Etiotropic Therapy of Mild COVID-19 in Outpatient Patients: Molnupiravir is in Focus

DOI: 10.47026/2413-4864-2023-3-1-15

UDC: 616-085:616-036.21
BBC: Р28

Balykova L.A., Pshenichnaya N.Yu., Omarova Kh.G., Pushkar D.Yu., Zaslavskaia K.Ya., Zemskov D.N., Taganov A.V., Belyi P.A., Gorelov A.V., Kozlov E.D., Shepeleva O.I., Prekina V.I., Semenova E.V.

Etiotropic Therapy of Mild COVID-19 in Outpatient Patients: Molnupiravir is in Focus

Keywords: COVID-19, SARS-CoV-2, etiotropic therapy, disease progression, Molnupiravir, virus elimination

The aim of the study was to evaluate the efficacy and tolerability of the drug Molnupiravir in adult outpatients with mild Covid–19. Materials and methods. A randomized comparative open clinical trial of Molnupiravir (800 mg twice daily for 5 days in addition to symptomatic/pathogenetic therapy) was conducted in confirmed COVID-19 in comparison with a standard therapy. 240 patients (average age – 43.5 years; 70% had risk factors) were randomized in a 1:1 ratio to the Molnupiravir group and the standard therapy group. Clinical efficacy was assessed based on the analysis of the patient's daily diary, physical examination data and SARS-CoV-2 RNA in the smear from the oropharynx and nasopharynx. The primary endpoint was the proportion of patients with the transition of COVID-19 course to a more severe degree relative to the initial state 2 weeks after the onset of the disease. Significance was assessed using a two-sided version of the Fisher Exact test. Results. Molnupiravir: a) reduced the risk of disease progression by 4 times by the 14^th –15^th day of follow-up, compared with the risk in the control group (2.5% and 10% of patients, respectively, p = 0.0149); b) accelerated virus elimination by the 6^th – 7^th day of follow-up (71.67% vs. 58.33%, respectively); c) accelerated clinical recovery (which by day 6-7 had 19% of patients in the Molnupiravir group, and 6% of patients on standard therapy); d) reduced the frequency and severity of COVID-19 symptoms: cough, ageusia. The incidence of adverse events in the study participants was comparable. Conclusions. Molnupiravir administration reduces the risk of COVID-19 progression to a severe course, reduces the severity of COVID-19 clinical manifestations, probably by accelerating the virus elimination. The data obtained indicate feasibility of using Molnupiravir for COVID-19 treatment on an outpatient basis.

