Emtricitabine/tenofovir: Difference between revisions
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==Society and culture== |
==Society and culture== |
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The patent for the drug combination is owned by [[Gilead Sciences]] in some regions. The [[European patent convention|European patent]] EP0915894B1<ref>{{cite web|title=EP0915894B1 - NUCLEOTIDE ANALOGS|url=https://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=0915894B1&KC=B1&FT=D&ND=4&date=20030514# |website=Espacenet|access-date=13 December 2017}}</ref> expired in July 2018, Gilead Sciences wished the patent to be extended, however "four rival labs—Teva, Accord Healthcare, Lupin and Mylan—had sought to have that overturned in the courts in Britain", the High Court of England and Wales invalidated Gilead's patent,<ref>https://www.fiercepharma.com/pharma/u-k-court-invalidates-gilead-s-truvada-patent-extension-allowing-prep-generics</ref> however the company appealed <ref>https://pharmaphorum.com/news/truvada-ruling-could-allow-cheap-hiv-prevention-in-the-uk/</ref> and the UK referred the case to the [[European Court of Justice]] who refused to extend the patent.<ref>https://medicalxpress.com/news/2018-07-eu-door-version-aids-medicine.html</ref> An Irish court rejected an injunction request to prevent the launch of generic Emtricitabine/tenofovir prior to the resolution of the case.<ref>{{cite web|title=Gilead loss of generic HIV drug battle a boost for gay community|url=https://www.irishtimes.com/business/health-pharma/gilead-loss-of-generic-hiv-drug-battle-a-boost-for-gay-community-1.3284747|website=[[The Irish Times]]|access-date=18 May 2018}}</ref><ref>{{cite web|title=Gilead in row with generics manufacturers over HIV drug in Ireland|url=https://www.irishtimes.com/business/health-pharma/gilead-in-row-with-generics-manufacturers-over-hiv-drug-in-ireland-1.3144610|website=[[The Irish Times]]|access-date=30 October 2017}}</ref> Despite the expiration of the Gilead Sciences patent, as of 2021, there are still widespread challenges to the availability and uptake of generic PrEP throughout Europe. <ref>https://www.aidsmap.com/news/jan-2021/european-prep-programmes-face-two-big-issues-how-get-more-people-coming-forward-and</ref> |
The patent for the drug combination is owned by [[Gilead Sciences]] in some regions. The [[European patent convention|European patent]] EP0915894B1<ref>{{cite web|title=EP0915894B1 - NUCLEOTIDE ANALOGS|url=https://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=0915894B1&KC=B1&FT=D&ND=4&date=20030514# |website=Espacenet|access-date=13 December 2017}}</ref> expired in July 2018, Gilead Sciences wished the patent to be extended, however "four rival labs—Teva, Accord Healthcare, Lupin and Mylan—had sought to have that overturned in the courts in Britain", the High Court of England and Wales invalidated Gilead's patent,<ref>{{Cite web|url=https://www.fiercepharma.com/pharma/u-k-court-invalidates-gilead-s-truvada-patent-extension-allowing-prep-generics|title=U.K. Court invalidates Gilead's Truvada patent extension, allowing PrEP generics}}</ref> however the company appealed <ref>{{Cite web|url=https://pharmaphorum.com/news/truvada-ruling-could-allow-cheap-hiv-prevention-in-the-uk/|title = Truvada ruling could allow cheap HIV prevention in the UK -|date = 19 September 2018}}</ref> and the UK referred the case to the [[European Court of Justice]] who refused to extend the patent.<ref>{{Cite web|url=https://medicalxpress.com/news/2018-07-eu-door-version-aids-medicine.html|title = EU door opens for generic version of AIDS medicine Truvada}}</ref> An Irish court rejected an injunction request to prevent the launch of generic Emtricitabine/tenofovir prior to the resolution of the case.