Discussion
T1D, hemolysis, autoimmunity, hypoglycemia
DISEASE PROGRESSION, VIRUS, SIDE EFFECT, PERSISTENT INFECTION, AUTOIMMUNE RESPONSE, INFLAMMATION, HEMOLYSIS, DYSFUNCTION, HYPOGLYCEMIA, SECONDARY, AUTOIMMUNITY, PATHOGENESIS
In this phase 2 trial involving children and adolescents with newly diagnosed T1D, combination therapy with the antiviral drugs pleconaril and ribavirin for 6 months resulted in a higher endogenous insulin production than placebo 12 months from baseline. The treatment was safe and tolerable.Viruses contribute to the pathogenesis of T1D, both by damaging β cells or triggering the autoimmune response. Establishment of a low-grade persistent infection in β cells maintains inflammation, leading to the breakdown of tolerance to β cell antigens, β cell dysfunction and stress, each of which might then contribute to autoimmunity as part of a vicious circleBeneficial effects of antiviral treatment on β cell function have been observed in the present study at the onset of clinical stage 3 T1D, in a situation where disease progression had been ongoing for months or years. At this late stage of pathogenesis, patients might still have considerable numbers of β cells but they may not function normallyThis trial was not designed to distinguish the individual effects of the two study drugs included in this treatment. The main reason for including ribavirin was to prevent the development of viral drug resistance. Ribavirin has a broader antiviral effect both on enteroviruses and several other viruses, and may also have immunomodulatory effectsThe scale of the observed difference in C-peptide secretion between the pleconaril and ribavirin group and the placebo group after 12 months is comparable to the scale of improvement reported for anti-inflammatory medications and lately verapamil, which have been evaluated for newly diagnosed T1D in randomized control trialsThe observed difference in C-peptide AUC at baseline was not significant (The observed moderate effect of pleconaril and ribavirin may have clinical implications. In general, even a limited preservation of C-peptide levels is associated with improved metabolic control, reduced hypoglycemia and lower long-term microvascular complicationsLower HbA1c was observed in the pleconaril and ribavirin group during the antiviral treatment period (3 and 6 months from baseline) than in the placebo group; at the later time point, 6 months after the end of treatment, the difference in HbA1c between the groups was less pronounced. A known side effect of ribavirin is that it can induce hemolysis, leading to reduced lifespan of erythrocytes and lowering of HbA1c (ref. The trial has some limitations. First, the study included a small number of participants. The statistical power calculation for this trial was aimed at the primary endpoint and was not designed to estimate the power to detect secondary endpoints, which have greater between-person variation and laboratory analytical variation. Effects beyond those in the population studied, that is, centers, age, sex and potential role of COVID-19, could not be credibly examined. Second, the observed significant difference between the treatment and placebo group should be replicated using a higher number of participants of different ages and living in different countries, thus representing different microbiological environments. Third, information regarding continuous glucose monitoring was not available for all participants. Possible persisting low-grade enterovirus infection in the pancreas is difficult to detect from serum or samples taken from the periphery, even if the virus is detected in the pancreatic isletsIn conclusion, this study shows that among children and adolescents with newly diagnosed T1D, the combination therapy of two antiviral drugs, pleconaril and ribavirin, resulted in higher residual endogenous insulin production than placebo. These results provide a rationale for future studies to evaluate the efficacy of antiviral drugs in the prevention and treatment of T1D.