TABLE 2.

Summary of reported clinical effects on use of antivirals from non-randomized studies.

Study ID, Country	Study design	Disease severity	Efficacy outcomes	Safety outcomes, n (%)
Prospective Open-label/Cohort Study
Antinori et al. (2020) Italy	Prospective open-label study, n = 35 Int: Remdesivir (compared between patients in intensive care unit and infectious diseases ward)	Severe	Intensive care unit patients: By 10 days of treatment, 4/18 (22.2%) of patients improved in hospitalization Status (1 not requiring supplemental oxygen and 3 weaned from invasive ventilation), 10/18 (55.5%) still undergoing invasive ventilation, and 4/18 (22.2%) died; By the 28 days of follow-up, 7/18 (38.9%) of patients improved in hospitalization Status (6 discharged, 1 weaned from invasive ventilation), 16.7% still undergoing mechanical ventilation and the other 44.4% died. Infectious diseases ward patients: By 10 days of treatment, 6/17 (35.3%) of patients improved in hospitalization Status (1 discharged, 3 no longer required oxygen supplementation, 2 no longer required high-flow therapy and/or non-invasive mechanical ventilation); 10 still required high-flow therapy and/or non-invasive mechanical ventilation, and 1 died. By day 28 of follow-up, hospitalization status had improved in 88.2% of the IDW patients (14 had been discharged, one no longer required oxygen supplementation) but one still required high-flow therapy and/or non-invasive mechanical ventilation.	Severe adverse advents: Hypertransaminasemia 15/35 (42.8%) Increased total bilirubin levels 7/35 (20.0%) Acute kidney injury 8/35 (22.8%) Rash 2/35 (5.7%) Any adverse event leading to treatment discontinuation 8/35 (22.8%)
Cai et al. (2020) China ChiCTR2000029600	Prospective open-label, non-randomized, n = 80 Int: Favipiravir 1600 mg twice daily on day 1, 600 mg twice daily from day 2–14 Ctr: Lopinavir–ritonavir (400 mg and 100 mg) twice daily for up to 14 days		Median days to viral clearance, (IQR) Int: 4 (2.5–9) Ctr: 11 (8–13) P < 0.001 Improvement in chest CT scans at day 14, n (%) Int: 32 (91.4) Ctr: 28 (62.2) P = 0.004	Adverse effect (all), n (%) Int: 4 (11.4) Ctr: 25 (55.6)
Chen W. et al. (2020) China	Prospective open-label study, n = 62 Int: Arbidol Ctr: Standard of care including interferon antiviral treatment	NR	Hospitalization period in the test group and control group: (16.5 ± 7.14) days and (18.55 ± 7.52) days Fever and cough in the test group were relieved markedly faster than those in the control group (p < 0.05); time for two consecutive negative nucleic acid tests in the test group were shorter than that in the control group.	No significant difference between the two groups for any adverse drug reaction.
Grein et al. (2020) United States, Japan, Europe, Canada	Prospective cohort study, n = 53 Int: Remdesivir 200 mg on day 1, then 100 mg daily for the following 9 days.	NR	Over a median follow up of 18 days (IQR 13–23) after receiving the first dose of remdesivir, 36/53 (68%) showed improvement in oxygen support, 8/53 (15%) showed worsening. By the date of most recent follow up, 25/53 (47%) had been discharged. By 28 days of follow-up, cumulative incidence of clinical improvement was 84% (95% CI 70–99). Clinical improvement was less frequent among those receiving invasive ventilation than among those receiving non-invasive oxygen support (HR 0.33; 95% CI 0.16–0.68) and among patients 70 years and older as compared to patients younger than 50 years (HR 0.29; 95% CI 0.11–0.74). 7/53 patients (13%) died after the completion of remdesivir treatment. Overall mortality from the date of admission was 0.56 per 100 hospitalization days (95% CI 0.14–0.97) and did not differ among patient receiving invasive ventilation and non-invasive oxygen support. Hazard ratio for patient receiving invasive ventilation as compared with patient receiving non-invasive oxygen support was 2.78 (95% CI 0.33–23.19). Mortality rate was higher among patients 70 years and older as compared with patients younger than 70 years (HR 11.34; 95% CI 1.36–94.17) and among those with higher serum creatinine at baseline (HR 191; 95% CI 1.22–2.99).	32 patients (60%) reported adverse events during follow up. Most common adverse events were increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension. 12 patients (23%) had serious adverse events, which all received invasive ventilation at baseline. Most common serioys adverse events were multiple organ dysfunction syndrome, septic shock, acute kidney injury, and hypotension. 4 patients (8%) discontinued remdesivir prematurely, due to worsening of pre-existing renal failure (n = 1), multiple organ failure (n = 1), elevated aminotransferases (n = 1), including one patient with a maculopapular rash.