<ref>{{cite web|title=Gilead loss of generic HIV drug battle a boost for gay community|url=https://www.irishtimes.com/business/health-pharma/gilead-loss-of-generic-hiv-drug-battle-a-boost-for-gay-community-1.3284747|website=[[The Irish Times]]|access-date=18 May 2018}}</ref><ref>{{cite web|title=Gilead in row with generics manufacturers over HIV drug in Ireland|url=https://www.irishtimes.com/business/health-pharma/gilead-in-row-with-generics-manufacturers-over-hiv-drug-in-ireland-1.3144610|website=[[The Irish Times]]|access-date=30 October 2017}}</ref> Despite the expiration of the Gilead Sciences patent, as of 2021, there are still widespread challenges to the availability and uptake of generic PrEP throughout Europe. <ref>{{Cite web|url=https://www.aidsmap.com/news/jan-2021/european-prep-programmes-face-two-big-issues-how-get-more-people-coming-forward-and|title = European PrEP programmes face two big issues: How to get more people coming forward, and how to serve them if they do}}</ref> |
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In 2019, Gilead Sciences challenged patents held by the United States for the drug combination.<ref>{{cite news | last=Rowland | first=Christopher | title=Gilead defied a government HIV patent. The Justice Department has opened a review. | website=[[The Washington Post]] | date=24 April 2019 | url=https://www.washingtonpost.com/business/economy/gilead-defied-a-government-hiv-patent-the-justice-department-has-opened-a-review/2019/04/24/16e4e20e-62bc-11e9-bfad-36a7eb36cb60_story.html | archive-url=https://web.archive.org/web/20191101010542/https://www.washingtonpost.com/business/economy/gilead-defied-a-government-hiv-patent-the-justice-department-has-opened-a-review/2019/04/24/16e4e20e-62bc-11e9-bfad-36a7eb36cb60_story.html | archive-date=1 November 2019 | url-status=live | access-date=31 October 2019 | name-list-style=vanc }}</ref><ref>{{cite news | last=Rowland | first=Christopher | title=Gilead files challenge to government patents for HIV prevention pill | website=[[The Washington Post]] | date=21 August 2019 | url=https://www.washingtonpost.com/business/economy/gilead-files-challenge-to-government-patents-for-hiv-prevention-pill/2019/08/21/43baa61e-c43d-11e9-b5e4-54aa56d5b7ce_story.html | archive-url=https://web.archive.org/web/20191101011634/https://www.washingtonpost.com/business/economy/gilead-files-challenge-to-government-patents-for-hiv-prevention-pill/2019/08/21/43baa61e-c43d-11e9-b5e4-54aa56d5b7ce_story.html | archive-date=1 November 2019 | url-status=live | access-date=29 October 2019 | name-list-style=vanc }}</ref><ref>{{cite press release | title=Petitions to US Patent and Trademark Office on HIV PrEP Patents | website=[[Gilead Sciences]] | date=21 August 2019 | url=https://www.gilead.com/news-and-press/company-statements/petitions-to-us-patent-and-trademark-office-on-hiv-prep-patents | archive-url=https://web.archive.org/web/20191030023128/https://www.gilead.com/news-and-press/company-statements/petitions-to-us-patent-and-trademark-office-on-hiv-prep-patents | archive-date=30 October 2019 | url-status=live | access-date=29 October 2019}}</ref> |
In 2019, Gilead Sciences challenged patents held by the United States for the drug combination.<ref>{{cite news | last=Rowland | first=Christopher | title=Gilead defied a government HIV patent. The Justice Department has opened a review. | website=[[The Washington Post]] | date=24 April 2019 | url=https://www.washingtonpost.com/business/economy/gilead-defied-a-government-hiv-patent-the-justice-department-has-opened-a-review/2019/04/24/16e4e20e-62bc-11e9-bfad-36a7eb36cb60_story.html | archive-url=https://web.archive.org/web/20191101010542/https://www.washingtonpost.com/business/economy/gilead-defied-a-government-hiv-patent-the-justice-department-has-opened-a-review/2019/04/24/16e4e20e-62bc-11e9-bfad-36a7eb36cb60_story.html | archive-date=1 November 2019 | url-status=live | access-date=31 October 2019 | name-list-style=vanc }}</ref><ref>{{cite news | last=Rowland | first=Christopher | title=Gilead files challenge to government patents for HIV prevention pill | website=[[The Washington Post]] | date=21 August 2019 | url=https://www.washingtonpost.com/business/economy/gilead-files-challenge-to-government-patents-for-hiv-prevention-pill/2019/08/21/43baa61e-c43d-11e9-b5e4-54aa56d5b7ce_story.html | archive-url=https://web.archive.org/web/20191101011634/https://www.washingtonpost.com/business/economy/gilead-files-challenge-to-government-patents-for-hiv-prevention-pill/2019/08/21/43baa61e-c43d-11e9-b5e4-54aa56d5b7ce_story.html | archive-date=1 November 2019 | url-status=live | access-date=29 October 2019 | name-list-style=vanc }}</ref><ref>{{cite press release | title=Petitions to US Patent and Trademark Office on HIV PrEP Patents | website=[[Gilead Sciences]] | date=21 August 2019 | url=https://www.gilead.com/news-and-press/company-statements/petitions-to-us-patent-and-trademark-office-on-hiv-prep-patents | archive-url=https://web.archive.org/web/20191030023128/https://www.gilead.com/news-and-press/company-statements/petitions-to-us-patent-and-trademark-office-on-hiv-prep-patents | archive-date=30 October 2019 | url-status=live | access-date=29 October 2019}}</ref> |
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In the United Kingdom, PrEP is widely available to all at risk groups following the Department for Health and Social Care's decision to make it available across England from 2020. Wales, Scotland, and Northern Ireland made it available in 2017 and 2018. <ref>https://www.gov.uk/government/news/hiv-drug-prep-to-be-available-across-england</ref> <ref>https://www.iwantprepnow.co.uk/prep-on-the-nhs/</ref> |
In the United Kingdom, PrEP is widely available to all at risk groups following the Department for Health and Social Care's decision to make it available across England from 2020. Wales, Scotland, and Northern Ireland made it available in 2017 and 2018. <ref>{{Cite web|url=https://www.gov.uk/government/news/hiv-drug-prep-to-be-available-across-england|title = HIV drug PrEP to be available across England}}</ref> <ref>{{Cite web|url=https://www.iwantprepnow.co.uk/prep-on-the-nhs/|title = Free PrEP on the NHS}}</ref> |
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==References== |
==References== |
Revision as of 21:03, 2 August 2021
Combination of | |
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Emtricitabine | Nucleoside reverse transcriptase inhibitor |
Tenofovir disoproxil | Nucleotide analogue reverse transcriptase inhibitor |
Clinical data | |
Trade names | Truvada, Tenvir-EM, other |
Other names | Emtricitabine/tenofovir disoproxil fumarate |
AHFS/Drugs.com | Professional Drug Facts |
MedlinePlus | a612036 |
License data | |
Pregnancy category |
|
Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status | |
Identifiers | |
CAS Number | |
PubChem CID | |
NIAID ChemDB | |
(verify) |
Emtricitabine/tenofovir, sold under the brand name Truvada among others, is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS.[3][4] It contains the antiretroviral medications emtricitabine and tenofovir disoproxil.[5] For treatment, it must be used in combination with other antiretroviral medications.[5][6] For prevention before exposure, in those who are at high risk, it is recommended along with safer sex practices.[5] It does not cure HIV/AIDS.[3] Emtricitabine/tenofovir is taken by mouth.[5]
Common side effects include headache, tiredness, trouble sleeping, abdominal pain, weight loss, and rash.[3] Serious side effects may include high blood lactate levels and enlargement of the liver.[5] Use of this medication during pregnancy does not appear to harm the baby, but has not been well studied.[1]
Emtricitabine/tenofovir was approved for medical use in the United States in 2004.[3] It is on the World Health Organization's List of Essential Medicines.[7] In the United States, emtricitabine/tenofovir was under patent until 2020, but is now available as a generic worldwide.[8]
Medical uses
Emtricitabine/tenofovir is used both to treat and to prevent HIV/AIDS.[3] It is a tablet taken by mouth.[5] The U.S. National Institutes of Health (NIH) recommends antiretroviral therapy (ART) for all people with HIV/AIDS.[9]
HIV prevention
