Researchers in the U.S. and other countries have identified that a combination of two drugs—tenofovir DF (TDF) + FTC—has antiviral potential against SARS-CoV-2 in simulations and possibly in studies of coronavirus-infected cells. The combination of TDF + FTC is co-formulated into one pill and sold under the brand name Truvada; it is also available in generic formulations.

Other drugs that have been considered for repurposing against COVID-19 include the following:

• abacavir
• atazanavir + ritonavir
• azithromycin
• AZT
• chloroquine (CQ) and hydroxychloroquine (HCQ)
• d4T (stavudine)
• entecavir
• ganciclovir
• ivermectin
• lopinavir + ritonavir (in Kaletra)

On one hand, some of these drugs—particularly CQ, HCQ and lopinavir-ritonavir—have been tested in people with COVID-19. Large well-designed clinical trials have almost always found that they don’t have a clinically significant impact. On the other hand, an older and commonly used corticosteroid, dexamethasone, has been associated with a reduced risk of death in people with COVID-19.

CQ and HCQ are interesting in that they have traditionally been used for malaria in some low-income countries, and HCQ has been used for the treatment of some autoimmune conditions (such as arthritis) in both high- and low-income countries.

About two decades ago, laboratory experiments suggested that CQ and/or HCQ had anti-HIV activity in lab experiments with cells and virus. However, subsequent clinical trials in people with HIV found that CQ and/or HCQ only had very modest anti-HIV activity. This is par for the course; many drugs first appear to have potential in lab experiments with cells and virus. However, when such drugs are tested in people, they can sometimes fail or have very modest effects. This is a normal part of the drug development process. Experienced scientists estimate that nine out of 10 drugs that appear useful in the test-tube or animal models of human disease subsequently do not pass over the hurdles of human experiments (clinical trials). This happens because experiments in the lab or in animals, while a good first step, cannot capture the complexity of the human body. These challenges are even more pronounced with attempts at repurposing drugs.

COVID-19 and repurposed drugs

Due to the pandemic nature of SARS-CoV-2 infection, CQ and HCQ were rushed into studies in the hope that they could help people with COVID-19 recover. Many initial studies of CQ and HCQ in COVID-19 were not well designed, and this led some scientists to erroneously conclude that these drugs, particularly HCQ, were useful against COVID-19. Interestingly, experiments with animal models (monkeys and hamsters) have found that HCQ does not prevent infection with SARS-CoV-2. Also, HCQ was not effective as a treatment in animals—a finding confirmed in well-designed clinical trials in people with SARS-CoV-2 infection.

TDF + FTC

As reported earlier in this issue of TreatmentUpdate, one study from Spain suggested the possibility that some HIV-positive people who were using TDF + FTC had a reduced risk of developing infection with SARS-CoV-2. These findings are from an observational study. Another study, also observational in design, has found no protective effect from TDF + FTC (or from the newer formulation of tenofovir, TAF + FTC) in HIV-negative people who used these drugs as HIV pre-exposure prophylaxis (PrEP). A French study, retrospective in design, examined the impact of TDF + FTC in people with and without HIV who were using the combination as HIV treatment or PrEP. In either case, the combination was not protective against SARS-CoV-2. All of these studies, whether observational or retrospective, cannot prove that the combination of TDF + FTC can prevent SARS-CoV-2 infection. These studies are limited by issues related to their design.

However, a large prospective, randomized, placebo-controlled study of TDF + FTC is underway in Spain. The trial is being done in healthcare personnel to see if these drugs can reduce the risk of becoming infected with SARS-CoV-2. The results are expected in late 2020 or early 2021.

—Sean R. Hosein

REFERENCES:

1. Del Amo J, Polo R, Moreno S, et al. The Spanish HIV/COVID-19 Collaboration. Incidence and severity of COVID-19 in HIV-positive persons receiving antiretroviral therapy: a cohort study. Annals of Internal Medicine. 2020 Oct 6;173(7):536-541.
2. Charre C, Icard V, Pradat P, et al. Coronavirus disease 2019 attack rate in HIV-infected patients and in preexposure prophylaxis users. AIDS. 2020 Oct 1;34(12):1765-1770.
3. Ayerdi O, Puerta T, Clavo P, et al. Preventive efficacy of tenofovir/emtricitabine against SARS-CoV-2 among PrEP users. Open Forum Infectious Diseases. 2020; in press.
4. Edwards A. What are the odds of finding a COVID-19 drug from a lab repurposing screen? Journal of Chemical Information and Modeling. 2020; in press.
5. Arshad U, Pertinez H, Box H, et al. Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clinical Pharmacology and Therapeutics. 2020 Oct;108(4):775-790.
6. Jockusch S, Tao C, Li X, Anderson TK, et al. A library of nucleotide analogues terminates RNA synthesis catalyzed by polymerases of coronaviruses that cause SARS and COVID-19. Antiviral Research. 2020 Aug;180:104857.
7. Fintelman-Rodrigues N, Sacramento CQ, Ribeiro Lima C, et al. Atazanavir, alone or in combination with ritonavir, inhibits SARS-CoV-2 replication and proinflammatory cytokine production. Antimicrobial Agents and Chemotherapy. 2020 Sep 21;64(10):e00825-20.
8. Martinez MA. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrobial Agents and Chemotherapy. 2020 Apr 21;64(5):e00399-20.
9. Park SJ, Yu KM, Kim YI, et al. Antiviral efficacies of FDA-approved drugs against SARS-CoV-2 infection in ferrets. mBio. 2020 May 22;11(3):e01114-20.
10. Chien M, Anderson TK, Jockusch S, Tao C, Li X, Kumar S, Russo JJ, Kirchdoerfer RN, Ju J. Nucleotide analogues as inhibitors of SARS-CoV-2 polymerase, a key drug target for COVID-19. Journal of Proteome Research. 2020; in press.
11. Routy JP, Angel JB, Patel M, et al. Assessment of chloroquine as a modulator of immune activation to improve CD4 recovery in immune nonresponding HIV-infected patients receiving antiretroviral therapy. HIV Medicine. 2015 Jan;16(1):48-56.
12. Vaccari M, Fenizia C, Ma ZM, et al. Transient increase of interferon-stimulated genes and no clinical benefit by chloroquine treatment during acute simian immunodeficiency virus infection of macaques. AIDS Research and Human Retroviruses. 2014 Apr;30(4):355-62.
13. Piconi , Parisotto S, Rizzardini G, Passerini S, Terzi R, Argenteri B, Meraviglia P, Capetti A, Biasin M, Trabattoni D, Clerici M. Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders. Blood. 2011 Sep 22;118(12):3263-72.
14. Savarino A, Di Trani L, Donatelli I, Cauda R, Cassone A. New insights into the antiviral effects of chloroquine. Lancet Infectious Diseases. 2006 Feb;6(2):67-9.