Type 1 diabetes (T1D) is brought on by the progressive deterioration of pancreatic beta cell functions, which results in lifelong insulin dependency. Despite extensive immunological, biochemical, clinical, and epidemiological research, T1D etiology stays unclear.

Previous studies have reported that viral infections can lead to pancreatic autoimmunity and cause diabetes. Specifically, enteroviral infections can contribute to T1D pathogenesis.

In a recent study published within the journal Nature Medicine, researchers investigate whether ribavirin and pleconaril administration could stimulate endogenous insulin production amongst individuals with incident type 1 diabetes (T1D).

Study: Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial. Image Credit: VGstockstudio / Shutterstock.com

Concerning the study

The Diabetes Virus Detection (DiViD) placebo-controlled, parallel-group, double-blinded randomized control trial (RCT) was conducted on the Steno Diabetes Center Copenhagen/Herlev University Hospital in Denmark and the Oslo University Hospital in Norway. The RCT included 96 individuals between six and 15 years of age with incident T1D who were divided into the intervention group and the placebo group.

The intervention group included 47 individuals, 28 of whom were male and 19 female, who received oral antiviral therapy with ribavirin at a dose of seven.5 mg/kg and pleconaril at a dose of 5 mg/kg, two times a day for six months to preserve pancreatic beta cell function.

The placebo group included 49 individuals, 28 male and 21 female, who received a placebo treatment. The screening period began from the T1D diagnosis until the study initiation of up to 3 weeks. All study participants were followed for 26 weeks with an prolonged ongoing two-year follow-up.

The first study endpoint was the endogenous secretion of insulin, which was assessed using the mean two-hour serological C-peptide area under the receiver-operating characteristic curve (AUC) values during mixed-meal tolerance tests (MMTTs) after one yr of treatment. Linear mixed modeling was performed to find out the common marginal effect (AME) for the endpoint.

Longitudinal log-transformed serological C-peptide AUCs were also determined at study initiation, three months, six months, and one yr. Secondary study endpoints included peak serological C-peptide values exceeding 0.20 picomoles (pmol)/ml during MMTT, glycated albumin, insulin dose, glycated hemoglobin (HbA1c), and hypoglycemic events akin to seizures and unconsciousness.

MMTT tests were performed early morning within the hospitals in a fasting condition with blood samples obtained at 15, 30, 60, 90, and 120 minutes following the ingestion of normal liquid meals. Liquid chromatography with tandem mass spectrometry (LC-MS) was performed to find out glycated albumin levels.

Enterovirus was detected using reverse transcription-polymerase chain response (RT-PCR) assay using nasopharyngeal aspirates, nasal swabs, salivary samples, stool samples, and serological samples.

Individuals diagnosed with stage three T1D using the American Diabetes Association criteria and the International Classification of Diseases, tenth revision (ICD-10) codes were recruited from August 20, 2018, to October 20, 2020.

The team excluded individuals treated with injectable or oral non-insulin antidiabetic medications, suffered from hemolytic anemia or exhibited significant hematological alterations at screening, suffered from severe heart problems within the prior six months, and had renal impairment. As well as, individuals who participated in other clinical studies within the prior three months, pregnant or lactating females, sexually lively individuals unwilling to make use of efficient contraceptives, and people with serious medical conditions were excluded.

Study findings

The first study endpoint was attained, with serological C-peptide AUC values higher amongst antiviral treatment recipients than placebo recipients at one yr. Antiviral treatment was well tolerated among the many study participants.

At study initiation, the mean non-log-transformed two-hour C-peptide area under the curve values within the intervention and placebo groups were 0.6 and 0.5 pmol/ml, respectively. After one yr, the corresponding values were 0.6 and 0.4 pmol/ml, respectively. In a single yr, the relative reductions in serological C-peptide AUC values were 11% amongst therapy recipients and 24% amongst placebo recipients.

About 86% of antiviral treatment recipients and 67% of placebo recipients exhibited C-peptide levels above baseline, with a risk ratio of 1.3. HbA1c values within the intervention and placebo groups were 48 and 51 mmol/mol, respectively.

HbA1c values were significantly lower at three and 6 months amongst individuals who received antiviral treatment. Glycated albumin levels were barely reduced within the intervention group after three and 6 months of therapy.

Insulin dosage-adjusted glycated hemoglobin (IDAA1c) values were comparable in each study groups at one yr. Nevertheless, at three and 6 months, IDAA1c values were lower amongst antiviral treatment recipients as in comparison with placebo recipients. The day by day dosage of insulin was similar amongst each groups across follow-up.

Severe hypoglycemic episodes were observed in two placebo recipients but no antiviral treatment recipients within the initial follow-up yr. Hostile event incidence rates within the initial yr were 94% and 96% within the intervention and placebo groups, respectively.

There have been no serious opposed events reported in any group. Two antiviral therapy recipients developed a gentle severe acute respiratory coronavirus 2 (SARS-CoV-2) infection after three and five months of treatment; nevertheless, this was not reported in any placebo recipients.

Conclusions

Based on the study findings, the ribavirin and pleconaril combination antiviral therapy might help maintain residual endogenous insulin secretion amongst young incident T1D patients. The study findings provide a rationale for further research to judge the effectiveness of antiviral agents in T1D prevention and treatment.

Journal reference:

• Krogvold, L., Mynarek, I. M., Ponzi, E., et al. (2023). Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial. Nature Medicine. doi:10.1038/s41591-023-02576-1