Array ( [0] => {{short description|Chemical compound}} [1] => {{cs1 config|name-list-style=vanc}} [2] => {{Use dmy dates|date=February 2020}} [3] => {{Drugbox [4] => | drug_name = [5] => | INN = [6] => | type = [7] => | image = Sofosbuvir structure.svg [8] => | width = [9] => | alt = [10] => | caption = [11] => [12] => [13] => | pronounce = [14] => | tradename = Sovaldi, others [15] => | Drugs.com = {{Drugs.com|monograph|sofosbuvir}} [16] => | MedlinePlus = a614014 [17] => | licence_CA = [18] => | licence_EU = yes [19] => | DailyMedID = Sofosbuvir [20] => | licence_US = Sofosbuvir [21] => | pregnancy_AU = B1 [22] => | pregnancy_AU_comment = {{cite web | title=Sofosbuvir (Sovaldi) Use During Pregnancy | website=Drugs.com | date=16 December 2019 | url=https://www.drugs.com/pregnancy/sofosbuvir.html | access-date=5 February 2020}} [23] => | pregnancy_category = [24] => | routes_of_administration = [[Oral administration|By mouth]] [25] => | class = [[HCV polymerase inhibitor]] [26] => | ATCvet = [27] => | ATC_prefix = J05 [28] => | ATC_suffix = AP08 [29] => | ATC_supplemental = {{ATC|J05|AP51}} {{ATC|J05|AP55}} {{ATC|J05|AP56}} [30] => [31] => [32] => | legal_AU = S4 [33] => | legal_AU_comment = {{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2014 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | access-date=10 April 2023}} [34] => | legal_BR = [35] => | legal_BR_comment = [36] => | legal_CA = [37] => | legal_CA_comment = [38] => | legal_DE = [39] => | legal_DE_comment = [40] => | legal_NZ = [41] => | legal_NZ_comment = [42] => | legal_UK = POM [43] => | legal_UK_comment = [44] => | legal_US = Rx-only [45] => | legal_US_comment = {{cite web | title=Sovaldi Access- sofosbuvir tablet, film coated | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b66d2de5-8550-4015-9c2c-d7a9150926b4#S2.2 | access-date=26 January 2022}} [46] => | legal_EU = Rx-only [47] => | legal_EU_comment = [48] => | legal_UN = [49] => | legal_UN_comment = [50] => | legal_status = [51] => [52] => [53] => | bioavailability = 92% [54] => | protein_bound = 61–65% [55] => | metabolism = Quickly activated to triphosphate ([[Cathepsin A|CatA]]/[[carboxylesterase 1|CES1]], [[histidine triad nucleotide-binding protein 1|HIST1]], [[phosphorylation]]) [56] => | metabolites = [57] => | onset = [58] => | elimination_half-life = 0.4 hrs (sofosbuvir)
27 hrs (inactive metabolite GS-331007) [59] => | duration_of_action = [60] => | excretion = 80% urine, 14% feces (mostly as GS-331007) [61] => [62] => [63] => | CAS_number_Ref = [64] => | CAS_number = 1190307-88-0 [65] => | CAS_supplemental = [66] => | PubChem = 45375808 [67] => | IUPHAR_ligand = 7368 [68] => | DrugBank_Ref = [69] => | DrugBank = DB08934 [70] => | ChemSpiderID_Ref = [71] => | ChemSpiderID = 26286922 [72] => | UNII_Ref = {{fdacite|correct|FDA}} [73] => | UNII = WJ6CA3ZU8B [74] => | KEGG_Ref = [75] => | KEGG = D10366 [76] => | ChEBI_Ref = {{ebicite|correct|EBI}} [77] => | ChEBI = 85083 [78] => | ChEMBL_Ref = [79] => | ChEMBL = 1259059 [80] => | NIAID_ChemDB = [81] => | PDB_ligand = [82] => | synonyms = PSI-7977; GS-7977 [83] => [84] => [85] => | IUPAC_name = Isopropyl (2''S'')-2-[[[(2''R'',3''R'',4''R'',5''R'')-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate [86] => | C=22 | H=29 | F=1 | N=3 | O=9 | P=1 [87] => | SMILES = C[C@@H](C(=O)OC(C)C)N[P@](=O)(OC[C@@H]1[C@H]([C@@]([C@@H](O1)N2C=CC(=O)NC2=O)(C)F)O)OC3=CC=CC=C3 [88] => | StdInChI = 1S/C22H29FN3O9P/c1-13(2)33-19(29)14(3)25-36(31,35-15-8-6-5-7-9-15)32-12-16-18(28)22(4,23)20(34-16)26-11-10-17(27)24-21(26)30/h5-11,13-14,16,18,20,28H,12H2,1-4H3,(H,25,31)(H,24,27,30)/t14-,16+,18+,20+,22+,36-/m0/s1 [89] => | StdInChI_comment = [90] => | StdInChIKey = TTZHDVOVKQGIBA-IQWMDFIBSA-N [91] => | density = [92] => | density_notes = [93] => | melting_point = [94] => | melting_high = [95] => | melting_notes = [96] => | boiling_point = [97] => | boiling_notes = [98] => | solubility = [99] => | sol_units = [100] => | specific_rotation = [101] => }} [102] => [103] => [104] => '''Sofosbuvir''', sold under the brand name '''Sovaldi''' among others, is a [[medication]] used to treat [[hepatitis C]].{{cite web|title=Sofosbuvir|url=https://www.drugs.com/monograph/sofosbuvir.html|publisher=The American Society of Health-System Pharmacists|access-date=November 30, 2016|url-status=live|archive-url=https://web.archive.org/web/20161201144328/https://www.drugs.com/monograph/sofosbuvir.html|archive-date=2016-12-01 }} It is taken [[Oral administration|by mouth]]. [105] => [106] => [107] => Common side effects include fatigue, headache, nausea, and trouble sleeping. Side effects are generally more common in interferon-containing regimens.{{cite web | title=Sovaldi- sofosbuvir tablet, film coated Sovaldi- sofosbuvir pellet | website=DailyMed | date=27 September 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=80beab2c-396e-4a37-a4dc-40fdb62859cf | access-date=4 February 2020}}{{rp|7}} Sofosbuvir may reactivate [[hepatitis B]] in those who have been previously infected.{{cite web|title=Direct-Acting Antivirals for Hepatitis C: Drug Safety Communication - Risk of Hepatitis B Reactivating|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm523690.htm|website=FDA|access-date=6 October 2016|date=4 October 2016|url-status=dead|archive-url=https://web.archive.org/web/20161006160327/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm523690.htm|archive-date=6 October 2016 }} In combination with [[ledipasvir]], [[daclatasvir]] or [[simeprevir]], it is not recommended with [[amiodarone]] due to the risk of an [[bradycardia|abnormally slow heartbeat]]. Sofosbuvir is in the [[nucleotide analog]] family of medications and works by blocking the hepatitis C [[NS5B]] protein.{{cite web|title=Sovaldi 400 mg film coated tablets - Summary of Product Characteristics|url=https://www.medicines.org.uk/emc/medicine/28539|publisher=UK Electronic Medicines Compendium|access-date=10 November 2016|date=September 2016|url-status=live|archive-url=https://web.archive.org/web/20161110235042/https://www.medicines.org.uk/emc/medicine/28539|archive-date=10 November 2016 }} [108] => [109] => [110] => Sofosbuvir was discovered in 2007 and approved for medical use in the United States in 2013.