Mechanisms of Hepatitis C Viral Resistance to Direct Acting Antivirals

Abstract

There has been a remarkable transformation in the treatment of chronic hepatitis C in recent years with the development of direct acting antiviral agents targeting virus encoded proteins important for viral replication including NS3/4A, NS5A and NS5B. These agents have shown high sustained viral response (SVR) rates of more than 90% in phase 2 and phase 3 clinical trials; however, this is slightly lower in real-life cohorts. Hepatitis C virus resistant variants are seen in most patients who do not achieve SVR due to selection and outgrowth of resistant hepatitis C virus variants within a given host. These resistance associated mutations depend on the class of direct-acting antiviral drugs used and also vary between hepatitis C virus genotypes and subtypes. The understanding of these mutations has a clear clinical implication in terms of choice and combination of drugs used. In this review, we describe mechanism of action of currently available drugs and summarize clinically relevant resistance data.

Management of Chronic Hepatitis C Virus Infection: A Consensus Report of the Study Group for Viral Hepatitis of the Turkish Society of Clinical Microbiology and Infectious Diseases-2017 Update

“…Ayrıca doğal dirençlerin KVY üzerine önemli bir etkisi de gösterilmemiştir. Bu nedenle tedavi öncesinde rutin direnç analizi yapılması bugün için önerilmemektedir (51,60,61 …”

“…Proteaz inhibitörlerinin ise genetik bariyerleri düşüktür ve tedavi sırasında bu ilaçlara direnç gelişebileceği gibi, tedaviden önce de proteaz inhibitörüne doğal olarak dirençli suşlar bulunabildiği bildirilmektedir (61,129). Proteaz inhibitörü ilaçlara tedavi sırasında direnç geliştirerek seçi-len suşlar, tedavi kesildikten sonra birkaç haftayla birkaç ay arasında değişen sürelerde tamamen kaybolmaktadır.…”

“…Özellikle Q80K mutasyonu SMV ve ASV'ye duyarlılığın azalmasına neden olmaktadır. Ancak bu mutasyonu taşıyan suşlar, kombinasyon rejimlerindeki diğer ilaçlara duyarlı oldukları için direnç durumunun tedavi önce-sinde rutin olarak araştırılması önerilmemektedir (61).…”

Resistance to Direct-Acting Antiviral Agents in Treatment of Hepatitis C Virus Infections

“…So far, four classes of DAAs targeting three HCV proteins [NS3, NS5A, and NS5B] [nucleotide/nucleoside polymerase inhibitors (NPI) and non-nucleotide polymerase inhibitors (NNPI)] are approved for HCV treatment in several countries around the globe as shown in Figure 1. Multiple DAAs target specific HCV-encoded nonstructural proteins leading to arrest of viral replication [6], thus achieving higher rates of SVR even in cirrhotic and difficultto-treat patients.…”

Virological response to daclatasvir and asunaprevir combination therapy for chronic hepatitis C virus genotype 1b infection in dialysis patients: a prospective, multicenter study

“…Presently, direct-acting antiviral agents (DAAs) have assumed a more prominent role in the treatment of patients with HCV [6][7][8][9][10]. The introduction of DAAs has improved SVR rates and shortened treatment durations.…”