HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy

Kazuaki Chayama, C Nelson Hayes, Kazuaki Chayama, C Nelson Hayes

Abstract

Sustained virological response (SVR) rates have increased dramatically following the approval of direct acting antiviral (DAA) therapies. While individual DAAs have a low barrier to resistance, most patients can be successfully treated using DAA combination therapy. However, DAAs are vulnerable to drug resistance, and resistance-associated variants (RAVs) may occur naturally prior to DAA therapy or may emerge following drug exposure. While most RAVs are quickly lost in the absence of DAAs, compensatory mutations may reinforce fitness. However, the presence of RAVs does not necessarily preclude successful treatment. Although developments in hepatitis C virus (HCV) therapy in Asia have largely paralleled those in the United States, Japan's July 2014 approval of asunaprevir plus daclatasvir combination therapy as the first all-oral interferon-free therapy was not repeated in the United States. Instead, two different combination therapies were approved: sofosbuvir/ledipasvir and paritaprevir/ritonavir/ombitasvir/dasabuvir. This divergence in treatment approaches may lead to differences in resistance challenges faced by Japan and the US. However, the recent approval of sofosbuvir plus ledipasvir in Japan and the recent submissions of petitions for approval of paritaprevir/ritonavir plus ombitasvir suggest a trend towards a new consensus on emerging DAA regimens.

Keywords: NS5A inhibitor; direct-acting antivirals; hepatitis C; protease inhibitor; resistance; sustained viralresponse.

Figures

Figure 1
Figure 1
HCV genome architecture and DAA targets. The HCV RNA genome is initially translated as a polyprotein which is initially cleaved by host proteases after which the NS3/NS4A protease cleaves itself and the remaining nonstructural proteins. Direct acting antivirals have been developed against the NS3 protease, the NS5A replication complex, and the NS5B polymerase.
Figure 2
Figure 2
Position of frequently reported resistance mutations for selected DAAs [12].

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