Recombinant HCV type 5 Nonstructural Protein 5 (a.a. 2212-2313)

We examined the proliferative responses of peripheral blood mononuclear cells obtained from 60 untreated patients who were seropositive by enzyme immunoassay, but negative for hepatitis C virus (HCV) RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). We used second- and third-generation recombinant immunoblot assay (RIBA) for further serological characterization. In vitro HCV-specific proliferative responses of mononuclear cells were compared to those of both untreated chronic HCV patients and patients who showed sustained virological response to interferon-alpha monotherapy, in order to assess the relative contribution of the immune response to the eradication of HCV. We found that frequency of responses to nonstructural proteins showed statistically significant differences, which were attributable to vigorous, polyspecific responses by cells from the RIBA-positive patients. In this group, core-specific proliferation was significantly associated with intravenous drug use as route of acquisition. Both other patient groups and the RIBA-indeterminate patients showed indistinguishable frequencies of proliferative responses. No association was detected between residual humoral responses, as determined from the RIBA results, and elapsed time since infection. The frequency of antibodies to NS5 differs between spontaneous cure and chronically infected patients. Cell-mediated and humoral immunity appear to be maintained in this population of patients.

Failure to respond to the approved combinations of multiple direct-acting antiviral agents is relatively low in hepatitis C virus treatment registration studies, with rates of 1% to 7%, depending on the patients' baseline characteristics. In real life, failure is slightly higher, likely because of lower compliance. Treatment failures are usually related to relapse and less often to on-treatment viral breakthrough. Hepatitis C drug-resistant variants are detected in most patients who do not achieve viral eradication. The risk of developing these variants depends on host- and virus-related factors, the properties of the drugs used, and the treatment strategies applied. Patients who carry resistance-associated variants may not obtain benefits from treatment and are at risk of disease progression and transmission of the variants. Whether hepatitis C resistance-associated variants persist depends on their type: NS3-4A variants often disappear gradually after therapy is stopped, whereas NS5A variants tend to persist for more than 2 years. The best way to prevent emergence of resistant variants is to eliminate the virus at the first treatment using highly potent antivirals with genetic barriers to resistance. In patients failing first-generation protease inhibitors, combination therapies with sofosbuvir and NS5 inhibitors have proven effective. Some salvage regimens can be shortened to 12 weeks by addition of ribavirin. The optimal treatment for patients who fail an NS5A inhibitor and those with multidrug-resistant variants remains to be defined, and research efforts should continue to focus on treatment for these patients. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.