The potential benefits of ribavirin and pleconaril treatment on type 1 diabetes

Type 1 diabetes (T1D) is caused by the progressive deterioration of pancreatic beta cell functions, which leads to lifelong insulin dependency. Despite extensive immunological, biochemical, clinical, and epidemiological research, T1D etiology remains unclear.

Previous studies have reported that viral infections can result in pancreatic autoimmunity and cause diabetes. In particular, enteroviral infections can contribute to T1D pathogenesis.

In a recent study published in the journal Nature Medicine, researchers investigate whether ribavirin and pleconaril administration could stimulate endogenous insulin production among 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

About the study

The Diabetes Virus Detection (DiViD) placebo-controlled, parallel-group, double-blinded randomized control trial (RCT) was conducted at 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 7.5 mg/kg and pleconaril at a dose of five 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 three weeks. All study participants were followed for 26 weeks with an extended ongoing two-year follow-up.

The primary 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 year of treatment. Linear mixed modeling was performed to determine the average 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 year. 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 such as seizures and unconsciousness.

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

Enterovirus was detected using reverse transcription-polymerase chain reaction (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 cardiovascular disease in the prior six months, and had renal impairment. In addition, individuals who participated in other clinical studies in the prior three months, pregnant or lactating females, sexually active individuals unwilling to use efficient contraceptives, and those with serious medical conditions were excluded.

Study findings

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

At study initiation, the mean non-log-transformed two-hour C-peptide area under the curve values in the intervention and placebo groups were 0.6 and 0.5 pmol/ml, respectively. After one year, the corresponding values were 0.6 and 0.4 pmol/ml, respectively. In one year, the relative reductions in serological C-peptide AUC values were 11% among therapy recipients and 24% among 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 in the intervention and placebo groups were 48 and 51 mmol/mol, respectively.

HbA1c values were significantly lower at three and six months among individuals who received antiviral treatment. Glycated albumin levels were slightly reduced in the intervention group after three and six months of therapy.

Insulin dosage-adjusted glycated hemoglobin (IDAA1c) values were comparable in both study groups at one year. However, at three and six months, IDAA1c values were lower among antiviral treatment recipients as compared to placebo recipients. The daily dosage of insulin was similar among both groups across follow-up.

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

There were no serious adverse events reported in any group. Two antiviral therapy recipients developed a mild severe acute respiratory coronavirus 2 (SARS-CoV-2) infection after three and five months of treatment; however, 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 among young incident T1D patients. The study findings provide a rationale for further research to evaluate the effectiveness of antiviral agents in T1D prevention and treatment.

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.