key: cord-0728958-ujwq4ft3
authors: Hsu, Chi-Kuei; Chen, Ching-Yi; Chen, Wang-Chun; Lai, Chih-Cheng; Hung, Shun-Hsing; Lin, Wei-Ting
title: The effect of sofosbuvir-based treatment on the clinical outcomes of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials
date: 2022-02-06
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2022.106545
sha: e0a74fa2020dfb0d28d827af8546588c30d4c09f
doc_id: 728958
cord_uid: ujwq4ft3

Objective This systematic review and meta-analysis examined the efficacy of sofosbuvir-based antiviral agents against coronavirus disease 2019 (COVID-19). Methods PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from inception to 15 August 2021. Studies comparing the clinical efficacy and safety of sofosbuvir-based antiviral regimens (study group) with other antivirals or standard of care (control group) in patients with COVID-19 were included. Results Overall, 687 patients with COVID-19 were included, of which 377 patients received sofosbuvir-based treatment. Mortality was lower in the study group than in the control group (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.30-0.79; I 2 = 0%). The overall clinical recovery rate was higher in the study group than in the control group (OR, 1.82; 95% CI, 1.20-2.76; I 2 = 28%). The study group presented a lower requirement for mechanical ventilation (OR, 0.33; 95% CI, 0.13-0.89; I 2 = 0%) and intensive care unit (ICU) admission (OR, 0.42; 95% CI, 0.25-0.70; I 2 = 0%) than the control group. Furthermore, the study group exhibited a shorter length of hospital stay (mean deviation [MD], -1.49; 95% CI, -2.62 to -0.37, I 2 = 56%) and recovery time (MD, -1.34; 95% CI, -2.29, -0.38, I 2 = 46%) than the control group. Conclusions Sofosbuvir-based treatment may help reduce mortality in patients with COVID-19 and improve associated clinical outcomes. Furthermore, sofosbuvir-based treatment was as safe as the comparator in patients with COVID-19. However, further large-scale study is warranted to validate these findings.

By late August 2021, more than 210 million confirmed cases of coronavirus disease 2019 (COVID -19) had been reported, with more than 4 million documented deaths [1] .

Despite the rapid development of COVID-19 vaccination, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a major challenge globally [2, 3] . Therefore, identification of effective treatment regimens for patients with COVID-19 remains critical. Despite large-scale search for therapeutic regimens to manage patients with COVID-19, effective treatments against SARS-CoV-2 infection remain limited. At the time of writing, only corticosteroid and tocilizumab have been reported to reduce mortality in patients with COVID-19 by the WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group [4, 5] . A meta-analysis of clinical trials involving 1073 critically ill patients with COVID-19 revealed that administration of systemic corticosteroids can be associated with lower 28-day all-cause mortality when compared with usual care or placebo (summary odds ratio

[OR], 0.66; 95% confidence interval [CI], 0.53-0.82) [4] . Another prospective meta-analysis of 27 clinical trials assessing patients hospitalised with COVID-19 has reported that administration of interleukin-6 (IL-6) antagonists was associated with lower 28-day all-cause mortality (summary OR, 0.86; 95% CI, 0.79-0.95) when compared with typical care or placebo [5] . However, in addition to corticosteroids and tocilizumab, there is a persistent need for superior strategies to combat SARS-CoV-2.

The clinical efficacies of several antiviral agents, including remdesivir, lopinavir/ritonavir, favipiravir, baloxavir, umifenovir, and darunavir/cobicistat, as well as their combinations, have been evaluated for treating patients with COVID-19 [6] ; of these, only remdesivir has been approved by the Food and Drug Administration as a treatment for patients with COVID-19 requiring hospitalisation [7] . Although remdesivir can help improve clinical outcomes of hospitalised patients with COVID-19, no additional mortality benefit has been observed with this treatment [8] .

Both hepatitis C virus and SARS-CoV-2 are positive sense RNA viruses, so the anti-HCV agent sofosbuvir has been repurposed as the promising treatment for COVID-19. Moreover, sofosbuvir has a broad antiviral spectrum, which also exhibit potent activity against yellow fever, Zika, dengue and chikungunya virus. Various sofosbuvir-based regimens, including sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, and sofosbuvir/velpatasvir, have been assessed as potential therapeutic regimens in patients with COVID-19 [9] [10] [11] [12] [13] [14] [15] [16] . In contrast to remdesivir, an individual patient data meta-analysis revealed that sofosbuvir/daclatasvir improved clinical recovery (risk ratio [RR], 1.34; 95% CI, 1.05-1.71, p = 0.020), as well as survival (RR, 0.31; 95% CI, 0.12-0.78, p = 0.013) in patients with moderate to severe COVID-19 [17] . Similar findings were reported in another meta-analysis examining four clinical studies; sofosbuvir/daclatasvir was found to be associated with lower mortality (RR, 0.31; 95% CI, 0.12-0.78; p=0.013) and reduced need for intensive care unit (ICU) admission or invasive mechanical ventilation (MV) (RR, 0.35; 95% CI, 0.18-0.69; p=0.002) [18] . However, these two meta-analyses have only focused on sofosbuvir/daclatasvir and included only three or four clinical trials [17, 18] .

