**4. Results**

A total of 8 literature databases were screened and 76 non-duplicate articles were identified, which were evaluated for possible inclusion using titles and abstracts. Out of these, 32 articles were selected for full-text screening and finally, 14 articles (total participants = 9036) were included in the systematic review, and eight articles were included in the meta-analysis; 18 articles were excluded following full-text screening (reasons: review = 5, study with no relative data = 6, LPV/RTV use data not available = 2, no control patients in the study = 1, combined LPV/RTV use with other antiviral therapies/other medications data = 2, no extractable data = 2). The PRISMA chart for the studies included is displayed in Figure 1. The details of the included studies are depicted in Table 1. Among these, two articles were in preprint versions [26,27].

**Figure 1.** Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) flow chart of the included studies. LPV/RTV, lopinavir/ritonavir.

*TMID* **2020**, *5*, 180




**Table 1.** *Cont.*



**Table 1.** *Cont.*


**Table 1.** *Cont.*

LPV/RTV, lopinavir/ritonavir; NA, not applicable; NEWS2, National Early Warning Score 2; NHC, National Health Commission of China; NOS, Newcastle Ottawa Scale; PaO2, partial pressure of oxygen; RR, rate ratio; RoB 2, Version 2 of the Cochrane risk-of-bias tool for randomized trials; ROBINS-I, Risk of bias in non-randomized studies—of interventions; RT-PCR, real-time reverse transcription-polymerase chain reaction; SaO2, oxygen saturation; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SCI, subcutaneous injection; SEs, side effects. \* Standard care comprised, as necessary, supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, vasopressor support, renal replacement therapy,

and extracorporeal membrane oxygenation (ECMO).


*4.1. Comparison 1: <sup>E</sup>*ffi*cacy and Safety of Lopinavir-Ritonavir (LPV*/*RTV) versus No Antiviral Therapy (Conventional Therapy) or Control*

A total of eight studies [26–29,32–34,36] reported on LPV/RTV versus no antiviral therapy (conventional therapy) or control (*n* = 8405) in terms of efficacy and safety.

4.1.1. Virological Cure on Day 7 Post-Initiation of Therapy (<sup>+</sup>ve to −ve PCR: Non-Detection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Nasopharyngeal Swab)

LPV/RTV Versus No Antiviral Therapy (Conventional Cure): Virologic Cure at Day 7 Post-Initiation of Therapy

Three studies reported on virological cure (*n* = 171 in LPV/RTV alone arm vs. *n* = 117 in conventional arm) on day 7 [27,32,34]. Significant mean difference was observed between the two arms in terms of virological cure (mean difference = −0.81 day; 95% CI, −4.44 to 2.81; *p* = 0.007, *I*2 = 80%; Figure 2).


**Figure 2.** Time from +ve to −ve PCR (days) (LPV/RTV vs no antiviral treatment or conventional). CI, confidence interval; df, degrees of freedom; lopinavir/ritonavir (LPV/RTV).

LPV/RTV vs. Umifenovir: Virologic Cure at Day 7 Post-Initiation of Therapy

Three studies reported on virological cure (*n* = 127 in LPV/RTV alone arm vs. *n* = 87 in umifenovir arm) on day 7 [27,32,36]. No significant mean difference was observed between the two arms in terms of virological cure (mean difference = 0.95 day; 95% CI, −1.11 to 3.01; *p* = 0.09, *I*2 = 58%; Figure 3).


**Figure 3.** Time from +ve to −ve PCR (days) (LPV/RTV vs. umifenovir). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir.

LPV/RTV vs. Umifenovir Plus Lopinavir/Ritonavir: Virologic Cure at Day 7 Post-Initiation of Therapy

Two studies reported on virological cure (*n* = 93 in LPV/RTV alone arm vs. *n* = 75 in umifenovir plus LPV/RTV arm) on day 7 [26,32]. No significant mean difference was observed between the two arms in terms of virological cure (mean difference = −0.83 day; 95% CI, −2.45 to 0.78; *p* = 0.66, *I*2 = 0%; Figure 4).

**Figure 4.** Time from +ve to−ve PCR (days) (LPV/RTV vs LPV/RTV plus umifenovir combination). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir; UFV, umifenovir.

