Redefining baseline demographics: the role of genetic testing in hepatitis C virus infection.
ABSTRACT The current standard of care for hepatitis C virus (HCV) infection is pegylated interferon and ribavirin. Unfortunately, treatment cures at best only 40% to 50% of patients infected with genotype 1 HCV, the most common HCV genotype in Western countries. Treatment is also expensive and is often poorly tolerated. Therefore, the identification of patients most likely to benefit from treatment is clinically important. Genome-wide association studies have recently identified genetic variants, most notably IL28B and ITPA, which will enhance the ability of clinicians to personalize antiviral therapy for HCV infection.
- SourceAvailable from: Daniel Pineda-Tenor[Show abstract] [Hide abstract]
ABSTRACT: Background The Fat Mass and Obesity-Associated Protein (FTO) gene rs9939609 single nucleotide polymorphism (SNP) has been associated with obesity, metabolic syndrome, insulin resistance (IR), and type 2 diabetes mellitus in the general population. The aim of our study was to examine for the first time the association of the rs9939609 polymorphism with metabolic disturbances, liver disease and virologic response to hepatitis C virus (HCV) therapy with pegylated-interferon-alpha plus ribavirin (pegIFN¿/RBV) in human immunodeficiency virus (HIV)/HCV coinfected patients.Methods We carried out a cross-sectional study in 261 patients, of whom 178 were subsequently treated with pegIFN¿/RBV therapy. FTO rs9939609 and IFNL3 rs12980275 polymorphisms were genotyped by GoldenGate®. The main outcomes were: 1) metabolic disturbances: insulin resistance (homeostatic model assessment (HOMA-IR)) and overweight (body mass index (BMI)); 2) liver disease (Metavir score): significant fibrosis (F ¿2) and steatosis (>10% fatty hepatocytes); and 3) virologic response to HCV treatment: sustained virologic response (SVR).ResultsThe rs9939609 AA genotype was associated with higher values of BMI (adjusted arithmetic mean ratio (aAMR) =1.08; 95% confidence interval (95%CI) =1.03 to 1.14; P =0.002) and HOMA-IR (aAMR =1.32; 95%CI =1.03 to 1.69; P =0.027). Patients with an rs9939609 AA genotype had higher likelihoods of achieving values of BMI ¿27.5 kg/m2 (adjusted odds ratio (aOR) =3.46; 95%CI =1.17 to 10.21; P =0.024), HOMA-IR ¿2.5 (aOR =2.09; 95%CI =1.02 to 4.32; P =0.045), significant fibrosis (aOR =2.34; 95%CI =1.02 to 5.36; P =0.045) and steatosis (aOR =3.65; 95%CI =1.29 to 10.36; P =0.015). The rs9939609 AT/AA genotype decreased the likelihood of achieving SVR (aOR =0.58; 95%CI =0.34 to 0.99; P =0.044). A decision tree was performed with the genotypes of HCV, IFNL3 and FTO. The incorporation of rs9939609 significantly improves the prediction of SVR (P <0.05). The overall accuracy was 68.2%.Conclusions Patients carrying the unfavourable AT/AA genotype of rs9939609 polymorphism had higher odds of metabolic disturbances and a lower likelihood of achieving successful virologic response to HCV therapy.BMC Medicine 11/2014; 12(1):198. · 7.28 Impact Factor
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ABSTRACT: To analyze whether human leukocyte antigen (HLA)-E allelic variants are associated with and may predict response to peg-interferon (IFN) alpha and ribavirin treatment in HIV/hepatitis C virus (HCV)-coinfected patients. Retrospective follow-up study. We studied 321 naive patients who started HCV treatment. HLA-E genotyping was performed by restriction fragment length polymorphism. A sustained virological response (SVR) was defined as undetectable plasma HCV-RNA up through 24 weeks after the end of HCV treatment. The HLA-E*0101 allele increased the odds of achieving SVR for all patients [adjusted odds ratio (aOR) = 2.03 (95% confidence interval, 95% CI = 1.35-3.06); P = 0.001], for HCV genotype (GT) 1/4 patients (aOR = 1.62 (95% CI = 1.03-2.54), P = 0.035), and for GT2/3 patients [aOR = 9.87 (95% CI = 2.47-31.89), P = 0.001]. For