Original Article
Interferon-free treatment choice according to baseline RASs leads to high SVR rates in HCV genotype 1 infected patients

https://doi.org/10.1016/j.jiac.2018.02.008Get rights and content

Abstract

Aim

Different combinations of direct antiviral agents (DAA) lead to high SVR rates in HCV genotype 1 infected patients. However, presence of baseline resistance-associated substitutions (RASs) represents a major risk factor for treatment failure. It is unknown whether choice of treatment based on RASs has the potential to decrease virologic failure rates.

Methods

Population-based sequencing of NS3 and NS5A genes was performed in HCV genotype 1 infected patients at a German university hospital. Treatment was individually selected based on resistance analyses.

Results

In total, 319 patients (50% treatment-experienced and 30% with cirrhosis) were included. With the treatment choice based on the baseline NS3 and NS5A resistance profile SVR rates between 96 and 100% were observed in all subgroups, including treatment-experienced patients with cirrhosis and HCV genotype 1a infected cirrhotic patients.

Conclusions

The choice of treatment based on the RASs status at baseline may be beneficial for optimizing treatment efficacy in patients with HCV genotype 1 infection and risk factors for treatment failure.

Introduction

An estimated 130–150 million people worldwide are chronically infected with the hepatitis C virus (HCV) which is a major cause for the development of cirrhosis and hepatocellular carcinoma [1]. With the recent development of several direct acting antivirals (DAAs) against the viral non-structural (NS) proteins NS3, NS5A, and NS5B, a new era has begun for the treatment of HCV infection. Several combinations of different DAAs have been approved in many countries worldwide and have proven to achieve high sustained virologic response (SVR) rates in HCV genotype 1 infected patients [1], [2], [3], [4]. Four different highly-potent IFN-free regimens consisting of sofosbuvir (SOF) plus ledipasvir (LDV) +/− ribavirin (RBV), ritonavir boosted paritaprevir (rPTV) plus ombitasvir (OBV) plus dasabuvir (DSV) +/− RBV, SOF plus daclatasvir (DCV) +/− RBV and SOF plus simeprevir (SMV) have been used for the treatment of genotype 1 infected patients and have proven their efficacy in phase 3 studies as wells as in “real-life” [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. More recently, three additional regimens were also approved for the treatment of patients with HCV genotype 1 infection: grazoprevir plus elbasvir, SOF plus velpatasvir and glecaprevir and pibrentasvir. While high SVR rates were also observed for these regimens in the respective approval studies, only few “real-life”-data are available so far [16], [17], [18].

Due to the relatively low resistance barrier of NS3-, NS5A- and non-nucleotide NS5B polymerase inhibitors, resistance associated substitutions (RASs) may compromise treatment success in some patients [19], [20]. For example, in patients treated with SOF + LDV, a retrospective analysis revealed SVR rates that were approximately 10% lower in patients treated for 12 weeks who also had highly resistant NS5A RASs at baseline [19], [20]. Moreover, patients treated for 8 weeks with the same regimen also had reduced SVR rates if highly resistant baseline NS5A RASs were present [21], [22].

Interestingly, it appears that baseline RASs become more clinically relevant in the presence of other risk factors for treatment failure, including cirrhosis, specific HCV genotypes [3] or subtypes (1a vs. 1b), and prior treatment failure [19], [20]. For example, in patients treated with SOF + SMV, the chances of achieving SVR were markedly reduced in genotype 1a infected patients with cirrhosis who also had the Q80K variant present at baseline (74% vs. 92% in patients without Q80K) [12].

Different treatment approaches for these patients were recently respectively are currently tested in clinical trials including the dual combination of two DAAs with a very high barrier to resistance (glecaprevir and pibrentasvir), and triple-DAA regimens like the combination of sofosbuvir, velpatasvir and voxilaprevir and the combination of grazoprevir, ruzasvir and MK-3682.

In the present study, we analyzed whether choice of an already approved IFN-free treatment regimen that is based on the presence or absence of baseline RASs has also the potential to reduce the rate of virologic failures in patients with HCV genotype 1 infection.

Section snippets

Study design

Chronically infected patients with HCV genotype 1 infection not included in clinical phase 2 and phase 3 studies were treated in our university outpatient clinic based on current guideline recommendations [19], [23] and also when available on baseline resistance analyses.

Therefore, resistance-testing in the NS3 and NS5A genes was performed by population-based sequencing in the majority of patients with HCV genotype 1 infection before treatment was started and these patients were prospectively

Primers

All primers used in the present analysis have been described recently [26].

HCV RNA extraction and cDNA synthesis

Viral RNA was extracted from serum samples using the QIAamp Viral RNA Mini Kit (Qiagen, Hilden, Germany) and DNA was synthesized from viral RNA using Life Technologies' SuperScript III First Strand Synthesis System according to the manufacturer's protocol.

Amplification of the HCV NS3-protease and NS5A genes

The complete regions encoding the NS3-protease and NS5A gene were amplified by nested PCR in two rounds. The region encoding the NS5B-polymerase was amplified by

Baseline characteristics

In total, 319 patients with HCV genotype 1 infection were included in this study (Table 1). 57% of the patients were male and the medium age was 55 years. While 44% (n = 140/319) of the patients were infected with HCV genotype 1a, 55% (n = 176/319) were infected with HCV genotype 1b (for demographic details see Table 1). Fifty-percent of all patients were treatment-experienced (n = 158/319), including 21 DAA-experienced patients (n = 21/158; 13%) who had been previously treated with a

Discussion

While high SVR rates can be achieved with most approved IFN-free DAA combinations, there are several risk factors for treatment failure, including prior treatment failure, presence of cirrhosis, HCV subtype 1a, and presence of baseline RASs.

However, the combination of two DAAs with a very high barrier to resistance might reduce failure rates in these populations. For example, the combination of glecaprevir (ABT-493) and pibrentasvir (ABT-530) achieved high SVR rates of 95–100% (mITT analysis)

Financial support/conflicts of interest

KHP: travel grants from AbbVie, Bristol-Myers Squibb and Gilead.

JV: speaking and/or consulting fees from Abbott, AbbVie, Gilead, Bristol-Myers Squibb, Medtronic, Merck/MSD, and Roche.

SZ: Consultancies for Abbvie, BMS, Gilead, Janssen und Merck/MSD.

CS: Consultancies for Gilead, Merck, Abbvie, BMS.

Acknowledgements

Funding:

This study was supported by a DZIF (Deutsches Zentrum für Infektionsforschung) grant entitled “Geno- & phenotypic NS3, NS5A and NS5B inhibitor resistance analysis” to Christoph Sarrazin (TTU 05.902).

Meetings the study was presented:

ILC April 2016 in Barcelona, Spain; Journal of Hepatology, Vol. 64, Issue 2, S404.

DGVS September 2016 in Hamburg, Germany; short presentation 228.

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