277535) were studied. The SNPs were genotyped by PCR-based DNA sequencing (rs2856718) and allele specific TaqMan genotyping assays (rs3077, rs7453920, rs9277535 and rs9275572). The results showed that rs2856718, rs3077, rs9277535 and rs9275572 were associated with HBV infection (p = 0.0003, OR = 1.351, CI = 1.147-1.591; p = 0.041, OR = 1.20, CI = 1.007-1.43; p = 0.045, OR = 1.198, CI = 1.004-1.43 and p = 0.0018, OR = 0.776, CI = 0.662-0.910, respectively). However, allele frequency of rs2856718, rs7453920 and rs9275572 were found more in chronically infected patients when compared to clearance group infection (p = 0.0001, OR = 1.462, CI = 1.204-1.776; p = 0.0178, OR = 1.267, CI = 1.042-1.540 and p = 0.010, OR = 0.776, CI = 0.639-0.942, respectively). No association was found when polymorphisms in HLA genes were compared in active carriers versus cirrhosis/HCC patients. In conclusion, these results suggest that variations in HLA genes could affect susceptibility to and clearance of HBV infection in Saudi Arabian patients.

Lung transplantation triggered "jackhammer esophagus": a case report and review of literature.

A 19-years-old girl was referred for lung transplant due to end stage lung disease secondary to idiopathic bilateral bronchiectasis. Her routine pre lung transplant evaluation showed normal esophageal high-resolution manometry (HRM) and 24-hours impedance pH monitoring. Four weeks after the bilateral sequential lung transplantation (LTx), she developed dysphagia, chest pain and regurgitation, complicated by aspiration pneumonia. Repeated HRM showed Jackhammer esophagus, delayed gastric emptying and abnormal 24-hour pH impedance monitoring consistent with the diagnosis of gastroesophageal reflux disease. Twelve weeks after LTx, she was symptom free, HRM and 24-hour impedance pH monitoring returned to normal. To the best of our knowledge, this rare transient esophageal hypercontractility episode occurred after LTx and recovered without any specific treatment was never reported in literature. The etiopathogenesis of Jackhammer esophagus in general and LTx induced dysmotility in particular is discussed and reviewed.

Relationship of interferon-γ-inducible protein-10 kDa with viral response in patients with various heterogeneities of hepatitis C virus genotype-4.

INTRODUCTION: The role of serum interferon-γ-inducible protein-10 kDa (IP-10) level in the treatment of chronic hepatitis C genotype-4 (HCV-4) and its various subtypes remains unknown. We aimed to study the impact of pretreatment IP-10 levels on the sustained viral response (SVR) in HCV-4 patients (n=64) undergoing peginterferon α-2a/ribavirin therapy. PATIENTS AND METHODS: Pretreatment IP-10 levels and HCV-4 subtypes (4a=48.4%, 4d=39%, others=12.5%) were measured and correlated with treatment responses. Variables significantly associated with SVR on univariate analysis were included in a multivariate logistic regression model. RESULTS: Patients with SVR had lower pretreatment IP-10 levels (462.4±282.7 vs. 840.1±490.6 pg/ml; P=0.002), but the levels were not significantly different in those with a rapid (P=0.245) or an early viral response (P=0.221). IP-10 levels were similar across all subtypes. The pretreatment level was significantly lower in subtype 4d patients with SVR (465.9±349.1) compared with non-SVR patients (904.9±532.1; P<0.001), but not when compared with genotype 4a patients (564.7±288.9 vs. 658.6±374.9, respectively; P=0.330). IP-10 levels [odds ratio (OR), 0.998; 95% confidence interval (CI): 0.996-0.999; P=0.006], low viremia (OR, 8.852; 95% CI: 1.244-63.03; P=0.029), and early viral response (OR, 4.162; 95% CI: 1.023-16.94; P=0.046) were independent predictors of SVR. Receiver operating characteristic curve analysis identified a threshold IP-10 level of 359 pg/ml (area under receiver operating characteristic curve, 0.737; sensitivity, 81.8%; specificity, 45.2; positive predictive value, 43.9%; negative predictive value, 82.6%) for SVR. CONCLUSION: Pretreatment serum IP-10 level is a predictor for SVR in HCV-4-infected patients. The baseline IP-10 level is significantly lower in responders among HCV genotype-4d patients as compared with 4a patients.

IL28B polymorphisms predict the virological response to standard therapy in patients with chronic hepatitis C virus genotype 4 infection.

BACKGROUND: Genome-wide association studies have recently revealed that several single-nucleotide polymorphisms (SNPs) in the interleukin (IL) 28B genes can predict the sustained virological response (SVR) to pegylated interferon-α2a/b plus ribavirin in hepatitis C virus (HCV)-genotype 1 patients. However, data for patients infected with HCV genotype 4 (HCV-G4) are limited. AIM: We analyzed the association of IL28B SNPs (hematological, biochemical, virological, and pathological factors) with SVR in the HCV-G4 monoinfected cohort of patients. PATIENTS AND METHODS: One hundred twenty-nine treatment-naïve HCV-G4 patients undergoing treatment were recruited from three tertiary care centers in Saudi Arabia. Five IL28B SNPs (rs12979860, rs12980275, rs8105790, rs8099917, and rs72486680) were identified by polymerase chain reaction and DNA sequencing. SVR was statistically correlated with various clinical, histopathological, virological, and genetic parameters. RESULTS: SVR was significantly associated with the CC and AA alleles of rs12979860 (p = 0.008) and rs12980275 (p = 0.004), respectively. Moreover, albumin levels (p = 0.002) and platelet count (p = 0.039) showed significant differences in the SVR and No SVR groups. On multivariate analysis, the CC allele of rs12979860 (OR, 2.89; 95 % CI 1.6-6.2, p = 0.006) and albumin levels (OR, 1.2; 95 % CI 1.1-1.4, p = 0.001) independently predicted SVR. CONCLUSIONS: IL28B polymorphism (CC allele of rs12979860) predicts the sustained response to antiviral therapy in HCV-G4.

Hepatitis C genotype 4: genotypic diversity, epidemiological profile, and clinical relevance of subtypes in Saudi Arabia.

BACKGROUND/AIM: Hepatitis C virus genotypes 4 (HCV-4) is the most prevalent genotype in Saudi Arabia, although it's various subtypes, mode and route of transmission remains unknown. The aim of this study was to analyze (i) the variability of the HCV-4 subtypes, the route and source of HCV transmission and (ii) the influence of HCV-4 subtypes on their therapeutic response. PATIENTS AND METHODS: Sixty-four HCV-4 patients were analyzed retrospectively for the prevalence of various sub-genotypes and the possible mode of transmission, and it was correlated with their treatment response to pegylated interferon (PEG-IFN) α-2a and ribavirin therapy. RESULTS: Positive history of blood or blood products transfusion was noted in 22 patients (34%), hemodialysis in 10 patients (15.6%), surgery in 7 patients (11%), and unknown etiology in 25 patients (39%). Prevalence of HCV-4 subtypes was 4a = 48.4% (31/64), 4d = 39% (25/64), 4n = 6.25% (4/64), and remaining combined (4m, 4l, 4r, 4o) 6.25% (4/64). No significant correlation between subtypes and the source of transmission was recognized ( P = 0.62). Sustained virological response in all HCV-4 patients was 64% (41/64), while in each subtypes separately it was 4a 77.4% (24/31), 4d 52% (13/25), and combined (4n, 4m, 4l, 4r, 4o) 62.5% (5/8) ( P = 0.046). CONCLUSION: No obvious cause for the mode of HCV transmission was noted in majority of the patients. No significant correlation was observed between HCV-4 subtypes and the source of HCV infection. 4a and 4d subtypes were the most common in Saudi Arabia, and patients infected with 4a subtype responded significantly better to combination therapy than to 4d subtype.