emDOCs.net Podcast – Episode 3: COVID-19 Therapies Update

Welcome to emDocs cast with Brit Long, MD (@long_brit) and Manpreet Singh, MD (@MprizzleER)! The goal of this podcast is for us to briefly review some of the high-yield posts from the site, which we hope you will read in more detail below.

This episode covers therapies in COVID, first looking at antivirals, and second, at hydroxychloroquine (HC) and chloroquine (CQ). The original antiviral post was released on March 30 and the HC and CQ post on April 6. Needless to say, there have been several significant updates in the literature concerning these agents. The details of all studies discussed in the podcast are below in the post. Keep in mind that the literature with COVID-19 is constantly changing…

Antivirals

Antiviral medications have become one of the main focuses of potential treatment options. These include remdesivir, liponavir and ritonover, and interferon beta-1b and ribavirin.

Remdesivir:

Remdesivir is a nucleotide analogue RNA polymerase inhibitor that has previously been tested in a limited number of patients with Ebola, SARS-CoV-1, and MERS.

Observational study: Grein et al. published a case series of 61 patients and found clinical improvement in 36 patients (1). There were many limitations, including no control group, unclear patient selection (and inclusion of what seems to be healthier patients), very poor information about the patients included, and no clear primary endpoint.

RCT: Wang et al. included 158 receiving remdesivir versus 79 receiving placebo and found no difference in clinical improvement and no impact on viral load (2). This study was also stopped early.

The ACTT-1 trial was released on May 22, 2020 (3). It included patients from 60 sites with COVID-19 and radiographic pulmonary infiltrates, oxygen saturation < 94% or requiring supplemental oxygen, or mechanically ventilated or ECMO patients. Patients were excluded if LFT > 5 times ULN, impaired renal function via eGFR (though they don’t provide a specific cutoff value), hemodialysis/hemofiltration, pregnant, breast feeding. Patients received remdesivir vs. placebo. Primary outcome included time to clinical recovery, with patients receiving remdesivir demonstrating median time to recovery of 11 days vs. 15 days with placebo. Mortality was assessed at 14 days, but there is not enough high quality data with this study do demonstrating a definitive reduction in mortality. Subgroup analyses were also under-powered. There was no increase in harm with remdesivir. There are some limitations, including missing data: lab results, viral load, and most importantly, renal function. For more, see this great PulmCrit post from Josh Farkas.

Liponavir and Ritonovir:

Lopinavir is a protease inhibitor for HIV, and ritonovir is a CYP inhibitor that increases lopinavir bioavailability. This combination drug has typically been used to treat HIV and has demonstrated in vitro effects on MERS and SARS-CoV-1.

RCT: Cao et al. published an open-label, single center RCT which included 199 patients with positive PCR for COVID-19, pneumonia on imaging, and oxygen saturation of <94% (4). Patients were randomized to treatment versus standard care. The treatment group failed to demonstrate an improvement against standard care in time to clinical improvement, mortality, or percentage of patients with detectable viral RNA at various time points. There were many limitations including no treatment until day 13 of illness, authors were able to exclude patients if “treatment was not in their best interest”, and there was no blinding. Mortality rate was 22% overall, which is much higher than many other studies.

Combination therapy: interferon beta-1b, lopinavir-ritonavir, and ribavirin

RCT: Hung et al. published a multicenter, open label RCT which recruited 127 patients who presented within 14 days of symptoms. Authors evaluated the combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin versus lopinavir-ritonavir, with no placebo group (5). The primary outcome was time to negative nasopharyngeal swab, with secondary outcomes including time to resolution of symptoms, hospital length of stay, mortality at 30 days, daily viral load changes in the first 7 days, and frequency and duration of adverse events (nausea and diarrhea). The combination treatment group demonstrated shorter time to negative nasopharyngeal swab, time to alleviation of symptoms, hospital length of stay, and time to negative viral load. There was no difference in adverse events. However, there was unclear consecutive enrollment, the primary outcome is not patient centered, it was open label, and there were no critically ill patients. Importantly, the median time from symptom onset to the start of treatment was 5 days.

Bottom Line:

While remdesivir and combination therapy may be promising, we need high quality RCT data that includes patients earlier in the disease course when viral replication occurs.  Currently, the IDSA states these agents should not be used outside of a clinical trial (6).

Hydroxychloroquine and Chloroquine

There was initially a great deal of support for HC and CQ, but more recent evidence suggests harm with no benefit. These medications alter intracellular endosomal pH and are thought to reduce viral replication.

Observational: An initial study released in March stated CQ was safe and effective in China (7). Two observational studies released in France found improved viral clearance, but as discussed in the emDocs post released on April 6, there are some major issues (8,9). The first observational study primarily looked at viral clearance on day 6, with no patient centered outcomes, and the second had no control group. Significant bias, lack of adequate controls, poor blinding, and many other problems severely limit the clinical implications.

A chart review of 368 patients admitted in the U.S. found higher rates of death in patients receiving HC compared to those who were not (28% vs. 11%) (10). Another observation study including 1376 patients in New York City found those receiving HC did worse, but with propensity matching, authors did not find a difference in time to death or intubation (11).

Prepublication RCT: A study in Chinese, not released in English, compared 30 patients receiving HC to standard care and found no difference in viral swabs or patient outcomes (12). A second study included 62 adults with COVID-19. This study was not blinded, included patients with mild disease, and had a primary outcome of time to clinical recovery (no fever and no cough for 72 hours) (13). Authors found 1 day faster time to clinical recovery with HC, but there were several issues. The study was stopped early, there was no placebo, and while authors state randomization was to be stratified by site, there was only one center involved.

RCT: An open label trial of 150 patients (75 received HC and 75 standard care) with mild COVID-19 found no difference in symptoms or rates of negative conversion, but significant increases in adverse events (30% vs. 9%) with therapy (14). A double blind RCT in Brazil found higher mortality in patients receiving HC, necessitating study discontinuation (15).

Bottom Line:

Currently, the IDSA only recommends use in the setting of a clinical trial. However, it is difficult to discount the significant harms found in several of the higher quality studies, with no demonstrable positive outcome.

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References:

1. Grein J, Ohmagari N, Shin D, Diaz G. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl Journ Med. Published April 10, 2020. DOI: 10.1056/NEJMoa2007016
2. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. April 2020. doi:10.1016/s0140-6736(20)31022-9
3. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report. N Engl J Med. Published online May 22, 2020. doi:10.1056/nejmoa2007764
4. Cao B, Wang Y, Wen D, et al.A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19[published online ahead of print, 2020 Mar 18]. N Engl J Med. 2020;10.1056/NEJMoa2001282. PMID: 32187464
5. Hung IF-N, Lung K-C, Tso EY-K, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial.The Lancet. Published online May 2020. doi:10.1016/s0140-6736(20)31042-4
6. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Mar 16;14(1):72-73.
7. Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 Infection. Published April 11, 2020. Available at https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
8. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20.
9. Gautret P, Lagier J, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study. Available at https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf
10. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. 2020. Not published.Available preprint here.
11. Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 N Engl J Med. 2020; [article]
12. Jun C, Danping L, Li L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). JOURNAL OF ZHEJIANG UNIVERSITY. Available at http://subject.med.wanfangdata.com.cn/UpLoad/Files/202003/43f8625d4dc74e42bbcf24795de1c77c.pdf
13. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. doi:https://doi.org/10.1101/2020.03.22.20040758Available at https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3
14. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. 2020. Not published.Available preprint here.
15. Borba MGS, Val FFA, Sampaio VS, et al. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). 2020. Not published.Available preprint here.