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Oral Nirmatrelvir-Ritonavir as Postexposure Prophylaxis for Covid-19. BACKGROUND: Clinical trials of treatments for coronavirus disease 2019 (Covid-19) have not shown a significant benefit of postexposure prophylaxis. METHODS: We conducted a phase 2-3 double-blind trial to assess the efficacy and safety of nirmatrelvir-ritonavir in asymptomatic, rapid antigen test-negative adults who had been exposed to a household contact with Covid-19 within 96 hours before randomization. The participants were randomly assigned in a 1:1:1 ratio to receive nirmatrelvir-ritonavir (300 mg of nirmatrelvir and 100 mg of ritonavir) every 12 hours for 5 days or for 10 days or matching placebo for 5 or 10 days. The primary end point was the development of symptomatic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, confirmed on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or rapid antigen testing, through 14 days in participants who had a negative RT-PCR test at baseline. RESULTS: A total of 2736 participants were randomly assigned to a trial group - 921 to the 5-day nirmatrelvir-ritonavir group, 917 to the 10-day nirmatrelvir-ritonavir group, and 898 to the placebo group. Symptomatic, confirmed SARS-CoV-2 infection developed by day 14 in 2.6% of the participants in the 5-day nirmatrelvir-ritonavir group, 2.4% of those in the 10-day nirmatrelvir-ritonavir group, and 3.9% of those in the placebo group. In each nirmatrelvir-ritonavir group, the percentage of participants in whom symptomatic, confirmed SARS-CoV-2 infection developed did not differ significantly from that in the placebo group, with risk reductions relative to placebo of 29.8% (95% confidence interval [CI], -16.7 to 57.8; P = 0.17) in the 5-day nirmatrelvir-ritonavir group and 35.5% (95% CI, -11.5 to 62.7; P = 0.12) in the 10-day nirmatrelvir-ritonavir group. The incidence of adverse events was similar across the trial groups, with dysgeusia being the most frequently reported adverse event (in 5.9% and 6.8% of the participants in the 5-day and 10-day nirmatrelvir-ritonavir groups, respectively, and in 0.7% of those in the placebo group). CONCLUSIONS: In this placebo-controlled trial, postexposure prophylaxis with nirmatrelvir-ritonavir for 5 or 10 days did not significantly reduce the risk of symptomatic SARS-CoV-2 infection. (Funded by Pfizer; ClinicalTrials.gov number, NCT05047601.).

This phase 2–3, double-blind, randomized, placebo-controlled trial evaluated two nirmatrelvir–ritonavir regimens as postexposure prophylaxis for household contacts of persons with Covid-19. The trial involved persons 18 years of age or older who were asymptomatic, had a negative screening rapid antigen test for SARS-CoV-2, and had been exposed to a household contact who was symptomatic with confirmed Covid-19 (the index patient) within 96 hours before randomization. Participants underwent randomization within 24 hours after their negative test and within 96 hours after the collection of the index patient’s positive test. Key exclusion criteria were a history of SARS-CoV-2 infection as determined on the basis of an antibody, antigen, or nucleic acid test; signs or symptoms of Covid-19 (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org); or receipt of any SARS-CoV-2 vaccine within 6 months before the screening visit. Additional details regarding the inclusion and exclusion criteria, prohibited previous or concomitant therapies, ethical trial conduct, and responsibilities related to the trial drugs are provided in the Supplementary Appendix. The protocol, available at NEJM.org, contains additional details. Representatives of Pfizer were responsible for the design and conduct of the trial; the collection, analysis, and interpretation of the data; and the writing of the manuscript. All the authors could access the data and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

epresentatives of Pfizer were responsible for the design and conduct of the trial; the collection, analysis, and interpretation of the data; and the writing of the manuscript. All the authors could access the data and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. Eligible participants were randomly assigned in a 1:1:1 ratio to receive 300 mg of nirmatrelvir and 100 mg of ritonavir for 5 days (the 5-day nirmatrelvir–ritonavir group) or 10 days (the 10-day nirmatrelvir–ritonavir group) or matching placebo capsules (consisting of inactive filler ingredients) for 10 days (Fig. S1); those in the 5-day nirmatrelvir–ritonavir group received placebo for 5 days after the completion of the 5-day regimen of nirmatrelvir–ritonavir. Randomization was stratified according to the presence of risk factors associated with severe Covid-1923 and geographic region (outlined in Table S2). Details regarding administration of the trial drugs or placebo and blinding procedures are summarized in the Supplementary Appendix.

y regimen of nirmatrelvir–ritonavir. Randomization was stratified according to the presence of risk factors associated with severe Covid-1923 and geographic region (outlined in Table S2). Details regarding administration of the trial drugs or placebo and blinding procedures are summarized in the Supplementary Appendix. Administration of the trial drugs or placebo and daily signs and symptoms of Covid-19, including severity as rated on a 4-point scale (with 0 indicating none, 1 mild, 2 moderate, and 3 severe), were recorded by the participants in an electronic diary. The recorded signs and symptoms that were collected included stuffy or runny nose, sore throat, shortness of breath or difficulty breathing, cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, and diarrhea. Severity definitions of signs and symptoms as suggested by the Food and Drug Administration for clinical trials24 and a description of how a diagnosis of SARS-CoV-2 was determined are provided in the Supplementary Appendix.

y aches, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, and diarrhea. Severity definitions of signs and symptoms as suggested by the Food and Drug Administration for clinical trials24 and a description of how a diagnosis of SARS-CoV-2 was determined are provided in the Supplementary Appendix. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection, confirmed on reverse-transcriptase–polymerase-chain-reaction (RT-PCR) or rapid antigen testing, through day 14 in the primary efficacy population, which included all the participants who had undergone randomization, had a negative RT-PCR test for SARS-CoV-2 at baseline (i.e., before administration of any trial drugs or placebo), and received at least one dose of the trial drugs or placebo. The key secondary end point was the development of symptomatic, confirmed SARS-CoV-2 infection in participants at high risk (i.e., with ≥1 risk factor) for progression to severe Covid-19 (Table S2). To understand the effect of SARS-CoV-2 variants on efficacy, a predefined subgroup analysis of the primary efficacy end point examined the efficacy of nirmatrelvir–ritonavir as compared with placebo according to an enrollment cutoff date of before December 20, 2021, or on or after December 20, 2021 (i.e., during the periods of delta and omicron predominance, respectively). The development of symptomatic, confirmed SARS-CoV-2 infection through day 14 was also evaluated in participants who had a positive RT-PCR test at baseline and in those with any baseline RT-PCR result (negative, positive, or missing). Another secondary end point was the development of asymptomatic, confirmed SARS-CoV-2 infection. The development of any RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection (symptomatic or asymptomatic) through day 14 was assessed in a post hoc analysis.

baseline RT-PCR result (negative, positive, or missing). Another secondary end point was the development of asymptomatic, confirmed SARS-CoV-2 infection. The development of any RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection (symptomatic or asymptomatic) through day 14 was assessed in a post hoc analysis. Viral load was a secondary end point and was evaluated with the use of nasal swab specimens that were collected daily from baseline through day 14 and assessed for viral RNA concentrations by means of RT-PCR assay (see the Supplementary Appendix). Changes in viral load over time were described in participants who had a negative or positive RT-PCR test for SARS-CoV-2 at baseline. Viral load rebound was defined as a change from day 5 to day 14 of at least 0.5 log10 copies per milliliter and a viral load at day 14 of at least 2.7 log10 copies per milliliter. Missing viral load data for day 5 or day 14 were imputed. The safety of the 5-day and 10-day regimens of nirmatrelvir–ritonavir as compared with placebo was evaluated through the end of the trial period (day 38) among all the participants who had undergone randomization and received at least one dose of the trial drugs or placebo. Safety end points were the incidence of adverse events that occurred during the trial period, serious adverse events, and adverse events that led to the discontinuation of nirmatrelvir–ritonavir or placebo.

