Pleconaril-ribavirin combo slows insulin loss in T1D

Treatment with pleconaril and ribavirin combination for 6 months helps to slow the decline of pancreatic insulin production in children and adolescents with newly diagnosed type 1 diabetes (T1D) in the phase II DiViD Intervention study presented at EASD 2023.

The study is the first-ever randomized, placebo-controlled trial of antivirals in T1D and opens the possibility of early intervention to delay the loss of beta cells that produce insulin.

“Our findings support the possible link between enteroviruses and T1D and provide a rationale for future evaluation of antiviral strategies in the treatment of this condition and the prevention of prediabetes progression to clinical T1D,” said study author Dr Ida Maria Mynarek, a research assistant at Oslo University Hospital in Oslo, Norway.

T1D is characterized by progressive loss of pancreatic beta-cell function, leading to lifelong dependence on insulin. Previous studies have shown an association between enterovirus infections, the appearance of autoantibodies, and the subsequent onset of T1D. In the DiViD study, for example, low-grade enteroviral infection was found in the pancreatic islets of six adult patients with newly diagnosed T1D. [Diabetes 2015;64:1682-1687]

“This provides a rationale for targeting antiviral strategies in the prevention and treatment of T1D,” said Mynarek.

Synergistic effects of antivirals

Included in the current trial were 96 individuals aged 6–15 years who had been diagnosed with new-onset T1D. They were randomly assigned to pleconaril and ribavirin combination (n=47) or placebo (n=49), given as oral solutions twice daily for 26 weeks. [Nat Med 2023;doi:10.1038/s41591-023-02576-1]

Pleconaril was chosen because it was developed specifically against enteroviruses. Ribavirin, a broad-spectrum antiviral, was added for synergistic effects and to prevent viral drug resistance, according to Mynarek.

The primary endpoint was endogenous insulin production at 12 months as assessed by the 2-hour serum C-peptide area under the curve (AUC) – a gold standard measure of beta cell loss – based on a mixed meal tolerance test (MMTT).

C-peptide typically rises in the first weeks to months after T1D diagnosis and then falls over time, indicating disease progression.

After 12 months, the relative decrease in C-peptide AUC was 11 percent with pleconaril-ribavirin vs 24 percent with placebo. The C-peptide levels were higher in the pleconaril-ribavirin treatment arm vs the placebo arm (average marginal effect, 0.057; p=0.037).

The proportion of participants with clinically relevant residual insulin production, defined as a C-peptide peak >0.2 pmol/mL, at 12 months was 86 percent with the antiviral combination vs 67 percent with placebo (p=0.04).

HbA_1c levels, although similar between groups at baseline, were significantly lower in the antiviral-treated group. Glycated albumin was also comparable at baseline, 3, 6, and 12 months. There were no significant differences between groups in insulin dose or frequency of severe hypoglycaemia (defined as unconsciousness or seizures) nor the frequency of intercurrent infections.

The antiviral combination was well-tolerated and there were no serious adverse events reported. As expected, there were more patients in the antiviral group with suppressed haptoglobin, a marker of haemolysis, compared with the placebo group (27 vs 23).

Promising results

Commenting on the study, Dr Emily Sims, paediatric endocrinologist from the Indiana University School of Medicine, Indianapolis, Indiana, US said the results are promising. “I am on board with as many different options in our arsenal. I think there won’t be one tool for everybody … it would be great if we could have a way to attack the process from lots of different angles.”