The Centers for Disease Control and Prevention (CDC) recommends the use of emtricitabine/tenofovir for pre-exposure prophylaxis (PrEP) for uninfected, HIV-1 negative individuals that may be at risk for HIV-1 infection.[10][5] A Cochrane review found that both tenofovir alone, as well as the tenofovir/emtricitabine combination, decreased the risk of contracting HIV by 51%.[11] It was approved for PrEP against HIV infection in the United States in 2012.[12]
The CDC recommends PrEP be considered for the following high-risk groups:[13]
- Individuals in an ongoing sexual relationship with an HIV-positive partner
- Gay or bisexual men who either have had anal sex without a condom or been diagnosed with an STD in the past six months
- Heterosexual men or women who do not regularly use condoms during sex with partners of unknown HIV status who are substantial risk
- Injection of drugs in the last six months with sharing of equipment
- Sero-discordant heterosexual and homosexual partners where one partner is HIV-positive and the other HIV-negative
The consideration of utilizing emtricitabine/tenofovir as a reduction strategy involves discussion with a health professional who can help the patient navigate the benefits and risks. Patients are advised to discuss any history of bone issues, kidney issues, of hepatitis B infection with their health care provider.[14] Effectiveness of PrEP for prevention of infection is reliant on an individual's ability to take the medication consistently.[15]
Emtricitabine/tenofovir is also used for HIV post-exposure prophylaxis. People who start taking emtricitabine/tenofovir see HIV reduction benefit up to 72 hours after starting, but the medicine must be taken for thirty days after a high-risk sexual event to ensure HIV transmission levels are optimally reduced.[16][17]
Truvada as PrEP should not be used for individuals that are positive for HIV-1.[5]
HIV treatment
Emtricitabine/tenofovir has been approved in the United States as part of antiretroviral combination therapy for the treatment of HIV-1.[5] The combination therapy is suggested as one of the options for adults who have not received any prior treatment for HIV infection.[18]
Hepatitis B
Both emtricitabine and tenofovir are indicated for the treatment of hepatitis B, with the added benefit that they can target HIV for those with co-infection.[19] Emtricitabine/tenofovir may also be considered for some antiviral resistant hepatitis B infections.[20]
Pregnancy and breastfeeding
In the United States, it is recommend that all pregnant HIV-infected women start antiretroviral therapy (ART) as early in pregnancy as possible to reduce risk of transmission. ART generally does not increase risk of birth defects with exception of dolutegravir, which is not recommended during first trimester of pregnancy only due to potential risk of neural tube defects.[21]
Emtricitabine/tenofovir is secreted in breast milk.[22] In developed countries, HIV-infected mothers are generally recommended to not breastfeed due to slight risk of mother-to-children HIV transmission.[23][24] In developing countries, where avoiding breastfeeding may not be an option, the World Health Organization recommends a triple drug regimen of tenofovir, efavirenz, and either lamivudine or emtricitabine.[24]
Side effects
Emtricitabine/tenofovir is generally well tolerated. Some of its side effects include:[5]
- Rare: lactic acidosis, liver dysfunction, worsening of hepatitis B infection
- Common: headache, abdominal pain, decreased weight, nausea, diarrhea, and decreased bone density
Fat redistribution and accumulation (lipodystrophy) has been observed in people receiving antiretroviral therapy, including fat reductions in the face, limbs, and buttocks and increases in visceral fat of the abdomen and accumulations in the upper back.[5] When used as pre-exposure prophylaxis (PrEP) this effect may not be present.[25] Weight changes have however been linked to the medication.[26]
Drug interactions
Drug-drug Interaction | Coadministration | |
---|---|---|
Tenofovir | Didanosine |
|
Atazanavir |
| |
Lopinavir/ritonavir, atazanavir coadministered with ritonavir & darunavir coadministered with ritonavir |
| |
Ledipasvir/sofosbuvir |
| |
