Viral Load Rebound in Placebo and Nirmatrelvir-Ritonavir Treated COVID-19 Patients is not Associated with Recurrence of Severe Disease or Mutations

Soares, Holly; Baniecki, Mary Lynn; Cardin, Rhonda D.; Leister-Tebbe, Heidi; Zhu, Yuao; Guan, Shunjie; Hyde, Craig; He, Wen; Wang, Zhenyu; Li, Hao; Perrin, B. Scott; Bao, Weihang; Chan, Phylinda L. S.; Damle, Bharat; Menon, Sandeep; Hammond, Jennifer; Anderson, Annaliesa S.

doi:10.21203/rs.3.rs-1720472/v1

Cited by 5 publications

(7 citation statements)

References 11 publications

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“…With the anecdotal reports of clinical relapse after nirmatrelvir-ritonavir treatment, it is important to understand the natural history of COVID-19 and underlying rates of viral and symptom rebound. In the analysis of the EPIC-HR phase 3 outpatient study of nirmatrelvir-ritonavir for mild-moderate COVID-19, a 0.5 log 10 or greater increase in nasal SARS-CoV-2 RNA levels from post-treatment levels was detected in approximately 4% of participants receiving placebo and 7% of participants receiving nirmatrelvir-ritonavir 7 . However, viral RNA levels were only quantified at two follow-up time points (5 and 9 days after the end of nirmatrelvir-ritonavir/placebo) and this may explain why we found a much higher rate of viral rebound with intensive daily sampling.…”

Section: Discussionmentioning

confidence: 99%

“…For both the viral and symptom rebound calculations, we have defined a simulated post-nirmatrelvir/ritonavir baseline time point in our analyses that is comparable to the baseline time point in the analysis of viral rebound from the phase 3 trial of nirmatrelvir-ritonavir (EPIC-HR) 7 . For the primary analysis, we restricted to participants with ≤5 days of symptoms at the time of study enrollment and then designated the 5 th day of the study (study day 4) as the baseline time point ( Supplementary Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

“…For both the viral and symptom rebound calculations, we have defined a simulated postnirmatrelvir/ritonavir baseline time point in our analyses that is comparable to the baseline time point in the analysis of viral rebound from the phase 3 trial of nirmatrelvir-ritonavir (EPIC-HR) 7 .…”

Section: Definition Of "Baseline" Time Point For Both Viral and Sympt...mentioning

confidence: 99%

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Viral and Symptom Rebound in Untreated COVID-19 Infection

Deo

Choudhary

Moser

et al. 2022

Preprint

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Background: There are reports of viral RNA and symptom rebound in people with COVID-19 treated with nirmatrelvir/ritonavir. Since the natural course of viral and symptom trajectories of COVID-19 has not been well described, we evaluated the incidence of viral and symptom rebound in untreated outpatients with mild-moderate COVID-19. Methods: The study population included 568 participants enrolled in the ACTIV-2/A5401 platform trial who received placebo. Anterior nasal swabs were collected for SARS-CoV-2 RNA testing on days 0-14, 21 and 28. Participants recorded the severity of 13 targeted symptoms daily from day 0 to 28. Viral rebound was defined as ≥0.5 log10 viral RNA copies/mL increase and symptom rebound was defined as a 4-point total symptom score increase from baseline. Baseline was defined as study day 4 (primary analysis) or 8 days from symptom onset (secondary analysis). Findings: In both the primary and secondary analyses, 12% of participants had viral rebound. Viral rebounders were older than non-rebounders (median 54 vs 47 years, P=0.04). Symptom rebound occurred in 27% of participants after initial symptom improvement and in 10% of participants after initial symptom resolution. The combination of high-level viral rebound to ≥5.0 log10 RNA copies/mL and symptom rebound after initial improvement was observed in 1-2% of participants. Interpretation: Viral RNA rebound or symptom relapse in the absence of antiviral treatment is common, but the combination of high-level viral and symptom rebound is rare. Funding: This study was supported by the National Institute of Allergy and Infectious Diseases; ACTIV-2/A5401 ClinicalTrials.gov number NCT04518410.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Viral and Symptom Rebound in Untreated COVID-19 Infection

Deo

Choudhary

Moser

et al. 2022

Preprint

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“…Clinical data suggest that patients treated with nirmatrelvir/ritonavir may experience a resurgence of COVID-19, although to date these phenomena have only been associated with mild-stage COVID-19 cases 21,[46][47][48][49][50][51][52][53][54][55][56][57][58][59] . A brief return of symptoms may be part of the natural history of SARS-CoV-2 infection, regardless of nirmatrelvir/ritonavir use or vaccination status, and there is no evidence to recommend additional treatment with nirmatrelvir/ritonavir or another therapy for SARS-CoV-2 when a resurgence of COVID-19 is suspected.…”

Section: Discussionmentioning

confidence: 99%

Real-World Effectiveness of Nirmatrelvir/Ritonavir on Covid-19-Associated Hospitalization Prevention: A Population-Based Cohort Study in the Province of Québec, Canada

