Three therapies have received either full FDA approval or Emergency Use Authorization (EUA) for COVID-19 treatment, based on randomized data that indicated reduced deaths and hospitalizations. However, the emergence of new viral strains and increased population immunity have changed the treatment landscape. Recent evaluations suggest that while initial trial data indicated effectiveness, the overall pooled effects are now not significant. This highlights the need to reassess recommendations for these approved oral COVID-19 treatments.1
Out of the 23 studies identified, 11 evaluated nirmatrelvir/ritonavir, 10 focused on molnupiravir, and two examined both therapies. The pooled estimate for reducing deaths and hospitalizations with molnupiravir was .62 (95% confidence interval (CI), .15–2.53), while for nirmatrelvir/ritonavir, it was .33 (95% CI, .03–3.35).1
A systematic review searched PubMed, Web of Science, Embase, and ClinicalTrials.gov for clinical trials assessing these therapies. All relevant trials were included, and a meta-analysis was performed to evaluate pooled efficacy in terms of hospitalization and mortality rates.1
Notably, the one nirmatrelvir/ritonavir trial demonstrating significant benefits primarily involved participants infected with earlier COVID-19 variants, whereas the two trials showing no significant effects were conducted with individuals infected by more recent variants. Similarly, the two positive molnupiravir trials involved participants primarily infected with the Delta variant, while the null trials were conducted later with more recent variants.1
Key Takeaways
- The effectiveness of nirmatrelvir/ritonavir and molnupiravir for treating COVID-19 is questioned due to non-significant effects on mortality and hospitalization, particularly against new variants.
- The PANORAMIC trial indicated that molnupiravir may improve recovery time and quality of life, although it did not significantly impact hospitalization rates over the long term.
- Continued research is essential to refine treatment guidelines and explore the potential of antivirals in addressing long COVID and adapting to emerging viral strains.
Notably, no randomized controlled trials are evaluating the long-term effectiveness of molnupiravir for COVID-19 outcomes. Although, the PANORAMIC trial demonstrated its ability to shorten recovery time within 28 days. This study aimed to assess the impact of molnupiravir treatment on well-being, severe and persistent symptoms, new infections, healthcare and social service utilization, medication use, and time off work at 3 and 6 months post-randomization. In this vaccinated population, individuals treated with molnupiravir reported improved well-being, experienced fewer and less severe symptoms, accessed healthcare less frequently, and took less time off work at the 6-month mark.2
From December 8, 2021, to April 27, 2022, 25,783 participants were randomly assigned to receive either molnupiravir with usual care (12,821 participants) or just usual care (12,962 participants). Long-term follow-up data were available for 23,008 participants (89.2%), with most having received at least one dose of a SARS-CoV-2 vaccine.2
Results indicated that severe symptoms were reduced at both 3 months (by 1.6%) and 6 months (by 1.9%) in the molnupiravir group. Persistent symptoms decreased by 2.1% at 3 months and 2.5% at 6 months. Health-related quality of life improved significantly at both time points.2
This study is a follow-up to the main analysis that reported outcomes from the first 28 days. It was a multicenter, open-label, multi-arm, prospective randomized controlled trial conducted in the UK. Participants were eligible if they were at least 50 years old or at least 18 with a comorbidity, and had confirmed COVID-19 for 5 days or less.2
Ziyad Al-Aly, MD, highlighted that the systematic review combined low- and high-risk patients and hospitalization and death outcomes, despite antivirals showing little effect in low-risk patients. He noted the wide confidence intervals, indicating uncertainty. Al-Aly also emphasized that the evidence base for using COVID-19 antivirals in preventing long COVID is growing.3
There were notable reductions in symptom persistence at 6 months and less time taken off work at both 3 and 6 months among those treated with molnupiravir. No differences in hospitalization rates were found during long-term follow-up.2
“The hypothesis that patients with established long COVID and evidence of viral persistence could also respond to antiviral therapy is plausible and should be thoroughly evaluated. We have made substantial progress during the past several years in characterising the epidemiology and mechanisms of long COVID, but much remains to be done in preventing and treating the condition.”3
Participants were randomly assigned to either the usual care group or the molnupiravir group (800 mg twice daily for 5 days), stratified by age (<50 or ≥50 years) and vaccination status. The primary outcome was hospitalization or death within 28 days, while secondary outcomes included self-reported wellness ratings, symptom severity, health and social care utilization, quality of life, time off work or school, new infections, and hospitalization rates.2
Overall, while nirmatrelvir/ritonavir and molnupiravir have received approval for COVID-19 treatment, their effectiveness appears limited, especially against new variants. Some benefits in symptom management and recovery have been observed, but their overall impact on mortality and hospitalization remains uncertain. Continued research is essential to refine treatment guidelines and address Long COVID complexities, ensuring optimal patient outcomes as the pandemic evolves.
References
Alyson Haslam, Vinay Prasad, A Systematic Review of Nirmatrelvir/Ritonavir and Molnupiravir for the Treatment of Coronavirus Disease 2019, Open Forum Infectious Diseases, Volume 11, Issue 9, September 2024, ofae497, https://doi.org/10.1093/ofid/ofae497
Harris V, Holmes J, Gbinigie-Thompson O, et. al. Health outcomes 3 months and 6 months after molnupiravir treatment for COVID-19 for people at higher risk in the community (PANORAMIC): a randomised controlled trial. The Lancet. September 9, 2024. Accessed Septmeber 18, 2024. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(24)00431-6/fulltext
