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ORIGINAL ARTICLE
Ahead of print publication  

Efficacy of lopinavir/ritonavir plus interferon beta compared to hydroxychloroquine in the treatment of COVID-19: A retrospective observational study


1 Student Research Committee, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
2 Infectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
3 Health Information Technology Department, Faculty of Paramedicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
4 Department of Clinical Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
5 Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
6 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Hormozgan University of Medical Sciences; Endocrinology and Metabolic Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

Date of Submission15-Apr-2022
Date of Acceptance29-Jul-2022
Date of Web Publication23-Sep-2022

Correspondence Address:
Mohammad Fathalipour,
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Hormozgan University of Medical Sciences; Endocrinology and Metabolic Research Center, Hormozgan University of Medical Sciences, Bandar Abbas
Iran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aihb.aihb_70_22

  Abstract 


Introduction: Although a long time past since COVID-19 was broken out, it is hard to determine which pharmacological combination regimen is more efficacious. The present study aimed to evaluate the efficacy of lopinavir/ritonavir (LPV/r) plus interferon (IFN) beta-1a regimen compared to the hydroxychloroquine (HCQ) regimen in moderately ill patients with COVID-19. Methods: A multiple-centre retrospective observational case-controlled study was performed between March and September 2020, including adults with confirmed COVID-19. The patients were categorised into age- and sex-matched two groups; LPV/r plus IFN beta-1a (n = 102) and HCQ (n = 298) regimens. Clinical outcomes and mortality rates were compared between the groups. Results: LPV/r plus interferon (INF) beta-1a regimen had improved none of the clinical outcomes and mortality rate compared to the HCQ regimen. The length of stay (LOS) in the hospital and the need for oxygen therapy were slightly worse in the LPV/r plus INF beta-1a regimen (4.73 ± 2.93 days, 63%) than in the HCQ group (3.74 ± 3.30 days, 48.3%). No statistically significant difference was observed between the two groups in care of intensive care unit (ICU) admission, LOS in ICU, the need for non-invasive ventilation and the need for invasive mechanical ventilation as well as in-hospital mortality rate. Conclusions: LPV/r plus IFN beta-1a regimen did not show any meaningful improvement in clinical outcomes or mortality compared to the HCQ regimen. Larger randomised controlled trials are needed to assess the efficacy of this combination further.

Keywords: COVID-19, efficacy, hydroxychloroquine, interferon, lopinavir/ritonavir



How to cite this URL:
Amirizadeh M, Sarvestani FS, Khorrami F, Safa O, Davoodian P, Hassaniazad M, Akhlaghi B, Fathalipour M. Efficacy of lopinavir/ritonavir plus interferon beta compared to hydroxychloroquine in the treatment of COVID-19: A retrospective observational study. Adv Hum Biol [Epub ahead of print] [cited 2022 Sep 27]. Available from: https://www.aihbonline.com/preprintarticle.asp?id=356798




  Introduction Top


Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which emerged in Wuhan, China, in December 2019, is a novel virus that caused a pandemic outbreak.[1] Although the virus causes mild and limited symptoms in most patients, it can lead to severe respiratory symptoms and life-threatening situations that need intensive care support and mechanical ventilation.[2] Due to the lack of appropriate definite treatment, the death toll of this disease during the 1st month was more than 500,000 worldwide.[3] At the time of conducting this study, there is no specific treatment for coronavirus disease (COVID-19), except for some repurposed medications that have shown in vitro efficacy against coronaviruses. These include lopinavir/ritonavir (LPV/r),[4],[5] Type I interferons (IFNs)[6],[7] and hydroxychloroquine (HCQ),[8],[9] which are being investigated in studies and clinical trials worldwide.

A combination of antiviral drugs from the protease inhibitor class, LPV/r, used in the treatment of human immunodeficiency virus has shown controversial outcomes in different studies in the case of COVID-19.[10] A meta-analysis demonstrated that LPV/r has a good effect on radiological findings, viral eradication and reduction of acute respiratory distress syndrome rate in comparison with other anti-coronavirus medications.[11] Results from some clinical trials showed that LPV/r has a little or no benefit in mild-to-severe hospitalised patients with COVID-19 over standard and supportive care.[12],[13],[14] Type 1 interferons (INFs), including IFN-α and IFN-β, play an essential role in the immune response against viral infections by controlling viral replication.[15],[16] The antiviral effect of IFN-beta on SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) has been shown in previous in vitro studies.[17],[18],[19] Some clinical trials have also demonstrated the positive effect of Type I INFs administered in the early phase of the disease. A retrospective cohort study showed that early treatment with IFN alpha-2b decreased the length of stay (LOS) in hospitals, while delayed therapy decreased recovery rate and increased death risk.[20] In one study, coadministration of LPV/r and IFN beta in patients infected with MERS-CoV improved the function of the lung without significant reduction in virus replication and severity of lung pathology.[21] In addition, another study reported potential benefits from LPV/r in combination with IFN beta in reducing the duration of SARS-CoV-2 shedding in hospitalised patients.[22] Another therapeutic option for COVID-19 is the anti-malaria drug HCQ, which has been reported to have in vitro activity against SARS-CoV.[23] It is documented that HCQ and azithromycin synergistically protect against intense respiratory tract infections.[24],[25] A randomised controlled trial has shown the beneficial effect of HCQ on the improvement of pneumonia and shortening the time to clinical recovery in patients with COVID-19.[26] In contrast, some other studies have not shown promising results.[27],[28],[29]

