Effectiveness of Remdesivir, Lopinavir/Ritonavir, and Favipiravir for COVID-19 Treatment: A Systematic Review

Figures & data

Figure 1 PRISMA flow diagram depicting the process of the study selection.

Note: Adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.⁶⁰

Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RCT, randomized controlled trial.

Table 1 Clinical Studies That Reported Antiviral Therapy for Treatment COVID-19

Author; Year	Sample Size	Status of COVID-19 Patients	Antiviral Agent	Comparator	Population/Patients (n)	Dosage	Duration of Treatment	Main Findings
Kalil, A. C. et al (2021)^Citation17	1033	Moderate- severe	Remdesivir	Baricitinib/Remdesivir	509	1st day: 200 mg 2 - until hospital discharge or death: 100 mg	10 days	Patients treated with the combination recovered on average one day faster than patients given remdesivir alone (median = 7 vs 8 days; recovery rate ratio = 1.16; 95% CI = 1.01 to 1.32, p = 0.03). Fewer 28-day mortality in the combination group (5.1% vs 7.8%; HR = 0.65; 95% CI = 0.39–1.09). Serious side effects were less in the combination group (16% vs 21%).
Goldman, J. D. et al (2020)^Citation14	402	Severe	Remdesivir	N/A	397	1st day: 200 mg 4 or 9 days ahead: 100 mg once daily	5 days: 200 patients 10 days: 197 patients	At day 14, patients receiving remdesivir for 10 days had a distribution of clinical status that was not significantly different from those receiving remdesivir for 5 days (p = 0.14). More patients were discharged from hospital (60% vs 52%) and reduced death rate (8% vs 11%) in the 5 day group and the 10 day group.
Wang, Y. et al (2020)^Citation13	237	Severe	Remdesivir	Placebo	158	1st day: 200 mg 2–10: 100 mg daily	10 days	Remdesivir compared with placebo was not significantly increased time it takes for clinical improvement (HR = 1.23; 95% CI = 0.87–1.75), and mortality in serious COVID-19 patients (difference 1.1%; 95% CI = [–8.1 to 10.3])
Beigel, J. H. et al (2020)^Citation8	1062	Mild - severe	Remdesivir	Placebo	541	1st day: 200 mg 2–10: 100 mg daily	10 days	Remdesivir was found to be superior to placebo in reducing recovery time in adults hospitalized with COVID-19 (rate ratio for recovery = 1.29; 95% CI = 1.12 to 1.49; p <0.001), lower mortality (HR = 0.73; 95% CI = 0.52 to 1.03) and serious adverse effects are less likely to occur. (24.6% vs 31.6%).
Spinner, C. D et al (2021)^Citation15	584	Moderate	Remdesivir	Standard care	10-day course of remdesivir: 193 5 day course of remdesivir: 191	1st day: 200 mg Following days: 100 mg	5 days and 10 days	Patients in 5-day remdesivir group had a larger chance of improving their clinical condition than those in the standard care group (OR = 1.65; 95% CI = 1.09–2.48; p = 0.02). Patients receiving 10-day remdesivir group and standard care group had no significant difference (p = 0.18).
Pan, H. et al (2021)^Citation16	11,266	N/A	Remdesivir and lopinavir	Standard care	Remdesivir: 2743 Lopinavir: 1399	Remdesivir: 1st day: 200 mg 2nd-10th day: 100 mg Lopinavir: 1st-14th day: 200 mg lopinavir (plus 50 mg ritonavir) BID	Remdesivir: 10 days Lopinavir: 14 days	There was no effect of remdesivir (RR = 0.95; 95% CI = 0.81–1.11; P = 0.50) or lopinavir (RR = 1.00; 95% CI = 0.79–1.25; P = 0.97) treatment in reducing mortality or early use of mechanical ventilation.
Cao, B et al (2020)^Citation19	199	Severe	Lopinavir/Ritonavir	Standard care group	99	400 mg lopinavir - 100 mg ritonavir twice daily	14 days	Lopinavir-ritonavir treatment had a better effect than the standard care group, but did not make a significant difference by clinical outcome (HR = 1.31; 95% CI, 0.95–1.80; p = 0.09), mortality (19.2% vs 25.0%; 95% CI = −17.3–5.7) in patients with serious COVID-19.
Reis, G. et al (2021)^Citation18	685	N/A	Lopinavir/Ritonavir	Hydroxychloroquine	244	1st day: 800+200 mg lopinavir/ritonavir, BID. 2nd-10th day: 400+100 mg lopinavir/ritonavir, BID.	10 days	No significant difference for COVID-19-associated hospitalization and viral clearance up to day 14 was found from using lopinavir/ritonavir (HR =1.16; 95% CI = 0.53–2.56 and OR = 1.04 and 95% CI, 0.94–1.16) compared with the hydroxychloroquine group (HR = 0.76; 95% CI = 0.30–1.88 and OR = 0.91; 95% CI = 0.82–1.02).