{{cite web|title=Sofosbuvir (Sovaldi) - Treatment - Hepatitis C Online|url=http://www.hepatitisc.uw.edu/page/treatment/drugs/sofosbuvir-drug|website=www.hepatitisc.uw.edu|access-date=8 January 2017 |url-status=live |archive-url=https://web.archive.org/web/20161223152415/http://www.hepatitisc.uw.edu/page/treatment/drugs/sofosbuvir-drug|archive-date=23 December 2016 }}{{cite magazine| vauthors = Gounder C |title=A Better Treatment for Hepatitis C|url=http://www.newyorker.com/tech/elements/a-better-treatment-for-hepatitis-c|magazine=[[The New Yorker]]|date=9 December 2013|url-status=live|archive-url=https://web.archive.org/web/20160920171440/http://www.newyorker.com/tech/elements/a-better-treatment-for-hepatitis-c|archive-date=20 September 2016 }} It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }} [111] => [112] => {{TOC limit|3}} [113] => [114] => == Medical uses == [115] => [[File:Sovaldi 400mg.jpg|thumb|Sofosbuvir (Sovaldi) 400mg]] [116] => [117] => === Initial HCV treatment === [118] => In 2016, the [[American Association for the Study of Liver Diseases]] and the [[Infectious Diseases Society of America]] 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.{{cite web|title=EPCLUSA (sofosbuvir and velpatasvir) Prescribing information|url=https://www.gilead.com/~/media/files/pdfs/medicines/liver-disease/epclusa/epclusa_pi.pdf?la=en|publisher=Gilead Sciences, Inc.|access-date=16 June 2017|url-status=live|archive-url=https://web.archive.org/web/20170630220003/http://gilead.com/~/media/files/pdfs/medicines/liver-disease/epclusa/epclusa_pi.pdf?la=en|archive-date=30 June 2017 }} [119] => [120] => 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]].{{cite web | title=Harvoni- ledipasvir and sofosbuvir tablet, film coated Harvoni- ledipasvir and sofosbuvir tablet, film coated Harvoni- ledipasvir and sofosbuvir pellet | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f4ec77e4-bae8-4db0-b3d5-bde09c5fa075 | access-date=26 January 2022}} In genotype 2 and 3 HCV infections, sofosbuvir can be used in combination with [[daclatasvir]]. For the treatment of cases with cirrhosis or liver transplant patients, weight-based ribavirin is sometimes added. [[pegylated interferon|Peginterferon]] with or without sofosbuvir is not recommended in an initial HCV treatment.{{cite web|title=Recommendations for Testing, Managing, and Treating Hepatitis C|url=http://hcvguidelines.org/sites/default/files/HCV-Guidance_October_2016_a.pdf|publisher=AASLD/IDSA|access-date=10 November 2016|date=27 September 2016|url-status=live|archive-url=https://web.archive.org/web/20161110173045/http://hcvguidelines.org/sites/default/files/HCV-Guidance_October_2016_a.pdf|archive-date=10 November 2016 }} [121] => [122] => 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.{{cite journal | vauthors = Berden FA, Kievit W, Baak LC, Bakker CM, Beuers U, Boucher CA, Brouwer JT, Burger DM, van Erpecum KJ, van Hoek B, Hoepelman AI, Honkoop P, Kerbert-Dreteler MJ, de Knegt RJ, Koek GH, van Nieuwkerk CM, van Soest H, Tan AC, Vrolijk JM, Drenth JP | display-authors = 6 | title = Dutch guidance for the treatment of chronic hepatitis C virus infection in a new therapeutic era | journal = The Netherlands Journal of Medicine | volume = 72 | issue = 8 | pages = 388–400 | date = October 2014 | pmid = 25387551 }}{{cite journal | vauthors = Cholongitas E, Papatheodoridis GV | title = Sofosbuvir: a novel oral agent for chronic hepatitis C | journal = Annals of Gastroenterology | volume = 27 | issue = 4 | pages = 331–337 | year = 2014 | pmid = 25332066 | pmc = 4188929 }}{{cite journal | vauthors = Tran TT | title = A review of standard and newer treatment strategies in hepatitis C | journal = The American Journal of Managed Care | volume = 18 | issue = 14 Suppl | pages = S340–S349 | date = December 2012 | pmid = 23327540 }} 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.{{cite journal | vauthors = Yau AH, Yoshida EM | title = Hepatitis C drugs: the end of the pegylated interferon era and the emergence of all-oral interferon-free antiviral regimens: a concise review | journal = Canadian Journal of Gastroenterology & Hepatology | volume = 28 | issue = 8 | pages = 445–451 | date = September 2014 | pmid = 25229466 | pmc = 4210236 | doi = 10.1155/2014/549624 | doi-access = free }}{{cite journal | vauthors = Calvaruso V, Mazza M, Almasio PL | title = Pegylated-interferon-α(2a) in clinical practice: how to manage patients suffering from side effects | journal = Expert Opinion on Drug Safety | volume = 10 | issue = 3 | pages = 429–435 | date = May 2011 | pmid = 21323500 | doi = 10.1517/14740338.2011.559161 | hdl-access = free | s2cid = 207487328 | hdl = 10447/73456 }} [123] => [124] => === Prior failed treatment === [125] => 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]] or not, and whether the liver damage is classified as compensated cirrhosis or [[Cirrhosis#Decompensated cirrhosis|decompensated cirrhosis]]. [126] => [127] => ===Pregnancy and breastfeeding=== [128] => No adequate human data are available to establish whether or not sofosbuvir poses a risk to pregnancy outcomes. However, [[ribavirin]], 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.{{cite web | title=Ribavirin Use During Pregnancy | website=Drugs.com | date=21 August 2019 | url=https://www.drugs.com/pregnancy/ribavirin.html | access-date=4 February 2020}} Pregnant women with hepatitis C who take ribavirin have shown some cases of birth defects and death in their fetus.{{cite web | title=Rebetol- ribavirin capsule Rebetol- ribavirin liquid | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=04d2b6f4-bd9b-4871-9527-92c81aa2d4d0 | access-date=26 January 2022}} 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. [129] => [130] => 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. [131] => [132] => == Contraindications == [133] => There are no specific contraindications for sofosbuvir when used alone. However, when used in combination with [[ribavirin]] or peginterferon alfa/ribavirin, or others, the contraindications applicable to these agents are applied. [134] => [135] => == Side effects == [136] => Sofosbuvir used alone and in combination with other drugs such as [[ribavirin]] 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]] is almost absent in interferon-free treatment.{{rp|7}}{{cite journal | vauthors = Bhatia HK, Singh H, Grewal N, Natt NK | title = Sofosbuvir: A novel treatment option for chronic hepatitis C infection | journal = Journal of Pharmacology & Pharmacotherapeutics | volume = 5 | issue = 4 | pages = 278–284 | date = October 2014 | pmid = 25422576 | pmc = 4231565 | doi = 10.4103/0976-500X.142464 | doi-access = free }} [137] => [138] => Sofosbuvir may reactivate hepatitis B in those who have been previously infected. The [[European Medicines Agency]] (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.