Because these medicines were recommended for COVID-19 in the foretime previous guidelines published by the Iranian Ministry of Health, the present study aimed to evaluate the efficacy of LPV/r plus IFN beta-1a regimen compared to HCQ in the treatment of moderately ill patients with COVID-19.


  Methods Top


Study design and setting

This is a multiple-centre retrospective observational study. It was conducted at two hospitals affiliated with Hormozgan University of Medical Sciences, Hormozgan, Iran. Patients with diagnosed COVID-19 and well-documented clinical data and outcomes from 1 March, 2020 to 1 September, 2020, were enrolled in the study.

The study protocol and manuscript were reviewed and approved by the Ethics Committee of Hormozgan University of Medical Sciences (IR.HUMS.REC.1400.054). All methods and analyses were conducted in accordance with the local guidelines as well as ethical guidelines of the Declaration of Helsinki.

Study population

The intended population included hospitalised males and females (age ≥18 years), with positive qualitative reverse transcription-polymerase chain reaction (RT-PCR) tests for SARS-CoV2, who developed the moderate disease. All patients' files contained information on follow-up from the time of admission until the time of discharge. Patients with negative or undetermined RT-PCR results, severe disease (oxygen saturation [O2Sat] <93%, respiratory rate >30/min at rest and/or arterial oxygen partial pressure to fractional inspired oxygen ratio ≤300 mmHg) or those who received other antiviral drugs were excluded from the study.

Treatments

Patients were divided into two groups based on the treatment regimens. The studied group contained patients who received LPV/r plus INF beta-1a (LPV/r-INF group). The control group included age- and sex-matched patients who received only HCQ (HCQ group). The treatment regimens were: oral LPV/r at a dose of 400/100 mg twice a day for the 1st day and 200/50 mg twice a day for the following 6 days, along with 3–5 subcutaneous injections of INF beta-1a at a dose of 12 million IU every other, and oral HCQ at a dose of 400 mg twice a day for the 1st day and 200 mg twice a day for the following 6 days. All patients took supportive care, including supplemental oxygen, intravenous hydration as well as antibiotics, antipyretics, analgesics and corticosteroids, when needed.

Data sources

We obtained the necessary information from the regional COVID-19 registry in Hormozgan (RCovidRH), which is a well-designed, organised and web-based system. In this registry, data are collected from hospitals affiliated with the Hormozgan University of Medical Sciences.[30]

The obtained data included demographic characteristics (age, gender, smoking status and comorbidities), treatment plan, clinical symptoms, laboratory findings (haematologic, biochemical, infection-related and coagulation parameters) and clinical outcomes.

Outcomes

The outcomes of the study were LOS in hospital for survivors, intensive care unit (ICU) admission, LOS in ICU for patients admitted in ICU, need for O2 therapy, need for non-invasive ventilation, need for invasive mechanical ventilation and in-hospital mortality rate.

Statistical analysis

The normality of data was examined using the Kolmogorov–Smirnov test. Continuous variables were expressed as mean ± standard deviations and categorical variables as frequency (percentage). The independent t-test and Fisher's exact test were performed to compare continuous and categorical variables between groups, respectively. P < 0.05 was considered statistically significant. The statistical analyses were performed using SPSS software (Statistical Package for the Social Sciences, version 18.0, SPSS Inc., Chicago, IL, USA).