ll the participants who had undergone randomization and received at least one dose of the trial drugs or placebo. Safety end points were the incidence of adverse events that occurred during the trial period, serious adverse events, and adverse events that led to the discontinuation of nirmatrelvir–ritonavir or placebo. Sample-size calculations are provided in the Supplementary Appendix. Multiple comparisons (i.e., the 5-day and 10-day regimens of nirmatrelvir–ritonavir vs. placebo) for the primary efficacy end point were adjusted for multiplicity with the use of the Hochberg method.25 Results of the comparisons are reported as risk reductions relative to placebo, which were calculated as a percentage: 1 minus the risk ratio multiplied by 100. A generalized estimating equation with compound symmetry variance–covariance structure was used to account for clustering. Because the primary end point was not met, 95% confidence intervals are presented for all secondary end points; these were not adjusted for multiplicity and should not be used to infer treatment effects.

Eligible participants were randomly assigned in a 1:1:1 ratio to receive 300 mg of nirmatrelvir and 100 mg of ritonavir for 5 days (the 5-day nirmatrelvir–ritonavir group) or 10 days (the 10-day nirmatrelvir–ritonavir group) or matching placebo capsules (consisting of inactive filler ingredients) for 10 days (Fig. S1); those in the 5-day nirmatrelvir–ritonavir group received placebo for 5 days after the completion of the 5-day regimen of nirmatrelvir–ritonavir. Randomization was stratified according to the presence of risk factors associated with severe Covid-1923 and geographic region (outlined in Table S2). Details regarding administration of the trial drugs or placebo and blinding procedures are summarized in the Supplementary Appendix. Administration of the trial drugs or placebo and daily signs and symptoms of Covid-19, including severity as rated on a 4-point scale (with 0 indicating none, 1 mild, 2 moderate, and 3 severe), were recorded by the participants in an electronic diary. The recorded signs and symptoms that were collected included stuffy or runny nose, sore throat, shortness of breath or difficulty breathing, cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, and diarrhea. Severity definitions of signs and symptoms as suggested by the Food and Drug Administration for clinical trials24 and a description of how a diagnosis of SARS-CoV-2 was determined are provided in the Supplementary Appendix.

The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection, confirmed on reverse-transcriptase–polymerase-chain-reaction (RT-PCR) or rapid antigen testing, through day 14 in the primary efficacy population, which included all the participants who had undergone randomization, had a negative RT-PCR test for SARS-CoV-2 at baseline (i.e., before administration of any trial drugs or placebo), and received at least one dose of the trial drugs or placebo. The key secondary end point was the development of symptomatic, confirmed SARS-CoV-2 infection in participants at high risk (i.e., with ≥1 risk factor) for progression to severe Covid-19 (Table S2). To understand the effect of SARS-CoV-2 variants on efficacy, a predefined subgroup analysis of the primary efficacy end point examined the efficacy of nirmatrelvir–ritonavir as compared with placebo according to an enrollment cutoff date of before December 20, 2021, or on or after December 20, 2021 (i.e., during the periods of delta and omicron predominance, respectively). The development of symptomatic, confirmed SARS-CoV-2 infection through day 14 was also evaluated in participants who had a positive RT-PCR test at baseline and in those with any baseline RT-PCR result (negative, positive, or missing). Another secondary end point was the development of asymptomatic, confirmed SARS-CoV-2 infection. The development of any RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection (symptomatic or asymptomatic) through day 14 was assessed in a post hoc analysis.

Viral load was a secondary end point and was evaluated with the use of nasal swab specimens that were collected daily from baseline through day 14 and assessed for viral RNA concentrations by means of RT-PCR assay (see the Supplementary Appendix). Changes in viral load over time were described in participants who had a negative or positive RT-PCR test for SARS-CoV-2 at baseline. Viral load rebound was defined as a change from day 5 to day 14 of at least 0.5 log10 copies per milliliter and a viral load at day 14 of at least 2.7 log10 copies per milliliter. Missing viral load data for day 5 or day 14 were imputed.

The safety of the 5-day and 10-day regimens of nirmatrelvir–ritonavir as compared with placebo was evaluated through the end of the trial period (day 38) among all the participants who had undergone randomization and received at least one dose of the trial drugs or placebo. Safety end points were the incidence of adverse events that occurred during the trial period, serious adverse events, and adverse events that led to the discontinuation of nirmatrelvir–ritonavir or placebo.

