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Julie Sohier - One of the best experts on this subject based on the ideXlab platform.
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glomerular common gamma chain confers b and t cell independent protection against glomerulonephritis
Kidney International, 2017Co-Authors: Yosu Luque, Dominique Cathelin, Sophie Vandermeersch, Julie Sohier, Xiaoli XuAbstract:Crescentic glomerulonephritis is a life-threatening renal disease that has been extensively studied by the experimental anti–glomerular basement membrane glomerulonephritis (anti-GBM-GN) model. Although T cells have a significant role in this model, athymic/nude mice and rats still develop severe renal disease. Here we further explored the contribution of intrinsic renal cells in the development of T-cell–independent GN lesions. Anti-GBM-GN was induced in three strains of immune-deficient mice ( Rag2 -/- , Rag2 -/- Il2rg -/- , and Rag2 -/- IL2RB -/- ) that are devoid of either T/B cells or T/B/NK cells. The Rag2 -/- Il2rg -/- or Rag2 -/- IL2RB -/- mice harbor an additional deletion of either the common gamma chain (γC) or the interleukin-2 receptor β subunit (IL-2Rβ), respectively, impairing IL-15 signaling in particular. As expected, all these strains developed severe anti-GBM-GN. Additionally, bone marrow replenishment experiments allowed us to deduce a protective role for the glomerular-expressed γC during anti-GBM-GN. Given that IL-15 has been found highly expressed in nephritic kidneys despite the absence of lymphocytes, we then studied this cytokine in vitro on primary cultured podocytes from immune-deficient mice ( Rag2 -/- Il2rg -/- and Rag2 -/- IL2RB -/- ) compared to controls. IL-15 induced downstream activation of JAK1/3 and SYK in primary cultured podocytes. IL-15–dependent JAK/SYK induction was impaired in the absence of γC or IL-2Rβ. We found γC largely induced on podocytes during human glomerulonephritis. Thus, renal lesions are indeed modulated by intrinsic glomerular cells through the γC/IL-2Rβ receptor response, to date classically described only in immune cells.
Chunjen Liu - One of the best experts on this subject based on the ideXlab platform.
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value of interleukin 28b genetic polymorphism on retreatment outcomes of chronic hepatitis c genotype 1 relapsers by peginterferon alfa plus ribavirin
Journal of Gastroenterology and Hepatology, 2014Co-Authors: Mingyao Chen, Chenhua Liu, Tingchih Chen, Peijer Chen, Dingshinn Chen, Jiahorng Kao, Chunjen LiuAbstract:Background and Aim Chronic hepatitis C (CHC) infection is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy remains the standard of care for CHC genotype 1 in many Asian countries, and single nucleotide polymorphism or genotype of the interleukin-28B (IL28B) gene is associated with the development of sustained virologic response (SVR). The predictive value of IL28B genotype for retreatment outcomes of patients with CHC was only partly clarified and deserves further investigation. Methods A total of 75 CHC genotype 1 Taiwanese patients who relapsed after 24-week PEG-IFN/RBV combination therapy and received retreatment with a 48-week PEG-IFN/RBV therapy were consecutively enrolled since November 2009. The associations among IL28B rs8099917 genotype, virologic kinetics, and treatment outcomes were evaluated. Results Rapid virologic response (RVR) at week 4, end-of-treatment virologic response (EOT-VR) and SVR was 37%, 73%, and 52%, respectively. Relapse rate was 29%. None of patients had rs8099917 GG genotype. Patients with TT genotype (n = 54, 72%) had higher rates of RVR (50% vs 5%, P = 0.0002), end-of-treatment virologic response (85% vs 43%, P = 0.0001), and SVR (67% vs 14%, P = 0.0001) than those with GT genotype (n = 21, 28%). Combination of IL28B TT genotype and achieving RVR had 85% positive and 90% negative predictive values of SVR. Conclusions About half of the Taiwanese CHC relapsers to a previous 24-week combination therapy achieve SVR after retreatment for 48 weeks. IL28B genotype influences on-treatment viral kinetics and SVR rate in these retreated patients. Baseline IL28B genotype and RVR can serve as early predictors for treatment success.
