Grazoprevir/elbasvir for the treatment of adults with chronic hepatitis C: a short review on the clinical evidence and place in therapy

Figures & data

Table 1 C-WORTHY – study treatment groups

Treatment arm	Number of patients*	Infection	HCV genotype	Treatment	Duration	SVR12
1	25	Mono-infected	1a + 1b	Grazoprevir 100 mg + elbasvir 20 mg + ribavirin	12 weeks	93%
2	27	Mono-infected	1a + 1b	Grazoprevir 100 mg + elbasvir 50 mg + ribavirin	12 weeks	93%
3	13	Mono-infected	1b	Grazoprevir 100 mg + elbasvir 50 mg	12 weeks	98%
4	30	Mono-infected	1a	Grazoprevir 100 mg + elbasvir 50 mg + ribavirin	8 weeks	80%
5	33	Mono-infected	1a + 1b	Grazoprevir 100 mg + elbasvir 50 mg + ribavirin	12 weeks	93%
6	31	Mono-infected	1a	Grazoprevir 100 mg + elbasvir 50 mg	12 weeks	98%
7	29	Co-infected	1a + 1b	Grazoprevir 100 mg + elbasvir 50 mg + ribavirin	12 weeks	97%
8	30	Co-infected	1a + 1b	Grazoprevir 100 mg + elbasvir 50 mg	12 weeks	87%

Notes:

* Treatment-naïve and non-cirrhotic patients. Data from Sulkowski et al.²³

Abbreviations: HCV, hepatitis C virus; SVR₁₂, sustained virologic response 12 weeks after treatment completion

Table 2 C-WORTHY – Part B study treatment groups

	Treatment arm	Number of patients	Treatment	Duration	SVR12
Previously untreated; with cirrhosis	1	31	Grazoprevir 100 mg/elbasvir 50 mg + ribavirin	12 weeks	90%
	2	29	Grazoprevir 100 mg/elbasvir 50 mg	12 weeks	97%
	3	32	Grazoprevir 100 mg/elbasvir 50 mg + ribavirin	18 weeks	97%
	4	31	Grazoprevir 100 mg/elbasvir 50 mg	18 weeks	94%
PR-null, with or without cirrhosis	5	32	Grazoprevir 100 mg/elbasvir 50 mg + ribavirin	12 weeks	94%
	6	33	Grazoprevir 100 mg/elbasvir 50 mg	12 weeks	91%
	7	33	Grazoprevir 100 mg/elbasvir 50 mg + ribavirin	18 weeks	100%
	8	32	Grazoprevir 100 mg/elbasvir 50 mg	18 weeks	97%

Note: Data from Lawitz et al.²⁴

Abbreviations: SVR₁₂, sustained virologic response 12 weeks after treatment completion; PR-null, previously untreated with Peg-interferon and Ribavirin.

Table 3 Additional studies evaluating use of grazoprevir/elbasvir for treatment of HCV

Study	Study design	Treatment	Genotype	Patient population	SVR
Brown et al^Citation32	Randomized, open-label, Phase II	Genotype 2: GZR 100 mg + RBV ± EBR 50 mg for 12 weeks; genotype 4, 5 or 6: randomized to GZR/EBR ± RBV for 12 weeks.	2, 4, 5, or 6	Treatment naïve, non-cirrhotic patients	Genotype 2: SVR12 of 80% in GZR/EBR + RBV and 73% in GZR + RBV. Genotype 4: SVR12 of 90% in GZR/EBR and 100% in GZR/EBR + RBV. Genotype 5: SVR12 of 25% in GZR/EBR vs 100% in GZR/EBR + RBV. Genotype 6: SVR12 of 75% in both groups
Hezode et al^Citation33	Randomized, placebo-controlled, Phase III study	12 weeks of GZR/EBR 100 mg/50 mg in ITG vs DTG	1, 4, or 6	159 patients with HCV and sickle cell anemia, thalassemia, or hemophilia A/B or von Willebrand disease	SVR12 of 93.5% in the ITG. SVR12 was achieved in 94.7%, 97.6%, and 89.4% of patients with sickle cell disease, b-thalassemia, and hemophilia A/B or von Willebrand disease, respectively
Kwo et al^Citation34	Randomized, open-label, Phase III study	12 vs 16 weeks of treatment with GZR/EBR 100 mg/50 mg ± RBV	1,4, or 6	420 patients included: 35% with cirrhosis, 64% with null or partial response to PR treatment.	12 weeks of treatment: SVR12 of 92% in GZR/EBR vs SVR12 of 94% in GZR/EBR + RBV 16 weeks of treatment: SVR12 of 92% in GZR/EBR vs 98% in GZR/EBR + RBV
Sperl et al^Citation35	Randomized, open-label, Phase III study	12 weeks of GZR/EBR 100 mg/50 mg (n=129) vs sofosbuvir 400 mg + PR (n=128)	1 or 4	83% non-cirrhotic, 75% treatment naïve, 82% genotype 1b	SVR12 of 99% in GZR/EBR group and 90% in sofosbuvir/PR group

