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ACADEMIA Letters Incorrect Disqualification of Lopinavir/ritonavir in SARS-CoV-2 Pandemic Ma. de la Paz Mireles-Vieyra, Clínica Profin VIH. Marlene Rodríguez-Lara , Clínica Profin VIH. Raúl Martín Cruz-Mireles, Clínica Profin VIH. Since the emergence of coronavirus pandemic, medicine has busily searched for options to stop and even extinguish the disease. Because SARS-CoV-2 belongs to RNA viruses group, the possibility that already known antiretroviral drugs could have some inhibitory effect on SARS-CoV-2 enzymes is real. To date there is conflicting reports on the effect of Lopinavir /ritonavir, a powerful inhibitor of HIV aspartyl protease, in various types of patients with mild to severe damage by COVID-19; those reports ranges from no therapeutic effect at all in randomized trials (1-5) to an important one in vitro, molecular docking, clinical and observational studies (6-11). In our opinion the main cause because these reports seems contradictory it’s because they are not looking for the right effect of these drugs. Lopinavir/ritonavir cannot have any direct effect on the control of tissue damage caused by SARS CoV-2 infection, so their action should not be expected in this area; but over SARS CoV-2 viral multiplication. Lopinavir/ritonavir are not drugs capable of solve any of the problems related to the DAMAGE that various elements contribute to cause on the tissues of a specific COVID-19 patient (previous pathologies, interleukin storm, bronchopathies, etc.), so the effect of Lopinavir/ritonavir therapy should be evaluated by its anti-multiplier effect on SARS-CoV-2; it is at this level where their protective effect must be assessed, because these antiretrovirals reduce the viral load, not only of HIV but very likely also of SARS-CoV-2, through the putative inhibition of 3CLpro, its main protease. This reduction is essential for the evolution and prognosis of a patient, representing the difference between life and death. Administering Lopinavir/ritonavir at an early stage of infection (maybe even at the intermediate stage) will prevent the extremely intense multipliAcademia Letters, July 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Raúl Martín Cruz-Mireles, director@expresionespiritual.org Citation: Mireles-Vieyra, M.D.L.P., Rodríguez-Lara , M., Cruz-Mireles, R.M. (2021). Incorrect Disqualification of Lopinavir/ritonavir in SARS-CoV-2 Pandemic. Academia Letters, Article 2043. https://doi.org/10.20935/AL2043. 1 cation that SARS-CoV-2 seems to have, and if this is achieved, the natural defense by immune system (IgM, IgG, killer cells, etc.) will be capable of counteract this multiplication, preventing the damage that is generated during the first days of infection which triggers an intense inflammatory response in various regions of the body (12). These damages must be treated with different therapies in order to solve the devastating effect but assessing Lopinavir for its effect at the level of body DAMAGE is erroneous, and evaluating its effect in patients with different degrees of general affectation obscure the role that the drug has in COVID-19 which is just related to the speed and intensity of growing SARS-CoV-2 viral load, which in turn will determine the medical evolution of a patient. In a group of 110 HIV+ adult patients of both sexes under current antiretroviral treatment in our medical clinic the relative risk of catch COVID-19 for patients under integrase inhibitors during the COVID pandemic has been, up to date, of 3.17, while the relative risk for patients under protease Inhibitors and non nucleoside analogs is far below 3. The apparent protective effect of protease Inhibitors and the lack of protection of integrase Inhibitors can be perfectly understood from theoretical grounds in terms of their possible effects on SARS-CoV-2 viral multiplication; nevertheless in our group of patients non nucleoside analogs also seems to offer some protective effect against COVID-19, although the size of the group is too small to be sure about these effects. Non nucleoside analogs are competitive inhibitors of HIV reverse transcriptase, a kind of enzyme not present in SARS-CoV-2 virions or genome, so, no protective effect against SARS-CoV-2 infection must be expected from this kind of drugs. Nevertheless Chien and co workers has shown recently that nucleotide analogs are capable of inhibit the SARS-CoV nsp12 RNA-dependent RNA