Timothy O'Shea, PharmD
Timothy O'Shea, PharmD
Timothy O'Shea, PharmD, is a Clinical Pharmacist working at a large health insurance plan on the east coast. Additionally he works per diem at a retail pharmacy chain. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.

Mavyret for Hepatitis C: What Pharmacists Should Know

OCTOBER 03, 2017
Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). It is one of the leading causes of chronic liver disease in the United States, with the CDC estimating that between 2.7 and 3.9 million people are infected with chronic HCV.1 Over the past several years, a number of direct-acting antivirals have been approved to treat the infection.
 
In August 2017, the FDA approved AbbVie’s Mavyret, a fixed-dose combination product containing glecaprevir, an HCV NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor for treatment in adults with HCV genotype 1, 2, 3, 4, 5, or 6 infection, without cirrhosis or with mild cirrhosis. It is also approved for adult patients with HCV genotype 1 infection who have been previously treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor but not both. With its approval, Mavyret became the antiviral approved for an 8-week treatment duration for all HCV genotypes in treatment-naïve adult patients without cirrhosis.
 
This article highlights several key therapeutics areas with Mavyret that every pharmacist should know.  

Indication2
Mavyret is indicated for the treatment of patients with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection, without cirrhosis and with compensated cirrhosis (Child-Pugh A). Mavyret is also indicated for the treatment of adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor but not both.

Mechanism of Action
Mavyret is a combination of 2 direct-acting antiviral agents, with distinct mechanisms of action. Glecaprevir is an inhibitor of the HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV encoded polyprotein and for viral replication. Pibrentasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly.
 
Formulation and Storage
Mavyret is dispensed in a 4-week or 8-week carton. Each weekly carton contains 7 daily dose wallets. Within each daily dose wallet there are 3 100 mg/40mg Mavyret tablets. The tablets are pink-colored and film-coated. Mavyret should be stored below at or below 30°C (86ºF).
 
Dosing
Mavyret is administered as 3 tablets taken orally once daily with food. The recommended treatment duration is 8 weeks for all genotypes in treatment-naïve individuals without cirrhosis. For treatment-naïve patients with compensated cirrhosis (Child-Pugh A) the duration is extended to 12 weeks. For treatment-experienced patients the treatment duration ranges from 8 to 16 weeks (table 1).
 
Table 1. Recommended Duration for Treatment-Experienced Patients
  Treatment Duration
HCV Genotype Previous Regimen No Cirrhosis Comp. Cirrhosis
1 NS5A inhibitor1 16 weeks 16 weeks
NS3/4A protease inhibitor2 12 weeks 12 weeks
1, 2, 4, 5, or 6 Interferon, ribavirin, or sofosbuvir-based regimen1,2 8 weeks 12 weeks
3 Interferon, ribavirin, or sofosbuvir-based regimen1,2 16 weeks 16 weeks
1 = without prior treatment with an NS3/4A protease inhibitor
2 = without prior treatment with an NS5A inhibitor
 
Mavyret is not recommended in patients with moderate (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C) due to higher exposures of glecaprevir and pibrentasvir. Prior to initiation of Mavyret, all patients should be tested for evidence of current or prior hepatitis B infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc).
 
Efficacy
The efficacy of Mavyret to treat chronic HCV was established in 9 clinical trials in more than 2300 subjects, with genotype 1, 2, 3, 4, 5, or 6 HCV. The primary endpoint across all trials was sustained virologic response (SVR12), defined as HCV RNA less than the lower limit of quantification (LLOQ) at 12 weeks after the cessation of treatment.
 
Across all studies, SVR12 rates were high, ranging from 92% to 100%. Several studies, including ENDURANCE-1 and ENDURANCE-1, compared Mavyret for 12 weeks versus 8 weeks and found numerically similar results. A subgroup analysis of individuals who received 8-weeks of treatment found no differences across varying characteristics including treatment-experienced individuals, advanced age, BMI greater than or equal to 30, use of proton pump inhibitors, and non-compliance.
 
Due to higher rates of virologic failure and treatment-emergent drug resistance, data from trials do not support the treatment of HCV genotype 1 infected patients who are both NS3/4A PI and NS5A inhibitor-experienced.

Safety
The most common adverse reactions of Mavyret reported in clinical trials include headache and fatigue. The safety profile was similar in patients with and without cirrhosis. Co-administration with rifampin or atazanavir is contraindicated. The safety and effectiveness of Mavyret have not been established in pediatric patients.
 
