Liverpool COVID-19 Drug Interactions (www.covid19-druginteractions.org)
Lead Research Organisation:
University of Liverpool
Department Name: Molecular and Clinical Pharmacology
Abstract
The Liverpool University Drug Interactions group has over twenty years' experience in developing prescribing support resources in infectious diseases, demonstrated by our world-renowned HIV and Hepatitis drug interaction websites (www.hiv-druginteractions.org and www.hep-druginteractions.org) and associated Apps. In 2019, these websites had over 50,000 unique monthly visitors searching for >4.5 million interactions. Our websites are recommended in over 30 international treatment guidelines and many national guidelines. In response to the COVID-19 pandemic and to address the pressing need for prescribing support for studies and clinical situations where experimental COVID-19 therapies are being used, we have developed a static drug interactions website (www.covid19-druginteractions.org) providing information on the likelihood of interactions between the experimental agents and commonly prescribed co-medications. We now have to move to develop a fully interactive and searchable website resource with an associated App. The website will be constantly updated and populated with the latest information on experimental therapies with guidance given to clinicians for managing complex patients.
Technical Summary
One of the key developments in the fight against HIV/AIDS was the introduction of protease inhibitors in the mid-1990's. This class of drugs in combination with a nucleoside analogue backbone (highly active antiretroviral therapy, HAART) had a huge impact on viral suppression and patient outcome. However, an important trade off was that the protease inhibitors were either the perpetrator or victim of multiple drug-drug interactions. The Liverpool University Drug Interactions group recognised the problem and began developing a web-based resource (www.hiv-druginteractions.org) which over the last 20 years has become very much the gold standard and is now recommended in over 30 international guidelines and many national guidelines. The website has an associated App. In 2011, direct acting antivirals were introduced to treat Hepatitis C and the Liverpool team responded with a new website (www.hep-druginteractions.org) and App. In 2019, these websites had over 50,000 unique monthly visitors searching for >4.5 million interactions. In response to the COVID-19 pandemic and to address the pressing need for prescribing support for studies and clinical situations where experimental COVID-19 therapies are being used, we have developed a static drug interactions website (www.covid19-druginteractions.org) providing information on the likelihood of interactions between the experimental agents and commonly prescribed co-medications. We now have to move to develop a fully interactive and searchable website resource with an associated App. The website will be constantly updated and populated with the latest information on experimental therapies as it emerges with guidance given to clinicians for managing complex patients.
Organisations
- University of Liverpool (Lead Research Organisation)
- National Institute for Health Research (Co-funder)
- European AIDS Clinical Society (EACS) (Project Partner)
- Novartis (Switzerland) (Project Partner)
- British HIV Association (Project Partner)
- AbbVie (United Kingdom) (Project Partner)
- Gilead Sciences Limited (Project Partner)
Publications
Back D
(2021)
COVID-19 treatment in patients with comorbidities: Awareness of drug-drug interactions.
in British journal of clinical pharmacology
De Francesco D
(2021)
Associations between plasma nucleoside reverse transcriptase inhibitors concentrations and cognitive function in people with HIV.
in PloS one
Deutschmann E
(2021)
Prevalence of Potential Drug-Drug Interactions in Patients of the Swiss HIV Cohort Study in the Era of HIV Integrase Inhibitors
in Clinical Infectious Diseases
Hodge D
(2021)
Pharmacokinetics and Drug-Drug Interactions of Long-Acting Intramuscular Cabotegravir and Rilpivirine.
in Clinical pharmacokinetics
Justice AC
(2021)
Polypharmacy-associated risk of hospitalisation among people ageing with and without HIV: an observational study.
in The lancet. Healthy longevity
Kawuma AN
(2021)
Dolutegravir pharmacokinetics during co-administration with either artemether/lumefantrine or artesunate/amodiaquine.
in The Journal of antimicrobial chemotherapy
López-Centeno B
(2020)
Potentially inappropriate medications in older adults living with HIV.
