The long-term consequences of HIV-infection and exposure to antiretroviral therapy (ART) have been extensively studied in HIV-infected adults, suggesting a higher risk of non-AIDS complications in those with HIV, characterized by diseases typically associated with aging.1,2 Higher rates of low bone mineral density (BMD) at hip and spine and osteoporosis are found in HIV-infected adults compared with uninfected controls,3 with an almost 5-fold increased risk of hip fracture incidence in the HIV-infected adults [hazard ratio: 4.7, 95% confidence interval (CI): 2.4 to 9.5], found in a recent population-based study in Spain independent of sex, age, smoking, alcohol drinking, and comorbidities.4 Initiation of ART is associated with a 2%–6% BMD decrease,5–7 and higher rates of fractures8 largely limited to the first 2 years of ART, with the greatest decreases occurring during the first 48 weeks. Besides traditional risk factors and ART effects, it was recently suggested that low baseline CD4+ count9 is also associated with greater bone loss in ART-naive adults initiating ART.
Only a few studies have described the effects of the integrase inhibitor ART class on BMD, and most results have been limited to changes up to 48 weeks of exposure,10–12 with only 1 study examining BMD changes with antiretroviral initiation, limited to measurement of total body rather than hip or spine BMD.13 Given that the use of combination ART (cART) is lifelong, it becomes increasingly important to characterize long-term outcomes of treatment.
Almost all studies examining the association between HIV and bone disease have been performed in high-income countries3 and predominantly in white populations. There are little data collected on the adverse effects of HIV and ART on BMD in individuals from different ethnic backgrounds in low- or middle-income countries, where the majority of the world's population receiving cART resides and where the focus to date has been on reducing mortality, maintaining virological suppression and reconstituting immunity.
We have previously shown that over the first 48 weeks, participants who virologically failed their first-line ART regimen and were randomized to LPV/r + 2-3 nucleoside/nucleotide reverse transcriptase inhibitors [N(t)RTIs] had greater BMD loss compared with RAL + LPV/r (total hip: −5.2% vs. −2.9%, P = 0.0001; spine: −4.2% vs. −2.0%; P = 0.0006, respectively).14 The BMD decrease was greater in participants exposed to tenofovir disoproxil fumarate (TDF), and the magnitude of bone loss was similar to that observed in treatment-naive patients initiating first-line ART.14 The aim of this analysis was to compare BMD changes in the same cohort over a further 48 weeks, up until the 96-week time point after randomization, to assess whether the BMD decreases observed during the first 48 weeks persisted, reversed, or progressed.
The Second-Line study is a 96-week phase IV multi-center, open-label, randomized controlled trial in HIV-infected adults who have virologically failed first-line ART consisting of an NNRTI + 2 N(t)RTIs. The primary results to week 48, eligibility criteria, and study methods of the Second-Line study have been previously reported.15 Eligible participants were randomized 1:1 to a World Health Organization–recommended second-line treatment, 2-3 N(t)RTI + LPV/r (NtRTI group+LPV/r) or RAL (400 mg twice daily) + LPV/r (400/100 mg 2 times daily or 800/200 mg 4 times daily). A subset of patients enrolled into the Second-Line dual-energy x-ray absorptiometry (DXA) substudy before randomization in 5 middle-income countries: South Africa (n = 94), India (n = 49), Thailand (n = 48), Malaysia (n = 13), and Argentina (n = 7). Recruitment was open to all participants screened at these sites between July 2010 and July 2011. The substudy was approved by each site ethics committee, and all participants provided written informed consent (clinicaltrials.gov identifier: NCT01513122).
