Ultrasensitive HCV RNA Quantification in Antiviral Triple Therapy: New Insight on Viral Clearance Dynamics and Treatment Outcome Predictors.

Anna Rosa Garbuglia,Gianpiero D’Offizi,Maria Rosaria Capobianchi,Filippo Castiglione,Ubaldo Visco-Comandini,Chiara Taibi,Marzia Montalbano,Raffaella Lionetti,Daniele Lapa,Paola Paci,Tatsuo Kanda

doi:10.1371/journal.pone.0158989

Abstract

ObjectivesIdentifying the predictive factors of Sustained Virological Response (SVR) represents an important challenge in new interferon-based DAA therapies. Here, we analyzed the kinetics of antiviral response associated with a triple drug regimen, and the association between negative residual viral load at different time points during treatment.MethodsTwenty-three HCV genotype 1 (GT 1a n = 11; GT1b n = 12) infected patients were included in the study. Linear Discriminant Analysis (LDA) was used to establish possible association between HCV RNA values at days 1 and 4 from start of therapy and SVR. Principal component analysis (PCA) was applied to analyze the correlation between HCV RNA slope and SVR. A ultrasensitive (US) method was established to measure the residual HCV viral load in those samples which resulted “detected <12IU/ml” or undetectable with ABBOTT standard assay, and was retrospectively used on samples collected at different time points to establish its predictive power for SVR.ResultsAccording to LDA, there was no association between SVR and viral kinetics neither at time points earlier than 1 week (days 1 and 4) after therapy initiation nor later. The slopes were not relevant for classifying patients as SVR or no-SVR. No significant differences were observed in the median HCV RNA values at T0 among SVR and no-SVR patients. HCV RNA values with US protocol (LOD 1.2 IU/ml) after 1 month of therapy were considered; the area under the ROC curve was 0.70. Overall, PPV and NPV of undetectable HCV RNA with the US method for SVR was 100% and 46.7%, respectively; sensitivity and specificity were 38.4% and 100% respectively.ConclusionHCV RNA “not detected” by the US method after 1 month of treatment is predictive of SVR in first generation Protease inhibitor (PI)-based triple therapy. The US method could have clinical utility for advanced monitoring of virological response in new interferon based DAA combination regimens.

Highlights

In 2011, the first direct-acting antiviral drugs (DAA), telaprevir (TPV) and boceprevir (BCV) were approved for treatment of chronic HCV genotype 1 infection [1,2,3,4,5]
HCV RNA “not detected” by the US method after 1 month of treatment is predictive of sustained virological response (SVR) in first generation Protease inhibitor (PI)-based triple therapy
The importance of HCV RNA decline in early phases of treatment as a predictor of SVR has been observed in triple therapy with simeprevir, Peg-interferon and ribavirin in patients infected with genotype 1 [12]

Summary

Introduction

In 2011, the first direct-acting antiviral drugs (DAA), telaprevir (TPV) and boceprevir (BCV) were approved for treatment of chronic HCV genotype 1 infection [1,2,3,4,5]. HCV RNA measurements at baseline and during treatment were used to define the optimum moment for early discontinuation of treatment in virological non-responders and the treatment duration for patients responding to therapy (response guided therapy, RGT). Several studies underlined the importance of accurate quantification of the HCV RNA viral load when making decisions about shortening or extending treatment [8,9]. In the definition of sustained virological response (SVR) for patients treated with a triple combination of TPV/PEG-IFN/RBV, a viral load

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