Table 1.

Trials/studies involving lopinavir/ lopinavir + ritonavir.

Study type	Trial outcome and design	Conclusion	Comments
Case series [10]	•Out of 10 COVID patients, 09 received LPV and interferon α2b atomization inhalation and one only LPV.	Recovery of eosinophil count in patients on LPV were associated with improvement in viral load	Role of prior azithromycin in recovery is possible.
	Five patients received antibiotics (azithromycin) therapy before the antiviral course.
	Out of 10, 7 patients discharged and three patients stopped LPV due to intolerable adverse effects, two of them deteriorated and transferred to other hospital.
Case report [11]	COVID-19 patient (43 year-old), received oxygen inhalation, LPV/RTN, recombinant human interferon a1b and ribavirin.	After discontinuation of antiviral drugs in some patients, the residual virus causes the pulmonary lesions to re-aggravate, resulting in subsequent positive viral nucleic acid test results.	Study based on single case, confounders are possible.
	On 7th day, clinical symptoms improved significantly.
	Discharged on day 13 and antiviral therapy discontinued.
	Three days later, her nucleic acid test reversed to positive, and chest CT scan showed completely absorbed lesion. Restarted with aerosol inhalation of recombinant human interferon a1b.
	•7 days later, showed clinical improvement and thereafter discharged.
Analysis of five cases [12]	Two of the five cases received LPV/RTN along with supportive care, whereas, three cases were given only supportive care.	LPV/RTN didn’t reduce the duration of illness in patients with COVID 19.	Small sample size
	Oropharyngeal swabs and sputum samples obtained daily from all cases.
	Upon follow up (10 days), there was no significant difference between treatment and control group in duration of illness and PCR negative conversion.
Randomized, controlled, open-label trial [13]	99 patients received LPV/RTN, in addition to standard care (supportive management), and 100 were assigned to receive to standard care (supportive management), alone.	No benefit of LPV/RTN over the standard care in clinical improvement and mortality.	Good number of patients in both group make this study more reliable.
	Tested group required shorter time to clinical improvement by 1 day than standard care. No significant difference was showed in other parameters.
Case report [14]	A 54-year-old Korean confirmed COVID 19 man with mild respiratory illness and small lung consolidation received LPV/RTN.	LPV/RTN showed improvement in clinical symptoms and reduction of viral loads.	It is possible that the decreased load of SARS-CoV-2 resulted from the natural course of the healing process rather than administration of LPV/RTN,or both.
	β-coronavirus viral loads significantly decreased and no or little coronavirus titers were observed in daily reports.
Pilot retrospective study [15]	Of 73 cases COVID-19, 34 cases received LPV/RTN and 39 cases given LPV/RTN with arbidol (ARB); for at least 3 days.	Reduced median hospital stay in group with addition of ARB.	Only few severe cases enrolled in this study.
	No significant difference in the end points of COVID-19 patients including cure rate, hospitalization time, rate and the time of virus turning negative between both arms.		Small sample size.
			Retrospective study.
Exploratory double blind randomized controlled trial [16]	Of 86 mild/moderate COVID-19 patients, 34 randomly assigned (2:2:1) to receive LPV/RTN, 35 to ARB and 17 with no antiviral medication as control.	LPV/RTN or ARB monotherapy present little benefit for improving the clinical outcome of patients hospitalized with mild/moderate COVID-19 over supportive care	Small sample size
	LPV/RTN or ARB neither shorten the time of negative PCR conversion nor improve the symptoms of COVID-19 or pneumonia on lung CT.		Didn’t include severe/ critical cases patients.
	On day 7, LPV/RTN group showed higher deterioration from moderate to severe/critical clinical status compared with the other two groups.
Retrospective study [17]	In addition to the conventional therapy (oxygen inhalation and interferon-ɑ2b Injection to total 50 COVID cases, 34 of them received LPV/RTN and 16 were given ARB.	ARB monotherapy may be superior to	Didn’t mention the severity of the patients.
	None of the patients developed severe pneumonia or ARDS, with no significant difference in fever duration between both groups.	LPV/RTN in treating COVID-19.	Retrospective data subject to confounding.
Retrospective observational study [18]	53 COVID-19 patients (45 with mild illness and 8 with severe illness).	Early administration of antiviral drugs can be	Didn’t mention the doses of antiviral been used.
	Among mild illness; 17 patients received ARB, 17 received ARB + LPV/RTN, and five received LPV/RTN.	considered. ARB may benefit patients with mild symptoms, while LPV/RTN may benefit those with severe symptoms. Prophylactic administration of common antibiotics may reduce the risk of co infection.	Most of the patients received antiviral therapy, thus there is absence of any control.
	Whereas, among severe patients 4 were treated with LPV/RTN, three with ARB + LPV/RTN, and one with ARB.		All patients with severe symptoms received antibiotics, it is possible that antibiotics are more potent than LPV/RTN.
	29 patients treated with antibiotics (moxifloxacin, linezolid).
	All patients recovered and achieve negative SARS-COVID-2 PCR.
Prospective cohort study [19]	47 patients with confirmed cases of COVID 19 enrolled, 42 patients received LPV/RTN + adjuvant drugs (Interferon aerosol inhalation, ARB, Methoxyphenamine, eucalyptol limonene along with moxifloxacin) and 5 patients received adjuvant therapy alone.	The combination treatment of LPV/RTN and routine adjuvant medicine against pneumonia could produce much better efficacy on patients with COVID-19 infection compared to treatment with adjuvant medicine alone.	Only mild cases were included in this study.
	All patients evaluated daily for body temperature, CBC, biochemistry and days of nCov-RNA turning negative after treatment.		Small number of cases in control group
	Both groups returned to the normal therapeutic temperature, but LPV/RTN group returned to the normal body temperature with shorter time compared with the control group.
Retrospective cohort study [20]	Out of 33 patients, 16 treated with LPV/RTN + ARB and 17 given LPV/RTN.	Addition of ARB to LPV/RTN has beneficial impact.	Retrospective analysis, thus increase the risk of unmeasured confounding bias.
	At 7 days, SARS-CoV-2 could not be detected in 12/16 (75%) in combination group and in 6/17 (35%) in monotherapy group and significant improvement in chest scan in combination group (11/16-69%) compared to monotherapy group (5/17(29%)).		Small sample size.
	After 14 days, SARS-CoV-2 could not be detected in 15/16 (94%) of LPV/RTN + ARB and 9/17 (52·9%) LPV/RTN.