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Sofosbuvir, sold under the brand name Sovaldi among others, is a
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
used to treat
hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, a ...
. It is taken
by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...
. Common side effects include fatigue, headache, nausea, and trouble sleeping. Side effects are generally more common in interferon-containing regimens. Sofosbuvir may reactivate
hepatitis B Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. Fo ...
in those who have been previously infected. In combination with ledipasvir, daclatasvir or simeprevir, it is not recommended with
amiodarone Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibrilla ...
due to the risk of an abnormally slow heartbeat. Sofosbuvir is in the nucleotide analog family of medications and works by blocking the hepatitis C
NS5B Nonstructural protein 5B (NS5B) is a viral protein found in the hepatitis C virus (HCV). It is an RNA-dependent RNA polymerase, having the key function of replicating HCV's viral RNA by using the viral positive RNA strand as a template to catalyze ...
protein. Sofosbuvir was discovered in 2007 and approved for medical use in the United States in 2013. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
.


Medical uses


Initial HCV treatment

In 2016, the
American Association for the Study of Liver Diseases The American Association for the Study of Liver Diseases (AASLD) is a leading organization of scientists and health care professionals committed to preventing and curing liver disease. AASLD was founded in 1950 by a group of leading liver specialist ...
and the
Infectious Diseases Society of America The Infectious Diseases Society of America (IDSA) is a medical association representing physicians, scientists and other health care professionals who specialize in infectious diseases. It was founded in 1963 and is based in Arlington, Virginia. ...
jointly published a recommendation for the management of hepatitis C. In this recommendation, sofosbuvir used in combination with other drugs is part of all first-line treatments for HCV genotypes 1, 2, 3, 4, 5, and 6, and is also part of some second-line treatments. Sofosbuvir in combination with velpatasvir is recommended for all genotypes with a cure rate greater than 90%, and close to 100% in most cases. The duration of treatment is typically 12 weeks. Sofosbuvir is also used with other medications and longer treatment durations, depending on specific circumstances, genotype and cost-effectiveness–based perspective. For example, for the treatment of genotypes 1, 4, 5, and 6 hepatitis C infections, sofosbuvir can be used in combination with the viral NS5A inhibitor
ledipasvir Ledipasvir is a drug for the treatment of hepatitis C that was developed by Gilead Sciences. After completing Phase III clinical trials, on February 10, 2014, Gilead filed for U.S. approval of a ledipasvir/sofosbuvir fixed-dose combination table ...
. In genotype 2 and 3 HCV infections, sofosbuvir can be used in combination with
daclatasvir Daclatasvir, sold under the brand name Daklinza, is an antiviral medication used in combination with other medications to treat hepatitis C (HCV). The other medications used in combination include sofosbuvir, ribavirin, and interferon, vary depe ...
. For the treatment of cases with cirrhosis or liver transplant patients, weight-based ribavirin is sometimes added. Peginterferon with or without sofosbuvir is not recommended in an initial HCV treatment. Compared to previous treatments, sofosbuvir-based regimens provide a higher cure rate, fewer side effects, and a two- to four-fold reduction in therapy duration. Sofosbuvir allows most people to be treated successfully without the use of peginterferon, an injectable drug with severe side effects that is a key component of older drug combinations for the treatment of hepatitis C virus.


Prior failed treatment

For people who have experienced treatment failure with some form of combination therapy for hepatitis C infection, one of the next possible steps would be retreatment with sofosbuvir and either ledipasvir or daclatasvir, with or without weight-based ribavirin. The genotype and particular combination therapy a person was on when the initial treatment failed are also taken into consideration when deciding which combination to use next. The duration of retreatment can range from 12 weeks to 24 weeks depending on several factors, including which medications are used for the retreatment, whether the person has liver
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
or not, and whether the liver damage is classified as compensated cirrhosis or decompensated cirrhosis.


