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ZepatierTM: A New Alternative Oral Treatment for Hepatitis C Virus

Friday, September 2, 2016   (0 Comments)
Posted by: Elizabeth Maynard
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Elizabeth Bracco, PharmD Candidate 2017
Amanda Gerberich, PharmD Candidate 2017
Jaclyn Werkheiser, PharmD Candidate 2016
Dana Manning, PharmD, RD, LDN 

Currently over 170 million people worldwide suffer from chronic Hepatitis C.1  ZepatierTM is an oral treatment option for chronic hepatitis C virus (HCV) of genotypes 1 and 4, which received FDA approval in January 2016.  ZepatierTM is a combination oral tablet of elbasvir, a NS5A inhibitor, and grazoprevir, a NS3/4A protease inhibitor. Both ingredients are not yet available separately but rather only in the combination form of ZepatierTM. The labeled indication of ZepatierTM is 12 or 16 week treatment course that can be used with or without ribavirin.  The goal of ZepatierTM therapy is to target difficult-to-treat patients including Genotype 1(GT1) with end stage renal disease on hemodialysis or patients infected with Genotype 4 (GT4), a rare form of HCV.2  

HCV genotype testing is recommended prior to initiating treatment to determine dosage regimen and duration. ZepatierTM can be used in patients with a Human Immunodeficiency Virus (HIV) co-infection.   ZepatierTM is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C), patients using organic anion transporting polypeptide (OATPB1/3) inhibitors, strong CYP3A inducers, or efavirenz.2 Patients should be monitored for a decrease in the hepatitis C virus-RNA viral load from baseline to monitor for efficacy of ZepatierTM.  Patients should also be monitored for toxicity with hepatic function testing prior to therapy, 8 weeks into therapy, and at conclusion of therapy at 12 or 16 weeks (depending on indication), and as clinically indicated.  Additionally patients should be monitored for signs of liver inflammation such as fatigue, weakness, lack of appetite, nausea, vomiting, signs of jaundice (discolored feces, eyes, skin). The most common side effects include diarrhea (2-5%), nausea (5-11%), headache (7-11%), and insomnia (5%).  Depression (2%) and irritability (3%) have also been noted.  Rare but serious side effects of an increase in ALT/SGPT levels (1%) and increase in serum bilirubin (6%) have also been documented.

Adherence to ZepatierTM is important to prevent resistance.  This includes taking the medication at the same time everyday, with or without food, and maintaining treatment for the entire course.  ZepatierTM should be stored in its original blister packaging to protect the drug from moisture in order to maintain its clinical efficacy.3  

There are currently a variation of treatment options available to patients with different genotypes of Hepatitis C. Fortunately there are thorough and reliable published guidelines available to practitioners that are updated frequently when new medications become available. The guidelines that are most well known are those published by the American Association for the Study of Liver Diseases (AADLD) and the Infectious Diseases Society of America (IDSA). These guidelines have recently updated their recommendations to include the use of ZepatierTM and have recommended its use for both genotype 1 (Class I, Level A recommendation), and genotype 4 (Class 2a, Level B), depending on the patient's specific characteristics (refer to guidelines). Additionally the guidelines also recommend ZepatierTM for patients with moderate to severe renal impairment (Class 2a, Level B).8 Many other first line treatment options are also availabe (Table 1), and therapy should always be chosen based on the hepatitis genotype, specific patient characteristics, and prescriber familiarity with drug regimen. There have been several phase 3 clinical trials published which have been able to show efficacy of this regimen compared to other regimens.

Several phase 3 clinical trials examined the efficacy of ZepatierTM.  Sustained virologic response 12 weeks after completion (SVR12) of ZepatierTM was examined based on HCV genotype, length of therapy, and presence of comorbidities.  In the trial C-EDGE TN, which was a randomized double-blind, placebo-controlled trial, 306 treatment naive patients with or without cirrohsis were randomized in a 3:1 manner to either ZepatierTM for 12 weeks or a deferred treatment group.  SVR12 was achieved in 95% of patients with genotype 1 and 97% of patients with genotype 4.8   

In the comparative randomized open-label trial C-EDGE TE, patients with GT1 or GT4 with or without cirrhosis and/or HIV-1 coinfection who had failed therapy with PegIFN + RBV were randomized to treatment of either: ZepatierTM for 12 weeks (SVR12=92%), ZepatierTM + RBV for 12 weeks (SVR12=94%), ZepatierTM for 16 weeks (SVR12=92%), or ZepatierTM + RBV for 16 weeks (SVR12=97%).8

