From the Oxford University Clinical Research Unit and Wellcome Trust Major Overseas Programme (C.P.S., J.J.F., B.W.), Hospital for Tropical Diseases (N.V.C.), Ho Chi Minh City, Vietnam; and the Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (C.P.S., J.J.F., B.W.). Address reprint requests to Dr. Farrar at the Hospital for Tropical Diseases, Oxford University Clinical Research Unit, 190 Ben Ham Tu, Quan 5, Ho Chi Minh City, Vietnam, or at jfarrar@oucru.org.

/pdf/current-concepts-dengue-6c6i5h8gym.pdf

Current concepts: Dengue

New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?

For dengue viruses 1 to 4 (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such antibody-dependent enhancement of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of preexisting anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern.

https://science.sciencemag.org/content/sci/358/6365/929.full.pdf

Antibody-dependent enhancement of severe dengue disease in humans

No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection.

Of chloroquine and COVID-19.

Background
There is currently no licensed antiviral drug for treatment of dengue. Chloroquine (CQ) inhibits the replication of dengue virus (DENV) in vitro.

/pdf/a-randomized-controlled-trial-of-chloroquine-for-the-3gx699v1wb.pdf

A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults.

Results: Of the 248 patients with laboratory-confirmed dengue and defined serological and clinical classifications 29 (11.7%) had primary DF, 150 (60.5%) had secondary DF, 4 (1.6%) had primary DHF and 65 (26.2%) had secondary DHF. DENV-1 was the commonest serotype (57.3%), then DENV-2 (20.6%), DENV-3 (15.7%) and DENV-4 (2.8%). DHF was associated with secondary infection (Odds ratio=3.13, 95% CI 1.04‐12.75). DENV-1 infections resulted in significantly higher viremia levels than DENV-2 infections. Early viremia levels were higher in DENV-1 patients with DHF than with DF, even if the peak viremia level was often not observed because it occurred prior to enrolment. Peak viremias were significantly less often observed during secondary infections than primary for all disease severity grades (P=0.001). The clearance of DENV viremia and NS1 antigenemia occurs earlier and faster in patients with secondary dengue (P,0.0001). The maximum daily rate of viremia clearance was significantly higher in patients with secondary infections than primary (P,0.00001). Conclusions: Collectively, our findings suggest that the early magnitude of viremia is positively associated with disease severity. The clearance of DENV is associated with immune status, and there are serotype dependent differences in infection kinetics. These findings are relevant for the rational design of randomized controlled trials of therapeutic interventions, especially antivirals.

Kinetics of Viremia and NS1 Antigenemia Are Shaped by Immune Status and Virus Serotype in Adults with Dengue

The correct title and legend of Figure 3 presently appears with Figure 4. The correct, complete Figure 3 legend and title are:

Time to negative NS1 antigenaemia.

Kaplan – Meier survival analysis of time to resolution of NS1 antigenaemia by treatment group (CQ or placebo) and population; A) Intention to treat population and B) Per Protocol population. Two patients NS1 negative at enrollment were later positive (both in the CQ arm) and for the purposes of analysis were considered positive at the time of enrolment.

doi:10.1371/journal.pntd.0000785.g004

Nguyet Nguyen Minh

Papers

A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults.

Kinetics of Viremia and NS1 Antigenemia Are Shaped by Immune Status and Virus Serotype in Adults with Dengue

Correction: A Randomized Controlled Trial of Chloroquine for the Treatment of Dengue in Vietnamese Adults