Pregnancy and breastfeeding

No adequate human data are available to establish whether or not sofosbuvir poses a risk to pregnancy outcomes. However,
ribavirin Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pegin ...
, a medication that is often given together with sofosbuvir to treat hepatitis C, is assigned a Pregnancy Category X (contraindicated in pregnancy) by the FDA. Pregnant women with hepatitis C who take ribavirin have shown some cases of birth defects and death in their fetus. It is recommended that sofosbuvir/ribarivin combinations be avoided in pregnant females and their male sexual partners in order to reduce harmful fetal defects caused by ribavirin. Females who could potentially become pregnant should undergo a pregnancy test 2 months prior to starting the sofosbuvir/ribavirin/peginterferon combination treatment, monthly throughout the duration of the treatment, and six months post-treatment to reduce the risk of fetal harm in case of accidental pregnancy. It is unknown whether sofosbuvir and ribavirin pass into breastmilk; therefore, it is recommended that the mother does not breastfeed during treatment with sofosbuvir alone or in combination with ribavirin.


Contraindications

There are no specific contraindications for sofosbuvir when used alone. However, when used in combination with
ribavirin Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pegin ...
or peginterferon alfa/ribavirin, or others, the contraindications applicable to these agents are applied.


Side effects

Sofosbuvir used alone and in combination with other drugs such as
ribavirin Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pegin ...
with or without a peginterferon has a good safety profile. Common side effects are fatigue, headache, nausea, rash, irritability, dizziness, back pain, and anemia. Most side effects are more common in interferon-containing regimens as compared to interferon-free regimens. For example, fatigue and headache are nearly reduced by half, influenza-like symptoms are reduced to 3–6% as compared to 16–18%, and
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
is almost absent in interferon-free treatment. Sofosbuvir may reactivate hepatitis B in those who have been previously infected. The
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
(EMA) has recommended screening all people for hepatitis B before starting sofosbuvir for hepatitis C in order to minimize the risk of hepatitis B reactivation.


Interactions

Sofosbuvir (in combination with
ledipasvir Ledipasvir is a drug for the treatment of hepatitis C that was developed by Gilead Sciences. After completing Phase III clinical trials, on February 10, 2014, Gilead filed for U.S. approval of a ledipasvir/sofosbuvir fixed-dose combination table ...
,
daclatasvir Daclatasvir, sold under the brand name Daklinza, is an antiviral medication used in combination with other medications to treat hepatitis C (HCV). The other medications used in combination include sofosbuvir, ribavirin, and interferon, vary depe ...
or
simeprevir Simeprevir, sold under the trade names Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with inclu ...
) should not be used with
amiodarone Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibrilla ...
due to the risk of abnormally slow heartbeats. Sofosbuvir is a substrate of
P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...
, a transporter protein that pumps drugs and other substances from
intestinal epithelium The intestinal epithelium is the single cell layer that form the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelial cells, it serves two main functi ...
cells back into the gut. Therefore, inducers of intestinal P-glycoprotein, such as rifampicin and
St. John's wort ''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''. Possibly a hybrid between ''Hypericum maculatum, H. maculatum'' and ''Hypericum attenuatum, H. ...
, could reduce the absorption of sofosbuvir. In addition, coadministration of sofosbuvir with anticonvulsants (
carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...
, phenytoin, phenobarbital, oxcarbazepine), antimycobacterials (
rifampin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. It is almost always used tog ...
, rifabutin, rifapentine), and the HIV protease inhibitor tipranavir and
ritonavir Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor a ...
is expected to decrease sofosbuvir concentration. Thus, coadministration is not recommended. The interaction between sofosbuvir and a number of other drugs, such as
ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, ...
,
darunavir Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir or ...
/
ritonavir Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor a ...
,
efavirenz Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlest ...
,
emtricitabine Emtricitabine (commonly called FTC, systematic name 2',3'-dideoxy-5-fluoro-3'-thiacytidine), with trade name Emtriva (formerly Coviracil), is a nucleoside reverse-transcriptase inhibitor (NRTI) for the prevention and treatment of HIV infection i ...
,
methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid dependence. It is used to treat chronic pain, and it is also used to treat addiction to heroin ...
,
raltegravir Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential ex ...
,
rilpivirine Rilpivirine, sold under the brand names Edurant and Rekambys, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer ...
,
tacrolimus Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After allogeneic organ transplant, the risk of organ rejection is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also ...
, or
tenofovir disoproxil Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for preven ...
, were evaluated in clinical trials and no dose adjustment is needed for any of these drugs.


