How common is viral burden rebound in hospitalized COVID-19 patients with or without oral antiviral treatment?

A real-world study during Hong Kong’s Omicron BA.2.2 wave has shown that viral burden rebound is uncommon in hospitalized COVID-19 patients not requiring supplemental oxygen on admission, regardless of whether they were treated with nirmatrelvir/ritonavir or molnupiravir. However, immunocompromised patients, regardless of oral antiviral use, are more likely to have viral burden rebound.

No association was found between viral burden rebound and the composite adverse outcome of mortality, invasive mechanical ventilation (IMV) initiation and intensive care unit (ICU) admission, suggesting that oral antivirals should be used in COVID-19 patients at high risk of disease progression. [Lancet Infect Dis 2023;doi:10.1016/S1473-3099(22)00873-8]

The population-wide, retrospective cohort study involved 4,592 adult patients with confirmed SARS-CoV-2 infection hospitalized and observed between 26 February and 3 July 2022. Of these patients, 242 received nirmatrelvir/ritonavir and 563 received molnupiravir, initiated at a median of 1 day since symptom onset or diagnosis confirmation. The remaining 3,787 patients not receiving any oral antivirals served as the control group.

The median time to peak viral load was 0 days in the nirmatrelvir/ritonavir group and 1 day in the molnupiravir and control groups, while median time to low viral burden (ie, cycle threshold [Ct] value >30) was 8 days, 11 days and 10 days, respectively.

Viral burden rebound was defined as viral load increase with a reduction in Ct value of ≥3 between two consecutive tests, which was sustained in ≥1 subsequent Ct measurement if ≥3 tests were performed.

Rates of viral burden rebound were 6.6 percent with nirmatrelvir/ritonavir, 4.8 percent with molnupiravir, and 4.5 percent in the control group. After adjusting for baseline covariables, post hoc logistic regression showed no significant differences in viral burden rebound rates across study groups (nirmatrelvir/ritonavir vs control: adjusted odds ratio [adjOR], 1.599; 95 percent confidence interval [CI], 0.937–2.727; p=0.085) (molnupiravir vs control: adjOR, 1.193; 95 percent CI, 0.781–1.823; p=0.41) (nirmatrelvir/ritonavir vs molnupiravir: adjOR, 1.340; 95 percent CI, 0.703–2.553; p=0.37).

However, immunocompromised patients were more likely to experience viral burden rebound, regardless of whether they were treated with oral antivirals (nirmatrelvir/ritonavir: odds ratio [OR], 7.37; 95 percent CI, 2.56–21.26; p=0.0002) (molnupiravir: OR, 3.05; 95 percent CI, 1.28–7.25; p=0.012) (control: OR, 2.21; 95 percent CI, 1.50–3.27; p<0.0001).

For both antivirals, the likelihood of viral burden rebound was significantly increased in patients aged 18–65 years vs >65 years (nirmatrelvir/ritonavir: OR, 3.09; 95 percent CI, 1.00–9.53; p=0.050) (molnupiravir: OR, 2.68; 95 percent CI, 1.09–6.58; p=0.032), and in patients on concomitant corticosteroids (nirmatrelvir/ritonavir: OR, 7.51; 95 percent CI, 1.67–33.82; p=0.0086) (molnupiravir: OR, 3.11; 95 percent CI, 1.23–7.82; p=0.016).

Among patients who received nirmatrelvir/ritonavir, the likelihood of viral burden rebound was significantly increased in those with high comorbidity burden (Charlson Comorbidity Index >6; OR, 6.02; 95 percent CI, 2.09–17.38; p=0.0009), but significantly lower in those without complete COVID-19 vaccination (≤1 dose of BNT162b2 or ≤2 doses of CZ02; OR, 0.16; 95 percent CI, 0.04–0.67; p=0.012). According to the researchers, vaccine-induced immune imprinting is a possible reason for the increased occurrence of viral burden rebound in fully vaccinated individuals, which warrants further investigation.

Notably, viral burden rebound did not appear to be associated with the composite adverse clinical outcome of mortality, IMV initiation and ICU admission from day 5 of follow-up (nirmatrelvir/ritonavir: adjOR, 1.90; 95 percent CI, 0.48–7.59; p=0.36) (molnupiravir: adjOR, 1.05; 95 percent CI, 0.39–2.84; p=0.92) (control: adjOR, 1.27; 95 percent CI, 0.89–1.80; p=0.18). “Oral antivirals should be prescribed to COVID-19 patients at [high] risk of severe or fatal outcomes,” they concluded.