BACKGROUND

In the phase 1–2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern.

METHODS

In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated.

RESULTS

Covid-19–related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P=0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody–positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was −0.71 log₁₀ copies per milliliter (95% confidence interval [CI], −0.90 to −0.53) in the 1200-mg group and −0.86 log₁₀ copies per milliliter (95% CI, −1.00 to −0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups.

CONCLUSIONS

REGEN-COV reduced the risk of Covid-19–related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629. opens in new tab.)

It would be nice if there is something that you could take orally at home.  Here is an article from the New York Times on two new drugs to treat Covid 19 as an ouptatient.  The Merck drug soesn’t sound that good, but the Pfizer drug is very promising.  Merck’s drug has been approved by the FDA, but the vote was 13 to 10.

For body and mind

 

A new generation of Covid-19 treatments will soon be available, and they matter more than many people realize.

They have the potential to substantially reduce hospitalization and death. And they are likely to be effective against the Omicron variant, many scientists believe, even if Omicron makes the Covid vaccines weaker at preventing infections. As Dr. Monica Gandhi of the University of California, San Francisco, told me, the treatments are “a huge deal.”

 

In the simplest terms, they can help turn Covid into a more ordinary respiratory disease, similar to the common cold or flu, rather than one that’s killing about 1,000 Americans a day and dominating daily life for millions.

Two treatments are on the way — one from Pfizer and one from Merck — and they will have both medical and psychological benefits. Not only can they reduce serious Covid illness, but they can also reduce Covid fears and help society move back to normalcy, lessening the pandemic’s huge social and economic side effects.

 

Both Pfizer’s and Merck’s treatments are pill regimens that people take for five days after a positive Covid test. The pills prevent the virus from replicating inside the body and are broadly similar to treatments that revolutionized H.I.V. care in the 1990s.

 

Pfizer’s version, which is likely to become widely available early next year, appears to be the more effective: It reduced the risk of hospitalization or death by 85 percent in a research trial. Merck’s version, which should be available sooner, reduced risk by 30 percent.

An F.D.A. panel of experts this week voted narrowly — 13 to 10 — to recommend the approval of the Merck treatment. The agency has not yet said when its experts might vote on Pfizer.

 

“These will be game-changing for our ability to control Covid worldwide in 2022,” Gandhi said.

Pandemic side effects

 

In truth, the virus has already been largely defanged for most Americans, and it would be surprising if Omicron changed that. The death rate for vaccinated adults under 50 is virtually zero, according to data from Minnesota and King County, Wash. (which publish detailed statistics); the hospitalization rate is similar to that of a typical flu. For children, vaccinated and not, the risks are even smaller.

But I know that many Americans remain terrified of Covid. After nearly two years of pandemic living, returning to normal can be hard, especially with the genuine uncertainty about Omicron. Once the treatments are widely available, they can offer reassurance, as a last line of defense against severe Covid.

 

Of course, the medical benefits will be even bigger than the psychological benefits for people who remain vulnerable to Covid.

Deaths are predominantly occurring among the unvaccinated, although vaccinated Americans older than 65 — especially those with existing medical problems — are also at some risk. So are a small percentage of younger Americans, like those who have had an organ transplant or are receiving some cancer treatments. (Find the death rate for any county.)

 

One major advantage of the pills is that people can take them at home. Current Covid treatments, like monoclonal antibodies, are typically administered in a hospital.

Another advantage is that they do not attack the part of the virus that changes most with each new variant: the spike protein. That’s why scientists expect the treatments will work even as the virus evolves.

 

30 pills, 5 days

 

Pfizer has projected that it will produce enough doses to treat 20 million people in the first half of next year and another 60 million in the second half. The Biden administration has agreed to buy 10 million of the treatments, known as Paxlovid, at a cost of about $530 each. Americans will probably not have to pay much, if anything, out of pocket.

As a rough sense of scale, 10 million treatments would have covered every American 65 and above who tested positive for Covid in the past year — with millions of doses left over.

