Antivirals for COVID-19

REMDESIVIR

Remdesivir (GS-5734) is an adenosine analog antiviral drug that inhibits viral RNA polymerase and has demonstrated in vitro activity against various viruses including Ebola, SARS-CoV, and Middle Eastern respiratory syndrome (MERS-CoV). More recently, remdesivir has demonstrated potent activity against SARS-CoV-2 in in vitro and animal model studies, and holds some promise for treatment of COVID-19.^2,3 A recent case series describing the compassionate use of remdesivir in 61 adult hospitalized patients with COVID-19 demonstrated that 68% of patients experienced an improvement in the need for oxygen support over a median 18 day follow-up period, while 15% of patients clinically worsened. Clinical improvement was observed in 84% of patients, but was less frequent among older patients (70 or older vs less than 50), and in patients who were on invasive ventilation compared with patients on noninvasive ventilator support. Mortality occurred in 13% of patients, with older patients (70 or older) and patients with higher baseline serum creatinine demonstrating a higher risk. Adverse events were reported by 60% of patients, most commonly increased hepatic transaminases (23%), diarrhea (9%), rash (8%), renal impairment (8%) and hypotension (8%).⁴ The lack of a comparator control arm is a significant limitation to the interpretation of the data presented in this compassionate use experience.

On April 29, 2020, the National Institutes of Health released a statement regarding promising preliminary data from the ongoing randomized Adaptive COVID-19 Treatment Trial involving 1,063 patients. According to the interim analysis, preliminary data suggest that remdesivir conferred a 31% faster median time to recovery compared with placebo of 11 days in the remdesivir group vs 15 days in the placebo group (P < 0.001) and mortality of 8% in the remdesivir group vs 11.6% in the placebo group (P = 0.059).⁵ On the same day, the maker of remdesivir (Gilead Sciences, Inc.) also released a statement regarding their open-label phase III SIMPLE trial that demonstrated similar rates of clinical improvement with a 5-day treatment course of remdesivir therapy compared with a 10-day treatment course.⁶ Both studies are pending complete data analysis and peer review. Finally, a randomized placebo-controlled trial of 236 adult hospitalized patients with COVID-19 in Wuhan, China, was also published on April 29, 2020. Contrary to the press releases for the aforementioned studies, this study demonstrated no significant difference in time to clinical improvement (21 days for remdesivir vs 23 days for placebo) or 28-day mortality (14% for remdesivir vs 13% for placebo). In a subgroup of patients initiated on treatment early (ie, within 10 days of symptom onset), time to clinical improvement was 18 days for remdesivir vs 23 days for placebo and 28-day mortality was 11% for remdesivir vs 15% for placebo, although the differences were not statistically significant. Of note, enrollment in this trial was terminated early due to achievement of infection control in China, thus the sample size may represent a limitation of this study.⁷

Remdesivir is currently still undergoing rigorous evaluation in multiple phase III randomized clinical trials as a possible treatment option for COVID-19. On May 1, 2020, the US Food & Drug Administration (FDA) issued an emergency use authorization (EUA) for remdesivir for the treatment of patients hospitalized with COVID-19. Logistics on medication access through the EUA are still in process between Gilead and the United States government. Currently, remdesivir is only available in the US through one of the clinical trials, a compassionate use program reserved for pediatric and pregnant hospitalized patients, and eventually through the EUA.

LOPINAVIR/RITONAVIR (KALETRA)

Lopinavir/ritonavir is a combination antiretroviral drug comprising 2 protease inhibitors. Lopinavir, the primary agent, acts through viral protease inhibition and ritonavir inhibits CYP3A4-mediated metabolism of lopinavir thus increasing its plasma concentrations. Currently approved by the FDA for the treatment of HIV, lopinavir/ritonavir was studied as an antiviral agent in both the SARS and MERS outbreaks due to demonstrable in vitro activity against both coronaviruses.^8,9 In SARS, patients who received lopinavir/ritonavir (often in combination with ribavirin and corticosteroids) compared with historical controls had lower mortality rates, lower mechanical ventilation requirements, required less rescue corticosteroid treatment, and had lower viral loads after treatment.^9,10

