Sofosbuvir

Generic Name
Sofosbuvir
Brand Names
Epclusa, Harvoni, Sovaldi, Vosevi
Drug Type
Small Molecule
Chemical Formula
C22H29FN3O9P
CAS Number
1190307-88-0
Unique Ingredient Identifier
WJ6CA3ZU8B
Background

Sofosbuvir (tradename Sovaldi) is a direct acting antiviral medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients . Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as sofosbuvir. As a prodrug nucleotide analog, Sofosbuvir is metabolized into its active form as the antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate (also known as GS-461203), which acts as a defective substrate for NS5B (non-structural protein 5B) . NS5B, an RNA-dependent RNA polymerase, is essential for the transcription of Hepatitis C viral RNA and for its high replicative rate and genetic diversity . Sofosbuvir and other direct acting antivirals are therefore very potent options for the treatment of Hepatitis C, as they exhibit a high barrier to the development of resistance . This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid development of resistance has proven to be an important cause of therapeutic failure.

In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Sofosbuvir as first line therapy in combination with other antivirals for all six genotypes of Hepatitis C . Depending on the genotype, sofosbuvir is often used in combination with other antivirals such as Ledipasvir, Velpatasvir, Daclatasvir, Simeprevir, Elbasvir, Grazoprevir, Ribavirin, Peginterferon alfa-2a, or Peginterferon alfa-2b with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality . Treatment with direct acting antivirals such as sofosbuvir is associated with very minimal side effects, with the most common being headache and fatigue . Lack of significant side effects and short duration of therapy is a considerable advantage over older interferon- and ribavirin-based regimens, which were limited by infusion site reactions, reduced blood count, and neuropsychiatric effects .

Since 2014, sofosbuvir has been available as a fixed dose combination product with Ledipasvir (tradename Harvoni) used for the treatment of chronic Hepatitis C. Approved in October 2014 by the FDA, Harvoni is indicated for the treatment of HCV genotypes 1, 4, 5, and 6 with or without Ribavirin depending on the level of liver damage or cirrhosis . When combined together, ledipasvir and sofosbuvir as the combination product Harvoni has been shown to achieve a SVR between 93 and 99% after 12 weeks of treatment . Its use has also proven successful in the treatment of HCV in patients co-infected with HIV .

Sofosbuvir is also available as a fixed dose combination product with Velpatasvir as the commercially available product Epclusa. First approved in June 2016, Epclusa is the first combination HCV product indicated for the treatment of all genotypes of Hepatitis C with or without cirrhosis. Epclusa is also currently the most potent HCV antiviral medication on the market with a sustained virologic response (SVR) after 12 weeks of therapy of 93-99% depending on genotype and level of cirrhosis . Both Canadian and American guidelines list Epclusa as a first line recommendation for all genotypes of HCV .

Notably, sofosbuvir has come under intense scrutiny since its release to market in 2013. With the price per pill set at $1000, a 12-week treatment can cost upwards of $84,000 per patient .

Indication

Sofosbuvir is used in combination therapy with other antiviral medications to treat chronic hepatitis C virus (HCV) infected patients with HCV genoptypes 1-6, and to treat HCV and HIV co-infected patients. Depending on the level of cirrhosis or decompensation, combination therapy can also include either ribavirin alone or ribavirin and peg-interferon alfa.

When used in combination with Ledipasvir, sofosbuvir has the following indications: treatment of genotypes 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis; in combination with Ribavirin for genotype 1 infection with decompensated cirrhosis; or in combination with Ribavirin for the treatment of genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis.

When used in combination with Velpatasvir as the combination product Epclusa, sofosbuvir is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotypes 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis, or in combination with Ribavirin if associated with decompensated cirrhosis.

Resistance: Reduced susceptibility to sofosbuvir has been associated with the NS5B substitution mutation S282T .

Associated Conditions
Chronic Hepatitis C - Genotype 3, Chronic Hepatitis C Genotype 1, Chronic Hepatitis C Virus (HCV) Infection, Chronic hepatitis C genotype 1a, Chronic hepatitis C genotype 2, Chronic hepatitis C genotype 5, Genotype 4 Chronic Hepatitis C, Genotype 6 chronic hepatitis C infection
Associated Therapies
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Short Duration Combination Therapy With Daclatasvir, Asunaprevir, BMS-791325 and Sofosbuvir in Subjects Infected With Chronic Hepatitis-C (FOURward Study)

First Posted Date
2014-06-26
Last Posted Date
2020-08-11
Lead Sponsor
Bristol-Myers Squibb
Target Recruit Count
35
Registration Number
NCT02175966
Locations
🇺🇸

Inland Empire Liver Foundation, Rialto, California, United States

🇺🇸

Indiana University Health - University Hospital, Indianapolis, Indiana, United States

🇺🇸

Northwestern University Feinberg School Of Medicine, Chicago, Illinois, United States

and more 4 locations

The SIM-SOF Trial for Hepatitis C

First Posted Date
2014-06-20
Last Posted Date
2016-03-14
Lead Sponsor
Center For Hepatitis C, Atlanta, GA
Target Recruit Count
93
Registration Number
NCT02168361
Locations
🇺🇸

Center for Hepatitis C, Atlanta, Georgia, United States

A Multicenter Treatment Protocol of Daclatasvir (BMS-790052) in Combination With Sofosbuvir for the Treatment of Post-Liver Transplant Subjects With Chronic Hepatitis C

First Posted Date
2014-06-12
Last Posted Date
2016-01-29
Lead Sponsor
Bristol-Myers Squibb
Registration Number
NCT02161939
Locations
🇺🇸

University of Florida, Gainesville, Florida, United States

🇺🇸

Mayo Clinic, Phoenix, Arizona, United States

🇺🇸

Piedmont Transplant, Atlanta, Georgia, United States

and more 17 locations

Sofosbuvir-Containing Regimens Without Interferon For Treatment of Acute Hepatitis C Virus (HCV) Infection

First Posted Date
2014-05-01
Last Posted Date
2018-04-27
Lead Sponsor
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Target Recruit Count
44
Registration Number
NCT02128217
Locations
🇺🇸

7804 Weill Cornell Chelsea CRS, New York, New York, United States

🇺🇸

2701 Northwestern University CRS, Chicago, Illinois, United States

🇺🇸

Rush Univ. Med. Ctr. ACTG CRS (2702), Chicago, Illinois, United States

and more 9 locations

Efficacy and Safety of Sofosbuvir+Ribavirin in Genotype 2 HCV-infected U.S. Veterans With Cirrhosis

Phase 4
Completed
Conditions
Interventions
First Posted Date
2014-05-01
Last Posted Date
2016-08-03
Lead Sponsor
Gilead Sciences
Target Recruit Count
66
Registration Number
NCT02128542

EU: A Multicenter Compassionate Use Program of Daclatasvir (BMS-790052) in Combination With Sofosbuvir With or Without Ribavirin for the Treatment of Subjects With Chronic Hepatitis C

First Posted Date
2014-03-27
Last Posted Date
2016-01-27
Lead Sponsor
Bristol-Myers Squibb
Registration Number
NCT02097966
Locations
🇬🇧

Local Institution, Wrexham, United Kingdom

🇬🇧

Local Instituition, Liverpool, Merseyside, United Kingdom

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