Hepatitis C: Oral Direct-Acting Antivirals Are Standard of Care

MAY 17, 2017
Jennifer Andres, PharmD, BCPS
INTRODUCTION

Chronic hepatitis C virus (HCV) infection, estimated to affect up to 4 million Americans, is a leading cause of end-stage liver disease, hepatocellular carcinoma, and liver transplant.1 Six distinct genotypes of HCV exist, with genotype 1 (comprising subtypes 1a and 1b) being the most common in the United States.1 Treatment varies based on genotype, degree of liver impairment, and treatment history, but all methods have a common goal: clinical cure, defined as the attainment of sustained virologic response (SVR) evaluated by a lack of HCV RNA 12 weeks after completing drug therapy (SVR12). Since 2014, oral direct-acting antivirals (DAAs) have been the mainstay of treatment for chronic HCV. DAAs offer high SVR12 rates, improved tolerance, and decreased duration of treatment compared with interferon-containing regimens of the past. In 2016, 2 novel DAA combinations, elbasvir/grazoprevir (Zepatier; by Merck) and sofosbuvir/velpatasvir (Epclusa; by Gilead), were approved by the FDA for treatment of HCV as was an extended-release formulation of ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira XR; by AbbVie).2-4

PHARMACOLOGY

HCV is a small positive-strand RNA virus that replicates within the hepatocyte and causes inflammation; it contains structural and nonstructural proteins (NS) that are essential for replication.1,5 Currently available DAAs inhibit NS, including NS3/4A protease, NS5B polymerase, and NS5A protein, and are used in combination with agents that inhibit different areas of replication. The NS3/4A protease is responsible for cleaving and processing the HCV-encoded polyprotein5; inhibitors include grazoprevir and paritaprevir.2,4 The NS5A protein is responsible for organizing the replication complex, regulating replication, and assembling the viral particle5; elbasvir, ombitasvir, and velpatasvir are NS5A protein inhibitors.2-4 The NS5B polymerase is essential for replication5; sofosbuvir is a nucleotide analog NS5B polymerase inhibitor and dasabuvir is a nonnucleoside NS5B polymerase inhibitor.2,4 Ritonavir is not active against HCV, but acts as a pharmacologic booster for paritaprevir via CYP3A4 inhibition.4

THERAPEUTIC USE, DOSING, AND ADMINISTRATION




Zepatier2 
Zepatier is FDA-approved for the treatment of chronic HCV genotypes 1 and 4. The dosage is 50 mg/100 mg administered orally once daily with or without food. It can be used in patients with end-stage renal disease, including patients on hemodialysis, without dose adjustment. In most cases, elbasvir/grazoprevir is administered for 12 weeks, although 16 weeks is typical if resistance-associated variants (RAVs) are detected. This medication should not be used in patients with Child-Pugh Class B or C hepatic impairment. Baseline resistance testing is recommended prior to initiation in patients with genotype 1a infection.

Epclusa3
Epclusa is the first FDA-approved combination agent for the treatment of all genotypes of HCV in adults and can be used in patients with decompensated cirrhosis. The dosage is 400 mg/100 mg administered orally once daily without regard to food. In most cases, sofosbuvir/velpatasvir is administered for 12 weeks. When treating patients with decompensated cirrhosis, ribavirin should be added.

Viekira XR4
Viekira XR is FDA-approved for the treatment of chronic HCV genotype 1 in adults. The dose is 3 extended-release tablets of 200-mg dasabuvir/8.33-mg ombitasvir/50-mg paritaprevir/33.33-mg ritonavir administered orally once daily; tablets should not be broken or crushed. In most cases, it is administered for 12 weeks. In patients with HIV co-infection, a fully suppressive HIV regimen must be used. And when treating a genotype 1a infection, ribavirin will need to be added. This combination should not be used in patients with Child-Pugh B or C hepatic impairment.

ADVERSE REACTIONS (FDA DRUG WARNINGS)

Compared with interferon-containing regimens, all DAA combinations are well tolerated and have limited adverse effect (AE) profiles. In October 2016, a boxed warning was added to all DAA agents highlighting the risk of hepatitis B reactivation.6 All patients should be assessed for hepatitis B infection prior to DAA initiation. Vaccination should be recommended in appropriate patients and monitoring performed in patients with inactive HBV infection.6 Regimens containing ribavirin contain a risk of hemolytic anemia that will need to be monitored. Ribavirin is teratogenic and pregnancy should be avoided during and at least 6 months following completion of therapy for women and men. 

Zepatier2
The most common AEs in phase 3 trials include fatigue, headache, and nausea. A potential for increases above 5 times the upper limit of normal in alanine aminotransferase levels exists, usually at or after 8 weeks of therapy, with resolution after completion of therapy.

Epclusa3 
The most common AEs in phase 3 trials were headache and fatigue.