Kaboré

Laffont

Diop

et al. 2023

Preprint

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Introduction The nirmatrelvir/ritonavir (PAXLOVIDTM) is an antiviral blocking the replication of SARS-CoV-2. Early treatment with this antiviral has showed to reduce COVID-19 hospitalization and death in unvaccinated outpatients with mild-to-moderate COVID-19 and high risk of progression to severe disease with variants before Omicron. However, the current epidemiological context and the level of immunity in the population (vaccination and/or natural infection) have evolved considerably since the disclosure of these results. Thus, real-world evidence studies in vaccinated outpatients with lineage and sublineage of the variant are needed. Objective To assess whether nirmatrelvir/ritonavir treatment reduces the risk of COVID-19-associated hospitalization among Québec outpatients with mild-to-moderate COVID-19 at high risk of progression to severe disease in a real-world context, regardless of vaccination status and circulating variants, in the province of Québec. Methods This was a retrospective cohort study of SARS-CoV-2-infected outpatients who received nirmatrelvir/ritonavir between March 15 and August 15, 2022, using data from the Québec provincial clinico-administrative databases. Outpatients treated with nirmatrelvir/ritonavir were compared to unexposed ones. The treatment group was matched with controls using propensity-score matching in a ratio of 1:1. The outcome was COVID-19-associated hospitalization occurring within 30 days following the index date. Poisson regression with robust error variance was used to estimate the relative risk of hospitalization among the treatment group compared to the control group. Results A total of 16,601 and 242,341 outpatients were eligible to be included in the treatment (nirmatrelvir/ritonavir) and control groups respectively. Among treated outpatients, 8,402 were matched to controls. Regardless of vaccination status, nirmatrelvir/ritonavir-treated outpatient status was associated with a 69% reduced relative risk of COVID-19-associated hospitalization (RR: 0.31 [95% CI: 0.28; 0.36]). The effect was more pronounced in outpatients without a complete primary vaccination course (RR: 0.04 [95% CI: 0.03; 0.06]), while treatment with nirmatrelvir/ritonavir was not associated with benefit when outpatients with a complete primary vaccination course were considered (RR: 0.93 [95% CI: 0.78; 1.08]) Subgroups analysis among outpatients with a primary vaccination course showed that nirmatrelvir/ritonavir treatment was associated with a significant decrease in relative risk of hospitalization in severely immunocompromised outpatients (RR: 0.66 [95% CI: 0.50; 0.89]) and in outpatients aged 70 years and older (RR: 0.50 [95% CI: 0.34; 0.74]) when the last dose of the vaccine was received more than six months before. Conclusions Among SARS-CoV-2 infected outpatients at high risk for severe COVID-19 during Omicron BA.2 and BA.4/5 surges, treatment with nirmatrelvir/ritonavir was associated with a significant reduced relative risk of COVID-19-associated hospitalization. This effect was observed in outpatients with incomplete primary vaccination course and in outpatients who were severely immunocompromised. Except for severely immunocompromised outpatients, no evidence of benefit was found in any category of outpatient with a complete primary vaccination course whose last dose of COVID-19 vaccine was received within six months.

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“…Despite its effectiveness at reducing viral titers and the risk of progressing to severe COVID-19 (5,6), the impact of nirmatrelvir treatment on the development of adaptive immunity to SARS-CoV-2 is unknown. It is also unclear why some patients experience a surprising rebound of viral load and a rapid relapse of COVID-19 symptoms shortly after the completion of an early and effective nirmatrelvir treatment (7)(8)(9)(10)(11)(12)(13)(14)(15). Viral sequencing indicates that the relapse is not associated with the selection of treatment-resistant mutations, nor due to infection with different SARS-CoV-2 variants (7,8).…”

Section: Main Textmentioning

confidence: 99%

Nirmatrelvir treatment blunts the development of antiviral adaptive immune responses in SARS-CoV-2 infected mice

Fumagalli

Lucia

Ravà

et al. 2022

Preprint

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Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS-CoV-2 pandemic. Nirmatrelvir, an orally available inhibitor of the 3- chymotrypsin-like cysteine protease, has been shown to reduce the risk of progression to severe COVID-19. However, the impact of nirmatrelvir treatment on the development of SARS-CoV-2-specific adaptive immune responses is unknown. Here, by using a mouse model of SARS-CoV-2 infection, we show that nirmatrelvir administration early after infection blunts the development of SARS-CoV-2-specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir-treated mice recruited significantly fewer memory T and B cells to the infected lungs and to mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals.

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Viral Load Rebound in Placebo and Nirmatrelvir-Ritonavir Treated COVID-19 Patients is not Associated with Recurrence of Severe Disease or Mutations

Cited by 5 publications

References 11 publications

Viral and Symptom Rebound in Untreated COVID-19 Infection

Viral and Symptom Rebound in Untreated COVID-19 Infection

Real-World Effectiveness of Nirmatrelvir/Ritonavir on Covid-19-Associated Hospitalization Prevention: A Population-Based Cohort Study in the Province of Québec, Canada

Nirmatrelvir treatment blunts the development of antiviral adaptive immune responses in SARS-CoV-2 infected mice

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