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association of il28b genotypes with metabolic profiles and viral clearance rate in chronic hepatitis c patients
Hepatology International, 2013Co-Authors: Chingsheng Hsu, Chenhua Liu, Peijer Chen, Dingshinn Chen, Chunjen Liu, Shihjer Hsu, Hungchia Chen, Jenher Jeng, Jiahorng KaoAbstract:Purpose IL28B genotypes have a strong impact on treatment outcomes of chronic hepatitis C (CHC) and on-treatment viral kinetics. Since metabolic regulation and interferon response are highly integrated, metabolic profiles may play an important role in the link between IL28B genotypes and hepatitis C virus (HCV) infection. Thus, the association of IL28B rs8099917 genotypes with metabolic profiles and the impact of metabolic profiles on hepatitis C viral kinetic parameters were examined.
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interleukin 28b genetic polymorphisms play a minor role in identifying optimal treatment duration in hcv genotype 1 slow responders to pegylated interferon plus ribavirin
Antiviral Therapy, 2012Co-Authors: Chenhua Liu, Peijer Chen, Chunjen Liu, Chengchao Liang, Taichung Tseng, Chihlin Lin, Shengshun Yang, Jouwei Lin, Junherng Chen, Dingshinn ChenAbstract:BACKGROUND Pegylated interferon and ribavirin for 72 weeks improve sustained virological response (SVR) in HCV genotype 1 (HCV-1) slow viral responders. Whether interleukin 28B (IL28B) single nucleotide polymorphism (SNP) genotypes and on-treatment viral responses can identify non-rapid virological response (RVR) patients who benefit from 48 or 72 weeks of therapy remains unclear. METHODS Treatment-naive HCV-1 patients who failed to achieve RVR were randomly assigned to receive 48 (n=168) or 72 (n=167) weeks of therapy. Baseline factors and on-treatment virological responses at weeks 8 and 12 were evaluated for SVR in 289 compliant patients who received ≥80% of drug dosages and treatment duration, and had end of follow-up viral response. The stratified SVR rates for independent factors were compared by treatment duration. RESULTS Treatment duration, IL28B rs8099917 genotypes, cirrhosis, week-8 viral response (undetectable HCV RNA at treatment week 8) and complete early virological response (cEVR) predicted SVR. In week-8 viral response patients, the SVR rates of 72-week and 48-week treatment were similar (75-88%), regardless of IL28B SNP genotypes or cirrhosis. In non-week-8 viral response patients who achieved cEVR, the SVR rate of 72-week treatment was higher than that of 48-week treatment for non-cirrhotic patients, regardless of IL28B SNP genotypes (91-100% versus 13-44%; P=0.001). CONCLUSIONS Although IL28B SNP genotypes predict SVR, they play a minor role when on-treatment viral responses are taken into consideration. On-treatment viral responses at weeks 8 and 12 are the key determinants to decide the optimal treatment duration in HCV-1 patients without RVR.