{{cite web | title=Direct-acting antivirals indicated for treatment of hepatitis C (interferon-free) | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/referrals/direct-acting-antivirals-indicated-treatment-hepatitis-c-interferon-free | access-date=4 February 2020}} [139] => [140] => == Interactions == [141] => {{anchor|Interactions}} [142] => Sofosbuvir (in combination with [[ledipasvir]], [[daclatasvir]] or [[simeprevir]]) should not be used with [[amiodarone]] due to the risk of [[bradycardia|abnormally slow heartbeats]]. [143] => [144] => Sofosbuvir is a substrate of [[P-glycoprotein]], a transporter protein that pumps drugs and other substances from [[intestinal epithelium]] cells back into the gut. Therefore, inducers of intestinal P-glycoprotein, such as rifampicin and [[St. John's wort]], could reduce the absorption of sofosbuvir. [145] => [146] => In addition, coadministration of sofosbuvir with anticonvulsants ([[carbamazepine]], phenytoin, phenobarbital, oxcarbazepine), antimycobacterials ([[Rifampicin|rifampin]], rifabutin, rifapentine), and the HIV protease inhibitor [[tipranavir]] and [[ritonavir]] is expected to decrease sofosbuvir concentration. Thus, coadministration is not recommended. [147] => [148] => The interaction between sofosbuvir and a number of other drugs, such as [[ciclosporin]], [[darunavir]]/[[ritonavir]], [[efavirenz]], [[emtricitabine]], [[methadone]], [[raltegravir]], [[rilpivirine]], [[tacrolimus]], or [[tenofovir disoproxil]], were evaluated in clinical trials and no dose adjustment is needed for any of these drugs.{{cite journal | vauthors = Karageorgopoulos DE, El-Sherif O, Bhagani S, Khoo SH | title = Drug interactions between antiretrovirals and new or emerging direct-acting antivirals in HIV/hepatitis C virus coinfection | journal = Current Opinion in Infectious Diseases | volume = 27 | issue = 1 | pages = 36–45 | date = February 2014 | pmid = 24305043 | doi = 10.1097/QCO.0000000000000034 | s2cid = 24286602 }} [149] => [150] => == Pharmacology == [151] => ===Mechanism of action=== [152] => Sofosbuvir inhibits the hepatitis C [[NS5B]] protein. Sofosbuvir appears to have a high barrier to the development of resistance.{{cite journal | vauthors = Pol S, Corouge M, Vallet-Pichard A | title = Daclatasvir-sofosbuvir combination therapy with or without ribavirin for hepatitis C virus infection: from the clinical trials to real life | journal = Hepatic Medicine: Evidence and Research| volume = 8 | pages = 21–26 | date = March 2016 | pmid = 27019602 | pmc = 4786064 | doi = 10.2147/HMER.S62014 | doi-access = free }} [153] => [154] => Sofosbuvir is a [[prodrug]] of the [[Protide]] 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.{{cite journal | vauthors = Fung A, Jin Z, Dyatkina N, Wang G, Beigelman L, Deval J | title = Efficiency of incorporation and chain termination determines the inhibition potency of 2'-modified nucleotide analogs against hepatitis C virus polymerase | journal = Antimicrobial Agents and Chemotherapy | volume = 58 | issue = 7 | pages = 3636–3645 | date = July 2014 | pmid = 24733478 | pmc = 4068585 | doi = 10.1128/AAC.02666-14 }} 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]] with an incoming NTP.{{cite journal | vauthors = Ma H, Jiang WR, Robledo N, Leveque V, Ali S, Lara-Jaime T, Masjedizadeh M, Smith DB, Cammack N, Klumpp K, Symons J | display-authors = 6 | title = Characterization of the metabolic activation of hepatitis C virus nucleoside inhibitor beta-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130) and identification of a novel active 5'-triphosphate species | journal = The Journal of Biological Chemistry | volume = 282 | issue = 41 | pages = 29812–29820 | date = October 2007 | pmid = 17698842 | doi = 10.1074/jbc.M705274200 | doi-access = free }} Sofosbuvir may act in a similar way.{{cn|date=November 2022}} [155] => [156] => === Pharmacokinetics === [157] => {{anchor|Pharmacokinetics}} [158] => Sofosbuvir is only administered orally. The peak concentration after oral administration is 0.5–2 hours post-dose, regardless of initial dose.{{cite journal | vauthors = Kirby BJ, Symonds WT, Kearney BP, Mathias AA | title = Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir | journal = Clinical Pharmacokinetics | volume = 54 | issue = 7 | pages = 677–690 | date = July 2015 | pmid = 25822283 | doi = 10.1007/s40262-015-0261-7 | s2cid = 20488837 }} Peak plasma concentration of the main circulating metabolite GS-331077 occurs 2–4 hours post-dose. GS-331077 is the pharmacologically inactive [[nucleoside]]. [159] => [160] => [[Plasma protein binding]] of sofosbuvir is 61–65%, while GS-331077 has minimal binding. [161] => [162] => Sofosbuvir is activated in the liver to the triphosphate GS-461203 by [[hydrolysis]] of the [[carboxylate]] ester by either of the enzymes [[cathepsin A]] or [[carboxylesterase 1]], followed by cleaving of the [[phosphoramidate]] by the enzyme [[histidine triad nucleotide-binding protein 1]] (HINT1), and subsequent repeated [[phosphorylation]].{{cite book|title=Arzneistoff-Profile| veditors = Dinnendahl V, Fricke U | publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|date=2015|edition=28|volume=9|isbn=978-3-7741-9846-3|language=de}} [[Dephosphorylation]] 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. [163] => [164] => ==Chemistry== [165] => 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]] 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.{{cite journal | vauthors = Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA | display-authors = 6 | title = Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977 | journal = The Journal of Biological Chemistry | volume = 285 | issue = 45 | pages = 34337–34347 | date = November 2010 | pmid = 20801890 | pmc = 2966047 | doi = 10.1074/jbc.M110.161802 | doi-access = free }} The NS5B protein is a [[RNA-dependent RNA polymerase]] critical for the viral reproduction cycle.{{cn|date=November 2022}} [166] => [167] => [[File:Sofosbuvir prodrug chemistry.svg|thumb|center|upright=3.0|Sofosbuvir metabolism. Nucleoside = GS-331077, active triphosphate = GS-461203]] [168] => [169] => == History == [170] => Sofosbuvir was discovered in 2007 by [[Michael Sofia]], a scientist at [[Pharmasset]], and the drug was first tested in people in 2010. In 2011, [[Gilead Sciences]] bought Pharmasset for about $11 billion. Gilead submitted the [[New Drug Application]] for sofosbuvir in combination with [[ribavirin]] in April 2013, and in October 2013 it received the FDA's [[Breakthrough therapy|Breakthrough Therapy Designation]].