DXA scans of the lumbar spine and right hip were performed at baseline, week 48, and week 96 using a standardized protocol at the same imaging facility on the same bone densitometer: Thailand, Malaysia, and Argentina (Lunar Prodigy; GE Healthcare, Madison, WI), India (Lunar iDXA; GE Healthcare), South Africa and Thailand (Hologic Discovery; Hologic Inc, Bedford, MA). The following measures were recorded: total hip BMD derived from the right side, lumbar spine (L2-L4) BMD, associated standardized T scores and Z scores, and total and regional body fat and lean mass. Given the age of the study's participants (<50 years) and based on the International Society for Clinical Densitometry recommendations,16 Z scores of −2.0 or lower were used to define low BMD. The measurement of interest was the change in BMD from baseline; while reproducibility was not assessed as part of this study (phantoms were not used and no central reading), within-patient reproducibility was maximized by each participant, having all their study measures being taken at the same site on the same machine.
The primary endpoint of the study was percent change in total hip BMD over 96 weeks. Secondary endpoints included percent change in lumbar spine BMD, assessment of low BMD incidence at week 96 at the hip or spine, and predictors of BMD change.
In a modified on-treatment analysis, we included available data from all participants who consented to the substudy, underwent randomization, received at least 1 dose of study medication, and who completed both a week 0 and week 96 DXA scan. Sensitivity analyses were conducted on the per-protocol population comprising all participants with BMD data who remained on randomized therapy through to week 96. At baseline, there were differences between the 2 treatment groups for gender, body mass index (BMI), and smoking status that were deemed by a clinician as clinically meaningful and potentially related to the outcomes of interest, therefore, all randomized arms comparisons were adjusted for imbalances in these covariates. Three participants (1.4%) took vitamin D supplements during the study and were included in the analysis.
Linear regression was used to compare mean percentage and absolute change in total hip and lumbar spine BMD from baseline to week 96 between randomized groups. Results are reported as regression coefficients, that is, differences between groups. The interaction between gender or ethnicity and randomized group in predicting BMD change was tested using linear regression. The associations between predictors and 96-week percentage change in hip and spine BMD were analyzed using linear regression. Covariates included age, gender, ethnicity, BMI, BMI change over 96 weeks, smoking, alcohol consumption, hepatitis C virus co-infection status, time since HIV diagnosis, CD4+ lymphocyte count (baseline and nadir), CD4+ change over 12 weeks (absolute and relative, defined as log10[CD4+ wk12/CD4+ wk0]), baseline plasma HIV RNA, HIV RNA change over 12 weeks, randomized arm, prior and on-study duration of TDF, zidovudine (AZT), and stavudine (d4T), body composition (total body fat and lean mass), prior hypogonadism, socioeconomic variables (maximum educational grade achieved and annual income), and physical activity (days per week estimated by the participant). The multivariable model was built using backward stepwise methods. Covariates that achieved a P-value <0.1 in univariate analysis were assessed and retained in the multivariate model if P < 0.05.
Incidence over 96 weeks of new cases of low BMD at the spine or hip was compared between treatment groups using logistic regression. A predefined exploratory analysis tested median change in BMD by on-study exclusive exposure to 4 groups of drugs (RAL, AZT, TDF, and TDF + AZT), which were compared by Kruskal–Wallis test. Statistical significance was defined as a 2-sided α of 0.05. A sample size of 100 per randomized treatment group was required to achieve 80% power to detect a mean between-group difference of 1.7% change in BMD. Statistical analyses were performed with STATA (version 12.0; StataCorp, College Station, TX).
Patient disposition is described in Figure 1. Of the 669 individuals screened to the parent Second-Line study, 236 consented to the substudy and 210 participants comprised the analysis population. Ninety-one participants reached week 96 in the NtRTI + LPV/r group and 105 in the RAL + LPV/r group. Baseline characteristics are summarized in Table 1. Median [interquartile range (IQR)] age at baseline was 38.8 years (33.0–44.2 years), 52% were female, 52% were Asians, and 43% Africans. The median (IQR) baseline BMI was 23 kg/m2 (20–26 kg/m2). Median (IQR) CD4+ count was 202 cells per microliter (104–307 cells/μL), and HIV-RNA plasma level was 4.1 log10 copies per milliliter (3.5–4.7 log10 copies/mL). Duration of cART was 3.3 years (1.9–5.9 years), 34% were on AZT and 48% on d4T at study entry.