Pharmacology


Mechanism of action

Sofosbuvir inhibits the hepatitis C
NS5B Nonstructural protein 5B (NS5B) is a viral protein found in the hepatitis C virus (HCV). It is an RNA-dependent RNA polymerase, having the key function of replicating HCV's viral RNA by using the viral positive RNA strand as a template to catalyze ...
protein. Sofosbuvir appears to have a high barrier to the development of resistance. Sofosbuvir is a
prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
of the
Protide The ProTide technology is a prodrug approach used in molecular biology and drug design. It is designed to deliver nucleotide analogues (as monophosphate) into the cell (ProTide: PROdrug + nucleoTIDE). It was invented by Professor Chris McGuigan (S ...
type, whereby the active phosphorylated nucleotide is granted cell permeability and oral bioavailability. It is metabolized to the active antiviral agent GS-461203 (2'-deoxy-2'-α-fluoro-β-''C''-methyluridine-5'-triphosphate). GS-461203 serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase, thus acts as an inhibitor of viral RNA synthesis. Although sofosbuvir has a 3' hydroxyl group to act as a nucleophile for an incoming NTP, a similar nucleotide analogue, 2'-deoxy-2'-α-fluoro-β-C-methylcytidine, is proposed to act as a chain terminator because the 2' methyl group of the nucleotide analogue causes a
steric clash Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...
with an incoming NTP. Sofosbuvir would act in a similar way.


Pharmacokinetics

Sofosbuvir is only administered orally. The peak concentration after oral administration is 0.5–2 hours post-dose, regardless of initial dose. Peak plasma concentration of the main circulating metabolite GS-331077 occurs 2–4 hours post-dose. GS-331077 is the pharmacologically inactive
nucleoside Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide ...
.
Plasma protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...
of sofosbuvir is 61–65%, while GS-331077 has minimal binding. Sofosbuvir is activated in the liver to the triphosphate GS-461203 by
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of the
carboxylate In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an ion with negative charge. Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylat ...
ester by either of the enzymes
cathepsin A Cathepsin A is an enzyme that is classified both as a cathepsin and a carboxypeptidase. In humans, it is encoded by the ''CTSA'' gene. Function This gene encodes a glycoprotein that associates with lysosomal enzymes beta-galactosidase and ne ...
or
carboxylesterase 1 Liver carboxylesterase 1 also known as carboxylesterase 1 (CES1, hCE-1 or CES1A1) is an enzyme that in humans is encoded by the ''CES1'' gene. The protein is also historically known as serine esterase 1 (SES1), monocyte esterase and cholesterol e ...
, followed by cleaving of the
phosphoramidate Phosphoramidates (sometimes also called amidophosphates) are a class of phosphorus compounds structurally related to phosphates (or organophosphates) via the substitution of an OR for a NR2. They are derivatives of phosphoramidic acids O=P(OH)(NR2 ...
by the enzyme
histidine triad nucleotide-binding protein 1 Histidine triad nucleotide-binding protein 1 also known as adenosine 5'-monophosphoramidase is an enzyme that in humans is encoded by the ''HINT1'' gene. HINT1 hydrolyzes purine nucleotide phosphoramidates with a single phosphate group. In additi ...
(HINT1), and subsequent repeated
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
.
Dephosphorylation In biochemistry, dephosphorylation is the removal of a phosphate (PO43−) group from an organic compound by hydrolysis. It is a reversible post-translational modification. Dephosphorylation and its counterpart, phosphorylation, activate and deac ...
creates the inactive metabolite GS-331077. The half life of sofosbuvir is 0.4 hours, and the half life of GS-331077 is 27 hours. Following a single 400 mg oral dose of sofosbuvir, 80% is excreted in urine, 14% in feces, and 2.5% in expired air recovery. However, of the urine recovery 78% was the metabolite (GS-331077) and 3.5% was sofosbuvir.


