Post-COVID-19 condition (also known as long COVID)—the term that encapsulates the long-term health effects caused by SARS-CoV-2 infection—is a complex multisystemic chronic disease with profound consequences.
1,2 Shortly after long COVID was first reported, the search begun to find pharmaceutical agents to prevent and treat it. Because SARS-CoV-2 itself is the causative agent of long COVID and because viral persistence is postulated to play a major role in the pathogenesis of the condition, antivirals, which block viral replication, were seen as potential candidates for the prevention and treatment of long COVID.
Early promising evidence of effectiveness came from observational analyses that showed that among non-hospitalised individuals (with mild to moderate COVID-19) who have at least one risk factor for the development of severe COVID-19, use of the SARS-CoV-2 antivirals (ritonavir-boosted nirmatrelvir and molnupiravir) in the acute phase could reduce the risk of long COVID.
3–5
In this issue of
The Lancet Infectious Diseases, Victoria Harris and colleagues
6 report results of extended follow-up from the PANORAMIC trial, which to the authors' knowledge is the first randomised controlled trial to evaluate the effects of molnupiravir on long-term health outcomes at 3 months and 6 months after randomisation.
6 This open-label trial included people with SARS-CoV-2 infection in the community and at least one risk factor for progression to severe COVID-19 illness.
6 The results of a pre-specified analysis show that people who were randomly assigned to molnupiravir during the acute phase of COVID-19 had better outcomes at 3 months and 6 months than those randomly assigned to usual care, including better self-reported wellbeing, fewer and less severe COVID-19 associated symptoms, less health care utilisation, less absenteeism from work or study, and improved quality of life. The effect sizes included a median estimate of 0·74 for persistent symptoms and 0·8 for severe symptoms at 6 months, translating into 2·5 and two fewer cases per 100 treated people, respectively.
6
The promising results from the PANORAMIC trial are consistent with results from well conducted observational analyses as they both converge on finding a modest effect of molnupiravir in reducing the risk of long COVID in high-risk individuals. Concerns, however, have been raised about the mutagenicity of molnupiravir. Furthermore, effectiveness of molnupiravir (or other SARS-CoV-2 antivirals including ritonavir and nirmatrelvir) in reducing risk of long COVID in low-risk populations, including younger individuals with no comorbid medical conditions, has not been evaluated. In at-risk individuals, simnotrelvir resulted in an earlier reduction in viral load and faster resolution of acute symptoms than placebo,
7 but its effectiveness against long COVID has not yet been evaluated. Expanding the pipeline of SARS-CoV-2 antivirals and evaluating their effectiveness in reducing the risk of long COVID in various populations including low-risk groups should be prioritised by funding agencies and the pharmaceutical industry.
In addition to preventing long COVID, SARS-CoV-2 antivirals are being evaluated for the treatment of long COVID. Several randomised trials are underway with results of one trial reporting that treatment with nirmatrelvir and ritonavir for 15 days has not ameliorate symptoms of long COVID.
8 However, the trial enrolled people with a mean of 17·5 months after index SARS-CoV-2 infection. The key for successful treatment trials will probably hinge (among other things) on targeting the disease early; whether earlier initiation of antiviral therapy, longer duration of treatment, or a combination of different antivirals (with different mechanisms of action) yields better effectiveness in reducing the risk of long COVID should be evaluated. Identifying (or at least risk stratifying) individuals with viral persistence could help select individuals who might respond more favourably to antiviral therapy.
The use of antivirals to reduce the risk of long COVID is grounded in the hypothesis that viral persistence and possible ongoing replication of SARS-CoV-2 are major mechanistic pathways responsible for long COVID. Evidence for this hypothesis is growing. Data from multiple settings have shown evidence of viral persistence (ie, persistence of viral RNA or protein fragments) for months or years in multiple organ systems including the gut, brain, kidneys, and blood vessels.
9,10 Evidence also suggests the presence of subgenomic RNA (a surrogate marker of viral replication) in solid tissue obtained months after SARS-CoV-2 infection.
9 A recent study this year has showed persistence of SARS-CoV-2 viral RNA and sustained (up to 2 years) tissue-based T-cell activation in people with mild acute COVID-19; and that these abnormalities appear to correlate with long COVID symptomatology.
10 This study also showed the presence of double-stranded RNA in some patients up to nearly 2 years following initial infection; double-stranded RNA is present during active viral transcription and translation activity or viral replication.
10 Altogether, these data suggest ongoing replication or transcriptional activity and possible persistence of active SARS-CoV-2 reservoirs that could drive long-term tissue-based immune disturbances and raises the plausibility that targeting viral persistence (via antivirals) could be a key therapeutic avenue to both prevent and treat long COVID.
Overall, the evidence base is growing for a role of SARS-CoV-2 antivirals in the prevention of long COVID. The hypothesis that patients with established long COVID and evidence of viral persistence could also respond to antiviral therapy is plausible and should be thoroughly evaluated. We have made substantial progress during the past several years in characterising the epidemiology and mechanisms of long COVID, but much remains to be done in preventing and treating the condition. Addressing the research and care needs of people with long COVID must remain a high priority for governments. The health and wellbeing of millions of people now and in the future depends on us making this progress.
