Antiviral resistance summary

Please note that the HCV-GLUE drug resistance interpretation system has not yet been formally validated for clinical use.

HCV-GLUE detects the presence of resistance-associated substitutions (RAS) and variants in viral genome sequences and summarises the evidence that these confer resistance to direct-acting antiviral drugs (DAAs). It is essential to note that the prediction of reduced susceptibility to an individual DAA by HCV-GLUE is unlikely to be of clinical relevance in treatment-naïve, non-cirrhotic patients, with the exception of elbasvir. In the presence of cirrhosis or with a history of prior exposure to DAA, the antiviral susceptibility results may be of value in choosing an optimal treatment regimen. As such decisions are complex, we recommend that treatment selection should be taken by a multi-professional expert team only after review of relevant viral, patient and DAA-related factors.

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Drug category	Drug	Resistance-associated polymorphisms¹			Resistance detection level²
Drug category	Drug	Category I	Category II	Category III	Resistance detection level²
NS3/4A protease inhibitors	glecaprevir	-	-	-	No resistance detected
	grazoprevir	-	I170V (80%)	-	Probable resistance detected
	paritaprevir	-	-	-	No resistance detected
	voxilaprevir	-	-	-	No resistance detected
NS5A inhibitors	daclatasvir	L31M (32%)	-	-	Resistance detected
	elbasvir	L31M (32%)	-	-	Resistance detected
	ledipasvir	L31M (32%)	-	-	Resistance detected
	ombitasvir	-	L31M (32%)	-	Probable resistance detected
	pibrentasvir	-	-	-	No resistance detected
	velpatasvir	L31M (32%)	-	-	Resistance detected
NS5B RNA polymerase inhibitors	dasabuvir	-	-	-	No resistance detected
NS5B RNA polymerase inhibitors	sofosbuvir	-	-	-	No resistance detected

Resistance-associated polymorphism details

Virus protein	Polymorphism	Read proportion	Read depth	Genotype / Subtype	Resisted drug	Resistance category¹	In vitro resistance level (EC50 log fold change)	Clinical trials / study cohort	Associated drug regimens	Found at baseline?	Treatment-emergent?	Reference
NS3	I170V	80%	416	Subtype 1a	grazoprevir	II	-	Pooled study of multiple trials: C-EDGE CO-INFECTION; C-EDGE TE; C-EDGE TN; C-SALVAGE; C-SURFER; C-WORTHy	EBR/GZR	Yes	No	Komatsu et al., 2017 [1]
							-	C-EDGE TE	EBR/GZR; EBR/GZR/RBV	Yes	No	Kwo et al., 2017 [2]
							-	Pooled study of multiple trials: NCT01710501; NCT01716156	IFN/RBV/GZR	Yes	No	Bonsall et al., 2018 [3]
NS5A	L31M	32%	284	Subtype 1a	daclatasvir	I	350	-	-	-	-	Gao et al., 2010 [4]
							-	Retrospective epidemiological study (Europe)	SOF/DCV	No	Yes	Dietz et al., 2018 [5]
							341	-	-	-	-	Fridell et al., 2011 [6]
							-	Phase I monotherapy	DCV mono	No	Yes	Fridell et al., 2011 [6]
							-	NCT01012895	DCV/ASV; DCV/ASV/PR	No	Yes	Lok et al., 2012 [7]
					elbasvir	I	-	C-WORTHy	EBR/GZR; EBR/GZR/RBV	Yes	No	Sulkowski et al., 2015 [8]
							-	C-WORTHy	EBR/GZR; EBR/GZR/RBV	No	Yes	Lawitz et al., 2015 [9]
							-	C-WORTHy	EBR/GZR; EBR/GZR/RBV	Yes	No	Lawitz et al., 2015 [9]
							10	-	-	-	-	Liu et al., 2015 [10]
							10	-	-	-	-	Lahser et al., 2016 [11]
							-	Pooled study of multiple trials: C-EDGE CO-INFECTION; C-EDGE TE; C-EDGE TN; C-SALVAGE; C-SURFER; C-WORTHy	EBR/GZR; EBR/GZR/RBV	Yes	No	Komatsu et al., 2017 [1]
							0.50 - 10	-	-	-	-	Komatsu et al., 2017 [1]
							-	Pooled study of multiple trials: C-EDGE CO-INFECTION; C-EDGE TE; C-EDGE TN; C-SALVAGE; C-SURFER; C-WORTHy	EBR/GZR; EBR/GZR/RBV	Yes	No	Jacobson et al., 2017 [12]
							-	Pooled study of multiple trials: C-EDGE CO-INFECTION; C-EDGE TE; C-EDGE TN; C-SALVAGE; C-SURFER; C-WORTHy	EBR/GZR; EBR/GZR/RBV	No	Yes	Jacobson et al., 2017 [12]
					ledipasvir	I	-	RESCUE	SOF/LDV; SOF/LDV/RBV	Yes	No	Tam et al., 2018 [13]
							-	Pooled study of multiple trials: ELECTRON; ION-1; ION-2; ION-3; LONESTAR	SOF/LDV; SOF/LDV/RBV	Yes	Yes	Wyles et al., 2017 [14]
							-	Retrospective epidemiological study (Europe)	SOF/LDV	No	Yes	Dietz et al., 2018 [5]
							489.70 - 619.10	-	-	-	-	Wyles et al., 2017 [14]
					ombitasvir	II	2	-	-	-	-	Krishnan et al., 2015 [15]
					ombitasvir	II	-	AVIATOR	PTV/r/OBV/DSV; PTV/r/OBV/DSV/RBV	Yes	No	Krishnan et al., 2015 [16]
					velpatasvir	I	11.80	-	-	-	-	Cheng et al., 2013 [17]
							16	-	-	-	-	Lawitz et al., 2016 [18]
							-	POLARIS-4	SOF/VEL	Yes	No	Bourlière et al., 2017 [19]

