Low-density lipoprotein receptor genotyping enhances the predictive value of IL28B genotype in HIV/hepatitis C virus-coinfected patients
ABSTRACT The aims of this study were to appraise the predictive value of variations in a single-nucleotide polymorphism (SNP) in the low-density lipoprotein receptor (LDLR) gene for sustained virological response (SVR) to pegylated interferon (Peg-IFN) and ribavirin (RBV), as well as to analyze the relationship between LDLR genotype and other predictors of SVR, particularly IL28B genotype, in patients coinfected with HIV and hepatitis C virus (HCV).
One hundred and eighty-four HIV/HCV-coinfected, treatment-naive patients with chronic HCV infection, who received Peg-IFN and RBV, were included. Variations in the SNP rs14158 and rs12979860 were tested by Taqman PCR assay.
Twenty-eight (38%) patients with rs14158 TT/TC and 61 (55%) with CC (P = 0.028) achieved SVR. The rates of SVR in patients with rs14158 TT/TC and with CC harboring HCV 1-4 were 20 and 41% (P = 0.020), respectively, and, in those with HCV genotype 2-3, 75 and 84% (P = 0.513), respectively. Patients with rs14158 CC showed less commonly plasma HCV-RNA load at least 600000 IU/ml (57 vs. 71%, P = 0.047) and lower likelihood of relapse (13 vs. 30%, P = 0.023). In patients with HCV genotype 1-4, the rates of SVR according to the combination of IL28B/LDLR genotypes were: CC/CC = 69%; CC/non-CC: 30%; non-CC/CC: 25%; non-CC/non-CC: 14% (P < 0.001).
Variations in rs14158 are associated with SVR to Peg-IFN and RBV in HIV/HCV-coinfected patients harboring HCV genotype 1-4. LDLR and IL28B genotypes seem to have a synergistic effect on SVR. The combined use of LDLR and IL28B genotypes in routine clinical practice could enhance the predictive value of IL28B genotype alone.
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ABSTRACT: The aim of this study was to analyze the impact of core variations on sustained virological response (SVR) to pegylated interferon plus ribavirin (PEG-IFN/RBV) and its association with predictive factors of response in Caucasian patients infected with genotype 1 hepatitis C virus (HCV-1). Full-length core sequences were analyzed in 100 Caucasian HCV-1-infected patients who received therapy with PEG-IFN/RBV. The associations between variations in the core protein and SVR, as well as with predictors of SVR, were analyzed. Variations at core 62, 70 and 110 were selected as candidates. There were almost no variations at these positions among patients harboring HCV-1a. However, they were identified in 10 (30.3 %), 21 (63.6 %) and 13 (39.4 %) subjects with HCV-1b, respectively. Among the HCV-1b patients, 39.1 % individuals carrying core R62 and 70 % subjects with core R62G showed SVR (p = 0.141), and 66.7 % of HCV-1b patients harboring core R70 and 38.1 % with core R70Q achieved SVR (p = 0.157), whereas the rate of SVR was 70 % for individuals with core T110 and 15.4 % for those with core T110N (p = 0.004). No statistical interaction between core variations and IL28B genotype was observed. Patients with R70 showed higher median (interquartile range) baseline plasma levels of low-density-lipoprotein cholesterol (LDL-C) than those with R70Q (96 [86-118] mg/dL vs. 76 [54-88] mg/dL, p = 0.014). We concluded that a substitution at core 110 is associated with a lower rate of SVR in Caucasian HCV-1b-infected patients receiving PEG-IFN/RBV. Furthermore, the variation at the core 70 position is related to plasma levels of LDL-C in these patients.Archives of Virology 08/2014; 159(12). DOI:10.1007/s00705-014-2209-x · 2.28 Impact Factor
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ABSTRACT: Despite the great successes achieved in the fields of virology and diagnostics, several difficulties affect improvements in hepatitis C virus (HCV) infection control and eradication in the new era. New HCV infections still occur, especially in some of the poorest regions of the world, where HCV is endemic and long-term sequelae have a growing economic and health burden. An HCV vaccine is still no available, despite years of researches and discoveries about the natural history of infection and host-virus interactions: several HCV vaccine candidates have been developed in the last years, targeting different HCV antigens or using alternative delivery systems, but viral variability and adaption ability constitute major challenges for vaccine development. Many new antiviral drugs for HCV therapy are in preclinical or early clinical development, but different limitations affect treatment validity. Treatment predictors are important tools, as they provide some guidance for the management of therapy in patients with chronic HCV infection: in particular, the role of host genomics in HCV infection outcomes in the new era of direct-acting antivirals may evolve for new therapeutic targets, representing a chance for modulated and personalized treatment management, when also very potent therapies will be available. In the present review we discuss the most recent data about HCV epidemiology, the new perspectives for the prevention of HCV infection and the most recent evidence regarding HCV diagnosis, therapy and predictors of response to it.
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ABSTRACT: Hepatitis C virus (HCV) was identified for the first time more than 20 years ago. Since then, several studies have highlighted the complicated aspects of this viral infection in relation to its worldwide prevalence, its clinical presentation, and its therapeutic response. Recently, two landmark scientific breakthroughs have moved us closer to the successful eradication of chronic HCV infection. First, response rates in treatment-naïve patients and in prior non-responders to pegylated-interferon-α and ribavirin therapy are increasing as a direct consequence of the development of direct-acting antiviral drugs. Secondly, the discovery of single-nucleotide polymorphisms near the interleukin 28B gene significantly related to spontaneous and treatment-induced HCV clearance represents a milestone in the HCV therapeutic landscape. The implementation of this pharmacogenomics finding as a routine test for HCV-infected patients has enhanced our understanding of viral pathogenesis, has encouraged the design of ground-breaking antiviral treatment regimens, and has become useful for pretreatment decision making. Nowadays, interleukin 28B genotyping is considered to be a key diagnostic tool for the management of HCV-infected patients and will maintain its significance for new combination treatment schemes using direct-acting antiviral agents and even in interferon-free regimens. Such pharmacogenomics insights represent a challenge to clinicians, researchers, and health administrators to transform this information into knowledge with the aim of elaborating safer and more effective therapeutic strategies specifically designed for each patient. In conclusion, the individualization of treatment regimens for patients with hepatitis C, that may lead to a universal cure in future years, is becoming a reality due to recent developments in biomarker and genomic medicine. In light of these advances, we review the scientific evidence and clinical implications of recent findings related to host genetic factors in the management of HCV infection.Pharmacogenomics and Personalized Medicine 01/2014; 7:339-47. DOI:10.2147/PGPM.S52624