References

Vremennye metodicheskie rekomendatsii po profilaktike, diagnostike i lecheniyu novoi koronavirusnoi infektsii (COVID-19) Minzdrava Rossii (versiya 17 ot 14.12.2022) [Interim guidelines for the prevention, diagnosis, and treatment of novel coronavirus infection (COVID-19) in Russia (version 17 of 12/14/2022)]. Available at: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/061/252/original/%D0%92%D0%9C%D0%A0_COVID-19_V17.pdf (Accessed 10 May 2023).
Radaeva O.A., Balykova L.A., Zaslavskaya K.Ya. et al. Izuchenie otdalennykh kliniko-patogeneticheskikh effektov protivovirusnogo lekarstvennogo preparata na osnove favipiravira v postkovidnom periode u patsientov s metabolicheskim sindromom [Study of long-term clinical and pathogenetic effects of favipiravir-based anti-viral drug in patients with metabolic syndrome in post-covid period]. Farmatsiya i farmakologiya, 2022, no. 10(2), pp. 217–228. DOI: 10.19163/2307-9266-2022-10-2-217-228.
Instruktsiya po primeneniyu lekarstvennogo preparata Esperavir® (molnupiravir) [Instructions for use of the drug Esperavir® (molnupiravir)]. Available at: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=62a879e9-2c06-4028-8a58-5bac4e01d9ef (Accessed 10 May 2023).
Otkrytoe mnogotsentrovoe issledovanie po otsenke effektivnosti i bezopasnosti lekarstvennogo preparata Esperavir (molnupiravir), kapsuly (OOO «PROMOMED RUS», Rossiya) u vzrosloi populyatsii s COVID-19. Protokol issledovaniya: № MOL-112021 [Open Multicenter Study for Assessment of Efficacy and Safety of the the Drug Esperavir® (Molnupiravir), Capsules (PROMOMED RUS LLC, Russia) in Adult Patients With COVID-19. Clinical Trial Protocol: No. MOL-112021] Available at: https://ichgcp.net/ru/clinical-trials-registry/NCT05595824 (Accessed 10 May 2023).
Bakhitov V.V., Aliev S.R., Martsinkevich V.M. et al. Struktura smertnosti patsientov ambulatornogo tsentra v period pandemii novoi koronavirusnoi infektsii (COVID-19) [Structure of mortality among patients of an outpatient center during the pandemic of the new coronavirus infection (COVID-19)]. Sovremennye problemy zdravookhraneniya i meditsinskoi statistiki, 2022, no. 2, pp. 67–76. DOI: 10.24412/2312-2935-2022-2-67-76.
Shcherbak S.G., Kamilova T.A., Golota A.S., Vologzhanin D.A. Faktory riska tyazhelogo techeniya i letal’nogo iskhoda COVID-19 [Risk factors of the severe course and fatal outcome in COVID-19]. Fizicheskaya i reabilitatsionnaya meditsina, meditsinskaya reabilitatsiya, 2022. no. 4(1), pp. 14–36. DOI: 10.35425/rehab 104997.
Butler C.C., Hobbs F.D.R., Gbinigie O.A. 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, vol. 401(10373), pp. 281–293. DOI: https://doi.org/10.1016/S0140-6736(22)02597-1.
Fischer W.A., Eron J.J. Jr., Holman W. et al. A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl Med, 2022, vol. 14(628), p. 7430. DOI: https://doi.org/10.1126/scitranslmed.abl7430.
Guo X., Jie Y., Ye Y. et al. Upper Respiratory Tract Viral Ribonucleic Acid Load at Hospital Admission Is Associated With Coronavirus Disease 2019 Disease Severity. Open Forum Infect Dis, 2020, vol. 7(7), p. 282. DOI: https://doi.org/10.1093/ofid/ofaa282.
Harvey W.T., Carabelli A.M., Jackson B. et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol, 2021, vol. 19(7), pp. 409–424. DOI: https://doi.org/10.1038/s41579-021-00573-07.
Jayk Bernal A., Gomes da Silva M.M., Musungaie D.B. et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med, 2022, vol. 386(6), pp. 509–520. DOI: https://doi.org/10.1056/NEJMoa2116044.
Jiang S., Xia S., Ying T. et al. A novel coronavirus (2019-nCoV) causing pneumonia-associated respiratory syndrome. Cell Mol Immunol, 2020, vol. 17(5), p. 554. DOI: https://doi.org/10.1038/s41423-020-0372-4.