{{cite web|title=Application Number: 204671Orig1s000: Medical Reviews|url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204671Orig1s000MedR.pdf|publisher=FDA|date=November 20, 2013|url-status=live|archive-url=https://web.archive.org/web/20161110175252/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204671Orig1s000MedR.pdf|archive-date=November 10, 2016 }} In December 2013, the [[FDA]] approved sofosbuvir in combination with ribavirin for oral dual therapy of [[Hepatitis C virus#Genotypes|HCV genotypes]] 2 and 3, and for triple therapy with injected [[pegylated interferon]] (pegIFN) and RBV for treatment-naive people with HCV genotypes 1 and 4.{{cite web | url = https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm377888.htm | title = FDA approves Sovaldi for chronic hepatitis C | date = 2013-12-06 | work = FDA New Release | publisher = U.S. Food and Drug Administration | url-status = live | archive-url = https://web.archive.org/web/20131209000157/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm377888.htm | archive-date = 2013-12-09 }}{{cite web| url = http://www.medscape.com/viewarticle/817371| title = FDA Approves 'Game Changer' Hepatitis C Drug Sofosbuvir| author = Tucker M| date = December 6, 2013| website = Medscape| url-status = live| archive-url = https://web.archive.org/web/20150517012529/http://www.medscape.com/viewarticle/817371| archive-date = May 17, 2015}} Two months before, the FDA had approved another drug, [[simeprevir]], as a hepatitis C treatment. [171] => [172] => In 2014, the fixed dose [[combination drug]] sofosbuvir/[[ledipasvir]], the latter a viral [[NS5A]] inhibitor, was approved; it had also been granted breakthrough status.{{cite web |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418365.htm |title=FDA approves first combination pill to treat hepatitis C |website=[[Food and Drug Administration]] |url-status=live |archive-url=https://web.archive.org/web/20150504075208/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418365.htm |archive-date=2015-05-04 }} [173] => [174] => 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.{{cite news|url=https://www.wsj.com/articles/SB10001424127887323293704578330712442353712|title=Hepatitis C Dilemma: Treat Illness With Interferon Now or Wait? - WSJ|newspaper=Wall Street Journal|date=5 March 2013|url-status=live|archive-url=https://web.archive.org/web/20170602215108/https://www.wsj.com/articles/SB10001424127887323293704578330712442353712|archive-date=2017-06-02 | vauthors = Loftus P }} Sofosbuvir's U.S. launch was the fastest of any new drug in history.{{cite news| vauthors = Herper M |title= Gilead's Hepatitis C Pill Takes Off Like A Rocket|url=https://www.forbes.com/sites/matthewherper/2014/02/21/gileads-hepatitis-c-pill-takes-off-like-a-rocket/|work=Forbes|date=February 21, 2014|url-status=live|archive-url=https://web.archive.org/web/20170831233640/https://www.forbes.com/sites/matthewherper/2014/02/21/gileads-hepatitis-c-pill-takes-off-like-a-rocket/|archive-date=August 31, 2017 }} [175] => [176] => == Society and culture == [177] => Sofosbuvir is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]]. [178] => [179] => === Economics === [180] => 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.{{cite news | vauthors = Harris G |title=Maker of Costly Hepatitis C Drug Sovaldi Strikes Deal on Generics for Poor Countries |url=https://www.nytimes.com/2014/09/16/business/international/maker-of-hepatitis-c-drug-strikes-deal-on-generics-for-poor-countries.html |work=[[The New York Times]] |date=15 September 2014 |url-status=live |archive-url=https://web.archive.org/web/20170131153408/https://www.nytimes.com/2014/09/16/business/international/maker-of-hepatitis-c-drug-strikes-deal-on-generics-for-poor-countries.html?_r=0 |archive-date=31 January 2017 }} and £35,000 in the United Kingdom for a 12-week regimine,{{cite news | vauthors = Boseley S |title=Hepatitis C drug delayed by NHS due to high cost |url=https://www.theguardian.com/society/2015/jan/16/sofosbuvir-hepatitis-c-drug-nhs |work=[[The Guardian]] |date=15 January 2015 |url-status=live |archive-url=https://web.archive.org/web/20161110174558/https://www.theguardian.com/society/2015/jan/16/sofosbuvir-hepatitis-c-drug-nhs |archive-date=10 November 2016 }} 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]] for approximately $300 per course of treatment; it had signed agreements with generic manufacturers by September 2015.{{cite journal | vauthors = van de Ven N, Fortunak J, Simmons B, Ford N, Cooke GS, Khoo S, Hill A | title = Minimum target prices for production of direct-acting antivirals and associated diagnostics to combat hepatitis C virus | journal = Hepatology | volume = 61 | issue = 4 | pages = 1174–1182 | date = April 2015 | pmid = 25482139 | pmc = 4403972 | doi = 10.1002/hep.27641 }}{{cite news | vauthors = Kalra A, Siddiqui Z |title=Gilead licenses hepatitis C drug to Cipla, Ranbaxy, five others|url=http://in.reuters.com/article/gilead-sciences-india-idINKBN0HA0TI20140915 |publisher=Reuters India |date=September 15, 2014 |url-status=live |archive-url=https://web.archive.org/web/20141210072017/http://in.reuters.com/article/2014/09/15/gilead-sciences-india-idINKBN0HA0TI20140915 |archive-date=December 10, 2014 }} [181] => [182] => ====United States==== [183] => Since its launch, the price of sofosbuvir declined as more competitors entered the [[Direct-acting antivirals|direct-acting antiviral]] (DAA) market.{{cite web|title=Analysis of prescription drugs for the treatment of hepatitis C in the United States|url=https://www.milliman.com/en/insight/analysis-of-prescription-drugs-for-the-treatment-of-hepatitis-c-in-the-united-states|access-date=2022-02-04|website=www.milliman.com|language=en}} In 2020, the price for a course of sofosbuvir was $64,693 in the United States.{{cite journal | vauthors = Barber MJ, Gotham D, Khwairakpam G, Hill A | title = Price of a hepatitis C cure: Cost of production and current prices for direct-acting antivirals in 50 countries | journal = Journal of Virus Eradication | volume = 6 | issue = 3 | pages = 100001 | date = September 2020 | pmid = 33251019 | pmc = 7646676 | doi = 10.1016/j.jve.2020.06.001 }} In 2014, the list price of a 12-week combination treatment with a sofosbuvir-based regimen ranged from {{currency|84000|US}} to $94,000.