Emtricitabine/tenofovir | P-glycoprotein and breast cancer resistance protein (BCRP) transporters inhibitors |
|
Drugs may decrease renal function (e.g. acyclovir, adefovir, dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides, etc.) |
| |
High-dose or multiple NSAIDs |
| |
Orlistat |
|
Other drugs with adverse reactions include dabigatran etexilate, lamivudine, and vincristine. Dabigatran etexilate used with p-glycoprotein inducers require monitoring of decreased levels and effects of dabigatran. Lamivudine may increase the adverse or toxic effect of emtricitabine. Vincristine used with P-glycoprotein/ABCB1 inducers can decrease the serum concentration of vincristine.[28]
Society and culture
The patent for the drug combination is owned by Gilead Sciences in some regions. The European patent EP0915894B1[29] expired in July 2018, Gilead Sciences wished the patent to be extended, however "four rival labs—Teva, Accord Healthcare, Lupin and Mylan—had sought to have that overturned in the courts in Britain", the High Court of England and Wales invalidated Gilead's patent,[30] however the company appealed [31] and the UK referred the case to the European Court of Justice who refused to extend the patent.[32] An Irish court rejected an injunction request to prevent the launch of generic Emtricitabine/tenofovir prior to the resolution of the case.[33][34] Despite the expiration of the Gilead Sciences patent, as of 2021, there are still widespread challenges to the availability and uptake of generic PrEP throughout Europe. [35]
In 2019, Gilead Sciences challenged patents held by the United States for the drug combination.[36][37][38]
In the United Kingdom, PrEP is widely available to all at risk groups following the Department for Health and Social Care's decision to make it available across England from 2020. Wales, Scotland, and Northern Ireland made it available in 2017 and 2018. [39] [40]
References
- ^ a b c "Emtricitabine / tenofovir Pregnancy and Breastfeeding Warnings". Drugs.com. 1 August 2018. Archived from the original on 10 October 2019. Retrieved 10 October 2019.
- ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
- ^ a b c d e "Truvada". Drugs.com. Archived from the original on 20 December 2016. Retrieved 12 December 2016.
- ^ "UK label Truvada film-coated tablets". Electronic Medicines Compendium. August 2016. Archived from the original on 20 December 2016.
- ^ a b c d e f g h i j k l "Truvada- emtricitabine and tenofovir disoproxil fumarate tablet, film coated label". DailyMed. 18 May 2018. Archived from the original on 31 October 2019. Retrieved 31 October 2019.
- ^ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 160. hdl:10665/44053. ISBN 9789241547659.
- ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
- ^ "AOC asks pharma CEO why $2,000 HIV drug costs just $8 in Australia". The Independent. 17 May 2019. Retrieved 15 November 2019.
- ^ "Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV" (PDF). AIDSinfo Clinical Guidelines. July 2019. Retrieved 30 October 2019.
- ^ "PrEP". Centers for Disease Control and Prevention (CDC). 17 October 2019. Archived from the original on 31 October 2019. Retrieved 31 October 2019. This article incorporates text from this source, which is in the public domain.
- ^ Okwundu CI, Uthman OA, Okoromah CA (2012). "Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals". Cochrane Database Syst Rev. 7 (7): CD007189. doi:10.1002/14651858.CD007189.pub3. PMID 22786505. S2CID 35672491.
- ^ Perrone M (16 July 2012). "FDA approves first pill to help prevent HIV". The Seattle Times. Associated Press. Archived from the original on 19 July 2012.
- ^ "Pre-Exposure Prophylaxis (PrEP)". Archived from the original on 5 June 2015. Retrieved 4 June 2015.
{{cite web}}
: CS1 maint: unfit URL (link) This article incorporates text from this source, which is in the public domain. - ^ "Administration of pre-exposure prophylaxis against HIV infection". UpToDate. Retrieved 31 October 2019.
- ^ "Pre-exposure prophylaxis of HIV in adults at high risk: Truvada (emtricitabine/tenofovir disoproxil)".
