Abstract
Objective:
Initial antiretroviral therapy (ART) causes loss of bone mineral density (BMD) over the first 1–2 years. Whether this loss continues with longer therapy is unclear.
Design and Methods:
In the START BMD substudy, ART-naïve adults with CD4 counts >500 cells/μL were randomised to immediate or deferred ART. Deferred group participants not yet on ART were offered ART after May 2015. Mean percent changes in total hip and lumbar spine BMD (measured annually by dual-energy X-ray absorptiometry) were compared between groups using longitudinal mixed models. Fracture rates were also compared between groups for all START participants.
Results:
Substudy participants (lmmediate group, n=201, Deferred group, n=210; median age 32 years, 80% non-white, 24% female) were followed for mean 4.5 years through December 2016. In the Immediate group, >96% used ART throughout. In the Deferred group, 16%, 58%, and 94% used ART at Years 1, 3 and 5, respectively. BMD decreased more in the Immediate group initially; groups converged by Year 3 at the spine and Year 4 at the hip by ITT. BMD changes after Year 1 were similar in the Immediate group versus those off ART in the Deferred group (mean difference: spine 0.03% per year [95%CI: −0.4, 0.4, p=0.88]; hip −0.2% per year [−0.7, 0.3, p=0.37]). Fracture incidence did not differ significantly between groups: Immediate group 0.86/100 PY vs. Deferred group 0.85/100 PY, HR=1.01 (95%CI 0.76, 1.35, p=0.98).
Conclusion:
Significant ART-induced bone loss slows after the first year of ART and becomes similar to that in untreated HIV.
Keywords: antiretroviral therapy, bone mineral density, HIV, clinical trial
Introduction
Bone mineral density declines in the first one to two years of initial antiretroviral therapy (ART; (1)). This decline is greater in those receiving tenofovir disoproxil fumarate (TDF) and/or a boosted protease inhibitor. But even in those not receiving either of these medications there appears to be a decline of about 1% over 1–2 years (2–5), a decline greater than would be expected in a young adult population and that has been attributed to altered immune function following suppression of HIV replication (6,7).
Whether BMD continues to decline after the first year of initial ART is less clear. Some studies have reported stable BMD after Year 1 (8), in some cases through Year 5 (9). But other studies have reported ongoing decline (10). Unfortunately, most studies only have follow-up of one or two years.
Data on the impact of treated versus untreated HIV infection are sparse. The INSIGHT Strategic Timing of Antiretroviral Therapy (START) study randomised ART-naïve adults with CD4+ lymphocyte counts >500 cells/μL to immediate ART versus deferring ART until CD4 <350 cells/μL; the study results were unblinded in May 2015 because immediate ART was found to decrease the risk of clinical events. At that time, we reported that immediate ART in the START BMD substudy resulted in steeper BMD decline (1–2%) relative to deferred ART after a mean follow-up of 2.2 years (11). After May 2015, all participants were offered ART. We now report final START BMD data collected through December 2016 after a mean follow-up of 4.5 years, complemented with fracture data collected for all participants in the parent START study.
Methods
Study Design and Participants
Details regarding the START trial’s design, participants and assessments have been published (12), as have the baseline characteristics, assessments, endpoints, sample size calculations and statistical plan of its BMD substudy (13).
START randomized 4684 HIV-positive, ART-naïve adults to immediate ART initiation versus deferring ART. ART regimens were not protocol-specified, but were selected pre-randomisation. All remaining untreated participants in the Deferred group were offered ART in May 2015 after mean follow-up of 3.0 years due to demonstration of significant clinical benefit of immediate ART (12).
The START BMD substudy co-enrolled 424 START participants at 33 clinical sites in 11 countries between June 2011 and June 2013, with follow-up completed on December 31, 2016. Participants underwent annual dual-energy x-ray absorptiometry (DXA) on a single Hologic or Lunar scanner to measure BMD at the hip and lumbar spine (L1-L4); all scans were performed using a standardised protocol and were centrally analysed (11).
The substudy was approved by the institutional review board at each participating site and performed in compliance with the Declaration of Helsinki and local regulatory requirements. All participants provided written, informed consent prior to enrolment.
Study Outcomes
The co-primary outcomes were the percent changes from baseline in total hip BMD and lumbar spine BMD. Pre-specified secondary outcomes included change in femoral neck BMD, and rates of BMD loss upon ART initiation in the immediate ART group and among participants in the deferred group prior to ART start (untreated HIV). Evaluation of clinical parameters associated with rates of BMD change was also planned. Fractures were reported for all participants in the parent START study at baseline and annually.