 

Merck projects that it will produce more than 10 million courses of its drug, called molnupiravir, by the end of this year, and at least 20 million more in 2022. The federal government has agreed to buy 3.1 million of those courses for around $700 each. A Merck spokesperson said that the government would provide the drug to patients for free.

Both treatments will present logistical challenges. People will likely need to prove that they have tested positive for Covid and then receive a doctor’s prescription. At least for the next several months, only vulnerable people — those who are older or have medical conditions — may be eligible. And the treatments involve a detailed schedule of pill-taking: three pills, twice a day, for five days, in Pfizer’s case, and two additional pills per day in Merck’s case.

 

Ideally, the treatment should begin within five days of the first Covid symptoms.

For people who can get access to the pills and take them as prescribed, they may make all the difference. In Pfizer’s research trial, the treatment reduced the risk of hospitalization by about 90 percent among people who started it within three days of having symptoms. There were zero deaths among the patients who received it.

 

“These treatments are not going to single-handedly end the pandemic, nor are they going to be anywhere near as impactful as vaccines,” Rebecca Robbins, who covers pharmaceuticals for The Times, told me. “But if they can reach people fast enough, and that’s a big if, they have very real potential to save lives and ease the burden on hospitals.”

Finally, here is a summary from Up To Date.  It is a very comprehensive overview.

COVID-19-specific therapy — The most promising treatments evaluated in outpatients with nonsevere COVID-19 include monoclonal antibody therapy and novel antiviral agents.

Monoclonal antibodies have shown a benefit for patients with certain risk factors for severe disease. However, availability may be limited, the agents require parenteral administration, and they must be given early in the course of illness; these factors make administration operationally complicated in many outpatient settings. (See ‘Monoclonal antibodies’ below.)

Monoclonal antibodies

●Monoclonal antibody therapy – Monoclonal antibodies that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to be evaluated in outpatients with mild to moderate disease, and trial results suggest a benefit from these agents [85-87]. In the United States, the following monoclonal antibody therapies are available through emergency use authorization (EUA) for select outpatients at risk for severe disease (table 5):

 

•Casirivimab-imdevimab (600-600 mg, administered as a single intravenous [IV] dose [preferred], although may be given subcutaneously if IV is not feasible or would delay treatment)

 

•Sotrovimab (500 mg, administered as a single IV dose)

 

•Bamlanivimab-etesevimab (700-1400 mg, administered as a single IV dose). Authorization of this combination had previously been suspended because of variants with likely resistance; however, it has since been reinstated with decline in prevalence of those variants [88].

 

For patients with early, symptomatic COVID-19 who have risk factors for progression to severe illness (table 5), we suggest monoclonal antibody therapy. The choice among monoclonal antibody options depends on local availability. According to the EUA, monoclonal antibody treatment should be given as soon as possible after diagnosis and within 10 days of symptom onset; we favor administering it within seven days. Although direct data on timing of monoclonal antibody therapy are limited, indirect evidence from studies of convalescent plasma suggest that benefit is maximized with early administration.

 

An important additional practical consideration is that the resources and supporting infrastructure required for administration may divert resources from other COVID-19 care efforts and may favor use in resource-rich over resource-limited communities. Thus, it is essential that equitable access to these treatments be ensured.

 

Our approach is largely consistent with that of other expert groups including the National Institutes of Health (NIH) treatment guidelines panel and the Infectious Disease Society of America (IDSA), which recommend treatment with monoclonal antibody therapy in high-risk groups as defined by the EUA criteria outlined below [89,90], with consideration of the local prevalence of viral variants and the potential for resistance.

