https://orcid.org/0009-0002-1916-2678
Figures
Abstract
Background
Dengue is a growing public health threat with increasing case numbers globally. Despite the substantial burden, there are no licensed therapeutics for patients with dengue. To inform the design of large-scale practice-changing clinical trials and to assess the feasibility of an individual patient data platform for meta-analysis, we conducted a systematic mapping review of clinical trials evaluating dengue therapeutics. Our aims were to characterise published and registered dengue therapeutic trials, describe their endpoints, and assess study design quality and internal validity to inform feasibility of meta-analysis and future research.
Methods
We systematically searched Ovid MEDLINE, Ovid EMBASE, WHO ICTRP and ClinicalTrials.gov for prospective clinical trials evaluating therapeutics in patients with symptomatic dengue. Two independent reviewers screened records using Covidence. Data were extracted into a REDCap database, and risk of bias was assessed using the ROB-2 and ROBINS-I tools to describe trial design rigour. Descriptive analyses summarised the interventions, trial characteristics, study populations, and primary endpoints. This systematic review was pre-registered with PROSPERO (CRD42023469022).
Results & discussion
A total of 121 clinical studies were identified, comprising 72 published trials and 49 registered but unpublished studies. Interventions were categorised according to the authors’ proposed mechanism of action: antiviral (n = 10), host-directed (HDT, n = 34), supportive (n = 31), or undefined (n = 46). Aside from the studies of supportive therapies (n = 31) and unpublished studies (n = 37) which were only reviewed for their primary outcomes, 53 publications remained for review of therapeutic efficacy. Methodological concerns were common – 24 of 53 published trials (45%) were classified as having high or critical risk of bias. Corticosteroids were the most frequently evaluated intervention, involving a total of 944 randomised patients. The primary endpoints used in both antiviral and HDT trials were highly heterogeneous, limiting comparability. The combination of methodological concerns and non-standardised endpoints precluded meta-analysis for any intervention. No single treatment had sufficient or consistent evidence to support recommendations for use in clinical practice.
Conclusions
Our findings highlight a remarkably sparse evidence base for dengue therapeutics and a lack of standardised, clinically meaningful endpoints. These factors have hindered progress in evaluating candidate treatments and limited the potential for individual patient data meta-analyses. Large, high-quality trials - powered for harmonised and clinically relevant endpoints - are urgently needed to advance the development of effective therapies for dengue.
Author summary
Dengue is a viral infection spread by mosquitoes that causes approximately 100 million symptomatic cases worldwide each year. Despite this growing global burden, there are still no approved drugs to treat the virus itself or the inflammation it causes in the body. To assess the current state of treatment options and guide future research, we systematically reviewed all clinical trials that have tested potential treatments for dengue. We also looked at whether data from past studies could be combined to reveal new insights. We identified 121 studies covering diverse treatments. The overall quality of the studies were low. Most were small, early-phase trials using inconsistent methods, which made it impossible to combine results in a meaningful way or draw firm conclusions about effectiveness. No treatment had enough consistent evidence to recommend for clinical use. Our findings show that research on dengue therapeutics has been fragmented, underpowered, and limited by non-standardised outcomes. Moving forward, the dengue research community needs to coordinate large, standardized trials. By harmonizing how we measure success, researchers can generate the robust evidence needed to improve patient care.
Citation: Huyen TB, McBride A, Thein T-L, Le KM, Luu T, Huy NQ, et al. (2026) A systematic mapping review of therapeutic clinical trials in dengue. PLoS Negl Trop Dis 20(6): e0014382. https://doi.org/10.1371/journal.pntd.0014382
Editor: Kentaro Iwata, Kobe University, JAPAN
Received: December 29, 2025; Accepted: May 14, 2026; Published: June 5, 2026
Copyright: © 2026 Huyen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The extracted data have been included in supplementary information (S2 Data).
Funding: JC received a University of Oxford - Medical Research Council Doctoral Training Partnership [MR/W006731/1]. DM reports received grants from the Bill and Melinda Gates Foundation [INV-063472]. PKL received funding from the National Research Foundation, Singapore [SG Academies South-East Asia Fellowship (SASEAF) Programme]. TBH received funding from the Wellcome Trust core grant at OUCRU Vietnam [106680]. SY received funding from the Wellcome Trust [223004]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I have read the journal’s policy and the authors of the manuscript have the following competing interests: DM acknowledges a leadership role in the DEN-CORE project that developed core outcome measurement set for dengue clinical trials. SY serves on the scientific committee for the Takeda dengue vaccine program and has participated in an advisory board for Novartis, for which she has received consulting fees. She is also Chair of the DSMB for a Phase 2 antiviral trial conducted by Novartis.
