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T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee.

ABSTRACT: Memory CD8+ T cells generated by spontaneous resolution of hepatitis C virus (HCV) infection rapidly control secondary infections and reduce the risk of virus persistence. Here, CD8+ T-cell immunity and response to reinfection were assessed in a chimpanzee cured of an earlier chronic infection with an interferon (IFN)-free antiviral regimen. CD8+ T cells expanded from liver immediately before and 2 years after cure of chronic infection with two direct-acting antivirals (DAAs) targeted epitopes in the E2, nonstructural (NS)5a, and NS5b proteins. A second infection to assess CD8+ T-cell responsiveness resulted in rapid suppression of HCV replication by week 2, but viremia rebounded 3 weeks later and the infection persisted. The E2, NS5a, and NS5b proteins remained dominant CD8+ T-cell targets after reinfection. Resurgent HCV replication was temporally associated with mutational escape of NS5a and NS5b class I epitopes that had also mutated during the first chronic infection. Two epitopes in E2 remained intact throughout both persistent infections. Intrahepatic CD8+ T cells targeting intact and escape-prone epitopes differed in expression of phenotypic markers of functional exhaustion 2 years after successful DAA therapy and in the capacity to expand in liver upon reinfection.The intrahepatic HCV-specific CD8+ T-cell repertoire established during chronic infection was narrowly focused, but very stable, after cure with DAA. Existing intrahepatic CD8+ T cells targeting dominant epitopes of the challenge virus failed to prevent persistence. Vaccination after DAA cure may be necessary to broaden T-cell responses and reduce the risk of a second persistent infection.

SUBMITTER: Callendret B

PROVIDER: S-EPMC4242208 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee.

Callendret Benoit B Eccleston Heather B HB Hall Shelby S Satterfield William W Capone Stefania S Folgori Antonella A Cortese Riccardo R Nicosia Alfredo A Walker Christopher M CM

Hepatology (Baltimore, Md.) 20140925 5

<h4>Unlabelled</h4>Memory CD8+ T cells generated by spontaneous resolution of hepatitis C virus (HCV) infection rapidly control secondary infections and reduce the risk of virus persistence. Here, CD8+ T-cell immunity and response to reinfection were assessed in a chimpanzee cured of an earlier chronic infection with an interferon (IFN)-free antiviral regimen. CD8+ T cells expanded from liver immediately before and 2 years after cure of chronic infection with two direct-acting antivirals (DAAs) ...[more]

PMID: 24975498

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Project description:Patients' experience during treatment may affect treatment adherence. Our aim was to assess the impact of patient-reported outcomes (PROs) on adherence to different anti-hepatitis C virus (HCV) regimens.Clinical, demographic, and PRO data (short form-36 [SF-36], chronic liver disease questionnaire-hepatitis C version [CLDQ-HCV], functional assessment of chronic illness therapy-fatigue [FACIT-F], work productivity and activity impairment: specific health problem [WPAI:SHP]) from 13 multinational clinical trials of anti-HCV treatment were available. Treatment adherence was defined as >80% of prescribed doses taken.Included were 4825 HCV patients. Regimens were grouped into: interferon- and ribavirin (RBV)-containing (±sofosbuvir [SOF]), interferon-free RBV-containing (RBV?+?SOF?±?ledipasvir [LDV]), and interferon-free RBV-free (LDV/SOF). The adherence to these regimens were 77.6%, 84.3%, and 96.2%, respectively (P?<?0.0001). Nonadherent patients were more likely to be unemployed and to have a greater PRO impairment at baseline (up to -5.3% lower PRO scores, P?<?0.0001). During treatment with interferon- or RBV-based regimens, nonadherent patients experienced lower PROs and had larger decrements from their baseline PRO scores. In contrast, there were no significant declines in PRO scores (all P?>?0.05) for the small number of patients who were nonadherent to LDV/SOF. In multivariate analysis, being treatment-naive, longer treatment duration, and receiving an interferon- or RBV-containing regimen were associated with a lower likelihood of adherence (all P?<?0.003). Better baseline and on-treatment PRO scores were associated with a higher likelihood of adherence to interferon and RBV.The use of interferon and/or RBV, longer duration of treatment, and lower baseline and on-treatment PRO scores were linked to a decreased likelihood of being adherent to interferon?+?RBV-containing or interferon-free RBV-containing antiviral regimens. Interferon- and RBV-free regimens were associated with excellent adherence.

Project description:Background and Aims: Genotype (GT) 1 remains the predominant hepatitis c virus (HCV) GT in Chinese patients. Over 80% of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860, which is favorable for interferon-based treatment regimens. This phase III clinical trial aimed to evaluate the efficacy and safety of the ritonavir-boosted danoprevir plus pegylated-interferon α-2a and ribavirin regimen for 12 weeks in treatment-naïve mainland Chinese patients infected with HCV GT1 without cirrhosis. Methods: One hundred and forty-one treatment-naïve, non-cirrhotic HCV GT1 Chinese patients (age ≥18 years) were enrolled for this single-arm, multicenter, phase III MANASA study (NCT03020082). Patients received a combination of ritonavir-boosted danoprevir (100 mg/100 mg) twice a day plus subcutaneous injection of weekly pegylated-interferon α-2a (180 μg) and oral ribavirin (1000/1200 mg/day body weight <75/≥75 kg) for 12 weeks. The primary end-point was sustained virologic response rate at 12 weeks after the end of treatment. The secondary end-points were safety outcomes, tolerability, virologic response over time and relapse rate. Results: All enrolled patients were HCV GT1-infected, and most among them (97.9%, 123/141) had the HCV GT1b subtype. Single-nucleotide polymorphism test showed that the majority of patients were of the IFNL4 rs12979860 CC genotype (87.2%, 123/141). Overall, 140 patients completed the 12-week treatment, and 97.1% (136/140) patients achieved sustained virologic response at 12 weeks (per protocol population group, 95% confidence interval: 92.9-99.2%). Only drug-related serious adverse event occurred. Most of the adverse events were grade 1 and grade 2 alanine aminotransferase elevation or liver dysfunction. One patient discontinued treatment because of severe head injury in a car accident. Conclusions: The triple regimen of ritonavir-boosted danoprevir plus pegylated-interferon α-2a and ribavirin produced a sustained virologic response rate of 97.1% after 12 weeks treatment in noncirrhotic HCV GT1-infected Chinese patients, and was safe and well tolerated. Trial Registration Clinical-Trials.gov Identifier: NCT03020082.

Dataset Information

T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee.

Publications

T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee.

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