Drug Interactions
Glecaprevir and pibrentasvir are substrates and inhibitors of drug transporters P-gp and BCRP. They are also weak inhibitors of CYP3A, CYP1A2, and UGT 1A1.
 
Drugs that are inducers of CYP3A4 (eg, rifampin, St. John’s wort, and carbamazepine) may decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect of Mavyret. Therefore, the use of these agents with Mavyret is not recommended. Concurrent use with atazanavir is contraindicated due to an increased risk of ALT elevations. Additionally, Mavyret is not recommended concurrently with atorvastatin, lovastatin, and simvastatin due to increased statin concentration and increased risk of myopathy.
  
Table 2. Product Comparison3
  FDA Indication Dosing # Tablets/ Day AWP
(28 days)
Mavyret (glecaprevir/pibrentasvir) GT 1, 2, 3, 4, 5, 6 QD x 8-16 weeks 3 $15,840
Vosevi (sofosbuvir/velpatasvir/ voxilaprevir) GT 1, 2, 3, 4, 5, 6 QD x 12 weeks 1 $29,904
Epclusa
(sofosbuvir/velpatasvir)
GT 1, 2, 3, 4, 5, 6 QD x 12 weeks 1 $29,904
Harvoni
(ledipasvir/sofosbuvir)
GT 1, 4, 5, 6 QD x 12-24 weeks 1 $37,800
Zepatier
(elbasvir/grazoprevir)
GT 1, 4 QD x 12-16 weeks 1 $21,840
Viekira Pak
(ombitasvir/paritaprevir/ ritonavir and dasabuvir)
GT 1 BID x 12-24 weeks 4 $33,328
Viekira Pak XR
(ombitasvir/paritaprevir/ ritonavir and dasabuvir)
GT 1 QD x 12-24 weeks 3 $33,328
Daklinza (daclatasvir) + Sovaldi (sofosbuvir) GT 1, 3 QD x 12-24 weeks 2 $58,800
Olysio (simeprevir) + Sovaldi (sofosbuvir) GT 1 QD x 12-24 weeks 2 $60,144
Technivie
(ombitasvir/paritaprevir/ ritonavir)
GT 4 QD x 12 weeks 2 $32,851
 
Cost based on AWP, per Lexi-Drugs. Cost to the patient will vary based on individual insurance coverage.
 
Guideline recommendations4
Current guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America recommend Mavyret as a recommended first-line treatment option in HCV genotypes 1, 2, 3, 4, 5, and 6 in those without cirrhosis or compensated cirrhosis. It is also a recommended first-line agent in treatment-experienced individuals in accordance with its FDA-approved indications (not recommended in Viekira Pak and Zepatier treatment failures).
 
Conclusion2,4,5
In clinical studies, Mavyret was shown to be highly effective in treating HCV genotypes 1, 2, 3, 4, 5, and 6 in both treatment-naïve and treatment-experienced individuals. Additionally, the medication was well-tolerated across all studies. Current HCV AASLD guidelines recommend Mavyret as a recommended first-line agent in treatment-naïve and experienced adults. Although the medication requires 3 tablets to be taken daily most individuals only require an 8-week treatment duration, which is shorter than other treatment options. Additionally, Mavyret is the least costly HCV agent on the market. Some health experts speculate that having a less expensive agent that only requires 8 weeks of treatment may make it easier for more insurers, particularly for the Medicaid population and correctional facilities to expand treatment.
 
References
  1. CDC. Viral hepatitis. cdc.gov/hepatitis/hcv/. Updated May 31, 2015. Accessed September 30, 2017.
  2. Mavyret [prescribing Information]. AbbVie Inc. North Chicago, IL. August 2017. hrxabbvie.com/pdf/mavyret_pi.pdf. Accessed October 3, 2017.
  3. Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc. online.lexi.com/lco/action/home. Accessed September 30, 2017.
  4. AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. hcvguidelines.org. Accessed September 30, 2017.
  5. Andrews M. Hepatitis C drug’s lower cost paves way for Medicaid, prisons to expand treatment. Kaiser Health News. October 3 2017. khn.org/news/hepatitis-c-drugs-lower-cost-paves-way-for-medicaid-prisons-to-expand-treatment. Accessed October 3, 2017.



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