Accordingly, no meta-analysis assesses the effect of all sofosbuvir-based antiviral agents including sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, and sofosbuvir/velpatasvir on the clinical outcomes in patients with COVID-19, especially in terms of mortality. Therefore, we conducted the present systematic review and meta-analysis to assess the impact of sofosbuvir-based treatment on the mortality of patients with COVID-19.

PubMed, Embase, Cochrane Central Register of Controlled Trials, and

ClinicalTrials.gov databases were searched for relevant articles up to 15 August 2021.

We used the following search terms, including "sofosbuvir," "sofosbuvir/daclatasvir," "sofosbuvir/ledipasvir," "sofosbuvir/ investigators independently screened and reviewed each study. In the case of any disagreement, a third investigator was responsible for establishing consensus. The following data were extracted from each included study: year of publication, study design, study patients, sofosbuvir-based antiviral regimens, comparative agents, clinical outcomes, and risk of AEs. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines [19] .

The primary outcome was all-cause mortality. Secondary outcomes included clinical recovery, length of hospital stay, ICU admission, MV requirement, and risk of AEs.

The Cochrane risk-of-bias tool [20] was used to assess the quality and risk-of-bias of included randomised control trials and non-randomised clinical trials. Statistical analyses were performed using Review Manager (version 5.3; Nordic Cochrane

Centre, Copenhagen, Denmark). Meanwhile, we assessed the degree of heterogeneity using Q statistics generated from  2 tests and I 2 measure. The fixed-effects model was employed when data were homogeneous, and the random-effects model was used when data were heterogeneous (I 2 > 50%). Finally, the pooled ORs and 95% CIs were calculated for outcome analysis.

The search of online databases yielded 623 studies, of which 107 duplicate studies were excluded. In addition, 488 studies were deemed irrelevant after screening titles, abstracts, and publications with no full text available. Furthermore, 20 studies were excluded after the full texts of 28 articles were screened. Finally, eight articles [9] [10] [11] [12] [13] [14] [15] [16] were included in the meta-analysis ( Figure 1 and Appendix 1).

Five studies [9, 11, 12, 13, 14] were conducted at a single centre, and three studies [10, 15, 16] were multicentre studies (Table 1) . Except for two studies conducted in Egypt [10, 16] , all other studies were conducted in Iran [9, [11] [12] [13] [14] [15] . Six studies [9, 11, 13, 14, 15, 16] focused on hospitalised patients, and one study [12] focused on outpatients with COVID-19. Six studies [9-12, 15, 16] used sofosbuvir/daclatasvir alone or in combination with ribavirin or hydroxychloroquine as experimental drugs; sofosbuvir/ledipasvir [13] , sofosbuvir/velpatasvir [14] , and sofosbuvir/ravidasvir [16] were used as experimental antiviral agents in the remaining studies. Overall, 687

patients with COVID-19 were included in the present study. Of these, 377 patients were allocated to receive sofosbuvir-based treatment regimens (n=231 patients received sofosbuvir/daclatasvir; n=42 patients received sofosbuvir/ledipasvir; n=40 patients received sofosbuvir/velpatasvir; n=40 patients received sofosbuvir/ravidasvir).

The risk-of-bias is shown in Fig. 2 . High risks of performance bias were found in six studies [9, 11, [13] [14] [15] [16] and Eslami et al's study [11] had high risk of selection bias, too.

Mortality in the study group, which included patients who received sofosbuvir-based treatment, was only 8.0% (30/377), lower than that documented in the control group (14.5%, 45/310). A significant difference in the mortality rate was observed between the study and control groups using fix-effects models (OR, 0.49; 95% CI, 0.30-0.79; Figure 3 ). The lower mortality among study group than control group was unaltered using the random-effects model. In the subgroup analysis, hospitalised patients with COVID-19 receiving sofosbuvir-based treatment were associated with lower mortality than those in the control group (OR, 0.46; 95% CI, 0.24-0.88; I 2 = 0%). In addition, patients receiving sofosbuvir/daclatasvir treatment were associated with a lower mortality than the comparator (OR, 0.42; 95% CI, 0.23-0.75; I 2 = 0%) in the subgroup analysis of 6 RCTs using sofosbuvir/daclatasvir treatment as intervention [9-12, 15, 16] .

