J Korean Med Sci.  2024 Nov;39(42):e272. 10.3346/jkms.2024.39.e272.

Nationwide Target Trial Emulation Evaluating the Clinical Effectiveness of Oral Antivirals for COVID-19 in Korea

• Huh K
• Jo Y
• Bae GH
• Joo H
• Radnaabaatar M
• Lee H
• Kim J
• Kim DH
• Yoo MG
• Jo IU
• Lee PH
• Lee GW
• Jung HS
• Jung J

• KMID: 2560622
• DOI: http://doi.org/10.3346/jkms.2024.39.e272

Abstract

Background
Despite the proven effectiveness of oral antivirals against severe acute respiratory syndrome coronavirus 2 in randomized trials, their clinical reevaluation is vital in the context of widespread immunity and milder prevalent variants. This study aimed to assess the effectiveness of oral antivirals for coronavirus disease 2019 (COVID-19).
Methods
This retrospective cohort study utilized a target trial emulation framework to analyze patients with COVID-19 aged 60+ from January to December 2022. Data were obtained from the Korea Disease Control and Prevention Agency and Health Insurance Review and Assessment Service. The study involved 957,036 patients treated with nirmatrelvir/ritonavir and 243,360 treated with molnupiravir, each compared with the matched control groups. Primary outcome was progression to critical COVID-19 requiring advanced respiratory support. Secondary outcomes included progression to severe COVID-19, need for supplemental oxygen, and death within 30 days of the onset of COVID-19. Number needed to treat (NNT) derived from the absolute risk reduction.
Results
Nirmatrelvir/ritonavir was significantly associated with a reduced risk of severe (adjusted odds ratio [aOR], 0.823; 95% confidence interval [CI], 0.803–0.843), critical (aOR, 0.560; 95% CI, 0.503–0.624), and fatal COVID-19 (aOR, 0.694; 95% CI, 0.647–0.744). Similarly, molnupiravir reduced the risk of severe (aOR, 0.895; 95% CI, 0.856–0.937), critical (aOR, 0.672; 95% CI, 0.559–0.807), and fatal cases (aOR, 0.679; 95% CI, 0.592–0.779). NNTs for nirmatrelvir/ritonavir were 203.71 (severe), 1,230.12 (critical), and 691.50 (death); for molnupiravir, they were 352.70 (severe), 1,398.62 (critical), and 862.98 (death). Higher effectiveness was associated with older adults, unvaccinated individuals, and the late pandemic phase.
Conclusion
Nirmatrelvir/ritonavir and molnupiravir are effective in preventing progression to severe disease in elderly adults with COVID-19.

Keyword

SARS-CoV-2; COVID-19; Oral Antivirals; Effectiveness; Target Trial Emulation

Figure

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  Fig. 1 Study flow.HIRA = Health Insurance Review and Assessment Service, KDCA = Korea Disease Control and Prevention Agency, COVID-19 = coronavirus disease 2019.

Reference

1. Galmiche S, Luong Nguyen LB, Tartour E, de Lamballerie X, Wittkop L, Loubet P, et al. Immunological and clinical efficacy of COVID-19 vaccines in immunocompromised populations: a systematic review. Clin Microbiol Infect. 2022; 28(2):163–177. PMID: 35020589.

2. Tan TT, Ng HJ, Young B, Khan BA, Shetty V, Azmi N, et al. Effectiveness of vaccination against SARS-CoV-2 and the need for alternative preventative approaches in immunocompromised individuals: a narrative review of systematic reviews. Expert Rev Vaccines. 2023; 22(1):341–365. PMID: 36920116.

3. Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19. N Engl J Med. 2022; 386(15):1397–1408. PMID: 35172054.

4. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, et al. Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients. N Engl J Med. 2022; 386(6):509–520. PMID: 34914868.

5. Pfizer. Highlights of prescribing information (paxlovid). Updated 2023. Accessed December 10, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217188s000lbl.pdf .

6. Bhimraj A, Morgan RL, Shumaker AH, Lavergne V, Baden L, Cheng VC, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19 (September 2022). Clin Infect Dis. 2024; 78(7):e250–e349. PMID: 36063397.

