Effects on Vitamin D, Bone and the Kidney of Switching from Fixed-Dose Tenofovir Disoproxil Fumarate/Emtricitabine/Efavirenz to Darunavir/ Ritonavir Monotherapy: A Randomized, Controlled Trial (MIDAS)

Background Efavirenz (EFV) has been associated with reductions in vitamin D (25[OH]D) and tenofovir (TDF) with increased bone turnover, reductions in bone mineral density (BMD) and renal tubular dysfunction. We hypothesized that switching from fixed-dose TDF/emtricitabine (FTC)/EFV to darunavir/ritonavir monotherapy (DRV/r) might increase 25(OH)D and BMD, and improve renal tubular function. Methods Subjects with HIV RNA <50 copies/ml on TDF/ FTC/EFV for ≥6 months were randomized 1:1 to ongoing TDF/FTC/EFV or DRV/r (800/100 mg once daily) for 48 weeks. The primary end point was change from baseline in 25(OH)D at week 48. Secondary end points included changes in BMD, bone turnover markers and renal tubular function. Results A total of 64 subjects (86% male, 66% white, mean [sd] CD4 + T-cell count 537.3 [191.5]/mm 3 ) were analysed. After adjustment for baseline 25(OH)D and demographics, at week 48 DRV/r monotherapy was associated with a +3.6 (95% CI 0.6, 6.6) ng/ml increase in 25(OH)D compared to TDF/FTC/EFV ( P=0.02). DRV/r monotherapy was associated with an increase in BMD (+2.9% versus -0.003% at the neck of femur and +2.6% versus +0.008% at the lumbar spine for DRV/r versus TDF/FTC/EFV; P<0.05 for all) and reductions in bone biomarkers compared with those remaining on TDF/FTC/EFV. No significant difference in renal tubular function was observed. Reasons for discontinuation in the DRV/r arm included side effects ( n=4) and viral load rebound ( n=3), all of which resolved with DRV/r discontinuation or regimen intensification. Conclusions Switching from TDF/FTC/EFV to DRV/r in patients with suppressed HIV RNA resulted in significant improvements in 25(OH)D and bone biomarkers, and a 2–3% increase in BMD.