polymerase (RdRp), thus it is conceivable that non-nucleoside analogs could also act by inhibiting this enzyme in an striking, not yet reported, way (13). On the other hand,12 HIV- patients who received Lopinavir/ritonavir as part of their therapeutic management during the first 48 hours from the start of COVID-19 symptoms, developed a mild form of the infection with moderate to negligible discomfort and all 12 made a full recovery within the following 2.5 weeks, which seems to support the idea that the early administration of Lopinavir/ritonavir could give excellent results if it is administered as early as possible during SARS-CoV-2 infection. In any case, carefully designed studies with larger populations that take into account the organic damage caused by COVID-19 disease are needed to confirm the apparent protection that these antiretrovirals seems to confer against SARS-CoV-2 multiplication. Academia Letters, July 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Raúl Martín Cruz-Mireles, director@expresionespiritual.org Citation: Mireles-Vieyra, M.D.L.P., Rodríguez-Lara , M., Cruz-Mireles, R.M. (2021). Incorrect Disqualification of Lopinavir/ritonavir in SARS-CoV-2 Pandemic. Academia Letters, Article 2043. https://doi.org/10.20935/AL2043. 2 References 1. Alhumaid S, Al Mutair A, Al Alawi Z et al. Efficacy and Safety of Lopinavir/Ritonavir for Treatment of COVID-19: A Systematic Review and Meta-Analysis. Trop. Med. Infect. Dis. 2020; 5(4):180. DOI: 10.3390/tropicalmed5040180 2. Cao B, Wang Y, Wen D et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020; 382:1787-1799. DOI: 10.1056/NEJMoa2001282 3. Joseph BA, Dibas M, Evanson KW et al. Efficacy and safety of lopinavir/ritonavir in the treatment of COVID-19: A systematic review. Expert Rev. Anti-infect. Ther 2020. DOI: 10.1080/14787210.2021.1848545 4. Li Y, Xie Z, Lin W et al. Efficacy and safety of lopinavir/ ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med 2020; 1:105-113. DOI: 10.1016/j.medj.2020.04.001 5. RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet 2020; 396(10259): 1345-1352. DOI: 10.1016/S0140-6736(20)32013-4. 6. Choy KT, Wong AYL, Kaewpreedee P et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Research 2020, 178. DOI: 10.1016/j.antiviral.2020.104786 7. Chu CM, Cheng VCC, Hung IFN et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004; 59: 252–6. DOI: 10.1136/thorax.2003.012658 8. Kang CK, Seong M-W, Choi S-J et al. In vitro activity of lopinavir/ritonavir and hydroxychloroquine against severe acute respiratory syndrome coronavirus 2 at concentrations achievable by usual doses. Korean J Intern Med. 2020 35(4): 728–787.DOI: 10.3904/kjim.2020.157 9. Muralidharan N, Sakthivel R, Velmurugan D et al. Computational studies of drug repurposing and synergism of lopinavir, oseltamivir and ritonavir binding with SARS-CoV-2 protease against COVID-19. J Biomol Struct Dyn 2020. DOI: 10.1080/07391102.2020.1752802 10. Ye XT, Luo YL, Xia SC et al. Clinical efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease 2019. Eur. Rev. Med. Pharmacol. Sci. 2020. 24:390–3396. DOI: 10.26355/eurrev_202003_20706. Academia Letters, July 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Raúl Martín Cruz-Mireles, director@expresionespiritual.org Citation: Mireles-Vieyra, M.D.L.P., Rodríguez-Lara , M., Cruz-Mireles, R.M. (2021). Incorrect Disqualification of Lopinavir/ritonavir in SARS-CoV-2 Pandemic. Academia Letters, Article 2043. https://doi.org/10.20935/AL2043. 3 11. Zhong H, Wang Y, Zhang Z-L et al. Efficacy and safety of current therapeutic options for COVID-19 - lessons to be learnt from SARS and MERS epidemic: A systematic review and meta-analysis. Pharmacol Res. 2020. 157: 104872. DOI: 10.1016/j.phrs.2020.104872 12. Wu J, Li W, Shi X et al. Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus Disease (COVID-19). J Intern Med. 2020; 288(1):128-138. DOI: 10.1111/joim.13063. 13. Chien M, Anderson T K, Jockusch S et al. Nucleotide Analogues as Inhibitors of SARSCoV‑2 Polymerase, a Key Drug Target for COVID-19. J. Proteome Res. 2020; 19(11): 4690−4697. DOI: 10.1021/acs.jproteome.0c00392 Academia Letters, July 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Raúl Martín Cruz-Mireles, director@expresionespiritual.org Citation: Mireles-Vieyra, M.D.L.P., Rodríguez-Lara , M., Cruz-Mireles, R.M. (2021). Incorrect Disqualification of Lopinavir/ritonavir in SARS-CoV-2 Pandemic. Academia Letters, Article 2043. https://doi.org/10.20935/AL2043. 4
