Nirmatrelvir–Ritonavir and Viral Load Rebound in Covid-19

Anderson, Annaliesa S.; Caubel, Patrick; Rusnak, James M.

doi:10.1056/nejmc2205944

Cited by 88 publications

(95 citation statements)

References 5 publications

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“…In summary, when compared to matched non-recipients, recipients of nirmatrelvir-ritonavir were 87–88% less likely to have a COVID-19-related hospitalization following a positive outpatient SARS-CoV-2 test across all ages and in a population that was highly vaccinated. These findings confirm the added value of nirmatrelvir-ritonavir in preventing severe clinical outcomes, despite the potential risk of prolonged viral shedding after treatment, 28 in populations with high levels of immunity derived either from vaccination or prior natural infection.…”

Section: Discussionsupporting

confidence: 69%

Effectiveness of nirmatrelvir-ritonavir against hospital admission or death: a cohort study in a large US healthcare system

Lewnard

Malden

Hong

et al. 2022

Preprint

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Background: In the United States, oral nirmatrelvir-ritonavir (PaxlovidTM) is authorized for use among patients aged ≥12 years with mild-to-moderate SARS-CoV-2 infection who are at risk for progression to severe COVID-19, including hospitalization. However, effectiveness under real-world conditions has not been well established. Methods: We undertook a matched, observational cohort study of non-hospitalized individuals with SARS-CoV-2 infection to compare outcomes between those who received or did not receive nirmatrelvir-ritonavir within the Kaiser Permanente Southern California healthcare system. Individuals were matched on testing date, age, sex, treatment/care setting, symptoms status (including presence or absence of acute COVID-19 symptoms at testing, and time from symptom onset to testing), history of vaccination and SARS-CoV-2 infection, Charlson comorbidity index, and prior-year healthcare utilization. Time to hospital admission was compared between matched COVID-19 cases who received or did not receive nirmatrelvir-ritonavir. Primary analyses evaluated treatment effectiveness against any hospital admission and acute respiratory infection (ARI)-associated hospital admission, with dispense occurring 0-5 days symptom onset. Secondary analyses evaluated effectiveness against the same endpoints for all treatment dispenses. We measured treatment effectiveness as (1-adjusted hazards ratio [aHR])*100%, estimating the aHR via Cox proportional hazards models accounting for match strata and additional patient characteristics. Results: Analyses included 4,329 nirmatrelvir-ritonavir recipients and 20,980 matched non-recipients who were followed ≥30 days after a positive SARS-CoV-2 outpatient test. Overall, 23,603 (93.3%) and 19,564 (78.1%) of 25,039 participants had received ≥2 and ≥3 COVID-19 vaccine doses, respectively. A total of 23,858 (94.2% of 25,039) patients were symptomatic at the point of testing, with a 2.1 day mean time from symptom onset to testing. For patients dispensed nirmatrelvir-ritonavir 0-5 days after symptom onset, effectiveness in preventing all hospital admissions was 88.1% (95% confidence interval: 49.0-97.5%) over 15 days and 71.9% (25.3-90.0%) over 30 days, respectively. Effectiveness in preventing ARI-associated hospital admissions was 88.3% (12.9-98.8%) and 87.3% (18.3-98.5%) over 15 and 30 days, respectively. In expanded analyses that included patients receiving treatment at any point during their clinical course, effectiveness was 86.6% (54.9-96.3%) and 78.0% (46.2-91.4%) in preventing all hospital admissions over 15 and 30 days, respectively, and 93.7% (52.5-99.4%) and 92.8% (53.9-99.1%) in preventing ARI-associated hospital admissions over 15 and 30 days. Subgroup analyses identified similar effectiveness estimates among patients who had received ≥2 COVID-19 vaccine doses. Implications: In a real-world setting with high levels of COVID-19 vaccine and booster uptake, receipt of nirmatrelvir-ritonavir 0-5 days after symptom onset was associated substantial reductions in risk of hospital admission among individuals testing positive for SARS-CoV-2 infection in outpatient settings.

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Section: Discussionsupporting

confidence: 69%

Effectiveness of nirmatrelvir-ritonavir against hospital admission or death: a cohort study in a large US healthcare system

Lewnard

Malden

Hong

et al. 2022

Preprint

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“…For our next phase, we will collect testing swabs for viral sequencing as well as serum from participants to understand any virus specific or host specific factors that provide insight into Paxlovid rebound. Retrospective analyses have reported the lack of an association between viral load rebound and low nirmatrelvir exposure or resistance to nirmatrelvir, however, they were done during the B.1.617.2 (delta) variant rather than the B1.1.529 (omicron) variant [23]. Notably, the EPIC-HR study focused on viral load based rebound only, which does not translate into the presence of infectious virus, and more importantly does not include symptom rebound [4].…”

Section: Discussionmentioning

confidence: 99%

The Paxlovid Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences Between Paxlovid and Untreated COVID-19 Participants