Viekira XR4
AEs are extrapolated from Viekira Pak trials.7 The most common AEs observed in clinical trials with Viekira Pak (without ribavirin) were fatigue, nausea, pruritus, other skin reactions, insomnia, and asthenia. There is a drug safety warning for the risk of serious liver injury, mostly in patients with underlying advanced liver disease, within the first 4 weeks of treatment.7 Due to this risk, Viekira Pak should not be used in patients with decompensated cirrhosis.

DRUG INTERACTIONS

Zepatier2 
Concomitant use of OATP1B inhibitors, efavirenz, and CYP3A inducers is contraindicated and can cause significant increases in the plasma levels of grazoprevir. Concomitant use of elbasvir-grazoprevir with strong CYP3A inducers or efavirenz can result in significant lowering of elbasvir and grazoprevir plasma levels, which may result in reduced efficacy of both; accordingly, these combinations are contraindicated. Furthermore, using moderate CYP3A inducers or strong CYP3A inhibitors is not recommended.

Epclusa3
Velpatasvir requires acid for absorption and should not be co-adminstered with acid-suppressing agents. Specific timing and maximum doses of acid-suppressing agents are recommended. Co-administration of sofosbuvir and amiodarone can cause fatal bradycardia. Therefore, if medications must be co-administered or if an adequate wash-out period for amiodarone is not taken, patients should be monitored in the hospital for the first 48 hours of therapy. Sofosbuvir and velpatasvir are substrates for P-glycoprotein (P-gp) and breast cancer resistant protein inhibitors. Moderate to strong P-gp inducers should be avoided. Velpatasvir is metabolized by CYP2B6, CYP2C8, and CYP3A4, so it should not be coadministered with moderate to strong inducers of these enzymes.

Viekira XR4,7
Ritonavir is a potent CYP3A4 inhibitor. Because of this, there are a number of drugs that should not be coadministered. Dasabuvir is metabolized by CYP2C8, and all components are P-gp substrates. The concomitant use of ethinyl estradi- ol-containing medications can result in significant elevations in hepatic aminotransferase levels. Patients should discontinue any ethinyl estradiol-containing medications prior to initiating therapy. The table details the efficacy of drugs in genotype 1 infection.

PLACE IN THERAPY

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America have collaborated on “living” clinical guidelines for the care of patients with HCV. Guidelines are updated as agents are approved and following major therapeutic research.12 The DAA agents approved in 2016 can be used as first-line treatment for chronic genotype 1 HCV infection, in addition to other DAA agents approved prior to 2016. Selection of a DAA regimen should be based on patient-specific factors, including treatment experience, stage of liver disease, presence of insurance coverage, comorbidities, and concomitant medications.

CONCLUSION

DAA therapy is effective at treating chronic HCV infection of all genotypes, including genotype 1. Due to the safety and efficacy of DAA therapy, many patients are eligible for treatment. All current DAAs come with a high price. However, the estimated cost of a liver transplant exceeds even the price of the medication.
 

JENNIFER ANDRES, PHARMD, BCPS, is a clinical assistant professor of pharmacy practice at Temple University School of Pharmacy. She teaches the therapeutics of hepatitis to pharmacy students each year. She has developed a clinic in hepatitis C where she evaluates and educates patients on Hepatitis C drug therapy. 



REFERENCES 
  1. Hepatitis C FAQs for health professionals. CDC website. cdc.gov/hepatitis/ hcv/hcvfaq.htm. Accessed January 6, 2017.
  2. Zepatier (elpasvir/grazoprevir) [product information]. Kenilworth, NJ: Merck; 2016.
  3. Epclusa (sofosbuvir/velpatasvir) [product information]. Foster City, CA: Gilead; 2016.
  4. Viekira XR (dasabuvir, ombitasvir, paritaprevir and ritonavir) [product information]. North Chicago, IL: AbbVie; 2016.
  5. Scheel T, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med. 2013;19(7):837-849. doi: 10.1038/ nm.3248.
  6. FDA drug safety communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. FDA website. www.fda.gov/Drugs/DrugSafety/ucm522932.htm. Published October 4, 2016. Accessed February 5, 2017.
  7. Viekira Pak [package insert]. Chicago, IL: AbbVie; 2015.
  8. Zezeum S, Ghalib R, Reddy KR, et al. Grazoprevir–elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis c virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med. 2015;163(1):1-13. doi: 10.7326/M15-0785.
  9. Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir 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 study. Lancet. 2015;386(10003):1537-1545. doi: 10.1016/ S0140-6736(15)00349-9.
  10. Feld JJ, Jacobson IM, Hézode C, et al; ASTRAL-1 Investigators. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015;373(27):2599-2607. doi: 10.1056/NEJMoa1512610.
  11. Curry MP, O’Leary JG, Bzowej N, et al; ASTRAL-4 Investigators. Sofosbu- vir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373(27):2618-2628. doi: 10.1056/NEJMoa1512614.
  12. American Association for the Study of Liver Disease; Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. hcvguidelines.org/full-report-view. Accessed January 6, 2017.


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