ACADEMIA Letters Incorrect Disqualification of Lopinavir/ritonavir in SARS-CoV-2 Pandemic Ma. de la Paz Mireles-Vieyra, Clínica Profin VIH. Marlene Rodríguez-Lara , Clínica Profin VIH. Raúl Martín Cruz-Mireles, Clínica Profin VIH. Since the emergence of coronavirus pandemic, medicine has busily searched for options to stop and even extinguish the disease. Because SARS-CoV-2 belongs to RNA viruses group, the possibility that already known antiretroviral drugs could have some inhibitory effect on SARS-CoV-2 enzymes is real. To date there is conflicting reports on the effect of Lopinavir /ritonavir, a powerful inhibitor of HIV aspartyl protease, in various types of patients with mild to severe damage by COVID-19; those reports ranges from no therapeutic effect at all in randomized trials (1-5) to an important one in vitro, molecular docking, clinical and observational studies (6-11). In our opinion the main cause because these reports seems contradictory it’s because they are not looking for the right effect of these drugs. Lopinavir/ritonavir cannot have any direct effect on the control of tissue damage caused by SARS CoV-2 infection, so their action should not be expected in this area; but over SARS CoV-2 viral multiplication. Lopinavir/ritonavir are not drugs capable of solve any of the problems related to the DAMAGE that various elements contribute to cause on the tissues of a specific COVID-19 patient (previous pathologies, interleukin storm, bronchopathies, etc.), so the effect of Lopinavir/ritonavir therapy should be evaluated by its anti-multiplier effect on SARS-CoV-2; it is at this level where their protective effect must be assessed, because these antiretrovirals reduce the viral load, not only of HIV but very likely also of SARS-CoV-2, through the putative inhibition of 3CLpro, its main protease. This reduction is essential for the evolution and prognosis of a patient, representing the difference between life and death. Administering Lopinavir/ritonavir at an early stage of infection (maybe even at the intermediate stage) will prevent the extremely intense multipliAcademia Letters, July 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Raúl Martín Cruz-Mireles, director@expresionespiritual.org Citation: Mireles-Vieyra, M.D.L.P., Rodríguez-Lara , M., Cruz-Mireles, R.M. (2021). Incorrect Disqualification of Lopinavir/ritonavir in SARS-CoV-2 Pandemic. Academia Letters, Article 2043. https://doi.org/10.20935/AL2043. 1 cation that SARS-CoV-2 seems to have, and if this is achieved, the natural defense by immune system (IgM, IgG, killer cells, etc.) will be capable of counteract this multiplication, preventing the damage that is generated during the first days of infection which triggers an intense inflammatory response in various regions of the body (12). These damages must be treated with different therapies in order to solve the devastating effect but assessing Lopinavir for its effect at the level of body DAMAGE is erroneous, and evaluating its effect in patients with different degrees of general affectation obscure the role that the drug has in COVID-19 which is just related to the speed and intensity of growing SARS-CoV-2 viral load, which in turn will determine the medical evolution of a patient. In a group of 110 HIV+ adult patients of both sexes under current antiretroviral treatment in our medical clinic the relative risk of catch COVID-19 for patients under integrase inhibitors during the COVID pandemic has been, up to date, of 3.17, while the relative risk for patients under protease Inhibitors and non nucleoside analogs is far below 3. The apparent protective effect of protease Inhibitors and the lack of protection of integrase Inhibitors can be perfectly understood from theoretical grounds in terms of their possible effects on SARS-CoV-2 viral multiplication; nevertheless in our group of patients non nucleoside analogs also seems to offer some protective effect against COVID-19, although the size of the group is too small to be sure about these effects. Non nucleoside analogs are competitive inhibitors of HIV reverse transcriptase, a kind of enzyme not present in SARS-CoV-2 virions or genome, so, no protective effect against SARS-CoV-2 infection must be expected from this kind of drugs. Nevertheless Chien and co workers has shown recently that nucleotide analogs are capable of inhibit the SARS-CoV nsp12 RNA-dependent RNA polymerase (RdRp), thus