Adults with HIV infection have a higher prevalence of low bone mineral density (BMD) (40–83%) than HIV-uninfected adults , and HIV-positive adults on antiretroviral therapy (ART) have lower BMD than ART-naïve, HIV-infected adults . Initiation of ART is associated with loss of BMD . BMD declines by 3–5% at the hip and spine in the first year of tenofovir disoproxil fumarate (TDF)-based ART, and these declines are significantly greater (approximately two-fold) than for ART regimens not including TDF [4–6]. In some studies, BMD continues to decline by approximately 1% per year, a rate higher than in healthy controls [7,8]. TDF is the most popular component of the nucleoside reverse transcriptase backbone in ART regimens in low-income and middle-income countries, so measures to minimize its adverse effects on bone are desirable.
Fragility fractures are the clinical consequence of low BMD. Prospective cohort studies report a significant increase in fractures in HIV-infected relative to HIV-uninfected men [9,10]. Use of ART is also associated with a significant increase in fractures , whereas cumulative and current use of TDF was associated with a significant increase in fractures in a large European cohort study [12,13]. Fracture prevalence increases with age to a greater extent in HIV-positive patients [12,14], which has implications for the HIV population that is successfully aging because of effective ART.
There are several proven interventions for low BMD in HIV-positive adults: either antiresorptive therapy with a bisphosphonate or switching TDF to another active antiretroviral drug. Trials of bisphosphonate therapy in HIV-positive adults have reported increases in BMD with oral alendronate 70 mg per week or zoledronic acid 5 mg intravenously once a year [15–18]. BMD also increases after switching TDF to abacavir, raltegravir or tenofovir alafenamide (TAF) in virologically suppressed adults [19–22]. Cross-study comparisons suggest that the effects of bisphosphonate therapy may be greater than for TDF switching at 2 years, but there has been no head-to-head study to determine which strategy is superior. The aim of the ZolEdronic acid versus Switching Tenofovir for low BMD (ZEST) study was to compare the effects of zoledronic acid 5 mg intravenously yearly for 24 months to switching from tenofovir to another antiretroviral drug on lumbar spine and hip BMD in HIV-infected adults with low BMD. We hypothesised that zoledronic acid would increase BMD more effectively over 24 months than switching from TDF.
The primary objective of the study was to compare the effects of an annual intravenous infusion of 5 mg zoledronic acid to switching from TDF to another antiretroviral drug on lumbar spine BMD (primary endpoint) and hip BMD (secondary endpoint) over 24 months. Mean percentage change in lumbar spine BMD from baseline was chosen as the primary outcome measure in preference to total hip BMD, because of lumbar spine BMD responding more rapidly to interventions as it contains a higher proportion of metabolically active trabecular bone . The secondary objectives of the study were to compare the randomized groups for mean percentage change in hip BMD, incidence of osteoporosis (defined by a T-score < − 2.5), fracture risk assessment using the appropriate Australian or Spanish version of the Fracture Risk Assessment equation (FRAX), occurrence of fractures, and safety (clinical and laboratory adverse events of all grades, all serious adverse events, death, progression to AIDS, and virological failure defined by a plasma HIV RNA greater than 200 copies/ml on two occasions at least 4 weeks apart, and any antiretroviral regimen modification after baseline).
Study design and participants
The study was a randomized, open-label, 24-month trial, with eligible participants randomly assigned to either commence zoledronic acid 5 mg intravenously, yearly (two doses; and continue TDF-containing ART) or to switch from TDF to another potent antiretroviral drug selected by the investigator (without commencing a bisphosphonate). The study was conducted prior to the availability of tenofovir alafenamide. Randomization was stratified by radiology facility (one each in Sydney, Melbourne, and Barcelona), and by screening BMD (T-score greater than −2.0 or less than or equal to −2.0). The study was approved by the institutional review board at each participating clinical site, and was performed in compliance with the principles of the Declaration of Helsinki and local regulatory requirements. All participants provided written, informed consent prior to enrolment. The study was registered on the Australian New Zealand Clinical Trials Registry (ACTRN 12612000776808).
Eligible patients were adults with confirmed HIV infection, virologically suppressed (HIV RNA <50 copies/ml) for a minimum of 3 months on TDF-containing ART for at least 6 months, and had a T-score of less than −1.0 at the spine (L1–L4) or the left neck of femur on bone densitometry using dual-energy X-ray absorptiometry (DXA). Participants were not eligible if they had received prior bisphosphonate therapy, had received other anti-osteoporotic therapy for low BMD, had evidence of secondary osteoporosis, required treatment for low BMD (e.g. prior fragility fracture) or contraindications to administration of zoledronic acid (e.g. hypocalcaemia, recent or planned major dental surgery, uncorrected vitamin D deficiency), required tenofovir for treatment of chronic hepatitis B, had prior virological failure, resistance, intolerance or contraindications to the proposed ART-switch regimen (including HLA-B*5701 positivity or prior cardiovascular disease for abacavir-containing regimens) or had an estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m2. The switch antiretroviral drug(s) was/were selected prior to randomization.