4.1.2. Clinical Cure (Time to Body Temperature Normalization and Time to Cough Relief)

Time to Body Temperature Normalization

#### 1. LPV/RTV vs. Umifenovir

Two studies reported on time to temperature normalization (*n* = 93 in LPV/RTV alone arm vs. *n* = 71 in umifenovir arm) [27,32]. No significant association was observed between the two arms in terms of temperature normalization (OR = 0.87 day; 95% CI, 0.42 to 1.78; *p* = 0.61, *I*2 = 0%; Figure 5).

**Figure 5.** Time to body temperature normalization (days) (LPV/RTV vs umifenovir). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir.

#### 2. LPV/RTV versus No Antiviral Therapy (Conventional)

Two studies reported on time to temperature normalization (*n* = 93 in LPV/RTV alone arm vs. *n* = 75 in conventional arm) [27,32]. No significant association was observed between the two arms in terms of temperature normalization (OR = 0.99 day; 95% CI, 0.49 to 1.99, *p* = 0.35, *I*2 = 0%; Figure 6).

**Figure 6.** Time to body temperature normalization (days) (LPV/RTV vs. no antiviral treatment or conventional). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir.

### Duration of Cough

1. LPV/RTV Versus Umifenovir: Rate of Cough Alleviation after 7 Days of Therapy

Two studies reported on cough alleviation (*n* = 93 in LPV/RTV alone arm vs. *n* = 71 in umifenovir arm) [27,32]. LPV/RTV alone arm had a significant lower number of cough days by 0.62 (95% CI 0.06 to 6.53, *p* = 0.02; *I*2 = 81%; Figure 7).


**Figure 7.** Rate of cough alleviation after 7 days of treatment (LPV/RTV vs. umifenovir). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir.

2. LPV/RTV vs. No Antiviral Therapy (Conventional): Rate of Cough Alleviation after 7 Days of Therapy

Two studies reported on cough alleviation (*n* = 93 in LPV/RTV alone arm vs. *n* = 75 in conventional arm) [27,32]. No significant association was observed between the two arms in terms of cough alleviation (OR = 0.87 day; 95% CI, 0.10 to 7.16; *p* = 0.08, *I*2 = 67%; Figure 8).

**Figure 8.** Rate of cough alleviation after 7 days of treatment (LPV/RTV vs. no antiviral treatment or conventional). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir.

#### 4.1.3. Radiological Progression during Drug Treatment

Rate of Improvement on Chest Computed Tomography (CT) after 7 Days of Treatment

#### 1. LPV/RTV vs. Umifenovir

In terms of CT evidence for radiological progression of pneumonia/lung damage (*n* = 59 in the LPV/RTV arm vs. *n* = 71 in the umifenovir arm), treatment with LPV/RTV resulted in no significant decrease in the radiological progression (OR = 0.80; 95% CI, 0.42 to 1.54; *p* = 0.59, *I*2 = 81%; Figure 9) [27,32].

**Figure 9.** Rate of improvement on chest CT after 7 days of treatment (LPV/RTV vs. umifenovir). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir.

#### 2. LPV/RTV vs. No Antiviral Therapy (Conventional)

In terms of CT evidence for radiological progression of pneumonia/lung damage (*n* = 71 in the LPV/RTV arm vs. *n* = 75 in conventional arm), treatment with LPV/RTV resulted in no significant decrease in the radiological progression (OR = 0.69; 95% CI, 0.36 to 1.31; *p* = 0.42, *I*2 = 0%; Figure 10) [27,32].


**Figure 10.** Rate of improvement on chest CT after 7 days of treatment (LPV/RTV vs. no antiviral treatment or conventional). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir.

4.1.4. Mortality at 28 Days and Death during Treatment at Any Time

#### Mortality at 28 Days

#### 1. LPV/RTV vs. Standard of Care

Two trials reported on mortality at 28 days (*n* = 1715 in LPV/RTV plus standard of care arm vs. *n* = 3524 in standard of care arm) [15,28]. No significant association was observed between the two arms in terms of mortality at 28 days (OR = 1.00; 95% CI, 0.79 to 1.26; *p* = 0.28, *I*2 = 15%; Figure 11).

**Figure 11.** Rate of mortality at 28 days (LPV/RTV plus standard of care vs. standard of care alone). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir.

#### Death during Treatment at Any Time

#### 1. LPV/RTV vs. Standard of Care

Two large trials reported on death during treatment at any time (*n* = 3015 in LPV/RTV plus standard of care arm vs. *n* = 4796 in standard of care arm) [28,29]. No significant association was observed between the two arms in terms of death during treatment at any time (OR = 1.03; 95% CI, 0.93 to 1.14; *p* = 0.78, *I*2 = 0%; Figure 12).