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interleukin 28b genetic polymorphisms and viral factors help identify hcv genotype 1 patients who benefit from 24 week pegylated interferon plus ribavirin therapy
Antiviral Therapy, 2011Co-Authors: Chenhua Liu, Chunjen Liu, Chengchao Liang, Taichung Tseng, Chihlin Lin, Shengshun Yang, Shihjer Hsu, Jouwei Lin, Junherng Chen, Peijer ChenAbstract:BACKGROUND Interleukin 28B (IL28B) single nucleotide polymorphism (SNP) genotypes and viral factors can predict sustained virological response (SVR) in HCV genotype-1 (HCV-1) patients receiving 48 weeks of pegylated interferon and ribavirin. Whether these factors would identify those patients who can benefit from a shorter duration of therapy remains unclear. METHODS Treatment-naive HCV-1 patients (n=662) receiving 24 or 48 weeks of combination therapy were enrolled. Baseline demographic data, HCV viral load, IL28B SNP genotypes (rs8099917), duration of therapy and rapid virological response (RVR) were evaluated to predict SVR. The SVR rates were further stratified by the independent factors and compared. RESULTS The IL28B rs8099917 TT genotype, low baseline viral load (HCV RNA≤600,000 IU/ml), RVR and 48-week therapy independently predicted SVR. In RVR patients with the IL28B rs8099917 TT genotype, the SVR rate of 24-week therapy was comparable to 48-week therapy (95% versus 99%; P=0.21) at low baseline viral load, but was inferior to 48-week therapy (70% versus 97%; P<0.001) at high baseline viral load. In non-RVR patients, the SVR rate of 24-week therapy was inferior to 48-week therapy for those with the IL28B rs8099917 TT genotype but high baseline viral load (23% versus 62%; P<0.001), and those with the IL28B rs8099917 GT/GG genotype but low baseline viral load (0% versus 33%; P=0.02). CONCLUSIONS HCV-1 patients simultaneously bearing the IL28B rs8099917 TT genotype, low baseline viral load and RVR can benefit from a shorter duration of combination therapy.
Susanna Naggie - One of the best experts on this subject based on the ideXlab platform.
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dysregulation of innate immunity in hepatitis c virus genotype 1 il28b unfavorable genotype patients impaired viral kinetics and therapeutic response
Hepatology, 2012Co-Authors: Susanna Naggie, Alexander J Thompson, Paul J Clark, Keyur Patel, Anu Osinusi, Antonios Katsounas, Richard A Lempicki, Eva Herrmann, Andrew J Muir, John G MchutchisonAbstract:Recent studies have shown that a single-nucleotide polymorphism upstream of the interleukin-28B (IL28B) gene plays a major role in predicting therapeutic response in hepatitis C virus (HCV)-infected patients treated with pegylated interferon (PEG-IFN)/ribavirin. We sought to investigate the mechanism of the IL28B polymorphism, specifically as it relates to early HCV viral kinetics, IFN pharmacokinetics, IFN pharmacodynamics, and gene expression profiles. Two prospective cohorts (human immunodeficiency virus [HIV]/HCV-coinfected and HCV-monoinfected) completing treatment with IFN/ribavirin were enrolled. Patients were genotyped at the polymorphic site rs12979860. In the HIV/HCV cohort, frequent serum sampling was completed for HCV RNA and IFN levels. DNA microarray of peripheral blood mononuclear cells and individual expression of IFN-stimulated genes (ISGs) were quantified on IFN therapy. The IL28B-favorable (CC) genotype was associated with improved therapeutic response compared with unfavorable (CT or TT) genotypes. Patients with a favorable genotype had greater first- and second-phase viral kinetics (P = 0.004 and P = 0.036, respectively), IFN maximum antiviral efficiency (P = 0.007) and infected cell death loss (P = 0.009) compared with unfavorable genotypes. Functional annotation analysis of DNA microarray data was consistent with depressed innate immune function, particularly of natural killer cells, from patients with unfavorable genotypes (P <0.004). Induction of innate immunity genes was also lower in unfavorable genotypes. ISG expression at baseline and induction with IFN was independent of IL28B genotype. Conclusion: Carriers of the IL28B-favorable genotype were more likely to have superior innate immune response to IFN therapy compared with unfavorable genotypes, suggesting that the unfavorable genotype has aberrant baseline induction of innate immune response pathways resulting in impaired virologic response. IL28B genotype is associated with more rapid viral kinetics and improved treatment response outcomes independent of ISG expression. (HEPATOLOGY 2012)
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interleukin 28b polymorphisms are the only common genetic variants associated with low density lipoprotein cholesterol ldl c in genotype 1 chronic hepatitis c and determine the association between ldl c and treatment response
Journal of Viral Hepatitis, 2012Co-Authors: Alexander J Thompson, Paul J Clark, Mingfu Zhu, David M Vock, Qianqian Zhu, Keyur Patel, Stephen A Harrison, Thomas J Urban, Susanna NaggieAbstract:Low-density lipoprotein cholesterol (LDL-C) levels and interleukin 28B (IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B has been linked with LDL-C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL-C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome-wide association study and developed multivariable predictive models of SVR. IL28B polymorphisms were the only common genetic variants associated with pretreatment LDL-C level in Caucasians (rs12980275, P = 4.7 × 10(-17), poor response IL28B variants associated with lower LDL-C). The association was dependent on HCV infection, IL28B genotype was no longer associated with LDL-C in SVR patients after treatment, while the association remained significant in non-SVR patients (P 130 mg/dL and HCV RNA ≤600 000 IU/mL may anticipate cure rates >80%, while the absence of these two criteria was associated with an SVR rate of <35%. IL28B polymorphisms are the only common genetic variants associated with pretreatment LDL-C in G1-HCV. LDL-C remains significantly associated with SVR for heterozygous IL28B genotype patients, where LDL-C and HCV RNA burden may identify those patients with high or low likelihood of cure with pegIFN/RBV therapy.
