Abstract / Summary
TDF exposure is associated with reduced bone mineral density (BMD) in people living with HIV (PLWH). Data remain limited evaluating changes in BMD and bone turnover markers (BTMs) after switching to tenofovir alafenamide (TAF), TDF/TAF-free regimens such as dolutegravir/lamivudine (DTG/3TC), or receiving treatment with zoledronic acid (ZOL). In this prospective cohort study, 223 virologically suppressed male PLWH with low BMD on TDF-based regimens were evaluated across four groups: (1) continuing TDF ( n = 48); (2) TDF plus intravenous ZOL 5 mg at baseline ( n = 37); (3) switching to BIC/FTC/TAF(bictegravir/emtricitabine/TAF) ( n = 70); or (4) switching to DTG/3TC ( n = 68). Primary outcomes were multivariable-adjusted absolute BMD change from baseline to week 48 across the femoral neck (FN), total hip (TH), and lumbar spine (LS), estimated using ANCOVA with 2,000 bootstrap resamples. Secondary outcomes included percent BMD changes and unadjusted BTM changes (β-CTX and P1NP) as median (IQR). Sensitivity analyses using 20 imputed datasets under the intention-to-treat principle were also conducted. A total of 189 participants completed the 48-week follow-up. Persistent BMD loss occurred at week 48 in the TDF group [median change: FN -0.01 (-0.04, 0.01)g/cm²; TH -0.01 (-0.06, 0.01)g/cm²; LS -0.02 (-0.05, 0.00)g/cm²]. In multivariable-adjusted models, all three intervention regimens were associated with significantly greater absolute BMD gains compared with TDF across all sites ( P < 0.05). At LS, adjusted mean differences were 0.09 g/cm² (95% BCa CI: 0.07 to 0.12) for TDF + ZOL, 0.07 g/cm² (95% BCa CI: 0.04 to 0.11) for BIC/FTC/TAF, and 0.11 g/cm² (95% BCa CI: 0.07 to 0.14) for DTG/3TC (all P ≤ 0.001). No significant pairwise differences were found among the three intervention regimens. Regarding BTMs, TDF + ZOL was associated with the greatest percentage reduction in P1NP compared with both switch groups (both P < 0.001), as well as in β-CTX versus DTG/3TC ( P < 0.001). Conversely, the TDF group exhibited a significant increase in BTMs from baseline. Multiple imputation sensitivity analyses yielded consistent findings. In relatively young male PLWH with low BMD and without chronic hepatitis B co-infection, switching from TDF to BIC/FTC/TAF or DTG/3TC, as well as ZOL co-administration, were associated with favorable 48-week BMD recovery. ZOL co-administration was characterized by the strongest suppression of bone turnover among all evaluated strategies. These findings reflect the overall benefits of diverse regimen-switching strategies in this specific population, supporting individualized bone management for PLWH receiving TDF. Not applicable.