International COVID-19 study launches in Africa but with drugs that have little chance of working (ANTICOV)
9 December 2020. Related: COVID-19: investigational drugs, COVID-19: research studies, COVID-19.
Simon Collins, HIV i-Base
On 24 November 2020, plans for a large randomised COVID-19 study in 13 African countries were announced by the international and well-respected charity DNDi (Drugs for Neglected Diseases initiative) on behalf of a large multinational coalition. 
Although the press release refers to using “drugs with proven efficacy”, both the proposed drugs in the current online protocol – hydroxychloroquine (HCQ) and lopinavir/r (LPV/r) – have already been shown not to work in people hospitalised with COVID-19 in several large randomised studies. [2, 3, 4]
There is also considerable research showing that at current dosing, both drugs are absorbed at levels that are much too low to have any potential effect and that higher doses would not be tolerable. [5, 6, 7, 8, 9, 10]
Similar to other large COVID studies, the ANTICOV study uses an adaptive platform design that should in theory rapidly decide whether or not potential treatments are effective. It plans to randomise 2000-3000 participants in early/moderate stage infection. All participants will know which drugs they are taking and more promising drugs are also being reviewed to be added later. 
Innovations in the study design include using potential treatment in earlier stages of infection and looking for changes in symptoms and oxygen saturation after 21 days rather than mortality after 28 days. The study is part of the international WHO ACT-Accelerator collaboration. 
ANTICOV is planned to run in Burkina Faso, Cameroon, Côte d’Ivoire, the Democratic Republic of Congo (DRC), Equatorial Guinea, Ethiopia, Ghana, Guinea, Kenya, Mali, Mozambique, Sudan and Uganda.
The ANTICOV study is an interesting and well-designed study that it is being funded by organisations that are committed to global health. The absolute first priority should be to develop therapeutics (and vaccines) that are safe and effective – and prove them as such through rigorous clinical evaluation.
But the commitment invested in ANTICOV will be wasted unless it uses drugs that have better chance of efficacy – or at least drugs with less evidence showing the lack of activity.
If other potential drugs are not yet finalised then the study should wait until better compounds are ready. The study was perhaps easier to understand six months ago but the urgency now is for better drugs.
The volume of evidence against both HCQ and LPV/r mean that ANITCOV would be unlikely to pass ethical approval in the UK, or likely in any high-income country. The study doesn’t become more ethical just because current choices in many of these countries are limited. Instead, this should force researchers to fast-track some of the many other repurposed drugs that have tentative evidence of potential benefits.
On the same day as this launch, results from the large randomised Barcelona study reported no benefit from HCQ when given as prophylaxis either to prevent infection or to reduce symptoms in those who became positive. 
So while the aim of setting-up a multi-arm platform trial for non-hospitalised patients with COVID-19 is laudable, more careful attention needs to be given to drugs that are chosen for study.
Dr Nathalie Strub-Wourgaft, Director of COVID-19 Response for DNDi explained the ANTICOV trial as “a scientific study to guide policy in a crisis” and emphasised that if the WHO critical review of data changes on either HCQ or LPV/r for the treatment of mild/moderate COVID-19 outpatients, “then of course we will stop using these drugs”.
The study is balancing desperate need for treatment in countries that have so few current treatments, with a hope that this strategy might work, despite a volume of evidence suggesting it won’t.
Unfortunately, negative results from the study also risk undermining confidence in future research, including trust in upcoming vaccines.
Although mainstream media have reported from the ANTICOV press release, none of this coverage has discussed the choice of treatment. 
- DNDi press release. Largest clinical trial in Africa to treat COVID-19 cases before they become severe is launched in 13 countries: Will test a number of promising treatments in urgently needed focus on mild and moderate cases. (24 November 2020).
- UK RECOVERY study stops hydroxychloroquine (HCQ) for COVID-19: more than 1100 deaths question ethics and safety overall. HTB (26 June 2020).
- UK RECOVERY study stops hydroxychloroquine (HCQ) for COVID-19: more than 1100 deaths question ethics and safety overall. (26 June 2020).
- No survival benefit from remdesivir hydroxychloroquine lopinavir/r or interferon-β1a in moderate and severe COVID-19: interim results from the WHO SOLIDARITY study. HTB (11 November 2020).
- Owen A. Are antiretrovirals active against SARS-COV-2? HIV Glasgow 2020, 5-8 October 2020. Virtual Conference.
- High-dose chloroquine study for COVID-19 stopped with worse outcomes: high risk of cardiovascular events. HIV and COVID-19, HTB. (17 April 2020).
- Modelling paper suggests hydroxychloroquine dosing was too low to be active against COVID-19 and that higher doses would risk toxicity. HTB (26 June 2020).
- Smolders EJ et al. SARS-CoV-2 and HIV protease inhibitors: why lopinavir/ritonavir will not work for COVID-19 infection. Antivir Ther. 2020 Jun 26. doi: 10.3851/IMP3365. https://pubmed.ncbi.nlm.nih.gov/32589165
- Arshad U et al. Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin Pharmacol Ther. 2020 Oct;108(4):775-790. doi: 10.1002/cpt.1909. Epub 2020 Jun 14.
- Boffito M et al. Toward consensus on correct interpretation of protein binding in plasma and other biological matrices for COVID-19 therapeutic development. Clin Pharmacol Ther. 2020 Oct 28. doi: 10.1002/cpt.2099.
- COVID-19 Clinical Research Coalition. The ANTICOV study.
- WHO. The Access to COVID-19 Tools (ACT) frequently asked questions.
- Mitjà et al. A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19. NEJM. DOI: 10.1056/NEJMoa2021801. (24 November 2020).
- Beaumont P. Africa’s largest Covid treatment clinical trial launched by 13-country network. (24 November 2020).
This article was first posted on 25 November 2020.