Chemistry

Prior to the discovery of sofosbuvir, a variety of nucleoside analogs had been examined as antihepatitis C treatments, but these exhibited relatively low potency. This low potency arose in part because the enzymatic addition of the first of the three phosphate groups of the triphosphate is slow. The design of sofosbuvir, based on the
ProTide The ProTide technology is a prodrug approach used in molecular biology and drug design. It is designed to deliver nucleotide analogues (as monophosphate) into the cell (ProTide: PROdrug + nucleoTIDE). It was invented by Professor Chris McGuigan (S ...
approach, avoids this slow step by building the first phosphate group into the structure of the drug during synthesis. Additional groups are attached to the phosphorus to temporarily mask the two negative charges of the phosphate group, thereby facilitating entry of the drug into the infected cell. The NS5B protein is a
RNA-dependent RNA polymerase RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand complementary to a given RNA template. This is in contrast to t ...
critical for the viral reproduction cycle.


History

Sofosbuvir was discovered in 2007 by Michael Sofia, a scientist at
Pharmasset Pharmasset Inc. was a pharmaceutical company based in Princeton, New Jersey in the United States. The company develops antiviral drugs for HIV (including racivir), hepatitis B (including clevudine, marketed as Levovir), and hepatitis C. In N ...
, and the drug was first tested in people in 2010. In 2011,
Gilead Sciences Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and CO ...
bought Pharmasset for about $11 billion. Gilead submitted the New Drug Application for sofosbuvir in combination with
ribavirin Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pegin ...
in April 2013, and in October 2013 it received the FDA's
Breakthrough Therapy Designation Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...
. In December 2013, the
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
approved sofosbuvir in combination with ribavirin for oral dual therapy of
HCV genotypes Hepatitis C virus (HCV) genotypes refer to the genetic variations that occurs in the hepatitis C virus. Hepatitis C is a contagious disease that primarily affects the liver, causing severe damage as the disease progresses. It is caused by the Hepati ...
2 and 3, and for triple therapy with injected
pegylated interferon Pegylated interferon (PEG-IFN) is a class of medication that includes three different drugs as of 2012: * Pegylated interferon-alpha-2a * Pegylated interferon-alpha-2b * Pegylated interferon-beta-1a In these formulations, Polyethylene glycol (PEG ...
(pegIFN) and RBV for treatment-naive people with HCV genotypes 1 and 4. Two months before, the FDA had approved another drug,
simeprevir Simeprevir, sold under the trade names Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with inclu ...
, as a hepatitis C treatment. In 2014, the fixed dose
combination drug A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC prod ...
sofosbuvir/
ledipasvir Ledipasvir is a drug for the treatment of hepatitis C that was developed by Gilead Sciences. After completing Phase III clinical trials, on February 10, 2014, Gilead filed for U.S. approval of a ledipasvir/sofosbuvir fixed-dose combination table ...
, the latter a viral
NS5A Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication. It appears to be a dimeric form without ''trans''-membrane helices. Structure NS5A is deriv ...
inhibitor, was approved; it had also been granted breakthrough status. Prior to the availability of sofosbuvir, hepatitis C treatments involved 6 to 12 months of treatment with an interferon-based regimen. This regimen provided cure rates of 70% or less and was associated with severe side effects, including anemia, depression, severe rash, nausea, diarrhea, and fatigue. As sofosbuvir clinical development progressed, physicians began to "warehouse" people in anticipation of its availability. Sofosbuvir's U.S. launch was the fastest of any new drug in history.


Society and culture

Sofosbuvir is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
.


Economics

Following its approval by the FDA in 2013, the price of sofosbuvir as quoted in various media sources in 2014 ranged from $84,000 to $168,000 depending on course of treatment in the U.S. and £35,000 in the United Kingdom for a 12-week regimine, causing considerable controversy. Sofosbuvir was more affordable in Japan and South Korea at approximately $300 and $5900 respectively for a 12-week treatment, with each government covering 99% and 70% of the cost respectively. In 2014, Gilead announced it would work with generic manufacturers in 91 developing countries to produce and sell sofosbuvir, and that it would sell a name brand version of the product in
India India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the seventh-largest country by area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the so ...
for approximately $300 per course of treatment; it had signed agreements with generic manufacturers by September 2015.