Khoo S.H., Fitzgerald R., Fletcher T. et al. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study. J Antimicrob Chemother, 2021, vol. 76(12), pp. 3286–3295. DOI: https://doi.org/10.1093/jac/dkab318.
Khoo S.H., Fitzgerald R., Saunders G. et al. Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Infect Dis, 2023, vol. 23(2), pp. 183–195. DOI: https://doi.org/10.1016/S1473-3099(22)00644-2.
Lamontagne F., Agarwal A., Rochwerg B. et al. A living WHO guideline on drugs for COVID- BMJ, 2020, vol. 370, p. 3379. DOI: https://doi.org/10.1136/bmj.m3379.
Liu P.P., Blet A., Smyth D., Li H. The Science Underlying COVID-19: Implications for the Cardiovascular System. Circulation, 2020, vol. 142(1), pp. 68–78. DOI:10.1161/CIRCULATIONAHA.120.047549.
Magleby R., Westblade L.F., Trzebucki A., et al. Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load on Risk of Intubation and Mortality Among Hospitalized Patients With Coronavirus Disease 2019. Clin Infect Dis, 2021, vol. 73(11), pp. 4197–4205. DOI: https://doi.org/10.1093/cid/ciaa851.
Malone B., Campbell E.A. Molnupiravir: coding for catastrophe. Nat Struct Mol Biol, 2021, vol. 28(9), pp. 706–708. DOI: 10.1038/s41594-021-00657-8.
Mostafavi E., Dubey A.K., Teodori L. et al. SARS-CoV-2 Omicron variant: A next phase of the COVID-19 pandemic and a call to arms for system sciences and precision medicine. MedComm, 2022, vol. 3(1), p. 119. DOI: https://doi.org/10.1002/mco2.119.
Pan H., Peto R., Henao-Restrepo A.M. et al. WHO Solidarity Trial Consortium, Repurposed Antiviral Drugs for Covid-19 – Interim WHO Solidarity Trial Results. N Engl J Med, 2021, vol. 384(6), pp. 497-511. DOI: https://doi.org/10.1056/NEJMoa2023184.
Pourkarim F., Pourtaghi-Anvarian S., Rezaee H. Molnupiravir: A new candidate for COVID-19 treatment. Pharmacol Res Perspect, 2022, vol. 10(1), p. 00909. DOI:10.1002/prp2.909.
Rosenke K., Hansen F., Schwarz B. et al. Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model. Nat Commun, 2021, vol. 12(1), p. 2295. DOI: https://doi.org/10.1038/s41467-021-22580-8.
Shanmugaraj B., Malla A., Khorattanakulchai N., Phoolcharoen W. SARS-CoV-2 omicron variant: Could it be another threat? J Med Virol, 2022, vol. 94(4), pp. 1284-1288. DOI: 10.1002/jmv.27532.
Susilo R., Hidayati N. R., Asmarandani D., Fadhilah D. Study of the severity and early antiviral treatment for the duration of the recovery COVID-19 patients. Jurnal Farmasi Sains dan Praktis, 2022, vol. 9(1), pp. 20–26. DOI: 10.31603/pharmacy.v9i1.7916.
Toots M., Yoon J.J., Cox R.M. et al. Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci Transl Med, 2019, vol. 11(515), p. 5866. DOI: https://doi.org/10.1126/scitranslmed.aax5866.
Torjesen I. Covid-19: Omicron may be more transmissible than other variants and partly resistant to existing vaccines, scientists fear. BMJ, 2021, vol. 375, n2943. DOI: 10.1136/bmj.n2943.
Wahl A., Gralinski L.E., Johnson C.E. et al. SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature, 2021, vol. 591(7850), pp. 451–457. DOI: https://doi.org/10.1038/s41586-021-03312-w.
Wai A.K., Chan C.Y., Cheung A.W. et al. Association of Molnupiravir and Nirmatrelvir-Ritonavir with preventable mortality, hospital admissions and related avoidable healthcare system cost among high-risk patients with mild to moderate COVID-19. Lancet Reg Health West Pac, 2023, vol. 30, p. 100602. DOI: https://doi.org/10.1016/j.lanwpc.2022.100602.
Yuanlin He, Xin Xu, Qun Lu et al. High viral load suggests increased COVID-19 severity in a longitudinal cohort, 2020, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-34267/v1].
Zheng Z., Peng F., Xu B. et al. Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis. J Infect, 2020, vol. 81(2), pp. 16–25. DOI: https://doi.org/10.1016/j.jinf.2020.04.021.

