Antivirals Slow Insulin Loss in New-Onset Type 1 Diabetes

HAMBURG, Germany — A combination of the antiviral drugs pleconaril and ribavirin slowed the decline of pancreatic insulin production compared with placebo in children and adolescents with newly diagnosed type 1 diabetes, new phase 2 data show.

Results from the first-ever randomized, placebo-controlled trial of antivirals in type 1 diabetes suggest the possibility of a new way to intervene early either prior to clinical diagnosis or soon after to slow the condition’s characteristic loss of insulin-producing beta cells, said study co-author Ida Maria Mynarek, a doctoral student at the University of Oslo and a research assistant at Oslo University Hospital, Norway.

“The results strengthen the possible link between enteroviruses and the development of type 1 diabetes. They provide a rationale for future evaluation of antiviral strategies in the treatment of newly-diagnosed type 1 diabetes and in the prevention of progression from prediabetes (stage 2/presence of autoantibodies with dysglycemia) to clinical type 1 diabetes (stage 3),” Mynarek said in her presentation of the results at the annual meeting of the European Association for the Study of Diabetes (EASD). The data were simultaneously published in Nature Medicine.

Type 1 diabetes results from a complex interplay between genetic predisposition, the immune system, and environmental factors. There has been increasing evidence of an association between enterovirus infections, the appearance of autoantibodies, and the subsequent onset of type 1 diabetes. A recent analysis also found low-grade enteroviral infection with live virus in islets from six adults recently diagnosed with type 1 diabetes, thereby providing rationale for an investigation of the antiviral treatment approach, Mynarek said.

Asked to comment, Professor Mikael Knip, head of the Pediatric Diabetes Research Group at the University of Helsinki, Finland, told Medscape Medical News, “It’s an interesting outcome. I think this is an issue that should be explored further. It would also be good to know if antiviral treatment would affect the disease process earlier than at diagnosis.”

The role of enterovirus in type 1 diabetes has been controversial until recently, Knip noted. “I think the field has been divided regarding the potential role of viruses, especially enterovirus, in the development of type 1 diabetes. Now, we have more and more evidence generated supporting a role for these viruses, at least in a portion of the patients. I don’t think this is true for every patient.”

Another type 1 diabetes researcher, pediatric endocrinologist Emily K. Sims, MD, also believes that the approach is promising, perhaps in combination with other approaches to forestalling beta-cell loss such as the monoclonal antibody teplizumab.

“I’m on board with as many different options in our arsenal as we can have. I think there won’t just be one tool for everybody. Even with teplizumab, it’s just delayed and [many of] those individuals are still dysglycemic, so I think it would be great if we had a way to attack the process from lots of different angles,” said Sims, associate professor, Division of Pediatric Endocrinology and Diabetology, Indiana University School of Medicine, Indianapolis.

Sims, who studies teplizumab, also noted, “I think optimally it would be great if you could catch people early on in the process, when enterovirus is initiating their autoimmunity, if that’s what’s initiating their autoimmunity…The more people we can screen, the better.”

Antiviral Combination Slowed C-Peptide Loss

The study included 96 individuals aged 6-16 years who had been diagnosed with type 1 diabetes within the prior 3 weeks. They were randomly assigned to either the antiviral combination or placebo, given as oral solutions twice daily for 26 weeks. The study drug doses were 10 mg/kg/d of pleconaril and 15 mg/kg/d of ribavirin.

Pleconaril was chosen because it was developed specifically to combat enteroviruses. Ribavirin, a broad-spectrum antiviral, was added to increase the potential for synergistic effects and also to prevent viral drug resistance, Mynarek explained.

(Knip pointed out that pleconaril is no longer on the market but that other antiviral combinations should be studied.)

A total of 87 participants, 42 in the treatment group and 49 taking placebo, were analyzed for the primary endpoint: stimulated C-peptide during a 2-hour mixed meal tolerance test at 12 months. The relative decrease in C-peptide area under the curve during the 12 months was 11% with pleconaril-ribavirin vs 24% in the placebo group. The serum C-peptide area under the curve was higher in the pleconaril-ribavirin treatment group compared with the placebo group (average marginal effect, 0.057; P = 0.037).

The proportions of participants with clinically relevant residual insulin production, defined as a C-peptide peak > 0.2 pmol/mL, at 12 months was 86% with the antivirals vs 67% with placebo, a statistically significant difference (P = .04).

A1c levels, which were similar between groups at baseline, were significantly lower in the antiviral-treated group. However, because ribavirin induces mild hemolysis, the investigators also measured glycated albumin. Here, the results were similar at baseline, 3, 6, and 12 months.

There were no significant differences between the groups in insulin dose or frequency of severe hypoglycemia nor in the frequency of intercurrent infections.

The antiviral combination was well-tolerated and there were no severe adverse events. As expected, a higher proportion of the antiviral-treated group had suppressed haptoglobin, a marker of hemolysis.

In the Future, a Vaccine?

Knip’s group is currently working on a vaccine against the enterovirus coxsackie for potential use in people at increased risk for type 1 diabetes. Thus far they’ve completed a safety study in healthy adults.

“If we get data that the vaccine prevents the development of beta cell autoimmunity, then we have to consider whether we should vaccinate all babies or just those at genetic risk for type 1 diabetes,” he told Medscape Medical News.

The genetic risk would be key, he noted, because the appearance of coxsackie virus often precedes the first appearance of type 1 diabetes-associated autoantibodies (stage 1).

The study was supported by grants from the South-Eastern Norway Regional Health Authority and Juvenile Diabetes Research Foundation in affiliation with the INNODIA consortium. Mynarek has no disclosures. Sims is a consultant for Sanofi and has received compensation for lectures from Medscape and the American Diabetes Association. Knip is co-founder and current board member of VacTech.

Nature Medicine. Published online October 4, 2023. Full text

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.

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