Statistical analyses
Changes in BMD from baseline were expressed as percent of baseline BMD. The primary analysis was the intent-to-treat (ITT) comparison between the Immediate and Deferred ART groups for percent change in BMD using longitudinal mixed models, adjusted for baseline BMD and visit. Groups were compared for changes in BMD to each year of follow-up using ANCOVA models adjusted for baseline BMD. We also compared the Immediate group (excluding those who did not start ART during Year 1) versus the Deferred group censored at ART start. Methods to estimate annual rates of BMD change, for subgroup analyses, and to estimate associations of baseline factors with changes in BMD, were described previously (11).
Fracture incidence rates were estimated in the parent START population using data acquired through December 31, 2016. Treatment groups were compared by ITT using a Cox proportional hazards model, stratified by region.
Analyses were performed with SAS version 9.3 (SAS Institute, Cary, North Carolina, United States) and R version 3 (14).
Results
Participant characteristics
The present analysis includes 411 (96.9%) of the 424 BMD substudy participants (Immediate group, n=201; Deferred group, n=210); we excluded 13 participants with no analysable DXA scan at baseline or during follow-up (Supplementary Figure S1). Baseline characteristics of these two groups were well matched (Supplementary Table S1). The racially-diverse population had a median age of 32 years; 26% were female and 80% non-Caucasian.
Participants were followed for a mean 4.5 (SD 0.5) years; data completeness was >90% at each visit (Supplementary Table S2). In the Immediate group, >96% used ART each year through Year 5. In the Deferred group, 16%, 29%, 58%, 84%, and 94% used ART at Years 1–5, respectively (Supplementary Figure S2). Initial ART contained TDF for 82.8% of participants, efavirenz for 78.1%, and a protease inhibitor for 13.0%. No tenofovir alafenamide (TAF) was used.
Changes in BMD
Mean percent changes in BMD from baseline and annual rates of BMD change at the spine and total hip are summarized in Table 1. BMD declined more in the Immediate than the Deferred group by Year 1 (estimated difference −1.7% [95% CI −2.3, −1.2] at the spine and −1.6% [95% CI −2.2, −0.9] at the total hip; Figure 1A-B). BMD values in the Immediate and Deferred groups had largely converged by Years 3–4 as Deferred group participants progressively initiated ART. In the Immediate group after Year 1, rates of change in BMD were stable at the spine, but continued to decline by about 0.5% per year at the total hip.
Table 1.
Mean percent changes in BMD from baseline, and annual rates of change, by treatment group
| Immediate ART group versus Deferred ART group by Intention to treat | Immediate group versus Deferred ART group participants prior to ART start* | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Immediate ART | Deferred ART | Difference (95%CI) |
P | Immediate ART | Deferred ART | Difference (95%CI) |
P | |||||
| n | Mean change (95% CI) | n | Mean change (95% CI) | n | Mean change (95% CI) | n | Mean change (95% CI) | |||||
