*3.6. Comparisons*


### *3.7. Searching Keywords*

The search keywords included 2019-nCoV, 2019 novel coronavirus, COVID-19, coronavirus disease 2019, SARS-COV-2, lopinavir, ritonavir, combination, kaletra, treatment, efficacy, clinical trial, cohort, retrospective, and prospective.

#### *3.8. Exclusion Criteria*

Types of articles that were excluded included duplicate articles, editorials, reviews, case reports, and letters to editors.

Any research articles that did not include data on lopinavir/ritonavir use, did not include control patients' group, or reported combined use of lopinavir/ritonavir with other antiviral medications were also excluded. Given the lack of clear benefit and potential for toxicity of hydroxychloroquine [21], studies with evidence on the benefit of LPV/RTV in combination with hydroxychloroquine use in hospitalized COVID-19 patients were excluded in our review.

#### *3.9. Data Extraction and Analysis*

Two reviewers (SA and MT) independently screened the titles with abstracts using the selection criteria. For relevant articles, full texts were obtained for further evaluation. Disagreements between the two reviewers after full text screening were reconciled via consensus by a third reviewer (AA) [22].

Inclusions and exclusions were recorded following PRISMA guidelines presented in the form of a PRISMA flow diagram and detailed reasons recorded for exclusion. Articles were categorized as clinical trials or cohort studies. The following data were extracted from the selected studies: authors; publication year; study location; study design and setting; sample size, age, and gender; details of study intervention and control therapies in addition to data on adverse events and treatment outcomes; time from symptom onset to treatment initiation; assessment of study risk of bias; and remarks on notable findings.

#### *3.10. Risk of Biased Evaluation of Included Studies*

The quality assessment of the studies was undertaken based on the revised Cochrane risk of bias tool (RoB 2.0) for randomized controlled studies [23]. The Risk of bias in non-randomized studies—of interventions (ROBINS-I) tool was used to assess non-randomized interventional studies [24], and the Newcastle Ottawa Scale for observational cohort studies [25]. Critical appraisal checklists appropriate to each study design were applied and checked by a third team member.

Three investigators (SA, MT, and AA) separately evaluated the possibility of bias using these tools. Publication bias was not evaluated by funnel plot as there were only three studies that were included in the meta-analysis part of the study.

#### *3.11. Assessment of Heterogeneity*

Statistical heterogeneity was evaluated using the χ2 test and *I*2 statistics [19]. An *I*2 value of 0 to <40% was not considered as significant, 30% to 60% was regarded as moderate heterogeneity, 50% to 90% was considered substantial heterogeneity, and 75% to 100% was considered significant heterogeneity.

### *3.12. Statistical Analysis*

Because all of the data were continuous and dichotomous data, either odds ratio (OR) or mean difference were used for estimating the point estimate, along with a 95% confidence interval (CI). In the absence of significant clinical heterogeneity, the meta-analysis using the Mantel Hazel method or inverse variance method for dichotomous data and continuous data were performed, respectively. Employing a conservative approach, a random effects model was used, which produces wider CIs than a fixed effect model. Review Manager (Version 5.3, Oxford, UK; The Cochrane Collaboration, 2014) was used to conduct all statistical analyses and generate forest plots.
