Hepatitis C virus protease inhibitor-resistance mutations: Our experience and review

Table 1 Overview of representative clinical trials of hepatitis C virus NS3/4A protease inhibitors

Name of drug (other name)	G	Trial phase	Features of clinical trials (ClinicalTrials.gov Identifier)
Telaprevir (VX-950)	1	FDA approved	Telaprevir, PEG-IFN alpha-2a, RBV
	1b	3	Telaprevir, Daclatasvir (NS5A inhibitor), PEG-IFN alpha-2a, RBV (COMMAND-3) (NCT01492426)
	1	3	Telaprevir, PEG-IFN lambda-1a, RBV (NCT01598090)
	4	2	Telaprevir, PEG-IFN alpha-2a, RBV (NCT0050801)
Boceprevir	1	FDA approved	Boceprevir, PEG-IFN alpha-2a, RBV
(SCH 503034)Simeprevir (TMC435)	1	3	Simeprevir, PEG-IFN alpha-2a, RBV (NCT01290731)
	1b/4	2	Simeprevir, IDEX719 (NS5A inhibitor), RBV (NCT01852604)
Faldaprevir (BI201335)	1	3	Faldaprevir, PEG-IFN alpha-2a, RBV
	1a	2	Faldaprevir, PPI-668 (NS5A inhibitor), BI207127 (non-nucleoside NS5B inhibitor), (+ RBV) (NCT01859962)
	1b	2	Faldaprevir, BI207127, RBV (NCT01858961)
Danoprevir (ITMN-191)	1	2	Danoprevir, PEG-IFN alpha-2a, RBV (NCT00963885)
	1/4	2	Danoprevir, Ritonavir, PEG-IFN alpha-2a, RBV (NCT01220947)
	1	2	Danoprevir, Ritonavir, RO5024048 (NS5B inhibitor), RBV, (± PEG-IFN alpha-2a) (NCT01331850)
Vaniprevir (MK-7900)	1	3	Vaniprevir, PEG-IFN alpha-2b, RBV (NCT01405937)
Asunaprevir (BMS-650032)	1	3	Asunaprevir, Daclatasvir (NCT01497834)
	1	2	Asunaprevir, PEG-IFN lambda, RBV (NCT01309932)
	1/4	2	Asunaprevir, PEG-IFN alpha-2a, RBV (NCT01030432)
	1a/1b/4	2	Asunaprevir, Daclatasvir, BMS-791325 (NS5B inhibitor) (NCT01455090)

Data from http://www.clinicaltrials.gov accessed on September 8, 2013. FDA: United States Food and Drug Administration; G: Genotype; HCV: Hepatitis C virus; PEG-IFN: Peginterferon; RBV: Ribavirin.

Table 2 Clinical characteristics of hepatitis C virus genotype 1b-infected patients in sequence analysis study of the hepatitis C virus NS3 region

No. of patients (men/women)	88 (43/45)
Age (yr)	55 ± 14
HCV RNA levels (low/high)	1/87
ALT (IU/L)	67 ± 44
WBC (x 103/mcL)	5.2 ± 1.5
Hemoglobin (g/dL)	14 ± 1.2
Platelet counts (x 104/mcL)	20 ± 18
IL28B rs8099917, TT/TG/GG/unknown	45/29/0/14

HCV RNA levels, low: less than 5 log IU/mL; HCV RNA levels, high: equal to or more than 5 log IU/mL; ALT: Alanine aminotransferase; HCV: Hepatitis C virus; WBC: White blood cell.

Table 3 Naturally occurring pre-existing resistance amino acid mutations in the hepatitis C virus NS3 regions of 28 protease inhibitor-naive patients infected with hepatitis C virus genotype 1

PatientNo.	V36	T54	V55	Q80	R155	A156	D168	V170Y/N/L
	A/M	S	A	L	K/T/Q	S/T/V	N	Y	N	L
31		S		L
95				L
15				L
17				L
24				L
26		S		L
29		S
81		S		L
61								Y
72								Y
11				L
12				L
2								Y
53				L
55				L
66				L
84				L
85				L
110				L
112								Y
114		S		L
100				L
101									N
107							N
111									N
99										L
92				L
97		S		L					N

Table 4 Nucleotide changes were required for amino acid substitutions at position 155 of hepatitis C virus NS3 among hepatitis C virus genotype 1 samples

Amino acid at position 155	HCV genotype 1a	HCV genotype 1b
R	AGG	CGG
K	AAG	AAG
T	ACG	ACG
S	AGC	AGC
I	ATC	ATC

Bold-faced nucleotides nucleotides were required for amino acid substitutions at position 155. HCV: Hepatitis C virus.