Sample-size calculations are provided in the Supplementary Appendix. Multiple comparisons (i.e., the 5-day and 10-day regimens of nirmatrelvir–ritonavir vs. placebo) for the primary efficacy end point were adjusted for multiplicity with the use of the Hochberg method.25 Results of the comparisons are reported as risk reductions relative to placebo, which were calculated as a percentage: 1 minus the risk ratio multiplied by 100. A generalized estimating equation with compound symmetry variance–covariance structure was used to account for clustering. Because the primary end point was not met, 95% confidence intervals are presented for all secondary end points; these were not adjusted for multiplicity and should not be used to infer treatment effects.

From September 9, 2021, to April 12, 2022, a total of 2736 participants were randomly assigned to a trial group — 921 to the 5-day nirmatrelvir–ritonavir group, 917 to the 10-day nirmatrelvir–ritonavir group, and 898 to the placebo group. A total of 2579 participants completed the treatment period (Figure 1). The majority of participants (69.5%) were from the United States. The demographic characteristics at baseline were similar across the trial groups (Table 1) and largely representative of the expected patient population (Table S3); 46.8% of the participants were men, the median age was 42 years (range, 18 to 91), and 72.0 to 73.3% of the participants across the trial groups had coexisting medical conditions associated with the risk of severe Covid-19. A total of 580 participants (21.2%) underwent randomization before December 20, 2021, and 2156 participants (78.8%) underwent randomization on or after December 20, 2021. Adherence to the assigned regimen within the range of 80 to 115% of tablets intended to be taken was 95.3%; adherence was similar across the trial groups. Details of the index patients are summarized in Table S4.

ore December 20, 2021, and 2156 participants (78.8%) underwent randomization on or after December 20, 2021. Adherence to the assigned regimen within the range of 80 to 115% of tablets intended to be taken was 95.3%; adherence was similar across the trial groups. Details of the index patients are summarized in Table S4. The incidence of symptomatic, confirmed SARS-CoV-2 infection by day 14 (primary end point) did not differ significantly between each nirmatrelvir–ritonavir group and the placebo group. Symptomatic SARS-CoV-2 infection through day 14 was confirmed by means of a RT-PCR assay or rapid antigen test in 2.6% of the participants in the 5-day nirmatrelvir–ritonavir group, 2.4% of those in the 10-day nirmatrelvir–ritonavir group, and 3.9% of those in the placebo group (Table 2). Corresponding risk reductions relative to placebo were 29.8% (95% confidence interval [CI], –16.7 to 57.8; P=0.17) in the 5-day nirmatrelvir–ritonavir group and 35.5% (95% CI, –11.5 to 62.7%; P=0.12) in the 10-day nirmatrelvir–ritonavir group. The primary efficacy objective of the trial was not met, and P values are not presented for the secondary end points. The number of days to RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection through day 14 is shown in Figure 2. Among the participants at high risk for progression to severe Covid-19, the incidence of symptomatic, RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection by day 14 did not differ significantly between the 5-day or 10-day nirmatrelvir–ritonavir group (2.9% and 2.6%, respectively) and the placebo group (3.5%) (Table 2).

e participants at high risk for progression to severe Covid-19, the incidence of symptomatic, RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection by day 14 did not differ significantly between the 5-day or 10-day nirmatrelvir–ritonavir group (2.9% and 2.6%, respectively) and the placebo group (3.5%) (Table 2). The results of a protocol-specified subgroup analysis that compared participants who were enrolled before December 20, 2021, with those who were enrolled on or after December 20, 2021 (during the periods of delta and omicron predominance, respectively) showed no obvious difference in efficacy according to the likely variant associated with the infection (Fig. S2). Among the participants who met the primary end-point criteria, the results of viral sequencing showed that infection had developed during the period of omicron predominance (Table S5).