Abbreviations: DTG, deferred treatment group; EBR, elbasvir; GZR, grazoprevir; HCV, hepatitis C virus; ITG, immediate treatment group; RBV, ribavirin; SVR₁₂, sustained virologic response 12 weeks after treatment completion; PR, Peg-interferon + ribavirin.

Table 4 Use of medications contraindicated with grazoprevir/elbasvir³⁸

Contraindicated medications that cause decreases in grazoprevir and elbasvir plasma concentrations due to CYP3A induction, leading to loss of virologic response:

• Phenytoin

• Carbamazepine

• Rifampin

• St. John’s Wort (Hypericum perforatum)

• Efavirenz

Contraindicated medications that cause significant increase in grazoprevir plasma concentrations due to OATP1B1/3 inhibition which may lead to ALT elevations:

• Atazanavir

• Darunavir

• Lopinavir

• Saquinavir

• Tipranavir

• Cyclosporine

Table 5 Drug-drug interactions of grazoprevir and elbasvir

Medication	Effect on concentration	Comment
Nafcillin	Decreases grazoprevir and elbasvir concentrations	Co-administration not recommended
Ketoconazole	Increases grazoprevir and elbasvir concentrations
Bosentan	Decreases grazoprevir and elbasvir concentrations
Etravirine	Decreases grazoprevir and elbasvir concentrations
Elvitegravir/cobicistat/emtricitabine/tenofovir (disoproxil fumarate or alafenamide)	Increases grazoprevir and elbasvir concentrations
Modafinil	Decreases grazoprevir and elbasvir concentrations
Tacrolimus	Increased tacrolimus concentrations	Frequent monitoring of tacrolimus whole blood concentrations, renal function, and adverse events upon initiation of co-administration is recommended
Atorvastatin	Increases concentrations of statins	Do not exceed atorvastatin 20 mg daily dose while on grazoprevir/elbasvir
Fluvastatin Lovastatin Simvastatin		Use lowest necessary statin dose and monitor closely for myopathy while on grazoprevir/elbasvir
Rosuvastatin		Do not exceed rosuvastatin 10 mg daily dose while on grazoprevir/elbasvir

Note: Data from Zepatier™ (elbasvir/grazoprevir) [package insert].³⁸

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

 PubMed Web of Science ®Google Scholar

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

 PubMed Web of Science ®Google Scholar

BrownAHézodeCZuckermanEC-SCAPE Study InvestigatorsEfficacy and safety of 12 weeks of elbasvir ± grazoprevir ± ribavirin in participants with HCV genotype 2, 4, 5, or 6 infection: the C-SCAPE studyJ Viral Hepat Epub20171120

 Web of Science ®Google Scholar

HézodeCColomboMBourlièreMC-EDGE IBLD Study InvestigatorsElbasvir/grazoprevir for patients with hepatitis C virus infection and inherited blood disorders: a phase III studyHepatology201766373674528256747

 PubMed Web of Science ®Google Scholar

KwoPGaneEJPengCYEffectiveness of elbasvir and grazoprevir combination, with or without ribavirin, for treatment- experienced patients with chronic hepatitis C infectionGastroenterology20171521164175.e427720838

 PubMed Web of Science ®Google Scholar

SperlJHorvathGHalotaWEfficacy and safety of elbasvir/grazoprevir and sofosbuvir/pegylated interferon/ribavirin: a phase III randomized controlled trialJ Hepatol20166561112111927542322

 PubMed Web of Science ®Google Scholar

Zepatier™ (elbasvir/grazoprevir) [package insert]Whitehouse Station, NJMerck & Co., INC2016

 Google Scholar