key: cord-0737403-bdq7o0o8 authors: Kalantari, Saeed; Fard, Soheil R.; Maleki, Donya; Taher, Mahshid T.; Yassin, Zeynab; Alimohamadi, Yousef; Minaeian, Sara title: Comparing the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID‐19 patients date: 2021-07-28 journal: J Med Virol DOI: 10.1002/jmv.27195 sha: 744dbaaebd0e4d2026dea4036eb44b46b44686fd doc_id: 737403 cord_uid: bdq7o0o8 The purpose of this study was to compare the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID‐19 patients based on clinical and laboratory parameters. We prospectively evaluated the clinical and laboratory outcomes of 62 moderate to severe COVID‐19 patients during a 10‐day treatment plan. Patients were randomly assigned to either KH (receiving Lopinavir/Ritonavir [Kaletra] plus Hydroxychloroquine) or ADH (receiving Atazanavir/Ritonavir, Dolutegravir, and Hydroxychloroquine) groups. During this period, clinical and laboratory parameters and outcomes such as intensive care unit (ICU) admission or mortality rate were recorded. Compared to the KH group, after the treatment period, patients in the ADH group had higher activated partial thromboplastin time (aPTT) (12, [95% confidence interval [CI]: 6.97, 17.06), p = <0.01), international normalized ratio (INR) (0.17, [95% CI: 0.07, 0.27), p = <0.01) and lower C‐reactive protein (CRP) (−14.29, (95% CI: −26.87, −1.71), p = 0.03) and potassium (−0.53, (95% CI: −1.03, −0.03), p = 0.04) values. Moreover, a higher number of patients in the KH group needed invasive ventilation (6 (20%) vs. 1 (3.1%), p = 0.05) and antibiotic administration (27 (90%) vs. 21(65.6), p = 0.02) during hospitalization while patients in the ADH group needed more corticosteroid administration (9 (28.1%) vs. 2 (6.7%), p = 0.03). There was no difference in mortality rate, ICU admission rate, and hospitalization period between the study groups. Our results suggest that the Atazanavir/Dolutegravir treatment regimen may result in a less severe disease course compared to the Lopinavir/Ritonavir treatment regimen and can be considered as an alternative treatment option beside standard care. However, to confirm our results, larger‐scale studies are recommended. More than a year after its emergence, the COVID-19 pandemic is still raging around the world and shows no signs of stopping. The disease that first emerged from Wuhan, China in December 2019, 1 has now infected more than 100 million people and caused more than two million deaths. 2 Based on the disease characteristics and virus lineage, the first worldwide line of treatment was considered to be the drugs that had shown positive outcomes in the treatment of similar conditions like severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS); drugs such as Ribavirin, Interferon, Lopinavir/Ritonavir, and Arbidol. [3] [4] [5] [6] [7] Unfortunately, these drugs were not quite successful in lowering the mortality rate of COVID-19, thus genomic characterization of the virus initiated an international effort to find a cure for the disease. 8 The virus responsible for the disease, first named 2019-nCOV and later officially designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a member of Coronaviridae family of viruses. SARS-CoV-2 is the seventh coronavirus strain that has been associated with human diseases including common cold (HCoV-229E, HCoV-HKU1, and HCoV-OC43), respiratory tract infections and bronchitis (HCoV-NL63), SARS (SARS-CoV), and MERS (MERS-CoV). [9] [10] [11] [12] [13] SARS-CoV-2 contains four different structural proteins: Envelope (E) protein that facilitates virus assembly and budding, Membrane (M) that is associated with maturity and the final form of the virus, Nucleocapsid (N) which is involved in virus assembly by binding to RNA and Spike (S) that is responsible for virus entry to the host cell via the angiotensin-converting enzyme 2 (ACE2) receptor and is vital to its infectivity. [14] [15] [16] After cell entry, the viral genome will be translated into two major polypeptide chains and subsequently truncated into 16 nonstructural proteins (nsp1-nsp16) by viral proteases such as coronaviral principal protease (3CLpro) and papain-like protease (PLpro). These proteins are responsible for virus production and assembly. [17] [18] [19] One of the more common treatment regimens for COVID-19 is Lopinavir/Ritonavir that is generally used in human immunodeficiency virus (HIV) treatment. Lopinavir is an aspartate protease inhibitor for HIV-1 and has the ability to inhibit 3CLpro activity, a major enzyme in viral replication, and Ritonavir is responsible for extending Lopinavir half-life in plasma via inhibiting cytochrome p450. 20, 21 There is also evidence regarding their effectiveness against SARS-CoV and MERS-CoV. 4 Atazanavir is another HIV/AIDS targeting drug that is seeing more and more use as a COVID-19 treatment option. It is one of the 10 Food and Drug Administration-approved protease inhibitors of HIV and can effectively reduce HIV viral load to undetectable levels. 26 Bioinformatics studies show that this drug might be able to inhibit vital SARS-CoV-2 enzymes such as helicase and 3CLpro 27, 28 thus making it a viable treatment candidate for COVID-19. Dolutegravir, like previously mentioned drugs, is primarily used in HIV treatment. This relatively new drug is an integrase strand transfer inhibitor (INSTI) and is able to prevent the integration process of viral DNA into the host genome. 29 Recent findings suggest that Dolutegravir is capable of inhibiting SARS-CoV-2's 3CLpro protease by binding to the enzyme active sites. 