inance, respectively) showed no obvious difference in efficacy according to the likely variant associated with the infection (Fig. S2). Among the participants who met the primary end-point criteria, the results of viral sequencing showed that infection had developed during the period of omicron predominance (Table S5). No notable between-group differences were observed among the participants with asymptomatic, confirmed SARS-CoV-2 infection through day 14; among those who were rapid antigen test–negative at screening or baseline but were subsequently determined to have detectable levels of SARS-CoV-2 by means of RT-PCR testing at baseline; or among those with any baseline RT-PCR result (positive, negative, or missing) (Table S6). Among the participants who were seropositive at baseline, RT-PCR– or rapid antigen test–confirmed Covid-19 developed by day 14 in 2.2% of those in the 5-day nirmatrelvir–ritonavir group, 2.0% of those in the 10-day nirmatrelvir–ritonavir group, and 3.6% of those in the placebo group; the corresponding risk reductions relative to placebo were 41.0% (95% CI, –3.3 to 66.8) in the 5-day nirmatrelvir–ritonavir group and 43.0% (95% CI, –7.7 to 69.3) in the 10-day nirmatrelvir–ritonavir group.

itonavir group, 2.0% of those in the 10-day nirmatrelvir–ritonavir group, and 3.6% of those in the placebo group; the corresponding risk reductions relative to placebo were 41.0% (95% CI, –3.3 to 66.8) in the 5-day nirmatrelvir–ritonavir group and 43.0% (95% CI, –7.7 to 69.3) in the 10-day nirmatrelvir–ritonavir group. Asymptomatic, RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection developed by day 14 in 17 of 844 participants (2.0%) in the 5-day nirmatrelvir–ritonavir group, 16 of 830 participants (1.9%) in the 10-day nirmatrelvir–ritonavir group, and 26 of 840 participants (3.1%) in the placebo group. Among the participants who were seronegative at baseline, symptomatic, RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection developed by day 14 in 5 of 61 participants (8.2%) in the 5-day nirmatrelvir–ritonavir group, 5 of 72 participants (6.9%) in the 10-day nirmatrelvir–ritonavir group, and 4 of 62 participants (6.5%) in the placebo group.

seronegative at baseline, symptomatic, RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection developed by day 14 in 5 of 61 participants (8.2%) in the 5-day nirmatrelvir–ritonavir group, 5 of 72 participants (6.9%) in the 10-day nirmatrelvir–ritonavir group, and 4 of 62 participants (6.5%) in the placebo group. Viral loads over time among the participants who had a positive RT-PCR test at baseline are shown in Figure S3. On day 5, the mean viral load was 1.470 log10 copies per milliliter among the participants in the 5-day nirmatrelvir–ritonavir group, 1.413 log10 copies per milliliter among those in the 10-day nirmatrelvir–ritonavir group, and 2.994 log10 copies per milliliter among those in the placebo group; the values at day 7 were 1.199, 0.913, and 1.478 log10 copies per milliliter, respectively. A rebound in the viral load was observed in one participant (2.6%) in the 5-day nirmatrelvir–ritonavir group, one participant (2.1%) in the 10-day nirmatrelvir–ritonavir group, and zero participants in the placebo group.

group; the values at day 7 were 1.199, 0.913, and 1.478 log10 copies per milliliter, respectively. A rebound in the viral load was observed in one participant (2.6%) in the 5-day nirmatrelvir–ritonavir group, one participant (2.1%) in the 10-day nirmatrelvir–ritonavir group, and zero participants in the placebo group. The incidence of adverse events during the trial period was similar in the 5-day and 10-day nirmatrelvir–ritonavir groups and the placebo group (21.7 to 23.9% across trial groups), and the incidence of serious adverse events was similar across trial groups (0.1 to 0.3%) (Table 3). The most frequently reported adverse events were dysgeusia (in 5.9% in the 5-day nirmatrelvir–ritonavir group, 6.8% in the 10-day nirmatrelvir–ritonavir group, and 0.7% in the placebo group), Covid-19 (in 3.0%, 2.9%, and 4.0%, respectively), and diarrhea (in 2.5%, 2.4%, and 1.7%, respectively) (Table S7).