About authors

Balykova Larisa A.: Doctor of Medical Sciences, Professor, Corresponding Member of RAS, Director of the Medicine Institute, Head of the Pediatrics Department, National Research Ogarev Mordovia State University, Russia, Saransk (larisabalykova@yandex.ru; ORCID: https://orcid.org/0000-0002-2290-0013)

Pshenichnaya Natalia Yu.: Doctor of Medical Sciences, Professor, Deputy Director for Clinical and Analytical Work, Central Research Institute of Epidemiology of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, Russia, Moscow (natalia-pshenichnaya@yandex.ru; ORCID: https://orcid.org/0000-0003-2570-711X)

Omarova Khadizhat G.: Candidate of Medical Sciences, Head of the Clinical Research Department, Central Research Institute of Epidemiology of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, Russia, Moscow (omarova@cmd.su; ORCID: https://orcid.org/0000-0002-9682-2230)

Pushkar Dmitrii Yu.: Academician of RAS, Doctor of Medical Sciences, Professor, Member of the Academic Consortium of the Academic Community for the Study of COVID-19, Chief Freelance Urologist of the Ministry of Health of the Russian Federation, Head of the Urology Department, A.I. Evdokimov Moscow University of Medicine and Dentistry, Russia, Moscow (pushkardm@mail.ru; ORCID: https://orcid.org/0000-0002-6096-5723)

Zaslavskaia Kira Ya.: Assistant Lecturer, Department of Biological and Pharmaceutical Chemistry with the Course of Organization and Management of Pharmacy, Institute of Medicine, National Research Ogarev Mordovia State University, Russia, Saransk (kiryonok@yandex.ru; ORCID: https://orcid.org/0000-0002-7348-9412)

Zemskov Dmitrii N.: Assistant Lecturer, Department of Pharmacology and Clinical Pharmacology with a Course in Pharmaceutical Technology, Institute of Medicine, National Research Ogarev Mordovia State University, Russia, Saransk (dizem1978@gmail.com; ORCID: https://orcid.org/0000-0002-0181-4327)

Taganov Aleksei V.: Doctor of Medical Sciences, Professor, Department of Dermatovenereology with a Course of Cosmetology, Faculty of Continuous Medical Education, Institute of Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba, Russia, Moscow (matis87177@yandex.ru; ORCID: https://orcid.org/0000-0001-5056-374X)

Belyi Petr A.: Candidate of Medical Sciences, Senior Laboratory Assistant, Department of Propaedeutics of Internal Diseases and Gastroenterology, A.I. Evdokimov Moscow University of Medicine and Dentistry, Russia, Moscow (pbely@ncpharm.ru; ORCID: https://orcid.org/0000-0001-5998-4874)

Gorelov Aleksandr V.: Academician of RAS, Doctor of Medical Sciences, Professor, Deputy Director for Research, Central Research Institute of Epidemiology of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing; Professor, Department of Pediatric Diseases, I.M. Sechenov First Moscow State Medical University (Sechenovskiy University), Russia, Moscow (zdn@pcr.ru; ORCID: https://orcid.org/0000-0001-9257-0171)

Kozlov Evgenii D.: Senior Lecturer, Department of Outpatient Therapy, Institute of Medicine, National Research Ogarev Mordovia State University, Russia, Saransk (dr.kozlov@yandex.ru; ORCID: https://orcid.org/0000-0001-8373-6109)

Shepeleva Olga I.: Candidate of Medical Sciences, Associate Professor, Department of Hospital Therapy, Institute of Medicine, National Research Ogarev Mordovia State University, Russia, Saransk (shepeleva-oi@mail.ru; ORCID: https://orcid.org/0000-0001-8307-2787)

Prekina Valentina I.: Candidate of Medical Sciences, Associate Professor, Department of Outpatient Therapy, Institute of Medicine, National Research Ogarev Mordovia State University, Russia, Saransk (vprekina@mail.ru; ORCID: https://orcid.org/0000-0002-2306-722X)

Semenova Elena V.: Candidate of Medical Sciences, Associate Professor, Department of Pharmacology and Clinical Pharmacology with a Course in Pharmaceutical Technology, National Research Ogarev Mordovia State University, Russia, Saransk (yelenadan@mail.ru; ORCID: https://orcid.org/0000-0001-7671-7110)

Article link

Balykova L.A., Pshenichnaya N.Yu., Omarova Kh.G., Pushkar D.Yu., Zaslavskaia K.Ya., Zemskov D.N., Taganov A.V., Belyi P.A., Gorelov A.V., Kozlov E.D., Shepeleva O.I., Prekina V.I., Semenova E.V. Etiotropic Therapy of Mild COVID-19 in Outpatient Patients: Molnupiravir is in Focus [Electronic resource] // Acta medica Eurasica. – 2023. – №3. P. 1-15. – URL: https://acta-medica-eurasica.ru/en/single/2023/3/1/. DOI: 10.47026/2413-4864-2023-3-1-15.

Single article

Balykova L.A., Pshenichnaya N.Yu., Omarova Kh.G., Pushkar D.Yu., Zaslavskaia K.Ya., Zemskov D.N., Taganov A.V., Belyi P.A., Gorelov A.V., Kozlov E.D., Shepeleva O.I., Prekina V.I., Semenova E.V.