 

The NIH and CDC suggest that administration of monoclonal antibodies be prioritized for those at highest risk for progression to severe disease, and that when supplies of these agents are limited and triage decisions are necessary, patient vaccination status in addition to underlying risk factors be considered [91,92]. Limited observational data suggest that administration of monoclonal antibodies in fully vaccinated outpatients with symptomatic COVID-19, particularly those with multiple risk factors for severe disease, is associated with a reduced risk for hospitalization [93]. When supplies or resources are limited, we agree with the NIH treatment guidelines panel to prioritize monoclonal antibody therapy for individuals who are likely to have a suboptimal response to vaccination (ie, immunocompromised patients) and for individuals who are not fully vaccinated [94]. Specifically, we prioritize immunocompromised patients, and, among others, older patients and those with multiple comorbidities.

 

SARS-CoV-2 variants, particularly those with mutations affecting the spike protein, are likely to impact the clinical efficacy of available monoclonal antibody therapies [95-98]. Information on the in vitro neutralization of various recognized SARS-CoV-2 variants’ spike proteins by each monoclonal antibody therapy is available for review on the US Food and Drug Administration (FDA) EUAs for casirivimab-imdevimab, sotrovimab, and bamlanivimab-etesevimab; clinicians should be aware of the prevalence of variants in their local area [99,100] and the potential resistance of variants to these agents (table 6). Additional clinical studies in populations affected by SARS-CoV-2 variants are needed to determine the efficacy of these therapies with the continued evolution of variants of concern. (See “COVID-19: Epidemiology, virology, and prevention”, section on ‘Variants of concern’.)

 

The FDA EUAs are for non-hospitalized COVID-19 patients with mild to moderate illness (eg, not requiring supplemental oxygen or, if on chronic supplemental oxygen, without an increased oxygen requirement) who have certain risk factors for severe disease (table 5) [101,102]. These risk factors for adults (≥18 years) include any of the following:

 

•Older age (≥65 years)

 

•Body mass index (BMI) ≥25 kg/m²

 

•Pregnancy

 

•Chronic kidney disease

 

•Diabetes mellitus

 

•Immunosuppression (immunosuppressive disease or treatment)

 

•Cardiovascular disease (including congenital heart disease) or hypertension

 

•Chronic lung disease (eg, chronic obstructive pulmonary disease [COPD], asthma [moderate to severe], interstitial lung disease, cystic fibrosis, pulmonary hypertension)

 

•Sickle cell disease

 

•Neurodevelopmental disorders (eg, cerebral palsy) or other medically complex conditions (eg, genetic or metabolic syndromes and severe congenital anomalies)

 

•Dependence on a medical-related technology (eg, tracheostomy, gastrostomy, or positive pressure ventilation [unrelated to COVID-19])

 

In addition, other conditions may place an individual at high risk for progression to severe COVID-19, and the use of monoclonal antibody therapy is not strictly limited to those with the risk factors listed above.

 

•Casirivimab-imdevimab – In a phase 3 randomized controlled trial including more than 4000 non-hospitalized adults with mild to moderate COVID-19 and one or more risk factors for severe disease, combination casirivimab-imdevimab, at two different doses (1200 and 2400 mg total doses) administered intravenously within seven days of symptom onset was compared with placebo [86]. At 29 days, there was a reduction in the combined outcome of hospitalization and death among those treated with both doses of casirivimab-imdevimab compared with placebo (1200 mg total dose, 1 versus 3.2 percent [70 percent relative risk (RR) reduction, 95% CI 32-87]; 2400 mg dose, 1.3 versus 4.6 percent [71 percent RR reduction, 95% CI 52-83]). There were five deaths in the placebo group and two deaths among those receiving casirivimab-imdevimab. Treatment with IV casirivimab-imdevimab was associated with rare infusion-related reaction events of moderate severity, including fever, chills, urticaria, pruritus, abdominal pain, and flushing [86,103]. A single episode of anaphylaxis was also reported. Subcutaneous administration was associated with greater local injection site reactions compared with placebo (12 versus 4 percent) [104].

 

The EUA for casirivimab-imdevimab is for the combined 1200 mg dose, administered IV (preferred) or subcutaneous if IV administration is not feasible or would delay treatment [104]. There are no outcomes data regarding subcutaneous administration; dosing is based upon safety and pharmacokinetic data in healthy subjects.

