Hepatitis C Late Relapse in Patients With Directly Acting Antiviral-related Sustained Virological Response at Week 12

Mariantonietta Pisaturo; Carmine Minichini; Mario Starace; Mara Caroprese; Margherita Macera; Giuseppina Brancaccio; Stefania De Pascalis; Antonella Santonicola; Alfonso Galeota Lanza; Rosa Zampino; Gaetano Cotticelli; Evangelista Sagnelli; Giovanni Battista Gaeta; Nicola Coppola

Disclosures

Liver International. 2019;39(5):844-853. 

In This Article

Abstract and Introduction

Abstract

Aim: The aim of the present study was to identify, among the patients with failure to DAA regimen, those with a late relapse (after the achievement of a sustained virological response at week 12) and to characterize the clinical, epidemiological and virological features of these patients.

Material and methods: A total of 129 HCV patients with non-response to an IFN-free regimen were enrolled. Sanger sequencing of NS3, NS5A and NS5B was performed at failure by home-made protocols.

Results: Of the 129 patients enrolled, 8 (6.2%) experienced a breakthrough, 15 (11.7%) non-response, 99 (76.7%) a relapse by week 12 after the end of DAA therapy, and 7 (5.4%) a late relapse (after week 12; median 24 weeks, range 24-72). For two of the seven patients with a late relapse, a serum sample collected before the start of the DAA regimen was available; phylogenetic analysis showed no change in sequences of NS3, NS5A and NS5B regions, suggesting a reactivation of the initial HCV strain; for the remaining five patients, no serum collected before the DAA regimen was available, and thus, a re-infection cannot be excluded.

Conclusions: Although a late relapse is infrequent, the study suggests a post-treatment follow-up of 72 weeks.

Introduction

The World Health Organization has estimated that 71 million people are infected with hepatitis C virus (HCV) worldwide and that more than 399 000 people die each year of HCV-related liver diseases.[1] Chronic hepatitis from HCV infection is characterized by an indolent course or a slow progression to cirrhosis and hepatocellular carcinoma.[2,3]

For nearly 15 years and until 2014, pegylated interferon alpha (IFN) plus ribavirin (RBV) combination therapy was the standard treatment for HCV infection.[4] The definition of sustained clearance of circulating HCV was HCV-RNA negativity at week 24 after stopping treatment (sustained virological response—SVR). This combination therapy provided an SVR in half of the patients infected with HCV genotype 1, in around 70% of those with HCV genotype 2 and around 60% of those with HCV genotype 3; however, the frequency and severity of the side effects (flu-like symptoms, depression, cytopenia and haemolytic anaemia) made this therapy burdensome for many patients.[5,6]

Since 2014, regimens without interferon, which combine several classes of directly acting antiviral agents (DAAs), have improved the response rate and tolerability even in difficult-to-treat patients such as patients with an advanced liver disease. Since the high and rapid effect of the DAA regimen, in the clinical trials and real-world practice, HCV-RNA negativity at week 12 after stopping treatment is used as the marker of sustained clearance of HCV. These IFN-free regimens yield a sustained virological response rate at week 12 (SVR12) of approximately 95%, even in patients with cirrhosis.[10,11]

However, an important unresolved question is how long follow-up should last after stopping treatment and when effectively a patient is considered free of HCV infection. In fact, although the international guidelines indicate a follow-up to week 12 after stopping therapy, recently Sarrazin et al[12] by phylogenetic analysis demonstrated that, of the 12 patients with a late relapse enrolled in trials on sofosbuvir-based regimens, seven had been re-infected with a different HCV strain and five had a late virological relapse from the same strain. No data are available in the literature on this topic from observational or real-world studies. Thus, the aim of the present study was to identify among the patients with a failure to a DAA regimen those with a late relapse (after week 12) and characterize the clinical, epidemiological and virological features of these patients.

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