| Spine | ||||||||||||
| Year 1 | 194 | −2.1 (−2.5, −1.6) |
197 | −0.3 (−0.7, 0.1) |
−1.7 (−2.3, −1.2) |
<0.001 | 189 | −2.1 (−2.5, −1.6) |
171 | −0.04 (−0.5, 0.4) |
−2.0 (−2.6, −1.4) |
<0.001 |
| Year 2 | 189 | −1.5 (−2.1, −1.0) |
195 | −0.4 (−0.9, 0.1) |
−1.1 (−1.9, −0.4) |
<0.01 | 184 | −1.5 (−2.1, −0.9) |
134 | 0.5 (−0.1, 1.0) |
−2.0 (−2.8, −1.2) |
<0.001 |
| Year 3 | 184 | −1.6 (−2.2, −1.0) |
194 | −1.1 (−1.7, −0.5) |
−0.5 (−1.4, 0.4) |
0.26 | 180 | −1.6 (−2.2, −0.9) |
79 | 0.2 (−0.6, 1.0) |
−1.8 (−2.9, −0.7) |
<0.01 |
| Year 4 | 146 | −1.8 (−2.6, −1.0) |
147 | −1.4 (−2.1, −0.7) |
−0.4 (−1.4, 0.7) |
0.52 | 142 | −1.7 (−2.5, −1.0) |
27 | −0.6 (−2.3, 1.0) |
−1.1 (−3.0, 0.9) |
0.27 |
| Year 5 | 27 | −4.1 (−5.7, −2.6) |
32 | −1.7 (−3.4, 0.02) |
−2.5 (−4.8, −0.1) |
0.05 | 27 | −4.1 (−5.7, −2.6) |
2 | 4.9 (1.7, 8.0) |
−9.0 (−15.1, −3.0) |
<0.01 |
| Overall | 201 | −1.8 (−2.3, −1.4) |
210 | −0.9 (−1.3, −0.4) |
−1.0 (−1.6, −0.3) |
<0.01 | 196 | −1.8 (−2.2, −1.4) |
176 | 0.2 (−0.3, 0.7) |
−2.0 (−2.7, −1.3) |
|
| Rate of change | ||||||||||||
| Year 1–2 | 184 | 0.5 (0.03, 0.9) |
185 | −0.1 (−0.5, 0.3) |
0.6 (−0.1, 1.2) |
0.08 | 179 | 0.5 (0.1, 0.9) |
130 | 0.5 (0.1, 1.0) |
−0.02 (−0.6, 0.6) |
0.95 |
| Year 2−3 | 177 | 0.02 (−0.4, 0.5) |
185 | −0.8 (−1.2, −0.3) |
0.8 (0.1, 1.4) |
0.02 | 173 | −0.01 (−0.5, 0.4) |
75 | −0.5 (−1.2, 0.1) |
0.5 (−0.3, 1.3) |
0.20 |
| Year 3−4 | 143 | 0.2 (−0.4, 0.7) |
145 | −0.7 (−1.3, −0.2) |
0.9 (0.1, 1.7) |
0.02 | 139 | 0.2 (−0.3, 0.8) |
25 | 0.1 (−1.2, 1.4) |
0.12 (−1.3, 1.5) |
0.86 |
| Year 4−5 | 26 | −0.9 (−2.2, 0.4) |
32 | −0.4 (−1.6, 0.7) |
−0.5 (−2.3, 1.2) |
0.55 | 26 | −0.9 (−1.8, −0.1) |
2 | 2.2 (−0.9, 5.2) |
−3.1 (−6.5, 0.4) |
0.08 |
| From year 1 overall | 197 | 0.1 (−0.1, 0.3) |
204 | −0.5 (−0.7, −0.3) |
0.5 (0.3, 0.8) |
<0.001 | 192 | 0.1 (−0.1, 0.3) |
140 | 0.2 (−0.1, 0.5) |
0.03 (−0.4, 0.4) |
0.88 |
| Total hip | ||||||||||||
| Year 1 | 193 | −2.0 (−2.6, −1.5) |
197 | −0.5 (−0.9, −0.1) |
−1.6 (−2.2, −0.9) |
<0.001 | 188 | −2.2 (−2.7, −1.6) |
171 | −0.2 (−0.6, 0.2) |
−2.0 (−2.6, −1.3) |
<0.001 |
| Year 2 | 188 | −2.8 (−3.5, −2.1) |
195 | −1.4 (−2.0, −0.8) |
−1.3 (−2.2, −0.4) |
<0.01 | 183 | −2.9 (−3.5, −2.2) |
133 | −0.7 (−1.2, −0.1) |
−2.2 (−3.1, −1.3) |
<0.001 |
| Year 3 | 183 | −3.2 (−3.9, −2.5) |
193 | −2.1 (−2.9, −1.4) |
−1.0 (−2.0, 0.0) |
0.05 | 179 | −3.2 (−3.9, −2.5) |
79 | −0.6 (−1.3, 0.1) |
−2.6 (−3.8, −1.5) |
<0.001 |
| Year 4 | 146 | −3.5 (−4.4, −2.6) |
148 | −3.2 (−4.0, −2.4) |
−0.2 (−1.4, 0.9) |
0.68 | 142 | −3.6 (−4.5, −2.7) |
27 | −1.2 (−3.1, 0.6) |
−2.4 (−4.6, −0.3) |
0.03 |
| Year 5 | 27 | −5.6 (−7.6, −3.6) |
32 | −3.8 (−5.8, −1.8) |
−2.0 (−4.9, 1.0) |
0.20 | 27 | −5.6 (−7.6, −3.6) |
2 | 5.7 (−1.9, 13.2) |
−11.3 (−19.0, −3.5) |
<0.01 |
| Overall | 200 | −2.8 (−3.3, −2.2) |
210 | −1.7 (−2.2, −1.1) |
−1.1 (−1.9, −0.3) |
<0.01 | 195 | −2.9 (−3.3, −2.4) |
176 | −0.5 (−1.0, 0.1) |
−2.1 (−2.9, −1.4) |
<0.001 |
| Rate of change | ||||||||||||
| Year 1−2 | 183 | −0.8 (−1.3, −0.4) |
185 | −0.8 (−1.2, −0.3) |
0.0 (−0.7, 0.7) |
>0.99 | 178 | −0.8 (−1.2, −0.4) |
129 | −0.3 (−0.8, 0.2) |
−0.5 (−1.1, 0.2) |