 

•Sotrovimab – In a randomized clinical trial of non-hospitalized adults with early, mild to moderate COVID-19 and one or more risk factors for severe disease or age ≥55 years, sotrovimab (500 mg) administered within five days of illness onset was compared with placebo [105]. According to an interim analysis that included 583 participants, sotrovimab reduced the combined rates of hospitalization and death at 29 days compared with placebo (1 versus 7.2 percent; 85 percent RR reduction, 97% CI 44-96). The five intensive care admissions and the single study death occurred in the placebo group. The rate of adverse events was similar in both groups; infusion-related reactions and diarrhea each occurred in 1 percent of patients taking sotrovimab.

 

•Bamlanivimab-etesevimab – In randomized trials, bamlanivimab-etesevimab reduced the risk of hospitalization and death in outpatients with mild to moderate COVID-19 and risk factors for progression to severe disease [101,106,107]. As an example, in a trial of 1035 non-hospitalized adults with mild to moderate COVID-19 and risk factors for severe disease, a single infusion of bamlanivimab-etesevimab (2800 mg of each) administered within three days of a positive SARS-CoV-2 test reduced rates of COVID-19-related hospitalization or death at one month compared with placebo (2.1 versus 7.0 percent; risk difference -4.8 percent, 95% CI -7.4 to -2.3) [106]. There were no deaths among those who received bamlanivimab-etesevimab and nine COVID-19-related deaths among those who received placebo. Nausea and infusion-related adverse effects (pruritus, fever, rash) were reported with administration of monoclonal antibody therapy but were generally uncommon and mild.

 

The EUA is for 700 mg of bamlanivimab and 1400 mg of etesevimab. This dosage is supported by unpublished results of BLAZE-1 including 769 outpatients with mild to moderate illness and risk factors for severe disease, in which treatment with this dose reduced the combined rates of hospitalization and death compared with placebo (0.8 versus 6 percent) [101]. All four deaths among study participants occurred in the placebo group.

 

In Europe, the European Medicines Agency (EMA) has provisionally approved the use of the monoclonal antibody regdanvimab for outpatients with COVID-19 who have certain risk factors for severe disease and who do not require supplemental oxygen [108,109]. In an unpublished report of a randomized clinical trial including 327 adult outpatients with early, mild to moderate COVID-19, treatment with regdanvimab (40 mg/kg) within three days of symptom onset reduced the risk of hospitalization, oxygen requirement, and death compared with placebo (4 versus 8.7 percent). Among patients with risk factors for progression to severe disease, the benefit was greater (4.3 versus 12.7 percent). Regdanvimab is administer as a single intravenous dose of 40 mg/kg, with a maximum dose of 8000 mg.

 

Novel antiviral agents — Novel antiviral agents have been developed which may have a role in the management in patients with early, symptomatic COVID-19 and risk factors for progression for severe disease, although clinical trial results are not yet available for review and none of these agents are available for use in the United States.

●Molnupiravir – This is an oral antiviral agent, a nucleoside analogue that inhibits SARS-CoV-2 replication and is active against prevalent viral variants (including the Delta variant). The drug has been authorized in the United Kingdom, but it is not yet clinically available in the United States, where the manufacturer is seeking EUA for treatment of mild to moderate COVID-19 in nonpregnant adults at risk for severe disease. Interim results of an international randomized phase III trial were announced in a manufacturer’s press release [110]. Among over 750 non-hospitalized adults who had onset of mild to moderate COVID-19 within five days and at least one risk factor for severe disease, molnupiravir reduced the risk of hospitalization or death by approximately 50 percent (7.3 versus 14.1 percent with placebo); all eight deaths in the trial occurred among placebo recipients. The rates of drug-related adverse events were comparable between the two groups. Publication of complete trial details is necessary to critically assess these results.