7. Kang JM, Kang M, Kim YE, Choi Y, An SJ, Seong J, et al. Severe coronavirus disease 2019 in pediatric solid organ transplant recipients: big data convergence study in Korea (K-COV-N cohort). Int J Infect Dis. 2023; 134:220–227. PMID: 37352913.

8. Wang H, Marquez PV, Figueras A, Bieliaieva K. Overview of the Republic of Korea Pharmacovigilance System. Washington, D.C., USA: International Bank for Reconstruction and Development, The World Bank;2022.

9. COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. Updated 2023. Accessed December 3, 2023. https://www.covid19treatmentguidelines.nih.gov/ .

10. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40(5):373–383. PMID: 3558716.

11. Lee E, Kim S, Lee SY, Jeong J, Bang J, Oh J, et al. Risk factors for the prescription of ineffective antiviral candidates for COVID-19 during the early pandemic period in Korea. J Korean Med Sci. 2023; 38(36):e280. PMID: 37698205.

12. Schilling WHK, Jittamala P, Watson JA, Boyd S, Luvira V, Siripoon T, et al. Antiviral efficacy of molnupiravir versus ritonavir-boosted nirmatrelvir in patients with early symptomatic COVID-19 (PLATCOV): an open-label, phase 2, randomised, controlled, adaptive trial. Lancet Infect Dis. 2024; 24(1):36–45. PMID: 37778363.

13. Kim JM, Yoo MG, Bae SJ, Kim J, Lee H. Effectiveness of paxlovid, an oral antiviral drug, against the omicron BA.5 variant in Korea: severe progression and death between July and November 2022. J Korean Med Sci. 2023; 38(27):e211. PMID: 37431541.

14. Xie Y, Bowe B, Al-Aly Z. Nirmatrelvir and risk of hospital admission or death in adults with COVID-19: emulation of a randomized target trial using electronic health records. BMJ. 2023; 381:e073312. PMID: 37041016.

15. Xie Y, Choi T, Al-Aly Z. Molnupiravir and risk of post-acute sequelae of COVID-19: cohort study. BMJ. 2023; 381:e074572. PMID: 37161995.

16. Souza KM, Carrasco G, Rojas-Cortés R, Michel Barbosa M, Bambirra EH, Castro JL, et al. Effectiveness of nirmatrelvir-ritonavir for the treatment of patients with mild to moderate COVID-19 and at high risk of hospitalization: systematic review and meta-analyses of observational studies. PLoS One. 2023; 18(10):e0284006. PMID: 37824507.

17. Wan EY, Yan VK, Mok AH, Wang B, Xu W, Cheng FW, et al. Effectiveness of molnupiravir and nirmatrelvir-ritonavir in hospitalized patients with COVID-19: a target trial emulation study. Ann Intern Med. 2023; 176(4):505–514. PMID: 36913693.

18. Butler CC, Hobbs FD, Gbinigie OA, Rahman NM, Hayward G, Richards DB, et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet. 2023; 401(10373):281–293. PMID: 36566761.

19. Van Heer C, Majumdar SS, Parta I, Martinie M, Dawson R, West D, et al. Effectiveness of community-based oral antiviral treatments against severe COVID-19 outcomes in people 70 years and over in Victoria, Australia, 2022: an observational study. Lancet Reg Health West Pac. 2023; 41:100917. PMID: 37927380.

20. Whitley R. Molnupiravir—a step toward orally bioavailable therapies for Covid-19. N Engl J Med. 2022; 386:592–593. PMID: 34914869.

21. Kim YE, Huh K, Park YJ, Peck KR, Jung J. Association between vaccination and acute myocardial infarction and ischemic stroke after COVID-19 infection. JAMA. 2022; 328(9):887–889. PMID: 35867050.

22. Lim Y, Lee MH, Jeong S, Han HW. Association of physical activity with SARS-CoV-2 infection and severe clinical outcomes among patients in South Korea. JAMA Netw Open. 2023; 6(4):e239840. PMID: 37097636.