Retrospective cohort studies
Deng et al. (2020) China ChiCTR2000030254	Retrospective cohort, n = 33 Int: Umifenovir 200 mg three times daily and lopinavir–ritonavir (400 mg and 100 mg) twice daily for 5–12 days Ctr: Lopinavir–ritonavir (400 mg and 100 mg) twice daily for 5–12 days	Moderate to severe	Negative SARS-CoV-2 detection at day 7, n (%) Int: 12 (75) Ctr: 6 (35) p < 0.05 Negative SARS-CoV-2 detection at day 14, n (%) Int: 15 (94) Ctr: 9 (53) p < 0.05 Improvement in chest CT scans at day-7 Int: 11 (69) Ctr: 5 (29) p < 0.05	Adverse effect (all) Total patients, n (%) Favipiravir : 37 (31.9) Umedipavir: 28 (23.3) Total events, n Favipiravir : 43 Umedipavir: 33
Giacomelli et al. (2020) Italy	Retrospective intent-to-treat analysis, n = 172 Lopinavir/ritonavir (LPV/r) + hydroxychloroquine (HCQ): Int: Treatment started within 5 days of symptom onset (early treatment) (25% of patients) Ctr: Treatment started later (delayed treatment) (75% of patients)		Rate of clinical improvement increased over time to 73.3% on day 30, without any significant difference between the two groups (Gray’s test P = 0.213). No significant association between the timing of the start of treatment and the probability of 30-day mortality (adjusted odds ratio [aOR] early treatment vs delayed treatment = 1.45, 95% confidence interval 0.50–4.19).	8% of the patients discontinued the treatment because of severe gastrointestinal disorders attributable to LPV/r.
Kim et al. (2020) Korea	Retrospective cohort study, n = 65 Lopinavir–ritonavir 400 mg/100 mg twice daily (n = 31) Hydroxychloroquine 400 mg once daily (n = 34)		Median duration of treatment was 7 days Median time to negative conversion of viral RNA Lopinavir–ritonavir: 21 days Hydroxychloroquine: 28 days Lopinavir–ritonavir (aHR 2.28; 95% CI 1.24–4.21) and younger age (aHR 2.64; 95%CI 1.43–4.87) were associated with negative conversion of viral RNA. No significant difference in time to clinical improvement between lopinavir–ritonavir-treated patients and hydroxychloroquine-treated patients (median 18 days vs. 21 days).	Lymphopenia and hyperbilirubinemia were more frequent in lopinavir–ritonavir group compared with hydroxychloroquine group. One serious adverse event (ARDS) occurred in one patient treated with lopinavir–ritonavir, two serious adverse events (ARDS and shock) occurred in patients treated with hydroxychloroquine.
Lian et al. (2020) China	Retrospective cohort, n = 81 Int: Umifenovir 0.2 g three times a day + symptomatic treatment Ctr: symptomatic treatment	Moderate and severe	Rate of negative pharyngeal swab tests for SARS-CoV-2 within 1 week after admission: Int: 33 (73%) Ctr: 28 (78%) Time from admission to first negative test of SARS-CoV-2: Int: 6 days (4–8) Ctr: 3 days (1–7) Time from onset of symptoms to first negative test of SARS-CoV-2: Int: 18 days (12–21) Ctr: 16 days (11–21) Length of hospital stay: Int: 13 days (9–17) Ctr: 11 days (9–14)	5/45 (45%) patients in Umifenovir group and 3/36 (8%) in control group demonstrated digestive symptoms, including diarrhea and nausea.