**Figure 12.** Rate of mortality at 28 days (LPV/RTV plus standard of care vs. standard of care alone). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir.

#### 4.1.5. Safety and Tolerability

Rate of Adverse Events of Treatment: LPV/RTV vs. Umifenovir

A greater number of adverse events were reported in the LPV/RTV arms (*n* = 45) compared to the umifenovir groups (*n* = 14) (OR = 2.66; 95% CI, 1.36 to 5.19; *p* = 0.44, *I*2 = 0%; Figure 13) [27,32,33].


**Figure 13.** Rate of adverse events of treatment (LPV/RTV vs. umifenovir). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir.

Rate of Adverse Events of Treatment: LPV/RTV vs. No Antiviral Treatment (Conventional)

A greater number of adverse events were reported in the LPV/RTV arms (*n* = 45) compared to the no antiviral treatment or conventional arms (*n* = 10) (OR = 4.6; 95% CI, 1.91 to 11.07; *p* = 0.29, *I*2 = 18%; Figure 14) [27,32,33].


**Figure 14.** Rate of adverse events of treatment (LPV/RTV vs. no antiviral treatment or conventional). CI, confidence interval; df, degrees of freedom; LPV/RTV, lopinavir/ritonavir.

*4.2. Comparison 2: <sup>E</sup>*ffi*cacy and Safety of LPV*/*RTV along in Combination with Other Agents versus No Antiviral Therapy (Conventional Therapy) or Control*

A total of four studies evaluated the efficacy of LPV/RTV plus interferon (IFN) [30,31,35,37] and three studies [30,31,37] evaluated the safety of the combination. Other studies evaluated the efficacy of LPV/RTV plus standard care [15,28], ribavirin [31], or umifenovir [26,32,37], and evaluated the safety of these combinations.

In terms of the efficacy of the combination in patients with COVID-19, LPV/RTV plus IFN combination in addition to ribavirin was safe and superior to LPV/RTV alone by shortening the median time from the start of study treatment to negative nasopharyngeal swab (7 days [IQR 5–11]) compared to the LPV/RTV arm (12 days [IQR 8–15]; hazard ratio 4.37 [95% CI 1.86–10.24], *p* = 0.001) [31]. Additionally, combination treatment with LPV/RTV plus IFN and umifenovir had a more evident therapeutic effect in a shorter time by normalizing body temperature (4.8 ± 1.94 days vs. 7.3 ± 1.53 days, *p* = 0.03) and turning PCRs negative (7.8 ± 3.09 days vs. 12.0 ± 0.82 days, *p* = 0.02) compared to the umifenovir plus IFN arm with no evident toxic and side effects [37]. However, the use of LPV/RTV plus IFN combination resulted in fewer therapeutic responses on COVID-19 in terms of viral clearance [median (interquartile range, IQR), 4 (2.5–9) d versus 11 (8–13) d, *p* < 0.001) and chest CT changes (91.43% vs. 62.22%), *p* = 0.004] compared to the favipiravir plus IFN combination. Favipiravir arm patients had fewer adverse events (AEs) compared to the LPV/RTV arm (11.43% vs. 55.56%) (*p* < 0.001) [30]. Additionally, no significant difference in average PCR negative conversion times among IFN plus LPV/RTV or IFN plus LPV/RTV plus ribavirin treatment arms [35]. In another cohort study, more patients turned SARS-CoV-2 PCR negative in the LPV/RTV plus umifenovir combination group compared to the LPV/RTV monotherapy group (after 7 days: 75% vs. 35% of patients were PCR negative in the combination therapy and monotherapy, respectively, *p* < 0.05; and after 14 days: 94% vs. 52.9% of patients were PCR negative in the combination therapy and monotherapy, respectively, *p* < 0.05) [38]. Moreover, chest CT scans were improving for 69% of patients in the combination group after seven days, compared with 29% in the monotherapy group (*p* < 0.05) [38].

The combination of LPV/RTV, in addition to standard care, or standard care alone exhibited no di fference in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% CI, 0.95 to 1.80) with similar 28-day mortality (19.2% vs. 25.0%; di fference, −5.8 percentage points; 95% CI, −17.3 to 5.7) [15]. In another recent large study, LPV/RTV combined with standard care was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death [28].