Background
Dengue is an arboviral infection of major public health importance, with an estimated 96 million symptomatic infections globally each year [1]. The rise in cases over the past three decades has been driven by urbanisation, human mobility and climate change [2,3]. Climate change is lengthening transmission seasons in endemic regions, driving expansion of the mosquito vector to altitudes and latitudes where sustained transmission was not previously reported, and rendering new populations susceptible to infection [2,4]. In endemic countries within Asia and Latin America, dengue is one of the leading causes of hospital admission and outbreaks regularly overwhelm health systems. While most clinical cases of dengue resolve within 10 days, 25–40% of patients require hospital admission for monitoring, and 5–10% of hospitalised patients develop severe manifestations including shock, bleeding and organ impairment [5–7]. Despite the considerable public health burden, there are currently no licensed therapies, and treatment is limited to supportive care only.
The therapeutic goal for early dengue is to prevent the development of more severe manifestations necessitating hospitalisation, while treatment of severe dengue aims to prevent worsening of organ failure and death. Studies on the pathogenesis of dengue have highlighted two major potential therapeutic strategies: antiviral agents and host-directed therapeutics (HDTs). Viraemia peaks early in the illness (day 2–3) whereas severe manifestations occur later (days 4–6). Higher viral densities in blood and slower clearance of virus are both associated with more severe outcomes [8,9], raising the hypothesis that an effective antiviral administered during the early phase of illness may reduce progression to severe disease. HDTs may have a role in reducing progression to severe disease in those at highest risk, or improving outcomes in those with established severe disease. Accumulating evidence suggests that immunopathogenesis is a major driver of severe disease; higher inflammatory biomarkers in early symptomatic dengue are associated with progression to severe disease, and a hyperinflammatory phenotype in established severe dengue is associated with poor clinical outcomes, including death [10–13]. In addition to immunomodulation, HDT targeting endothelial hyperpermeability may have a role in ameliorating vascular leakage to reduce shock and respiratory distress.
The aims of this systematic mapping review were to characterise published and registered dengue therapeutic trials, describe their endpoints, and assess study design quality and internal validity to inform feasibility of meta-analysis. Our goal is to use the results to prioritise therapeutics for upcoming adequately powered platform trials evaluating both antiviral and host-directed treatments, and contribute to the development of a consensus core outcome set for use by the dengue trials community in future clinical trials [14].
Methods
Inclusion criteria
We included prospective clinical trials of dengue treatment which met the PICO criteria specified in Table 1. The studies could be randomised controlled trials, non-randomised trials or single-arm trials of all clinical phases. Registered but unpublished clinical trials were also included.
Exclusion criteria
We excluded animal studies, trials of non-therapeutic interventions (e.g., diagnostics, vector-control, disease prevention studies etc.), pharmacokinetics and pharmacodynamics studies, human challenge studies and non-primary research studies, including post-hoc analysis, systematic reviews, meta-analyses, letters, opinions, editorials etc. We also excluded studies whose full-text or registration written in English could not be found.
Search methods for identification of studies
An information specialist (EH) searched the following databases on 02/08/2023 and updated the search in full on 24/10/2024 using the search terms and strategy described in detail in S1 File Search strategies: Ovid MEDLINE, Ovid Embase, World Health Organisation International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov. Results from both searches were incorporated in this report. Date of publication/registration was not restricted in this review. The search strategy was not restricted by the comparator to capture single-arm trials.
We imported the retrieved studies into excel sheets (for studies from WHO ICTRP) and Covidence (other databases) for screening. Pairs of assessors (TBH; TLT; NQH; LHBT and LMK) screened each study by title and abstract independently and retrieved full texts for potentially relevant trials, which were then reviewed by the same assessors in duplicate. We listed excluded studies and recorded reasons for exclusion. If new publications arising from the included trial registrations were identified during the review process, we incorporated the published full-text articles at the time of detection. We contacted trial authors for clarification where necessary and resolved any discrepancies through discussion with three of the other authors (NLV, JAW and SY).
Data extraction and analysis
Data was extracted into a structured REDCap database. Three independent reviewers (TBH, TLT, NQH) extracted summary data on therapeutics used (antiviral or host-directed interventions), the day of illness, primary outcomes, study design, participant characteristics, recruitment methods, study country, date of study publication and study results if published. We did not extract secondary/exploratory outcomes. Two reviewers extracted data from a sample of eligible studies and achieved good agreement (above 80 percent), with the remainder extracted by one reviewer. TBH, LHBT and LMK performed data cleaning.
