Clinical trials investigating treatments for COVID-19 have not demonstrated a notable advantage in post-exposure prophylaxis. This phase 2-3 placebo-controlled trial examined the administration of nirmatrelvir–ritonavir over 5 or 10 days, revealing no significant reduction in the risk of symptomatic SARS-CoV-2 infection
Among 2736 participants randomly assigned to trial groups—921 to the 5-day nirmatrelvir–ritonavir group, 917 to the 10-day group, and 898 to placebo—symptomatic infections by day 14 occurred in 2.6% and 2.4% of the nirmatrelvir–ritonavir groups respectively, versus 3.9% in the placebo group. Despite risk reductions relative to placebo (29.8% in the 5-day group and 35.5% in the 10-day group), these differences were not statistically significant. Adverse events, predominantly dysgeusia, were similar across all groups.
“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,” explains investigators. “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.”1
3 Key Takeaways
- The clinical trial investigating nirmatrelvir–ritonavir for COVID-19 postexposure prevention did not show statistically significant reductions in symptomatic SARS-CoV-2 infections compared to placebo among asymptomatic adults.
- Challenges such as blinding issues due to the drug's taste and incomplete data on index patients were noted during the trial, complicating the interpretation of its results.
- While effectiveness in preventing infections among asymptomatic adults was limited, separate studies indicate potential benefits of nirmatrelvir–ritonavir in treating severe cases among pediatric and hospitalized patients with COVID-19.
A double-blind phase 2–3 trial assessed nirmatrelvir–ritonavir in asymptomatic adults recently exposed to COVID-19 within households. Participants, who tested negative on rapid antigen tests, were randomly assigned in a 1:1:1 ratio to receive either nirmatrelvir–ritonavir (300 mg nirmatrelvir and 100 mg ritonavir) every 12 hours for 5 or 10 days, or a placebo. The study aimed to determine the incidence of symptomatic SARS-CoV-2 infection confirmed by RT-PCR or rapid antigen testing within 14 days among initially RT-PCR-negative participants.
“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,” explains investigators.1
Limitations from this study include the distinctive taste of nirmatrelvir–ritonavir potentially compromising blinding efficacy, and limited data on index patients due to their non-participation and lack of consent. Household member factors and concurrent treatments also pose limitations. Despite the trial being powered for a significant risk reduction, observed results fell short. Larger trials evaluating SARS-CoV-2 antiviral agents may be necessary for further insights.
The clinical trial discussed in the article focuses on evaluating nirmatrelvir–ritonavir for post-exposure prophylaxis among asymptomatic adults exposed to COVID-19. According to the findings, neither the 5-day nor the 10-day regimen significantly reduced symptomatic SARS-CoV-2 infections compared to placebo. This suggests uncertainty regarding the drug's preventive efficacy in this particular population.
In contrast, a recent study examining nirmatrelvir–ritonavir's impact on hospitalized pediatric patients infected with the Omicron variant yielded more promising results. This separate trial demonstrated a significant reduction in 28-day hospitalization rates among non-hospitalized adolescents aged 12-17 years, without reporting any instances of mortality or adverse clinical outcomes. These findings highlight a potential therapeutic benefit in treating severe cases of COVID-19 among younger patients, contrasting with the limited preventive effects observed in asymptomatic adults.2
Similarly, research focusing on nirmatrelvir–ritonavir's effects on hospitalized adults with Covid-19 complications also reveals notable outcomes. Studies indicate a decrease in post-acute mortality and reductions in cardiovascular and respiratory complications compared to control groups. This suggests that while the drug may not prevent symptomatic infections in asymptomatic adults, it could play a crucial role in mitigating severe outcomes among hospitalized patients.3
These comparisons underscore the nuanced challenges in assessing the efficacy of antiviral treatments across different patient populations and disease severities. Variations in trial designs, patient demographics, and clinical endpoints contribute to the complex landscape of COVID-19 treatment strategies. Further large-scale trials are essential to clarify the broader therapeutic potential of nirmatrelvir–ritonavir amidst evolving viral variants and clinical contexts.
In conclusion, the trial testing nirmatrelvir–ritonavir for COVID-19 post-exposure prophylaxis did not significantly reduce symptomatic SARS-CoV-2 infections compared to placebo. Continued research in larger trials is needed to clarify the efficacy of SARS-CoV-2 antiviral agents across variants and populations. While promising in other patient groups, nirmatrelvir–ritonavir's preventive role in asymptomatic adults remains uncertain.
References
Hammond J, Yunis C, Fountatine R, et. Al. Oral Nirmatrelvir–Ritonavir as Postexposure Prophylaxis for Covid-19. The New England Journal of Medicine. Published July 17, 2024. Accessed July 22, 2024. DOI: 10.1056/NEJMoa2309002