In light of these findings in SARS, lopinavir/ritonavir was evaluated in patients with COVID-19. Of note, there are no in vitro studies of lopinavir/ritonavir against SARS-CoV-2. In March 2020, a randomized, controlled, open-label trial comparing lopinavir/ritonavir (400 mg and 100 mg, respectively) twice daily for 14 days vs standard care in 199 hospitalized patients with COVID-19 at a single hospital in China demonstrated no statistically significant difference in the primary outcome of time to clinical improvement (hazard ration [HR] 1.39; 95% confidence interval [CI] 1.00 to 1.91).¹¹ Furthermore, mortality rates were not significantly different in the cohort of patients who received lopinavir/ritonavir (19.2% vs 25.0%; 95% CI –17.3 to 5.7). There was no difference between groups for detection of viral RNA over time. Based on these findings, the authors concluded that no benefit was observed with lopinavir/ritonavir treatment in COVID-19 beyond standard care.

Moreover, lopinavir/ritonavir is associated with many adverse reactions (Table 1) and drug interactions due to the strong inhibition of CYP3A4. In fact, 48% of patients who received lopinavir/ritonavir for COVID-19 experienced adverse reactions, most commonly gastrointestinal effects. Of these, 19 events were noted to be serious, and 13 patients discontinued the drug due to adverse reactions.¹¹ Overall, based on the lack of supportive data for its use in COVID-19, its adverse effect profile and significant drug interactions, lopinavir/ritonavir for COVID-19 should be reserved for use only in the context of a clinical trial.¹²

OTHER ANTIVIRAL AGENTS

Various other antiretrovirals such as darunavir-based regimens have also been purported to have in vitro activity against SARS-CoV-2. However, there are no human clinical data on the utility of these agents in the management of COVID-19.¹³ Johnson & Johnson, the makers of darunavir/cobicistat (Prezcobix) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (Symtuza), recently published a statement on the lack of evidence to support the use of darunavir-based treatments for SARS-CoV-2.¹⁴ Furthermore, 1 of 3 randomized, open label clinical trials evaluating darunavir/cobicistat for COVID-19 recently concluded that the agent was not effective at achieving viral clearance at day 7 post-randomization compared with standard care.¹² The neuraminidase inhibitor antiviral oseltamivir was used empirically in several patients during the COVID-19 outbreak in China due to the overlap with peak influenza season. However, oseltamivir has no documented in vitro activity against SARS-CoV-2 and is not expected to play a role in the management of COVID-19.¹³

Umifenovir (Arbidol), a viral envelope membrane fusion inhibitor, is an influenza antiviral agent available in Russia and China with suggested in vitro activity against SARS. An observational study from China of 67 patients with COVID-19 demonstrated lower mortality rates and higher discharge rates among 36 patients treated with umifenovir versus the umifenovir-untreated group.¹⁵ Conversely, in another retrospective study from China of 81 hospitalized (not in an intensive care unit) patients, umifenovir failed to demonstrate a reduction in the proportion of patients testing negative for SARS-CoV-2 within 1 week of admission (73% umifenovir vs 78% control, P = 0.19), or hospital length of stay compared with standard of care.¹⁶ Of note, patients in the umifenovir group had higher baseline chest computed tomographic scan scores based on an ordinal scoring tool. Although median time from admission to first negative test was longer in the umifenovir group (6 days vs 3 days, P < 0.05), the median time from onset of disease to first negative test was comparable with the control group (18 days vs 16 days, P > 0.05). Randomized controlled trials of the utility of umifenovir in COVID-19 are still lacking. Similarly, favipiravir (Avigan), a purine nucleotide RNA polymerase inhibitor that is available in Japan for treatment of influenza, has also demonstrated in vitro activity against SARS-CoV-2.^2,13 In a randomized study comparing favipiravir with umifenovir in 240 patients with moderate and severe COVID-19, favipiravir demonstrated higher clinical recovery rates at day 7 in moderate illness but failed to demonstrate any difference in severe illness.¹⁷ Ongoing clinical trials evaluating these and other antiviral agents for COVID-19 are described in Table 1.