{{cite news | vauthors = Pollack A |url=https://www.nytimes.com/2014/10/11/business/harvoni-a-hepatitis-c-drug-from-gilead-wins-fda-approval.html |title=Harvoni, a Hepatitis C Drug from Gilead, Wins F.D.A. Approval |date=October 10, 2014 |work= [[The New York Times]] |url-status=live |archive-url=https://web.archive.org/web/20170126220951/https://www.nytimes.com/2014/10/11/business/harvoni-a-hepatitis-c-drug-from-gilead-wins-fda-approval.html |archive-date=January 26, 2017 }}{{cite news |agency=[[Associated Press]] |date=December 11, 2014 |title=Gilead Faces Lawsuit Over Hepatitis C Drug Pricing |work=Drug Discovery & Development |publisher=Advantage Business Media |url=http://www.dddmag.com/news/2014/12/gilead-faces-lawsuit-over-hepatitis-c-drug-pricing |url-status=live |archive-url=https://web.archive.org/web/20141213080109/http://www.dddmag.com/news/2014/12/gilead-faces-lawsuit-over-hepatitis-c-drug-pricing |archive-date=December 13, 2014 }}{{cite web |title=F. D. A. Approves Pill to Treat Hepatitis |url=https://www.nytimes.com/2013/12/07/business/fda-approves-pill-to-treat-hepatitis-c.html | vauthors = Pollack A |date=December 6, 2013 |work=[[The New York Times]] |url-status=live |archive-url=https://web.archive.org/web/20170203145754/http://www.nytimes.com/2013/12/07/business/fda-approves-pill-to-treat-hepatitis-c.html |archive-date=February 3, 2017 }} In April 2014, U.S. House Democrats Henry Waxman, [[Frank Pallone]] Jr., and [[Diana DeGette]] wrote Gilead Sciences Inc. questioning the $84,000 price for sofosbuvir. They specifically asked Gilead CEO [[John C. Martin (businessman)|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."{{cite web |url=https://www.bloomberg.com/news/articles/2014-03-21/gilead-s-84-000-treatment-questioned-by-congress |title=Gilead's $84,000 Treatment Questioned by U.S. Lawmakers |publisher=Bloomberg |date=21 March 2014 |access-date=27 October 2015 | vauthors = Armstrong D | url-status=live |archive-url=https://web.archive.org/web/20151208203321/http://www.bloomberg.com/news/articles/2014-03-21/gilead-s-84-000-treatment-questioned-by-congress |archive-date=8 December 2015 }} Sofosbuvir is cited as an example of how specialty drugs present both benefits and challenges.{{cite web |url=http://www.pppmag.com/article_print.php?articleid=1637 |title=The Increasing Impact of High-Cost Specialty Therapies |volume=12 |number=2 |date=February 2015 |work=Pharmacy Purchasing & Products |access-date=4 December 2015 | vauthors = Lucio S |url-status=dead |archive-url= https://web.archive.org/web/20151208051829/http://www.pppmag.com/article_print.php?articleid=1637 |archive-date=8 December 2015 }}{{cite journal | vauthors = Brennan T, Shrank W | title = New expensive treatments for hepatitis C infection | journal = JAMA | volume = 312 | issue = 6 | pages = 593–594 | date = August 2014 | pmid = 25038617 | doi = 10.1001/jama.2014.8897 }} [184] => [185] => {{blockquote|Sofosbuvir also is an excellent example of both the benefit and the challenge of specialty medications. On one hand, this agent offers up to a 95% response rate as part of an interferon-free treatment regimen for hepatitis C. Generally speaking, it is more effective and better tolerated than alternative treatments. Unfortunately, the current per pill cost—$1,000—results in an $84,000 treatment course, creating barriers to therapy for many. Patients, providers, and payors alike have expressed outrage, and the debate has even drawn the attention of the US Congress. Despite these concerns, sofosbuvir rapidly has become a top seller in the United States...}} [186] => [187] => 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%.{{cite web |url=http://seekingalpha.com/article/2880996-gilead-sciences-gild-ceo-john-martin-on-q4-2014-results-earnings-call-transcript?page=4 |title=Gilead Q4 2014 Earnings Call |date=3 February 2015 |url-status=live |archive-url=https://web.archive.org/web/20150222163149/http://seekingalpha.com/article/2880996-gilead-sciences-gild-ceo-john-martin-on-q4-2014-results-earnings-call-transcript?page=4 |archive-date=2015-02-22 }} 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.{{cite press release |url=http://www.ctaf.org/about-ctaf/news/2015/new-lower-prices-gilead-hepatitis-c-drugs-reach-ctaf-threshold-high-health |title=New Lower Prices for Gilead Hepatitis C Drugs Reach CTAF Threshold for High Health System Value |date=2015-02-17 |access-date=2015-02-22 |url-status=live |archive-url=https://web.archive.org/web/20150222163142/http://www.ctaf.org/about-ctaf/news/2015/new-lower-prices-gilead-hepatitis-c-drugs-reach-ctaf-threshold-high-health |archive-date=2015-02-22 }}{{cite web| title = Treatments for Hepatitis C| author = California Technology Assessment Forum| date = 2014-03-10| url = http://www.ctaf.org/reports/treatments-hepatitis-c| url-status = dead| archive-url = https://web.archive.org/web/20141020015735/http://www.ctaf.org/reports/treatments-hepatitis-c| archive-date = 2014-10-20}}{{cite news |url=https://www.nytimes.com/aponline/2014/03/11/business/ap-us-hepatitis-c-drug-cost.html |title=Medical Groups Question Price of New Hep C Drug|date=11 March 2014|agency=[[Associated Press]] |work=[[The New York Times]]}} [188] => [189] => Because of sofosbuvir's high price in the United States, by 2017, some states—such as Louisiana—were withholding the medicine from [[Medicaid]] patients with hepatitis until their livers were severely damaged.{{cite news |url=https://www.washingtonpost.com/business/economy/louisiana-considers-radical-step-to-counter-high-drug-prices-federal-intervention/2017/07/03/456b99f6-4a59-11e7-a186-60c031eab644_story.html?tid=sm_tw |title=Louisiana considers radical step to counter high drug prices: Federal intervention | vauthors = Johnson CY |date=July 3, 2017 |access-date=July 4, 2017 |location=Baton Rouge, Louisiana |url-status=live |archive-url=https://web.archive.org/web/20170923235702/https://www.washingtonpost.com/business/economy/louisiana-considers-radical-step-to-counter-high-drug-prices-federal-intervention/2017/07/03/456b99f6-4a59-11e7-a186-60c031eab644_story.html?tid=sm_tw |archive-date=September 23, 2017 }} This puts "patients at increased risk of medical complications" and contributes to the "transmission of the hepatitis C virus".