Season-adjusted longitudinal changes in serum 25-hydroxyvitamin D during pegylated interferon add-on to ongoing tenofovir alafenamide therapy in chronic hepatitis B: a real-world cohort study

ObjectivesTo characterize serum 25-hydroxyvitamin D [25(OH)D] trajectories during peginterferon alfa-2b (Peg-IFN) add-on to ongoing tenofovir alafenamide (TAF) therapy in chronic hepatitis B and explore associations with hepatitis B surface antigen (HBsAg).MethodsThis retrospective cohort identified 203 consecutive patients, of whom 190 contributed longitudinal data through week 48. The primary random-intercept mixed-effects model used categorical visit time and adjusted for seasonality, age, and sex. Continuous-time, random-slope, visit-timing, and HBsAg-censoring analyses assessed sensitivity.ResultsThe primary adjusted week-48 25(OH)D difference was −7.9 nmol/L (95% CI, −9.8 to −6.0) (P < 0.001); the secondary continuous-time estimate was −8.3 nmol/L over 48 weeks. Observed concentrations declined through week 36 and partially rebounded at week 48. The proportion below 47.7 nmol/L increased from 21.1% to 34.7%. The adjusted total serum calcium trend was −0.061 mmol/L (95% CI, −0.074 to −0.049). Triglycerides increased while cholesterol fractions decreased. At week 48, 104/190 patients (54.7%) had an HBsAg decline of at least 1 log10 and 50/190 (26.3%) had visit-specific HBsAg loss. The concurrent 48-week change correlation was weak (ρ = 0.150; FDR-adjusted P = 0.117), and the magnitude of 25(OH)D decline was not independently associated with either binary endpoint. Within patients, each 10 nmol/L increase in 25(OH)D was associated with a 0.068-log10 IU/mL increase in concurrent HBsAg (95% CI, 0.020 to 0.116; P = 0.006).ConclusionsSerum 25(OH)D showed a non-linear decline during 48 weeks of follow-up, and the week-48 difference remained evident after adjustment for seasonality. However, without a concurrent comparator, the observed change cannot be attributed specifically to Peg-IFN, TAF, or their combination. Exploratory analyses suggested only a weak concurrent relationship between 25(OH)D and HBsAg, without evidence of prediction or causality. The clinical relevance of the observed changes in 25(OH)D and total serum calcium warrants further prospective investigation.