COMMENTARY

Ivermectin or Fluvoxamine for Outpatient Treatment of COVID-19

Charles P. Vega, MD

Disclosures

April 15, 2021

This transcript has been edited for clarity.

Hello. I'm Chuck Vega, a clinical professor of family medicine from the University of California, Irvine, School of Medicine. Today I'll be speaking about some recent trials among outpatients with drugs repurposed for COVID-19 therapy.

We've all been looking for better therapeutic options for COVID-19, particularly in the outpatient realm, where most of our patients with the infection are being treated. So I was intrigued by the use of a couple of particular agents: ivermectin and fluvoxamine. These agents have captured our consciousness and our imaginations, and they have been used fairly frequently in both the inpatient and outpatient settings for the treatment of COVID-19. But what's the evidence for the use of these agents?

Ivermectin

Ivermectin is an antiparasitic agent, typically used for Strongyloides infections, but it also has in vitro antiviral actions. The question is whether we can get the levels of ivermectin in vivo up to the point where they can reduce viral replication. There's some research that supports the use of ivermectin in COVID-19 that says yes, this may be the case. We can actually make this drug effective.

A retrospective review of 280 patients hospitalized with COVID-19 at four Florida facilities looked at patients who had received ivermectin. This study was done earlier in the pandemic; most of the patients received hydroxychloroquine, which we wouldn't use now. But it was a fairly sick group of patients with a median age of 56 years, and 55% of the cohort was Black. One fourth had severe pulmonary disease.

Comparing patients who received ivermectin with those who received usual care, there was no difference in terms of length of hospital stay or rates of extubation, but they found a significant and profound difference in mortality risk — the odds ratio was 0.27 in the ivermectin group. Moreover, folks with more severe illness were more likely to benefit from ivermectin therapy.

In addition, there is an unpublished, randomized controlled trial in 180 hospitalized patients that similarly found not only a reduced risk for mortality associated with ivermectin, but also shorter length of hospital stay. So, there's some smoke there suggesting that ivermectin might be effective, particularly for inpatients with COVID-19.

The only randomized controlled trial of ivermectin treatment for COVID-19 was done at a single site in Colombia, including 400 patients with mild symptoms of COVID-19 of less than 7 days' duration. They were randomized to receive ivermectin, 300 µg/kg for 5 days, or placebo. They had trouble matching placebo at the outset of study because ivermectin has a certain smell and taste. But they overcame that to a certain degree because only one person per household was allowed to participate in the study until they received placebo. So patients sharing a household couldn't compare the taste or feel of the treatment they were taking, giving clues as to who was receiving ivermectin and who was receiving placebo.

In this randomized study, the median age of the cohort was 37 years, 58% were women, 79% had a comorbidity, and 58% were treated at home. Overall, they found no difference comparing ivermectin and placebo. The average time to resolution of symptoms was 10 days in the ivermectin group and 12 days in the placebo group. The findings were similar when looking at clinical deterioration and care escalation (including hospital admission); these were fairly rare, less than 5% overall, with no difference between the ivermectin and placebo groups.

To summarize the evidence for ivermectin, there is a negative randomized controlled trial of ivermectin in patients with mild to moderate COVID-19 infection, and some weak observational data suggesting that ivermectin may be effective for patients who are hospitalized with COVID-19. Overall, however, there is no indication that we should be routinely using ivermectin for COVID-19 at this point. And it's worth noting that the US Food and Drug Administration (FDA), the World Health Organization (WHO), and even the drug manufacturer have all recommended against the use of ivermectin in COVID-19.

Fluvoxamine

The other agent I want to mention is fluvoxamine. This is a selective serotonin reuptake inhibitor that is used for depression. It's cheap and well tolerated, so it could have broad application. It does have some cytochrome p450 interaction, which is always something to be concerned about, but it doesn't appear to prolong the QT interval. Also, it has some effects in endoplasmic reticulum in terms of reducing cytokine production. The question is whether this drug could potentially help with the pathology of COVID-19, which involves an excess of inflammation.

A cohort study was completed at a California worksite where there was an outbreak of COVID-19. A broad group of workers were tested for SARS-CoV-2. Those who were positive were offered fluvoxamine (either a 50-mg or 100-mg loading dose, followed by 50 mg twice daily for 14 days) or usual care (observation group).

There were 113 positive tests, and half of these positive cases were asymptomatic. Only 65 participants opted to receive fluvoxamine, and 48 declined. Those who got fluvoxamine tended to be more symptomatic. They also had higher rates of diabetes. Fluvoxamine was associated with better outcomes in this study in terms of rates of hospitalization (0% in the fluvoxamine group and 12.5% in the observation group) and persistence of symptoms (none of the fluvoxamine group and 60% of the observation group). This wasn't a methodologically rigorous trial, but it still demonstrates some positive results for fluvoxamine.

A randomized controlled trial of fluvoxamine, conducted exclusively in telehealth patients, has been published as well. It's interesting because it reflects how we take care of patients with COVID-19. Most of the study patients had mild COVID-19, with symptoms less than 7 days' duration. All had an oxygen saturation above 91%. They were randomized either to fluvoxamine (100 mg three times daily) or placebo for 15 days. The outcomes they were looking at were hospitalization rates, shortness of breath, a need for supplemental oxygen, or falling oxygen saturations (< 92%).

Among the 152 adults who were randomized, the median age was 46 years, 76% were women, 25% were Black, and 76% completed the trial, with 24% dropping out. But there was a significant improvement in the fluvoxamine vs the placebo group in the broad outcome of clinical deterioration (0% in the fluvoxamine group and 8.3% in the placebo group). There was no difference in the rate of emergency department visits, but fluvoxamine was associated with a lower rate of side effects vs placebo. This study had some limitations. It was done at one geographic location, and it looked at a small number of outcomes. One in 5 patients dropped out by day 15.

Here are my takeaways from the clinical data on these two drugs for the treatment of COVID-19. There's some weak evidence that ivermectin reduces mortality in patients hospitalized with COVID-19, but among outpatients, the trial with ivermectin failed to demonstrate that it was effective for improving symptoms or preventing clinical deterioration.

Fluvoxamine has some support from a randomized, controlled trial among outpatients with COVID-19. But the authors of that study concluded that their results were more hypothesis-generating than a clear call that this is an effective treatment. More studies need to be done with fluvoxamine. But it is intriguing, and I look forward to seeing those studies and hopefully sharing the findings. Thanks for your attention, and be well.

Charles Vega is a clinical professor of family medicine at UC Irvine and also serves as the UCI School of Medicine assistant dean for culture and community education. He focuses on medical education with an intent to resolve health disparities.

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