At week 96, the mean (SD) percentage change from baseline in total hip BMD in the NtRTI + LPV/r group was −4.1% (5.9%) vs. −2.2% (4.5%) in the RAL + LPV/r group (adjusted treatment difference, −1.9%; 95% CI: −3.4 to −0.4; P = 0.012). For lumbar spine, the mean (SD) percentage BMD change over 96 weeks in the NtRTI + LPV/r group was −4.9% (4.9%) compared with −3.5% (5.0%) in the RAL + LPV/r group (adjusted treatment difference, −1.9%; 95% CI: −3.3 to −0.5; P = 0.009; Table 2, Fig. 2). BMD decrease was greatest at 48 weeks for both treatment groups (hip, −4.5% vs. −1.8%; spine, −4.8% vs. −3.0%), with minor changes between weeks 48 and 96. The relative BMD decrease at the spine was greater than the hip. BMD changes in the per-protocol (PP) population were of similar magnitude, and differences between treatment groups remained significant (results not shown).
Covariates significantly associated with greater decline in hip BMD over 96 weeks in multivariable analysis were lower baseline BMI (regression coefficient −0.18% per 1 kg/m2, P = 0.029), BMI decrease over 96 weeks (−0.37% per 1 kg/m2, P = 0.014), greater relative increase in CD4+ at week 12 (−5.11% per 10-fold higher, P = 0.001), and longer on-study exposure to TDF (−0.74% per 1 year, P = 0.02). Predictors of greater decline in spine BMD were female gender (−1.86%, P = 0.032), lower baseline BMI (0.26% per 1 kg/m2, P = 0.001), higher baseline plasma HIV RNA levels (−0.7% per 10-fold higher, P = 0.049), longer on-study exposure to TDF (−1.0% per 1 year, P = 0.004), and longer AZT exposure before study (−0.53% per 1 year, P = 0.002; Table 3). At week 12, 58% (n = 121) of the cohort had undetectable viral load. The mean (SD) change in log HIV RNA from baseline to week 12 was −2.0 (1.2) log10 copies per milliliter and was not independently associated with the change in BMD over 96 weeks. The absolute change in CD4+ T cell from baseline to week 12 was 87.9 (98.4) cells per microliter, and the median relative change (CD4+ wk12/CD4+ wk0) was 1.42 (IQR: 1.10–1.96). No association was found between baseline BMD and change in BMD over 96 weeks in a univariate regression analysis.
There was a significant interaction between treatment arm and gender on spine BMD percent change over 96 weeks (F = 3.05; P = 0.03): the mean difference between arms (NtRTI + LPV/r-RAL) in females was: −2.7; 95% CI: −4.7 to −0.7; P = 0.009, and in males was: 0.5; 95% CI: −1.6 to 2.5; P = 0.663. No interactions were found for treatment arm and gender on hip BMD percent change over 96 weeks (F = 2.21; P = 0.08) nor for treatment arm and ethnicity on hip or spine BMD percent change over 96 weeks (hip: F = 1.39; P = 0.23, spine: F = 1.23; P = 0.29).
For the whole cohort, low BMD (hip or spine) occurred in 15 participants (7.9%). No difference was found between treatment groups for the incidence to week 96 of low BMD (P = 0.878). Among RAL + LPV/r recipients, 1.0% developed low BMD at the hip and 7.7% at the spine compared with 1.2% and 7.7%, respectively, in the NtRTI + LPV/r group. Only 2 participants (1%) experienced a bone fracture over 96 weeks, 1 in the NtRTI + LPV/r group (supracondylar fracture of right femur due to road traffic accident) and 1 in the RAL group (right ankle fracture after a fall).
In an exploratory comparison of change in BMD over 96 weeks by on-study drug exposure, there was a significant difference between the 4 exclusive groups for percent change in hip BMD (H(2) = 10.25, P = 0.017), with median (IQR) percent change in hip BMD by group: RAL −2.0% (−4.4% to −0.1%), AZT −2.3% (−3.2% to −1.0%), TDF −3.8% (−6.4% to −1.6%), and TDF + AZT −5.0% (−9.5% to −0.3%). A significant difference was also found for change in spine BMD (H(2) = 10.71, P = 0.013), with a median (IQR) change for RAL −3.1% (−6.5% to −0.3%), AZT −0.9% (−3.6% to 0.0%), TDF −5.8% (−8.8% to −2.5%), and TDF + AZT −5.0% (−8.4% to −1.9%).