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influence of interleukin 28b single nucleotide polymorphisms on progression to liver cirrhosis in human immunodeficiency virus hepatitis c virus coinfected patients receiving antiretroviral therapy
The Journal of Infectious Diseases, 2011Co-Authors: Pablo Barreiro, Juan A Pineda, Norma Rallon, Susanna Naggie, Luz Martincarbonero, Karin Neukam, Antonio Rivero, Jose Miguel Benito, Antonio Caruz, Eugenia VispoAbstract:Background Single-nucleotide polymorphisms (SNPs) near the IL28B gene have recently been associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapies in patients with chronic hepatitis C. Because human immunodeficiency virus (HIV) coinfection appears to accelerate HCV-related liver fibrosis progression, any influence of IL28B SNP on the risk of developing cirrhosis might be more easily recognized in the coinfected population. Methods All HIV-HCV-coinfected patients who underwent hepatic elastography before initiating a course of pegylated interferon plus ribavirin therapy at 2 Spanish clinics were retrospectively identified. Liver cirrhosis was defined as >14.5 kPa by transient elastography. The IL28B rs12979860 SNP was examined in a blinded fashion. Results A total of 304 HIV-HCV-coinfected individuals were analyzed (mean age, 43 years; 80% were male; and 85% were receiving antiretroviral therapy), of whom 18% had cirrhosis. IL28B genotype distribution was as follows: CC, 46%; CT, 43%; and TT, 11%. Cirrhosis was more frequent in CC than CT/TT carriers (24% vs 13%; P = .01). Logistic regression analysis revealed that older age (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.99-1.12]; P = .08), past alcohol abuse (OR, 1.97; 95% CI, 0.95-4.06; P = .07), and CC IL28B genotype (OR, 2.32; 95% CI, 1.22-4.41; P = .01) were predictors of cirrhosis. Interestingly, mean (SD) alanine aminotransferase (ALT) levels were greater (90 ± 53 vs 71 ± 33 IU/L;, P = .01) in IL28B CC than CT/TT carriers during the prior 4.8 ± 3.8 years. Conclusions The IL28B rs12979860 CC genotype is associated with a higher prevalence of cirrhosis in HIV-HCV-coinfected patients than CT/TT genotypes, suggesting that IL28B CC carriers may experience a more rapid progression of HCV-related liver fibrosis, perhaps as result of increased liver inflammation. Thus, access to HCV treatment is of utmost importance in IL28B CC carriers, in whom treatment response is better and in whom progression to cirrhosis might occur more rapidly.
Peijer Chen - One of the best experts on this subject based on the ideXlab platform.