  Results Top


A total number of 2891 patients were admitted to the two hospitals (Shahid Mohammadi Hospital and Hazrat Abolfazl Hospital) between March and September 2020, from which 2323 patients were excluded due to non-confirmed COVID-19, age <18 years, pregnancy, severely ill with COVID-19 and concomitant use of antiviral drugs. The flowchart of patient eligibility and selection is demonstrated in [Figure 1]. Of the 400 patients included in this study, 102 patients received the LPV/r-INF regimen (LPV/r-INF group: 43.1% of males, age 43.90 ± 14.07 years) and 298 patients received the HCQ (HCQ group: 47.0% of males, age 45.16 ± 15.60 years). No differences were observed between the groups in the case of antibiotics and glucocorticoid administration and comorbidities. The demographic characteristics and treatment plans of patients in the studied group are presented in [Table 1].
Figure 1: Flowchart of patients' eligibility and selection

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Table 1: Demographic characteristics and treatment plan of patients

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Clinical symptoms and laboratory findings

The laboratory parameters on the hospitalisation day were compared between the groups, as shown in [Table 2]. We found a result on whether there is a difference between the groups in fever, fatigue, myalgia, neutrophil, platelets, blood urea nitrogen (BUN) and creatinine. However, other baseline clinical symptoms and laboratory parameters did not differ statistically between the studied groups [Table 3].
Table 2: Baseline clinical and laboratory characteristics of patients

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Table 3: Main outcomes of patients

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Outcomes

LPV/r plus INF beta-1a, as a therapeutic regimen for patients with COVID-19, had affected almost none of the clinical outcomes and mortality rate remarkably in comparison with the HCQ regimen [Table 3]. The total LOS in hospital of patients in the LPV/r-INF group (4.73 ± 2.93) was slightly longer than the HCQ group (3.74 ± 3.30) (P = 0.008). Furthermore, the need for oxygen therapy in patients treated with LPV/r plus INF beta-1a regimen (63.0%) was higher than in those treated with the HCQ regimen (48.3%) (P = 0.007). No statistically significant difference was observed between the two groups in case of ICU admission, LOS in ICU, need for O2 therapy, need for non-invasive ventilation and need for invasive mechanical ventilation as well as in-hospital mortality rate.


  Discussion Top


In this retrospective observational study conducted to evaluate the efficacy of LPV/r plus IFN beta-1a (LPV/r-INF) compared to HCQ in moderately ill patients with COVID-19, we have not observed beneficial effects from treatment with the LPV/r-INF regimen in the case of the studied outcomes. On the other hand, treatment with HCQ demonstrated better outcomes regarding LOS in hospitals and the need for oxygen therapy.

Our findings showed that the duration of hospitalisation in the LPV/R-INF group was higher than in the HCQ group. Since the population of both the studied groups was generally similar in age, gender and comorbidities at baseline, the difference in results could indicate that the LPV/r plus INF regimen prolonged hospital LOS. The effects of LPV/r plus IFN beta-1a regimen in COVID-19 patients were evaluated in another retrospective study by Baghaei et al. Although results of this study show lower mortality rate and need for non-invasive ventilation in LPV/r plus IFN group, duration of hospitalisation was prolonged compared to the control group receiving only LPV/r.[31] In contrast to our observation, Yan et al. conducted a retrospective study that showed possible benefits from the LPV/r regimen in reducing the time of SARS-CoV-2 shedding in patients hospitalised with moderate COVID-19, which could mean less duration of treatment.[32] Zuo et al. stated that early administration of LPV/r plus IFN alpha reduced the time of viral shedding and might shorten hospitalisation time.[22]

A randomised trial was conducted by Cao et al. to evaluate LPV/r use in severe COVID-19 patients. The results showed no significant benefits from this regimen compared to standard care.[13] Li et al. also indicated a slight advantage of the LPV/r regimen in critically ill patients with COVID-19. Their trial reported that treatment with LPV/r could result in more adverse drug events rather than beneficial impacts.[12]

Our findings demonstrated that the need for oxygen therapy was also higher in the LPV/R-INF group than in the HCQ group. It might suggest that coadministration of LPV/r with other drugs, especially INF, might diminish the efficacy of the regimen. Davoudi-Monfared et al. conducted a randomised trial to investigate the efficacy of IFN beta-1a in critically ill patients. According to their findings, monotherapy with IFN resulted in a lower mortality rate and reduced length of hospital stay, especially in patients who had received it in the early phase.[33]

This study had several limitations inherent to the design, including the retrospective approach, the non-randomised nature with the potential risk of selection bias, the potential for unassessed confounders that cannot be completely excluded and the relatively small sample size.


  Conclusions Top


The obtained results of patients with moderate COVID-19 infections revealed that the LPV/r plus IFN beta-1a regimen did not significantly improve clinical outcomes or mortality compared to the HCQ regimen. In contrast, some of the investigated outcomes turned out to be slightly worse in the LPV/R-INF group. Larger randomised controlled trials are needed to assess the efficacy of this combination further.

Acknowledgements

The author appreciably thanks the staff at the Shahid Mohammadi Hospital and Hazrat Abolfazl Hospital, Riyadh, for their valuable help and support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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