in HIV medicine
Marzolini C
(2022)
Recommendations for the Management of Drug-Drug Interactions Between the COVID-19 Antiviral Nirmatrelvir/Ritonavir (Paxlovid) and Comedications.
in Clinical pharmacology and therapeutics
Marzolini C
(2022)
Prescribing Nirmatrelvir-Ritonavir: How to Recognize and Manage Drug-Drug Interactions.
in Annals of internal medicine
Marzolini C
(2022)
Fluvoxamine for the treatment of COVID-19.
in The Lancet. Global health
| Description | The Liverpool COVID-19 Drug Interaction tools (covid19-druginteractions.org and COVID-19 iChart mobile app) were developed in response to the pandemic, where there was a clear immediate need to provide drug interaction (DDI) information to aid the clinical management of COVID-19. The COVID-19 Drug Interaction tools allow users to rapidly assess the likelihood of DDIs between COVID-19 therapies and concomitant medications, using an extended traffic light system to classify interaction recommendations. Since launch in March 2020, the tools have had over 1.7 million users from 238 countries and territories, searching for 11 million interactions, of which 26% were clinically significant (amber or red classification).The tools have been cited in over 20 clinical treatment guidelines worldwide including World Health Organization (WHO), National Institutes of Health (NIH), British HIV Association (BHIVA), European AIDS Clinical Society (EACS) and Infectious Diseases Society of America (IDSA). These metrics highlight the clear clinical need for DDI information. With 26% of queries identifying a potentially clinically signi?cant DDI, access to DDI information can result in avoidance of patient harm and reduced healthcare costs. Interactions classi?ed as green and yellow, and therefore possess little risk of DDIs can be of importance too. Knowledge of such interactions reinforces their safe prescription, especially vital with experimental therapies where DDI information may not be available. We continue to expand the number of COVID-19 therapies and comedication, based on clinical need. The tools currently have 25 COVID-19 therapies and 880 comedications (330 comedications added in 2022 alone). We regularly review the drugs included in the tools, removing COVID-19 therapies where relevant. Comedications are added based on clinical need and user request. |
| Exploitation Route | Our research outcomes would be described as the COVID-19 Drug Interactions website and mobile app, and we envision usage from healthcare professionals and researchers worldwide (as shown by the website metrics previously mentioned). The tools have already demonstrated improvements in DDI education and clinical management (healthcare) where through utilizing the tools, users have an increased knowledge and confidence in managing comorbidities, improving clinical decision making and thereby, improving patient outcomes. Through this outcome uptake and subsequent improvement in DDI education, the tools may also be used by the pharmaceutical sector (specifically pharmaceutical companies) to identify any areas where they may be able to provide targeted additional education. The COVID-19 Drug Interactions database has an Application Programming Interface (API) facility, whereby we can share our database with others. We have already established an API partnership with a healthcare start-up company based in Australia, with more in the pipeline. |
| Sectors | Education,Healthcare,Pharmaceuticals and Medical Biotechnology |
| URL | http://www.covid19-druginteractions.org |
| Description | The development and ongoing expansion/maintenance of the COVID-19 drug interaction tools has contributed to an improvement in COVID-19 patient outcomes and potentially reduced healthcare costs. As previously mentioned, 26% of database queries identify a potentially clinically signi?cant DDI, where access to DDI information can result in avoidance of patient harm and reduced healthcare costs. Interactions classi?ed as green and yellow, and therefore possess little risk of drug interactions can be of importance too. Knowledge of such interactions reinforces their safe prescription, especially vital with experimental therapies where DDI information may not be available. |
| First Year Of Impact | 2020 |
| Sector | Digital/Communication/Information Technologies (including Software),Education,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Societal,Economic,Policy & public services |
| Guideline Title | CLINICAL INSIGHTS FOR HEPATOLOGY AND LIVER TRANSPLANT PROVIDERS DURING THE COVID-19 PANDEMIC |
