Spotlight on grazoprevir–elbasvir once-daily combination and its potential in the treatment of hepatitis C

Figures & data

Table 1 Summary of SVR12 results from major clinical trials evaluating grazoprevir–elbasvir in treating HCV infection

Study	Phase	Regimen	Treatment naïve	Treatment failed	Cirrhosis	ESRD	HIV coinfection	Non-GT1
Lawitz et al^Citation17	II	GE (+R) 12 weeks	28/31 (90%)	30/32 (94%)	28/31 (90%)	NA	NA	NA
		GE (−R) 12 weeks	28/29 (97%)	30/33 (91%)	28/29 (97%)	NA	NA	NA
		GE (+R) 18 weeks	31/32 (97%)	33/33 (100%)	12/12 (100%)	NA	NA	NA
		GE (−R) 18 weeks	29/31 (94%)	31/32 (97%)	11/11 (100%)	NA	NA	NA
Sulkowski et al^Citation18	II	GE (+R) 8 weeks	24/30 (80%)	NA	NA	NA	NA	NA
		GE (+R) 12 weeks	79/85 (93%)	NA	NA	NA	28/29 (97%)	NA
		GE (−R) 12 weeks	43/44 (98%)	NA	NA	NA	26/30 (87%)	NA
Zeuzem et al^Citation19	III	GE (−R) 12 weeks	144/157 (95%)	NA	68/70 (97%)	NA	NA	GT4 18/18 (100%) GT6 8/10 (80%)
Buti et al^Citation20 and Forns et al^Citation21	II	GE (+R) 12 weeks	NA	76/79 (96%)	32/34 (94%)	NA	NA	NA
Roth et al^Citation23	III	GE (−R) 12 weeks	96/96 (100%)	19/20 (95%)	6/6 (100%)	115/116 (99%)	NA	NA
Rockstroh et al^Citation26	III	GE (+R) 12 weeks	210/218 (96%)	NA	35/35 (100%)	NA	210/218 (96%)	GT4 27/28 (96%) GT6 1/1 (100%)

Note: Data is presented as n (%).

Abbreviations: ESRD, end-stage renal disease; GE (+R), grazoprevir–elbasvir plus ribavirin; GE (−R), grazoprevir–elbasvir without ribavirin; GT, genotype; HCV, hepatitis C virus; HIV, human immunodeficiency virus; NA, not applicable; SVR12, sustained virologic response 12 weeks posttreatment.

Table 2 Baseline RAVs and SVR12 of varying HCV genotypes

Study	RAV	GT1	GT1a	GT1b	GT4	GT6	SVR12
Lawitz et al^Citation17	NS3	79/248 (32%)	NA	NA	NA	NA	73/79 (92%)
	NS5A	34/243 (14%)	NA	NA	NA	NA	28/34 (82%)
Sulkowski et al^Citation18	NS3	75/216 (35%)	NA	NA	NA	NA	68/75 (91%)
	NS5A	25/216 (12%)	NA	NA	NA	NA	17/25 (68%)
Zeuzem et al^Citation19	NS3	NA	86/151 (57%)	25/129 (19%)	7/18 (39%)	9/9 (100%)	GT1A: 83/86 (97%) GT1B: 24/25 (96%) GT4: 7/7 (100%) GT6: 7/9 (78%)
	NS5A	NA	19/154 (12%)	18/130 (14%)	9/18 (50%)	3/9 (33%)	GT1A: 11/19 (58%) GT1B: 17/18 (94%) GT4: 9/9 (100%) GT6: 7/9 (78%)
Buti et al^Citation20 and	NS3	34/78 (44%)	NA	NA	NA	NA	31/34 (91%)
Forns et al^Citation21	NS5A	8/79 (10)	NA	NA	NA	NA	6/8 (75%)
Roth et al^Citation23	NS3	36/112 (32%)	NA	NA	NA	NA	36/36 (100%)
	NS5A	17/115 (15%)	NA	NA	NA	NA	16/17 (94%)
Rockstroh et al^Citation26	NS3	NA	50% (69/139)	12% (5/43)	NA	NA	GT1A: 66/69 (96%) GT1B: 5/5 (100%)
	NS5A	NA	10/140 (7%)	5/43 (12%)	NA	NA	GT1A: 8/10 (80%) GT1B: 5/5 (100%)

Abbreviations: GT, genotype; HCV, hepatitis C virus; NA, not applicable; RAV, resistance-associated variant; SVR12, sustained virologic response 12 weeks posttreatment.