0.18 |
| Year 2−3 | 176 | −0.2 (−0.7, 0.4) |
184 | −0.8 (−1.3, −0.2) |
0.6 (−0.2, 1.4) |
0.12 | 172 | −0.1 (−0.7, 0.5) |
75 | −0.2 (−1.1, 0.7) |
0.1 (−0.9, 1.2) |
0.84 |
| Year 3−4 | 143 | −0.2 (−0.7, 0.3) |
145 | −1.1 (−1.6, −0.6) |
0.9 (0.2, 1.6) |
0.02 | 139 | −0.2 (−0.7, 0.2) |
25 | −0.1 (−1.1, 1.0) |
−0.1 (−1.3, 1.1) |
0.88 |
| Year 4−5 | 26 | −1.3 (−2.0, −0.5) |
32 | −0.6 (−1.2, 0.11) |
−0.8 (−1.8, 0.3) |
0.13 | 26 | −1.3 (−2.2, −0.4) |
2 | 0.6 (−2.7, 3.8) |
−1.8 (−5.4, 1.8) |
0.31 |
| From year 1 overall | 196 | −0.5 (−0.7, −0.2) |
204 | −0.9 (−1.1, −0.6) |
0.4 (0.02, 0.7) |
0.04 | 191 | −0.4 (−0.7, −0.2) |
139 | −0.3 (−0.6, 0.1) |
−0.2 (−0.7, 0.3) |
0.37 |
Participants in the Immediate ART group who did not start ART within the first year are excluded, and follow−up in the Deferred ART group is censored at ART start.
Figure 1. Mean percent change in BMD with 95% CIs from baseline through follow-up.
Panels A-C show the intent-to-treat comparison between the Immediate and Deferred ART groups. In panels D-F, follow-up in the Deferred group was censored at ART start, and in the Immediate group, participants who did not start ART in the first year were excluded.
* In the Immediate group, 5 participant who did not start ART in the first year were excluded.
When censoring follow-up at ART start in the Deferred group, the Immediate minus Deferred treatment difference at Year 1 was −2.0% (95% CI −2.6, −1.3) at the spine, and −2.0% (95% CI −2.6, −1.4) at the hip. After Year 1, the annual rates of BMD change in the Immediate group and those remaining off ART in the Deferred group were not significantly different (Figure 1D-F).
In subgroup analyses, the treatment difference in spine BMD was larger among those with baseline CD4 counts ≥650 cells/μL compared with those with lower CD4 counts (−1.7% and −0.3%, respectively, p=0.008 for heterogeneity). BMD losses were less steep among smokers than among non-smokers (spine −0.7% and −2.2%, respectively; hip −0.7% and −2.8%, respectively; p=0.05 for heterogeneity at both the hip and spine) (Supplementary Figure S3). There was no evidence for heterogeneity of the treatment effect among subgroups defined by age, sex, race, geographic region, baseline HIV RNA levels, and TDF in the pre-specified ART regimen.
Predictors of BMD decline
In the Immediate ART group, no baseline variable consistently predicted greater loss of BMD at both the hip and spine (Supplementary Table S3). Higher HIV viral load was associated with steeper decline of total hip BMD. A higher CD8 count was associated with steeper decline of spine BMD, and smoking was associated with steeper BMD loss at the hip. Within the Deferred group (censored at ART start), a lower CD4 count was associated with steeper BMD decline at the spine and femoral neck (Supplementary Table S4).
Incidence of fractures
In the parent START study, 182 (3.9%) of the 4684 participants experienced a fracture: 91 (0.86 per 100 PY) in the Immediate group and 91 (0.85 per 100 PY) in the Deferred group, (hazard ratio 1.01 [95% CI 0.76, 1.35, p=0.98]) (Supplemental Table S5, Supplemental Figure S4).