Panagopoulos et al. (2020) Greece	Retrospective cohort, n = 16 Group A: Lopinavir/ritonavir + hydroxychloroquine + azithromycin Group B: Hydroxychloroquine + azithromycin	NR	7/8 patients in group A recovered, one needed intubation and mechanical ventilation. 1/8 patient in group B recovered, 3/8 died, 4/8 patients needed intubation. Days of hospitalization: Group A: 14.71 ± 0.76 Group B: 11.40 ± 2.07 Days for clinical improvement (no fever): Group A: 6.00 ± 1.16 Group B: 4.4 ± 1.52 Days for negative result of RT-PCR for SARS-CoV-2: Group A: 8.86 ± 1.68 Group B: 13.8 ± 2.68	NR
Shi et al. (2020) China	Retrospective cohort study, total n = 184 (divided into seven groups). Symptomatic treatment group, Arbidol group, lopinavir/ritonavir group, Arbidol + lopinavir/ritonavir group, interferon group, interferon + lopinavir/ritonavir group, and interferon + darunavir group (Doses: interferon, interferon-α2β (aerosol inhalation), 100,000 U/kg, 2 times/day; Arbidol, 200 mg, 3 times/day; lopinavir/ritonavir, 2 tablets, 2 times/day; darunavir, 1 tablet, 1 time/day)	Not classified	Data extensive among seven groups, but no significant different among groups in the rates of pneumonia resolution and length of hospital stay. Pneumonia resolution after treatment, n (%) Int 1: 16 (53%) Int 2: 12 (44%) Int 3: 9 (36%) Int 4: 24 (59%) Int 5: 16 (76%) Int 6: 14 (61%) Ctr: 7 (41%) Length of hospital stay, mean ± SD Int 1: 15.7 days ± 6.4 Int 2: 18.4 ± 7.2 Int 3: 18.5 ± 9.5 Int 4: 16.5 ± 5.5 Int 5: 16.2 ± 7.1 Int 6: 17.4 ± 7.0 Ctr: 20.0 ± 6.0	NR
Vizcarra et al. (2020) Spain	Prospective cohort, n = 51 HIV-infected individuals diagnosed with COVID-19. Nine individual received protease inhibitor before COVID-19, 37 individuals received tenofovir before COVID-19 N = 39 HIV-infected individuals received off-label treatment for COVID-19. - Hydroxychloroquine (n = 30) - Azithromycin (n = 19) - Ritonavir/lopinavir (n = 14) - Tocilizumab (n = 4) - Systemic corticosteroids (n = 15)	Mild, moderate and severe	Clinical outcomes for HIV-infected COVID-19 individuals (n = 51): Respiratory failure, n (%) Mild or moderate: 4 (11%) Severe: 13 (100%) Sepsis, n (%) Mild or moderate: 2 (5%) Severe: 9 (69%) Critical disease or intensive care unit admission, n (%) Mild or moderate: 0 Severe: 6 (46%) Invasive mechanical ventilation, n (%) Mild or moderate: 0 Severe: 5 (38%) Death, n (%) Mild or moderate: 0 Severe: 2 (15%) Recovered, n (%) Mild or moderate: 35 (92%) Severe: 9 (69%) Duration of hospital stay, days Mild or moderate: 8 (6–17) Severe: 8 (6–19)	NR
Xu et al. (2020) China	Retrospective cohort, multi-center study (n = 141). Combined group (n = 71) patients were given Arbidol and IFNa2b Monotherapy group (n = 70): patients inhaled IFNa2b for 10 to 14 days.	Mild and moderate (non-ventilated)	The median hospitalization days was 27.1 vs. 24.2 days in two group (P = 0.056). After treatment for 7 to 14 days, there was no statistically differences of the viral RNA clearance days between two groups.	There were no differences between the two groups in hemoglobin, WBC count, platelet count, ALT, AST, or creatinine during or after treatment. Thirteen patients (18.8%) treated with Arbidol demonstrated mild nausea, stomachache, but all patients could tolerate without giving up treatment.
