Role of the Host Immunity in the Non-response to DAA Therapy

Study objective and Hypothesis The underlying hypothesis of the project is that the level of anti-viral immune dysfunction in chronic HCV infection is a causal factor which can influence non-response to therapy. However, information about the features of individual anti-viral T cell responses expressed by naïve chronic HCV patients before starting DAA therapy in relation to the subsequent outcome of treatment and their possible impact on the failure to control infection is not available. The few available results on anti-HCV immune responses in chronic HCV infection have been generated in patients treated with DAA regimens which are not included in the present guidelines without evaluation according to the outcome. Aim of the present study will be thus to understand whether non-response to therapy is associated with a wider and deeper anti-viral immune dysfunction, by comparing individual HCV-specific T cell responses in two groups of responder and non-responder patients. The assumption made is that possible defects of T cell responses associated with the failure to respond to DAA therapy should not be substantially modified by an ineffective treatment allowing to characterize the immunological background of non responder patients after the end of an ineffective cycle of therapy and to compare results with baseline pretreatment responses of naïve, viremic patients who subsequently clear the virus. A pre-treatment analysis also for non responder patients would require to enroll a huge number of naive patients in order to identify a sufficient number of non responder patients, making the study unfeasible and exceedingly long. By this strategy, recruitment will be instead very rapid because most patients enrolled at baseline are expected to be responder, while non responder patients who will be studied after the end of therapy and after an adequate wash-out period of 6 to 12 months and before starting re-treatment have already been identified in the collaborating Centers and will be readily available for the study as soon as the protocol is approved. Based on the results, possible objective of future analyses could be to characterize further at a molecular level the T cell functional defects of non-responder patients to define whether and by which strategies their correction can represent a feasible approach to induce/restore an efficient anti-viral response to complement and strengthen the effect of last generation DAA. Finally, characterization of protective immunity in non-responder patients could allow to identify baseline predictors of non-response to therapy to be used in the daily clinical practice.

Study background The rate of sustained viral response (SVR) in naïve non-cirrhotic patients treated with IFN-free DAAs is between 95% and 100%, but the response rate is lower in specific subgroups of patients, including genotype 3 cirrhotics and patients with decompensated cirrhosis, irrespective of the infecting genotype. The high efficacy of DAA-based therapies is confirmed in real-world cohorts, which show a rate of SVR only slightly lower than registration studies. Although the rate of failure to DAA therapy is quite limited (around 5%), the overall number of non-responder patients is expected to be high because of the high number of chronically HCV infected patients who need treatment. Treatment failure most frequently results in relapse and less often in on-treatment viral breakthrough. Different factors are believed to be implicated in non-response to therapy, including emergence of resistance mutations, suboptimal treatment due to incorrect genotype definition and advanced liver disease.

The role of baseline RAVs in determining treatment failure is still debated and baseline resistance testing appears to have limited clinical utility. Instead, emergence of RAVs during DAA-based regimens and its role in determining virological failure is well documented. Even if drug-resistant variants are detected in a large proportion of non-responder patients, their role in impairing treatment efficacy is however not totally clear.

The use of currently available second-generation commercial assays for HCV genotyping has reduced the risk of genotype misclassification, but the possibility of mixed infections with a percentage of different genotypes/subtypes below the sensitivity of the methods applied in the clinical practice is still a possible cause of non response to therapy due to suboptimal treatment.

Emergence of resistant strains and suboptimal treatment due to incorrect genotype detection can however explain only part of treatment failure cases and host-related factors may play a role, in particular the anti-viral immune response. Indeed, innate and adaptive immune responses are known to be deeply impaired in chronic HCV infection but very limited information is available about the possible contribution that background immune responses can give to the final outcome of DAA treatment. In contrast to PegIFN-based therapies, recent studies in DAA treated patients indicate that frequency and function of HCV-specific CD8 cells can increase under IFN-free therapies with partial reversal of their exhausted phenotype. Moreover, DAA therapy can modulate the NK cell compartment correcting the NK cell activated phenotype which is typical of chronic HCV patients. Thus, the level of baseline impairment of anti-viral immunity might influence the subsequent likelihood of immune restoration upon therapy with more chances of resistance to DAA treatment when baseline immune inhibition is deeper and wider. This hypothesis requires to be tested.