Disclaimer: The aim of these rapid reviews is to retrieve, appraise, summarize and update the available evidence on COVID-related health technology. The reviews have not been externally peer- reviewed; they should not replace individual clinical judgement and the sources cited should be checked. The views expressed represent the views of the authors and not necessarily those of their host institutions. The views are not a substitute for professional medical advice.

Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

BACKGROUND

Lopinavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor administered in fixed-dose combination with ritonavir, a potent CYP3A4 inhibitor that increases lopinavir concentration. In 2003 during the emergence of Severe Acute Respiratory Syndrome (SARS), screening of approved drugs identified Lopinavir/ Ritonavir (LPV/r) as having in vitro inhibitory activity on viral replication by blocking the main protease of Severe Acute Respiratory Syndrome Corona Virus-1 (SARS- CoV-1), the causative agent of SARS.1 That same year a study published by Chan et al, concluded that the addition of LPV/r to a standard treatment protocol for SARS as an initial treatment appeared to be associated with a significant reduction in the need for rescue pulse, corticosteroid therapy, avoidance of intubation, and a reduction in mortality rate.2

LPV/r is also currently being evaluated to treat Middle East respiratory syndrome coronavirus (MERS-CoV). It was found to have activity both in vitro3 and in an animal model4, against MERS-CoV. Case reports have suggested that the combination of LPV/r with ribavirin and interferon alpha resulted in virologic clearance and improved survival from MERS-CoV infection.5,6 SARS‐CoV-1, MERS‐ CoV, and SARS-CoV-2 belong to the same genera of corona virus(CoV) and all are beta‐corona viruses. SARS- CoV-2 shares 79.5% sequence identity with SARS‐CoV-

1.Therefore, the existing treatment LPV/r for SARS and MERS may be helpful for developing Corona Virus Disease 2019 (COVID‐19) therapeutics.

Case reports and case series from Korea and China found, decreased viral load and clinical improvement after LPV/r initiation for patients with COVID-19. The data however is very limited and difficult to interpret due to heterogeneity, varied time points of therapy initiation, concomitant drug use and lack of comparator treatments.7,8,9

Results from retrospective cohort studies were conflicting. Two retrospective cohorts reported shorter duration of conversion to negative of SARS CoV2 RNA or viral shedding for patients given LPV/r compared to those not given this medication.10,11 One of which specifically noted that viral shedding was significantly shorter, when LPV/r was administered within 10 days from the onset of symptoms. When given after 10 days, no significant difference was noted on the duration of viral shedding compared to those who were not given at all.12 On the other hand, another retrospective cohort showed that LPV/r when compared to Arbidol after 7 and 14 days of treatment showed higher percentage of viral shedding.12

This rapid review summarizes the available evidence on the efficacy and safety of lopinavir/ritonavir combination in treating patients with COVID-19.

METHODS

Literature Search Method

The following electronic databases were searched for evidences: Medline, CENTRAL, ISRCTN registry, ClinicalTrial.gov and Chinese Clinical Trial Registry. (Appendix 1)
,
Articles were selected based on the following inclusion criteria:

•Population: COVID-19 patients of any age, with any

co-morbidities, any severity 
Intervention: lopinavir/ ritonavir combination, any dose, any duration

•Comparator: placebo, any active control

•Outcomes: Proportion of clinically improved patients by 1 week and/or weeks, time to clinical improvement, mortality, duration of viral shedding, number of days

for SARS-CoV-2 RNA to turn negative 
from positive.

•Study designs: randomized controlled trials (RCTs), non-randomized studies 


RESULTS

Description of included studies

We found two (2) randomized controlled open label trials on lopinavir/ritonavir. Both trials were conducted in China among hospitalized adult patients with confirmed SARS-COV-2 infection. Characteristics of included studies were tabulated and summarized (Appendix 2).

The LOTUS trial13 enrolled 199 participants with severe pneumonia confirmed via chest imaging and with the following parameters: oxygen saturation (Sao2) of 94% or less, or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) (Pao2:Fio2) at or below 300 mg Hg. Treatment group (n=99) was given lopinavir- ritonavir at a dose 400mg/100mg twice a day for 14 days plus standard of care while the control group (n=100) was given standard of care alone. Standard of care comprised as necessary, supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation (ECMO). The primary end point was the time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first.