We used descriptive analyses to summarise the characteristics of all available trials on dengue, including the number of trials, treatments/arms, study populations, methods, main findings and the primary outcomes used. We chose not to carry out aggregate meta-analysis or effect estimation due to insufficient numbers of trials/patients for individual interventions, disparate endpoints, and concerns about methodological quality for many studies. Corticosteroids and Carica papaya leaf extract (CPLE, of variable regimens) were the most frequently studied interventions; given that recent meta-analyses already exist for these agents [15,16] and our search found no new high-quality trials to add, we did not perform an updated analysis.
Risk of bias assessment
For studies evaluating the efficacy of proposed antiviral or HDT in dengue, we assessed the risk of bias using the revised Cochrane risk of bias tools: RoB-2 version 22Aug2019 [17] for randomised trials and ROBINS-I for non-randomised studies of interventions; risk of bias assessments were primarily undertaken to systematically describe trial design rigour and assess feasibility for future data synthesis, not to support conclusions on treatment effect. We followed the Cochrane Handbook for Systematic Reviews of Interventions [18] to assess whether adequate steps had been taken to reduce the risk of bias across five domains: bias arising from the randomisation process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome and in selection of the reported result. We categorised the risk of bias as ‘high’, ‘some concerns’, or ‘low’ for randomised trials and ‘critical’, ‘serious’, ‘moderate’ or ‘low’ for non-randomised studies of interventions. For the three most frequently evaluated interventions (corticosteroids, Carica papaya leaf extract and montelukast), two reviewers (of TBH, LMK and LHBT) independently assessed the risk of bias for each study; discrepancies were resolved through discussion with PKL. For the remaining 29 studies, one reviewer assessed the risk of bias. Another independent reviewer (NLV) randomly checked 25% of these assessments (8 studies) to detect discrepancies.
Results
The search identified 7982 studies, of which 121 were included in this review; 72 were full-text publications and 49 were study registrations pending results, see Fig 1. The included trials were categorised into four groups based on the authors’ proposed mechanism of action: antiviral (n = 10), HDT (n = 34), supportive (n = 31), and undefined (n = 46). The 31 studies which evaluated supportive treatment for dengue (mostly fluid regimens and platelet transfusion) were only reviewed for primary endpoints. The remaining 90 trials were reviewed in full.
Overview of dengue therapeutic trials
Sample size of the included trials (the total number of participants enrolled in published studies and the planned sample sizes for unpublished trial registrations) are presented in Fig 2 - by country and region and in Fig 3 – by individual intervention. Most studies were conducted in South and Southeast Asia, with a few in Latin America. Only 11 of 72 (15.3%) published studies and 11 of 49 (22.4%) trial registrations had an actual or planned sample size of at least 250 participants.
After excluding supportive therapies, corticosteroids and Carica papaya leaf extract (CPLE) were the most frequently evaluated interventions, enrolling the largest number of participants (n = 944 and n = 920, respectively) and appearing in the greatest number of publications (n = 9 and n = 7, respectively). CPLE also had the highest number of trial registrations (n = 7), the majority from India, followed by vitamins C and D (n = 3 registrations each). The remaining 53 compounds were investigated in only one to three studies each.
With respect to age groups, children were the predominant participants in trials of supportive therapies and corticosteroids, but were under-represented in studies of other HDT, micronutrients and miscellaneous therapies (S1 Fig). No antiviral trials included paediatric participants.
Trials evaluating antivirals for dengue
We identified five published randomised, placebo-controlled clinical trials evaluating four repurposed agents with proposed antiviral activity against dengue: two trials evaluated the antiparasitic drug ivermectin [19], one evaluated chloroquine [20], and two investigated antiviral compounds originally developed for hepatitis C virus - celgosivir and balapiravir [21,22] (Table 2). None of these studies included participants under 15 years of age. No trial demonstrated a statistically significant difference in predefined virological or clinical outcomes between intervention and placebo groups. All but one of the studies were assessed as having a low risk of bias (Table 2 and S1 Table).
Review of WHO ICTRP and ClinicalTrials.gov identified five additional clinical trials that have either not yet concluded or have not published results. Two phase 2 trials - of AT-752, a nucleotide prodrug inhibitor of DENV polymerase (Clinicaltrials.gov: NCT05466240, Atea Pharmaceuticals, Inc) and JNJ-64281802, an NS3-NS4B inhibitor (Clinicaltrials.gov: NCT04906980, Janssen Research and Development) - were both terminated early due to recruitment challenges and sponsors’ decisions to deprioritise dengue research. A phase 2 trial of EYU688, an NS4B inhibitor (Clinicaltrials.gov: NCT060066559, Novartis Pharmaceuticals) is ongoing. A phase 2 dose-ranging trial of Dengue Monoclonal antibody (Clinical Trials Registry India: CTRI/2021/07/035290, Serum Institute of India) has completed, with publication pending. An adaptive phase 2 trial evaluating Dengue Monoclonal antibody and molnupiravir versus standard of care in early symptomatic dengue is registered but not yet recruiting (Clinicaltrials.gov: NCT06551844). All five registrations plan to enrol adult participants only.