United States

Since its launch, the price of sofosbuvir declined as more competitors entered the direct-acting antiviral (DAA) market. In 2020, the price for a course of sofosbuvir was $64,693 in the United States. In 2014, the list price of a 12-week combination treatment with a sofosbuvir-based regimen ranged from to $94,000. In April 2014, U.S. House Democrats Henry Waxman,
Frank Pallone Frank Joseph Pallone Jr. (; born October 30, 1951) is an American lawyer and politician serving as the U.S. representative for , serving since 1988. He is a member of the Democratic Party. The district, numbered as the 3rd district from 1988 to ...
Jr., and
Diana DeGette Diana Louise DeGette (; born July 29, 1957) is an American lawyer and politician serving as the U.S. representative for since 1997. A member of the Democratic Party, her district is based in Denver. DeGette was a Chief Deputy Whip from 2005 ...
wrote Gilead Sciences Inc. questioning the $84,000 price for sofosbuvir. They specifically asked Gilead CEO John Martin to "explain how the drug was priced, what discounts are being made available to low-income patients and government health programs, and the potential impact to public health by insurers blocking or delaying access to the medicine because of its cost." Sofosbuvir is cited as an example of how specialty drugs present both benefits and challenges. In February 2015, Gilead announced that due in part to negotiated discounts with pharmacy benefit managers and legally mandated discounts to government payers, the average discount-to-list price in 2014 was 22%. The company estimated that the average discount in 2015 would be 46%. According to the California Technology Assessment Forum, a panel of academic pharmacoeconomic experts, representatives of managed care organizations, and advocates for people with hepatitis, a 46% discount would bring the average price of treatment to about $40,000, at which price sofosbuvir-based treatment regimens represent a "high value" for people and healthcare systems. Because of sofosbuvir's high price in the United States, by 2017, some states—such as Louisiana—were withholding the medicine from
Medicaid Medicaid in the United States is a federal and state program that helps with healthcare costs for some people with limited income and resources. Medicaid also offers benefits not normally covered by Medicare, including nursing home care and pers ...
patients with hepatitis until their livers were severely damaged. This puts "patients at increased risk of medical complications" and contributes to the "transmission of the hepatitis C virus". In an article published in May 2016 in ''Health Affairs'', the authors proposed the invocation of the federal " government patent use" law which would enable the government to procure "important patent-protected" drugs at lower prices while compensating "the patent-holding companies reasonable royalties ... for research and development." By July 2017, Louisiana's health secretary Rebekah Gee, who described Louisiana as America's "public-health-crisis cradle", was investigating the use of the "government patent use" as a strategy.


Japan and South Korea

Unlike other comparable Western
developed countries A developed country (or industrialized country, high-income country, more economically developed country (MEDC), advanced country) is a sovereign state that has a high quality of life, developed economy and advanced technological infrastruct ...
, sofosbuvir is far more affordable in
Japan Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...
and
South Korea South Korea, officially the Republic of Korea (ROK), is a country in East Asia, constituting the southern part of the Korea, Korean Peninsula and sharing a Korean Demilitarized Zone, land border with North Korea. Its western border is formed ...
at approximately $300 and $2165 cost to patients respectively for a 12-week treatment, as each government covers 99% and 70% of the original cost respectively.


Germany

In Germany, negotiations between Gilead and health insurers led to a price of €41,000 for 12 weeks of treatment. This is the same price previously negotiated with the national healthcare system in France, except that additional discounts and rebates apply in France depending on the volume of sales and the number of treatment failures.


Switzerland

In Switzerland, the price is fixed by the government every three years. The price in 2016 was CHF 16,102.50 for 24 pills of 400 mg.


United Kingdom

In 2020, the originator price per course of sofosbuvir was . In 2013, the price in the United Kingdom was expected to be for a 12-weeks course.
NHS England NHS England, officially the NHS Commissioning Board, is an executive non-departmental public body of the Department of Health and Social Care. It oversees the budget, planning, delivery and day-to-day operation of the commissioning side of the ...
established 22 Operational Delivery Networks to roll out delivery, which was approved by the
National Institute for Health and Care Excellence The National Institute for Health and Care Excellence (NICE) is an executive non-departmental public body of the Department of Health and Social Care in England that publishes guidelines in four areas: * the use of health technologies withi ...
in 2015, and proposes to fund 10,000 courses of treatment in 2016–17. Each was given a "run rate" of how many people they were allowed to treat, and this was the NHS's single biggest new treatment investment in 2016.


