Early drugs being studied for COVID-19
27 March 2020. Related: Treatment strategies, COVID-19: investigational drugs, COVID-19.
Simon Collins, HIV i-Base
This section on potential treatment mainly includes links to other coverage of COVID-19.
It also includes links to several reviews of potential drugs.
Although some compounds have shown potential activity in vitro, the first results show little clinical effect.
The urgency to find treatment for people in critical care with high mortality often leads to optimistic reports from small or uncontrolled studies. This has difficult parallels with early HIV studies.
Many researchers are looking at potential drugs that could be repurposed for COVID-19. These include lopinavir/r, remdesivir, chloroquine (or hydroxychloroquine), favipiravir (favilavir) an anti-flu drug approved in Japan), corticosteroids, nitazoxanide and monoclonal antibodies (including tociluzimab and meplazumab).
Although there are too many potential compounds to report below, many articles reviewing these and other compounds for treatment or vaccines are online and provide more in-depth coverage. [1, 2, 3, 4]
The COVID-19 health crisis has also refocused use and debate about trial design and use of expanded/compassionate access programmes that were developed during the pre-ART era for HIV. [5]
Remdesivir
Remdesivir is an investigational antiviral drug developed for Ebola (but without benefit), that has in-vitro activity against CoV-2. It is currently in at least four randomised clinical studies. Early results from some studies is expected in April 2020.
Remdesivir is being developed by Gilead Sciences.
Recent news included an expanded access programme for off-label use in people unable to participate in clinical studies. This programme has since been restricted due to very high levels of demand although the company is also committed to reestablishing it. [6, 7]
A press release that announced that remdesivir had been granted FDA status for development as an orphan drug was shortly followed by a press release that Gilead would not be using the orphan drug benefits. [8]
First data on single case reports from expanded access use was also just published in several patients in France. [9]
ARVs: lopinavir/r
Although several early reports included using HIV protease inhibitors to treat COVID-19, notably lopinavir/r (Kaletra), the first results failed to show benefits in reducing symptoms or earlier clearance measure by PCR.
This was sufficient for the UK government to restrict lopinavir/r from parallel importing in order to maintain supplies for (the expected very few) HIV positive people who still use lopinavir/r as treatment.
An opposite approach was taken in Switzerland, where HIV positive people on lopinaivr/r were asked to switch to alternative ART in order to free up supplies for people in critical care with COVID-19 and who were without other treatment options.
Three papers have already been published (one of which is not peer-reviewed) from using lopinavir/r to treat COVID-19
A randomised study published in the NEJM reported no benefit of lopinavir/r compared to standard of care in 199 people with severe COVID-19. Endpoints included clinical benefit, mortality and viral load at different timepoints. [10]
A retrospective analysis of using either lopinavir/r alone or in combination with an influenza drug used in Russia and China called umifenovir (Arbidol) report significant benefits in the combination group with 12/16 vs 6/17 having undetectable viral load from throat swabs after one week. After 14 days these responses were 15/16 vs 9/17 respectively. [11]
A third study, not yet peer-reviewed, randomised 44 adults with mild/moderate COVID-19 to lopinavir/r, arbidol or standard of care. Neither of the monotherapy arms showed significant benefits compared to standard of care. [12]
A small UK study using lopinavir/r with the anti-inflammatory steroid dexamethasone was recently announced. [13]
Darunavir/r: not supported by data
A press release from Johnson & Johnson announced that although it is screening its antiviral compounds to determine potential in-vitro effect against CoV-2, there is no evidence that darunavir has any effect. [14]
It notes that the company is partnering with multiple organisations to support the development of research programmes and fast-track solutions for COVID-19.
Chloroquine and hydroxychloroquine (HCQ)
The preliminary research into using the anti-malarial drugs chloroquine and hydroxychloroquine in combination with azithromycin was widely reported as possibly having some effect (a problematic study due to small numbers) [15], it was certainly not helped by a Trump tweet touting this as “one of the biggest game changers in the history of medicine”. [16]
This not only jeoparised drugs supplies for people needing these drugs for existing conditions (notably for autoimmune diseases including lupus and rheumatoid arthritis) but led to unsupervised off-label used that resulted in at least one death. [17]
Other reports stress the limited data available and the potential side effects of both compounds. [18, 19, 20]
Passive antibody treatment
A paper in JAMA describes clinical outcomes in five Chinese patients with laboratory-confirmed COVID-19, acute respiratory distress syndrome and high viral loads that were given human plasma with SARS-CoV-2 antibodies obtained from previously infected and recovered patients. [21]
JAMA also include editorial commentary on this approach. [22]
Another paper in JCI looks at the the use of passive antibody therapy from people who have recovered from COVID-19 to mediate protection by viral neutralisation. [23]
Meplazumab
A small open-label study of meplazumab that used historical controls has not been peer reviewed yet, but reported significantly reduced severity of symptoms and short time to undetectable viral load. [24]
References
- McCreary EK. COVID-19 treatment: a review of early and emerging options. Open Forum Infectious Diseases, ofaa105, DOI: 10.1093/ofid/ofaa105. (23 March 2020).
