From current status to optimization of HCV treatment: Recommendations from an expert panel

Abstract

Chronic hepatitis C virus (HCV) infection is a major public health problem at a global level, causing an enormous burden of hepatic and extra-hepatic morbidity and mortality. Treatment of chronic HCV (CHC) has been revolutionized in the last few years by the introduction of highly effective and well tolerated direct acting antiviral agents (DAAs) able to achieve >90% rates of sustained virological response (SVR) in many groups of patients, including those previously excluded from interferon-based regimens. For such reason interferon-free regimens are now the treatments of choice for all patients. Successful anti-HCV treatment can stop liver disease progression and can solve the HCV-related extra hepatic manifestations, eventually reducing both liver-related and overall mortality. Together with the rapidly accumulating data about the evolution of treatment landscape, different guidelines from national and international Liver Scientific Societies have been published until today. However, these recommendations may not be applied worldwide as, due to high treatment costs, most of them identify as priority groups only patients with advanced liver disease. Moreover some types of patients pose clinical management problems for which even the guidelines do not always provide useful answers. With the aim of treatment optimization by filling some of the gaps of the current guidelines and addressing the remaining unmet needs in practice, a group of Italian experts, experienced on treatment of HCV infection, met in Stresa in February 2016. The summary of all the considerations arising from this two-day meeting and the final statements are reported in this position paper.

Multiclass HCV resistance to direct‐acting antiviral failure in real‐life patients advocates for tailored second‐line therapies

“…Considering all these aspects, today patients that failed a NS5A inhibitor‐containing regimen are considered “difficult‐to‐retreat”, and NS5A‐free retreatment strategies are generally encouraged, or retreatments should be based on triple or quadruple DAA regimens, including a drug with a high barrier to resistance (currently, SOF), plus a combination of NS3+NS5A inhibitors…”

“…Moreover, around 9.0% of failing patients presented “extra‐target” RASs, probably because of natural resistance. Patients who show RASs at three DAA classes, or in both NS3 and NS5A targets are currently the most difficult to retreat, indeed they have no chances of retreatment with commercially available IFN‐free regimens and could be managed only by multiple DAA combinations targeting nearly all replication steps …”

“…In these patients, it is recommended to test for NS5A and NS3 RASs . Interestingly, the resistance testing for all three genes (NS3, NS5A and NS5B), at virological failure after a DAA‐based regimen, was proposed, by a panel of Italian experts on HCV treatment in a recent paper, in order to better guide retreatment decisions …”

“…2 Interestingly, the resistance testing for all three genes (NS3, NS5A and NS5B), at virological failure after a DAA-based regimen, was proposed, by a panel of Italian experts on HCV treatment in a recent paper, in order to better guide retreatment decisions. 25 Therefore, more real-life data are required to improve knowledge regarding the types of failures, the characteristics of patients who fail and the role of HCV drug-resistance testing in this setting. Starting from all these observations, the aim of this study was to characterize the presence of clinically relevant RASs in all the three genes (including NS5B) in a real-life setting of patients who failed a DAA-containing regimen.…”

Implications of hepatitis C virus subtype 1a migration patterns for virus genetic sequencing policies in Italy

“…Due to the rapid evolution of HCV treatments that achieve high viral cure rates, the regimen simeprevir with sofosbuvir, largely used as first-line treatment so far in Europe and in Italy [18, 19], has recently been categorized as suboptimal for HCV1a infected patients [20]. Nonetheless, second-line NS5A inhibitor-based regimens can still be considered when the absence of relevant RAVs is confirmed [21]. Despite this shift from NS3-targeting DAAs to those that inhibit the NS5A protein, a thorough analysis of the patterns of virus flow based on the NS3 region remains valuable because HCV only rarely recombines [22], and migration patterns inferred from small genomic regions hence have a genome-wide representativeness.…”