 

●PF-07321332/ritonavir – This is a combination of oral protease inhibitors, PF-07321332 plus ritonavir. PF-07321332 blocks the activity of the SARS-CoV-2-3CL protease, an enzyme required for viral replication, and coadministration with ritonavir slows the metabolism of PF-07321332 so it remains active in the body for longer and at higher concentrations. In an interim analysis of phase 2/3 of the nonpublished randomized EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) trial including 1219 adult outpatients with at least one risk factor for severe disease, PF-07321332/ritonavir, administered within three days of symptom onset, reduced the risk of hospitalization or death at 28 days by 89 percent compared with placebo (0.8 versus 7 percent) [111]. Results were similar when the drug was administered within five days of symptom onset. Further, all 10 trial deaths occurred in the placebo groups; there was no increase in drug-related adverse effects compared with placebo. Publication of complete trial results are not yet available for review, and the medication has not yet received an EUA.

 

Outpatient therapies of limited value — Other COVID-19 treatments are under investigation but should not be prescribed in the ambulatory setting outside of a clinical trial [112]. Evidence continues to evolve, but high-quality data supporting the efficacy of many of these treatments are limited [113]. In addition, there are concerns for potential toxicities with some of these agents when administered in an unmonitored setting [114,115]. (See “COVID-19: Management in hospitalized adults”, section on ‘Specific treatments’.)

●Fluvoxamine – Data suggest that the antidepressant fluvoxamine may reduce progression to severe disease in early, mild COVID-19, although trials indicating benefit are hampered by methodologic issues, reducing certainty about any effect. Although potentially promising, additional data are needed to inform the utility of fluvoxamine before recommending its widespread use outside a clinical trial. In a randomized trial from Brazil that included 1497 outpatients who had COVID-19 onset or SARS-CoV-2 diagnosis within the past seven days (about 44 percent within the past three days) and had at least one risk factor for severe disease, fluvoxamine (100 mg twice daily for 10 days) reduced the 28-day rate of hospitalization compared with placebo (11 versus 16 percent, RR 0.68, 95% CI 0.52-0.88); however, the definition of hospitalization included stay in an emergency setting for at least six hours, and most of the reduction in hospitalization reflected a reduction in such emergency visits [116]. A mortality reduction was not identified among the entire trial population. Although a mortality reduction was observed among those who reported at least 80 percent adherence to the study medication (<1 versus 2 percent with placebo, RR 0.9, 0.01-0.47), the validity of this finding is uncertain because more individuals in the fluvoxamine than placebo group were nonadherent, and the resulting mortality rate among those who were nonadherent was disproportionately high compared with the overall rate, suggesting potential confounders. A prior smaller trial had suggested that fluvoxamine (100 mg orally twice daily for two days, then three times daily for a total of 15 days of treatment) reduced clinical (respiratory) deterioration compared with placebo (0 versus 8.3 percent; adjusted RR 8.7, 95% CI 1.8-16.4) but was limited by loss to follow-up and short study duration [113]. Observational data has also suggested that fluvoxamine is associated with lower hospitalization rates than observation alone [114].

 

●High-titer convalescent plasma – High-titer convalescent plasma therapy for outpatients remains investigational and should be administered through a clinical trial. Convalescent plasma has not demonstrated efficacy for most outpatients with mild illness [115,117], although limited high-quality data suggest that high-titer convalescent plasma given early to certain high-risk adult outpatients with mild illness may have efficacy in reducing the risk of progression to severe disease [118].

 

•A randomized controlled trial including 160 older adults (age ≥75 years or ≥65 years with one or more specific comorbidities [hypertension, chronic obstructive lung disease, diabetes mellitus on pharmacotherapy, cardiovascular disease, chronic renal failure, obesity]) and mild COVID-19 symptoms compared early treatment with high-titer convalescent plasma with placebo [118]. High-titer convalescent plasma therapy administered within 72 hours of symptom onset reduced the risk of developing severe respiratory disease compared with placebo (16 versus 31 percent; RR 0.52, 95% CI 0.29-0.94). Higher-titer anti-SARS-CoV-2 immunoglobulin G (IgG) plasma was associated with reduced risk of disease progression compared with lower-titer plasma.

 

However, other trials evaluating convalescent plasma given to adult outpatients with mild disease have not shown similar benefit. As an example:

 

•The Clinical Trial of COVID-19 Convalescent Plasma of Outpatients (C3PO), evaluating convalescent plasma given within seven days of symptom onset to adults age ≥18 years with mild illness and one or more risk factors for severe disease, was halted early for lack of clinical benefit [115]. Final trial analysis confirmed that there was no clinical benefit of high-titer convalescent plasma compared with placebo at 15 days [117,119].

 

The preparation, administration, and adverse effects of convalescent plasma are discussed in detail elsewhere. (See “COVID-19: Convalescent plasma and hyperimmune globulin”.)

 

●Systemic glucocorticoids – In non-hospitalized patients, we do not treat COVID-19 with dexamethasone, prednisone, or other corticosteroids [120]. Extrapolating from the results of studies of hospitalized patients, there is no evidence that corticosteroids benefit patients without a supplemental oxygen requirement, and further, they may be associated with poorer clinical outcomes [121]. However, in resource-limited settings with limited hospital capacity, it may be reasonable to treat select COVID-19 outpatients who have a new or increased supplemental oxygen requirement with dexamethasone if close clinical follow-up can be assured [122]. In addition, patients with COVID-19 and a concomitant acute exacerbation of asthma or COPD should receive appropriate treatment with systemic glucocorticoids as indicated by usual guidelines. This is reviewed in detail elsewhere. (See “COVID-19: Management in hospitalized adults” and “COVID-19: Management in hospitalized adults”, section on ‘Dexamethasone and other glucocorticoids’ and “An overview of asthma management”, section on ‘Advice related to COVID-19 pandemic’ and “Stable COPD: Overview of management”, section on ‘Advice related to COVID-19’.)

 

●Inhaled glucocorticoids – In trials evaluating inhaled glucocorticoids, there was some benefit in the treatment of mild, early, COVID-19, although no mortality reduction was demonstrated.

 

•In the non-placebo-controlled steroids in COVID-19 (STOIC) trial, 139 adult outpatients with mild, early COVID-19 were treated with inhaled budesonide 800 mcg twice daily (an average of seven days) or assigned to usual care [123]. Among those treated with inhaled budesonide, fewer patients required urgent medical evaluation or hospitalization (1.4 versus 14.4 percent) at 28 days.

 

•In a subsequent open-label trial (the PRINCIPLE trial) including 1856 COVID-19 outpatients ≥65 years old or ≥50 years old with risk factors for severe disease, treatment with inhaled budesonide 800 mcg twice daily reduced the time to self-reported recovery (12 versus 15 days; 95% CI 1.2-5.1) but did not reduce the risk of hospitalization or death at 28 days compared with usual care [124]. Furthermore, use of a subjective, self-reported outcome in an open-label trial, inclusion of participants with presumed but not microbiologically confirmed COVID-19, and enrollment of the usual care group over a longer period of time than the intervention group all increase the risk of bias and reduce confidence in the finding of a potential benefit of budesonide.

 

Despite a suggestion of benefit, additional randomized controlled trials are necessary to determine the efficacy of inhaled corticosteroids for outpatients with early, mild COVID-19 [125].

 

●Colchicine – Although there are some data demonstrating a benefit from the use of colchicine in early, mild to moderate COVID-19, the benefit is modest without a reduction in mortality, and adverse effects are common. In a randomized trial including over 4100 adult outpatients (≥age 40) with early, mild to moderate, testing-confirmed COVID-19, treatment with oral colchicine (0.5 mg twice daily for three days, followed by 0.5 mg daily for a total of 30 days), reduced the risk of hospitalization compared with placebo (4.5 versus 5.9 percent of patients; odds ratio [OR] 0.75, 95% CI 0.57-0.99) [126]. However, there was no reduction in mortality. Gastrointestinal side effects (eg, diarrhea) were more common, and pulmonary embolism occurred more frequently in the colchicine compared with the placebo group (24 versus 15 percent; and 0.5 versus 0.1 percent, respectively).