1. Polymorphisms are assigned to one of three categories according to the strength of evidence for drug resistance. Category I polymorphisms have the strongest evidence: either (a) in vitro resistance level ≥ 5 and found at baseline or treatment-emergent in vivo, or (b) both found at baseline and treatment-emergent. Category II: in vitro level ≥ 50 or found at baseline or treatment-emergent. Category III: in vitro level ≥ 5
2. Resistance detection for a given drug is assigned to one of four categories. Resistance detected: any category I polymorphisms. Probable resistance detected: any category II polymorphisms. Possible resistance detected: any category III polymorphisms. No significant resistance detected: none of the above.

References

Virus protein	Polymorphism	Read proportion	Read depth	Notes
NS5A	K24K+M28M	100%	239	Associated with resistance in other subtypes of genotype 1
NS5A	K24K+M28M+Q30Q	100%	239	Associated with resistance in other subtypes of genotype 1
NS5A	K24K+M28M+Q30Q+V37V+H54H	100%	169	Associated with resistance in other subtypes of genotype 1
NS5A	M28M	100%	284	Associated with resistance in other subtypes of genotype 1
NS5A	M28M+Q30Q+L31M	31%	284	Associated with resistance in other subtypes of genotype 1
NS5A	Q30Q	100%	283	Associated with resistance in other subtypes of genotype 1
NS5A	Q30Q+L31M	32%	284	Associated with resistance in other subtypes of genotype 1
NS5A	L31M+H54H	42%	213	Associated with resistance in other subtypes of genotype 1
NS5A	L31M+H54H+E62E	59%	149	Associated with resistance in other subtypes of genotype 1
NS3	I132I+I170I	44%	128	Associated with resistance in genotypes other than genotype 1
NS3	I170I	19%	416	Associated with resistance in genotypes other than genotype 1

[1] Regulatory Analysis of Effects of Hepatitis C Virus NS5A Polymorphisms on Efficacy of Elbasvir and Grazoprevir. T. E. Komatsu, S. Boyd, A. Sherwat, L. Tracy, L. K. Naeger, J. J. O'Rear and P. R. Harrington, Gastroenterology 152(3), 586-597 (2017)
https://doi.org/10.1053/j.gastro.2016.10.017

[2] Effectiveness of Elbasvir and Grazoprevir Combination, With or Without Ribavirin, for Treatment-Experienced Patients With Chronic Hepatitis C Infection. P. Kwo, E. J. Gane, C. Y. Peng, B. Pearlman, J. M. Vierling, L. Serfaty, M. Buti, S. Shafran, P. Stryszak, L. Lin, J. Gress, S. Black, F. J. Dutko, M. Robertson, J. Wahl, L. Lupinacci, E. Barr and B. Haber, Gastroenterology 152(1), 164-175.e4 (2017)
https://doi.org/10.1053/j.gastro.2016.09.045

[3] Characterization of hepatitis C virus resistance to grazoprevir reveals complex patterns of mutations following on-treatment breakthrough that are not observed at relapse. D. Bonsall, S. Black, A. Y. Howe, R. Chase, P. Ingravallo, I. Pak, A. Brown, D. A. Smith, R. Bowden and E. Barnes, Infect Drug Resist 1119-1135 (2018)
https://doi.org/10.2147/IDR.S156581

[4] Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. M. Gao, R. E. Nettles, M. Belema, L. B. Snyder, V. N. Nguyen, R. A. Fridell, M. H. Serrano-Wu, D. R. Langley, J. H. Sun, D. R. O'Boyle, J. A. Lemm, C. Wang, J. O. Knipe, C. Chien, R. J. Colonno, D. M. Grasela, N. A. Meanwell and L. G. Hamann, Nature 465(7294), 96-100 (2010)
https://doi.org/10.1038/nature08960