Pandit

Radin

Chiang

et al. 2022

Preprint

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Introduction: The uptake of Paxlovid in individuals infected with COVID-19 has been significantly limited by concerns around the Paxlovid rebound phenomenon despite the scarcity of evidence around its epidemiology. The purpose of this study was to prospectively compare the epidemiology of Paxlovid rebound in treated and untreated participants with acute COVID-19 infection Methods: We designed a digital, prospective observational study, which included participants who tested positive for COVID-19 and were clinically eligible for Paxlovid. Participants were assigned to a Paxlovid or control group based on their decision to take the medication. Both groups were provided 12 rapid antigen tests and asked to test and answer symptom surveys on a regular frequent schedule for 16 days. Viral rebound based on test results and COVID-19 symptom rebound based on patient reported symptoms were evaluated. Results: Viral rebound incidence was 14.2% in the Paxlovid group (n=127) and 9.3% in the control group (n=43). COVID-19 symptom rebound incidence was higher in the Paxlovid group (18.9%) compared to the control group (7.0%). There were no notable differences in viral rebound by age, gender, pre-existing conditions, or major symptom groups during the acute phase or at the 1-month interval. Conclusion: This preliminary report of our prospective study suggests that rebound after clearance of test positivity or symptom resolution is higher than previously reported. However, we observed a similar rate of rebound in both in the Paxlovid and control groups. Large studies with diverse participants and extended follow-up are needed to better understand the rebound phenomena.

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“…Whereas therapeutic molnupiravir had ultimately a sterilizing effect in infected ferrets and prophylactic molnupiravir prevented productive infection, shed virus titers in animals that received therapeutic or prophylactic paxlovid plateaued and/or increased towards the end of the treatment course. Two lines of evidence, clinical reports of rebounding virus replication in human patients who have received paxlovid 2,21,22 and failure of the EPIC-PEP trial of prophylactic use of paxlovid 19,20 , underscore relevance of these ferret-derived data for human disease. If the model predicts the impact of molnupiravir on virus transmission with equal accuracy, prophylactic use of molnupiravir may have the potential to lower the risk of close contact transmission.…”

Section: Discussionmentioning

confidence: 99%

“…Assessing the effect of post-exposure prophylactic treatment of household contacts of a confirmed SARS-CoV-2 case with paxlovid, the EPIC-PEP trial revealed no significant effect of paxlovid drug on preventing transmission 19,20 . Clinical reports demonstrated rebounding virus replication in patients who have received paxlovid 2,21,22 and anecdotal cases of SARS-CoV-2 transmission at rebound have further questioned whether paxlovid may provide epidemiologic benefit through reducing the risk of SARS-CoV-2 spread. Using the ferret SARS-CoV-2 transmission model, we have established in previous work that oral molnupiravir blocks direct-contact transmission of the virus to untreated sentinels within 18 hours of treatment start 23,24 .…”

Section: Introductionmentioning

confidence: 99%

Paxlovid-like nirmatrelvir/ritonavir fails to block SARS-CoV-2 transmission in ferrets

Cox

Lieber

Wolf

et al. 2022

Preprint

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Despite the continued spread of SARS-CoV-2 and emergence of variants of concern (VOC) that are capable of escaping preexisting immunity, therapeutic options are underutilized. In addition to preventing severe disease in high-risk patients, antivirals may contribute to interrupting transmission chains. The FDA has granted emergency use authorizations for two oral drugs, molnupiravir and paxlovid. Initial clinical trials suggested an efficacy advantage of paxlovid, giving it a standard-of-care-like status in the United States. However, recent retrospective clinical studies suggested a more comparable efficacy of both drugs in preventing complicated disease and case-fatalities in older adults. For a direct efficacy comparison under controlled conditions, we assessed potency of both drugs against SARS-CoV-2 in two relevant animal models; the Roborovski dwarf hamster model for severe COVID-19 in high-risk patients and the ferret model of upper respiratory tract disease and transmission. After infection of dwarf hamsters with VOC omicron, paxlovid and molnupiravir were efficacious in mitigating severe disease and preventing death. However, a pharmacokinetics-confirmed human equivalent dose of paxlovid did not significantly reduce shed SARS-CoV-2 titers in ferrets and failed to block virus transmission to untreated direct-contact ferrets, whereas transmission was fully suppressed in a group of animals treated with a human-equivalent dose of molnupiravir. Prophylactic administration of molnupiravir to uninfected ferrets in direct contact with infected animals blocked productive SARS-CoV-2 transmission, whereas all contacts treated with prophylactic paxlovid became infected. These data confirm retrospective reports of similar therapeutic benefit of both drugs for older adults, and reveal that treatment with molnupiravir, but not paxlovid, may be suitable to reduce the risk of SARS-CoV-2 transmission.

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Nirmatrelvir–Ritonavir and Viral Load Rebound in Covid-19

Cited by 88 publications

References 5 publications

Effectiveness of nirmatrelvir-ritonavir against hospital admission or death: a cohort study in a large US healthcare system

Effectiveness of nirmatrelvir-ritonavir against hospital admission or death: a cohort study in a large US healthcare system

The Paxlovid Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences Between Paxlovid and Untreated COVID-19 Participants

Paxlovid-like nirmatrelvir/ritonavir fails to block SARS-CoV-2 transmission in ferrets

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