| Description | Citation in AASLD Clinical Insights |
| Geographic Reach | North America |
| Policy Influence Type | Citation in clinical guidelines |
| URL | https://www.aasld.org/sites/default/files/2020-04/AASLD-COVID19-ClinicalInsights-4.07.2020-Final.pdf |
| Guideline Title | Considerations for the use of nirmatrelvir/ritonavir to treat COVID-19 in the context of limited supply |
| Description | Citation in Canadian COVID-19 clinical treatment guidelines |
| Geographic Reach | North America |
| Policy Influence Type | Citation in clinical guidelines |
| URL | https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-d... |
| Description | Citation in EACS & BHIVA COVID-19 and HIV statement |
| Geographic Reach | Europe |
| Policy Influence Type | Citation in other policy documents |
| URL | https://www.bhiva.org/EACS-BHIVA-Statement-on-risk-of-COVID-19-for-people-living-with-HIV |
| Guideline Title | Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With Coronavirus Disease 2019 (COVID-19) |
| Description | Citation in IDSA COVID-19 Clinical Treatment Guidelines |
| Geographic Reach | North America |
| Policy Influence Type | Citation in clinical guidelines |
| URL | https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa478/5825667 |
| Guideline Title | Coronavirus Disease 2019 (COVID-19) Treatment Guidelines |
| Description | Citation in NIH COVID-19 Treatment Guidelines |
| Geographic Reach | North America |
| Policy Influence Type | Citation in clinical guidelines |
| URL | https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdf |
| Description | COVID-19 DDI website |
| Amount | £18,000 (GBP) |
| Funding ID | 2021/1190930-0 |
| Organisation | World Health Organization (WHO) |
| Sector | Public |
| Country | Global |
| Start | 12/2021 |
| End | 03/2022 |
| Description | COVID-19 Drug Interactions |
| Amount | £86,677 (GBP) |
| Organisation | Pfizer Inc |
| Sector | Private |
| Country | United States |
| Start | 12/2022 |
| End | 11/2023 |
| Description | COVID-19 Drug Interactions |
| Amount | £75,000 (GBP) |
| Funding ID | 10114 |
| Organisation | Gilead Sciences, Inc. |
| Sector | Private |
| Country | United States |
| Start | 07/2020 |
| End | 07/2021 |
| Description | COVID-19 Drug Interactions |
| Amount | € 5,000 (EUR) |
| Organisation | European Aids Clinical Society |
| Sector | Charity/Non Profit |
| Country | Belgium |
| Start | 03/2020 |
| End | 03/2021 |
| Description | COVID-19 Drug Interactions |
| Amount | £70,000 (GBP) |
| Organisation | Gilead Sciences, Inc. |
| Sector | Private |
| Country | United States |
| Start | 12/2022 |
| End | 11/2023 |
| Description | COVID-19 Drug Interactions |
| Amount | £15,669 (GBP) |
| Funding ID | GRN2020101 |
| Organisation | AbbVie Inc |
| Sector | Private |
| Country | United States |
| Start | 03/2020 |
| End | 03/2021 |
| Description | COVID-19 Drug Interactions |
| Amount | £40,000 (GBP) |
| Organisation | Shionogi |
| Sector | Private |
| Country | United States |
| Start | 03/2023 |
| End | 02/2024 |
| Description | COVID-19 Drug Interactions |
| Amount | £1,000 (GBP) |
| Organisation | British HIV Association (BHIVA) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2020 |
| End | 03/2021 |
| Description | COVID-19 Drug Interactions |
| Amount | $60,000 (USD) |
| Funding ID | INT-20-129444 |
| Organisation | Merck |
| Sector | Private |
| Country | Germany |
| Start | 08/2020 |
| End | 08/2021 |
| Description | COVID-19 Drug Interactions |
| Amount | € 50,000 (EUR) |
| Organisation | Novartis |
| Sector | Private |
| Country | Global |
| Start | 04/2020 |
| End | 04/2021 |
| Description | COVID-19 Drug Interactions |
| Amount | £40,000 (GBP) |
| Organisation | GlaxoSmithKline (GSK) |
| Sector | Private |
| Country | Global |
| Start | 03/2023 |
| End | 02/2024 |
| Description | COVID-19 Drug Interactions Programme |
| Amount | £10,000 (GBP) |
| Funding ID | 2022/1207261-0 |
| Organisation | World Health Organization (WHO) |
| Sector | Public |
| Country | Global |
| Start | 02/2022 |
| End | 03/2022 |
| Description | COVID-19 Drug Interactions Research Programme |
| Amount | £40,000 (GBP) |
| Organisation | Novartis |
| Sector | Private |
| Country | Global |
| Start | 12/2021 |
| End | 11/2022 |
| Description | COVID-19 Drug Interactions Research Programme |
| Amount | £60,000 (GBP) |
| Organisation | Gilead Sciences, Inc. |
| Sector | Private |
| Country | United States |
| Start | 12/2021 |
| End | 11/2022 |
| Description | COVID-19 Drug Interactions Research Programme |
| Amount | £62,177 (GBP) |
| Organisation | Pfizer Inc |
| Sector | Private |
| Country | United States |
| Start | 12/2021 |
| End | 12/2022 |
| Description | COVID-19 Drug Interactions Research Programme |
| Amount | £23,569 (GBP) |
| Organisation | GlaxoSmithKline (GSK) |
| Department | GlaxoSmithKline, Stevenage |
| Sector | Private |
| Country | United Kingdom |
| Start | 11/2021 |
| End | 11/2021 |
| Title | COVID-19 Drug Interactions - additional prescribing resources |
| Description | At the start of the COVID-19 pandemic, the Liverpool Drug Interactions Group recognised that investigational therapies to treat COVID-19 presented a risk of causing harm to patients due to possible drug-drug interactions (DDIs), where those most susceptible to the worst outcomes of COVID-19 were the immunocompromised and those with underlying comorbidities. The COVID-19 Drug Interactions website was then developed in March 2020 to support clinical decision making and aid the safe prescribing of investigational therapies to treat COVID-19. We initially developed a static website containing our printable interaction charts, and whilst we have since developed a dynamic website with a searchable interactions checker and interaction summaries for all interactions, we still produce additional prescribing resources. To date, we have produced the following prescribing resources: dose recommendations for patients with hepatic and renal impairment, at-a-glance summaries of interactions with COVID-19 adjunct, host-directed and antiviral therapies, administration advice in cases of swallowing difficulties, treatment selector for key COVID-19 therapies, guidance for resuming paused or dose-adjusted comedications with Paxlovid, interactions with selected WHO essential medicines and Paxlovid, assessing a patient for treatment Paxlovid and evaluating the interaction risk of COVID-19 therapies. |
| Type Of Material | Improvements to research infrastructure |
| Year Produced | 2020 |
| Provided To Others? | Yes |
| Impact | Our initial interaction tables were heavily relied upon at the start of the pandemic, before the development of our interactive website. However, demand for our additional resources is always increasing and we strive to produce clinically relevant resources. Feedback from our recent documents for Paxlovid has been incredibly positive. |
| URL | https://www.covid19-druginteractions.org/prescribing_resources |
| Title | COVID-19 Drug Interactions - mobile apps |
| Description | In addition to the COVID-19 drug interactions website, we launched the freely accessible 'COVID-19 iChart' mobile app in June 2021. The app is available on android and iOS mobiles and tablets. We also provide offline capability with the app, where mobile data or Wi-Fi is only required on initial download of the database and for updates. This offline capability allows for the continued search for drug-drug interactions (DDIs) even when internet access may be limited, such as in hospitals or resource limited environments. The COVID-19 iChart app accesses the same drug interactions database as the website, providing interaction recommendations for 20,094 interaction pairs, comprising of 34 COVID-19 therapies and 591 comedications. In addition to the website, the COVID-19 Drug Interaction app also uses an 'extended tra?c light' system to classify drug interactions - red interactions denote a contraindicated drug combination that should not be coadministered. Amber interactions signify a drug combination that may require additional intervention such as monitoring or dose modi?cation. Yellow and green interactions represent drug combinations that are safe to coadminister but yellow interactions may come with additional advice. When adding a drug to the database we carry out in-depth analyses of controlled DDI studies, reviewing all probe substrate studies and results, understanding which key enzymes and transporters are affected and reviewing all published and unpublished data. We thoroughly review the SmPC (EU product label) and USPI (US product label) where available, and when data is interpreted differently between the two, our interaction recommendations reflect the most cautious option. However, we still consider and cite both labels in the recommendation. We develop DDI recommendations based on consideration of all available data and expert predictive pharmacokinetics. Before publication, we thoroughly quality