The Second-Line study is the first study examining BMD changes over 96 weeks in patients from middle-income countries virologically failing their first-line ART regimen. Participants were randomized to 2 reasonable alternative options for second-line cART with similar likelihood of suppression of viremia.16 In a cohort of 210 participants, we found that over 96 weeks, there was greater BMD decrease in 2-3 N(t)RTI + LPV/r recipients compared with RAL + LPV/r; the relative decrease at the spine was greater than the hip. Bone loss mostly occurred in the first year on study, with no further decline between week 48 and 96. Although there were greater BMD reductions in the NtRTI + LPV/r group compared with the RAL, there was no difference in the development of low BMD. Independent predictors for BMD decrease included lower baseline BMI, longer TDF exposure on study, higher relative change in CD4+ from baseline to week 12, and higher baseline plasma HIV RNA.
Our findings are consistent with other studies in ART-naive patients initiating first-line ART, showing an early accelerated loss of BMD largely limited to the first year of treatment that seems to plateau thereafter.5,6,17 The magnitude of bone loss observed with second-line ART in our cohort is similar to that with first-line ART. This acute decline during the first year after initiation of first- and second-line ART is likely clinically relevant, with previous studies reporting higher fracture rates in the first 2 years after ART initiation in ART-naive patients.8 In our study, only 2 participants experienced fractures over the 2 years of follow-up, 1 in each treatment group, reflecting a relatively small sample size and limited follow-up in determining fracture incidence.
The observed magnitude of bone loss was greater at the spine than the hip. Given that both treatment groups received protease inhibitors (PIs), this finding is consistent with the results from the A5224s substudy that found that PI recipients had a greater BMD decrease compared with NNRTI recipients, but only at the spine.6 The difference between the regions could be due to the fact that the spine comprises relatively more trabecular bone than the hip, and the rate of turnover is more rapid in trabecular bone compared with cortical bone (recently reviewed in Ref. 18). There are mixed reports regarding the effect of PIs on BMD. Although a meta-analysis of 10 studies found increased odds for reduced BMD PI-treated patients (odds ratio: 1.8, 95% CI: 1.2 to 2.6),3 other studies did not find this link.19,20 The inconsistent results could be due to the different nature of the studies (cross-sectional or prospective), and a possible different effect of the individual PIs included in each of the studies. PIs were also found to impact body fat in HIV-infected adults,21 which may lead to changes in BMD. However, in this cohort, change in total body fat did not appreciably alter the study findings (data not shown).
It is still not clear to what extent the early bone loss associated with ART initiation is due to direct effects of specific drugs or due to the ART-induced reduction in HIV viremia or indirect effects of associated immune reconstitution.22 Higher levels of the proinflammatory cytokines, such as TNF-α, are found in HIV-seropositive individuals and may stimulate bone resorption.23 Activation of CD4+ T cells can lead to production of receptor activator of NF-κB ligand and subsequent bone loss.24,25 Barkhordarian et al26 hypothesized that osteoimmune responses that lead to bone loss may be consequential to immune reconstitution inflammatory syndrome, which is characterized by heighted immune responses.27 Our findings of associations between that greater increases in CD4+ count at week 12, higher baseline HIV RNA, and subsequent loss of BMD support a role for direct viral-mediated or indirect immune-mediated effects on bone metabolism to explain at least part of the observed loss of BMD. These data are broadly consistent with results from a recent analysis of pooled data from 3 ACTG trials (n = 796) showing that low baseline CD4+ count (but not greater CD4+ increase) and predicted whole-body BMD decreases.9 However, further research is required to elucidate exact mechanisms underlying how either changes in immune function or viral burden affect bone metabolism or BMD.