{{cite journal | vauthors = Kapczynski A, Kesselheim AS | title = 'Government Patent Use': A Legal Approach To Reducing Drug Spending | journal = Health Affairs | volume = 35 | issue = 5 | pages = 791–797 | date = May 2016 | pmid = 27140984 | doi = 10.1377/hlthaff.2015.1120 | url = https://law.yale.edu/system/files/documents/faculty/papers/kapcyznski_govpatentuse.pdf | access-date = June 4, 2017 | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20170901111149/https://law.yale.edu/system/files/documents/faculty/papers/kapcyznski_govpatentuse.pdf | archive-date = September 1, 2017 }} In an article published in May 2016 in ''Health Affairs'', the authors proposed the invocation of the federal "[[Government patent use (United States)|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. [190] => [191] => ====Japan and South Korea==== [192] => Unlike other comparable Western [[developed countries]], sofosbuvir is far more affordable in [[Japan]] and [[South Korea]] 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.{{cite web|url=http://view.asiae.co.kr/news/view.htm?idxno=2016042011590218400|title=C형간염 치료제 건강보험 적용|date=20 April 2016|access-date=2 August 2016|url-status=live|archive-url=https://web.archive.org/web/20160530185816/http://view.asiae.co.kr/news/view.htm?idxno=2016042011590218400|archive-date=30 May 2016 }}{{cite web|url=http://www.edaily.co.kr/news/NewsRead.edy?SCD=JG11&newsid=02391126612618088&DCD=A00701&OutLnkChk=Y|title=C형 간염 치료제 신약, 내달 1일부터 건강보험 적용 | trans-title = New hepatitis C treatment to be covered by health insurance from the 1st of next month | language = Korean |date=20 April 2016|access-date=2 August 2016|url-status=live|archive-url=https://web.archive.org/web/20160531042623/http://www.edaily.co.kr/news/NewsRead.edy?SCD=JG11&newsid=02391126612618088&DCD=A00701&OutLnkChk=Y|archive-date=31 May 2016 }}{{cite web | url=https://www.medigatenews.com/news/3352513398 | title=Medi:gate News 6월 1일부터 하보니·소발디 가격 절반된다…하보니 급여도 확대 | trans-title = From the 1st of the month, the price of Harboni and Sovaldi will be halved… Harboni salary increase | language = Korean }} [193] => [194] => ====Germany==== [195] => 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.{{cite web|url=http://www.fiercepharma.com/story/gilead-strikes-sovaldi-price-deal-germany-it-picks-speed-eu/2015-02-13|title=Gilead strikes Sovaldi price deal in Germany as it picks up speed in EU|url-status=live|archive-url=https://web.archive.org/web/20150219041631/http://www.fiercepharma.com/story/gilead-strikes-sovaldi-price-deal-germany-it-picks-speed-eu/2015-02-13|archive-date=2015-02-19 }} [196] => [197] => ====Switzerland==== [198] => In Switzerland, the price is fixed by the government every three years. The price in 2016 was CHF 16,102.50 (about 1:1 to the US dollar) for 24 pills of 400 mg.{{cite web|url=https://www.deindoktor.ch/en/online-medication/sovaldi-400-mg_7680632180016.html|title=Sovaldi / Sofosbuvir medication in Switzerland|url-status=live|archive-url=https://web.archive.org/web/20161004000943/https://www.deindoktor.ch/en/online-medication/sovaldi-400-mg_7680632180016.html|archive-date=2016-10-04 }} [199] => [200] => ====United Kingdom==== [201] => In 2020, the originator price per course of sofosbuvir was {{currency|35443|GBP}}. In 2013, the price in the United Kingdom was expected to be {{currency|35000|GBP}} for a 12-weeks course. [[NHS England]] established 22 Operational Delivery Networks to roll out delivery, which was approved by the [[National Institute for Health and Care Excellence]] 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.{{cite news|title=NHS England rollout of ground-breaking drugs 'changes role of NICE'|url=http://www.hsj.co.uk/topics/policy-and-regulation/nhs-england-rollout-of-ground-breaking-drugs-changes-role-of-nice/7003752.article|access-date=14 May 2016|publisher=Health Service Journal|date=4 April 2016|url-status=live|archive-url=https://web.archive.org/web/20160605000053/http://www.hsj.co.uk/topics/policy-and-regulation/nhs-england-rollout-of-ground-breaking-drugs-changes-role-of-nice/7003752.article|archive-date=5 June 2016 }} [202] => [203] => ====Croatia==== [204] => 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.{{cite web|url=http://www.poslovni.hr/hrvatska/tri-skupa-lijeka-za-hepatitis-c-od-danas-na-besplatnoj-listi-hzzo-a-299564|title=Tri skupa lijeka za hepatitis C od danas na besplatnoj listi HZZO-a}} [205] => [206] => ==== India ==== [207] => 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]] rejected Gilead's application. Gilead's lawyers moved the [[Delhi High Court]] against this decision. That decision was overturned on appeal in February 2015.{{cite web|url=http://www.raps.org/Regulatory-Focus/News/2015/02/04/21240/India-Gilead-Patent/|title=Follow the Rules, Indian Court Tells Patent Office in Sovaldi Case| vauthors = Mezher M |date=February 4, 2015|publisher=Regulatory Affairs Professionals Society|archive-url=https://web.archive.org/web/20160501185954/http://www.raps.org/Regulatory-Focus/News/2015/02/04/21240/India-Gilead-Patent/|archive-date=2016-05-01|url-status=live}}{{cite web|url=http://www.thehindubusinessline.com/companies/more-patentopposition-on-gileads-hepatitis-c-drug-sofosbuvir/article6847904.ece|title=More patent-opposition on Gilead's hepatitis C drug, sofosbuvir| vauthors = Datta J |date=2 February 2015|work=Hindu Business Line|archive-url=https://web.archive.org/web/20170923235702/http://www.thehindubusinessline.com/companies/more-patentopposition-on-gileads-hepatitis-c-drug-sofosbuvir/article6847904.ece|archive-date=23 September 2017|url-status=live}} In the meantime, it{{clarify|date=July 2021}} 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.{{cite web|url=https://caravanmagazine.in/reportage/drug-deals|title=How big pharma and the Indian government are letting millions of patients down | vauthors = Krishnan V, Gahlot M |website=The Caravan|language=en|access-date=2019-07-25}} [208] => [209] => ====Developing world==== [210] => 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]]''.Divya Rajagopal for the Economic Times. Sept 12, 2015. [http://articles.economictimes.indiatimes.com/2015-09-12/news/66465866_1_sofosbuvir-sovaldi-drug-companies Can Indian generic makers find gold with a blockbuster Hepatitis C drug?] [211] => [212] => 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.{{cite news|url=https://www.nytimes.com/2015/12/16/health/hepatitis-c-treatment-egypt.html|title=Curing Hepatitis C, in an Experiment the Size of Egypt|date=Dec 15, 2015|work=New York Times}} [213] => [214] => The [[Access to Medicine Index]] 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."