%) (Table 3). The most frequently reported adverse events were dysgeusia (in 5.9% in the 5-day nirmatrelvir–ritonavir group, 6.8% in the 10-day nirmatrelvir–ritonavir group, and 0.7% in the placebo group), Covid-19 (in 3.0%, 2.9%, and 4.0%, respectively), and diarrhea (in 2.5%, 2.4%, and 1.7%, respectively) (Table S7). Adverse events that were considered by the investigator to be related to the trial drugs or placebo were more common among the participants in the 5-day and 10-day nirmatrelvir–ritonavir groups than in the placebo group (in 9.4%, 11.7%, and 5.5%, respectively) (Table S8). This difference was largely attributed to dysgeusia (in 5.9% of the participants in the 5-day nirmatrelvir–ritonavir group, 6.8% of those in the 10-day nirmatrelvir–ritonavir group, and 0.7% of those in the placebo group) and diarrhea (1.2%, 1.5%, and 0.8%, respectively). Dysgeusia, diarrhea, and nausea were the only treatment-related adverse events that were reported in at least 1% of nirmatrelvir–ritonavir recipients. The majority of these events were grade 1 or 2, other than grade 3 dysgeusia (reported in one participant in each of the nirmatrelvir–ritonavir 5-day and 10-day groups). Table S9 summarizes all adverse events of grade 2 or greater. No serious adverse events were considered to be treatment-related, and no participants had an adverse event that resulted in death. There were no adverse events that led to withdrawal from the trial, and few participants (≤1.6% in any group) discontinued the trial drugs or placebo owing to an adverse event.

The incidence of symptomatic, confirmed SARS-CoV-2 infection by day 14 (primary end point) did not differ significantly between each nirmatrelvir–ritonavir group and the placebo group. Symptomatic SARS-CoV-2 infection through day 14 was confirmed by means of a RT-PCR assay or rapid antigen test in 2.6% of the participants in the 5-day nirmatrelvir–ritonavir group, 2.4% of those in the 10-day nirmatrelvir–ritonavir group, and 3.9% of those in the placebo group (Table 2). Corresponding risk reductions relative to placebo were 29.8% (95% confidence interval [CI], –16.7 to 57.8; P=0.17) in the 5-day nirmatrelvir–ritonavir group and 35.5% (95% CI, –11.5 to 62.7%; P=0.12) in the 10-day nirmatrelvir–ritonavir group. The primary efficacy objective of the trial was not met, and P values are not presented for the secondary end points. The number of days to RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection through day 14 is shown in Figure 2. Among the participants at high risk for progression to severe Covid-19, the incidence of symptomatic, RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection by day 14 did not differ significantly between the 5-day or 10-day nirmatrelvir–ritonavir group (2.9% and 2.6%, respectively) and the placebo group (3.5%) (Table 2).

Viral loads over time among the participants who had a positive RT-PCR test at baseline are shown in Figure S3. On day 5, the mean viral load was 1.470 log10 copies per milliliter among the participants in the 5-day nirmatrelvir–ritonavir group, 1.413 log10 copies per milliliter among those in the 10-day nirmatrelvir–ritonavir group, and 2.994 log10 copies per milliliter among those in the placebo group; the values at day 7 were 1.199, 0.913, and 1.478 log10 copies per milliliter, respectively. A rebound in the viral load was observed in one participant (2.6%) in the 5-day nirmatrelvir–ritonavir group, one participant (2.1%) in the 10-day nirmatrelvir–ritonavir group, and zero participants in the placebo group.

The incidence of adverse events during the trial period was similar in the 5-day and 10-day nirmatrelvir–ritonavir groups and the placebo group (21.7 to 23.9% across trial groups), and the incidence of serious adverse events was similar across trial groups (0.1 to 0.3%) (Table 3). The most frequently reported adverse events were dysgeusia (in 5.9% in the 5-day nirmatrelvir–ritonavir group, 6.8% in the 10-day nirmatrelvir–ritonavir group, and 0.7% in the placebo group), Covid-19 (in 3.0%, 2.9%, and 4.0%, respectively), and diarrhea (in 2.5%, 2.4%, and 1.7%, respectively) (Table S7).

