Efficacy and safety of Ensitrelvir in asymptomatic or mild to moderate COVID-19: a systematic review and meta-analysis of randomized controlled trials

DOI record: { "DOI": "10.1007/s15010-025-02582-0", "ISSN": [ "0300-8126", "1439-0973" ], "URL": "http://dx.doi.org/10.1007/s15010-025-02582-0", "abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Introduction</jats:title>\n <jats:p>Since late 2019, COVID-19 has had a catastrophic impact on public health. Ensitrelvir, a new antiviral targeting the SARS-CoV-2 main protease, has reduced viral replication and disease severity. This meta-analysis and systematic review assessed Ensitrelvir’s efficacy and safety in patients with mild-to-moderate COVID-19 symptoms.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>A comprehensive search was conducted in PubMed (Medline), Scopus, Embase, and CENTRAL up to July 2024 to retrieve randomized controlled trials (RCTs) comparing Ensitrelvir to placebo in adults with mild to moderate, RT-PCR–confirmed COVID-19. Outcomes were assessed at standardized time points, with viral RNA measured at day 4. Mean differences (MD) for continuous outcomes and risk ratios (RR) for binary outcomes, both with 95% confidence intervals (CIs), were calculated using the Mantel–Haenszel random-effects model. Efficacy outcomes included SARS-CoV-2 viral RNA, while safety outcomes included HDL, triglycerides, bilirubin, AST, headache, diarrhea, TEAEs, TRAEs, serious TEAEs, and treatment discontinuation. The quality of the included RCTs was assessed with the Cochrane Risk of Bias 2 (ROB2) tool.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>The analysis included six RCTs with 2,793 participants: 1,860 received Ensitrelvir and 933 were given a placebo. Ensitrelvir gave significant results for reduced viral RNA levels of SARS-CoV-2 [MD: − 1.35; 95% CI − 1.58 to − 1.13; p &lt; 0.01] and the incidence of lower cholesterol levels [RR: 8.83; 95% CI 4.05 to 19.27; p &lt; 0.01] compared to the placebo group. However, it was associated with increased risks of decreased HDL levels, elevated triglycerides, increased bilirubin, more headaches, and a higher overall occurrence of treatment-emergent adverse events.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusion</jats:title>\n <jats:p>Ensitrelvir effectively reduces viral load in COVID-19 patients, but its safety profile raises concerns due to significant adverse effects. The benefits must be carefully weighed against the risks, and further research is needed to confirm its role in treatment and to find ways to mitigate these adverse effects.</jats:p>\n </jats:sec>", "alternative-id": [ "2582" ], "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "9 March 2025" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "5 June 2025" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "31 July 2025" }, { "group": { "label": "Declarations", "name": "EthicsHeading" }, "name": "Ethics", "order": 1 }, { "group": { "label": "Conflict of interest", "name": "EthicsHeading" }, "name": "Ethics", "order": 2, "value": "The authors declare no conflicts of interest." }, { "group": { "label": "Ethical compliance", "name": "EthicsHeading" }, "name": "Ethics", "order": 3, "value": "No ethical approval was required for this study design, as all data were obtained from publicly available sources." } ], "author": [ { "affiliation": [], "family": "Ul Haq", "given": "Muhammad Zain", "sequence": "first" }, { "affiliation": [], "family": "Ashraf", "given": "Saad", "sequence": "additional" }, { "affiliation": [], "family": "Shah", "given": "Muhammad Shahmeer Ullah", "sequence": "additional" }, { "affiliation": [], "family": "Sulaiman", "given": "Samia Aziz", "sequence": "additional" }, { "affiliation": [], "family": "Shaukat", "given": "Ayesha", "sequence": "additional" }, { "affiliation": [], "family": "Ansari", "given": "Muhammad Ahsan", "sequence": "additional" }, { "affiliation": [], "family": "Basaria", "given": "Areeba Aamir Ali", "sequence": "additional" }, { "affiliation": [], "family": "Fatima", "given": "Laveeza", "sequence": "additional" }, { "affiliation": [], "family": "Saeed", "given": "Humza", "sequence": "additional" }, { "affiliation": [], "family": "Goyal", "given": "Aman", "sequence": "additional" }, { "affiliation": [], "family": "Daoud", "given": "Mohamed", "sequence": "additional" } ], "container-title": "Infection", "container-title-short": "Infection", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2025, 7, 31 ] ], "date-time": "2025-07-31T06:34:10Z", "timestamp": 1753943650000 }, "deposited": { "date-parts": [ [ 2025, 7, 31 ] ], "date-time": "2025-07-31T06:34:14Z", "timestamp": 1753943654000 }, "indexed": { "date-parts": [ [ 2025, 7, 31 ] ], "date-time": "2025-07-31T07:10:03Z", "timestamp": 1753945803768, "version": "3.41.2" }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2025, 7, 31 ] ] }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 7, 31 ] ], "date-time": "2025-07-31T00:00:00Z", "timestamp": 1753920000000 } }, { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 7, 31 ] ], "date-time": "2025-07-31T00:00:00Z", "timestamp": 1753920000000 } } ], "link": [ { "URL": "https://link.springer.com/content/pdf/10.1007/s15010-025-02582-0.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/article/10.1007/s15010-025-02582-0/fulltext.html", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/content/pdf/10.1007/s15010-025-02582-0.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1007", "published": { "date-parts": [ [ 2025, 7, 31 ] ] }, "published-online": { "date-parts": [ [ 2025, 7, 31 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.1038/s41586-020-2012-7", "author": "P Zhou", "doi-asserted-by": "publisher", "first-page": "270", "issue": "7798", "journal-title": "Nature", "key": "2582_CR1", "unstructured": "Zhou P, Yang XL, Wang XG, et al. 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