Trials evaluating host-directed therapy for dengue
We identified 34 trials of therapeutic agents with proposed host-directed mechanisms of action.
Trials evaluating corticosteroids.
We identified nine completed trials evaluating oral or intravenous corticosteroid therapy in dengue of any severity, enrolling a total of 944 patients (329 with severe dengue, 290 with moderate disease, and 325 with early symptomatic dengue) (Table 3). The trials varied across several key parameters, including preparation, dose, duration, patient population (by age and disease severity), and primary outcomes. All were assessed as having either some concerns or a high risk of bias (Table 3 and S1 Table). An additional registered trial aims to evaluate dexamethasone in severe dengue (dose and duration not specified), but results have not been published.
Four randomised trials investigated the impact of corticosteroids on mortality in children with dengue shock, assessing different corticosteroid agents, doses and treatment durations. Sumarmo et al investigated a single dose of hydrocortisone [24], Tassniyom et al investigated a single dose of methylprednisolone [25] and two trials conducted in the 1970’s [26,27] evaluated hydrocortisone for either three days or an unspecified duration. Each trial enrolled fewer than 100 paediatric patients, and none included adults. Three studies found no difference in mortality, while Min et al reported lower mortality among patients receiving hydrocortisone [26]. However, all four trials raised concerns regarding risk of bias due to unclear allocation methods, and open-label or unspecified blinding (Table 3 and S1 Table). Interpretation of the findings by Min et al is limited by the absence of baseline data on disease severity and key prognostic factors such as shock duration, comorbidities, and organ dysfunction.
Three randomised controlled trials have evaluated corticosteroids in adults with non-severe dengue and thrombocytopaenia, with different doses and duration [28–30]. All measured changes in platelet count as the primary endpoint. None demonstrated a significant difference in platelet recovery between corticosteroid and placebo groups, except for one very small study assessed as having high risk of bias [30].
Two trials evaluated corticosteroids in early, uncomplicated dengue [31,32]. Tam et al evaluated low-dose and high-dose oral prednisolone administered within three days of illness onset, and found no significant difference in pre-defined clinical, haematological or virological outcomes (Table 3 and S1 Table). The remaining study was assessed as having high risk of bias.
Taken together, the available evidence is insufficient to draw conclusions regarding the impact of corticosteroid therapy on mortality in dengue shock, platelet recovery in dengue with thrombocytopaenia, or clinical and virological outcomes in early symptomatic dengue.
Trials evaluating other host-directed therapeutics.
We identified 19 published studies evaluating a range of other host-directed therapies (HDTs) in patients with dengue. These included three trials of doxycycline; two each of montelukast, rupatadine and interleukin-11; and one each of carbazochrome sodium sulfonate (AC-17), intravenous immunoglobulin, colchicine, pentoxifylline, chloroquine, lovastatin, anti-D immunoglobulin, eltrombopag, oseltamivir and metformin. In addition, we identified five registered trials, each investigating zanamivir, anakinra, eltrombopag, ketotifen or doxycycline (Table 4).
Among therapies proposed to attenuate endothelial dysfunction, Malavige et al reported two trials of the platelet-activating factor receptor inhibitor rupatadine in patients with non-severe dengue; treatment did not significantly reduce the proportion developing pleural effusion, ascites or dengue haemorrhagic fever [33,34]. Whitehorn et al evaluated the safety of lovastatin in early symptomatic dengue; although the study was not powered for clinical outcomes, there were no differences in time to fever clearance or progression to severe disease between treatment and placebo groups [35]. Nitinai et al found that the leukotriene receptor antagonist montelukast did not reduce the incidence of dengue warning signs [36]. Tunjungputri et al reported that the sialidase inhibitor oseltamivir did not reduce plasma leakage, time to platelet recovery or hospital discharge [37]. Salgado et al found that pentoxifylline infusion did not reduce mortality, duration of intensive care or hospital admission in children with DHF [38]. Tassniyom et al evaluated the proposed anti-permeability compound carbazochrome sodium sulfonate in children with DHF/DSS and found no difference in the proportion developing shock or pleural effusion between intervention and placebo groups [39]. We noted some concerns regarding risk of bias in the latter three publications.
