Can antivirals help in the treatment of long COVID?

Let me start by stating some basic emerging facts:

  1. COVID-19 vaccines are highly effective in combating COVID-associated mortality
  2. COVID-19 vaccines could reduce risk of getting long COVID by 50%
  3. Of all people infected with COVID-19 after vaccination, 15-30% will develop long COVID
  4. There is insufficient evidence to show that COVID-19 vaccines help relieve long pre-existing COVID symptoms
  5. We need different strategies to treat long COVID because vaccines do not fully protect against infection

My Experience with Mild Acute COVID-19: Persistent Symptoms

That said, allow me to share my experience. I am an immunologist studying how SARS-CoV-2 infection programs T cell responses differently in patients with long neuro-COVID compared to healthy convalescents. I am also a female in her 30s with an autoimmune disease and on immunosuppressants, and first became COVID positive in December 2021 when the Omicron wave began in the United States. Luckily, my symptoms were mild: persistent headaches, intense fatigue, and trouble sleeping that lasted 2-3 weeks.

I was on the lookout for the development of long COVID symptoms as my demographic is overrepresented among the patients we see in our long COVID clinic. Unsurprisingly, I continued to experience severe fatigue, headaches, and trouble sleeping for over 3 months after my initial COVID-19 infection. My symptoms came and went: at times they were severe enough to interfere with my ability to work in the lab, but then receded to manageable levels before returning. I was also testing positive for SARS-CoV-2 by nasal swab rapid antigen test for over 3 months after my initial positive test (I tested regularly 2-3 times a week), including after I received my booster dose of the vaccine Moderna in early February.

Testing a hypothesis: Could Paxlovid help me with my long-lasting 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 thought 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 recalling a possible chronic viral infection. Recent reports have revealed that even patients with mild COVID-19 who died of other causes showed viral persistence in the brain and other extra-respiratory tissues for up to 230 days after acute infection. Other studies have shown that patients with long-term COVID also had the virus in breast and appendix tissue more than a year after acute infection, and that the virus could be detected in feces for up to 7 months after diagnosis. Based on this data and the fact that there was no treatment available for long COVID, I decided to see if taking a SARS-CoV-2 specific antiviral might help ease my persistent symptoms.

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

Consistent with my original assumption, my symptoms of fatigue, headaches, and trouble sleeping slowly faded and completely disappeared about 3 weeks after my nirmatrelvir/ritonavir course ended. At this point I also tested negative rapid antigen for the first time in 4 months. It was very exciting for me initially – it’s rare that we get to test hypotheses in such a personal way, and some reports have suggested that the antiviral could help treat long-lasting COVID symptoms. However, some of my headache and sleep disturbance symptoms resurfaced 4 weeks after treatment ended, and I started testing positive again on a rapid antigen test. Curiously, the symptoms of fatigue remained at bay. Viral reactivation has been observed in some cases after taking nirmatrelvir/ritonavir, and I suspect this may also be a cause of symptom relapse in long-term COVID patients, highlighting the urgent need for clinical trials.

Where do we go from here?

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

Unfortunately, I have no illusions about the difficulty of finding treatments for long COVIDs. For one thing, I don’t think viral persistence is the only underlying cause of post-COVID sequelae. Studies have implicated blood clotting problems and a new autoimmune disease as other possible causes. Still, SARS-CoV-2 antivirals will likely be very important to add to the treatment arsenal after more research into their safety and effectiveness.

We have many questions that need to be answered as a research community. Mechanically, we need to know the proportion of long-term COVID patients who might have a persistent viral reservoir through repeated testing of nasal swabs and stool specimens. We also need to determine whether the viral life cycle of SARS-CoV-2 differs in subtle ways depending on the cell type it infects (lung vs gut vs brain, etc.); this could point us towards new antiviral targets. Finally, we need to differentiate how long COVID immune disruptions may be related to viral persistence versus autoimmunity. Clinically, there is a clear need to test Merck’s antiviral nirmatrelvir/ritonavir and molnupiravir in clinical trials to treat long COVID. We need to find out, initially, if changes in dosing strategies or duration of treatment can eliminate long COVID symptoms. However, both antivirals target only one aspect of the SARS-CoV-2 intracellular life cycle and may not be useful in treating all cases. Greater investment in clinical research should be devoted to the development of new 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 (pharmaceutical-funded) initiatives, much like what has been 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 that the only way to find a way out of this pandemic will be to invest more in treatments rather than limiting ourselves to the development of vaccines alone. I sincerely hope that our medical and scientific communities can face 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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