{{cite web|url=http://www.accesstomedicineindex.org/pricing-manufacturing-distribution-0|title=Pricing, Manufacturing & Distribution | Access to Medicine Index 2014|url-status=live|archive-url=https://web.archive.org/web/20150206113129/http://www.accesstomedicineindex.org/pricing-manufacturing-distribution-0|archive-date=2015-02-06 }} In contrast, Jennifer Cohn of [[Doctors Without Borders]] 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. [215] => [216] => In [[Algeria]], as of 2011 about 70,000 people were infected with hepatitis C.{{cite web | date = February 2015 | url = http://www.amfar.org/uploadedFiles/_amfarorg/Articles/On_The_Hill/2015/amfAR%20HCV%20Issue%20Brief%20Feb%202015.pdf | title = Hepatitis C and Drug Pricing: The Need for a Better Balance | work = mfAR, The Foundation for AIDS Research | access-date = 15 June 2016 | archive-date = 7 April 2016 | archive-url = https://web.archive.org/web/20160407153936/http://twww.amfar.org/uploadedFiles/_amfarorg/Articles/On_The_Hill/2015/amfAR%20HCV%20Issue%20Brief%20Feb%202015.pdf | url-status = dead }} As of August 2015, Gilead had licensed its partners in India to sell sofosbuvir in Algeria.{{cite web | work = Drugs for Neglected Diseases Initiative | date = April 2016 | url = http://www.dndi.org/wp-content/uploads/2016/04/AlternativeRDStrategyHepC.pdf | title = An Alternative Research and Development Strategy to Deliver Affordable Treatments for Hepatitis C Patients | archive-url = https://web.archive.org/web/20160809212440/http://www.dndi.org/wp-content/uploads/2016/04/AlternativeRDStrategyHepC.pdf | url-status = live | archive-date =2016-08-09 }}{{cite web | publisher = Gilead | date = August 2015 | url = https://www.gilead.com/~/media/files/pdfs/other/hcv%20generic%20agreement%20fast%20facts%2072815.pdf | title = Chronic Hepatitis C Treatment Expansion Generic Manufacturing for Developing Countries | archive-url = https://web.archive.org/web/20160316193957/http://www.gilead.com/~/media/files/pdfs/other/hcv%20generic%20agreement%20fast%20facts%2072815.pdf | url-status = live | archive-date=2016-03-16 }} It had been criticized for not making the drug available in middle-income countries including Algeria prior to that.{{cite web | work = Doctors without Borders. | date = May 2015 | url = https://www.msfaccess.org/sites/default/files/MSF_assets/HepC/Docs/HepC_brief_OvercomingbarriersToAccess_ENG_2015.pdf | title = Strategies to Secure Access to Generic Hepatitis C Medicines | archive-url = https://web.archive.org/web/20170118041230/https://www.msfaccess.org/sites/default/files/MSF_assets/HepC/Docs/HepC_brief_OvercomingbarriersToAccess_ENG_2015.pdf | url-status = live | archive-date=2017-01-18 }} [217] => [218] => ==Controversies== [219] => The price has generated considerable controversy.{{cite web | vauthors = Stanton T |title=Activists pounce on $1,000-a-day price for Gilead's hep C wonder drug, Sovaldi |url=http://www.fiercepharma.com/story/activists-pounce-1000-day-price-gileads-hep-c-wonder-drug-sovaldi/2013-12-09 |work=FiercePharma |access-date=22 February 2014 |url-status=live |archive-url=https://web.archive.org/web/20140218200421/http://www.fiercepharma.com/story/activists-pounce-1000-day-price-gileads-hep-c-wonder-drug-sovaldi/2013-12-09|archive-date=18 February 2014 }}{{cite web | vauthors = Waldman R |title=Gilead's HCV drug sofosbuvir approved by the FDA but accessible for how many?|url=http://doctorsoftheworld.org/wp-content/uploads/2013/07/Gileads-HCV-drug-sofosbuvir-approved-but-accessible-for-how-many-09DEC2013.pdf|publisher=Doctors of the World|access-date=22 February 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140226224657/http://doctorsoftheworld.org/wp-content/uploads/2013/07/Gileads-HCV-drug-sofosbuvir-approved-but-accessible-for-how-many-09DEC2013.pdf|archive-date=26 February 2014 }} In 2017, the range of costs per treatment varied from about $84,000{{cite journal | vauthors = Hill A, Simmons B, Gotham D, Fortunak J | title = Rapid reductions in prices for generic sofosbuvir and daclatasvir to treat hepatitis C | journal = Journal of Virus Eradication | volume = 2 | issue = 1 | pages = 28–31 | date = January 2016 | pmid = 27482432 | pmc = 4946692 | doi = 10.1016/S2055-6640(20)30691-9 }} to about $50. [220] => [221] => === Patent challenges === [222] => In February 2015, it was reported{{cite web|title=Doctors of the World—Médecins Du Monde opposes sofosbuvir patent in Europe|url=http://www.medecinsdumonde.org/gb/Doctors-of-the-World-Medecins-du-Monde-is-filing-a-patent-challenge-to-Gilead-s-patent-on-sofosbuvir-at-the-European-Patent-Office|publisher=Médecins du Monde|access-date=12 February 2015|url-status=live|archive-url=https://web.archive.org/web/20150212143338/http://www.medecinsdumonde.org/gb/Doctors-of-the-World-Medecins-du-Monde-is-filing-a-patent-challenge-to-Gilead-s-patent-on-sofosbuvir-at-the-European-Patent-Office|archive-date=12 February 2015 }} that [[Doctors of the World]] had submitted an objection to Gilead's patent{{cite web|title=European Patent EP2203462, granted 21 May 2014|url=https://register.epo.org/espacenet/regviewer?AP=08732818&CY=EP&LG=en&DB=REG|website=European Patent Register|publisher=European Patent Office|access-date=12 February 2015}} at the [[European Patent Office]], claiming that the structure of sofosbuvir is based on already known molecules.{{cite magazine |url=http://www.spiegel.de/wissenschaft/medizin/sovaldi-aerzte-der-welt-erhebt-einspruch-gegen-patent-a-1017728.html | vauthors = Kuhrt N |title=Hepatitis-Pille Sovaldi: "Ärzte der Welt" geht gegen Patent vor | trans-title = Hepatitis pill Sovaldi: "Doctors of the World" takes action against the patent |magazine=[[Der Spiegel]] |language=de |date=February 10, 2015 |access-date=February 10, 2015 |url-status=live |archive-url=https://web.archive.org/web/20150210201434/http://www.spiegel.de/wissenschaft/medizin/sovaldi-aerzte-der-welt-erhebt-einspruch-gegen-patent-a-1017728.html |archive-date=February 10, 2015 }} In particular, Doctors of the World argued that the [[Protide]] technology powering sofosbuvir was previously invented by the [[Chris McGuigan]] team at [[Cardiff University]] in the UK, and that the Gilead drug is not therefore inventive.{{cite news|title=Conflit autour d'un traitement contre l'hépatite C| newspaper=Le Monde.fr | url=http://www.lemonde.fr/planete/article/2015/02/10/conflit-autour-d-un-traitement-contre-l-hepatite-c_4573300_3244.html |language=fr |date=February 10, 2015 |access-date=March 4, 2015}}{{cite web|title=Charity challenges Gilead's European patent on hepatitis C therapy Sovaldi|url=http://www.firstwordpharma.com/node/1263122#axzz3RPviNrRF|date=February 10, 2015|access-date=March 4, 2015|url-status=live|archive-url=https://web.archive.org/web/20150402095143/http://www.firstwordpharma.com/node/1263122 |archive-date=April 2, 2015 }} The group filed challenges in other developing countries as well.