Pannu et al reported that among Rhesus-positive patients with dengue and severe thrombocytopaenia, those who received anti-D immunoglobulin were more likely to achieve platelet counts above 50 G/L within 48 hours of the intervention than controls [40]. Chakraborty et al reported that a higher proportion of participants receiving a single dose of the thrombopoietin receptor antagonist eltrombopag had platelet counts above 150 G/L by day 7 after starting treatment, compared with the control group [41]. A phase III trial evaluating eltrombopag in 300 patients with dengue with warning signs is currently recruiting (SLCTR/2022/023). Nguyen et al reported that treatment with metformin had no effect on clinical or virological outcomes in overweight patients with dengue, and was poorly tolerated due to gastrointestinal side effects, making it unsuitable for further evaluation [42]. The remaining studies were assessed as being at high or critical risk of bias [43–50].
Trials evaluating interventions with unclear mechanism(s) of action
Despite uncertain mechanisms of action, there has been considerable interest in Carica papaya leaf extract (CPLE), micronutrient supplementation, and other herbal preparations for dengue treatment. These accounted for 46 of the 89 studies identified. Table 5 summarises trials evaluating CPLE, while Table 6 presents studies of micronutrient supplementation and other interventions for which the proposed mechanism of action was not clearly specified by the investigators.
Trials evaluating Carica papaya leaf extract.
We identified 14 studies evaluating CPLE, of which seven full-text articles were available, enrolling a total of 829 participants (Table 5 and S1 Table). The studies used varying formulations and extractions, including commercially produced Caripill tablets or syrup (Micro Labs, Bengaluru), and preparations made from fresh leaves, precluding comparison of dosing between studies. Measured outcomes related to platelet recovery for all studies.
Subenthiran et al, the largest published trial (n = 290), reported higher platelet counts at 48 hours post-intervention in the CPLE group compared with controls [51]. However, the magnitude of this difference was small (69.5 vs 79.6 G/L at 48 hours) and we had some concerns regarding risk of bias from missing outcome data in the publication. The remaining six publications also reported efficacy measured by platelet count improvement, however, they were either very small trials or were assessed as being at high or critical risk of bias [52–57]. Taken together, there is insufficient high-quality evidence that CPLE improves clinical outcomes in dengue.
We also identified seven unpublished trials registered between 2014 and 2019 evaluating CPLE. Most examined platelet recovery as the primary endpoint, while one aimed to assess plasma leakage (SLCTR/2017/034). We were unable to confirm the current status of these trials.
Trials evaluating micronutrient supplementation.
We identified six published studies evaluating oral micronutrient supplementation in patients with dengue: three evaluated vitamin E, two Vitamin C, and one each zinc and calcium carbonate (Table 6). The proposed mechanisms of action, and rationale for the selected primary outcomes were not clearly described. Among the vitamin E trials, both Mittal et al and Vaish et al reported higher platelet counts in participants receiving vitamin E compared to controls, but we had some concerns regarding risk of bias for both studies [58,59]. Mittal et al also reported higher platelet counts in participants receiving vitamin C supplementation versus placebo; however, the vitamin doses were not specified. Rerksuppaphol et al, whose trial was assessed as having low risk of bias, found no difference in time to defervescence between children with dengue who received zinc for 5 days and those given placebo [60]. The remaining studies were assessed as being at high or critical risk of bias [61–63] (Table 6 and S1 Table). Overall, there is insufficient evidence to draw conclusions on the efficacy of vitamin E, vitamin C, zinc or calcium carbonate supplementation in dengue virus infection.
Miscellaneous studies.
Seven publications evaluated miscellaneous or unspecified compounds (Table 6 and S1 Table). We had some concerns regarding risk of bias in one study evaluating Propoelix [64]; the remaining studies were assessed as being at high or critical risk of bias [65–70]. There is no high-quality evidence that any of these compounds provide clinical benefit in dengue virus infection.
Patient endpoints
The primary endpoints used in dengue therapeutic trials showed high heterogeneity (Figs 4–5).
Primary endpoints used in trials of antiviral treatments.
Among interventions with a proposed antiviral mechanism of action (Table 2, n = 10), most studies (8/10) used virological outcomes based on viral kinetics as their primary endpoints (Fig 4). These included duration of detectable viraemia (2/8, 25%), change in absolute viral load (4/8, 50%), and log-transformed viral load area under the curve (AUC, 2/8, 25%). Measurement methods and time points varied between studies: one assessed infectious virus titres using the NSET assay (CTRI/2021/07/035290), while the others quantified viral RNA by RT-PCR. Two studies used time to NS1 antigen clearance as the primary endpoint, defined as the interval from treatment initiation to the first of two consecutive NS1 ELISA-negative plasma samples.
