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Head, Microbial Genomics
irsiCaixa AIDS Research Institute
Department of Infectious Diseases
Hospital Universitari Germans Trias i Pujol
Badalona, Catalonia, Spain
Roger Paredes, MD, PhD: consultant/advisor/speaker: Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer.
Since omicron became the dominant SARS-CoV-2 variant, countries with adequate COVID-19 vaccination coverage have witnessed overall decreases in COVID-19–related mortality and hospitalization rates despite steady increases in SARS-CoV-2 transmissibility.
Severe COVID-19 remains an important clinical problem, but nowadays it is largely confined to high-risk populations. These include individuals older than 65 years of age; individuals with obesity, cardiovascular or metabolic disease, or immunocompromising conditions; and individuals who are unvaccinated or undervaccinated. Studies have consistently shown that early COVID-19 antiviral therapy in high-risk, unvaccinated individuals prevents clinical deterioration, hospitalization, and death by 50% to 85%.
Such benefits, however, are much harder to prove in lower-risk people. Only a minority of them (<1%) end up developing severe COVID-19. Thus, the small expected effect size of early antiviral therapy on clinical progression would require very large (and expensive) clinical trials to be proven. Whereas 20-50 high-risk patients must be treated to prevent 1 hospitalization or death, preventing 1 hospitalization or death in low-risk patients requires treating several hundreds of them, which I believe is unlikely to be cost-effective at current drug prices.
But hospitalization and death are not the only important outcomes. Several studies have demonstrated that, in addition to reductions in mortality and hospitalization, early antiviral treatment may shorten symptom duration. Even mild forms of COVID-19 are often associated with annoying symptoms (eg, fever, malaise, dysgeusia, asthenia) that may persist for days or weeks and delay patients’ return to a full, productive life. Early treatment with some (but not all) antivirals may accelerate SARS-CoV-2 viral load decay in upper respiratory airways. This might help reduce viral transmission and facilitate a safer and faster return to work, school, and other aspects of life.
Molnupiravir in Low-Risk Patients
In the large PANORAMIC trial of 25,783 low-risk subjects, early molnupiravir treatment did not reduce already low hospitalizations or death compared with usual care (0.8% in both molnupiravir and usual care groups), with similar estimates among all the subgroups analyzed.
However, molnupiravir treatment led to a faster recovery of symptoms and reduced viral detection and load. The observed median time-to-first recovery (TTR) from randomization was 9 days in the molnupiravir group and 15 days in the usual care group. There was an estimated benefit of 4.2 days (95% Bayesian credible interval [BCI]: 3.8-4.6) in TTR, giving a posterior probability of superiority of >0.999 (estimated median TTR of 10.3 days vs 14.5 days, respectively; HR: 1.36 days; 95% BCI: 1.3-1.4), which met the prespecified superiority threshold.
Moreover, on Day 7, SARS-CoV-2 virus was below detection levels in 21% of patients in the molnupiravir group vs 3% in the usual care group (P = .039), and the mean viral load was lower in patients in the molnupiravir group compared with those receiving usual care. Only a small percentage (0.4% participants in each group) experienced serious adverse events.
Remdesivir in High-Risk Patients
Early remdesivir treatment of high-risk patients with COVID-19 in the PINETREE trial was also associated with sooner reduction in symptoms. Of the 126 patients who completed the baseline FLU-PRO Plus questionnaire before their first remdesivir infusion, 34.8% in the remdesivir group and 25.0% in the placebo group reported alleviation of symptoms by Day 14 (rate ratio: 1.41; 95% CI: 0.73-2.69).
In a post hoc analysis involving patients who completed the baseline questionnaire any time on the day of the first remdesivir infusion, 36.1% in the remdesivir group and 20.0% in the placebo group reported alleviation of symptoms by Day 14 (rate ratio: 1.92; 95% CI: 1.26-2.94). However, remdesivir administration did not affect upper respiratory viral load kinetics, consistent with findings from other trials.
Nirmatrelvir Plus Ritonavir in High-Risk Patients and Standard-Risk Patients
In high-risk patients, the EPIC-HR trial of early nirmatrelvir plus ritonavir reported a faster decay of upper respiratory viral load with nirmatrelvir plus ritonavir vs placebo. After adjustment for baseline viral load, serology status, and geographic region, nirmatrelvir plus ritonavir use reduced viral load at treatment Day 5 by a factor of 10 relative to placebo, when treatment was initiated within 5 days after symptom onset. However, no differences in symptom duration were reported.
In standard-risk patients in the EPIC-SR trial, early treatment with nirmatrelvir plus ritonavir did not meet the primary endpoint of self-reported, sustained alleviation of all symptoms for 4 consecutive days. There was a non–statistically significant 57% reduction in hospitalization or death in vaccinated patients treated with nirmatrelvir plus ritonavir (3/361, 0.83%) vs placebo (7/360, 1.94%) and a 62% decrease in medically attended visits (P = .0228).
Antivirals and Prevention of Long COVID
An important additional benefit of early antiviral therapy would be the potential reduction in long COVID. At least 10% of patients with mild COVID-19 will develop long COVID, which implies millions of people worldwide bearing a major disability toll.
In an analysis of healthcare databases within the US Department of Veterans Affairs, in patients who had a positive SARS-CoV-2 test between March 1 and June 30, 2022, and at least 1 risk factor for clinical progression, treatment with nirmatrelvir plus ritonavir during the first 5 days of symptoms showed a reduced risk of long COVID compared with those who did not receive treatment for COVID-19 (HR: 0.74; 95% CI: 0.69-0.81). They also showed an absolute risk reduction (ARR) of 2.32 (95% CI: 1.73-2.91), including reduced risk of 10 of 12 postacute sequelae.
In this group, nirmatrelvir plus ritonavir treatment was also associated with reduced risk of postacute death (HR: 0.52; 95% CI: 0.35-0.77 and ARR: 0.28; 95% CI: 0.14-0.41) and postacute hospitalization (HR: 0.70; 95% CI: 0.61-0.80 and ARR: 1.09; 95% CI: 0.72-1.46). Nirmatrelvir plus ritonavir was associated with a reduced risk of postacute sequelae in people who were unvaccinated, vaccinated, and boosted, and in people with primary SARS-CoV-2 infection and reinfection. Studies are underway to confirm and extend such findings to other antivirals.
Costs and Benefits
Early antiviral treatment may contribute to accelerated symptom resolution and, in some cases, decreases in upper respiratory viral loads, even in low-risk patients with mild COVID-19. But is the use of antivirals in this population for this purpose cost-effective? There are clear reasons for healthcare systems and insurers to invest in drugs that prevent hospitalizations, severe clinical events, long COVID, and deaths. But because mild COVID-19 symptoms can be managed with over-the-counter medicines, such as acetaminophen or nonsteroidal anti-inflammatory drugs, it is less clear whether antivirals are needed. To me, more data on the potential benefits in preventing poor outcomes and long COVID are needed to determine whether outpatient antiviral use for low-risk patients with mild COVID-19 is a cost-effective treatment option.
How often do you prescribe antiviral agents for patients with mild COVID-19 to reduce symptom duration? Join the conversation by leaving a comment below.