[5] Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals. J. Dietz, S. Susser, J. Vermehren, K. H. Peiffer, G. Grammatikos, A. Berger, P. Ferenci, M. Buti, B. Müllhaupt, B. Hunyady, H. Hinrichsen, S. Mauss, J. Petersen, P. Buggisch, G. Felten, D. Hüppe, G. Knecht, T. Lutz, E. Schott, C. Berg, U. Spengler, T. von Hahn, T. Berg, S. Zeuzem, C. Sarrazin and European HCV Resistance Study Group, Gastroenterology 154(4), 976-988.e4 (2018)
https://doi.org/10.1053/j.gastro.2017.11.007

[6] Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in humans: in vitro and in vivo correlations. R. A. Fridell, C. Wang, J. H. Sun, D. R. O'Boyle, P. Nower, L. Valera, D. Qiu, S. Roberts, X. Huang, B. Kienzle, M. Bifano, R. E. Nettles and M. Gao, Hepatology 54(6), 1924-35 (2011)
https://doi.org/10.1002/hep.24594

[7] Preliminary study of two antiviral agents for hepatitis C genotype 1. A. S. Lok, D. F. Gardiner, E. Lawitz, C. Martorell, G. T. Everson, R. Ghalib, R. Reindollar, V. Rustgi, F. McPhee, M. Wind-Rotolo, A. Persson, K. Zhu, D. I. Dimitrova, T. Eley, T. Guo, D. M. Grasela and C. Pasquinelli, N. Engl. J. Med. 366(3), 216-24 (2012)
https://doi.org/10.1056/NEJMoa1104430

[8] Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. M. Sulkowski, C. Hezode, J. Gerstoft, J. M. Vierling, J. Mallolas, S. Pol, M. Kugelmas, A. Murillo, N. Weis, R. Nahass, O. Shibolet, L. Serfaty, M. Bourliere, E. DeJesus, E. Zuckerman, F. Dutko, M. Shaughnessy, P. Hwang, A. Y. Howe, J. Wahl, M. Robertson, E. Barr and B. Haber, Lancet 385(9973), 1087-97 (2015)
https://doi.org/10.1016/S0140-6736(14)61793-1

[9] Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. E. Lawitz, E. Gane, B. Pearlman, E. Tam, W. Ghesquiere, D. Guyader, L. Alric, J. P. Bronowicki, L. Lester, W. Sievert, R. Ghalib, L. Balart, F. Sund, M. Lagging, F. Dutko, M. Shaughnessy, P. Hwang, A. Y. Howe, J. Wahl, M. Robertson, E. Barr and B. Haber, Lancet 385(9973), 1075-86 (2015)
https://doi.org/10.1016/S0140-6736(14)61795-5

[10] Susceptibilities of genotype 1a, 1b, and 3 hepatitis C virus variants to the NS5A inhibitor elbasvir. R. Liu, S. Curry, P. McMonagle, W. W. Yeh, S. W. Ludmerer, P. A. Jumes, W. L. Marshall, S. Kong, P. Ingravallo, S. Black, I. Pak, M. J. DiNubile and A. Y. Howe, Antimicrob. Agents Chemother. 59(11), 6922-9 (2015)
https://doi.org/10.1128/AAC.01390-15

[11] The Combination of Grazoprevir, a Hepatitis C Virus (HCV) NS3/4A Protease Inhibitor, and Elbasvir, an HCV NS5A Inhibitor, Demonstrates a High Genetic Barrier to Resistance in HCV Genotype 1a Replicons. F. C. Lahser, K. Bystol, S. Curry, P. McMonagle, E. Xia, P. Ingravallo, R. Chase, R. Liu, T. Black, D. Hazuda, A. Y. Howe and E. Asante-Appiah, Antimicrob. Agents Chemother. 60(5), 2954-64 (2016)
https://doi.org/10.1128/AAC.00051-16

[12] Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis. I. M. Jacobson, E. Lawitz, P. Y. Kwo, C. Hézode, C. Y. Peng, A. Y. M. Howe, P. Hwang, J. Wahl, M. Robertson, E. Barr and B. A. Haber, Gastroenterology 152(6), 1372-1382.e2 (2017)
https://doi.org/10.1053/j.gastro.2017.01.050

[13] Ledipasvir/sofosbuvir for treatment of hepatitis C virus in sofosbuvir-experienced, NS5A treatment-naïve patients: Findings from two randomized trials. E. Tam, A. F. Luetkemeyer, P. S. Mantry, S. K. Satapathy, P. Ghali, M. Kang, R. Haubrich, X. Shen, L. Ni, G. Camus, A. Copans, L. Rossaro, B. Guyer, R. S. Brown and RESCUE and ACTG A5348 study investigators, Liver Int. 38(6), 1010-1021 (2018)
https://doi.org/10.1111/liv.13616

