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Maintenance of Th1 hepatitis C virus (HCV)-specific responses in individuals with acute HCV who achieve sustained virological clearance after treatment.

ABSTRACT: T-cell responses against hepatitis C are believed to be critical in achieving both natural and treatment-induced clearance. However, rapid clearance of antigen with early treatment of primary infection may result in reduced or poorly sustained cellular immunity. This study longitudinally examined Th1 and Th2 hepatitis C virus (HCV)-specific cytokine production and T-cell effector function from subjects enrolled in the Australian Trial in Acute Hepatitis C comparing three groups: treatment-induced clearance (sustained virological response [SVR]), treatment non-response, and untreated spontaneous clearance.HCV-specific T-cell responses were characterized by HCV peptide ELISpot, in vitro cytokine production, and T-cell flow cytometry assays.Treated subjects with a sustained virological response (SVR) displayed a better maintenance of HCV-specific Th1 responses compared to treatment non-responders (higher interferon [IFN]-? and interleukin (IL)-2 magnitude at week 24, broader IFN-? responses at weeks 24 and 48, P?

SUBMITTER: Flynn JK

PROVIDER: S-EPMC3808486 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Maintenance of Th1 hepatitis C virus (HCV)-specific responses in individuals with acute HCV who achieve sustained virological clearance after treatment.

Flynn Jacqueline K JK Dore Gregory J GJ Hellard Margaret M Yeung Barbara B Rawlinson William D WD White Peter A PA Kaldor John M JM Lloyd Andrew R AR Ffrench Rosemary A RA

Journal of gastroenterology and hepatology 20131101 11

<h4>Background and aim</h4>T-cell responses against hepatitis C are believed to be critical in achieving both natural and treatment-induced clearance. However, rapid clearance of antigen with early treatment of primary infection may result in reduced or poorly sustained cellular immunity. This study longitudinally examined Th1 and Th2 hepatitis C virus (HCV)-specific cytokine production and T-cell effector function from subjects enrolled in the Australian Trial in Acute Hepatitis C comparing thr ...[more]

PMID: 23663030

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Project description:OBJECTIVE:The role of ribavirin (RBV) in the treatment of recent hepatitis C virus (HCV) (acute/early chronic) is unclear, particularly in HIV-infected individuals. This study evaluated early virological decline during recent HCV therapy in HIV-uninfected individuals receiving pegylated interferon (PEG-IFN) monotherapy and HIV-infected individuals receiving PEG-IFN/RBV. DESIGN:The Australian Trial in Acute Hepatitis C was a nonrandomized prospective study of patients with recent HCV. METHODS:All participants received PEG-IFN (24 weeks); HCV/HIV participants also received RBV. Early HCV RNA decline was assessed among adherent participants (?80% PEG-IFN, ?80% treatment). Logistic regression identified predictors of rapid virological response (RVR) (<10 IU/ml). RESULTS:Of 109 treated, 82% were adherent (HCV, n=57; HCV/HIV, n=32). Overall, RVR was 51% (HCV: 55% vs. HCV/HIV: 43%; P=0.323). Factors independently associated with RVR included duration of infection less than 26 weeks, HCV RNA below 5.6 log(10) IU/ml at baseline and HCV genotype 2/3 infection. Between baseline and week 12, mean decline in HCV RNA was greater in HCV/HIV participants (PEG-IFN/RBV) compared to HCV participants (PEG-IFN) (4.19 vs. 3.32 log(10) IU/ml; P=0.029). Greater HCV RNA decline was observed in those treated with RBV, particularly amongst those with an estimated duration of infection at least 26 weeks and those with unfavourable IL28B genotypes. Adherent HIV-uninfected and infected participants had similar early virological response (76 vs. 90%; P=0.102) and sustained virological response (63 vs. 75%; P=0.253), respectively. RVR was highly predictive of sustained virological response (adjusted odds ratio 4.09; 1.49, 11.25). CONCLUSION:The results of this study suggest a potential benefit for PEG-IFN and RBV combination therapy in maximizing virological responses in HCV/HIV participants with recent HCV, particularly those with a longer duration of HCV infection and unfavourable IL28B genotypes.

Project description:UnlabelledRetrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P < 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR.ConclusionPatients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/liver transplantation, and in liver-related morbidity/mortality, although they remain at risk for HCC.

Project description:BackgroundTo explore associations between PON1 rs854560, rs662, 705,379, HCV clearance, and interactions between tested PON1 single nucleotide variants (SNVs) and interferon-λ4 gene (IFNL4) rs368234815 variant in hemodialyzed individuals.MethodsThe study included 83 HD individuals who spontaneously resolved HCV infection (all had known IFNL4 rs368234815 variant) and 104 individuals with persistently positive blood tests for HCV RNA (102 were IFNL4 rs368234815 variant successfully genotyped). We genotyped PON1 by high-resolution melt analysis (rs662) or predesigned TaqMan SNV Genotyping Assay (rs854560, rs705379). We used a logistic regression model to assess the association between genetic data and HCV outcome while adjusting for clinical confounding variables. Epistatic interactions between tested PON1 SNVs and IFNL4 rs368234815 were analyzed by the multifactor dimensionality reduction method.ResultsIn the recessive inheritance model, PON1 rs662 GG (OR 9.94, 95% CI 1.20-82.7, P = 0.022) and rs854560 TT (OR 4.31, 95% CI 1.62-11.5, P = 0.003) genotypes were associated with a higher probability for HCV clearance. The haplotype composed of rs662A_rs854560A_rs705379 was not associated with spontaneous HCV clearance. The IFNL4 rs368234815 TT/TT variant was equally distributed among individuals bearing different PON1 SNVs. The epistatic gene-gene analysis did not reveal the interaction between tested PON1 SNVs and IFNL4 rs368234815 (P = 0.094). Regression model, including the PON1 rs662 GG genotype, the PON1 rs854560 genotype, the IFNL4 rs368234815 TT/TT genotype, age at RRT onset, RRT duration, and chronic glomerulonephritis as possible explanatory variables for spontaneous HCV clearance, showed that significant predictors of spontaneous HCV clearance were the IFNL4 rs368234815 TT/TT genotype (OR 2.607, 95% CI 1.298-5.235, P = 0.007), PON1 rs854560 TT (OR 6.208, 1.962-19.644, P = 0.002), PON1 rs662 GG (OR 10.762, 1.222-94.796, P = 0.032), and RRT duration (OR 0.930, 95% CI 0.879-0.984, P = 0.011).ConclusionIn HD individuals, PON1 rs662 GG and rs854560 TT are associated with a higher frequency of spontaneous HCV clearance.

Dataset Information

Maintenance of Th1 hepatitis C virus (HCV)-specific responses in individuals with acute HCV who achieve sustained virological clearance after treatment.

Publications

Maintenance of Th1 hepatitis C virus (HCV)-specific responses in individuals with acute HCV who achieve sustained virological clearance after treatment.

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