The ELACOI trial,14 on the other hand, was a 3-arm controlled trial which evaluated the efficacy and safety of LPV/r against arbidol and standard treatment alone in the treatment of mild/moderate COVID-19 patients. Mild clinical status was defined as patients having mild clinical symptoms but no signs of pneumonia on imaging while moderate clinical status was defined as having fever, respiratory symptoms and pneumonia on imaging. 21 patients were randomly assigned to receive LPV/r, 16 to arbidol, and 7 to no antiviral medication as control. The primary outcome was the time of positive-to-negative conversion of SARS-CoV-2 nucleic acid from the initiation of treatment. The secondary outcomes were the rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid and resolution of symptoms on day 7 and Day 14 of treatment.

Aside from abovementioned trials, there are at least

16ongoing clinical trials on lopinavir-ritonavir including a WHO-initiated worldwide clinical trial (Appendix 3).

Effectiveness Outcomes

Variation on the severity of illness in the population and two different sets of outcome measures prevented the authors from performing a meta-analysis. The results of each trials are briefly discussed here.

In the LOTUS trial,13 LPV/r group had no significant difference from the control in the time to clinical improvement (HR for clinical improvement, 1.24; 95%CI , 0.90 to 1.72). Lopinavir/ ritonavir also did not show benefit on mortality at 28 days (RR 0. 77; 95%CI 0.45 to 1.30). The percentages

of patients with detectable viral RNA at various time points were similar for both groups.

In the ELACOI trial,14 both LPV/r, arbidol and standard treatment had no significant difference regarding the time of positive-to-negative conversion of COVID-19 nucleic acid (P=0.751). There was also no significant difference in the rate of defervescence, cough improvement and radiologic improvement at day 7 and day 14 (P>0.05).

Safety Outcomes

In the LOTUS Study, nausea and vomiting were significantly higher in the LPV/r group (P<0.05).Diarrhea, stomach ache and abdominal discomfort were also higher but not statistically significant among the LPV/r group compared to the standard-care group. However, more serious adverse events such as respiratory failure, acute kidney injury, and secondary infection were reported in patients receiving standard care. The difference however was not significant except for respiratory failure (P=0.011). Serious adverse events occurred in 51 patients: 19 events in the lopinavir– ritonavir group and 32 events in the standard-care group. In the ELACOI study 5 of the patients on LPV/r developed diarrhea (n=2) lost of appetite (n=2) and deranged liver function test (n=1). None on the Arbidol and control groups developed any side effects.

For HIV patients, several studies regarding adverse effects of LPV/r treatment has already been published. A review by Croxtall et al, enumerated the following adverse events reported in phase II/III trials: diarrhea, nausea, vomiting, headache, increased in cholesterol level and hypertriglyceridemia.15 A meta analysis of randomized controlled trials (RCT) on the efficacy and biological safety of LPV/r based anti-retroviral therapy(ART) in HIV1 infected patients by Huang et al documented Grade 3 or 4 treatment related hyperlipidemia as most notable adverse effect. In two of the studies included in the meta analysis the incidence of dyslipidemia in ART-naïve patients were 23% and 18%.16

Critical Appraisal

Both RCTs were found to be of good quality. Both underwent randomization, and allocation concealment to treatment assignment. Primary efficacy analysis was on an intention-to-treat basis and included all the patients who had undergone randomization. However, clinicians were not blinded in both RCTs, their judgments on clinical improvement may have been influenced by the treatment assignment. The ELACOI study has a very small sample size (n=44) to reach the adequate power (1-Beta error > 0.8) in many parameters. It’s still on pre print, hence not been peer reviewed.

Recommendations from Other Guidelines

WHO interim guidance does not recommend any specific anti-viral or biologic agents and only recommends symptomatic treatment for patients with COVID-19.17

The National Health Commission (NHC) of the People’s Republic of China, in their latest version of the Diagnosis and Treatment of Pneumonia Caused by COVID‐19, suggest the use of lopinavir/ritonavir at a dose of 200mg/50mg/ tablet, 2 tablets twice daily; the length of treatment should not exceed 10 days.18

CONCLUSION

Based from two RCTs, there is inconclusive evidence on clinical improvement, 28-day mortality and viral shedding among patients with mild to moderate and severe COVID-19 treated with lopinavir/ritonavir. Clinical trials that investigate the efficacy and safety of lopinavir/ritonavir combination for COVID-19 patients are still limited. We are awaiting the results of other clinical trials.