The overall clinical recovery rate was significantly higher in the study group than in the control group using fixed-effects model ( (OR, 0.66; 95% CI, 0.14-3.10; I 2 = 0%) ( Figure 5 ).

In the present meta-analysis, seven articles [9] [10] [11] [12] [13] [14] [15] [16] were reviewed to assess the clinical efficacy and safety of sofosbuvir-based treatment regimens, including sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and sofosbuvir/ravidasvir, in the treatment of patients with COVID-19. Notably, this study revealed that sofosbuvir-based treatment could improve the clinical outcomes of patients with COVID-19, as supported by the following evidence. Most importantly, patients receiving sofosbuvir-based treatment exhibited a significantly lower mortality rate than the control group. However, this finding contrasts a previous report investigating the clinical efficacy of another commonly used antiviral agent, remdesivir, which did not afford a mortality benefit in patients with COVID-19 [6, 8, 21] . In addition, sofosbuvir-based treatment was associated with a significantly higher clinical recovery rate, lower rate of requiring MV and ICU admission, and shorter length of hospital stay and recovery time than the comparators. Moreover, the clinical benefits of sofosbuvir-based treatment were consistently observed in the subgroup analysis of hospitalised patients with COVID-19. In addition, consistent with findings of previous studies [17, 18] , the subgroup of patients receiving sofosbuvir/daclatasvir had better clinical outcomes than those receiving comparators. Finally, we observed that sofosbuvir-based treatment regimens were not associated with a higher risk of AEs than the comparators, indicating that these antiviral agents were tolerable. inflammatory mediators, such as IL-6 and tumour necrosis factor α, respectively [22] .

In addition, sofosbuvir was found to bind nsp12 with comparable binding energies to that of remdesivir [23] . Based on the findings of this meta-analysis of only 8 RCTs, sofosbuvir-based treatment regimens may help reduce the mortality of patients with COVID-19 and improve associated clinical outcomes, including clinical recovery, the risk of requiring MV and ICU admission, length of hospital stay, and recovery time. In addition, sofosbuvir-based treatment was as safe as the comparator for patients with COVID-19.

All these findings suggest the potential role of sofosbuvir-based anti-viral treatment against SARS-CoV-2 infections. However, further large-scale study, especially multi-national study is warranted to validate our findings. 

COVID vaccines slash viral spread -but Delta is an unknown

COVID-19 vaccines: concerns beyond protective efficacy and safety

Association between administration of systemic corticosteroids and mortality among critically Ill patients with COVID-19: a meta-analysis

Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis

Clinical efficacy of antiviral agents against coronavirus disease 2019: A systematic review of randomized controlled trials

Clinical efficacy and safety of remdesivir in patients with COVID-19: a systematic review and network meta-analysis of randomized controlled trials

Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial

Efficacy of combined sofosbuvir and daclatasvir in the treatment of COVID-19 patients with pneumonia: a multicenter Egyptian study

The impact of sofosbuvir/daclatasvir or ribavirin in patients with severe COVID-19

Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: a double-blind, randomized controlled trial

Efficacy and safety of sofosbuvir/ ledipasvir in treatment of patients with COVID-19; A randomized clinical trial

Efficacy and safety of sofosbuvir/velpatasvir versus the standard of care in adults hospitalized with COVID-19: a single-centre, randomized controlled trial

Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial

Efficacy and safety of sofosbuvir plus daclatasvir or ravidasvir in patients with COVID-19: a randomized controlled trial

Sofosbuvir/daclatasvir regimens for the treatment of COVID-19: an individual patient data meta-analysis

Sofosbuvir with daclatasvir and the outcomes of patients with COVID-19: a systematic review and meta-analysis with GRADE assessment

Updating guidance for reporting systematic reviews: development of the PRISMA 2020 statement

The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

Efficacy and safety of remdesivir in COVID-19 caused by SARS-CoV-2: a systematic review and meta-analysis

In vitro antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19

The anti-HCV, Sofosbuvir, versus the anti-EBOV Remdesivir against SARS-CoV-2 RNA dependent RNA polymerase in silico

SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution