By: Sebanti Bhowmik and Elissa Tam, PharmD Candidates c/o 2015

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On October 10, 2014, the Food and Drug Administration approved ledipasvir-sofosbuvir (Harvoni™) to treat chronic hepatitis C virus (HCV) genotype 1 infection in adults. Harvoni™, marketed by Gilead Sciences, consists of Gilead’s sofosbuvir (Sovaldi™) and a new drug, ledipasvir.¹ Harvoni™ is the first combination pill to be approved to treat HCV, and is also the first approved regimen that does not require co-adminsitraton with interferon or ribavirin.¹

HCV is a blood-borne disease that can be spread through blood transfusions, organ transplants, sharing needles and syringes, needlestick injuries in healthcare settings, and birth from a mother who is infected.² Though unlikely, transmission via sexual contact may occur, especially in those who have multiple partners or who are coinfected with human immunodeficiency virus (HIV).

HCV is highly heterogeneous; there are eleven HCV genotypes with several distinct subtypes.^3,4 Genotype 1 is most common, affecting 70% of the HCV-positive U.S. population. Although different strains have not been shown to differ dramatically in their virulence or pathogenicity, different genotypes do vary in their responsiveness to interferon and ribavirin combination therapy. Such heterogeneity has hindered both the development of vaccines and the effectiveness of treatments.⁴

An estimated 3.2 million people in the U.S. have chronic HCV, though many patients do not know they are infected until symptoms appear. In 2009, an estimated 16,000 acute HCV infections were reported. Approximately 75-85% of people who become infected with the virus develop chronic infection, which can lead to severe complications such as cirrhosis, liver cancer, liver failure, and even death.² HCV is the leading cause of cirrhosis and liver cancer, and is the most common reason for liver transplantation in the U.S. Approximately 15,000 people die every year from HCV related liver disease.²

Currently, there are no vaccinations available for HCV. However, there are several medications available to treat chronic HCV, and more therapies are currently being investigated. Harvoni™ is the third drug approved by the FDA in the past year, following simeprevir (Olysio™) in November 2013, and sofosbuvir in December 2013.¹ Guidance for treatment in adults is changing constantly due to the advent of new therapies. Before the approval of simeprevir and sofosbuvir, oral twice-daily ribavirin with once-weekly subcutaneously injectable peginterferon was the main regimen prescribed. Side effects of ribavirin include anemia, depression, and low neutrophils counts. Peginterferon can cause flu-like symptoms, hair thinning, and injection site reactions (redness and irritation). This regimen is administered over a period of 24 to 48 weeks, depending on co-infection with HIV, treatment status, and genotypes.³ With use of simeprevir and sofosbuvir, therapy duration has been shortened to 12 to 24 weeks with less requirements for interferon and ribavirin.³

Harvoni™ is a fixed-dose combination product containing 90 mg of ledipasvir and 400 mg of sofosbuvir in a single tablet. The recommended dosage of ledipasvir-sofosbuvir is one tablet taken orally once a day. This drug should be taken with food to reduce the incidence of gastrointestinal side effects such as nausea and diarrhea. Ledipasvir is a HCV NS5A protein inhibitor that interferes with viral replication. Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, an enzyme that is required for viral replication.⁵

The efficacy of ledipasvir-sofosbuvir was evaluated in three randomized Phase 3 trials for patients with genotype 1 chronic HCV with compensated liver disease: ION-3, ION-1, and ION-2. All three Phase 3 trials evaluated the efficacy of ledipasvir-sofosbuvir with or without ribavirin. Serum HCV RNA values were measured. The primary endpoint was sustained virologic response (SVR), which was defined as HCV RNA of less than 25 IU/mL at 12 weeks after the cessation of treatment. ION-3 evaluated treatment-naïve adults without cirrhosis and showed that the SVR was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir–sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir–sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir–sofosbuvir.⁶ ION-1 evaluated 12 and 24 weeks of treatment with ledipasvir-sofosbuvir with or without ribavirin in treatment-naïve adults with or without cirrhosis. The rates of SVR were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir–sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir–sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir–sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir–sofosbuvir plus ribavirin.⁷ ION-2 evaluated previously-treated adults with or without cirrhosis for 12 or 24 weeks of treatment with ledipasvir-sofosbuvir with or without ribavirin. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir–sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir–sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir–sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir–sofosbuvir and ribavirin.⁸ Results of all three Phase 3 trials indicated that ledipasvir-sofosbuvir was associated with a high SVR in both treatment-naive and previously-treated adults with or without cirrhosis with HCV genotype 1 infection, and that no additional benefit was seen when ribavirin was added.