it is conceivable that non-nucleoside analogs could also act by inhibiting this enzyme in an striking, not yet reported, way (13). On the other hand,12 HIV- patients who received Lopinavir/ritonavir as part of their therapeutic management during the first 48 hours from the start of COVID-19 symptoms, developed a mild form of the infection with moderate to negligible discomfort and all 12 made a full recovery within the following 2.5 weeks, which seems to support the idea that the early administration of Lopinavir/ritonavir could give excellent results if it is administered as early as possible during SARS-CoV-2 infection. In any case, carefully designed studies with larger populations that take into account the organic damage caused by COVID-19 disease are needed to confirm the apparent protection that these antiretrovirals seems to confer against SARS-CoV-2 multiplication. Academia Letters, July 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Raúl Martín Cruz-Mireles, director@expresionespiritual.org Citation: Mireles-Vieyra, M.D.L.P., Rodríguez-Lara , M., Cruz-Mireles, R.M. (2021). Incorrect Disqualification of Lopinavir/ritonavir in SARS-CoV-2 Pandemic. Academia Letters, Article 2043. https://doi.org/10.20935/AL2043. 2 References 1. Alhumaid S, Al Mutair A, Al Alawi Z et al. Efficacy and Safety of Lopinavir/Ritonavir for Treatment of COVID-19: A Systematic Review and Meta-Analysis. Trop. Med. Infect. Dis. 2020; 5(4):180. DOI: 10.3390/tropicalmed5040180 2. Cao B, Wang Y, Wen D et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020; 382:1787-1799. DOI: 10.1056/NEJMoa2001282 3. Joseph BA, Dibas M, Evanson KW et al. Efficacy and safety of lopinavir/ritonavir in the treatment of COVID-19: A systematic review. Expert Rev. Anti-infect. Ther 2020. DOI: 10.1080/14787210.2021.1848545 4. Li Y, Xie Z, Lin W et al. Efficacy and safety of lopinavir/ ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med 2020; 1:105-113. DOI: 10.1016/j.medj.2020.04.001 5. RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet 2020; 396(10259): 1345-1352. DOI: 10.1016/S0140-6736(20)32013-4. 6. Choy KT, Wong AYL, Kaewpreedee P et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Research 2020, 178. DOI: 10.1016/j.antiviral.2020.104786 7. Chu CM, Cheng VCC, Hung IFN et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004; 59: 252–6. DOI: 10.1136/thorax.2003.012658 8. Kang CK, Seong M-W, Choi S-J et al. In vitro activity of lopinavir/ritonavir and hydroxychloroquine against severe acute respiratory syndrome coronavirus 2 at concentrations achievable by usual doses. Korean J Intern Med. 2020 35(4): 728–787.DOI: 10.3904/kjim.2020.157 9. Muralidharan N, Sakthivel R, Velmurugan D et al. Computational studies of drug repurposing and synergism of lopinavir, oseltamivir and ritonavir binding with SARS-CoV-2 protease against COVID-19. J Biomol Struct Dyn 2020. DOI: 10.1080/07391102.2020.1752802 10. Ye XT, Luo YL, Xia SC et al. Clinical efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease 2019. Eur. Rev. Med. Pharmacol. Sci. 2020. 24:390–3396. DOI: 10.26355/eurrev_202003_20706. Academia Letters, July 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Raúl Martín Cruz-Mireles, director@expresionespiritual.org Citation: Mireles-Vieyra, M.D.L.P., Rodríguez-Lara , M., Cruz-Mireles, R.M. (2021). Incorrect Disqualification of Lopinavir/ritonavir in SARS-CoV-2 Pandemic. Academia Letters, Article 2043. https://doi.org/10.20935/AL2043. 3 11. Zhong H, Wang Y, Zhang Z-L et al. Efficacy and safety of current therapeutic options for COVID-19 - lessons to be learnt from SARS and MERS epidemic: A systematic review and meta-analysis. Pharmacol Res. 2020. 157: 104872. DOI: 10.1016/j.phrs.2020.104872 12. Wu J, Li W, Shi X et al. Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus Disease (COVID-19). J Intern Med. 2020; 288(1):128-138. DOI: 10.1111/joim.13063. 13. Chien M, Anderson T K, Jockusch S et al. Nucleotide Analogues as Inhibitors of SARSCoV‑2 Polymerase, a Key Drug Target for COVID-19. J. Proteome Res. 2020; 19(11): 4690−4697. DOI: 10.1021/acs.jproteome.0c00392 Academia Letters, July 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Raúl Martín Cruz-Mireles, director@expresionespiritual.org Citation: Mireles-Vieyra, M.D.L.P., Rodríguez-Lara , M., Cruz-Mireles, R.M. (2021). Incorrect Disqualification of Lopinavir/ritonavir in SARS-CoV-2 Pandemic. Academia Letters, Article 2043. https://doi.org/10.20935/AL2043. 4