Might Antivirals Have a Role in Long COVID Prevention or Treatment?

Key Takeaways:

• Many people are affected by long COVID, and efforts should be made to identify prevention and treatment modalities.
• Large studies are needed to confirm whether COVID-19 antivirals may be effective at preventing and/or treating long COVID.

A few months after the first wave of the COVID-19 pandemic started, healthcare professionals began to understand that, for some patients, the disease did not end with the resolution of the acute phase. The so-called long COVID syndrome is characterized by the persistence of unresolved COVID-19 signs and symptoms at least 4 weeks after the acute infection. These symptoms may last for several months (and even years) and are independent of the severity of the acute disease.

A recent meta-analysis of 63 studies involving 257,348 patients with COVID-19 found that 20% to 40% experienced at least 1 persistent symptom 3-12 months after recovery from the acute phase. Long COVID has a relevant impact on quality of life and should be considered a new disability when it is diagnosed.

At present, we are facing 2 clinical challenges: (1) Can we prevent the development of long COVID? and (2) How do we treat long COVID?

Hypotheses for Long COVID Treatment Targets
Currently, no specific treatment for long COVID exists. To find a treatment for long COVID, we need to understand its pathogenesis. There are several pathogenetic hypotheses, and one of them is the sustained persistence of SARS-CoV-2 in different bodily tissues after the end of the acute infection phase. The theory is that this residual viral presence sustains the immune response with an increased level of functional memory cells exerting antiviral cytotoxic activity, accompanied by chronic inflammation with high levels of interluekin-6, tumor necrosis factor, and C-reactive protein.

This hypothesis is supported by a small study by Tejerina and colleagues evaluating 29 patients with long COVID who showed symptoms for a median of 55 days after the acute phase. These symptoms were characterized by fatigue, muscle pain, tachycardia, dyspnea, and low-grade fever, which led to a reduction in functional status in 48% of these patients. Investigators found that a real-time polymerase chain reaction (RT-PCR) test for SARS-CoV-2 was positive in blood in 45% of the patients, whereas 55% had at least 1 positive RT-PCR test in a sample of either blood, urine, and/or stool.

Considering these findings, one could hypothesize that molecules with antiviral activity could play a role in either the prevention or treatment of long COVID.

Our armamentarium of treatment strategies for the early phase of the disease includes, at present, monoclonal antibodies and antivirals. The main problem with monoclonal antibodies—which bind the spike protein—is that the presence of different SARS-CoV-2 variants of concern can impair or nullify their neutralizing activity. By contrast, antivirals such as ritonavir-boosted nirmatrelvir, remdesivir, and molnupiravir retain activity even against omicron and other variants of concern. 

What We Know (And What We Don’t)
In a large observational study, oral nirmatrelvir demonstrated efficacy in preventing hospitalization due to COVID-19 in patients 65 years of age or older during the omicron surge. Other oral antiviral studies have shown an association between treatment of acute COVID-19 infection and accelerated negative RT-PCR conversion.

But what about long COVID? Evaluation of long COVID was not an endpoint of any study conducted in antivirals to date. We do not know if these antivirals can prevent the onset of long COVID when given in the early phase of the disease or if they can treat this syndrome once diagnosed.

Understanding if there is a role for antivirals in preventing the onset of long COVID requires trials with a large sample size and longer-term follow-up. To date, there are only small observational studies of antivirals as prevention, such as one by Boglione and colleagues that found a 36% reduction in the incidence of long COVID 6 months after hospital discharge in patients who received remdesivir vs those who did not. The situation is slightly different for the treatment of long COVID. Even if randomized studies are conducted to evaluate long COVID treatment with antivirals, it also will be important to consider observational studies. 

A recent case series of 4 patients who received ritonavir-boosted nirmatrelvir at different time points showed encouraging results. Two patients who received nirmatrelvir plus ritonavir reported improvement at 25 and 60 days after the onset of initial symptoms, respectively, and another individual with presumed long COVID for 2 years reported substantial improvement in chronic symptoms when receiving nirmatrelvir plus ritonavir following SARS-CoV-2 reinfection.

There are ongoing studies of molnupiravir, nirmatrelvir plus ritonavir, and remdesivir where data are being collected 3-24 months post antiviral treatment to evaluate whether there is a link between use of an antiviral agent for an acute COVID-19 infection and reduction in the incidence of long COVID afterward.

Long COVID is a major public health issue, and every effort should be made to prevent and treat the disease. Based on what is known of its pathogenesis, antivirals might play a role in treatment and prevention. More evidence is needed to confirm these ideas.

Your Thoughts?
Do you think COVID-19 antivirals play a role in prevention or treatment of long COVID? Join the discussion by posting a comment below.