Five trials (50%) used clinical primary endpoints, although definitions differed. Two studies assessed efficacy based on fever: one measured time to fever clearance, while the other used area under the curve (AUC) for temperature above 37°C. Safety endpoints also varied, with most reporting adverse event frequency. Only one study evaluated the proportion of participants developing DHF, defined as platelet count below 100,000/mm3 and evidence of plasma leakage (≥20% rise in haematocrit from baseline or presence of pleural effusion).
Primary endpoints used in trials of host-directed therapies.
The choice of primary endpoint in trials investigating HDT (Tables 3 and 4, n = 34) was highly heterogeneous (Fig 4). Overall, platelet count – measured using various metrics - was the most frequently reported endpoint (15/34, 44%), followed by mortality (7/34, 21%), plasma leakage (5/34, 15%), adverse events (5/34, 15%), DSS (4/34, 12%) and inflammatory markers (4/34, 12%). Less commonly reported endpoints (1/34 each, 3%) included dengue with warning signs, duration of illness and hospital stay, modified Sequential Organ Failure Assessment and ICU admission. Trials enrolling adults or mixed populations (n = 27) most often used platelet-related endpoints, whereas paediatric trials (n = 7) prioritised critical outcomes like mortality and dengue shock syndrome (DSS) (Fig 5). None of the trials enrolling patients with severe dengue (n = 8) used platelet measurements as primary endpoints.
Approaches to measuring outcomes also varied substantially (Fig 5). Plasma leakage was assessed using different combinations of criteria, including the presence of pleural effusion or ascites on imaging—measured by MRI in one study and ultrasound in others—alongside increases in haematocrit or plasma biomarkers (e.g., syndecan-1). Even for laboratory-based endpoints such as platelet count, diverse summary measures were applied, including absolute or relative change, nadir value, and the proportion of participants above or below prespecified thresholds.
Primary endpoints used in trials evaluating Carica papaya leaf extract, micronutrients and ‘miscellaneous’ treatments.
The other studies (Tables 5 and 6, n = 46) also employed a wide range of primary endpoints (Fig 4). Platelet count was again the most frequently used primary endpoint (25/46, 51%). Plasma leakage, defined by various criteria on ultrasound—with or without accompanying increases in haematocrit—was assessed in 6 studies (13%). Changes in haematocrit were specifically designated as the primary outcome in 5 studies (10.8%). Time to fever resolution was used in 6 trials (13%), although definitions of this endpoint were often unclear. The remaining endpoints were used in only 1 or 2 studies and included duration of illness, serum chloride and bicarbonate levels, clotting assays, endothelial biomarkers, requirement for intravenous fluids, liver enzyme levels, respiratory rate and treatment tolerability.
Discussion
Despite the considerable morbidity and public health burden caused by dengue, this review highlights the remarkably barren treatment landscape for patients with symptomatic infection. We identified very few clinical trials evaluating therapeutics with proposed antiviral or host-directed mechanisms of action, and no single intervention had a sufficiently sized, consistent or high-quality evidence base to make recommendations for use in clinical practice. Most published studies were small, underpowered to detect clinically meaningful outcomes, and many were assessed as having a high or critical risk of bias.
Antivirals
Our review identified only five published randomised trials evaluating therapeutic agents with putative antiviral activity against dengue. All five trials evaluated repurposed therapeutics originally developed for other indications, none recruited participants under 15 years of age, and none demonstrated significant antiviral activity.
Whether antiviral agents can be delivered early enough, and at concentrations sufficient to meaningfully reduce viral load within the narrow window between symptom onset and immune-mediated clearance, remains uncertain. Progress in this field will likely depend on the development of dengue-specific direct-acting antivirals, rather than relying on repurposed treatments. Trials of potentially potent dengue antiviral agents have recently suffered from early termination due to industry deprioritisation of dengue research. However, there are signs of renewed momentum, with novel drug discovery efforts [71–73] and ongoing phase 2 trials including a dengue-specific monoclonal antibody (SII, CTRI/2021/07/035290), a trial of molnupiravir for dengue and chikungunya in Brazil (Brazilian Clinical Trials Registry: U1111-1306–1425) and a small-molecule NS4B inhibitor (Novartis-EYU688). Sustaining this momentum will be essential to reinvigorate the neglected antiviral dengue therapeutics pipeline. Inclusion of paediatric populations in future trials is also critical for health equity, given that children are still bearing a substantial burden in hyper-endemic settings such as Vietnam [74].
