ESPE Yearbook of Paediatric Endocrinology

Brief Summary: The Diabetes Virus Detection (DiViD) Intervention phase 2, placebo-controlled, double-blind trial randomized 96 children and adolescents (age 6-15 years) with new-onset type 1 diabetes (T1D) to receive either the antivirals, Pleconaril and Ribavirin, (n=47) or placebo (n=49) for 6 months. The antiviral treatment improved β-cell function at 12 months, and it was well tolerated and safe.

Viral infections, particularly enteroviruses, have been implicated in the pathogenesis of T1D, by triggering the autoimmune response or damaging pancreatic β-cells directly [1]. Previous evidence of low-grade enterovirus infection in pancreatic islets of people with newly diagnosed T1D suggested that persistent chronic infection could lead to progressive β-cell damage (1). Hence the hypothesis that eradication of such low-grade infection might improve insulin secretion after the onset of T1D.

The DiViD trial was conducted at 2 sites, Oslo University Hospital (Norway) and Steno Diabetes Center Copenhagen (Denmark). Combination treatment with Pleconaril and Ribavirin, which both have antiviral activity against enteroviruses, was chosen to broaden the antiviral effect and reduce the risk of emergent drug-resistant variants.

The antivirals showed promising efficacy along with a good safety and tolerability profile. The primary endpoint was endogenous insulin production after 12 months, assessed by 2-h serum C-peptide area under the curve (AUC) during a mixed meal tolerance test, as used in previous immunotherapy trials (2).

C-peptide AUC at 12 months was higher in the treatment than in the placebo group. In addition, a higher proportion of participants in the antiviral group had a peak stimulated C-peptide >0.2 pmol/ml, a clinically relevant threshold. Some differences in HbA1c were seen at 3 and 6 months but not 12 months; however, those initial differences could be due to hemolysis related to antiviral treatment, leading to falsely lower HbA1c levels.

These findings provide solid evidence for the use of antiviral agents in people recently diagnosed with T1D. Limitations of the study include its relatively small sample size, which was sufficient only for the primary endpoint, the small age range and restricted location at only 2 centres in Northern Europe. Further studies are needed to confirm these results in larger and more diverse populations, to optimize the antiviral combination and also consider antiviral vaccinations as a preventive strategy for T1D.

References: 1. Dahl-Jørgensen K. Virus as the cause of type 1 diabetes. Trends Mol Med. 2024; 13:S1471-4914(24)00183-7.2. Latres E, Greenbaum CJ, Oyaski ML, Dayan CM, Colhoun HM, Lachin JM, et al. Evidence for C-Peptide as a Validated Surrogate to Predict Clinical Benefits in Trials of Disease-Modifying Therapies for Type 1 Diabetes. Diabetes. 2024;73(6):823-833.