Discussion
These final data from the START BMD substudy confirm that initial ART significantly accelerates BMD loss over the first 1–2 years in young adults. With up to 5 years of follow-up, there was evidence for ongoing BMD loss in both groups, but the between-group difference in later years was modest and not significant.
Our data provide reassurance that the steep rate of BMD loss in the first year of ART is ameliorated in subsequent years, as observed in other cohorts (15–17). Indeed, after Year 1, the rate of loss in the Immediate ART group was similar to those who remained ART naïve in the Deferred group. This finding supports similar data comparing adults on stable ART and matched HIV-negative controls (15). However, the rate of decline after Year 1 remains greater than might be expected in a population of this age (18). The normal rate of decline in BMD in later years is influenced by race/ethnicity and age (19, 20). Our participants were racially diverse, so a comparison with a cohort such as NHANES III may not be appropriate. Longitudinal data from a Canadian study suggests there is virtually no loss of BMD at either hip or spine until after the age of 40 years (18).
There was no consistent signal for level of CD4 cells, CD8 cells or CD4/CD8 ratio as predictors of greater bone loss at both the hip and the spine. Our results are in agreement with others who reported a higher pre-ART viral load predicted greater bone loss with initiation of ART (2, 17). Our study is also in agreement with another randomised trial of ART in which a lower CD4 count did not predict greater bone loss on initiation of ART (4), in contrast to other studies (17). The finding that higher CD8 counts were associated with greater bone loss in those initiating ART is novel and not previously reported. The finding that none of the traditional risk factors for bone loss predicted change in BMD may have been due to the young age of our study population.
Our analysis has limitations. Most participants in the Deferred group initiated ART by Year 4. Therefore, the ITT comparison between the Immediate and Deferred groups does not accurately quantify the effect of ART versus untreated HIV in the later years, while comparing the Immediate group versus untreated HIV in the Deferred group is not protected by randomization. However, given that immediate ART is now standard-of-care, it is highly unlikely that another study will ever evaluate the long-term effects of ART relative to no ART. Most ART regimens contained TDF, which is a well-known cause of BMD loss; TDF remains a common backbone, in part because of its preferred status within the WHO guidelines (21).
In summary, bone loss with initial ART slows after the first year of ART, and the rates of change in BMD after the first year were similar with or without ART. In this relatively young population, ART-related BMD loss did not translate into a greater incidence of fractures.
Supplementary Material
Acknowledgements
We thank all study participants, site co-ordinators and investigators, and staff at the radiology sites, the coordinating centres, and the UCSF QA Centre. See J Bone Min Res 2017; 32: 1945–55 for a complete list of START Bone Mineral Density Substudy investigators and N Engl J Med 2015; 373: 795–807 for a complete list of all START investigators.
This work was supported by the National Institute of Allergy and Infectious Diseases (Grants U01-AI068641, UM1-AI120197, 1U01-AI136780), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant RO1 – AR060057–01). The parent START study was supported by the National Institute of Allergy and Infectious DiseasesNational Institutes of Health Clinical Center, National Cancer Institute, National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (France), National Health and Medical Research Council (Australia), National Research Foundation (Denmark), Bundes ministerium für Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and University of Minnesota. Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. The content is solely that of the authors and does not represent the views of the National Institutes of Health, nor those of AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, or Merck.
AC has received research funding from Bristol-Myers Squibb, Gilead Sciences, and ViiV Healthcare; in-kind research support from Novartis; conference travel sponsorships from Bristol-Myers Squibb, Gilead Sciences, and ViiV Healthcare; and has served on advisory boards for Gilead Sciences, MSD and ViiV Healthcare. KE received travel support from Merck Sharp & Dohme for attendance at DMC meetings. AL received honoraria and salary from MSD and Janssen. AS has received a grant from Hologic Inc. JH’s institution received funding for her participation in Advisory Boards for Gilead Sciences, AbbVie and ViiV Healthcare. BG, NWE, AVS, AA, SBF, JIB, VE, ALR, PWGM, SP, and DW declare no conflict of interest.