[14] Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir/sofosbuvir. D. Wyles, H. Dvory-Sobol, E. S. Svarovskaia, B. P. Doehle, R. Martin, N. H. Afdhal, K. V. Kowdley, E. Lawitz, D. M. Brainard, M. D. Miller, H. Mo and E. J. Gane, J. Hepatol. 66(4), 703-710 (2017)
https://doi.org/10.1016/j.jhep.2016.11.022

[15] In vitro and in vivo antiviral activity and resistance profile of ombitasvir, an inhibitor of hepatitis C virus NS5A. P. Krishnan, J. Beyer, N. Mistry, G. Koev, T. Reisch, D. DeGoey, W. Kati, A. Campbell, L. Williams, W. Xie, C. Setze, A. Molla, C. Collins and T. Pilot-Matias, Antimicrob. Agents Chemother. 59(2), 979-87 (2015)
https://doi.org/10.1128/AAC.04226-14

[16] Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir. P. Krishnan, R. Tripathi, G. Schnell, T. Reisch, J. Beyer, M. Irvin, W. Xie, L. Larsen, D. Cohen, T. Podsadecki, T. Pilot-Matias and C. Collins, Antimicrob. Agents Chemother. 59(9), 5445-54 (2015)
https://doi.org/10.1128/AAC.00998-15

[17] GS-5816, A SECOND GENERATION HCV NS5A INHIBITOR WITH POTENT ANTIVIRAL ACTIVITY, BROAD GENOTYPIC COVERAGE AND A HIGH RESISTANCE BARRIER G. Cheng, M. Yu, B. Peng, Y.-J. Lee, A. Trejo-Martin, R. Gong, C. Bush, A. Worth, M. Nash, K. Chan, H. Yang, R. Beran, Y. Tian, J. Perry, J. Taylor, C. Yang, M. Paulson, W. Delaney and J.O. Link, J. Hepatol. 58(Supplement 1), S484-S485 (2013)
https://doi.org/10.1016/S0168-8278(13)61192-7

[18] Clinical Resistance to Velpatasvir (GS-5816), a Novel Pan-Genotypic Inhibitor of the Hepatitis C Virus NS5A Protein. E. J. Lawitz, H. Dvory-Sobol, B. P. Doehle, A. S. Worth, J. McNally, D. M. Brainard, J. O. Link, M. D. Miller and H. Mo, Antimicrob. Agents Chemother. 60(9), 5368-78 (2016)
https://doi.org/10.1128/AAC.00763-16

[19] Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. M. Bourlière, S. C. Gordon, S. L. Flamm, C. L. Cooper, A. Ramji, M. Tong, N. Ravendhran, J. M. Vierling, T. T. Tran, S. Pianko, M. B. Bansal, V. de Lédinghen, R. H. Hyland, L. M. Stamm, H. Dvory-Sobol, E. Svarovskaia, J. Zhang, K. C. Huang, G. M. Subramanian, D. M. Brainard, J. G. McHutchison, E. C. Verna, P. Buggisch, C. S. Landis, Z. H. Younes, M. P. Curry, S. I. Strasser, E. R. Schiff, K. R. Reddy, M. P. Manns, K. V. Kowdley, S. Zeuzem and POLARIS-1 and POLARIS-4 Investigators, N. Engl. J. Med. 376(22), 2134-2146 (2017)
https://doi.org/10.1056/NEJMoa1613512

File path	ngsData.bam
Sequance data format	Deep sequencing (SAM/BAM)
Report generation date	10/09/2019

Identified as hepatitis C?	Yes
Genotype	1
Subtype	1a
Closest reference sequence	HQ850279

Genome region	Proportion of nucleotide sites with depth
Genome region	≥ 1	≥ 10	≥ 100	≥ 1000
Precursor polyprotein	99.5%	99.4%	96.8%	8.5%
Core	100%	100%	93.7%	0%
E1	100%	100%	100%	0%
E2	99.7%	99.7%	97.9%	11.8%
p7	100%	100%	100%	0%
NS2	100%	100%	92.8%	0%
NS3	99.4%	99.2%	92.8%	4.2%
NS4A	100%	100%	100%	0%
NS4B	100%	100%	100%	0%
NS5A	100%	100%	99.3%	0%
NS5B	98%	98%	98%	31.6%

GLUE engine version	1.1.50
HCV project version	0.1.60
PHE drug resistance extension version	0.1.31
Minimum read proportion	15%
Minimum read depth	10
Minimum base quality	5
Minimum mapping quality	5

Hepatitis C virus sequence report

Phylogenetic classification

Antiviral resistance summary

Resistance-associated polymorphism details

Other polymorphisms of interest

Genome coding region coverage

System configuration

References