decision tree analysis, the SVR rate increased from 0 to 82.6% and then to 92.5% in GT2/3 patients when the count of HLA-E*0101 alleles increased. In GT1/4 patients with rs8099917 TT genotype, the SVR rate increased from 33.3 to 54.8% and then to 61.8% when the count of HLA-E*0101 alleles increased. In GT1/4 patients with rs8099917 GT/GG genotype, the SVR rate increased from 15.4 to 22% and then to 44% when the count of HLA-E*0101 alleles increased. The overall percentage of patients correctly classified was 73.2% and the area under the receiver operating characteristic curve (AUROC) was 0.803 ± 0.024. The HLA-E*0101 allele was associated with increased odds of HCV clearance and could help to predict SVR among HIV/HCV-coinfected patients on HCV therapy. This would be helpful to avoid treatment in those less likely to respond to pegylated-interferon-alpha and ribavirin treatment.AIDS 05/2013; 27(8):1231-1238. · 6.56 Impact Factor
Article: Burden of pediatric hepatitis C.[Show abstract] [Hide abstract]
ABSTRACT: Hepatitis C virus (HCV) is a major health burden infecting 170-210 million people worldwide. Additional 3-4 millions are newly-infected annually. Prevalence of pediatric infection varies from 0.05%-0.36% in the United States and Europe; up to 1.8%-5.8% in some developing countries. The highest prevalence occurs in Egypt, sub-Saharan Africa, Amazon basin and Mongolia. HCV has been present in some populations for several centuries, notably genotypes 1 and 2 in West Africa. Parenteral anti-schistosomal therapy practiced in the 1960s until the early 1980s had spread HCV infection throughout Egypt. Parenteral acquisition of HCV remains a major route for infection among Egyptian children. Insufficient screening of transfusions, unsterilized injection equipment and re-used needles and syringes continue to be major routes of HCV transmission in developing countries, whereas vertical transmission and adolescent high-risk behaviors (e.g., injection drug abuse) are the major routes in developed countries. The risk of vertical transmission from an infected mother to her unborn/newborn infant is approximately 5%. Early stages of HCV infection in children do not lead to marked impairment in the quality of life nor to cognitive, behavioral or emotional dysfunction; however, caregiver stress and family system strain may occur. HCV slowly progresses to serious complications as cirrhosis (1%-2%) and hepatocellular carcinoma (HCC) especially in the presence of risk factors as hemolytic anemias, obesity, treated malignancy, and concomitant human immune deficiency and/or hepatitis B virus co-infection. HCV vaccine remains elusive to date. Understanding the immune mechanisms in patients who successfully cleared the infection is essential for vaccine development. The pediatric standard of care treatment consists of pegylated interferon-α 2a or b plus ribavirin for 24-48 wk. The new oral direct acting antivirals, approved for adults, need further evaluation in children. Sustained virologic response varies depending on the viral load, genotype, duration of infection, degree of aminotransferase elevation, adiposity and single nucleotide polymorphisms of interleukin (IL)-28B locus. The goals of treatment in individual patients are virus eradication, prevention of cirrhosis and HCC, and removing stigmatization; meanwhile the overall goal is decreasing the global burden of HCV. IL-28B polymorphisms have been also associated with spontaneous clearance of vertically acquired HCV infection. The worldwide economic burden of HCV for children, families and countries is estimated to be hundreds of millions of US dollars per year. The United States, alone, is estimated to spend 199-336 million dollars in screening, monitoring and treatment during one decade. The emotional burden of having an HCV infected child in a family is more difficult to estimate.World Journal of Gastroenterology 11/2013; 19(44):7880-7888. · 2.43 Impact Factor