Corticosteroids
Although corticosteroids were the most frequently evaluated treatment for dengue, we identified only 944 patients across nine published studies, encompassing a wide spectrum of clinical phenotypes from early symptomatic dengue to refractory shock. Among patients with dengue shock, no trial demonstrated a mortality benefit with corticosteroid treatment; however, all were underpowered to evaluate this endpoint. While we did not perform a meta-analysis, a 2014 Cochrane review similarly found no effect of corticosteroids on mortality among 284 paediatric patients with dengue shock. However, based on an assumed 21.3% risk of death due to dengue shock, the authors estimated that a definitive trial would require more than 1600 participants to detect a 25% mortality reduction [15]. Recent trends in dengue shock mortality have been mixed: rates have declined in some settings with improved supportive care and monitoring but increased in others [3] particularly among patients with obesity, comorbidities, or limited access to expert clinical management. These observations underscore the importance of a large, adequately powered, multi-site trial with careful patient selection to evaluate corticosteroid efficacy in severe dengue.
In patients with non-severe dengue, corticosteroid therapy did not affect clinical or laboratory outcomes, but the studies were also underpowered. We consider that routine use of corticosteroids in early uncomplicated dengue would be hard to justify, given the low risk of progression to severe disease among unselected outpatients.
Despite the paucity of evidence, corticosteroids continue to be used empirically in many endemic settings, particularly for critically ill patients [75–77]. Experience from COVID-19 demonstrates that corticosteroids can reduce mortality in specific subgroups of patients with severe viral infections, but harm can also outweigh benefits in other groups [78]. Robust, adequately powered clinical trials are therefore essential to determine whether corticosteroids confer benefit—or potential harm—in moderate and severe dengue, and to explore whether treatment effects vary according to baseline characteristics or disease severity.
Other therapeutics
Given the variable formulations and methodological limitations of published studies, the current evidence base is insufficient to draw conclusions regarding the clinical efficacy of CPLE in acute dengue. Further low-quality studies using non-standardised preparations and surrogate laboratory endpoints are unlikely to add meaningfully to the evidence base. We recognise, however, the considerable regional interest and widespread informal use of CPLE across South and Southeast Asia and Indonesia. Formal evaluation of the proposed active compound is therefore warranted, but should begin with in vitro studies, followed by rigorously designed human trials using pharmaceutical-grade material in randomised, placebo-controlled settings with clinically relevant endpoints.
Among the other host-directed therapeutics, few trials were assessed as being at low risk of bias. Well-designed trials investigating agents such as rupatadine and montelukast have shown no significant clinical benefit despite using appropriate endpoints [33,34,36]. Trials with a higher risk of bias frequently lacked clear therapeutic rationale and focused primarily on reporting on laboratory outcomes such as platelet counts. In several cases, investigators proposed different mechanisms of action for the same agent – for example, doxycycline was hypothesised to act through both antiviral and host-directed pathways in separate studies [20,43]. These limited successes highlight persistent challenges in dengue clinical research: incomplete understanding of disease pathogenesis, difficulties in patient selection and the absence of standardised endpoints. While recent work has linked hyperinflammatory responses with adverse outcomes, no single, universally accepted pathway has been identified as the key driver of severe disease. This uncertainty complicates rational target selection. Moreover, the clinical heterogeneity of dengue, coupled with the lack of reliable predictors of disease progression, often results in trials enrolling mixed patient populations, potentially diluting treatment effects.
Overcoming these challenges will require innovation in both trial design and patient stratification. Adaptive and platform trial designs could enable concurrent evaluation of multiple candidate therapies—an efficient approach in the absence of established treatments. Future studies should incorporate biomarker-based or multi-omics approaches to identify subgroups most likely to benefit from targeted interventions. Although most existing trials have been underpowered to demonstrate clinical efficacy, mechanistic studies of anti-inflammatory or endothelial-stabilising therapies, when conducted with methodological rigour and harmonised endpoints, can still provide valuable insights and support future meta-analyses.
Endpoints
This review underscores the marked heterogeneity of primary endpoints used in dengue therapeutic trials. To date, no large clinical trial of either antiviral or host-directed therapy has been adequately powered to detect clinically meaningful effects on key outcomes such as hospitalisation (for early treatment) or mortality (for late treatment). Because only a small proportion of patients progress to severe disease, many early-phase studies have relied on surrogate endpoints to assess efficacy. However, there are currently no universally accepted surrogate outcomes for dengue, limiting comparability across trials.
Selecting appropriate endpoints poses particular challenges for antiviral trials. Viraemia peaks within the first few days of illness, whereas most patients are hospitalised later during the critical phase, when viral replication is already declining. This narrow therapeutic window is further complicated by variability in viraemia kinetics and viral clearance, which depend on immune status and infecting serotype [9]. Fever duration has been used as a pragmatic endpoint; however, it functions merely as a clinical proxy for viremia, and accurate determination requires frequent measurement, and early presentation, which is uncommon for a disease generally considered self-limiting.
