Evaluating the Suitability of Dengue Viraemia as a Surrogate Efficacy Outcome for Phase III Trials of Dengue Antivirals: A Systematic Review

Background: Dengue cases reached record levels in 2024 alongside geographic expansion into Europe and Africa. The low rate of progression to severe dengue presents a challenge for powering phase III dengue antiviral trials. Viraemia is used as a virological outcome in phase II trials, but whether treatment-induced reductions reliably predict clinical benefit remains uncertain. This systematic review assessed the association between dengue viraemia and disease severity and its suitability as a surrogate efficacy outcome for phase III antiviral trials. Methods: We searched Ovid MEDLINE, Ovid Embase, Scopus, and Web of Science on 20 June 2025 for studies indexed since 2017, extending a previous systematic review. We included clinical studies of laboratory-confirmed dengue measuring quantitative serum viral load by RT-PCR at enrolment and at least one subsequent timepoint and reporting severe dengue as a clinical outcome. The review was registered with PROSPERO (CRD420251077148) and followed PRISMA 2020 reporting guidelines. Results: We screened 3303 records and reviewed 60 full texts; 11 studies met the inclusion criteria, comprising predominantly hospitalised paediatric and younger adult cohorts from the Asia-Pacific. Seven studies reported higher early viraemia (typically during illness days 1– 5) in patients with more severe disease, whereas three found no significant association and one provided insufficient evidence. Two studies assessing viraemia kinetics found that faster viral clearance was associated with lower risk of severe dengue. Heterogeneity in sampling timing, severity classification, and adjustment for host and viral factors limited interpretation. Certainty of evidence was very low. Conclusions: Evidence for an association between dengue viraemia and disease severity was inconsistent and limited by methodological heterogeneity. Most studies assessed severity around the time of hospital admission and could not establish if viraemia predicted subsequent progression from non-severe to severe disease. None were designed to determine whether treatment-induced reductions in viraemia translate into clinical benefit. Dengue viraemia should therefore be regarded as a pharmacodynamic biomarker and supportive virological outcome for early-phase antiviral development, rather than as a validated surrogate efficacy outcome for phase III trials, for which clinically meaningful patient-centred outcomes remain necessary.