**1. Introduction**

Since the emergence of an unknown viral infection with its first cases in China in December 2019 and following the identification of this infection as 2019-new coronavirus disease (2019-nCoV, also known as COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1], the world has worked to find e ffective therapeutics and vaccinations to treat hundreds of thousands of affected patients and to reduce the spread of this global pandemic [2].

As of 2 June 2020, there were 1104 registered clinical trials of COVID-19 therapeutics or vaccinations worldwide that either had ongoing or were recruiting patients; however, at that stage no drug or vaccine had o fficially been approved for COVID-19 [2,3]. These trials have produced mixed and conflicting results of positive or negative outcomes and inclusive evidence of e fficacy or safety, that render the suspension of some trials inevitable, as in the hydroxychloroquine trials, which was suggested by the World Health Organization (WHO) in light of safety concerns [4]. This decision was reversed on 3 June 2020 [5], following a retraction of the research article by the Lancet as certain authors were not granted access to the underlying data [6]. As the pandemic evolves, the amount of evidence regarding the benefit of hydroxychloroquine in the treatment of COVID-19 patients has grown. A recent systematic review included 32 studies for a total 29,192 studied participants found treatment with hydroxychloroquine confers no benefit in terms of mortality in hospitalized patients with COVID-19 compared to standard care [7].

Lopinavir-ritonavir (LPV/RTV) is a protease inhibitor and nucleoside analog combination used for human immunodeficiency virus (HIV-1) and was also thought to be a potential treatment for COVID-19 [8], as its therapeutic value in the treatment of COVID-19 was assessed by in-vitro studies that claimed inhibition of several viral corona respiratory illnesses, including severe acute respiratory syndrome (SARS-CoV), and Middle East Respiratory Syndrome (MERS) [9–11]. Only recently, LPV/RTV therapy was hypothesized to be of no antiviral e fficacy against SARS-CoV or MERS-CoV because the recommended dosages supplied to patients included in the published studies were subtherapeutic [12] and doses higher than 400 mg/100 mg twice daily are suggested [13].

Lopinavir (LPV) is an aspartic acid protease inhibitor of HIV, where inhibition of proteases enzymes is essential for the intervening of the viral infectious cycle. LPV is co-formulated with ritonavir (RTV) to boost the pharmacokinetic activity and half-life of LPV through the inhibition of cytochromes P450, providing adequate suppression of viral load and constant improvements in CD4+ cell counts, as demonstrated in randomized trials in naïve and experienced adult and child HIV patients [8].

There is conflicting evidence regarding the use of LPV/RTV for the treatment of COVID-19 patients; and evidence is currently scarce and of low quality. LPV/RTV is available as a single-tablet formulation (Kaletra ®, North Chicago, IL, USA) in dosage strengths of 400/100 mg or 200/50 mg, and in clinical trials, this combination reduced rates of acute respiratory distress syndrome (ARDS) or death compared to supportive care or ribavirin alone in a matched cohort group during the early phase of viral acquisition [11].

LPV/RTV is being examined in several international clinical trials, including the RECOVERY trial and SOLIDARITY WHO trial [14], but did not gain authorization to be used emergently in the current pandemic in the USA by the Food and Drug Administration (FDA), which has approved only three pharmacologically di fferent therapeutics for treatments of COVID-19, including antibiotic-hydroxychloroquine, immunotherapy-convalescent plasma therapy, and antiviral-remdesivir [2,14].

Among the clinical trials that did not find positive results for LPV/RTV, a study conducted by Bin Cao et al. published in the New England Journal of Medicine [15] revealed that treatment with LPV/RTV was not associated with clinical improvement beyond standard care or reduction in mortality rate at 28 days in hospitalized adult patients with severe COVID-19.

To date, LPV/RTV combination is available in some countries' therapeutics guidelines including USA [16], Saudi Arabia [17], and Ireland [18], which means that the medicine has tenable evidence of efficacy; however, considering that early negative and conflicting results have emerged [15], there is a need to assess the efficacy and safety of this COVID-19 treatment in a systematic manner.

#### **2. Aim of the Study**

This systematic review and meta-analysis aimed to assess the efficacy and safety of LPV/RTV in COVID-19 patients in published research.