assure our content through multiple checks for scientific, clinical and editorial quality. Once content is published on the website and apps, we carry out ongoing QA ensuring recommendations are reflective of the latest data. We also give each interaction recommendation a 'Quality of Evidence' rating, based on the GRADE system. Ratings can be one of the following: Very Low, Low, Moderate or High, and as the name suggests reflects the quality of evidence that has been used to determine the recommendation. Each piece of evidence, be that published or unpublished data, will be assigned a GRADE rating based on consideration of several factors, such as study design, consistencies and limitations. |
| Type Of Material | Improvements to research infrastructure |
| Year Produced | 2021 |
| Provided To Others? | Yes |
| Impact | Since launch, the app has had over 6600 downloads from 176 countries and territories. As part of our initiative to support COVID-19 clinical trials, we encourage the use of our apps for the rapid screening of DDIs to aid clinical management of COVID-19. To date, we have supported (and continue to support) the PANORAMIC, AGILE and SOLIDARITY trials. |
| URL | http://www.covid19-druginteractions.org |
| Title | COVID-19 Drug Interactions - website |
| Description | At the start of the COVID-19 pandemic, the Liverpool Drug Interactions Group recognised that investigational therapies to treat COVID-19 presented a risk of causing harm to patients due to possible drug-drug interactions (DDIs), where those most susceptible to the worst outcomes of COVID-19 were the immunocompromised and those with underlying comorbidities. The COVID-19 Drug Interactions website was then developed in March 2020 to support clinical decision making and aid the safe prescribing of investigational therapies to treat COVID-19. Initially a static website to house PDF documents, a fully interactive, searchable website was launched in May 2020. The COVID-19 Drug Interactions website now provides interaction recommendations for 20,094 interaction pairs, comprising of 34 COVID-19 therapies and 591 comedications. The COVID-19 Drug Interaction website uses an 'extended tra?c light' system to classify drug interactions - red interactions denote a contraindicated drug combination that should not be coadministered. Amber interactions signify a drug combination that may require additional intervention such as monitoring or dose modi?cation. Yellow and green interactions represent drug combinations that are safe to coadminister but yellow interactions may come with additional advice. When adding a drug to the website we carry out in-depth analyses of controlled DDI studies, reviewing all probe substrate studies and results, understanding which key enzymes and transporters are affected and reviewing all published and unpublished data. We thoroughly review the SmPC (EU product label) and USPI (US product label) where available, and when data is interpreted differently between the two, our interaction recommendations reflect the most cautious option. However, we still consider and cite both labels in the recommendation. We develop DDI recommendations based on consideration of all available data and expert predictive pharmacokinetics. Before publication, we thoroughly quality assure our content through multiple checks for scientific, clinical and editorial quality. Once content is published on the website, we carry out ongoing QA ensuring recommendations are reflective of the latest data. We also give each interaction recommendation a 'Quality of Evidence' rating, based on the GRADE system. Ratings can be one of the following: Very Low, Low, Moderate or High, and as the name suggests reflects the quality of evidence that has been used to determine the recommendation. Each piece of evidence, be that published or unpublished data, will be assigned a GRADE rating based on consideration of several factors, such as study design, consistencies and limitations. |
| Type Of Material | Improvements to research infrastructure |
| Year Produced | 2020 |
| Provided To Others? | Yes |
| Impact | To date, the COVID-19 Drug Interaction website has had over 445,000 users from over 220 countries and territories search for over 980,000 interactions, of which 20% were classified as clinically significant (red or amber interaction recommendation). The tools have also been recommended in over 20 national and international treatment guidelines including British HIV Association (BHIVA), European AIDS Clinical Society (EACS), National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Disease (AASLD). |
