|Year : 2023 | Volume
| Issue : 1 | Page : 107-112
Efficacy of lopinavir/ritonavir plus interferon beta compared to hydroxychloroquine in the treatment of COVID-19: A retrospective observational study
Motahareh Amirizadeh1, Fatemeh Shafie Sarvestani2, Farid Khorrami3, Omid Safa4, Parivash Davoodian2, Mehdi Hassaniazad2, Boshra Akhlaghi5, Mohammad Fathalipour6
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 Submission||15-Apr-2022|
|Date of Acceptance||29-Jul-2022|
|Date of Web Publication||23-Sep-2022|
Prof. 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
Source of Support: None, Conflict of Interest: None
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 article:|
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 2023;13:107-12
|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 [serial online] 2023 [cited 2023 Mar 27];13:107-12. Available from: https://www.aihbonline.com/text.asp?2023/13/1/107/356798
| Introduction|| |
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. 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. Due to the lack of appropriate definite treatment, the death toll of this disease during the 1st month was more than 500,000 worldwide. 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),, Type I interferons (IFNs), and hydroxychloroquine (HCQ),, 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. 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. 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.,, 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., 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.,, 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. 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. 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. Another therapeutic option for COVID-19 is the anti-malaria drug HCQ, which has been reported to have in vitro activity against SARS-CoV. It is documented that HCQ and azithromycin synergistically protect against intense respiratory tract infections., 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. In contrast, some other studies have not shown promising results.,,
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|| |
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.
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.
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.
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.
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.
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.
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|| |
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].
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].
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|| |
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. 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. Zuo et al. stated that early administration of LPV/r plus IFN alpha reduced the time of viral shedding and might shorten hospitalisation time.
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. 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.
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.
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|| |
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.
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
Conflicts of interest
There are no conflicts of interest.
| References|| |
Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet 2020;395:470-3.
Meini S, Pagotto A, Longo B, Vendramin I, Pecori D, Tascini C. Role of lopinavir/ritonavir in the treatment of COVID-19: A review of current evidence, guideline recommendations, and perspectives. J Clin Med 2020;9:2050.
World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard. World Health Organization; 2020. Available from: https://covid19whoint/
. [Last accessed on 2021 Feb 23].
Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al.
Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings. Thorax 2004;59:252-6.
de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, et al.
Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother 2014;58:4875-84.
Sallard E, Lescure FX, Yazdanpanah Y, Mentre F, Peiffer-Smadja N. Type 1 interferons as a potential treatment against COVID-19. Antiviral Res 2020;178:104791.
Lokugamage KG, Hage A, de Vries M, Valero-Jimenez AM, Schindewolf C, Dittmann M, et al.
Type I Interferon Susceptibility Distinguishes SARS-CoV-2 from SARS-CoV. Journal of virology. 2020;94.
Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al.
Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro
. Cell Discov 2020;6:16.
Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro
antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020;71:732-9.
Gómez-Ríos D, López-Agudelo VA, Ramírez-Malule H. Repurposing antivirals as potential treatments for SARS-CoV-2: From SARS to COVID-19. J Appl Pharm Sci 2020;10:1-9.
Zhong H, Wang Y, Zhang ZL, Liu YX, Le KJ, Cui M, 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.
Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, et al.
Efficacy and safety of lopinavir/ritonavir or Arbidol in adult patients with mild/moderate COVID-19: An exploratory randomized controlled trial. Med (N Y) 2020;1:105-13.e4.
Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al.
A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020;382:1787-99.
Hassaniazad M, Farshidi H, Gharibzadeh A, Bazram A, Khalili E, Noormandi A, et al.
Efficacy and safety of favipiravir plus interferon-beta versus lopinavir/ritonavir plus interferon-beta in moderately ill patients with COVID-19: A randomized clinical trial. J Med Virol 2022;94:3184-91.
Sainz B Jr., Mossel EC, Peters CJ, Garry RF. Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV). Virology 2004;329:11-7.
Choi H, Shin EC. Roles of type I and III interferons in COVID-19. Yonsei Med J 2021;62:381-90.
Scagnolari C, Vicenzi E, Bellomi F, Stillitano MG, Pinna D, Poli G, et al.
Increased sensitivity of SARS-coronavirus to a combination of human type I and type II interferons. Antivir Ther 2004;9:1003-11.
Chan JF, Chan KH, Kao RY, To KK, Zheng BJ, Li CP, et al.
Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect 2013;67:606-16.
Hart BJ, Dyall J, Postnikova E, Zhou H, Kindrachuk J, Johnson RF, et al.
Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol 2014;95:571-7.
Wang N, Zhan Y, Zhu L, Hou Z, Liu F, Song P, et al.
Retrospective multicenter cohort study shows early interferon therapy is associated with favorable clinical responses in COVID-19 patients. Cell Host Microbe 2020;28:455-64.e2.
Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, et al.
Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020;11:222.
Zuo Y, Liu Y, Zhong Q, Zhang K, Xu Y, Wang Z. Lopinavir/ritonavir and interferon combination therapy may help shorten the duration of viral shedding in patients with COVID-19: A retrospective study in two designated hospitals in Anhui, China. J Med Virol 2020;92:2666-74.
Biot C, Daher W, Chavain N, Fandeur T, Khalife J, Dive D, et al.
Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities. J Med Chem 2006;49:2845-9.
Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, et al.
The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – An update on the status. Mil Med Res 2020;7:11.
Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al.
Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020;56:105949.
Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al.
efficacy of hydroxychloroquine in patients with COVID-19: Results of a randomized clinical trial. Medrxiv 2020.
Magagnoli J, Narendran S, Pereira F, Cummings TH, Hardin JW, Sutton SS, et al.
Outcomes of hydroxychloroquine usage in United States Veterans Hospitalized with COVID-19. Med (N Y) 2020;1:114-27.e3.
Mahévas M, Tran VT, Roumier M, Chabrol A, Paule R, Guillaud C, et al.
No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection and requiring oxygen: Results of a study using routinely collected data to emulate a target trial. Medrxiv 2020.
Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al.
A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. Zhejiang Da Xue Xue Bao Yi Xue Ban 2020;49:215-9.
Khorrami F, Shahi M, DavariDolatabadi N, Alishan Karami N, HasaniAzad M, Jafariyan F, et al.
Implementation of regional COVID-19 registry in Hormozgan (RCovidRH), Iran: Rationale and study protocol. Med J Islam Repub Iran 2020;34:96.
Baghaei P, Dastan F, Marjani M, Moniri A, Abtahian Z, Ghadimi S, et al.
Combination therapy of IFNβ1 with lopinavir-ritonavir, increases oxygenation, survival and discharging of sever COVID-19 infected inpatients. Int Immunopharmacol 2021;92:107329.
Yan D, Liu XY, Zhu YN, Huang L, Dan BT, Zhang GJ, et al.
Factors associated with prolonged viral shedding and impact of lopinavir/ritonavir treatment in hospitalised non-critically ill patients with SARS-CoV-2 infection. Eur Respir J 2020;56:2000799.
Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Salehi M, Abbasian L, et al.
A randomized clinical trial of the efficacy and safety of interferon β-1a in treatment of severe COVID-19. Antimicrob Agents Chemother 2020;64:e01061-20.
[Table 1], [Table 2], [Table 3]