Retreatment of patients with treatment failure of direct-acting antivirals: Focus on hepatitis C virus genotype 1b

Table 1 Representative direct-acting antivirals, their targets and hepatitis C virus genotypes

Target regions	DAAs	HCV GTs
NS3/4A	Glecaprevir	Pan-GTs
	Grazoprevir	1, 4
	Asunaprevir	1b
	Paritaprevir	1, 2a, 4
	Simeprevir	1, 4
	Telaprevir	1, 2
	Boceprevir	1
NS5A	Pibrentasvir	Pan-GTs
	Velpatasvir	Pan-GTs
	Elbasvir	Pan-GTs
	Daclatasvir	Pan-GTs
	Ledipasvir	1, 4, 5
	Ombitasvir	1, 4
NS5B	Sofosbuvir [nucleos(t)ide inhibitor]	Pan-GTs
	Dasabuvir [non-nucleos(t)ide inhibitor]	1

DAAs: Direct-acting antivirals; HCV GTs: Hepatitis C virus genotypes.

Table 2 Resistance-associated substitutions or treatment-emergent substitutions of hepatitis C virus NS5B nucleos(t)ide inhibitors

Domains of HCV NS5B polymerase[45]	HCV genotypes (GTs)			Ref.
	GT1	GT1a	GT1b
Fingers domain (AA1-188, 226-287)		C14R		[40]
		D61G		[40]
			T77T/A	[41]
	S96T			[42]
	N142T		N142S	[40,42]
	L159F			[40-44]
		E237G		[40]
	S282T	S282R		[40-42]
Palm domain (AA188-226, 287-371)	M289I/L			[42,44]
		L314P		[40]
			C316R	[41]
	L320F	L320I/V		[40-42]
	V321A	V321I		[40,42,43]
		T344I		[40]
Thumb domain (AA371-530)		F415Y		[43]
			E440G, E/G	[42]
		S470G		[40]

β-hairpin, AA443-453; C-term linker, AA530-565[44]. HCV: Hepatitis C virus.

Table 3 Retreatment regimens for patients with hepatitis C virus infection for whom the initial combination of direct-acting antivirals has failed

Patients	APASL (2016)[1]	AASLD (2017)[28]
GT1
Peginterferon and ribavirin plus HCV NS3/4A inhibitors-failure non-cirrhotic patients	Sofosbuvir/ledipasvir 12 wk	Sofosbuvir/ledipasvir 12 wk
		Sofosbuvir/velpatasvir 12 wk
		Glecaprevir/pibrentasvir 12 wk
Peginterferon and ribavirin plus HCV NS3/4A inhibitors-failure compensated cirrhotic patients	Sofosbuvir/ledipasvir 12 wk	Sofosbuvir/velpatasvir 12 wk
		Glecaprevir/pibrentasvir 12 wk
		(For GT1b) Elbasvir/grazoprevir 12 wk
HCV NS5A inhibitors-failure non-cirrhotic patients	Wait	Sofosbuvir/velpatasvir/voxilaprevir 12 wk
HCV NS5A inhibitors-failure compensated cirrhotic patients	RAS check	Sofosbuvir/velpatasvir/voxilaprevir 12 wk
Non-NS5A inhibitor/ sofosbuvir-failure non-cirrhotic patients	N/A	Glecaprevir/pibrentasvir 12 wk
		(For GT1a)
		Sofosbuvir/velpatasvir/voxilaprevir 12 wk
		(For GT1b) Sofosbuvir/velpatasvir 12 wk
Non-NS5A inhibitor/ sofosbuvir-failure compensated cirrhotic patients	N/A	Glecaprevir/pibrentasvir 12 wk
		(For GT1a)
		Sofosbuvir/velpatasvir/voxilaprevir 12 wk
		(For GT1b) Sofosbuvir/velpatasvir 12 wk
GT2
Sofosbuvir/ribavirin-failure patients	N/A	Sofosbuvir/velpatasvir 12 wk
		Glecaprevir/pibrentasvir 12 wk
GT3
DAA (including NS5A inhibitors) - failure patients	N/A	Sofosbuvir/velpatasvir/voxilaprevir 12 wk
		(For NS5A inhibitor-failure) weight-based ribavirin is recommended
GT4
DAA (including NS5A inhibitors) - failure patients	N/A	Sofosbuvir/velpatasvir/voxilaprevir 12 wk
GT5/GT6
DAA (including NS5A inhibitors) - failure patients	N/A	Sofosbuvir/velpatasvir/voxilaprevir 12 wk

DAAs: Direct-acting antivirals; HCV GTs: Hepatitis C virus genotypes; RAS: Resistance-associated variants; N/A: Not available.