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HIV Program and Division of Infectious Diseases
Brigham and Women's Hospital
Professor of Medicine
Harvard Medical School
Paul E. Sax, MD, has disclosed that he has served as a consultant or on a scientific advisory board for Gilead Sciences, GlaxoSmithKline/ViiV, Janssen, and Merck and has received funds for research support Gilead Sciences, GlaxoSmithKline/ViiV, and Merck.
Since COVID-19 vaccines first became available, much of the public attention has focused on the vaccines and issues about vaccination, and rightly so—they are our best way out of the pandemic. But research on COVID-19 treatments has been ongoing all the while, which remains important both because not everyone has been vaccinated, some immunocompromised people won’t respond to the vaccines, and the vaccines are not 100% effective even under optimal circumstances. Before we get into what’s new on the treatment horizon, let’s recap what we have now for COVID-19.
Current guidance from the expert societies and organizations supports the use of drugs that suppress an overactive immune response to SARS-CoV-2 in severe and/or critical disease. Ironically, for a viral disease, these options outnumber those that directly target the virus. These immunomodulators include dexamethasone or other available corticosteroids, the IL-6 inhibitors tocilizumab and sarilumab, and the JAK inhibitors baricitinib and tofacitinib. All are indicated in hospitalized patients with moderate to severe disease.
Also available for hospitalized patients is remdesivir, a repurposed antiviral approved by the FDA under Emergency Use Authorization for treatment of severe COVID-19.
Studies of remdesivir in patients hospitalized with severe disease have yielded mixed results, hence the lack of consensus among expert societies and organization on its use (Wang Lancet 2020; WHO Solidarity NEJM 2021; Ader Lancet 2021).
Supportive of remdesivir use are the double-blind ACTT-1 trial and several observational studies; the former showed that treatment started earlier after onset of symptoms was associated with greater benefits.
New retrospective, propensity-matched data analyses of remdesivir in patients hospitalized with COVID-19 were presented at the World Microbe Forum in June 2021 (Chokkalingam iPoster#WMF21-297; Go iPoster #WMF21-2969; Mozaffari iPoster #WMF21-2507). The results were consistent with the final results of the double-blind, placebo-controlled ACTT-1 trial, which demonstrated a reduction in mortality that achieved statistical significance in the subgroup of patients receiving low-flow oxygen at baseline (4% vs 13%; HR: 0.30; 95% CI: 0.14-0.64) and starting remdesivir within 2 days of hospitalization.
In summary, these newer data support what we’ve been doing for hospitalized patients, with ongoing trials on the use of remdesivir in combination with other agents.
But what about treatment for outpatients? Monoclonal antibodies against SARS-CoV-2 are useful in certain populations to treat COVID-19 in its early stages or even to prevent COVID-19 post exposure. Antibody therapies for COVID-19 were previously discussed in this program, so we won’t go into further detail here, except to say that monoclonal antibody therapy is quite resource intensive, requiring administration by a healthcare professional, a site that can handle COVID-19 infection control risks, and a 1-hour observation period afterwards.
Another Repurposed Drug in the Future?
Since the start of the pandemic, there has been intense interest in the use of repurposed drugs for the treatment of COVID-19. The benefit of this approach is that most of these medications are already approved by the FDA and have an established safety profile. Many are oral drugs that are also quite inexpensive, with readily available generic formulations. The negative studies (and controversies) over hydroxychloroquine, azithromycin, zinc, ivermectin, and others may lead us to think that this is too good to be true. But we shouldn’t give up on repurposed drugs just yet.
Enter fluvoxamine, a long off-patent antidepressant (frequently used for obsessive–compulsive disorder) that has quietly been going through high-quality clinical studies for treatment of COVID-19. The results definitely now deserve our attention. Here’s why I think we might finally be onto something, even after stumbling numerous times with other “repurposed” drugs.
First, there is a legitimate mechanism of action—actually, multiple mechanisms, as it has anti-inflammatory, antiplatelet, and potentially antiviral activity independent of its psychoactive properties. But, of course, many drugs have in vitro mechanisms of action that don’t pan out.
Second, there have been several well-designed and conducted studies that showed benefit.
Lenze and colleagues published a small double-blind clinical trial of fluvoxamine for COVID-19. Out of 152 participants enrolled, clinical deterioration occurred in 0 patients treated with fluvoxamine vs 6 (8.3%) patients treated with placebo, a difference that was statistically significant. But, of course, the impact of these results is limited by the very small sample size, and the authors appropriately concluded that further larger studies were necessary.
Then came another observational study of opt-in versus opt-out fluvoxamine among newly infected workers at a horse racing track. Despite having more symptoms at baseline, the opt-in group receiving fluvoxamine had better outcomes than those who declined treatment—specifically, 0/65 hospitalizations in the fluvoxamine group vs 6/48 in those who chose observation only.
But the observational nature of this study also couldn’t provide a high enough level of evidence to change practice. What if the people choosing fluvoxamine were just more “health seeking”—and thereby, healthier—than those who declined, biasing the result?
Still, these studies received enough attention to warrant further research, including the innovative TOGETHER trial, led by a multinational group of investigators primarily in Canada and Brazil. TOGETHER randomized 1480 adults with confirmed COVID-19, ≥1 risk factor for disease progression, and recent onset of symptoms (<7 days) to receive fluvoxamine (n = 742) or placebo (n = 738). Here’s where it gets exciting: At an interim report to the National Institutes of Health (NIH), lead investigator Dr. Edward Mills reported that fluvoxamine reduced the risk of disease progression by 29% (relative risk: 0.71; 95% CI: 0.54-0.93). Most of the secondary endpoints also favored fluvoxamine, although the differences were not always statistically significant given the smaller event rate. No data on safety were presented, but Dr. Mills verbally stated that there were no unexpected toxicities.
No, an interim analysis of an ongoing study is not enough to change treatment guidelines—but it’s getting close, especially given the paucity of other options and the favorable safety profile. The results were strong enough for the investigators to stop this comparison in this study, and a preprint and submitted paper should be coming soon for further review.
We’ve all been burned by promising studies of these repurposed drugs, and it’s quite reasonable to reserve final judgment until we see the complete data and even other studies. So keep your eyes out― the University of Minnesota COVID-OUT study and the NIH’s ACTIV-6 study include fluvoxamine arms.
Would fluvoxamine effects be additive with monoclonal antibodies, which we know work well in early disease but remain expensive, limited in availability, and cumbersome to administer? Should fluvoxamine be tried in combination with remdesivir, especially for those requiring oxygen, for whom anti-inflammatory approaches seem most beneficial?
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