Solaymani-Dodaran, M et al (2021)^Citation20	380	Patients based on positive RT-PCR	Favipiravir Lopinavir/Ritonavir	Hydroxychloroquine	Favipiravir (n=193) and Lopinavir/ritonavir (n=187)	Favipiravir: 1600 mg and then 600 mg every 8 hours plus Hydroxychloroquine 200 mg BID. The control group: single dose of 400 mg hydroxychloroquine followed by 100 plus 400 lopinavir/ ritonavir BID.	1 week	No significant difference in clinical recovery (HR = 0.94; 95% CI = 0.75–1.17), SpO2 changes during hospitalization (p= 0.46), mortality, intubation and ICU admission between favipiravir and lopinavir/ritonavir. However, lopinavir/ritonavir had more side effects than favipiravir.
Lou, Y et al (2021)^Citation22	30	N/A	Favipiravir	Baloxavir marboxil and the control group (lopinavir/ritonavir or darunavir/cobicistat or arbidol)	9	First dose: 1600–2200 mg Followed by 600 mg, three times a day.	14 days	The percentage of patients who became virally negative after 14 days of treatment was 77%, 70%, and 100% in the favipiravir, baloxavir marboxil, and control groups, with medians to clinical improvement being 14 days, 14 days and 15 days, respectively.
Zhao, H et al (2021)^Citation23	26	N/A	Favipiravir	Tocilizumab and combination (tocilizumab plus favipiravir)	7	1st day: 1600 mg twice daily. 2nd-7th day: 600 mg twice daily.	14 days	At day 14, the cumulative pulmonary lesion remission rate in combination group was significantly higher than the favipiravir group (HR 2.66; 95% CI = 1.08–6.53, p= 0.019). Significant difference was observed between tocilizumab and favipiravir (HR 3.16; 95% CI = 0.62–16.10, p= 0.034). No significant difference between combination and tocilizumab (HR 1.28; 95% CI = 0.39–4.23, p = 0.575).
Khamis, F et al (2021)^Citation21	89	Moderate -severe COVID-19 pneumonia patients	Favipiravir	Hydroxychloroquine	44	1st day: 1600 mg twice daily 2nd until maximum 10th day 600 mg twice daily	10 days	No significant difference between combination favipiravir with inhaled interferon beta-1b and the standard group in terms of duration hospital stay (7 days vs 7 days with p = 0.948), transfer to ICU (18.2% vs 17.8% with P = 0.960), discharge (65.9% vs 68.9% with P = 0.764) and mortality (11.4% vs 13.3% with P = 0.778).
Dabbous, H, M et al (2021)^Citation24	96	Mild to moderate	Favipiravir	Chloroquine	48 and 4 patients out from study	1st day: 1600 mg twice daily 2nd to 10th day: 600 mg twice daily	10 days	Favipiravir may be useful in reducing the duration of hospital stay and the mechanical ventilation. No patients in favipiravir group needed mechanical ventilation (p = 0.129)
Dabbous, H. M et al (2021)^Citation25	100	Mild/ moderate	Favipiravir	Hydroxychloroquine	50	1st day: 1600 mg, twice daily 2nd-10th day: 600 mg, twice daily	10 days	In mild to moderate patients, no significant differences in clinical benefit between favipiravir and hydroxychloroquine (P = 0.7). In COVID-19 therapy regimens, favipiravir can be an effective and safe alternative to hydroxychloroquine.
Udwadia, Z, F et al (2021)^Citation26	150	Mild/ moderate	Favipiravir	Standard supportive care	75	1st day: 1800 mg twice daily 2nd to 14th day: 800 mg twice daily	14	The addition of favipiravir to supportive therapy may be useful in patients categorized mild to moderate. The median time it takes to stop spreading was 5 days vs 7 days ((95% CI = 4 days, 7 days) vs (95% CI = 5 days, 8 days), p= 0.129), and the median time required for a patient to recover clinically was 3 days vs 5 days ((95% CI = 3 days, 4 days), vs (95% CI = 4 days, 6 days), P = 0.030).

Abbreviations: HR, hazard Ratio; RR, rate ratio; OR, odds ratio; 95% CI, 95% of confidence interval; N/A, not available; SpO2, oxygen saturation; ICU, intensive care unit; RT-PCR, reverse transcription polymerase chain reaction.

Figure 2 Risk-of-bias assessment of 15 included studies.

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