Yan et al. (2020) China	Retrospective cohort, n = 120 Int: Lopinavir–ritonavir (400 mg and 100 mg) twice daily for 10 or more days Ctr: Standard care	Mild, moderate, severe, and critical	Median duration of treatment was 10 days (IQR: 9–10 days Median duration of SARS-CoV-2 shedding, (IQR) Int: 22 (18–29) Ctr: 28.5 (19.5–38) p = 0.02	NR
Yang et al. (2020) China	Retrospective cohort, single-center study involving frontline health professionals (n = 164), including 82 infected with COVID-19 and 82 uninfected controls. Arbidol were taken by 23.2% if the participants in the infected group and 58.5% of the participants in the uninfected group as prophylaxis against symptomatic COVID-19 requiring hospital admission.	Asymptomatic infected and uninfected groups.	The cumulative uninfected rate of health professionals in the Arbidol group was significantly higher than that of individuals in the non-Arbidol group (log-rank test, χ2 = 98.74; P < 0.001). Forty-eight patients (58.5%) in the infection group were hospitalized, with a median age of 39 (31–49) years, of whom 7 (14.6%) were prophylactically administered Arbidol.	NR
Ye et al. (2020) China	Retrospective cohort, n = 47. Lopinavir/Ritonavir along with Arbidol and interferon (n = 42), and “control” (no lopinavir/ritonavir, with Arbidol and interferon only, n = 5). “The per ml of LPV/r oral liquid contained 80 mg lopinavir and 20 mg ritonavir. Usage and dosage: 5 ml/time (400/100 mg) for adults, twice a day or 10 ml/time (800/200 mg) once a day with food”	Not classified	“Compared with the control group, the patients in the test group returned to normal body temperature in a shorter time (test group: 4.8 ± 1.94 days vs. control group: 7.3 ± 1.53 days, p = 0.0364).” No significant differences between groups otherwise.	The abnormal percentage of ALT and AST in the test group was lower than that in the control group.
Zheng et al. (2020) China	Retrospective cohort, n = 55 Mild: Intermitted low-flow oxygen therapy (≤3 L/min) and antiviral treatment for 10 days Moderate: continuous middle-flow oxygen therapy (3∼5 L/min), triple antiviral treatment, ribavirin 500 mg twice daily and recombinant interferon-α2b (5 million units) twice daily for 10 days Severe: Oxygen support including mask oxygen (>5 L/min), high flow nasal oxygen therapy (HFNO), or non-invasive ventilation (NIV), triple antiviral treatment, ribavirin and recombinant interferon-α2b (5 million units) twice daily for 10 days. All patients also received methylprednisolone (0.5∼1 mg/kg/d × 5 days). Empirical antibiotic treatment given if bacteria infection was suspected. Treatment-failure patients were prepared early for intubation and invasive mechanical ventilation and considered for ECMO	Mild, moderate and severe	Improvement in clinical symptoms, n (%) Non-severe (mild/moderate cases): 31 (91.2) Severe: 18 (85.7) p = 0.85 At least 50% improvement in chest CT scans at 7 days, n (%) Non-severe: 22 (64.7) Severe: 12 (57.4) At least 75% improvement in chest CT scans at 14 days, n (%) Non-severe: 28 (82.4) Severe: 16 (76.2) Negative SARS-CoV-2 detection, n (%) Non-severe: 33 (97.1) Severe: 20 (95.2) P = 0.92	NR
Zhu et al. (2020) China	Retrospective cohort, n = 50 Lopinavir/ritonavir group received 400 mg/100 mg twice a day for a week Umedipavir 0.2 g Arbidol three times a day	NR	Negative SARS-CoV-2 detection at day 7, n (%) Lopinavir/ritonavir: 8 (23.5) Umedipavir: 8 (50) Negative SARS-CoV-2 detection at day 14, n (%) Lopinavir/ritonavir: 19 (55.9) Umedipavir: 16 (100)	Adverse event, all, n (%) Lopinavir/ritonavir: 4 (11.8) Umedipavir: 6 (33.3)
Case–control
Zhang et al. (2020) China	Case control, n = 190 Int: Umifenovir 200 mg three times daily for 5–10 days Ctr: Oseltamivir 75 mg once daily or placebo	NR	Number of individuals with positive COVID-19 diagnosis, n (%) Int: 2 (2) Ctr: 19 (21) (Odds ratio: 0.011, 95% CI: 0.001–0.125, p = 0.003)	NR