References
- 1.Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006;20(17):2165–74. [DOI] [PubMed] [Google Scholar]
- 2.McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203(12):1791–801. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Stellbrink HJ, Orkin C, Arribas JR, Compston J, Gerstoft J, Van Wijngaerden E, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis. 2010;51(8):963–72. [DOI] [PubMed] [Google Scholar]
- 4.Brown TT, Moser C, Currier JS, Ribaudo HJ, Rothenberg J, Kelesidis T, et al. Changes in Bone Mineral Density After Initiation of Antiretroviral Treatment With Tenofovir Disoproxil Fumarate/Emtricitabine Plus Atazanavir/Ritonavir, Darunavir/Ritonavir, or Raltegravir. J Infect Dis. 2015;212(8):1241–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Duvivier C, Kolta S, Assoumou L, Ghosn J, Rozenberg S, Murphy RL, et al. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naive patients. AIDS. 2009;23(7):817–24. [DOI] [PubMed] [Google Scholar]
- 6.Ofotokun I, Titanji K, Vunnava A, Roser-Page S, Vikulina T, Villinger F, et al. Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection. AIDS. 2016;30(3):405–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.McGinty T, Mirmonsef P, Mallon PW, Landay AL. Does systemic inflammation and immune activation contribute to fracture risk in HIV? Curr Opin HIV AIDS. 2016;11(3):253–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292(2):191–201. [DOI] [PubMed] [Google Scholar]
- 9.Bolland MJ, Grey A, Horne AM, Briggs SE, Thomas MG, Ellis-Pegler RB, et al. Stable bone mineral density over 6 years in HIV-infected men treated with highly active antiretroviral therapy (HAART). Clinical Endocrinology. 2012;76(5):643–8. [DOI] [PubMed] [Google Scholar]
- 10.Grund B, Peng G, Gibert CL, Hoy JF, Isaksson RL, Shlay JC, et al. Continuous antiretroviral therapy decreases bone mineral density. AIDS. 2009;23(12):1519–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Hoy JF, Grund B, Roediger M, Schwartz AV, Shepherd J, Avihingsanon A, et al. Immediate Initiation of Antiretroviral Therapy for HIV Infection Accelerates Bone Loss Relative to Deferring Therapy: Findings from the START Bone Mineral Density Substudy, a Randomized Trial. J Bone Miner Res. 2017;32(9):1945–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.INSIGHT Start Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. New England Journal of Medicine. 2015;373(9):795–807. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Carr A, Grund B, Neuhaus J, Schwartz A, Bernardino JI, White D, et al. Prevalence of and risk factors for low bone mineral density in untreated HIV infection: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. HIV Med. 2015;16 Suppl 1:137–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2016. [Available from: https://www.R-project.org/. [Google Scholar]
- 15.Tinago W, Cotter AG, Sabin CA, Macken A, Kavanagh E, Brady JJ, et al. Predictors of longitudinal change in bone mineral density in a cohort of HIV-positive and negative patients. AIDS. 2017;31(5):643–52. [DOI] [PubMed] [Google Scholar]
- 16.McComsey G, Kitch D, Daar E, Tierney C, Jahed N, Tebas P, et al. Bone and Limb Fat Outcomes of ACTG A5224s, a Substudy of ACTG A5202: A Prospective, Randomized, Partially Blinded Phase III Trial of ABC/3TC or TDF/FTC with EFV or ATV/r for Initial Treatment of HIV-1 Infection. 17th Conference on Retroviruses and Opportunistic Infections (CROI); San Francisco2010. [Google Scholar]
- 17.Grant PM, Kitch D, McComsey GA, Collier AC, Koletar SL, Erlandson KM, et al. Long-term Bone Mineral Density Changes in Antiretroviral-Treated HIV-Infected Individuals. J Infect Dis. 2016;214(4):607–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Berger C, Langsetmo L, Joseph L, Hanley DA, Davison KS, Josse R, et al. Change in bone mineral density as a function of age in women and men and association with the use of antiresorptive agents. CMAJ. 2008;178(13):1660–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Nam HS, Kweon SS, Choi JS, Zmuda JM, Leung PC, Lui LY, et al. Racial/ethnic differences in bone mineral density among older women. J Bone Miner Metab. 2013;31(2):190–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Araujo AB, Travison TG, Harris SS, Holick MF, Turner AK, McKinlay JB. Race/ethnic differences in bone mineral density in men. Osteoporos Int. 2007;18(7):943–53. [DOI] [PubMed] [Google Scholar]
- 21.Organization WH. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidance. Geneva: World Health Organization; 2018. [Available from: http://www.who.int/hiv/pub/guidelines/ARV2018update/en/. [Google Scholar]
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