27 Additionally, there are studies suggesting that people with HIV that also contracted COVID-19, may have favorable outcomes 30 All the subjects for this study were selected among patients who were referred to the Rasool-e-Akram general teaching hospital with COVID-19 symptoms between January 30 and February 14, 2021. Patients were randomly assigned to two treatment groups and re- Multiple biochemical parameters were measured both at the time of the admission and discharge using routine methods and commercial kits. These parameters include complete blood count (CBC), creatinine, sodium, potassium, activated partial thromboplastin time All demographics, clinical presentations, comorbidities, and drug history were collected from patients. Clinical and laboratory parameters were recorded both at the time of admission and discharge. During hospitalization, additional necessary administered drugs and procedures were also recorded. If patients were stable enough to be discharged before the completion of the 10-day treatment period, their well-being and drug consumption were monitored daily. The descriptive statistics such as mean ± standard deviation and ANCOVA analysis of the admission and discharge laboratory data ( One of the more common treatment options is Lopinavir/Ritonavir (Kaletra), a well-known protease inhibitor that is primarily used in HIV treatment. Computerized models revealed that Lopinavir/Ritonavir is able to effectively inhibit the SARS-CoV-1 and SARS-CoV-2 protease (3CLpro). 33, 34 Translating these computerized models into in-vitro and in-vivo studies showed that Lopinavir/Ritonavir is able to inhibit SARS-CoV-1 and MERS-CoV replication and cytopathic effects in fRhK4, Vero-E6, and Huh7 cells 21, 35 and improved the clinical, radiological and pathological findings in an animal (common marmoset) model of MERS-CoV infection. 22 Based on these results, Lopinavir/Ritonavir was considered as a treatment option in SARS and MERS disease outbreaks and a 400/100 mg dose for a period of 10-14 days proved to be effective in reducing the mortality, intubation, and ARDS development rates in SARS patients and showed a 40% decrease in the infection rates of healthcare workers exposed to patients with severe MERS-CoV infection. 3, 4, 36 Reproducing these relatively successful results in the COVID-19 pandemic has proven to be much more challenging as contradicting results are being reported. A case-control study consisting of a treatment group receiving a dose of Lopinavir/Ritonavir (400/200 mg twice daily) T A B L E 3 ANCOVA analysis of treatment efficacy between ADH and KH treatment groups regarding the laboratory parameters from before and after the treatment period and responding to these viral elements. 41 To the best of our knowledge, this is the first time that Dolutegravir has been used as a treatment option in COVID-19 patients. Atazanavir, another drug that's used primarily in HIV patients also shows potential as a candidate for COVID-19 treatment. Studies revealed that Atazanavir may be able to inhibit different SARS-CoV-2 proteins such as 3CLpro, 27 Helicase, 28 and these results have since been confirmed in an in-vitro study showcasing the inhibition of SARS-CoV-2 replication and ameliorating the induced interleukin-6 and tumor necrosis factor-α production in both Vero cells and human pulmonary epithelial cell line. 42 The following limitations were present in our study and should be taken into consideration before interpretation of our findings. In the current study, we could not determine the efficiency of either of the treatment regimens compared to standard care as we did not have a control group. Our study population was relatively small and our results showed an advantage in the Atazanavir/Dolutegravir A novel coronavirus from patients with pneumonia in China Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings Clinical efficacy of Аrbidol (umifenovir) in the therapy of influenza in adults: preliminary results of the multicenter double-blind randomized placebo-controlled study ARBITR Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding Understanding human coronavirus HCoV-NL63 A decade after SARS: strategies for controlling emerging coronaviruses A novel coronavirus associated with severe acute respiratory syndrome Direct diagnosis of human respiratory coronaviruses 229E and OC43 by the polymerase chain reaction Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia Structural basis of receptor recognition by SARS-CoV-2 Coronavirus genome structure and replication SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Coronaviruses: an overview of their replication and pathogenesis SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum The molecular biology of coronaviruses Lopinavir/ritonavir: a review of its use in the management of HIV infection Screening of an FDAapproved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model State-of-the-art tools unveil potent drug targets amongst clinically approved drugs to inhibit helicase in SARS-CoV-2 Dolutegravir-a review of the pharmacology, efficacy, and safety in the treatment of HIV Clinical features and outcomes of HIV patients with coronavirus disease 2019 COVID-19 in hospitalized adults with HIV Treatment options for COVID-19: a review Molecular dynamic simulations analysis of ritronavir and lopinavir as SARS-CoV 3CLpro inhibitors Why are lopinavir and ritonavir effective against the newly emerged Coronavirus 2019? Atomistic insights into the inhibitory mechanisms In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds Post-exposure prophylaxis for Middle East respiratory syndrome in healthcare workers Clinical efficacy of lopinavir/ritonavir in the treatment of coronavirus disease 2019 Arbidol combined with LPV/r versus LPV/r alone against corona virus disease 2019: a retrospective cohort study Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19 Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering (Beijing) Targeting SARS-CoV-2: a systematic drug repurposing approach to identify promising inhibitors against 3C-like proteinase and 2′-O-ribose methyltransferase Atazanavir, alone or in combination with ritonavir, inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production Comparing outcomes of hospitalized patients with moderate and severe COVID-19 following treatment with hydroxychloroquine plus atazanavir/ritonavir The authors declare that there are no conflict of interests.