Comparison of bone and renal effects in HIV-infected adults switching to abacavir or tenofovir based therapy in a randomized trial

Thomas A Rasmussen, Danny Jensen, Martin Tolstrup, Ulla S Nielsen, Erland J Erlandsen, Henrik Birn, Lars Østergaard, Bente L Langdahl, Alex L Laursen, Thomas A Rasmussen, Danny Jensen, Martin Tolstrup, Ulla S Nielsen, Erland J Erlandsen, Henrik Birn, Lars Østergaard, Bente L Langdahl, Alex L Laursen

Abstract

Introduction: Our objective was to compare the bone and renal effects among HIV-infected patients randomized to abacavir or tenofovir-based combination anti-retroviral therapy.

Methods: In an open-label randomized trial, HIV-infected patients were randomized to switch from zidovudine/lamivudine (AZT/3TC) to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). We measured bone mass density (BMD) and bone turnover biomarkers (osteocalcin, osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), alkaline phosphatase, type I collagen cross-linked C-telopeptide (CTx), and osteoprotegerin). We assessed renal function by estimated creatinine clearance, plasma cystatin C, and urinary levels of creatinine, albumin, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL). The changes from baseline in BMD and renal and bone biomarkers were compared across study arms.

Results: Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. BMD was measured in 33, 26, and 27 patients at baseline, week 24, and week 48, respectively. In TDF/FTC-treated patients we observed significant reductions from baseline in hip and lumbar spine BMD at week 24 (-1.8% and -2.5%) and week 48 (-2.1% and -2.1%), whereas BMD was stable in patients in the ABC/3TC arm. The changes from baseline in BMD were significantly different between study arms. All bone turnover biomarkers except osteoprotegerin increased in the TDF/FTC arm compared with the ABC/3TC arm, but early changes did not predict subsequent loss of BMD. Renal function parameters were similar between study arms although a small increase in NGAL was detected among TDF-treated patients.

Conclusion: Switching to TDF/FTC-based therapy led to decreases in BMD and increases in bone turnover markers compared with ABC/3TC-based treatment. No major difference in renal function was observed.

Trial registration: Clinicaltrials.gov NCT00647244.

Conflict of interest statement

Competing Interests: The study was supported by a grant of US$ 9,100 from GlaxoSmithKline (www.gsk.com). Lars Østergaard has received consultancy and speaker's fee from: Abbott, MSD, Pfizer, Bristol-Meyer Squibb, GlaxoSmithKline, ViiV Healthcare, Gilead, and Tibotec. Alex L Laursen has served on the advisory board for GlaxoSmithKline, Gilead, and Janssen. Lamivudine/zidovudine and abacavir/lamivudine are manufactured by GSK; tenofovir/emtricitabine is manufactured by Gilead. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Flow chart of inclusion and…
Figure 1. Flow chart of inclusion and follow up.
Figure 2. Changes from baseline in hip…
Figure 2. Changes from baseline in hip and lumbar spine BMD.
Percentage and absolute mean changes from baseline in lumbar spine (a, c) and hip (b, d) bone mass density as measured by dual energy x-ray absorptiometry (DXA). BMD = bone mass density; TDF/FTC = tenofovir/emtricitabine; ABC/3TC = abacavir/lamivudine. Error bars show 95% confidence intervals.
Figure 3. Changes from baseline in biomarkers…
Figure 3. Changes from baseline in biomarkers of bone turnover.
Baseline levels of 25-OH vitamin D (a) and percentage changes from baseline in biomarkers of bone turnover (b–f). P1NP = Procollagen type 1 N-terminal propeptide; CTx = Type I collagen cross-linked C-telopeptide (CTx); OPG = Osteoprotegerin; TDF/FTC = tenofovir/emtricitabine; ABC/3TC = abacavir/lamivudine. Mean values are depicted for normally distributed data and median values are depicted for skewed data. Accordingly, error bars show 95% confidence intervals or interquartile ranges.
Figure 4. Changes from baseline in markers…
Figure 4. Changes from baseline in markers of impaired renal function.
Changes from baseline to the indicated time points in estimated creatinine clearance (a), levels of plasma cystatin C at baseline and week 48 (b), changes from baseline to week 48 in plasma cystatin C (c), and changes from baseline to the last measurement in ratios of urinary biomarkers relative to urine creatinine concentration (d, e, f). Changes in urinary biomarkers (d, e, f) were evaluated in 29 patients (15 in the TDF/FTC arm and 14 in the ABC/3TC arm); of these, 24 were followed from baseline to week 48. Error bars in (a) show 95% confidence intervals; the horizontal line in (c) represents the mean value, while the horizontal lines in (d, e, f) represent median values. eCrCl = estimated creatinine clearance; NGAL = neutrophil gelatinase-associated lipocalin TDF/FTC = tenofovir/emtricitabine; ABC/3TC = abacavir/lamivudine.

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