 

●Ivermectin – As with other interventions that do not have a clear benefit, we recommend that ivermectin not be used for treatment of COVID-19 outside a clinical trial. Several meta-analyses have highlighted that the effect of ivermectin in patients with COVID-19 remains uncertain because of a lack of high-quality data [127-130]. As an example, in a July 2021 meta-analysis that identified four trials comparing ivermectin with placebo or standard care in outpatients with mild COVID-19, there was no clear reduction in all-cause mortality at 28 days (RR 0.33 in two trials, 95% CI 0.01-8.05), no reduction in need for invasive mechanical ventilation at 14 days (RR 2.97 in one trial; 95% CI 0.12-72.47), and no clear impact on symptom resolution at 14 days (RR 1.04 in one trial, 95% CI 0.89-1.21) [127]. The quality of the evidence for these outcomes was deemed low to very low because of imprecision and risk of bias. Although the meta-analysis also did not identify any increased risk of adverse effects with ivermectin, steep increases in calls to poison control centers about ivermectin toxicity compared with pre-pandemic rates have been reported [131,132]. Several of these calls involved ivermectin obtained without prescription (eg, from internet or veterinary sources); some patients were hospitalized for neurologic adverse effects related to uncertain dosages.

 

●Hydroxychloroquine and azithromycin – Hydroxychloroquine and azithromycin have received attention as agents with possible antiviral activity, but trials have not suggested a clinical benefit for patients with COVID-19, including those managed in the outpatient setting [133-138]. Although some observational and unpublished anecdotal reports have suggested a clinical benefit of hydroxychloroquine, those are subject to a number of potential confounders [139], and randomized trials offer higher-quality evidence that hydroxychloroquine has no proven role for COVID-19. As an example, in an open-label trial including 293 patients with mild COVID-19 who did not warrant hospitalization, hydroxychloroquine administered within five days of symptom onset did not reduce viral levels at day 3 or 7 compared with no treatment [133]. In addition, there was no statistically significant reduction in hospitalization rates or time to symptom resolution. The rate of adverse effects, primarily gastrointestinal symptoms, were greater with hydroxychloroquine.

 

●Others – Other treatments are being evaluated in outpatients with mild to moderate illness, including vitamin and mineral supplementation as well as antiviral agents and anticoagulants.

 

•Limited observational data suggest a possible association between certain vitamin and mineral deficiencies and more severe disease [140-143]. However, there are no high-quality data that supplementation with vitamin C, vitamin D, or zinc reduces the severity of COVID-19 in non-hospitalized patients [144]. Issues related to vitamin D and COVID-19 are reviewed in detail elsewhere. (See “Vitamin D and extraskeletal health”, section on ‘COVID-19’.)

 

•There is no evidence that treatment with lopinavir-ritonavir improves outcomes in outpatients with mild disease [136]. In addition, although treatment with peginterferon lambda may induce more rapid reduction in SARS-CoV-2 viral load in patients with early, mild disease, its impact on clinically important outcomes is unclear [145].

 

•In a randomized trial including 243 adults with mild to moderate COVID-19 but risk factors for progression to severe disease, treatment with sulodexide (a glycosaminoglycan with anticoagulant and antiinflammatory properties) within three days of symptom onset reduced hospitalizations and the need for supplemental oxygen compared with placebo (RR 0.60, 95% CI 0.37-0.96 and RR 0.71, 95% CI 0.50-1.00, respectively), but not mortality or thromboembolic events [146]. Further trials are required to determine if there is a clinical role for this agent in treating outpatients with COVID-19.

 

Other COVID-19 specific therapies, such as remdesivir and baricitinib, are being used to treat hospitalized patients; these therapies are discussed in detail elsewhere. (See “COVID-19: Management in hospitalized adults”, section on ‘COVID-19-specific therapy’.)