Oral pre-exposure prophylaxis (PrEP) containing emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) is associated with small decreases in bone mineral density (BMD) compared with placebo. Whether BMD recovers completely after stopping PrEP is not known.
The iPrEx trial was a blinded randomized trial of daily oral FTC/TDF PrEP versus placebo among men and transgender women who have sex with men. The randomized phase was followed by an open label extension (iPrEx OLE) that started after a variable gap in PrEP use. An optional substudy measured BMD by dual-energy X-ray absorptiometry (DXA) every 24 weeks during PrEP use, 24 weeks after stopping PrEP, and at the beginning of iPrEx OLE. A concentration of tenofovir-diphosphate (TFV-DP) of 16 fmol per million (fmol/m) viably cryopreserved peripheral blood mononuclear cells was associated with a 90% reduction in HIV incidence and indicated use of 2 to 3 tablets per week. BMD in participants with week 24 TFV-DP levels above 16 fmol/m were compared with those randomized to receive FTC/TDF who had lower drug concentrations and to those in the placebo group.
498 people were enrolled in the iPrEx DXA substudy, in which BMD decreased during the first 24 weeks of PrEP use (Figure). 352 (71%) had DXA scans 24 weeks after stopping study medication, and 289 (58%) had scans at the start of iPrEx OLE, which occurred a median of 73 weeks (interquartile range: 59 to 87) after stopping study medication. Among those with scans at the start of iPrEx OLE, the median age was 29, and 12% percent identified as trans. Average BMD in the spine and hip accumulated after PrEP use stopped: among those with TFV-DP >16 fmol/m at week 24, average annualized recovery rates after stopping PrEP were 1.81±0.36% in the spine (P=0.01 vs. placebo) and 1.13±0.27% in the hip (P=0.002 vs. placebo). In this group, average BMD recovered completely within 6 months after stopping PrEP in the spine, and by the start of iPrEx OLE in both the hip and spine (Figure). Evidence of BMD recovery persisted after adjusting for differences in study retention by age and drug concentrations and in multiple imputations of BMD values.
BMD loss is observed with levels of FTC/TDF PrEP use that are near the minimum required for providing high-level protection from rectal HIV exposure. In this predominately young adult population, there was recovery of BMD to placebo levels after stopping FTC/TDF PrEP.