Clinical value of on-treatment HCV RNA levels during different approved sofosbuvir-based antiviral regimens.
Maasoumy B., et al.
J Hepatology 2016 ; April 13 (Epub ahead of print)

Background & Aims : EASL guidelines recommend HCV-RNA measurements at specific time-points during sofosbuvir(SOF)-therapy. However, it remains unclear, how these results should be interpreted. We aimed to analyse whether on-treatment HCV-RNA levels predict relapse comparing the CobasAmpliPrep/CobasTaqMan v2.0 (CAP/CTM) and Abbott RealTime HCV (ART) assays.

Methods : Samples were collected from 298 patients(HCV-genotypes; GT1-5) at weeks(w) 0, 1, 2, 4, 8, 12, 16, 20 and 24 during SOF-based therapy at two University clinics and tested for HCV-RNA level by CAP/CTM and ART. Patients were treated with SOF/ribavirin(RBV) 12/24w (n=99), pegylated-interferon-alfa(Peg-IFN)/SOF/RBV 12w (n=51), SOF/simeprevir(SMV)±RBV 12w (n=69) or SOF/daclatasvir±RBV 12/24w (n=79).

Results : HCV-RNA levels during the first 4 weeks of SOF/RBV-therapy were significantly lower in GT3-patients who achieved SVR compared with those who relapsed. All GT3-patients with a week 2 result <45IU/ml by CAP/CTM achieved SVR but only 33% of those with ≥45IU/ml(p=0.0003). Similar results were documented with ART and 60IU/ml as cut-off (SVR:100% vs. 29%;p=0.0002). In contrast, HCV-RNA levels during early treatment phases were not significantly related to relapse in patients treated with other SOF-based regimens. Residual HCV-RNA was frequently detected by ART at later stages of therapy. However, SVR-rates remained high in these patients. At the end of SOF/SMV±RBV6 therapy HCV-RNA was detectable with ART in 20% of patients, of whom 92% achieved SVR.

Conclusions : HCV-RNA levels assessed at week 2 of SOF/RBV-therapy can predict relapse in GT3-patients. Detectable HCV-RNA results at later stages during SOF-based therapy may occur frequently with the more sensitive ART. However, this should not lead to treatment extension.

Expert's Commentary

The practical impact of this paper is not marginal. For years we have been using on- treatment viral kinetics to individualize IFN-based treatment duration for our chronic HCV infected patients. Now, with the use of Direct Antiviral Agents the meaning of this predictor can be considered insignificant. The only exception seems to be presented in this study identifying, in patients with genotype 3 infection a week 2 HCV RNA >45 IU/ml by Cobas Ampli Prep/CobaseTaqMan or >60 IU/ml by Abbott Real Time, as predictive of relapse. This result appears of immediate utility, although with the arrival of new and more potent combinations for treatment of genotype 3 patients, such as the combination of velpatasvir and sofosbuvir, the week 2 prediction can be expected to be less relevant. Interestingly, the study clarifies also the issue of a residual viremia at the end of treatment. Until now no systematic evaluation of this observed phenomenon was available. Detectable HCV RNA below the quantification threshold, at the end of the established treatment duration can be observed in up to 20% of patients receiving oral antivirals. According to the study results, we should not consider a residual viremia as predictive of relapse. As shown in this study, in 92% of subjects this residual HCV RNA was not followed by a relapse and should not generate attempts to extend treatment duration.

Alessandra Mangia, San Giovanni Rotondo, Italy