To compare bone mineral density (BMD) changes over 96 weeks in adults virologically failing standard first-line therapy, randomized to raltegravir plus lopinavir/ritonavir (RAL + LPV/r) or conventional 2-3 nucleoside/nucleotide reverse transcriptase inhibitors [N(t)RTIs] + LPV/r second-line therapy.
Participants underwent dual-energy x-ray absorptiometry at baseline and weeks 48 and 96 to measure total hip and lumbar spine BMD. Analyses were adjusted for gender, body mass index, and smoking. Linear regression was used to compare between-group differences, logistic regression for low BMD (hip or spine Z-score ≤ −2) incidence, and multivariate linear regression to determine predictors of BMD change. This work represents the extension and final results of the previously published initial 48 weeks of the study.
The population included 210 adults from 5 middle-income countries: 52% females, 52% Asians, 43% Africans, mean age, 39 years (SD, 8 years). In the 2-3 N(t)RTI group (vs. RAL), BMD reduction was greater at the spine (mean change, −4.9% vs. −3.5%; adjusted difference, −1.9%; 95% confidence interval: −3.3 to −0.5%, P = 0.009) and hip (−4.1% vs. −2.2%; −1.9%; −3.4 to −0.4; P = 0.012). BMD decrease was greatest at 48 weeks with stabilization to week 96. Overall, low BMD occurred in 15 participants (7.9%), with no between-group differences. Independent predictors for bone loss included lower body mass index (regression coefficient: hip, −0.18% and spine, −0.26% per 1 kg/m2), longer tenofovir exposure (hip, −0.74% and spine, −1.0% per year), greater change in CD4+ to week 12 (hip, −5.11% per 10-fold higher), and higher baseline HIV-RNA (spine, −0.7% per 10-fold higher).
Over 96 weeks, there was greater BMD decrease with 2-3 N(t)RTI + LPV/r compared with RAL + LPV/r; the relative decrease at the spine was greater than the hip. BMD decreases with second-line antiretroviral therapy largely occurred in the first 48 weeks with stabilization, but no recovery thereafter.
*The Kirby Institute, University of New South Wales, Sydney, Australia;
†UCD School of Medicine and Medical Science, Dublin, Ireland;
‡The Alfred Hospital, Melbourne, Australia;
§Thai Red Cross AIDS Research Center, Bangkok, Thailand;
‖Hopital Saint-Louis, Paris, France; and
¶CICAL, Buenos Aires, Argentina.
Correspondence to: Hila Haskelberg, PhD, The Kirby Institute, The University of New South Wales, Sydney, NSW 2052, Australia (e-mail: email@example.com).
Supported by The Kirby Institute, which is funded by the Australian Government Department of Health and Ageing. The Kirby Institute is affiliated with the Faculty of Medicine, University of New South Wales. Funding for the Second-Line study was provided by The Kirby Institute, Merck & Co. Inc, Abbott Laboratories, NHMRC, and amfAR. P.W.G.M. has received support in honoraria, research grants, lecture sponsorships, and advisory boards from Abbott, Merck Sharpe and Dohme, Bristol Myers Squibb, Pfizer, Gilead, Glaxo-Smith Kline, Janssen-Cilag, and ViiV Healthcare. J.H.'s institution has received funding for investigator-initiated research. She has served on advisory boards and received lecture and conference sponsorship from Janssen-Cilag, Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare. M.A.B. was paid to prepare and present educational materials for Boehringer-Ingelheim, Gilead, Janssen-Cilag, and Merck Sharpe and Dohme. D.A.C. has received AbbVie and Merck Sharpe and Dohme grants, consultant, and speaker fees. S.E. has received research grant support from Abbvie, Gilead Sciences, Merck Research Laboratories, Pfizer, and ViiV Healthcare.
Second-Line bone substudy sub-committee: study concept and analysis plan design: H.H., P.M., J.H., J.A., C.M., D.A.C., M.A.B., S.E.; overseeing study conduct and data acquisition: H.H., M.A.B., S.E.; data analysis: H.H.; data interpretation: H.H., P.M., J.H., J.A., C.M., D.A.C., M.A.B., S.E.; drafting manuscript: H.H.; revising manuscript content: H.H., P.M., J.H., J.A., C.M., S.F., W.B., D.A.C., M.A.B., S.E.; approving final version of manuscript: H.H., P.M., J.H., J.A., C.M., P.P., S.F., W.B., D.A.C., M.A.B. and S.E. Second-Line bone substudy investigators: Dr Nagalingeswaran Kumarasamy, Dr Sharne Foulkes, Prof Robin Wood, Dr Ploenchan Chetchotisakd, Prof Praphan Phanuphak, Dr Lerato Mohapi, Dr Adeeba Kamarulzaman, Dr Oscar Messina. Second-Line study team: Prof David Cooper, Prof Sean Emery, Dr Mark Boyd, Allison Humphries, Natalie Espinosa, Hila Haskelberg, Maria Arriaga, Sally Hough, Nisha Berthon-Jones, Dr Janaki Amin, Cecilia Moore, Rashelle Raymond, Rosemary Robson, Dr Steven Kerr, Kanitta Pussadee, Dr Marcelo Losso, Cecilia Abela.
Received February 25, 2014
Accepted May 30, 2014