All participants received calcium supplementation of 1500 mg daily, and all participants with vitamin D insufficiency or deficiency received vitamin D supplementation at baseline and either month 11 (for the zoledronic acid group) or month 12 for the TDF-switch group. For vitamin D insufficiency (25–50 nmol/l) participants in either group received a single tablet of 50 000 IU vitamin D, and for those with moderate deficiency (<25 nmol/l) a single dose of 100 000 IU Vitamin D (two tablets) was administered. Vitamin D levels were rechecked at month 3 and, if persistent insufficiency or deficiency was identified, participants continued to receive vitamin D 50 000 IU monthly for the duration of the study.
BMD at the lumbar spine (L1–L4) and hip were measured annually by DXA for 2 years. All DXA images were obtained using a standardized protocol, with central adjustment of BMD values for cross-sectional and longitudinal consistency based on locally acquired phantom scans. DXA scan results were not returned to sites until month 24, unless a minimal trauma fracture occurred, a BMD decline of greater than 5% occurred or a T-score less than −2.5 developed. By convention, T-scores were calculated relative to peak bone mass in young white women . z-scores were calculated relative to reference populations matched by age, sex and race/ethnicity. Low BMD for age (below the expected range) was defined by a z-score (spine, hip, femoral neck) −2.0 or less, consistent with recommendations for young populations by the US National Osteoporosis Foundation and the International Society for Clinical Densitometry [25,26]. Participants with BMD T-scores of −2.5 or less at any site (L1–L4 spine, total hip or femoral neck) were considered to have osteoporosis . The Fracture Risk Assessment Tool was used to generate FRAX scores for the 10-year probability of a hip fracture or a major osteoporotic fracture, using the relevant country of participation tool for each participant .
The sample size was calculated using data from published HIV BMD treatment studies [15–18,29,30], in which the mean response at the lumbar spine relative to control at 2 years was 6.1% [standard deviation (SD) <4%] with a bisphosphonate and 1% (SD 2%) with TDF switching [19,22]. Assuming a 4% (SD 6%) difference, the proposed study would require 36 participants in each group to be able to reject the null hypothesis that the population means of the experimental and control groups are equal with 80% power, and a type-1 error probability of 0.05. To allow for 15% loss to follow-up or strategy, we planned to recruit 42 subjects to each group.
All analyses were performed after all participants completed 2 years of follow-up or had permanently withdrawn or been lost to follow-up. The modified intention-to-treat (mITT) analyses include all patients who were randomized excluding two participants who withdrew consent immediately after randomization and did not cease TDF, and the per-protocol analyses censored participants once they restarted TDF (in the TDF-switch arm) or ceased TDF (zoledronic acid arm). Those with no follow-up after baseline and those who restarted or stopped TDF as protocol violations before month 12 (or the first postbaseline study visit for toxicity endpoints) were excluded from the per-protocol analyses.
The primary outcome was percentage change from baseline in BMD at the lumbar spine at 24 months by ITT analysis. For continuous data, mean change from baseline to months 12 and 24 was calculated for participants with baseline and at least one follow-up visit (mITT). Both ITT (last observation carried forward) and per-protocol analyses were performed for the BMD and fracture endpoints; toxicity endpoints used per-protocol datasets only. T-tests were used to compare groups, unless data was not normally distributed, in which case Wilcoxon's test was used. Fisher's exact test was used to assess differences in proportions. Formal comparisons of fracture numbers between arms were made with a random effects longitudinal Poisson model. All analyses used a two-sided α of 0.05. No adjustment was made for multiple comparisons. Analyses were performed with Stata version 15.0 (Statacorp, College Station, Texas, USA).
Participants and interventions
The study was performed at 10 clinical sites (9 in Australia and one in Spain). Of the 112 volunteers screened, 87 participants were randomized between July 2012 and January 2015. Two of the 44 participants randomized to the TDF switch arm revoked consent prior to ceasing TDF, and were excluded from analysis (Fig. 1, CONSORT diagram). Table 1 shows the baseline characteristics of the 85 participants analysed (43 in the zoledronic acid group and 42 in the TDF-switch group). The study population was predominantly Caucasian, with median age of 50 years; only 4% were women; the median CD4+ T-cell count was 618 cells/μl. The median duration of prior TDF exposure was 6.2 (IQR 3.4–8.1) years. Twenty-three participants (27%) had osteoporosis (T-score ≤−2.5) whereas 32 (38%) had low BMD for age (z-score ≤−2.0) at the spine, total hip or femoral neck. There was no difference in major osteoporotic or hip fracture probability between study arms at baseline.