Similar to our previously reported 48-week results, TDF exposure remains a strong and independent predictor of bone loss at both hip and spine over 96 weeks. This adds to the growing body of literature confirming that even after controlling for other risk factors, TDF has a greater effect on reducing BMD compared with other antiretrovirals.6,7,28 In our analysis by drug exposure, the degree of bone loss with TDF over 96 weeks (hip: −3.8%, spine: −5.8%) was larger than the decrease found in the Progress Study (−2.5%),13 although the 2 study cohorts differ in their demographic makeup, their prior cART exposure (Progress Study participants were ART-naive), and the BMD assessment; PROGRESS Study participants only underwent total-body BMD assessments, which are not routinely used for low BMD assessment. This may well explain why participants randomized to RAL in our study experienced reductions in BMD (hip: −2.2% and spine: −3.5%), whereas in Progress Study, the total body BMD at 96 weeks for the RAL group was essentially unchanged (+0.7%).13 Although consistent BMD reductions were observed in both studies, we would consider the assessment of BMD loss in this study to be a more robust estimate of clinically relevant change in BMD with raltegravir-containing ART used in second-line therapy. In contrast, a switch from PI/r to RAL in the SPIRAL-LIP study in virologically suppressed subjects led to a significant increase rather than decrease in femoral neck BMD,12 which suggests that the observed decreases in BMD observed with RAL in this study may be due to either the use of LPV/r or to changes in BMD induced by suppression of HIV viremia and the associated immune changes.
NRTI-sparing regimens with an anticipated lesser effect on bone loss and a smaller impact on bone turnover than TDF-containing regimens are alternative treatment options, albeit not recommended in treatment guidelines. The effects of RAL on bone metabolism have been described in a few studies. A post hoc analysis of the Progress bone substudy showed that early increases in bone turnover markers (BTMs) predicted bone loss and that the difference in regimens (TDF/FTC vs. RAL) on bone loss was largely dependent on the differences in the changes in BTMs.29 In the RADAR study of treatment-naive patients (n = 83), changes in BMD differed significantly (+1.02% with RAL vs. −0.76% with TDF/FTC; P = 0.002), and increasing levels of bone formation and resorption were seen with TDF/FTC but not with RAL.30
Our study has limitations. Our cohort is relatively young, and over 2 years, the number of fractures is too small to allow analysis of clinically meaningful outcomes. In addition, we were unable to stratify the analyses by TDF switch, as the subgroup size was too small. We used the BMD cutoffs as recommended by the National Osteoporosis Foundation guidelines. These are based on studies performed mainly in perimenopausal and postmenopausal white women and may not be applicable for different ethnicities, although the National Osteoporosis Foundation of South Africa recommend that until local reference values become available, reference data for whites should be used for subjects of all races.31 Testing BTMs or hormonal levels might provide more insight into the mechanisms underlying the observed BMD changes. The advantages of this study include an ethnically diverse cohort and enrollment of both men and women, which increases the ability to extrapolate the results. Bone assessment is not routinely performed in the management of HIV-infected adults from middle-income countries, and there are little data that include quantitative measurements of BMD using a standard DXA protocol. Our data set includes comprehensive information regarding known risk factors and secondary causes of osteoporosis.
To conclude, this is one of the first studies to describe BMD changes more than 2 years in participants from developing countries virologically failing first-line regimens with resuppression of viremia. We found that most of the BMD decrease occurred in the first 48 weeks of treatment with little change between weeks 48 and 96, very similar to the pattern described in people with HIV infection first exposed to cART. Participants randomized to the NtRTI + LPV/r-group had greater bone loss compared with the RAL group, but there was no difference in the proportion of subjects developing low BMD during the study. The significant loss of BMD that occurs with initiation of both first-line and second-line ART points to the need for strategies to monitor BMD in treated patients with HIV to prevent the rate of and impact from fractures in this vulnerable population.
The authors thank the participants of the Second-Line bone substudy.
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Keywords:© 2014 by Lippincott Williams & Wilkins
antiretroviral therapy; bone density; HIV infection; raltegravir; tenofovir