Abstract
BACKGROUND: Pharmacological treatments for COVID-19 remain limited, particularly for severe outcomes. Tenofovir, an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), has been proposed as a therapeutic agent to reduce hospitalization, intensive care unit (ICU) admissions, and mortality. OBJECTIVE: To assess the efficacy of tenofovir in COVID-19 patients based on randomized controlled trials (RCTs). METHODS: A systematic review of RCTs assessing tenofovir in COVID-19 was conducted. Searches in PubMed/MEDLINE, Scopus, Cochrane Library, LILACS, SciELO, and COVID-19 LOVE databases were last updated on April 16, 2025. Risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. As a meta-analysis was not feasible, a qualitative analysis was performed. The review protocol was registered in PROSPERO (CRD42023465336). RESULTS: Among 1241 retrieved trials, three met the inclusion criteria. These trials, conducted in 32 hospitals across Colombia, Spain and Iran included 1048 patients. In the Colombian study, the combination of tenofovir disoproxil/emtricitabine with colchicine and rosuvastatin was associated with reduced 28-day mortality (risk difference [RD] = -0.05; 95% CI: -0.07 to -0.04) and lower need for invasive mechanical ventilation (RD = -0.08; 95% CI: -0.11 to -0.04). However, randomization bias and small sample size limit the interpretation of these results. Conversely, the Spanish study was classified as having a low risk of bias, but found no significant benefit of tenofovir disoproxil/emtricitabine in reducing 28-day mortality (risk ratio [RR] = 1.76; 95% CI: 0.52 to 5.91) or for the composite outcome of ICU admission, disease progression, and mortality (RR = 0.95; 95% CI: 0.66 to 1.40). The Iranian study, in turn, demonstrated that tenofovir alafenamide, when combined with standard treatment, significantly reduced the need for mechanical ventilation (0.0% vs. 13.3%, p = 0.038) and ICU length of stay (3.3 days vs. 14.5 days; p = 0.04). However, the presence of a high risk of bias, with major concerns regarding co-interventions and statistical analyses, precludes a definitive conclusion regarding these results. CONCLUSIONS: This review identified three clinical trials evaluating the efficacy of tenofovir in COVID-19, with conflicting results. One study suggested a potential benefit in reducing mortality and the need for invasive mechanical ventilation in mild to moderate cases but methodological limitations, including risk of bias and small sample size, weaken its conclusions. The second study found no significant impact on mortality or disease progression. In the third study, no deaths were reported, but he significant reduction in the need for mechanical ventilation and ICU length of stay is extremely limited due to the high risk of bias. Given these inconsistencies and the limitations of available evidence, tenofovir cannot be recommended for COVID-19 treatment.