Can Antivirals Help in the Treatment of Long COVID?

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Let me begin by stating some basic emerging facts:

  1. COVID-19 vaccines are highly effective in combating COVID-associated mortality
  2. COVID-19 vaccines may reduce the risk of getting long COVID by 50%
  3. Of all people who get infected with COVID-19 after vaccination, 15-30% will develop long COVID
  4. There is no sufficient evidence to show COVID-19 vaccines help relieve pre-existing long COVID symptoms
  5. We need different strategies to treat long COVID because vaccines do not entirely protect against infection

My Experience With Mild Acute COVID-19: Lingering Symptoms

With that out of the way, let me share my experience. I am an immunologist studying how SARS-CoV-2 infection differentially programs T-cell responses in patients with long neuro-COVID versus healthy convalescents. I am also a woman in my 30s with an autoimmune disease who is on immunosuppressants, and I became COVID positive for the first time in December 2021 during the start of the Omicron wave in the U.S. Luckily, my symptoms were mild: persistent headaches, intense fatigue, and sleep disturbance that lasted 2 to 3 weeks.

I was on the lookout for the development of long COVID symptoms because my demographic is overrepresented in the patients we see in our long COVID clinic. Unsurprisingly, I continued to experience severe fatigue, headaches, and sleep disturbance for more than 3 months after my initial COVID-19 infection. My symptoms cycled: at times, they were severe enough to disrupt my ability to work in the lab, but then receded to manageable levels before coming back again. I was also testing SARS-CoV-2 positive by nasal swab rapid antigen test for more than 3 months after my initial positive test (I routinely tested 2 to 3 times per week), including after I received my booster dose of the Moderna vaccine in early February.

Testing a Hypothesis: Could Paxlovid Help With My Long COVID Symptoms?

At this point, 6 weeks after my booster dose, I decided to put my knowledge and experience as an infectious disease immunologist working on long COVID to the test. I reasoned there was substantial evidence that SARS-CoV-2 can persist in the body long after the acute infection phase based on my own data showing long COVID patients having a T-cell signature reminiscent of a possible chronic viral infection. Recent reports found that even patients with mild COVID-19 who died of other causes had viral persistence in the brain and other extra-respiratory tissues up to 230 days after acute infection. Further studies showed that long COVID patients also had virus in breast and appendix tissue more than 1 year after acute infection, and that virus could be detected in feces for up to 7 months after diagnosis. Based on these data and the fact that there were no treatments available for long COVID, I decided to see whether taking a SARS-CoV-2-specific antiviral might help with my lingering symptoms.

I was fortunate to have a physician who would work with me to test my hypothesis. I was prescribed nirmatrelvir/ritonavir (Paxlovid) in late March based on the following criteria: I continued to test positive for SARS-CoV-2 on the day of my appointment and I’m immunocompromised. I took the 5-day course with minimal side effects and waited to see what would happen.

Consistent with my initial hypothesis, my fatigue, headache, and sleep disturbance symptoms slowly faded and completely disappeared about 3 weeks after completing my course of nirmatrelvir/ritonavir. At this point, I also tested rapid antigen negative for the first time in 4 months. This was very exciting to me initially — it is rare that we get to test hypotheses in such personal ways, and some reports did suggest that the antiviral could help treat long COVID symptoms. However, some of my headache and sleep disturbance symptoms resurfaced 4 weeks after completing the treatment course, and I began testing positive on a rapid antigen test again. Intriguingly, the fatigue symptoms remained at bay. Viral reactivation has been observed in some instances after taking nirmatrelvir/ritonavir, and I suspect this also may be a cause of symptom relapse in long COVID patients, thus highlighting the urgent need for clinical trials.

Where Do We Go From Here?

Having studied long COVID since the beginning of the pandemic, I often hear from people with long COVID that they want treatments for their often debilitating conditions. Many people are experiencing chronic symptoms that significantly affect their quality of life and ability to work.

Unfortunately, I am under no illusions about how difficult it will be to find treatments for long COVID. For one, I don’t think viral persistence is the only underlying cause of post-COVID sequelae. Studies have implicated blood clotting issues and new-onset autoimmune disease as other possible causes. Still, SARS-CoV-2 antivirals will likely be very important to add to the treatment arsenal following more research into their safety and efficacy.

We have many remaining questions to answer as a research community. Mechanistically, we need to find out the proportion of long COVID patients who might have a persisting viral reservoir through repeated testing of nasal swabs and stool samples. We also need to determine whether the SARS-CoV-2 viral life cycle differs in subtle ways depending on the cell type it infects (lung vs intestine vs brain, etc.); this could point us toward new antiviral targets. Finally, we need to differentiate how long COVID immune perturbations may be related to viral persistence versus autoimmunity. On the clinical side, there is a clear need to test nirmatrelvir/ritonavir and Merck’s antiviral molnupiravir in clinical trials to treat long COVID. We need to find out, at a baseline, whether changes in dosing strategies or treatment duration can eliminate long COVID symptoms. However, both antivirals only target a single aspect of the SARS-CoV-2 intracellular life cycle and may not be useful in treating every case. A larger clinical research investment should be made into the development of novel SARS-CoV-2 specific antivirals that target multiple aspects of the viral life cycle. This type of research should be undertaken by both public (NIH-funded) and private (pharma-funded) initiatives, similar to what was done so successfully for the HIV epidemic.

COVID-19 has been incredibly difficult for us to navigate as a society. As an infectious disease immunologist, I believe the only way to find a path out of this pandemic will be to further invest in treatments rather than limiting ourselves to vaccine development alone. I sincerely hope our medical and scientific communities can meet this moment with the urgency it deserves.

Lavanya Visvabharathy, PhD, is a postdoctoral research associate in neurological manifestations of COVID-19 in the Department of Neurology at Northwestern University Feinberg School of Medicine in Chicago.

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