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value of interleukin 28b genetic polymorphism on retreatment outcomes of chronic hepatitis c genotype 1 relapsers by peginterferon alfa plus ribavirin
Journal of Gastroenterology and Hepatology, 2014Co-Authors: Mingyao Chen, Chenhua Liu, Tingchih Chen, Peijer Chen, Dingshinn Chen, Jiahorng Kao, Chunjen LiuAbstract:Background and Aim Chronic hepatitis C (CHC) infection is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy remains the standard of care for CHC genotype 1 in many Asian countries, and single nucleotide polymorphism or genotype of the interleukin-28B (IL28B) gene is associated with the development of sustained virologic response (SVR). The predictive value of IL28B genotype for retreatment outcomes of patients with CHC was only partly clarified and deserves further investigation. Methods A total of 75 CHC genotype 1 Taiwanese patients who relapsed after 24-week PEG-IFN/RBV combination therapy and received retreatment with a 48-week PEG-IFN/RBV therapy were consecutively enrolled since November 2009. The associations among IL28B rs8099917 genotype, virologic kinetics, and treatment outcomes were evaluated. Results Rapid virologic response (RVR) at week 4, end-of-treatment virologic response (EOT-VR) and SVR was 37%, 73%, and 52%, respectively. Relapse rate was 29%. None of patients had rs8099917 GG genotype. Patients with TT genotype (n = 54, 72%) had higher rates of RVR (50% vs 5%, P = 0.0002), end-of-treatment virologic response (85% vs 43%, P = 0.0001), and SVR (67% vs 14%, P = 0.0001) than those with GT genotype (n = 21, 28%). Combination of IL28B TT genotype and achieving RVR had 85% positive and 90% negative predictive values of SVR. Conclusions About half of the Taiwanese CHC relapsers to a previous 24-week combination therapy achieve SVR after retreatment for 48 weeks. IL28B genotype influences on-treatment viral kinetics and SVR rate in these retreated patients. Baseline IL28B genotype and RVR can serve as early predictors for treatment success.
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association of il28b genotypes with metabolic profiles and viral clearance rate in chronic hepatitis c patients
Hepatology International, 2013Co-Authors: Chingsheng Hsu, Chenhua Liu, Peijer Chen, Dingshinn Chen, Chunjen Liu, Shihjer Hsu, Hungchia Chen, Jenher Jeng, Jiahorng KaoAbstract:Purpose IL28B genotypes have a strong impact on treatment outcomes of chronic hepatitis C (CHC) and on-treatment viral kinetics. Since metabolic regulation and interferon response are highly integrated, metabolic profiles may play an important role in the link between IL28B genotypes and hepatitis C virus (HCV) infection. Thus, the association of IL28B rs8099917 genotypes with metabolic profiles and the impact of metabolic profiles on hepatitis C viral kinetic parameters were examined.
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interleukin 28b genetic polymorphisms play a minor role in identifying optimal treatment duration in hcv genotype 1 slow responders to pegylated interferon plus ribavirin
Antiviral Therapy, 2012Co-Authors: Chenhua Liu, Peijer Chen, Chunjen Liu, Chengchao Liang, Taichung Tseng, Chihlin Lin, Shengshun Yang, Jouwei Lin, Junherng Chen, Dingshinn ChenAbstract:BACKGROUND Pegylated interferon and ribavirin for 72 weeks improve sustained virological response (SVR) in HCV genotype 1 (HCV-1) slow viral responders. Whether interleukin 28B (IL28B) single nucleotide polymorphism (SNP) genotypes and on-treatment viral responses can identify non-rapid virological response (RVR) patients who benefit from 48 or 72 weeks of therapy remains unclear. METHODS Treatment-naive HCV-1 patients who failed to achieve RVR were randomly assigned to receive 48 (n=168) or 72 (n=167) weeks of therapy. Baseline factors and on-treatment virological responses at weeks 8 and 12 were evaluated for SVR in 289 compliant patients who received ≥80% of drug dosages and treatment duration, and had end of follow-up viral response. The stratified SVR rates for independent factors were compared by treatment duration. RESULTS Treatment duration, IL28B rs8099917 genotypes, cirrhosis, week-8 viral response (undetectable HCV RNA at treatment week 8) and complete early virological response (cEVR) predicted SVR. In week-8 viral response patients, the SVR rates of 72-week and 48-week treatment were similar (75-88%), regardless of IL28B SNP genotypes or cirrhosis. In non-week-8 viral response patients who achieved cEVR, the SVR rate of 72-week treatment was higher than that of 48-week treatment for non-cirrhotic patients, regardless of IL28B SNP genotypes (91-100% versus 13-44%; P=0.001). CONCLUSIONS Although IL28B SNP genotypes predict SVR, they play a minor role when on-treatment viral responses are taken into consideration. On-treatment viral responses at weeks 8 and 12 are the key determinants to decide the optimal treatment duration in HCV-1 patients without RVR.
