Ledipasvir-Sofobuvir

Ledipasvir-Sofosbuvir

Jasmine Woods

November 5^th, 2018

            The fixed-dose combination of Ledipasvir-Sofosbuvir (Harvoni) provides an effective and well-tolerated one-pill once-a-day option for treatment of genotypes 1, 4, 5, and 6 chronic hepatitis C (HCV) infection.¹ Hepatitis C is a viral infection that causes liver inflammation, sometimes leads to serious liver damage.² Ledipasvir is a potent inhibitor of HCV NS5A, a viral phosphoprotein that plays an important role in viral replication, assembly, and secretion.¹ Sofosbuvir is a nucleotide analog inhibitor of hepatitis C virus NS5B polymerase—the key enzyme mediating HCV RNA replication.¹ Until recently, hepatitis C treatment required weekly injections and oral medications that many HCV-infected people couldn't take because of other health problems or unacceptable side effects.²

            The FDA approved Harvoni on October 14, 2014, for chronic hepatitis C virus (HCV) infections with high cure rates and mild side effects.³ Gilead Sciences, Inc., commonly known as Gilead Sciences, is an American biopharmaceutical company that researches, develops and commercializes drugs.⁴ Their primary research focus is on antiviral drugs used for the treatment of HIV, Hepatitis B, Hepatitis C, and influenza.⁴ Ledipasvir and Sofobuvir were not always a combination. Sofosbuvir (Sovaldi) was approved by the FDA in 2013 but was later investigated due to the 12-week regimen totaling $84,000.⁴ After hearings and negotiations, mandated discounts were put into place and Gilead Sciences licensed other companies to produce generic versions.⁴ Gilead Sciences began experimenting with combining Sofosbuvir (Sovaldi) with other antivirals in single pill combinations.⁵ Sofosbuvir tends to be called the backbone of most combinations due to its high resistance barrier and a pan-genotypic activity.⁵ Sofosbuvir was combined with Dasabuvir and a 12 week clinical trial showed that people with cirrhosis’ results were unsatisfactory.⁵ Cirrhosis is scarring of the liver which can occur after battling hepatitis C 20 to 30 years.² Individuals who chose to continue the study for 12 additional weeks saw a slight increase in positive outcomes.⁵ A phase II trial analyzed the efficiency of Sofobuvir and Simeprevir and Ribavirin in two groups of patients with HCV genotype 1, one of the most common Hep C strands.⁵ This combination had a 94% cured outcome rate on the group battling advanced fibrosis or cirrhosis.⁵ Phase III had the combination of Sofobuvir, Ledipasvir and Ribavirin which gave a 100% outcome of the patients studied who also had cirrhosis.⁵ Some side effects documented were weight loss, fatigue, itchy skin, dark colored urine, and bruising easily.² Today, patients worldwide that may be fighting Hepatitis C (HCV) are being prescribed Ledipasvir-Sofobuvir (Harvoni).

            Before Harvoni, patients would be prescribed Peginterferon Alfa-2a (Pegasys) .⁶ This medication is used to treat chronic hepatitis B and hepatitis C infection.⁶ Before 2014, hepatitis treatment relied Peginterferon and Ribavirin which resulted in long treatments, many intense side effects, and difficult to take.^6,7 Ribavirin showed to have embryocidal effects therefore extreme care must be taken to avoid pregnancy.⁷ This meant that women had to choose between postponing having a baby at least 72 weeks or risk passing HCV to the baby.⁷ Everything changed once Harvoni was approved by the FDA in 2014.⁷ Studies showed that “animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.⁷ This statement shows that Harvoni could be used during pregnancy and an added benefit is shorter treatment (8-12 weeks), so if a women delayed pregnancy she would not have to wait long.⁷ Overall, the progressive movement researchers made in Hepatitis drug treatment is giving women today the choice of growing a family while also receiving medical attention.

