Trends in Serum Amylase Levels in People Living with HIV: A Comparison Between INSTI and NNRTI/PI-Based Regimens

<b>Background</b>: Antiretroviral therapy (ART) has transformed HIV into a chronic manageable condition, yet metabolic toxicities including pancreatic enzyme alterations remain concerns. While older ART regimens have been associated with hyperamylasemia, the impact of integrase strand transfer inhibitor (INSTI)-based therapies on serum amylase levels has not been specifically examined. <b>Purpose</b>: This study aimed to compare longitudinal patterns of serum amylase levels between people living with HIV receiving INSTI-based versus NNRTI/PI-based ART regimens. <b>Methods</b>: This retrospective observational study analyzed 99 HIV-positive patients at Kaplan Medical Centre, Israel (2002-2023). Participants received either INSTI-based (<i>n</i> = 49) or NNRTI/PI-based (<i>n</i> = 50) regimens for ≥24 months. Serum amylase, viral load, CD4 counts, and metabolic parameters were measured at baseline, one year, and two years. Repeated-measures ANOVA assessed longitudinal changes. <b>Results</b>: NNRTI/PI-treated patients maintained significantly higher mean amylase levels throughout follow-up (baseline: 122.9 ± 42.1 U/L; two years: 129.6 ± 38.0 U/L) compared to INSTI-treated patients (baseline: 78.7 ± 32.3 U/L; two years: 68.4 ± 23.4 U/L; <i>p</i> < 0.0001 at all timepoints). A significant linear time-by-group interaction (<i>p</i> = 0.037) demonstrated divergent trajectories. No clinical pancreatitis was observed in either treatment group during the follow-up period, and all observed variations in serum amylase were biochemical and asymptomatic. While these findings are reassuring regarding acute pancreatic toxicity, the clinical significance of chronic subclinical enzyme elevations remains uncertain. <b>Conclusion</b>: INSTI-based antiretroviral regimens suggest a favorable pancreatic and metabolic safety profile compared with NNRTI/PI-based therapies.