In this placebo-controlled trial, postexposure prophylaxis with nirmatrelvir–ritonavir did not result in a significant reduction in the risk of development of symptomatic SARS-CoV-2 infection among participants who were household contacts of persons with Covid-19 and initially had a negative RT-PCR or rapid antigen test. An important consideration when interpreting the results of the current trial is that it was conducted primarily during the period when omicron was the predominant circulating SARS-CoV-2 variant. Because of the continual mutation of the spike protein of SARS-CoV-2, the efficacy of monoclonal antibody products in treating or preventing Covid-19 may be negatively affected as new variants emerge.26 With the predominance of the omicron BQ.1 and BQ.1.1 sublineages in the United States in November 2022, the Food and Drug Administration withdrew the emergency use authorization for bebtelovimab because it was not expected to neutralize omicron subvariants.27 Similarly, the emergency use authorization for tixagevimab plus cilgavimab was modified in January 2023 to limit its use to when the combined frequency of nonsusceptible SARS-CoV-2 variants nationally is 90% or less.28

y use authorization for bebtelovimab because it was not expected to neutralize omicron subvariants.27 Similarly, the emergency use authorization for tixagevimab plus cilgavimab was modified in January 2023 to limit its use to when the combined frequency of nonsusceptible SARS-CoV-2 variants nationally is 90% or less.28 Another important aspect of the current trial is that a substantial percentage of participants were seropositive for SARS-CoV-2 (approximately 91%) at baseline. Seroprevalence is likely to remain in excess of 90% as a result of previous infection or vaccination.29 It is not known whether the high baseline seropositivity rates observed in this trial led to the lower-than-expected rates of household transmission.

were seropositive for SARS-CoV-2 (approximately 91%) at baseline. Seroprevalence is likely to remain in excess of 90% as a result of previous infection or vaccination.29 It is not known whether the high baseline seropositivity rates observed in this trial led to the lower-than-expected rates of household transmission. A particular strength of this trial is that it included participants from diverse age groups and geographical locations, a factor that enables broad generalizability of the results. However, there are several challenges and limitations of postexposure prophylaxis trials. Given the distinctive taste of nirmatrelvir–ritonavir, participants may have suspected that they were receiving active medication, which may have limited the effectiveness of the blinding. Another limitation is the lack of detailed data on the index patients (e.g., diagnostic details and details on treatments), since they are not direct participants in the trial and have not given consent to provide information. There is also a potential effect from other infected household members who did not participate in the trial or may have undergone randomization to receive or were receiving a different treatment. A small percentage (3%) of index patients were taking part in antiviral clinical trials; however, it is unlikely that this would have significantly affected the outcomes of this trial. It is also important to consider whether the design of postexposure prophylaxis trials should address whether the treatment of the index patient reduces the incidence of household transmission. The trial was powered to detect a 70% reduction in the risk of development of symptomatic, RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection through day 14 relative to placebo; the observed relative risk reductions were smaller and not significant. A maximum increase in sample size of 30% at the interim analysis was prespecified in the protocol, but an increase in sample size of this magnitude would not have achieved sufficient power to declare a significant difference on the basis of the observed risk reduction. Further evaluation of SARS-CoV-2 antiviral agents in larger trials may be warranted.

of 30% at the interim analysis was prespecified in the protocol, but an increase in sample size of this magnitude would not have achieved sufficient power to declare a significant difference on the basis of the observed risk reduction. Further evaluation of SARS-CoV-2 antiviral agents in larger trials may be warranted. No safety concerns were identified for the 5-day and 10-day regimens of nirmatrelvir–ritonavir; differences in adverse events as compared with placebo were largely attributed to mild-to-moderate dysgeusia. The safety profile of the 5-day and 10-day regimens was similar, a notable finding since although nirmatrelvir–ritonavir is authorized as a 5-day regimen, longer treatment durations are being explored in some patient populations.30,31 Among adult household contacts of symptomatic persons with confirmed Covid-19, nirmatrelvir–ritonavir given as postexposure prophylaxis for 5 or 10 days did not significantly reduce the risk of development of SARS-CoV-2 infection as compared with placebo.