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Background:  Didanosine (ddI) plus tenofovir (TDF) is a combination with several potential advantages (once a day and high genetic barrier), but also pitfalls (unexpected CD4 drops and increased risk of pancreatitis). Since several cases of transient insulin-dependent diabetes mellitus were seen in our clinic in patients on ddI- and TDF-containing regimens, we explored the rate of this complication in more detail.

Methods:  Retrospective analysis of plasma glucose levels in patients who completed 12 months follow-up under 3 different triple HAART regimens including ddI+TDF, TDF, or ddI. Patients under anti-diabetic agents and those whose baseline glucose level was > 125 mg/dL were excluded. Weight, age, concomitant ART, and ddI dosage were assessed. At 12 months without treatment changes, fasting glucose levels were compared with baseline. A multivariate analysis was performed to evaluate which variables were associated with glucose elevation.

Results:  We included 177 HIV⁺ patients in the analysis:  ddI+TDF (n = 78), TDF (n = 42), and ddI (n = 57). Mean values at baseline were balanced between groups:  age 39 ± 7 years; 78% male; CD4⁺ count 507 ± 300 cells/mm³; weight 67 ± 11 kg. There were only significant differences between groups regarding concomitant proetasae inhibitor (PI) use (13% with ddI+TDF vs 7% and 8% with TDF and ddI, respectively). At 12 months, ddI daily dose was 250 mg and 400 mg in 60% and 40% of ddI+TDF recipients, respectively (ddI dose reduction with concomitant TDF use had not been advised at that time). At 12 months, hyperglycemia was significantly more frequent in ddI+TDF recipients (33%) when compared with patients on TDF or ddI (5% and 10%, respectively). Multiple linear regression was performed considering variation of glucose levels at 12 months as dependent variable and treatment with ddI or TDF, weight, age, and PI concomitant use as independent factors. A lower baseline weight (b –0.35; 95% CI –0.67 to –0.03; p = 0.033) and use of regimens including ddI+TDF (b 13.05; 95% CI 0.2 to 26; p = 0.047) were independently associated with higher glucose values.

Conclusions:  The risk of hyperglycemia is increased in patients on ddI+TDF, particularly among those with lower baseline weight. As high ddI exposure has been related to endocrine pancreatic dysfunction and diabetes, ddI “overdosing” (related to lower weight and potentiated by TDF use) may be an explanation for our findings. Our results add a further note of caution to the concomitant use of TDF and ddI.

Keywords: Hyperglycemia; Didanosine; Tenofovir