Croatia

As of 2015, sofosbuvir is included on the list of essential medications in Croatia and its cost is fully covered by the Croatian Health Insurance Fund. As a result of negotiations with the manufacturer, only therapies with successful outcome would be paid by the Fund with the rest being covered by the manufacturer.Tri skupa lijeka za hepatitis C od danas na besplatnoj listi HZZO-a
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India

In July 2014, Gilead Sciences filed a patent for sofosbuvir in India. If the office of the controller general of patents had granted it, Gilead would have obtained exclusive rights to produce and sell sofosbuvir in the country. However, in January 2015, the
Indian Patent Office The Office of the Controller General of Patents, Designs and Trade Marks (CGPDTM) generally known as the Indian Patent Office, is an agency under the Department for Promotion of Industry and Internal Trade which administers the Indian law of ...
rejected Gilead's application. Gilead's lawyers moved the
Delhi High Court The High Court of Delhi (IAST: ''dillī uchcha nyāyālaya'') was established on 31 October 1966, through the ''Delhi High Court Act, 1966'', with four judges, Chief Justice K. S. Hegde, Justice I. D. Dua, Justice H. R. Khanna and Justice S. ...
against this decision. That decision was overturned on appeal in February 2015. In the meantime, it granted Indian companies voluntary licenses (VLs), which allowed them to make and sell in a selected few countries at a discounted price. This agreement also granted 7% of the royalties to Gilead. However, the list of countries open to Indian firms under this agreement excluded 73 million people with hepatitis C.


Developing world

In 2014, Gilead announced it would seek generic licensing agreements with manufacturers to produce sofosbuvir in 91 developing countries, which contained 54% of the world's HCV-infected population. Gilead also said it would sell a name brand version of the product in India for $300 per course of treatment, approximately double a third party estimate of the minimum achievable cost of manufacture. It had signed licenses with generic manufacturers by September 2015. The leader of one Indian activist group called this move inadequate, but nine companies launched products, which "unleashed a fierce marketing war", according to India's ''
The Economic Times ''The Economic Times'' is an Indian English-language business-focused daily newspaper. It is owned by The Times Group. ''The Economic Times'' began publication in 1961. As of 2012, it is the world's second-most widely read English-language bus ...
''.Divya Rajagopal for the Economic Times. Sept 12, 2015
Can Indian generic makers find gold with a blockbuster Hepatitis C drug?
/ref> In Egypt, which had the world's highest incidence of hepatitis C, Gilead offered sofosbuvir at the discounted price of $900 to the Egyptian government. The government in turn made it free to patients. Later, Gilead licensed a generic version to be available in Egypt. The
Access to Medicine Index The Access to Medicine Index is a ranking system published biennially since 2008 by the Access to Medicine Foundation in Amsterdam, the Netherlands, an international not-for-profit organisation, funded by the Dutch Ministry of Foreign Affairs, the ...
ranked Gilead first among the world's 20 largest pharmaceutical countries in the Pricing, Manufacturing and Distribution category in both 2013 and 2014, citing Gilead's "leading performance in equitable pricing." In contrast, Jennifer Cohn of
Doctors Without Borders Doctor or The Doctor may refer to: Personal titles * Doctor (title), the holder of an accredited academic degree * A medical practitioner, including: ** Physician ** Surgeon ** Dentist ** Veterinary physician ** Optometrist *Other roles ** ...
and the organization Doctors of the World criticized the price of sofosbuvir as reflecting "corporate greed" and ignoring the needs of people in developing countries. In
Algeria ) , image_map = Algeria (centered orthographic projection).svg , map_caption = , image_map2 = , capital = Algiers , coordinates = , largest_city = capital , relig ...
, as of 2011 about 70,000 people were infected with hepatitis C. As of August 2015, Gilead had licensed its partners in India to sell sofosbuvir in Algeria. It had been criticized for not making the drug available in middle-income countries including Algeria prior to that.


Controversies

The price has generated considerable controversy. In 2017, the range of costs per treatment varied from about $84,000 to about $50.


