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Nirmatrelvir-ritonavir (Paxlovid) did not prevent people exposed to COVID-infected household members from getting infected with the virus, according to the final results of the phase II/III EPIC-PEP study.

Across more than 2,700 exposed adults in the trial, symptomatic confirmed infections at 14 days occurred in 2.6% of those taking a 5-day course of the antiviral medication, 2.4% of those receiving a 10-day course, and 3.9% of the placebo recipients. Neither of those differences versus the placebo group were statistically significant (P=0.17 and P=0.12, respectively), reported Jennifer Hammond, PhD, head of antiviral development at Pfizer in Collegeville, Pennsylvania, and colleagues.

Asymptomatic infections developed in about 2% of participants in the 5- and 10-day nirmatrelvir-ritonavir groups versus 3.1% of the placebo group, but again the differences were not statistically significant, the researchers detailed in the .

"The secondary attack rate among household contacts of individuals infected with the Omicron variant is estimated to be up to 81%," Hammond and researchers wrote in the study's supplementary material. "Currently, postexposure prophylactic treatment for house contacts of SARS-CoV-2-infected individuals is not available, although such an approach is recommended in other infectious disease settings."

Currently, nirmatrelvir-ritonavir is FDA approved only as a 5-day regimen for treating adult outpatients with mild-to-moderate COVID-19 who are at risk for severe disease.

Hammond's team determined that the incidence for the development of symptomatic COVID-19 by day 14 among participants at high risk for severe disease did not differ significantly between the groups. And, in a subgroup analysis, no difference was noted in outcomes during periods when the Delta or Omicron variant predominated.

The study's final results come on the heels of the EPIC-SR trial, which found that nirmatrelvir-ritonavir failed to shorten illness duration as a treatment for COVID-19 in standard-risk and vaccinated at-risk patients. However, a subgroup analysis of that study found that the antiviral is still likely to keep higher-risk patients from developing severe disease. The earlier EPIC-HR trial found that unvaccinated, high-risk patients were significantly less likely to die or be hospitalized if they took nirmatrelvir-ritonavir, which supported the drug's 2023 approval.

In the EPIC-PEP trial, 91% of participants were seropositive for SARS-CoV-2 at baseline, most likely a result of previous infection or vaccination, Hammond and authors noted. "It is not known whether the high baseline seropositivity rates observed in this trial led to the lower-than-expected rates of household transmission," they wrote. About 13% in all three groups had received one or more doses of a COVID-19 vaccine.

Among participants seropositive at baseline, confirmed COVID-19 developed by day 14 in 2.2% and 2.0% in the 5- and 10-day nirmatrelvir-ritonavir groups and 3.6% in the placebo group. The between-group differences were not statistically significant.

Viral loads decreased over time among participants with a positive SARS-CoV-2 test across all groups. One participant each (2.6% and 2.1%) in the 5- and 10-day prophylaxis groups experienced a rebound in viral load. None of those in the placebo group had a viral load rebound.

The most common treatment-related adverse event in the nirmatrelvir-ritonavir prophylaxis groups was mild-to-moderate alterations in taste or metallic taste. Nausea and diarrhea occurred in at least 1% of prophylaxis recipients, with most events being mild.

Of note, the 10-day regimen had a similar safety profile to the shorter regimen. This may be important because in regards to treatment of confirmed COVID-19 with nirmatrelvir-ritonavir, "longer treatment durations are being explored in some patient populations," the authors wrote.

The trial took place from September 2021 to April 2022. Researchers randomized 921 participants to the 5-day nirmatrelvir-ritonavir group, 917 to the 10-day group, and 898 to the placebo group. About 21% underwent randomization before Dec. 20, 2021. Median age was 43 years, and 47% were men. Over 70% of participants had coexisting medical conditions putting them at risk for severe COVID-19. Adherence to assigned regimens was about 95% across the three trial groups.

COVID-19 infection was confirmed by reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or rapid antigen testing in all groups. All participants in the primary analysis of the study tested negative for COVID-19 on RT-PCR or rapid antigen testing at baseline.

Limitations of the study include limited effectiveness of the blinding due to the distinctive taste of nirmatrelvir-ritonavir, the lack of detailed data on index patients since they are not direct participants in the trial and did not consent to provide information, and a potential effect from other infected household members.

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