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Three Part Question

[In adult patients admitted to hospital with confirmed COVID-19] does [Lopinavir-Ritonavir] lead to [reduced mortality and/or reduced length of stay]

Clinical Scenario

A 52 year old presented to the Emergency Department with a 9 day history of coryzal symptoms including sore throat and fever, after 5 days developed a dry cough and shortness of breath on exertion. Shortness of breath had become more severe over the last 24 hours, now breathless at rest and complaining of right sided pleuritic chest pain. Chest X-Ray and blood result findings were highly suspicious of COVID-19 and this was confirmed on PCR testing. With ongoing research into novel therapies for COVID-19, you wonder if Lopinavir-Ritonavir would reduce mortality or length of hospital stay for this patient.

Search Strategy

Medline using OVID interface
EMBASE using OVID interface
Medline using PubMed
Cochrane Library
Further Google Scholar search to ensure no missing relevant material

PubMed:
("Lopinavir-Ritonavir"[All Fields] OR "Lopinavir/Ritonavir"[All Fields] OR "Kaletra"[All Fields]) AND ("Covid-19"[All Fields] OR "coronavirus"[All Fields] OR "Severe acute respiratory syndrome coronavirus 2"[All Fields] OR "SARS-CoV-2"[All Fields] OR "2019 novel coronavirus"[All Fields] OR "2019-nCoV"[All Fields] OR "coronavirus disease 2019"[All Fields]) AND (hasabstract[text] AND ("2019/12/01"[PDAT] : "3000/12/31"[PDAT]) AND English[lang])

OVID:
((Lopinavir-Ritonavir or Lopinavir-Ritonavir or Kaletra) and (Covid-19 or coronavirus or Severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 or 2019 novel coronavirus or 2019-nCoV or coronavirus disease 2019)).af. LIMIT to (2019 -Current and human and english language)

Cochrane:
Lopinavir-Ritonavir AND COVID-19

Google Search:
(Lopinavir-Ritonavir OR Lopinavir-Ritonavir OR Kaletra) AND (Covid-19 OR coronavirus OR Severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2 OR 2019 novel coronavirus OR 2019-nCoV OR coronavirus disease 2019) LIMIT to English AND Human

Search Outcome

Medline: 66 papers of which 10 were relevant to the clinical question.
EMBASE: 59 papers with no new papers found
Cochrane: 17 trials found, no new published research
Google Scholar search found no new papers

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Cao et al. 2020 Wuhan, China	199 Male and non-pregnant female adults >18 years of age. Positive RT-PCR, radiological changes and low oxygen sats	RCT “Off-label” tria	Time to clinical Improvement	No significant difference Marginal improvement in modified analysis (1 day)	no blinding Improvement only after exclusion of deceased patients in treatment group.
			Clinical status at day 7 and 14	No significant improvement
			28 day mortality	No significant difference
Ye et al 2020 Rui'an, China	47 patients between 5 and 68 years of age. PCR positive.	Retrospective Cohort Study	Fever	No significant difference	Outcomes not translatable to mortality or length of stay. N = 42 in test group and only 5 in control. Retrospective. Control group statistically underpowered. Claim of proof LPV/r “could produce better efficacy” without any demonstrable evidence
			Blood results	No significant difference
Yuan et al 2020 Shenzhen, China	94 patients, PCR positive. Between 1 and 78 years of age. 67 treated with lopinavir/ritonavir +/- other antivirals.	Retrospective cohort study single centre	Length of hospital stay	No statistical difference	Only discharged patients were included. Observational, No control Combination Treatments in both groups
Lim et al 2020 Goyang, Korea	1 54 year old male patient	Case report	Viral Load reduction	After treatment started, viral load reduced	N = 1, case report, low level evidence, no control, Observational with potential for bias
Wang et al 2020 Shanghai, China	4 patients diagnosed according to WHO guidance.	Retrospective observational case series	Clinical outcomes	Pneumonia observed to improve with treatment	Combination treatment - also with arbidol. Not all patients PCR positive Clinical outcomes fairly subjectively reported.
Zhou et al 2020 China	191 adult inpatients with confirmed covid-19 admitted to Jinyitan and Wuhan Pulmonary Hospitals. 41 (21%) received antivirals (lopinavir/ritonavir)	Retrospective multicentre cohort study	To assess risk factors/prognostic markers	Shortening of viral shedding with lopinavir/ritonavir. Prolonged viral shedding was associated with worse outcomes.	Descriptive study, no direct association with lopniavir/ritonavir and outcomes. Confounding factors not controlled for, concurrent use of steroids, differences in standard care
Young et al 2020 Singapore	First 18 patients diagnosed with SARS-CoV-2 in Singapore. 5 patients treated with Lopinavir-Ritonavir out of the 6 requiring supplemental oxygen.	Descriptive case series	Clinical outcomes	3 improved 2 deteriorated to respiratory failure	Descriptive. No control. Not set up to assess antiviral treatment outcomes.
Kim et al 2020 Korea	1st patient with covid related pneumonia in Korea	Case Report	Describe natural history		Descriptive case-report. Observational improvement.
Deng et al 2020 China	33 adult patients not required mechanical ventilation diagnosed with a laboratory diagnosis of COVID-19	Retrospective cohort study	Negative conversion rate of coronavirus	Improved outcomes with combination therapy compared to monotherapy	No control, comparing LPV/r with combination therapy. Outcomes not comparable to mortality and length of stay Confounding factors and concurrent use of steroids in some patients. Small study size
			Assessment of pneumonia by CT	Improved outcomes with combination therapy compared to monotherapy
Choy et al 2020 -	In vitro	In vitro	Inhibition of viral viability	Lopinavir but not ritonavir showed inhibition on covid-19 in vitro	In vitro study therefore not translatable to in vivo outcomes

Comment(s)

There is hope from in vitro observations that Lopinavir/Ritonavir will be effective against Covid-19. Most of the literature in humans thus far is descriptive. The only high level evidence is the randomised control trial by Cao et al published in the NEJM. This showed no significant difference in time to clinical improvement or 28 day mortality when compared to a control. Modified intention to treat analysis did show marginal improvement in length of stay (15 days vs 16 days) when patients excluded from the treatment group after death prior to administration of medication. There is some observational evidence that treatment with antivirals may shorten viral shedding and, separately, prolonged viral shedding has been shown to be an independent risk factor for mortality. There is however, no significant causative relationship thus demonstrated between Lopinavir-Ritonavir treatment and the outcomes in the clinical question.

Clinical Bottom Line

There is no current evidence to support the use of Lopinavir-Ritonavir in COVID-19 to improve clinical outcomes.

References

1. Cao, Wang, Wen, Liu A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19 NEJM
2. Ye, Lou, Xia et al Clinical Efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease 2019 ERMPS
3. Yuan, Zou, Zeng et al The correlation between viral clearance and biochemical outcomes of 94 COVID-19 infected discharged patients
4. Lim,Jeon, Shin 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 Quantita
5. Wang, Chen, Lu et al Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment.
6. Zhou, Ting, Ronghui et al Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study
7. Youngm Ong Kalimuddin et al Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore
8. Kim, Choe, Oh et al The First Case of 2019 Novel Coronavirus Pneumonia Imported into Korea from Wuhan, China: Implication for Infection Prevention and Control Measures
9. Deng, Li, Zeng et al Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study.
10. Choy, Wong, Kaewpreedee et al Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro