In This Article
- The most effective treatment strategy for patients with COVID-19 remains unknown
- The primary targets of therapies currently under investigation are viral replication and the inflammatory response
- Numerous clinical trials are ongoing around the world
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Most therapies being tried for COVID-19, the disease caused by the novel coronavirus SARS-CoV-2, have one of two purposes: to stop viral replication or dampen the elevated pro-inflammatory state.
Robert Hallowell, MD, director of the Pulmonary Clinic at Beth Israel Deaconess Medical Center, discussed leading drug and therapeutic candidates during Massachusetts General Hospital's virtual Medical Grand Rounds on March 26, 2020. The meeting was a joint presentation of Mass General, Beth Israel and Brigham and Women's Hospital.
Remdesivir is an investigational nucleoside analog that inhibits RNA polymerase. The intense excitement generated in the lay media is based on an in vitro study published in the Journal of Biological Chemistry, in which remdesivir was cytotoxic to SARS-CoV-2. A multisite clinical trial for the treatment has started nationally, including at Mass General. No clinical trial data are available yet.
Chloroquine showed inhibitory effects when primate cells were treated either before or after exposure in a study of SARS-CoV (the coronavirus responsible for the SARS epidemic of 2002–2003), published in Virology Journal. In addition to well-known mechanisms of action such as elevating endosomal pH, chloroquine appeared to interfere with the glycosylation of angiotensin-converting enzyme 2 (ACE2), the cellular receptor. That may have blocked the virus from binding to the receptor, thereby preventing infection. ACE2 is also the cellular receptor for SARS-CoV-2.
Hydroxychloroquine, a less toxic derivative of chloroquine, and chloroquine were recently studied in vitro against SARS-CoV-2. The results, published in Cell Discovery, were very promising: both drugs blocked the transport of SARS-CoV-2 from endosomes into endolysosomes, which appears to be a requirement to release the viral genome.
The International Journal of Antimicrobial Agents has published the only clinical study to date of hydroxychloroquine for COVID-19. The results were heartening in terms of viral load reduction. Caveats are that only 26 patients received hydroxychloroquine, six of whom were lost to follow-up, the trial was not randomized or double-blinded, there were no controls and the results were not adjusted for initial viral load.
For more information on the therapeutic potential of hydroxychloroquine and chloroquine as a potential treatment, please read the Q&A with Raghu Chivukula, MD, PhD.
Statins — Acute respiratory distress syndrome (ARDS), the primary cause of death in COVID-19, can be divided into two distinct subphenotypes: hypo-inflammatory and hyper-inflammatory. The Lancet Respiratory Medicine published a secondary analysis of a multicenter, randomized trial of simvastatin for ARDS and showed that the drug significantly improved 28-day survival compared with placebo, but only in the hyperinflammatory subtype.
The question is whether that data can be extrapolated to patients with COVID-19, who have elevated levels of interleukin-6 (IL-6) and other inflammatory markers, as described in a companion piece from this grand rounds.
Tocilizumab and sarilumab are monoclonal antibodies that block IL-6 on both soluble and membrane-bound receptors. Some of the excitement about these agents came from a small trial in China, in which 21 patients with severe ARDS received tocilizumab. According to preprint data, most had an instantaneous decrease in their temperature and substantially reduced levels of C-reactive protein. Mass General is part of a multicenter trial testing sarilumab.
More than 130 clinical trials of potential therapies for COVID-19 are currently underway, investigating everything from thalidomide to corticosteroids, sildenafil, anti-PD-1 immunotherapies, intravenous immunoglobulin and stem cells. The most effective treatment strategy clearly remains unknown, and clinicians should take care not to rush to judgment.
The grand rounds session also included a presentation by Ari Moskowitz, MD, of Beth Isreal Deaconess Medical Center, about managing respiratory distress in patients with COVID-19.
Massachusetts General Hospital has made its guidance for treating COVID-19 outpatients and inpatients publicly available. All documents are subject to revision.
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