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interleukin 28b genetic polymorphisms and viral factors help identify hcv genotype 1 patients who benefit from 24 week pegylated interferon plus ribavirin therapy
Antiviral Therapy, 2011Co-Authors: Chenhua Liu, Chunjen Liu, Chengchao Liang, Taichung Tseng, Chihlin Lin, Shengshun Yang, Shihjer Hsu, Jouwei Lin, Junherng Chen, Peijer ChenAbstract:BACKGROUND Interleukin 28B (IL28B) single nucleotide polymorphism (SNP) genotypes and viral factors can predict sustained virological response (SVR) in HCV genotype-1 (HCV-1) patients receiving 48 weeks of pegylated interferon and ribavirin. Whether these factors would identify those patients who can benefit from a shorter duration of therapy remains unclear. METHODS Treatment-naive HCV-1 patients (n=662) receiving 24 or 48 weeks of combination therapy were enrolled. Baseline demographic data, HCV viral load, IL28B SNP genotypes (rs8099917), duration of therapy and rapid virological response (RVR) were evaluated to predict SVR. The SVR rates were further stratified by the independent factors and compared. RESULTS The IL28B rs8099917 TT genotype, low baseline viral load (HCV RNA≤600,000 IU/ml), RVR and 48-week therapy independently predicted SVR. In RVR patients with the IL28B rs8099917 TT genotype, the SVR rate of 24-week therapy was comparable to 48-week therapy (95% versus 99%; P=0.21) at low baseline viral load, but was inferior to 48-week therapy (70% versus 97%; P<0.001) at high baseline viral load. In non-RVR patients, the SVR rate of 24-week therapy was inferior to 48-week therapy for those with the IL28B rs8099917 TT genotype but high baseline viral load (23% versus 62%; P<0.001), and those with the IL28B rs8099917 GT/GG genotype but low baseline viral load (0% versus 33%; P=0.02). CONCLUSIONS HCV-1 patients simultaneously bearing the IL28B rs8099917 TT genotype, low baseline viral load and RVR can benefit from a shorter duration of combination therapy.
Karin Neukam - One of the best experts on this subject based on the ideXlab platform.
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variations at multiple genes improve interleukin 28b genotype predictive capacity for response to therapy against hepatitis c infection
AIDS, 2013Co-Authors: Karin Neukam, Pablo Barreiro, Antonio Caruz, Antonio Riverojuarez, Dolores Merino, Luis Miguel Real, Rocio Herrero, Angela Camacho, Vicente Soriano, Federico A Di LelloAbstract:OBJECTIVE To identify genetic factors that predict sustained virological response (SVR) to pegylated interferon (Peg-IFN)/ribavirin (RBV) in HIV/hepatitis C virus (HCV) genotype 1 or 4-coinfected patients and that enhance the predictive capacity of IL28B genotype in this population. DESIGN Prospective cohort study. SETTING Five tertiary care centers in Spain. PATIENTS Two hundred and five HIV/HCV genotype 1 or 4-coinfected patients who received a complete course of Peg-IFN/RBV for 48 weeks. MAIN OUTCOME MEASURES All individuals were genotyped for 144 single-nucleotide polymorphisms (SNPs). RESULTS One hundred and sixty-two (79%) patients bore HCV genotype 1. Overall SVR was achieved by 73 (36%) individuals. SNPs at the following genes were associated with SVR: IL28B, low-density lipoprotein receptor (LDLR), transforming growth factor β (TGF-β), aquaporine 2 (AQP-2), very-low-density lipoprotein receptor, Sp110 nuclear body protein, interferon alpha/beta receptor 1, 2'-5'-oligoadenylate synthase 1 and apolipoprotein B. There was a strong synergy between SNPs at IL28B, TGF-β and AQP-2 genes: the number of patients reaching SVR with all three favorable genotypes versus unfavorable genotypes were 22 (78.6%) versus 1 (7.1%) (P = 2.1 × 10). HCV baseline viral load, IL28B, TGF-β, AQP-2 and LDLR haplotypes were independently associated with SVR. CONCLUSION A number of genetic factors modify the predictive capacity of IL28B genotype. These can be used to identify HCV genotype 1 or 4-infected patients with a very high or a very low probability to respond to bitherapy with Peg-IFN/RBV. Predictive models based on these factors could be helpful to tailor direct acting antiviral-based therapy.