- ^ Panlilio AL, Cardo DM, Grohskopf LA, et al. (September 2005). "Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis" (PDF). MMWR Recomm Rep. 54 (RR-9): 1–17. PMID 16195697.
- ^ Kuhar DT, Henderson DK, Struble KA, et al. (September 2013). "Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis" (PDF). Infection Control and Hospital Epidemiology. 34 (9): 875–92. doi:10.1086/672271. PMID 23917901. S2CID 17032413. 20711. This article incorporates text from this source, which is in the public domain.
- ^ "Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV" (PDF).
- ^ "Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance" (PDF).
- ^ "Emtricitabine and Tenofovir Disoproxil Fumarate (Professional Patient Advice)". Drugs.com. Retrieved 31 October 2019.
- ^ "Brief What's New in the Guidelines Perinatal". AIDSinfo. Retrieved 23 October 2019.
- ^ "Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States" (PDF). National Institutes of Health (NIH). Archived (PDF) from the original on 12 April 2014. Retrieved 21 October 2014.
- ^ "Emtricitabine / tenofovir Use During Pregnancy". Drugs.com. Retrieved 23 October 2019.
- ^ a b "Tenofovir". Drugs and Lactation Database (LactMed). National Library of Medicine (US). 2006. Retrieved 23 October 2019.
- ^ "PrEP does not raise lipids or alter body fat, safety study finds". Retrieved 16 February 2018.
- ^ Glidden DV, Mulligan K, McMahan V, et al. (July 2018). "Metabolic Effects of Preexposure Prophylaxis With Coformulated Tenofovir Disoproxil Fumarate and Emtricitabine". Clin. Infect. Dis. 67 (3): 411–419. doi:10.1093/cid/ciy083. PMC 6051460. PMID 29415175.
{{cite journal}}
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ignored (help) - ^ "DailyMed - XENICAL- orlistat capsule". dailymed.nlm.nih.gov. Retrieved 30 October 2019.
- ^ Ramanathan S, Shen G, Cheng A, et al. (July 2007). "Pharmacokinetics of emtricitabine, tenofovir, and GS-9137 following coadministration of emtricitabine/tenofovir disoproxil fumarate and ritonavir-boosted GS-9137". J. Acquir. Immune Defic. Syndr. 45 (3): 274–9. doi:10.1097/QAI.0b013e318050d88c. PMID 17414929. S2CID 31756102.
- ^ "EP0915894B1 - NUCLEOTIDE ANALOGS". Espacenet. Retrieved 13 December 2017.
- ^ "U.K. Court invalidates Gilead's Truvada patent extension, allowing PrEP generics".
- ^ "Truvada ruling could allow cheap HIV prevention in the UK -". 19 September 2018.
- ^ "EU door opens for generic version of AIDS medicine Truvada".
- ^ "Gilead loss of generic HIV drug battle a boost for gay community". The Irish Times. Retrieved 18 May 2018.
- ^ "Gilead in row with generics manufacturers over HIV drug in Ireland". The Irish Times. Retrieved 30 October 2017.
- ^ "European PrEP programmes face two big issues: How to get more people coming forward, and how to serve them if they do".
- ^ Rowland C (24 April 2019). "Gilead defied a government HIV patent. The Justice Department has opened a review". The Washington Post. Archived from the original on 1 November 2019. Retrieved 31 October 2019.
- ^ Rowland C (21 August 2019). "Gilead files challenge to government patents for HIV prevention pill". The Washington Post. Archived from the original on 1 November 2019. Retrieved 29 October 2019.
- ^ "Petitions to US Patent and Trademark Office on HIV PrEP Patents". Gilead Sciences (Press release). 21 August 2019. Archived from the original on 30 October 2019. Retrieved 29 October 2019.
- ^ "HIV drug PrEP to be available across England".
- ^ "Free PrEP on the NHS".
External links
- "Emtricitabine mixture with tenofovir disoproxil fumarate". Drug Information Portal. U.S. National Library of Medicine.