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

Abstract

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

Methods and findings: A double-blind, randomized, placebo-controlled trial of CQ in 307 adults hospitalized for suspected DENV infection was conducted at the Hospital for Tropical Diseases (Ho Chi Minh City, Vietnam) between May 2007 and July 2008. Patients with illness histories of 72 hours or less were randomized to a 3-day course of CQ (n = 153) or placebo (n = 154). Laboratory-confirmation of DENV infection was made in 257 (84%) patients. The primary endpoints were time to resolution of DENV viraemia and time to resolution of DENV NS1 antigenaemia. In patients treated with CQ there was a trend toward a longer duration of DENV viraemia (hazard ratio (HR) = 0.80, 95% CI 0.62-1.05), but we did not find any difference for the time to resolution of NS1 antigenaemia (HR = 1.07, 95% CI 0.76-1.51). Interestingly, CQ was associated with a significant reduction in fever clearance time in the intention-to-treat population (HR = 1.37, 95% CI 1.08-1.74) but not in the per-protocol population. There was also a trend towards a lower incidence of dengue hemorrhagic fever (odds ratio = 0.60, PP 95% CI 0.34-1.04) in patients treated with CQ. Differences in levels of T cell activation or pro- or anti-inflammatory plasma cytokine concentrations between CQ- and placebo-treated patients did not explain the trend towards less dengue hemorrhagic fever in the CQ arm. CQ was associated with significantly more adverse events, primarily vomiting.

Conclusions: CQ does not reduce the durations of viraemia and NS1 antigenaemia in dengue patients. Further trials, with appropriate endpoints, would be required to determine if CQ treatment has any clinical benefit in dengue.

Trial registration: Current Controlled Trials number ISRCTN38002730.

Figure 1. Participant flow in the randomized controlled trial of CQ vs. Placebo.

Figure 2. Time to fever clearance.

Kaplan – Meier survival analysis of time to fever clearance by treatment group (CQ or placebo) and population; A) Intention to treat population and B) Per Protocol population. Three patients afebrile at enrollment developed fever later (1 in the CQ arm and 2 in the Placebo arm) and for the purposes of analysis were considered positive at the time of enrolment.

Figure 3. Time to resolution of viraemia.

Kaplan – Meier survival analysis of time to resolution of plasma viraemia by treatment group (CQ or placebo) and population; A) Intention to treat population and B) Per Protocol population.

Figure 4. 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.

Figure 5. Surface phenotypes of CD4⁺ and CD8⁺ T cells in laboratory-confirmed dengue patients randomized to placebo or CQ.

The Box and Whisker plots show the median number and range (2.5–97.5 percentile) of percentages of surface-activated T cells in peripheral blood from CQ (n = 74) and Placebo (n = 73) treated laboratory-confirmed dengue patients at different time points. The median illness day (range) for enrolment samples was 2 (0–3) days, for hospital discharge was 6 (4–8) days and for follow-up was 15.5 (13–30) days. Shown are percentages of peripheral blood CD4⁺ T cells that were A) CD38⁺HLA-DR⁺, B) CD38⁺Ki67⁺, and C) Ki67⁺ HLA-DR⁺. Also shown are percentages of CD8⁺ T cells that were, D) CD38⁺, HLA-DR⁺, E) CD38⁺Ki67⁺, and F) Ki67⁺ HLA-DR⁺. The labels below the graphs indicate the time at which sample collection occurred.

Figure 6. Plasma concentrations of pro- and anti-inflammatory cytokines in laboratory-confirmed dengue patients randomized to placebo or CQ.

The Box and Whisker plots show the median and range (2.5^th–97.5^th percentile) of plasma concentrations of A) IL-6, B) IL-8, C) IL-10, D) GM-CSF, E) IFN- γ, and F) TNF-α from DF and DHF patients treated with CQ or Placebo. The dashed line represents the assay limit of detection. Concentrations of IL-2 and IL-4 are not shown because they were below the limit of detection.