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the impact of interleukin 28b rs12979860 single nucleotide polymorphism and liver fibrosis stage on response guided therapy in hiv hcv coinfected patients
AIDS, 2013Co-Authors: M Mandorfer, Karin Neukam, Antonio Rivero, T Reiberger, B A Payer, Massimo Puoti, Christoph Boesecke, A Baumgarten, Anna Grzeszczuk, Robert ZangerleAbstract:OBJECTIVE According to the European AIDS Clinical Society (EACS) guidelines for response-guided therapy (RGT) of chronic hepatitis C virus (HCV) infection in HIV-positive patients, HCV-genotype (GT) and rapid virologic response (RVR) exclusively determine the duration of antiviral therapy with pegylated interferon and ribavirin (PEGIFN+RBV). The aim of this study was to investigate the impact of interleukin 28B rs12979860 single nucleotide polymorphism (IL28B) and liver fibrosis stage on RGT in HIV/HCV-coinfected patients. DESIGN Four hundred and thirty HIV/HCV-coinfected patients treated with PEGIFN+RBV were included in this multinational, retrospective analysis. METHODS Advanced liver fibrosis was defined as either METAVIR F3/F4 or liver stiffness more than 9.5 kPa. RESULTS In patients with GT1/4 without RVR (GT1/4-noRVR), higher sustained virologic response (SVR) rates were observed in patients with extended treatment duration (48 weeks: 35% vs. 72 weeks: 60%; P = 0.008). In GT1/4-noRVR patients without advanced liver fibrosis (48 weeks: 45% vs. 72 weeks: 61%; P = 0.176), or with IL28B C/C (48 weeks: 48% vs. 72 weeks: 69%; P = 0.207), SVR rates did not vary significantly throughout the treatment duration subgroups. In contrast, in patients with advanced liver fibrosis (48 weeks: 11% vs. 72 weeks: 45%; P = 0.031), or IL28B non-C/C (48 weeks: 28% vs. 72 weeks: 56%; P = 0.011), extended treatment duration was associated with substantially higher SVR rates. GT2/3 patients with RVR (GT2/3-RVR) with shortened treatment duration (24 weeks) displayed SVR rates ranging from 83 to 100%, regardless of IL28B and liver fibrosis stage. CONCLUSION Our study confirms the concept of RGT in HIV/HCV coinfection and supports the extension of therapy duration to 72 weeks for patients with GT1/4-noRVR, especially in patients with IL28B non-C/C or advanced liver fibrosis. The results of our study strongly support the shortening of therapy duration to 24 weeks in GT2/3-RVR patients, regardless of IL28B and advanced liver fibrosis.