Patent challenges

In February 2015, it was reported that Doctors of the World had submitted an objection to Gilead's patent at the
European Patent Office The European Patent Office (EPO) is one of the two organs of the European Patent Organisation (EPOrg), the other being the Administrative Council. The EPO acts as executive body for the organisation
, claiming that the structure of sofosbuvir is based on already known molecules. In particular, Doctors of the World argued that the
Protide The ProTide technology is a prodrug approach used in molecular biology and drug design. It is designed to deliver nucleotide analogues (as monophosphate) into the cell (ProTide: PROdrug + nucleoTIDE). It was invented by Professor Chris McGuigan (S ...
technology powering sofosbuvir was previously invented by the
Chris McGuigan Chris is a short form of various names including Christopher, Christian, Christina, Christine, and Christos. Chris is also used as a name in its own right, however it is not as common. People with the given name *Chris Abani (born 1966), Nige ...
team at
Cardiff University , latin_name = , image_name = Shield of the University of Cardiff.svg , image_size = 150px , caption = Coat of arms of Cardiff University , motto = cy, Gwirionedd, Undod a Chytgord , mottoeng = Truth, Unity and Concord , established = 1 ...
in the UK, and that the Gilead drug is not therefore inventive. The group filed challenges in other developing countries as well. These challenges were unsuccessful and the court recognized the innovative step in pro-drug design and application to the specific example of sofosbuvir.


Medical tourism

Due to the high cost of sofosbuvir in the U.S., as of 2016 increasing numbers of Americans with hepatitis C were traveling to India to purchase the drug. Similarly, increasing numbers of Chinese were also traveling to India to purchase sofosbuvir, which had not yet been approved for sale in China by the country's State Food and Drug Administration (SFDA).


Research

Combinations of sofosbuvir with NS5A inhibitors, such as
daclatasvir Daclatasvir, sold under the brand name Daklinza, is an antiviral medication used in combination with other medications to treat hepatitis C (HCV). The other medications used in combination include sofosbuvir, ribavirin, and interferon, vary depe ...
,
ledipasvir Ledipasvir is a drug for the treatment of hepatitis C that was developed by Gilead Sciences. After completing Phase III clinical trials, on February 10, 2014, Gilead filed for U.S. approval of a ledipasvir/sofosbuvir fixed-dose combination table ...
or velpatasvir, have shown sustained virological response rates of up to 100% in people infected with HCV. Most studies indicate that the efficacy rate is between 94% and 97%; much higher than previous treatment options. That treatments could be conducted at very low costs was demonstrated by Hill and coworkers who presented data on 1,160 patients who used generic versions of solfosbuvir, ledipasvir, plus daclatasvir from suppliers in India, Egypt, China and other countries and reported over 90% success at costs of about $50 per therapy. Sofosbuvir has also been tested against other viruses such as the
Zika virus ''Zika virus'' (ZIKV; pronounced or ) is a member of the virus family ''Flaviviridae''. It is spread by daytime-active ''Aedes'' mosquitoes, such as '' A. aegypti'' and '' A. albopictus''. Its name comes from the Ziika Forest of Uganda, whe ...
and
severe acute respiratory syndrome coronavirus 2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a No ...
(SARS-CoV-2).


See also

* AT-527—a similar drug developed for the treatment of
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
*
Tenofovir alafenamide Tenofovir alafenamide, sold under the brand name Vemlidy, is a hepatitis B virus (HBV) nucleotide reverse transcriptase inhibitor medication for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver dise ...
—a nucleotide
reverse-transcriptase inhibitor Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs Enzyme inhibition, inhibit activity of reverse transcriptase, a viral DNA polymerase that is requi ...
that uses similar phosphoramidate prodrug technology *
Remdesivir Remdesivir, sold under the brand name Veklury, Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. is a broad-spectrum antiviral medication developed by the ...
—a nucleotide analogue RNA polymerase inhibitor originally intended to treat hepatitis C that uses similar phosphoramidate prodrug technology and displays very similar PK.


References


Further reading

*


External links

* {{Portal bar , Medicine , Viruses Breakthrough therapy Gilead Sciences Hepatitis C Isopropyl esters NS5B (polymerase) inhibitors Organofluorides Phenol esters Prodrugs Carboxylate esters Pyrimidinediones Specialty drugs World Health Organization essential medicines Wikipedia medicine articles ready to translate