In the TDF switch arm, the predominant switch occurred from TDF to abacavir (62%) or to raltegravir (19%). Of those randomized to the zoledronic acid arm, one participant died by month 3 and one moved overseas before month 6, one was lost to follow-up at the month 24 visit. One participant in the TDF-switch arm was incarcerated prior to month 12, but returned for continued follow-up by month 24. All planned zoledronic acid infusions were given (one was delayed because of dental work). Strategy was maintained in 40 (93%) of those allocated to zoledronic acid (three participants ceased TDF) and in 38 (90%) of those allocated to cease TDF (four participants restarted TDF, none received zoledronic acid).
Primary study endpoint: change in lumbar spine bone mineral density at 24 months
The mean percentage changes in BMD in the zoledronic acid and TDF-switch groups and the estimated overall mean treatment differences at month 24 were 7.4 vs. 2.9% [difference 4.4% (95% CI 2.6–6.3), P < 0.001] at the lumbar spine; 4.6 vs. 2.9% [difference 1.9% (95% CI 0.5–3.4), P = 0.009] by ITT analysis (Table 2). The increase in BMD was the greatest in the first 12 months for both strategies. The rate of increase slowed in the second year for the zoledronic acid group whereas the BMD change plateaued from 12 to 24 months in the TDF-switch group (Fig. 2). The per protocol analyses yielded similar treatment differences (Table S1, http://links.lww.com/QAD/B312).
The mean percentage changes in BMD in the zoledronic acid and TDF-switch groups and the estimated overall mean treatment differences at month 24 were 4.6 vs. 2.9% [difference 1.9% (95% CI 0.5–3.4), P = 0.009] at the total hip; and 4.0 vs. 2.1% [difference 1.9% (0.04–3.7), P = 0.045] at the femoral neck by ITT analysis (Table 2). Per protocol analyses are shown in Table S1, http://links.lww.com/QAD/B312.
The prevalence of osteoporosis at the hip or spine decreased from 30 and 24% at baseline to 12% in both groups at month 12, and was similar at 24 months (Table 3). The odds ratio for having osteoporosis at any visit after baseline in the zoledronic acid vs. TDF-switch groups was 0.96 (95% CI 0.0003–10.8), P = 0.29.
Five participants experienced eight fractures over the 24 months of follow-up. In the zoledronic acid group, one participant had a vertebral compression fracture (deemed a fragility fracture). In the TDF-switch group, four participants experienced seven fractures [hands/foot (three participants), multiple rib (two participants), wrist, and spine] of which only one was categorized as a fragility fracture. Although there were fewer fractures in the zoledronic acid group, the difference in the number of participants with fractures between strategies was not significant. Fracture numbers did not differ between the ITT and per protocol analyses.
There was no significant difference in the number of serious adverse events between arms during study follow-up, and none were considered related to the study arm. The rate of clinical or laboratory adverse events (grades 1–3) was not different between arms, and neither was the rate of events related to study strategy or study procedure (Table 3). There was some recovery in eGFR [mean (SD) increase of 3.3 (12.6) ml/min per 1.73 m2] in those allocated to the TDF-switch arm, and a continued mean decline of 5.4 (13.4) ml/min per 1.73 m2 in those allocated to zoledronic acid (and to continue TDF). In a random effects model adjusting for baseline eGFR, the mean (95% CI) change in eGFR over 24 months follow-up between the zoledronic acid arm vs. TDF switch was −3.1 (−6.4 to 0.13) ml/min per 1.73 m2; P = 0.06.
One participant in the zoledronic acid arm with low-level viraemia (which did not meet the definition of virological failure) had their ART regimen changed by their physician (ceasing TDF). Another participant in the TDF-switch arm experienced confirmed virological failure. This participant switched coformulated tenofovir–emtricitabine to abacavir–lamivudine at baseline. However, the participant continued his prestudy raltegravir but, for reasons that could not be clarified, did not take the abacavir–lamivudine. The patient's viral load was less than 50 copies/ml at month 3, but 17 400 copies/ml at month 6. The patient resuppressed on abacavir–lamivudine with ritonavir-boosted darunavir for the duration of the study.