{{cite news|url=https://www.nytimes.com/2015/05/20/business/high-cost-of-hepatitis-c-drug-prompts-a-call-to-void-its-patents.html|title=High Cost of Sovaldi Hepatitis C Drug Prompts a Call to Void Its Patents | work = The New York Times |date=20 May 2015 |url-status=live|archive-url=https://web.archive.org/web/20150523082146/http://www.nytimes.com/2015/05/20/business/high-cost-of-hepatitis-c-drug-prompts-a-call-to-void-its-patents.html?_r=0|archive-date=2015-05-23 | vauthors = Pollack A }} These challenges were unsuccessful and the court recognized the innovative step in pro-drug design and application to the specific example of sofosbuvir.{{cn|date=November 2022}} [223] => [224] => === Medical tourism === [225] => 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).{{cite web|title=More Americans and Chinese Traveling to India for Hepatitis C Treatment|url=http://webmd.cn/en/americans-chinese-travel-india-hepatitis-c-treatment/|publisher=WebMD China|date=June 3, 2016|access-date=30 August 2018|archive-date=30 August 2018|archive-url=https://web.archive.org/web/20180830174209/http://webmd.cn/en/americans-chinese-travel-india-hepatitis-c-treatment/|url-status=dead}} [226] => [227] => == Research == [228] => Combinations of sofosbuvir with NS5A inhibitors, such as [[daclatasvir]], [[ledipasvir]] or [[Velpatasvir/sofosbuvir|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.{{cite journal | vauthors = Childs-Kean LM, Hand EO | title = Simeprevir and sofosbuvir for treatment of chronic hepatitis C infection | journal = Clinical Therapeutics | volume = 37 | issue = 2 | pages = 243–267 | date = February 2015 | pmid = 25601269 | doi = 10.1016/j.clinthera.2014.12.012 }}{{cite journal | vauthors = Smith MA, Chan J, Mohammad RA | title = Ledipasvir-sofosbuvir: interferon-/ribavirin-free regimen for chronic hepatitis C virus infection | journal = The Annals of Pharmacotherapy | volume = 49 | issue = 3 | pages = 343–350 | date = March 2015 | pmid = 25515863 | doi = 10.1177/1060028014563952 | s2cid = 20944806 }}{{cite journal|url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm508915.htm|title = FDA approves Epclusa for treatment of chronic Hepatitis C virus infection| publisher = U.S. Food and Drug Administration | journal = News Release|date = June 28, 2016|url-status = live|archive-url = https://web.archive.org/web/20170603100010/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm508915.htm|archive-date = June 3, 2017}} 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.{{cite magazine |url=http://www.spiegel.de/gesundheit/diagnose/hepatitis-c-koennte-fuer-50-dollar-therapiert-werden-a-1176133.html | vauthors = Merlot J |title=Hepatitis C könnte für 50 Dollar geheilt werden |magazine=[[Der Spiegel]] |language=de| date=November 2, 2017 |access-date=November 2, 2017}} [229] => [230] => Sofosbuvir has also been tested against other viruses such as the [[Zika virus]]{{cite journal | vauthors = Sacramento CQ, de Melo GR, de Freitas CS, Rocha N, Hoelz LV, Miranda M, Fintelman-Rodrigues N, Marttorelli A, Ferreira AC, Barbosa-Lima G, Abrantes JL, Vieira YR, Bastos MM, de Mello Volotão E, Nunes EP, Tschoeke DA, Leomil L, Loiola EC, Trindade P, Rehen SK, Bozza FA, Bozza PT, Boechat N, Thompson FL, de Filippis AM, Brüning K, Souza TM | display-authors = 6 | title = The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 40920 | date = January 2017 | pmid = 28098253 | pmc = 5241873 | doi = 10.1038/srep40920 | bibcode = 2017NatSR...740920S | doi-access = free }} and [[severe acute respiratory syndrome coronavirus 2]] (SARS-CoV-2).{{cite journal | vauthors = Mesci P, de Souza JS, Martin-Sancho L, Macia A, Saleh A, Yin X, Snethlage C, Adams JW, Avansini SH, Herai RH, Almenar-Queralt A, Pu Y, Szeto RA, Goldberg G, Bruck PT, Papes F, Chanda SK, Muotri AR | display-authors = 6 | title = SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir | journal = PLOS Biology | volume = 20 | issue = 11 | pages = e3001845 | date = November 2022 | pmid = 36327326 | pmc = 9632769 | doi = 10.1371/journal.pbio.3001845 | doi-access = free }} [231] => [232] => == See also == [233] => * [[AT-527]]—a similar drug developed for the treatment of [[SARS-CoV-2]] [234] => * [[Tenofovir alafenamide]]—a nucleotide [[reverse-transcriptase inhibitor]] that uses similar phosphoramidate prodrug technology{{cite web|title=Comparison of tenofovir prodrugs: TAF vs TDF|url=https://yixiblog.wordpress.com/tag/tenofovir-alafenamide-fumarate/|website=DRUG R&D INSIGHT|date=24 January 2015 |access-date=24 November 2015|url-status=live|archive-url=https://web.archive.org/web/20151125032215/https://yixiblog.wordpress.com/tag/tenofovir-alafenamide-fumarate/|archive-date=25 November 2015 }} [235] => * [[Remdesivir]]—a nucleotide analogue [[RNA polymerase inhibitor]] originally intended to treat hepatitis C that uses similar phosphoramidate prodrug technology and displays very similar [[Pharmacokinetics|PK]]. [236] => [237] => == References == [238] => {{Reflist}} [239] => [240] => == Further reading == [241] => * {{cite book | title=Medical Genetics Summaries | chapter=Sofosbuvir Therapy and IFNL4 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK409960/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2017 | pmid=28520377 | id=Bookshelf ID: NBK409960 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }} [242] => [243] => == External links == [244] => * {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/sofosbuvir | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Sofosbuvir }} [245] => [246] => {{RNA antivirals}} [247] => {{Portal bar | Medicine | Viruses }} [248] => [249] => [[Category:Gilead Sciences]] [250] => [[Category:Hepatitis C]] [251] => [[Category:Isopropyl esters]] [252] => [[Category:NS5B (polymerase) inhibitors]] [253] => [[Category:Organofluorides]] [254] => [[Category:Phenol esters]] [255] => [[Category:Prodrugs]] [256] => [[Category:Carboxylate esters]] [257] => [[Category:Pyrimidinediones]] [258] => [[Category:Specialty drugs]] [259] => [[Category:World Health Organization essential medicines]] [260] => [[Category:Wikipedia medicine articles ready to translate]] [] => )
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Sofosbuvir

Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken by mouth.

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