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prediction of response to pegylated interferon plus ribavirin in hiv hepatitis c virus hcv coinfected patients using hcv genotype il28b variations and hcv rna load
Journal of Hepatology, 2012Co-Authors: Karin Neukam, Norma Rallon, Antonio Rivero, Jose Miguel Benito, Antonio Caruz, Angela Camacho, Almudena Torrescornejo, Jurgen K Rockstroh, Juan Macias, Luis F LopezcortesAbstract:Background & Aims: This study aimed at developing a predictive algorithm based on interleukin 28B (IL28B) genotype, hepatitis C virus (HCV) genotype, and plasma HCV-RNA load, which could accurately allow us to define the probability of response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy in HIV/HCV-coinfected patients. Methods: Five hundred and twenty-one treatment-naive HIVinfected patients, who initiated HCV therapy with Peg-IFN/RBV, were analysed in an on-treatment basis. Patients were categorized as unlikely responders, uncertain responders, and anticipated responders ( 60% probability to achieve SVR, respectively). Results: HCV genotype, baseline HCV-RNA load, and IL28B genotype were confirmed as independent predictors of SVR in a logistic regression analysis. A stepwise algorithm based on these three variables was created based on 321 patients and evaluated in the remaining 200 patients. Unlikely responders included patients with genotype 1 or 4, HCV-RNA load P600,000 IU/ml, and rs12979860 non-CC (rate of SVR: 17.3%). Anticipated responders were those with HCV genotype 2–3, patients harboring HCV genotype 4 and IL28B CC, as well as those who simultaneously bore HCV genotype 1, HCV-RNA load <600,000 IU/ml, and IL28B CC (rate of SVR 74.1%, 77.8%, and 64.4%, respectively). The area under the receiver operating characteristic curve of the model was 0.77 (0.733–0.814). Conclusions: The combined use of IL28B genotype, HCV genotype, and HCV-RNA load enables to easily identify patients with a high and very low likelihood of SVR. HCV therapy could be deferred in the latter patients, until more effective options are available, at least if they do not show advanced liver fibrosis. 2011 European Association for the Study of the Liver. Published
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influence of interleukin 28b single nucleotide polymorphisms on progression to liver cirrhosis in human immunodeficiency virus hepatitis c virus coinfected patients receiving antiretroviral therapy
The Journal of Infectious Diseases, 2011Co-Authors: Pablo Barreiro, Juan A Pineda, Norma Rallon, Susanna Naggie, Luz Martincarbonero, Karin Neukam, Antonio Rivero, Jose Miguel Benito, Antonio Caruz, Eugenia VispoAbstract:Background Single-nucleotide polymorphisms (SNPs) near the IL28B gene have recently been associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapies in patients with chronic hepatitis C. Because human immunodeficiency virus (HIV) coinfection appears to accelerate HCV-related liver fibrosis progression, any influence of IL28B SNP on the risk of developing cirrhosis might be more easily recognized in the coinfected population. Methods All HIV-HCV-coinfected patients who underwent hepatic elastography before initiating a course of pegylated interferon plus ribavirin therapy at 2 Spanish clinics were retrospectively identified. Liver cirrhosis was defined as >14.5 kPa by transient elastography. The IL28B rs12979860 SNP was examined in a blinded fashion. Results A total of 304 HIV-HCV-coinfected individuals were analyzed (mean age, 43 years; 80% were male; and 85% were receiving antiretroviral therapy), of whom 18% had cirrhosis. IL28B genotype distribution was as follows: CC, 46%; CT, 43%; and TT, 11%. Cirrhosis was more frequent in CC than CT/TT carriers (24% vs 13%; P = .01). Logistic regression analysis revealed that older age (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.99-1.12]; P = .08), past alcohol abuse (OR, 1.97; 95% CI, 0.95-4.06; P = .07), and CC IL28B genotype (OR, 2.32; 95% CI, 1.22-4.41; P = .01) were predictors of cirrhosis. Interestingly, mean (SD) alanine aminotransferase (ALT) levels were greater (90 ± 53 vs 71 ± 33 IU/L;, P = .01) in IL28B CC than CT/TT carriers during the prior 4.8 ± 3.8 years. Conclusions The IL28B rs12979860 CC genotype is associated with a higher prevalence of cirrhosis in HIV-HCV-coinfected patients than CT/TT genotypes, suggesting that IL28B CC carriers may experience a more rapid progression of HCV-related liver fibrosis, perhaps as result of increased liver inflammation. Thus, access to HCV treatment is of utmost importance in IL28B CC carriers, in whom treatment response is better and in whom progression to cirrhosis might occur more rapidly.