At the moment, clinical trials have only shown the efficacy of ledipasvir-sofosbuvir in adult subjects. Ledipasvir-sofosbuvir has not been studied adequately in pregnancy or during breastfeeding. Thus, use during pregnancy is only recommended if the potential benefits justify the potential risks to the fetus. Efficacy has not been established in pediatric patients, and no dosage adjustments are necessary in the geriatric population.⁵

The use of ledipasvir-sofosbuvir with P-glycoprotein inducers such as rifampin or St. John’s wort is not recommended due to decreased ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effects. The use of ledipasvir-sofosbuvir with other products containing sofosbuvir is also not recommended. Acid reducing agents such as antacids, H2-receptor antagonists, and proton-pump inhibitors decrease ledipasvir concentration, and administration of these agents should therefore be separated by a minimum of four hours. Furthermore, concomitant use of antiretrovirals containing tenofovir and ledipasvir-sofosbuvir may lead to increased tenofovir concentration. As a result, tenofovir-associated adverse reactions such as lactic acidosis, decreased bone mineral density, and gastrointestinal effects must be monitored in patients with HCV and HIV co-infection.

As the first single-tablet regimen for HCV infection, Harvoni™ presents many advantages. Primarily, it is taken once a day, which increases compliance in a patient population in which adherence to therapy is crucial to achieving treatment response. In addition, it may decrease HCV treatment length to as little as 8 weeks for patients who do not have cirrhosis, are treatment-naive and have a baseline HCV RNA below 6 million IU/mL.⁵ Ledipasvir-sofosbuvir also has the advantage of not requiring treatment with interferon or ribavirin, thus freeing those undergoing treatment from side effects of those medications and the need for weekly injections. The most common adverse effects of ledipasvir-sofosbuvir are fatigue and headache, which are far more manageable than adverse events caused by interferon and ribavirin. Additionally, clinical trials have shown that study participants achieve SVR rates of 94-99% ^6,7,8, bringing ledipasvir-sofosbuvir the closest to a potential cure. However, the cost of this medication ranges from approximately $63,000 for an 8-week course of treatment, to $94,500 for a 12-week course of treatment, and to $189,000 for a 24-week course of therapy, which is approximately $1,125 per tablet.⁹ When compared to combination regimens, however, the cost for ledipasvir-sofosbuvir (Harvoni™) becomes arguably comparable. Regardless, cost-effectiveness should be assessed on an individual basis.

Only a year ago, the limited number of available treatment options for HCV required administration with interferon and ribavirin. With the introduction of sofosbuvir and simeprevir, patients and healthcare professionals were provided with new alternatives. With the advent of ledipasvir-sofosbuvir (Harvoni™), there is now a combination medication that can increase compliance, reduce pill burden and need for injections, and lead to high SVR rates with minimal side effects. Although other medications are in the process of development for chronic HCV genotype 1 infection, such as AbbVie’s investigational, all-oral, interferon-free three-drug regimen, it is likely that with the advantages and simplicity of treatment with Harvoni™, Gilead’s product is here to stay.

 

SOURCES:

1. FDA approves first combination pill to treat Hepatitis C. Fda.gov. Published on 10/10/14. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418365.htm. Accessed 11/09/14.
2. Hepatitis C. Centers for Disease Control and Prevention. http://www.cdc.gov/hepatitis/c/cfaq.htm. Updated 12/09/14. Accessed 11/09/14.
3. Recommendation for testing, managing and treating Hepatitis C. Infectious Diseases Society of America. Updated 09/25/14. Accessed 11/09/14.
4. Hepatitis C. World Health Organization. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index2.html. Accessed 11/09/14.
5. Harvoni [Package Insert]. Foster City, CA: Gilead Sciences, Inc; 2014.
6. Kowdley KV, Gordon SD, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370: 1879-88.
7. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370: 1889-98.
8. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370: 1483-93.
9. Pollack A. Harvoni, a hepatitis C drug From Gilead, wins F.D.A. approval. New York Times. Published on 10/10/14. http://www.nytimes.com/2014/10/11/business/harvoni-a-hepatitis-c-drug-from-gilead-wins-fda-approval.html. Accessed 11/09/14.

Published by Rho Chi Post