Ledipasvir-Sofosbuvir (Harvoni) received FDA approval in 2013 and was the first drug deemed safe and effective without interferon.⁸ It was also the first approved curative treatment for HCV.⁸ No previous treatments has resulted in a sustained virologic response, which made sofosbuvir a highly sought-after drug.⁸ If the CDC estimates are correct and 3.5 billion Americans have HCV, then treatment with Harvoni would cost payers $331 billion, which was more than total drug spending in 2013.⁸ On the other hand, sofosbuvir only costs $900 in Egypt, and $55,000 in Canada, substantially less than the cost in the United States.⁸ Medicaid is unable to cover treatment for all patients, since covering 1 treatment with Harvoni costs the same as the annual health cost for 29 enrollees, which highlights the need for lower cost.⁸ Both private and public insurers have had to create eligibility requirements that prioritize patients with liver damage and those who have responded to less costly treatments due to the high price of newer drugs.⁸ Luckily the Department of Veterans Affairs recently announced they would cover HCV treatment cost for all veteran because of increased funding.⁸ After the approval of Viekira Pak, the pricing of Harvoni was impacted and Gilead Sciences took a 20% hit prompting them to offer discounts for Harvoni to certain payers.⁸ A pipeline drug, odalasvir, being developed by Achillion Pharmaceutical sand Johnson& Johnson also has the potential to reduce drug cost.⁸ The drug has shown a 100% cure rate in 6 weeks in combination with sofosbuvir meaning shorter treatment spans will likely result in a smaller cost.⁸ Gilead’s drugs remain some of he highest priced on the market but the introduction of lower cost drugs will likely decrease the cost of HCV treatment over time.⁸

Harvoni has encountered a safety issue for its patients causing liver failure.⁹ The FDA reported 524 cases of liver failure, including 165 deaths, and 1058 reports of severe liver injury. ⁹ Harvoni was approved in 2014 with a starting price of $1,000 per pill and has since had over a billion dollar in sales.⁹ These drug are able to cure Hepatitis C in 12 weeks in many patients.⁹ This New York Times article stated that 250,000 people took the drug in 2015 with the expense costing $55,000 to $125,000 per patient.⁹ In those treat during the year ending June 30, 2016, the report identified 524 with liver failure, 165 of whom died.⁹ An additional 1,058 had severe liver injury, and in 76 the drugs appeared not to work.⁹ While it was challenging to separate cases to which complication of hepatitis C might have contributed, 90% of the cases were submitted by healthcare professionals, who would be likely to understand the natural progression of the disease.¹⁰ Whether the drugs were to blame is not known, the doctors observed the problem and were not able to prove cause and effect. “Benefits and side effects evolve over the long term, not over 12 weeks”, stated Dr. Moore.⁹

Bibliography

¹Osinusi A, Townsend K, Kohli A, et al. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. JAMA. 2015;313:1232-9.

²Hepatitis C. (2018, March 06). https://www.mayoclinic.org/diseases-conditions/hepatitis-c/symptoms-causes/syc-20354278

³Porter, L. K. (2014, October 10). Harvoni: What You Need to Know about the Newest Hepatitis C Treatment. https://www.hepmag.com/blog/harvoni-what-you-nee

⁴Gilead Sciences. (2018, July 27). https://en.wikipedia.org/wiki/Gilead_Sciences

⁵Zopf, S., Kremer, A. E., Neurath, M. F., & Siebler, J. (2016). Advances in hepatitis C therapy: What is the current state - what come’s next? World Journal of Hepatology, 8(3), 139–147. http://doi.org/10.4254/wjh.v8.i3.139

⁶Peginterferon Alfa-2a (By injection) - National Library of Medicine - PubMed Health. (2018, August 1). https://www.ncbi.nlm.nih.gov/pubmedhealth/ PMHT0011620/?report=details#how_to_use

⁷Porter, L. K. (2017, March 08). Hepatitis C Treatment and Pregnancy. Retrieved from https://www.hepmag.com/article/hepatitis-c-pregnant-26893

⁸Toich, L. (2017, February 8). Will Hepatitis C Virus Medication Costs Drop in the Years Ahead? Retrieved from https://www.pharmacytimes.com/resource-centers/hepatitisc/will-hepatitis-c-virus-medicaton-costs-drop-in-the-years-ahead

⁹Grady, D. (2017, January 24). Are New Drugs for Hepatitis C Safe? A Report Raises Concerns. Retrieved from https://www.nytimes.com/2017/01/24/health/hepatitis-c-antiviral-drug-study.html

¹⁰Lamb, T. (2017, January 27). New Safety Issue: Direct-Acting Antivirals Drugs For Hepatitis C Such As Harvoni And Sovaldi Could Cause Liver Failure. Retrieved from https://www.drug-injury.com/druginjurycom/2017/01/sovaldi-hepatic-failure-harvoni-liver-injury-drug-safety-issues-side-effects-reports-ismp-fda-faers-database-review.html