Original research Postgrad Med J: first published as 10.1136/postgradmedj-2021-140287 on 8 June 2021. Downloaded from Sofosbuvir with daclatasvir and the outcomes of patients with COVID-19: a systematic review and meta- analysis with GRADE assessment Ahmad Fariz Malvi Zamzam Zein ,1,2 Catur Setiya Sulistiyana,1,2 Wilson Matthew Raffaello,3 Arief Wibowo,4 Raymond Pranata 3,4 1Department of Internal ABSTRACT indicate the potential activities of SOF and DCV on 9 10 Medicine, Faculty of Medicine Purpose This systematic review and meta- analysis SARS- CoV-2 RdRp, although the mixed results. Universitas Swadaya Gunung aimed to evaluate the effect of sofosbuvir/daclatasvir Several clinical studies indicate the potential benefit Jati, Cirebon, Indonesia 9 11 12 2Department of Internal (SOF/DCV) on mortality, the need for intensive care unit of SOF/DCV in patients with COVID-19. Medicine, Waled General (ICU) admission or invasive mechanical ventilation (IMV) These drugs have relatively mild side effects and are Hospital, Cirebon, Indonesia affordable. Thus, it can be used as a routine treat- 3 and clinical recovery in patients with COVID-19. Faculty of Medicine Universitas 9 13 Methods We performed a systematic literature ment if proven to be effective. This systematic Pelita Harapan, Tangerang, Indonesia search through the PubMed, Scopus and Embase review and meta- analysis aims to evaluate the effect 4Department of Cardiology from the inception of databases until 6 April 2021. of SOF/DCV on mortality, the need for intensive and Vascular Medicine, Faculty The intervention group was SOF/DCV, and the control care unit (ICU) admission or invasive mechanical of Medicine Universitas group was standard of care. The primary outcome was ventilation (IMV) and clinical recovery in patients Padjadjaran, Rumah Sakit with COVID-19. Umum Pusat Hasan Sadikin, mortality, defined as clinically validated death. The Bandung, Jawa Barat, Indonesia secondary outcomes were (1) the need for ICU admission or IMV and (2) clinical recovery. The pooled effect MATERIALS AND METHODS Correspondence to estimates were reported as risk ratios (RRs). This is a Preferred Reporting Items for Systematic Dr Ahmad Fariz Malvi Zamzam Results There were four studies with a total of 231 Reviews and Meta- Analyses compliant systematic Zein, Universitas Swadaya patients in this meta-analysis . Three studies were review and meta- analysis. This study is registered in Gunung Jati, Cirebon 45132, Indonesia; randomised controlled trial, and one study was non- PROSPERO (blinded for peer review). fariz_ zein_ dr@ yahoo. com randomised. SOF/DCV was associated with lower 2 mortality (RR: 0.31 (0.12, 0.78); p=0.013; I : 0%) and Search strategy and study selection Received 12 April 2021 reduced need for ICU admission or IMV (RR: 0.35 (0.18, We performed a systematic literature search 2 Accepted 21 May 2021 0.69); p=0.002; I : 0%). Clinical recovery was achieved through PubMed, Scopus and Embase using the more frequently in the SOF/DCV (RR: 1.20 (1.04, 1.37); terms ‘(SARS- CoV-2 or 2019- nCoV or COVID-19) 2 p=0.011; I : 21.1%). There was a moderate certainty of and (sofosbuvir or daclatasvir or Sofosbuvir/daclat- evidence for mortality and need for ICU/IMV outcome, asvir)’ from the inception of databases until 6 April http://pmj.bmj.com/ and a low certainty of evidence for clinical recovery. The 2021. Screening of title/abstracts were performed absolute risk reductions were 140 fewer per 1000 for by two independent authors. The eligibility of the mortality and 186 fewer per 1000 for the need for ICU/ articles was assessed based on the inclusion and IMV. The increase in clinical recovery was 146 more per exclusion criteria. Discrepancies that arose were 1000. resolved by discussion. Conclusion SOF/DCV may reduce mortality rate and need for ICU/IMV in patients with COVID-19 while Inclusion and exclusion criteria on September 27, 2021 by guest. Protected copyright. increasing the chance for clinical recovery. Studies that match the following criteria were Protocol registration PROSPERO: CRD42021247510. included: (1) randomised controlled trials (RCTs) or observational studies in patients with COVID- 19, (2) comprise of SOF/DCV arm and a control INTRODUCTION arm and (3) reporting either (a) mortality or (b) COVID-19 remains one of the most prevalent the need for ICU admission or IMV or (c) clinical diseases globally despite the best effort to contain recovery. them.1 Although most patients have mild–moderate Studies that match one of the following criteria © Author(s) (or their clinical symptoms, a significant proportion of them were excluded: (1) conference papers, (2) abstract- employer(s)) 2021. No developed lethal acute complications.2–4 Optimal only