Rapid Relapse of Symptomatic Omicron SARS-CoV-2 Infection Following Early Suppression with Nirmatrelvir/Ritonavir

Abstract

We describe relapse of COVID-19 symptoms and SARS-CoV-2 viral load following nirmatrelvir/ritonavir (NM/R) in 10 non-immunocompromised patients aged 31 to 71-years-old. Most patients improved rapidly after treatment with NM/R and had negative antigen or PCR tests prior to relapse on Days 9-12 of their illness. Relapse symptoms were described most frequently as cold symptoms, though some patients experiencing a recurrence of fatigue and headache. All relapses resolved without additional antiviral treatment. Viral load during relapse was comparable to levels during initial infection. Sequencing in three patients indicated that relapse was not due to a treatment-emergent mutation or infection with a different viral strain. One symptomatic and one presymptomatic patient transmitted SARS-CoV-2 to family members during relapse. The presence of high viral load and the occurrence of two transmission events suggest that patients with relapse should isolate until antigen testing is negative.

Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment — California, December 2021–May 2022

“…In this analysis of data from patients aged ≥12 years in a large integrated health care system who received Paxlovid treatment during December 2021-May 2022, hospitalizations or ED encounters for COVID-19-related illness during the 5-15 days after Paxlovid dispensation occurred among <1% of all patients. The rarity of these outcomes is consistent with evidence from recent case reports and large observational studies, which found that symptoms experienced by patients with COVID-19 rebound after treatment with Paxlovid are milder than those experienced during the primary infection (3)(4)(5) and are unlikely to lead to hospitalization (9,10).…”

Virologic characterization of symptom rebound following nirmatrelvir-ritonavir treatment for COVID-19

“…Finally, we did not identify emergence of any resistance-associated polymorphisms in any of the six specimens that were sequenced. Our findings add support to others that drug resistance does not appear to be a significant contributor to relapse [3,8] and suggest that nirmatrelvirritonavir may retain activity in most cases of symptom recrudescence.…”

“…The US Food and Drug Administration granted emergency use authorization (EUA) status for its use in December, 2021 and it is currently a preferred therapy for ambulatory individuals with COVID-19 at high risk of severe disease [2]. As nirmatrelvir-ritonavir has entered into broad clinical use, reports have emerged of recurrent symptoms in a subset of treated individuals who had initial symptomatic improvement [3]. However, the mechanism and viral characteristics of symptomatic relapse after nirmatrelvir-ritonavir therapy remain unclear.…”

Virologic and Immunologic Characterization of Coronavirus Disease 2019 Recrudescence After Nirmatrelvir/Ritonavir Treatment

“…This study suggests that neither development of NM resistance nor absence of neutralizing antibody were likely causes of the observed recrudescence. The phenomenon of relapse after NM/r has been described in a limited number of individuals, all of whom developed virologic rebound approximately 9–14 days after symptom onset and were likely infected with Omicron variants [ 2 ]. A small percentage of both NM/r- and placebo-treated individuals enrolled in the primary NM/r study, Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR), which was mostly conducted before Omicron emergence, also experienced increasing SARS-CoV-2 RNA levels after stopping NM/r treatment at day 10 or 14 after infection [ 1 , 4 ].…”

“…Early administration of the oral protease inhibitor nirmatrelvir combined with ritonavir (NM/r) (Paxlovid) can reduce severe disease due to coronavirus disease 2019 (COVID-19) [ 1 ]. Nirmatrelvir inhibits the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease, thus blocking viral replication, but virologic and symptomatic rebound after NM/r treatment was recently reported [ 2 ]. We evaluated if NM resistance or impaired humoral immunity contributed to a case of COVID-19 recrudescence after NM/r treatment.…”