| URL | http://www.covid19-druginteractions.org |
| Description | COVID-19 Drug Interactions website |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | At the start of the COVID-19 pandemic, the Liverpool Drug Interactions Group recognised that investigational therapies to treat COVID-19 presented a risk of causing harm to patients due to possible drug-drug interactions (DDIs), where those most susceptible to the worst outcomes of COVID-19 were the immunocompromised and those with underlying comorbidities. The COVID-19 Drug Interactions website was then developed in March 2020 to support clinical decision making and aid the safe prescribing of investigational therapies to treat COVID-19. Initially a static website to house PDF documents, a fully interactive, searchable website was launched in May 2020 with associated mobile apps launched in May 2021. The COVID-19 Drug Interaction tools now provide interaction recommendations for 20,094 interaction pairs, comprising of 34 COVID-19 therapies and 591 comedications. The COVID-19 Drug Interaction tools use an 'extended tra?c light' system to classify drug interactions - red interactions denote a contraindicated drug combination that should not be coadministered. Amber interactions signify a drug combination that may require additional intervention such as monitoring or dose modi?cation. Yellow and green interactions represent drug combinations that are safe to coadminister but yellow interactions may come with additional advice. To date, the COVID-19 Drug Interaction tools have had over 445,000 users from over 220 countries and territories search for over 980,000 interactions, of which 20% were classified as clinically significant (red or amber interaction recommendation). The tools have also been recommended in over 20 national and international treatment guidelines including British HIV Association (BHIVA), European AIDS Clinical Society (EACS), National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Disease (AASLD). The COVID-19 drug interaction tools endeavour to support COVID-19 clinical trials through app integration and content development, allowing for the easy search of drug interactions with drug candidates used in such trials. To date, we have supported (and continue to support) the PANORAMIC, AGILE and SOLIDARITY trials. |
| Year(s) Of Engagement Activity | 2020,2021,2022 |
| URL | http://www.covid19-druginteractions.org |
| Description | COVID-19 drug interactions website |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Given the uncertainty surrounding experimental COVID-19 therapies and the likelihood of polypharmacy in the worst outcomes of COVID-19, we knew there would be a clinical need to provide drug interaction information. In March 2020, the University of Liverpool Drug Interactions Group developed the COVID-19 drug interactions website (www.covid19-druginteractions.org) providing information on the likelihood of drug interactions between COVID-19 experimental agents and commonly prescribed co-medications. In May 2020, the website became dynamic, allowing users to search for specific drug combinations with interaction summaries available for each drug combination. Since the launch of the dynamic website in May 2020 we have had over 103,000 users from 193 countries (Google Analytics 2021). These users have searched for approximately 600,000 interactions, of which 21% were classed as clinically significant (i.e. given a red or amber interaction recommendation) (MixPanel 2021). To date, we have included 28 experimental therapies and 524 comedications to the website, totalling over 14,000 interaction recommendations/summaries. The website has been cited in 20 clinical treatment guidelines worldwide. |
| Year(s) Of Engagement Activity | 2020,2021 |
| URL | http://www.covid19-druginteractions.org |
| Description | COVID-19 drug interactions: Communication with Innovate UK |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Policymakers/politicians |
| Results and Impact | We have had some initial conversations with the team from Innovate UK regarding how the COVID-19 drug interactions resources can support the various ongoing clinical trials. The formalities and details are still to be determined but this is something we are very keen to support, and conversations with Innovate UK have been very positive. |
| Year(s) Of Engagement Activity | 2021 |