Trials of other therapeutics have often used platelet count–based metrics as primary endpoints. However, these measures are poor surrogates for clinical benefit, reflecting health-seeking behaviour and disease pathophysiology rather than treatment response. Patients typically present during the critical phase—at or near the platelet nadir—leaving little opportunity for an intervention to alter trajectory [79]. Consequently, absolute platelet counts are often dissociated from clinical outcomes.
More robust clinical outcomes, such as progression to severe dengue or mortality are difficult to use because they require very large sample sizes. Intermediate endpoints, such as warning signs or plasma leakage, are also limited by subjectivity and lack of standardisation; for example, fluid accumulation assessments depend heavily on operator technique and imaging modality. Although earlier efforts sought to standardise definitions for clinical endpoints [80], they have not achieved widespread adoption. As a result, the absence of uniformly defined clinical and virological outcomes has hampered meta-analyses and synthesis of existing data.
To address this gap, a standardised core outcome set has recently been developed through the DEN-CORE initiative [14]. This global consensus, involving stakeholders from 36 countries including patient representatives, defined a Core Outcome Set (COS) and Core Outcome Measurement Set (COMS) for dengue therapeutic trials. The group prioritised seven core outcomes for hospitalised patients and eleven for those with early symptomatic dengue. Adoption of this core outcome framework in all future dengue trials will address the long-standing inconsistencies in outcome selection and reporting, enabling meaningful data comparison and evidence synthesis across studies.
In line with global recognition of the growing dengue burden, the WHO has recently published Target Product Profiles (TPPs) for dengue therapeutics, defining the minimum and optimal characteristics required for treatments to be suitable for public health use [81]. Future drug discovery efforts and clinical trials should align with the TPPs to ensure that treatment candidates are developed with standardized, globally agreed benchmarks for both adults and children.
Table 7 summarises the key gaps identified from this systematic review and implications for future research.
Strengths and limitations
To our knowledge, this is the first systematic mapping review to comprehensively chart the landscape of dengue treatment trials. We conducted an extensive search in electronic databases and clinical trial registries, including both non-randomized studies alongside randomized controlled trials to ensure a comprehensive view of the evidence base. We also flagged ongoing studies to evaluate potential future shifts in therapeutic approaches.
However, several limitations exist. First, we only review English-language articles due to limited translation resources. This restriction might exclude relevant local data published in national journals from Latin American or other non-English speaking countries. Secondly, regarding the review process, while title, abstract, and full-text screening were performed independently by two reviewers to minimize selection error, data extraction was mainly performed by a single reviewer due to resource constraints. To mitigate potential inaccuracies, a random sample of the included studies underwent double data entry to assess the degree of agreement and identify systematic discrepancies before proceeding with single entry for the remaining studies. We also had a second reviewer verify all extracted primary endpoints and perform a comprehensive data cleaning process prior to analysis. Furthermore, we believe this approach does not materially affect the study’s conclusions, as meta-analysis was precluded due to the heterogeneity of study characteristics. Finally, regarding quality assessment, it is noted that we utilized the version of ROBINS-I available prior to the October 2025 update.
Conclusion
Our findings demonstrate the striking neglect of dengue in the field of therapeutic research, despite its substantial global burden and disproportionate impact on low- and middle-income countries. There is an urgent need for large, adequately powered clinical trials that use harmonised and clinically meaningful endpoints to generate robust evidence for treatment and inform policy. Innovative trial designs – such as adaptive platform trials employing factorial randomisation – offer an efficient and collaborative strategy to evaluate multiple candidate therapies concurrently. Prioritising equitable participation, including representation from a range of dengue-endemic regions and vulnerable populations including children, will be essential to ensure that future discoveries translate into accessible, evidence-based care for all patients affected by dengue.
Supporting information
S1 Fig. Numbers of adults (≥ 16 years old) and children (<16 years old) enrolled in each therapeutic category.
https://doi.org/10.1371/journal.pntd.0014382.s001
(TIFF)
S1 PRISMA Checklist. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71.
https://doi.org/10.1371/journal.pntd.0014382.s002
(PDF)
S1 File. Search terms used in the systematic review.
https://doi.org/10.1371/journal.pntd.0014382.s003
(PDF)
S1 Table. Risk of bias assessments of the included publications.
https://doi.org/10.1371/journal.pntd.0014382.s004
(PDF)
Acknowledgments
We would like to thank Ms Kalynn Kennon, Head of Data Engineering, Infectious Diseases Data Observatory for her support with this project.
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