C-EDGE Co-infection trial, a prospective, open-label, single-arm study, in which 218 HIV-HCV co-infected treatment-naive patients with GT 1, 4, or 6 were given ZepatierTM demonstrates that this regimen is effective and well-tolerated in co-infected patients both with and without cirrhosis.  C-EDGE Co-infection trial is consistent with previous trials of patients infected with only HCV.8  

C-SURFER, a randomized, double-blind trial in which 122 GT 1 chronic HCV patients with stage 4 or 5 chronic renal disease (including patients on hemodialysis) were given ZepatierTM to demonstrate the safety and 94% efficacy rate of SVR 12 in both treatment-naive and treatment-experienced patients with a low rate of adverse events.8  

Other oral treatment options for HCV genotype 1 treatment-naive patients include Harvoni4 and Viekira PakTM 5 (Table 1).  Over the past several years, the introduction of HCV medications to the market has provided patients with more efficacious and costly treatment options.  At a cost of $54,600, ZepatierTM is significantly more cost effective than Harvoni and Viekira PakTM.  Also, for privately-insured patients with difficulty affording the ZepatierTM copayment, Merck offers a co-pay assistance program, in which patients could pay as little as $5 per prescription.  Many regimens have a higher pill burden, and more complicated regimens. For example, the Viekira PakTM involves taking three tablets total at two different times in the day. In addition, other regimens include medications with a high potential for drug interactions,such as sofosbuvir in Harvoni,which presents a greater potential for drug interactions and adverse effects. In addition, Harvoni cannot be used in patients with severe or end stage renal disease due to sofosbuvir renal elimination.  The Viekira PakTM makes no comment on dosage adjustments in renal impairment as this drug has not been studied in such populations5. However, ZepatierTM can be used in patients with renal impairment, and dosage adjustments are not necessary. If the medication is to be used in addition to ribavirin (refer to recommended dosage regimens), dosage adjustments for ribavirin should be made according to the package insert of ribavirin.2

Table 1: Current Treatment Options for HCV genotype 1

Medication

Dosage (typical)

*Refer for package inserts for specific regimens for specific patient populations

Place in therapy evidence

**All regimens are contraindicated in Child-pugh classes B and C cirrhosis

ZepatierTM (grazoprevir/elbasvir)3

One tablet daily for 12 weeks

-Must undergo NS5A resistance testing

-Can be used in compensated cirrhosis

-Can be used in renal impairment

-Although the trial is still ongoing, study results suggest that Zepatier has cure rates of 96%.

Harvoni

(ledipasvir/sofosbuvir)4

One tablet daily for 12 weeks

-Treatment for only 8 weeks can be used in certain patients

-Cannot be used in renal impairment

-Many drug interactions with sofosbuvir

Viekira PakTM (paritaprevir/ritonavir/ombitasvirPLUS dasabuvir)5

One tablet once daily and one tablet twice daily for 12 weeks

-Large pill burden

-Many drug interactions with ritonavir

-Serious liver injury may occur if patient has pre-existing liver disease

Sovaldi (sofosbuvir) PLUS Olysio (simeprevir)6

Two tablets once daily for 12 weeks

-Large pill burden

-Many drug interactions with sofosbuvir

-Many side effects from sofosbuvir

-Cure rates 90%

Interferon PLUS ribavirin7

SQ injection for 24-48 weeks plus 1 tablet daily

-MANY side effects, intolerances

-Daily SQ injections

-Long treatment duration

-Cure rates 40-80% when used with ribavirin

 

References:

  1. Zepatier. In: DRUGDEX System [database on the Internet]. Greenwood Village, CO. Thomson Micromedex. [updated 2016 Feb 9; cited 2016 Apr 15]
  2. Zepatier [FDA press announcement]. Kenilworth, NJ: Merck & Co; 2016
  3. Zepatier (elbasvir/grazoprevir) [package insert]. Whitehouse Station, NJ. Merck & Co, INC. 2016. [cited 2016 April 19].
  4. Mullins C, Gibson W, Klibanov O. Harvoni (ledipasvir and sofosbuvir) for hepatitis C. The Nurse Practitioner. 2015;40(11):22-26.
  5. A 4-Drug Combination (Viekira Pak) for Hepatitis C. JAMA. 2015;313(18):1857.
  6. FDA Approves Sovaldi for Chronic Hepatitis C. MJHS. 2014;2(1):62-62.
  7. Hepatitis C: management. Clinical Pharmacist. 2013.
  8. Recommendations for Testing, Managing, and Treating Hepatitis C [Internet]. Hcvguidelines.org. 2016 [cited 6 May 2016].

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