https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofaa105/5811022 - Pogue J. Treatment options for COVID-19. The Society of Infectious Diseases Pharmacists. YouTube talk.
https://www.youtube.com/watch?v=bGk9uI81s_E - Clinical Trials Arena. Coronavirus treatment: vaccines/drugs in the pipeline for COVID-19. (26 March 2020).
https://www.clinicaltrialsarena.com/analysis/coronavirus-mers-cov-drugs/ - PharmaTimes. Potential pipeline medications may help patients with novel coronavirus (11 March 2020).
https://www.pharmacytimes.com/news/potential-pipeline-medications-for-the-coronavirus - Kalil AC. Treating COVID-19—off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA viewpoint. (24 March 2020).
https://jamanetwork.com/journals/jama/fullarticle/2763802 - Gilead press statement. Gilead Sciences Update on the company’s ongoing response To COVID-19. (22 March 2020).
https://www.gilead.com/purpose/advancing-global-health/covid-19 - O’Day, D. An Open Letter from our Chairman and CEO. (28 March 2020).
https://www.gilead.com/stories/articles/an-open-letter-from-our-chairman-and-ceo - Gilead press statement. Gilead sciences statement on request to rescind remdesivir orphan drug designation.
https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-request-to-rescind-remdesivir-orphan-drug-designation - Lescure FX et al. Clinical and virological data of the first cases of COVID-19 in Europe: a case series. Lancet Infectious Diseases. DOI: 10.1016/S1473-3099(20)30200-0. (27 March 2020)
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30200-0/fulltext - Cao B et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. NEJM. DOI: 10.1056/NEJMoa2001282. (18 March 2020).
https://www.nejm.org/doi/full/10.1056/NEJMoa2001282 - Deng L et al. Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study. Journal of Infections. doi: 10.1016/j.jinf.2020.03.002. (11 Mar 2020).
https://www.ncbi.nlm.nih.gov/pubmed/32171872 - Li Y et al. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). MedRxIV. 23 March 2020.
https://www.medrxiv.org/content/10.1101/2020.03.19.20038984v1 - Reuters Health News. UK begins trial of HIV medicine, steroid as possible COVID-19 treatments (23 March 2020).
https://www.reuters.com/article/us-health-coronavirus-britain-tests/uk-begins-trial-of-hiv-medicine-steroid-as-possible-covid-19-treatments-idUSKBN21A2JO - Johnson and Johnson press release. Lack of evidence to support use of darunavir-based treatments for SARS-CoV-2.
https://www.jnj.com/lack-of-evidence-to-support-darunavir-based-hiv-treatments-for-coronavirus - Gautret P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. DOI: 10.1016/j.ijantimicag.2020.105949 (20 March 2020).
https://www.sciencedirect.com/science/article/pii/S0924857920300996 - Piller C. ‘This is insane!’ Many scientists lament Trump’s embrace of risky malaria drugs for coronavirus. Science. (26 March 2020).
https://www.sciencemag.org/news/2020/03/insane-many-scientists-lament-trump-s-embrace-risky-malaria-drugs-coronavirus - Arizona man dies after attempting to take Trump coronavirus ‘cure’, The Guardian. (24 March 2020).
https://www.theguardian.com/world/2020/mar/24/coronavirus-cure-kills-man-after-trump-touts-chloroquine-phosphate - Touret F and de Lamballerie X. Of chloroquine and COVID-19. Antiviral Research. Commentary. Volume 177, May 2020,
https://www.sciencedirect.com/science/article/pii/S0166354220301145 - Highleyman L. Can Chloroquine Prevent or Cure COVID-19? POZ magazine. (23 March 2020).
https://www.poz.com/article/can-chloroquine-prevent-cure-covid19? - Escobar ZK. Chloroquine and hydroxychloroquine. The Society of Infectious Diseases Pharmacists. YouTube talk. (20 March 2020).
https://www.youtube.com/watch?v=an4WZv_spT4 (video) - Chen C et al Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. doi:10.1001/jama.2020.4783. (27 March 2020).
https://jamanetwork.com/journals/jama/fullarticle/2763983 - Robuck JD and Guarner J. Convalescent plasma to treat COVID-19: Possibilities and Challenges. JAMA Editorial. doi:10.1001/jama.2020.4940. (27 March 2020).
https://jamanetwork.com/journals/jama/fullarticle/2763982 - Casadevall A and Pirofski L-A. The convalescent sera option for containing COVID-19. JCI. DOI: 10.1172/JCI138003. (13 March 2020).
https://www.jci.org/articles/view/138003 - Bian H et al. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial. doi: 10.1101/2020.03.21.20040691
https://www.medrxiv.org/content/10.1101/2020.03.21.20040691v1