publications, (3) review articles and (4) commercial re- use. See rights medications for COVID-19 remained poorly commentaries. We did not impose any language and permissions. Published restriction for this systematic review. by BMJ. defined, and many completed trials showed nega- tive results.5 To cite: Zein AFMZ, SARS- CoV-2 is a positive- sense single- stranded Data extraction Sulistiyana CS, Raffaello WM, RNA virus that relies on RNA- dependent RNA- Two authors independently extracted data from the et al. Postgrad Med J Epub 6 ahead of print: [please polymerase (RdRp) for viral replication. Sofos- studies for the first author, study design, country include Day Month Year]. buvir/daclatasvir (SOF/DCV) is a direct-acting of origin, setting of the study (inpatients or outpa- doi:10.1136/ antiviral drug that has been shown to inhibit RdRp tients), details and dosing of the intervention group, postgradmedj-2021-140287 of hepatitis C virus (HCV).7 8 Preclinical studies details and dosing of the control group, sample size, Zein AFMZ, et al. Postgrad Med J 2021;0:1–6. doi:10.1136/postgradmedj-2021-140287 1 Original research Postgrad Med J: first published as 10.1136/postgradmedj-2021-140287 on 8 June 2021. Downloaded from age, gender, diabetes, chronic obstructive pulmonary disease, Statistical analysis chronic kidney diseases, cardiovascular diseases and the labo- DerSimonian Laird random- effects meta- analysis was used to ratory values, including haematology parameters and liver and calculate the pooled RRs for mortality, need for ICU admis- renal functions. Discrepancies were resolved by discussion. sion/IMV and clinical recovery in the SOF/DCV compared with the control group. P values (two- tailed) of ≤0.05 were consid- Risk of bias assessment ered statistically significant. To evaluate heterogeneity, we used We used the Cochrane Risk of Bias Assessment for RCTs14 and Cochran’s Q test and I2 statistics; I2 values above 50% and p Newcastle- Ottawa Scale (NOS).15 NOS comprises of selection, value below 0.10 indicate significant heterogeneity. Sensitivity comparability and outcome. Cochrane Risk of Bias Assessment analysis was performed for outpatient studies. STATA V.16.0 assessed the possibility for selection, performance, detection, was used to perform the statistical analysis. attrition, selective reporting and other biases. Discrepancies during the process were resolved by discussion. Grading of Recommendations Assessment, Development and Evaluation RESULTS framework was used to determine the certainty of evidence. Baseline characteristics There were four studies with a total of 231 patients in this Intervention and outcome systematic review and meta- analysis (figure 1).9 11 12 16 Three The intervention group was SOF/DCV, defined as 400 mg SOF studies were RCT, and one study was non- randomised (table 1). and 60 mg DCV to treat COVID-19. The control group was the standard of care or placebo set by each trial/studies. The primary outcome was mortality, defined as clinically validated death. SOF/DCV and outcomes The pooled effect estimate was reported as risk ratio (RR). SOF/DCV administration was associated with reduced mortality 2 The secondary outcomes were (1) the need for ICU admission (RR: 0.31 (0.12, 0.78)], p=0.013; I : 0%, p=0.400) (figure 2). or IMV and (2) clinical recovery. Clinical recovery was defined Use of SOF/DCV was associated with reduced need for ICU 2 as resolution of fever (≤37.2°C) with a normal respiratory rate admission or IMV (RR: 0.35 (0.18, 0.69), p=0.002; I : 0%, (≤24 breaths/min) and oxygen saturation (≥94%) without the p=0.700) (figure 3). Clinical recovery was achieved more need for supplementary oxygen therapy for at least 24 hours or frequently in the SOF/DCV (RR: 1.20 (1.04, 1.37), p=0.011; I2: can be discharged from the hospital based on clinical improve- 21.1%, p=0.284) (figure 4). Sensitivity analysis by removal of ment. The pooled effect estimate was reported as RRs. outpatient setting (Roozbeh et al16 2021) showed that SOF/DCV http://pmj.bmj.com/ on September 27, 2021 by guest. Protected copyright. Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart. 2 Zein AFMZ, et al. Postgrad Med J 2021;0:1–6. doi:10.1136/postgradmedj-2021-140287 Original research Postgrad Med J: first published as 10.1136/postgradmedj-2021-140287 on 8 June 2021. Downloaded from Table 1 Baseline characteristics of the included studies Eslami et al11 2020 Abbaspour Kasgari et al12 2020 Roozbeh et al16 2021 Sadeghi et al9 2020 Study design Open- label parallel RCT RCT RCT Trial registration number IRCT20200324046850N2 IRCT20200328046886N1 IRCT20200403046926N1 IRCT20200128046294N2 Country of origin Iran Iran Iran Iran Setting Inpatients Inpatients Outpatients Inpatients COVID-19 severity Severe