COMMENT|ONLINE FIRST

SARS-CoV-2 rebound with and without antivirals

Nicola Petrosillo

Lancet Infect Dis Published: February 13, 2023

DOI:https://doi.org/10.1016/S1473-3099(23)00063-4

As the COVID-19 pandemic continues, interventions for preventing SARS-CoV-2 transmission and progression to severe disease remain priorities. Vaccines against COVID-19 have an important role in preventing symptomatic infections that would otherwise lead to hospitalisation and death, but are less effective in preventing transmission. In addition, monoclonal antibodies have substantially reduced effectiveness against recently emerged strains,¹ and should be tailored to the variants. Therefore, antiviral compounds, specifically nirmatrelvir–ritonavir, molnupiravir, and remdesivir, when used promptly at the onset of SARS-CoV-2 infection, are currently the most effective drug therapies for inhibiting viral replication.

Targeting the early replication stage of SARS-CoV-2 is pivotal to prevent progression to severe COVID-19, especially in immunocompromised and older individuals. In the outpatient setting, both nirmatrelvir–ritonavir and molnupiravir administered for 5 days have led to greater reductions in the relative risk of hospitalisation or death versus placebo in unvaccinated patients at high risk of severe COVID-19, with an associated decrease in nasopharingeal viral load.2, 3

However, recently reported cases of virological rebound after completion of a 5-day course of nirmatrelvir–ritonavir have raised concerns around the real world effectiveness of antivirals againstSARS-CoV-2.⁴

In The Lancet Infectious Diseases, Wong and colleagues⁵ assessed the incidence of viral burden rebound, and evaluated associated risk factors and clinical outcomes, in a retrospective cohort of consecutive hospitalised patients with non-oxygen-dependent COVID-19 during the omicron BA.2.2 wave (from Feb 26 to July 3, 2022) in Hong Kong. Outcomes were compared between patients receiving and not receiving oral antivirals. Viral burden rebound was defined as a reduction in cycle threshold (Ct) value larger than or equal to 3 between two consecutive measurements, with this decrease sustained in at least an immediately subsequent Ct measurement for patients with three or more measurements.

Among 4592 patients, 213 (4·6%) were reported to have viral burden rebound. Rebound occurred in 16 (6·6%) of 242 patients receiving nirmatrelvir–ritonavir, 27 (4·8%) of 563 patients receiving molnupiravir, and 170 (4·5%) of 3787 patients who did not receive oral antivirals (control group). No significant difference in the incidence of viral burden rebound was found among the three groups. Additionally, a composite clinical outcome of invasive mechanical ventilation initiation, intensive care unit admission, and mortality from day 5 of follow-up was not significantly associated with viral burden rebound across the three groups.

As expected, immunocompromised status was associated with increased odds of viral burden rebound, regardless of the use of SARS-CoV-2 antivirals. Of note, in the nirmatrelvir–ritonavir group, patients with high comorbidity burden (Charlson Comorbidity Index >6) and those taking corticosteroids had increased odds of rebound; and in the molnupiravir group, patients taking corticosteroids had increased odds of rebound. Surprisingly, the odds of viral burden rebound in patients receiving nirmatrelvir–ritonavir were significantly reduced in individuals who were not fully vaccinated (defined as those who had received less than two doses of BNT162b2 or less than three doses of CoronaVac). Additionally, in patients receiving nirmatrelvir–ritonavir and in those receiving molnupiravir, individuals aged 18–65 years had higher odds of viral burden rebound than individuals aged 65 years or older. A limitation of the study was that no sequencing was performed, making it difficult to differentiate between relapse with the same strain and recurrence of reinfection by a different strain than the one responsible for the initial infection episode.

These rates of viral rebound from a real-world study⁵ are consistent, although higher, than the rates reported in the EPIC-HR trial, in which viral load rebound occurred in 23 (2·3%) of 990 patients receiving nirmatrelvir–ritonavir and 17 (1·7%) of 980 patients receiving placebo, without significant difference between these groups.⁶ Collectively the data show that COVID-19 rebound is rare but possible, with or without completion of a SARS-CoV-2 antiviral course. In the case of rebound following antiviral treatment, immune evasion due to early viral suppression has been hypothesised as a cause,⁷ and this could also partially explain why in the study by Wong and colleagues,⁵ fully vaccinated individuals were at increased risk of rebound.

Conversely, in one patient with COVID-19 recrudescence, Carlin and colleagues identified a robust antibody and T-cell immune response,⁸ accounting for a mild infection with a low risk of disease progression.

Emergence of SARS-CoV-2 resistance as a cause of viral rebound is unlikely, considering that in previous studies on COVID-19 rebound, resistance mutations have not been identified.⁹ Other noteworthy hypotheses include the proposal that antiviral exposure might be insufficient due to individual pharmacokinetics,⁸ or that SARS-CoV-2 persists in viral sanctuaries—sites where viruses can persist and potentially remain transmissible after drug treatments such as antivirals.¹⁰ In the case of SARS-CoV-2 persistence, perhaps a 5-day course of antivirals could be insufficient to eradicate SARS-CoV-2 in individuals with immunocompromised status or comorbidities, or in those taking steroids.

Given that no association was found between oral antiviral treatment and viral burden rebound, the study by Wong and colleagues emphasises the importance of continuing to offer antivirals to individuals with COVID-19 who are at increased risk of progression to severe COID-19. A major advance from this study is the identification of risk predictors of viral burden rebound. These predictors were immunocompromised status and concomitant use of corticosteroids for all patients; and high comorbidity burden in patients receiving nirmatrelvir–ritonavir. Further studies are needed to better define the causes of viral rebound in patients with COVID-19, and to understand how to tailor the administration of SARS-CoV-2 antivirals in accordance with patient pharmacokinetics.