In a sensitivity analysis assessing subsequent disease progression among all PWH, we identified similar associations between elevated HIV-specific IgG3 levels and the later development of bacterial pneumonia (HR 2.49, 95% CI: 1.32–4.66) and osteoporosis (HR 7.97, 95% CI: 1.63–38.91) (S13 Fig), suggesting that the IgG3 signature may reflect a broader shift in immune homeostasis. This evidence concerns the gene IGHG3 and osteoporosis.