Prevention of long COVID: progress and challenges

Long COVID—the umbrella term that encompasses the post-acute and long-term sequelae of SARS-CoV-2 infection—can be profoundly disabling and might affect people for a lifetime.¹ These health consequences affect not only patients and their life expectancy, but also societal wellbeing and economic indicators (labour participation and economic productivity). Preventing long COVID should be a public and a global health priority.

Emerging evidence suggests that SARS-CoV-2 antivirals might be effective in preventing long COVID. Work from our team suggested that nirmatrelvir (in combination with ritonavir) reduced the risk of long COVID by 26%,² and that molnupiravir reduced the risk by 14%.³ In exploratory analyses, ensitrelvir was shown to also reduce risk of long COVID.⁴ Taken together, these data on nirmatrelvir, molnupiravir, and ensitrelvir point in the same direction—antiviral use in the acute phase of COVID-19 might be an important strategy to prevent long COVID.

However, despite this progress, many uncertainties and challenges remain. Because in most countries, the available antivirals (nirmatrelvir and molnupiravir) are only authorised for use in people with risk factors for progression to severe COVID-19 illness, studies evaluating the effectiveness of these antivirals for long COVID were limited to this population. It is not clear whether the beneficial effect of nirmatrelvir and molnupiravir also extends to individuals at low risk. Studies evaluating the effectiveness of these antivirals in reducing the risk of long COVID in low-risk populations (who currently are not eligible for antiviral use) are urgently needed.

People with long COVID are getting reinfected; and evidence shows that reinfection contributes additional risks to long COVID (it might either exacerbate existing long COVID manifestations or contribute additional de novo symptoms or organ damage).⁵ Because randomised trials for antivirals were done before long COVID was widely recognised, it was not considered a risk factor for progression to severe COVID-19 illness; consequently, many patients with long COVID might not be eligible for antivirals upon reinfection. Long COVID should be evaluated as a putative risk factor for increased probability of reinfection and for increased risk of adverse health outcomes after reinfection. Understanding whether antivirals might reduce the consequences of reinfection in people who already have long COVID should also be investigated. While waiting for evidence, and because people with long COVID might be at high risk of serious adverse outcomes upon reinfection, serious consideration should be given for initiation of antivirals upon reinfection in this population.

Additionally, although both nirmatrelvir and molnupiravir were effective in reducing the risk of long COVID, the magnitude of effect was modest.2, 3 Studies examining whether higher doses or longer durations would yield greater effectiveness should also be prioritised.

Data from a 2023 study have shown that metformin might also reduce the risk of long COVID.⁶ Although this study is still preliminary and needs to be reproduced and validated mechanistically, testing whether a combination of metformin and antivirals would be more effective than either one alone should also be urgently tested.

Antivirals (nirmatrelvir and molnupiravir) remain massively underused.7, 8 In the US Department of Veterans Affairs health system where testing and treatment are ubiquitously available and free of charge to all patients, less than 36% of people with SARS-CoV-2 infection and at least one risk factor for progression to severe COVID-19 illness who would be eligible for antivirals receive them. Predictors of non-treatment include health behaviours (eg, being unvaccinated for COVID-19 and influenza vaccines) and Black race; the former group has the highest risk of adverse health outcomes, yet they are less likely than vaccinated individuals to receive a COVID-19 antiviral during acute infection. Because testing and treatment must be coupled, studies aimed at understanding barriers to treatment and strategies to address them are urgently needed.

Access to antiviral treatment is constrained in many countries around the world. Because death, disease, and disability in the acute and long phases of COVID-19 are not only human tragedies, they exact a heavy toll on economic productivity and undermine political stability, reducing the burden of death and disease in both acute and long COVID should be viewed not only as a public health priority, but also as an economic and political imperative. WHO, along with industry partners and non-governmental agencies, must work with low-income and middle-income countries to facilitate provision of testing and antivirals.

It is also crucial to expand the pipeline of antivirals; this improves competition, reduces prices, and diminishes reliance on a few antivirals, especially with increasing concern about antiviral resistance.⁹

Monoclonal antibodies have been effective in reducing progression to severe COVID-19 disease, but the pipeline of these antiviral agents did not keep up with the mutating SARS-CoV-2 virus, and all current monoclonal antibodies became obsolete in 2022. Investment is urgently needed in a strong new pipeline of monoclonal antibodies targeting shared epitopes among coronaviruses to circumvent potential future antigenic variations.

Finally, current vaccines reduce the risk of long COVID, but their effectiveness against long COVID is modest, and they do not prevent infections.¹⁰ Investment is needed in technologies to develop better vaccine approaches that achieve three important goals: to prevent infections (eg, mucosal immunity), to be variant-proof, and to be longer lasting. This should be viewed as an investment to reduce the risk of acute and long-term consequences of SARS-CoV-2 and as cornerstone for future pandemic readiness.

Although progress has been made in understanding how to prevent long COVID, the search for treatment has been disappointingly very slow. The millions of people with long COVID deserve better. Strong scientific and political leadership and ambitious strategies are needed to address the challenges and uncertainties in preventing long COVID and, with even more urgency, prioritise research for treatment of long COVID. This will not only help to prevent more long COVID and treat existing patients, but will also lead to a deeper understanding of the broader infection-associated chronic illness, and position us better to face the challenges of future pandemics.

© 2023 Flickr - Catarina Oberlander

I report receiving consultation fees from Gilead Sciences and Tonix pharmaceuticals. I also report consulting (uncompensated) for Pfizer; I have no other relationships or activities that could appear to have influenced the submitted work. This Comment was funded by the US Department of Veterans Affairs (to ZAA). The contents do not represent the views of the US Department of Veterans Affairs or the US government.