Zhou et al. (2020) China	Case–control, n = 238 Int: Arbidol	Mild and severe	Median duration of SARS-CoV-2 virus shedding: 23 days (IQR, 17.8–30 days) SARS-CoV-2 RNA clearance was significantly delayed in patients who received Arbidol > 7 days after illness onset, compared with those in whom Arbidol treatment was started ≤ 7 days after illness onset (HR, 1.738 [95% CI, 1.339–2.257], P < 0.001).	NR
Case series
Chen H. et al. (2020) China NCT04291729	Case series, n = 11 Int: Danoprevir 100 mg twice daily and ritonavir 100 mg twice daily ± with interferon-α2b atomization inhalation (5 million units) twice daily for 4–12 days with	Moderate	Use of danoprevir with ritonavir appears to be safe and effective in supressing the viral replication of SARS-CoV-2. Median days to negative SARS-CoV-2 detection, (range): 2 (1–8) Median days to improvement in chest CT scans, (range): 3 (2–4)	NR
Gautret et al. (2020) France	Case series, n = 80 Int: Hydroxychloroquine and azithromycin over a period of at least 3 days	Mild	Mean length of infectious disease unit stay before discharge: 5 days All patients improved clinically except one 86-year-old patient who died, and one 74-year-old patient still in intensive care. Observations: - Rapid fall of nasopharyngeal viral load was noted: 83% negative at   Day 7, and 93% at Day 8. - Virus cultures from patient respiratory samples were negative:   97.5% of patients at Day 5.	Nausea or vomiting: 2.5% Diarrhea: 5.0% Blurred vision: 1.2%
Haerter et al. (2020) Germany	Case series of PLWH with COVID-19, n = 17 out of 33 with tenofovir use in combination with: - Bictegravir/emtricitabine (n = 6) - Rilpivirine/emtricitabine (n = 3) - Darunavir/cobicistat/emtricitabine (n = 3) - Elvitegravir/cobicistat/emtricitabine (n = 3) - Nevirapine/emtricitabine (n = 2)	All mild except two critical and one severe	All recovered, one death (critical)	NR
Holshue et al. (2020) United States	Case report, n = 1 Remdesivir (dose and frequency not reported)	NR	Improvement reported in patient condition	NR
Lim et al. (2020) South Korea	Case report, n = 1 Lopinavir–ritonavir (400 mg and 100 mg) twice daily for 10 or more days	Mild	Reduced viral loads and improved clinical symptoms with treatment of antiviral	NR
Liu et al. (2020) China	Case series, n = 10 Int: Lopinavir 400 mg twice daily with interferon-α2b atomization inhalation (5 million unit) twice daily	Mild, moderate and severe	Use of lopinavir appears to be effective	Any adverse event (any grade), n (%) Int: 3 (30%)
Wang Z. et al. (2020) China	Case series, n = 4 Umifenovir 200 mg three times daily, lopinavir–ritonavir (400 mg and 100 mg) twice daily with traditional Chinese medicine for 6–15 days with supplemental oxygen	Mild, severe	Improvement reported in three patients, of which two were confirmed SARS-CoV-2 negative.
Young et al. (2020) Singapore	Case series, n = 18 Int: Lopinavir–ritonavir (200 mg and 100 mg) twice daily for up to 14 days and supportive therapy ± supplemental oxygen, n = 5 Ctr: Supportive therapy ± supplemental oxygen	Mild and moderate	Equivocal improvements between both groups	Adverse effect (all) Int: 4 (80%)
Other study types
Xi et al. (2020) China	Retrospective single-group study (n = 94). All patients were treated with Arbidol (100 mg TDS for 14 days) and moxifloxacin (0.4 g once a day for 7–14 days).	27 severe (ICU) and 57 “ordinary warded” patients	After treatment of Arbidol and moxifloxacin for 1 week, the rates of SARS-CoV-2 nucleic acid turning negative were 69.2% in the severe group and 77.8% in the ordinary group.	NR
Zuo et al. (2020) China	Retrospective cross-sectional, n = 181 Either lopinavir/ritonavir or lopinavir/ritonavir + IFN-α or lopinavir/ritonavir + IFN-α + Arbidol (dose, frequency not reported)	Mild, moderate and severe	Median duration of viral shedding 18.0 days (IQR 15.0–24.0) Median length of hospital stay: 17.0 days (IQR 14.0–21.0) Median time from illness onset to discharge: 23.0 days (IQR 19.0–28.5)	NR

Ctr, control; Int, intervention; NR, not reported; PLWH, people living with HIV.