Table 3 Emergent RAVs posttreatment in virologic failure patients

Study	RAVs in failure patients (%)	NS3 RAVs (%)	NS5A RAVs (%)	Common NS3	Common NS5A
Lawitz et al^Citation17	9/10 (90)	7/9 (78)	9/9 (100)	Y56H A156T/G/V D168A/Y	M28T Q30L/R L31M Y93H/N
Sulkowski et al^Citation18	10/12 (83)	9/10 (90)	9/10 (90)	Y56H A156T D168A/N	Q30R/H L31M Y93H/N
Zeuzem et al^Citation19	13/13 (100)	9/13	13/13 (100)	Y56H D168A Q80K	M28V/A/G Q30H/L/R L31M Y93H
Buti et al^Citation20 and Forns et al^Citation21	3/3 (100)	3/3 (100)	2/3 (67)	D168N Q80K A156T/A	Y93H Q30H L31M
Rockstroh et al^Citation26	3/7 (43)	2/7 (29)	4/7 (57)	Q80K D168A	Q30K Y93S L31M L28S

Abbreviation: RAV, resistance-associated variant.

Table 4 Potential serious drug–drug interactions with grazoprevir and elbasvir

Drug	Grazoprevir and elbasvir
Atzanavir/ritonavir^Citation30,Citation31	Increased levels of all drugs, coadministration not recommended
Darunavir/ritonavir^Citation30	Increased levels of grazoprevir and elbasvir, coadministration is not recommended
Efavirenz^Citation28,Citation29	Decreased levels of grazoprevir and elbasvir, coadministration may lead to subtherapeutic levels of grazoprevir
Lopinavir/ritonavir^Citation30	Increased levels of grazoprevir and elbasvir, coadministration is not recommended
Rosuvastatin^Citation34	Increased levels of rosuvastatin, avoid coadministration
Rifampin^Citation32	Increased levels of grazoprevir and elbasvir, coadministration is not recommended

LawitzEGaneEPearlmanBEfficacy 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 trialLancet201538599731075108625467591

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SulkowskiMHezodeCGerstoftJEfficacy 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 trialLancet201538599731087109725467560

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ZeuzemSGhalibRReddyKRGrazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trialAnn Intern Med2015163111325909356

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ButiMGordonSCZuckermanEGrazoprevir, elbasvir, and ribavirin for chronic hepatitis C virus genotype 1 infection after failure of pegylated interferon and ribavirin with an earlier-generation protease inhibitor: final 24-week results from C-SALVAGEClin Infect Dis2016621323626371152

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FornsXGordonSCZuckermanEGrazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agentJ Hepatol201563356457225895428

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RothDNelsonDRBruchfeldAGrazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 studyLancet2015386100031537154526456905

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RockstrohJKNelsonMKatlamaCEfficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trialLancet HIV201528e319e32726423374

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CaroLTalatyJEGuoZPharmacokinetic interactions between the HCV protease inhibitor MK-5172 and ritonavir-boosted HIV protease inhibitors (atazanavir, lopinavir, darunavir) in healthy volunteers [abstract 487]64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)November 1–5, 2013Washington, DC

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YehWYMarshallWMaJRitonavir-boosted atazanavir, lopinavir, & darunavir increase HCV NS5A inhibitor MK-8742 levels [abstract 635]Conference on Retroviruses and Opportunistic Infections (CROI)March 3–6, 2014Seattle, WA

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TalatyJECaroLYehWPharmacokinetic interaction between the HCV protease inhibitor MK-5172 and efavirenz in normal healthy volunteers [abstract 492]64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)November 1–5, 2013Washington, DC

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YehWMarshallWManginEPharmacokinetic interactions between the HCV NS5A inhibitor MK-8742 and efavirenz [abstract 498]Conference on Retroviruses and Opportunistic Infections (CROI)March 3–6, 2014Boston, MA

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CaroLMarshallWLFengHPCoadministration of HCV protease inhibitor grazoprevir with HCV NS5A inhibitor elbasvir has no effect on pravastatin but increases rosuvastatin exposure in healthy subjects [abstract 17]16th International Workshop on Clinical Pharmacology of HIV & Hepatitis TherapyMay 26–28, 2015Washington, DC

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CaroLTalatyJEGuoZPharmacokinetic interaction between the HCV protease inhibitor MK-5172 and IV and oral rifampin in healthy volunteers [abstract 495]64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)November 1–5, 2013Washington, DC

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