Declaration of Conflict of Interest

No conflict of interest.

REFERENCES

1.Chu CM, Cheng VCC, Hung IFN, Wong MML, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004. 59(3):252‐6.

2.Chan KS, Lai ST, Chu CM, Tsui E, Tam CY, Wong MML, et al. Treatment of severe acute respiratory syndrome with lopinavir/ ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003; 9(6):399-406.

3.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(8):4875-84.

4.Chan JF, Yao Y, Yeung ML, Deng W, Bao L, Jia L, et al. Treatment with lopinavir/ritonavir or interferon-beta1b improves outcome of MERSCoV infection in a nonhuman primate model of common marmoset. J Infect Dis. 2015; 212(12):1904-13.

5.Spanakis N,Tsiodras S, Haagmans BL, Raj VS, Pontikis K, Koutsoukou A, et al. Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. Int J Antimicrob Agents. 2014; 44(6):528-32.

6.Kim UJ, Won EJ, Kee SJ, Joon SI, Jang HC. Combination therapy with lopinavir/ritonavir, ribavirin and interferon-alpha for Middle East respiratory syndrome. Antivir Ther. 2016; 21(5):455-9.

7.Deng L,Li C,Zeng Q,Liu X,Li X,Zhang H,et al.Arbidol (Umifenovir) combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study. J Infect. 2020; 8(1):e1-e5.

8.Wang Z Chen X, Lu Y, Chen F, Zhang W. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci Trends. 2020; 14(1):64-8.

9.Lim J, Jeon S, Shin HY, Kim MJ, Seong YM, Lee WJ, et al. Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: the application of lopinavir/ritonavir for the treatment of COVID-19 infected pneumonia monitored by quantitative RT-PCR. J Korean Med Sci. 2020; 35(6):e79.


10.Yan D, Liu X, Zhu Y, Huang L, Dan B, Zhang G, et al. Factors associated with prolonged viral shedding and impact of Lopinavir/ Ritonavir treatment in patients with SARS-CoV-2 infection (preprint). medRxiv preprint. 2020.

11.Ye XT, Luo YL, Sia SC, Sun QF, Ding JG, Zhou Y, et al. Clinical efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease 2019. Eur Rev Med Pharmacol Sci. 2020; 24(6):3390-6.

12.Zhu Z, Lu Z, Xu T, Chen C, Yang G, Zha T, et al. Arbidol (Umifenovir) monotherapy is superior to lopinavir/ritonavir in treating COVID-19. J Infect. 2020; 81(1):e21-e23.

13.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(19):1787-99.

14.Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, et al. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ ritonavir or Arbidol (Umifenovir) treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). medRxiv preprint. 2020.

15.Croxtall JD, Perry CM. Lopinavir/Ritonavir a review of its use in the management of HIV- 1 infection. Drugs. 2010; 70(14):1885-915.

16.Huang X, Xu Y, Yang Q, Chen J, Zhang T, Li Z, et al. Efficacy and biological safety of lopinavir/ritonavir based anti-retroviral therapy in HIV-1-infected patients: a meta-analysis of randomized controlled trials. Sci Rep. 2015; 5:8528. 


17.World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected.

Interim guidance. V1.2. 2020, WHO: Geneva.			the People’s Republic
18. National Health	Commission	(NHC) of
of China. The	diagnosis and	treatment	guide of COVID-19

pneumonia caused by new coronavirus infection. 7th Edition. 2020.

Database	Search strategy / search terms
Medline	(((lopinavir AND ("last 5 years"[PDat])) OR (ritonavir AND
	("last 5 years"[PDat])) OR (lopinavir-ritonavir AND ("last
	5 years"[PDat])) OR ()) AND ("last 5 years"[PDat])) AND
	(((coronavirus) OR ("novel coronavirus") OR (COVID)
	OR (SARS-COV-2) OR (COVID 19) OR (COVID-19) OR
	(SARS COV 2) OR (NCOV)) AND ("last 5 years"[PDat]))

Date and time	Results
of search	Yield	Eligible
March 27, 2020		1