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Comparing the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID‐19 patients

Abstract 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.


| INTRODUCTION
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 (3) being consistently afebrile for 48 h without the use of antipyretics.

| Drug administration
Patients were randomly assigned to two treatment groups and re-

| Data collection
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.

| Statistical analysis
The descriptive statistics such as mean ± standard deviation and

| Laboratory parameter differences between study groups
ANCOVA analysis of the admission and discharge laboratory data ( 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 re-  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  | 6563 90% and the SpO 2 was the only predictor of outcome in the study population. 43 Studies regarding the therapeutic effect of Atazanavir in COVID-19 are scarce, thus the exact efficacy of Atazanavir as a treatment option has not been confirmed. In the present study, patients in the ADH group showed significant improvements in oxygen saturation and clinical and paraclinical characteristics. However, this fact should be considered that these results might have been due to a synergetic effect with Dolutegravir or even Dolutegravir alone.
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 group compared to Lopinavir/Ritonavir group, and to precisely determine the efficiency of the Atazanavir/Dolutegravir regimen a more comprehensive study with a larger study population is recommended.
Some laboratory tests required for determining the efficiency of treatment regimens were not repeated at discharge date for a number of patients.