In this randomized, controlled, strategy trial, annual infusions of zoledronic acid resulted in significantly greater increases in BMD over 24 months vs. TDF switching in virologically suppressed, HIV-infected adults on TDF-containing ART with osteopenia. Treatment with intravenous zoledronic acid was also associated with a significant reduction in the proportion of people with osteoporosis. The majority of the BMD increases occurred in the first 12 months in the zoledronic acid arm, with a slowing of the increase thereafter. In the TDF-switch arm, all the BMD increase occurred in the first 12 months, with BMD plateauing in the second 12 months. Both strategies were well tolerated.
The results of our study are in keeping with the increase in BMD over 1–2 years seen in the six randomized trials of bisphosphonate treatment in HIV-positive patients. Four of these studies used alendronate 70 mg weekly, and two trials used intravenous zoledronic acid 5 mg yearly, with all participants receiving calcium and vitamin D supplementation (usually 1000 mg/day and 400 IU/day, respectively). In these trials, BMD was higher at 2 years than at 1 year, and BMD increases were similar or greater at the lumbar spine than at the femoral neck and appeared similar or greater with zoledronic acid (3.7–8.9% at the spine, and 3.2–3.8% at the hip) than with alendronate (3.4–5.2% at the spine, and 1.8–4% at the hip) [15–18,29,30]. The 7.4% increase in spine BMD in our study was similar to the approximate 6% BMD increase with zoledronic acid relative to controls at 2 years in HIV-positive patients, and to that observed in large phase 3 trials in postmenopausal women with osteoporosis [31–33]. There was a suggestion that the BMD increase was greater in those receiving TDF vs. non-TDF ART in one alendronate trial, but this was not significant . The mean increase of 2.9% in BMD at the spine and the hip in our study is slightly greater than that seen in other TDF-switch studies in which change in BMD was evaluated where improvement in BMD was generally 1–2.5% [21,22,34]. The greater magnitude of change in BMD in our study may be because of the vitamin D supplementation for vitamin D insufficient and deficient individuals and calcium supplementation. Vitamin D with or without calcium has been shown in several studies to improve BMD in those on TDF-containing ART [35–37].
Although both alendronate and zoledronic acid were well tolerated in the above trials, zoledronic acid may be preferable to weekly alendronate for several reasons: the main side effect of alendronate is nausea, which is a common reason for poor adherence to this regimen. Nausea is also a common ART side effect, and the ART side effect most likely to cause ART nonadherence and cessation . Also, the addition of zoledronic acid would not increase pill burden or hinder ART adherence.
Only one individual experienced virological failure in the switch arm, and required a new treatment regimen. Switching ART in virologically suppressed individuals is always associated with a risk of new adverse events or loss of virological control and future treatment options . In this study, one participant in the TDF-switch arm experienced virological failure because of poor adherence to their new ART regimen, and four participants experienced new adverse effects and restarted TDF while maintaining virological suppression. One participant in the zoledronic acid arm experienced low-level viraemia only, with an ART-regimen switch (ceasing TDF) initiated by his physician. Another two participants in the zoledronic acid arm ceased TDF because of declining renal function. Continued decline in eGFR was seen in the zoledronic acid arm, compared with an increase in eGFR in the TDF-switch arm, most likely because of continued use of TDF in those allocated to zoledronic acid.
Our study has limitations. There were very few women recruited with the study population being predominantly Caucasian, adult men. The current follow-up is short at 24 months; follow-up is ongoing to 36 months. Although significantly more fractures occurred in the TDF-switch group, there was no difference in the number of participants experiencing a fracture between the two study arms. The study was not powered for fracture events and much larger and longer studies will be required to determine the impact on fracture outcomes. Finally, the study was initiated prior to the availability of TAF, which has been shown to be associated with less bone loss than with TDF, and reduced renal toxicity. However, the BMD increase seen after switching from TDF to TAF is similar to that seen after TDF switching to abacavir or an integrase inhibitor [19–22] so, although both strategies are likely to be effective in increasing BMD, it is also likely that treatment with intravenous zoledronic acid will be superior to switching from TDF to TAF in adults with HIV and low bone mass.
Although TDF switching is a reasonable approach in improving low BMD in HIV-infected adults on TDF, we have demonstrated that treatment with zoledronic acid is a superior strategy over 24 months. Continued follow-up to month 36 will be important to establish whether the effect of zoledronic acid is durable (participants received a 5 mg infusion at baseline and month 12 only), and whether there is a continued increase in BMD beyond month 24 in either group. Although the use of zoledronic acid is likely to be preferred for those with osteoporosis, the clinical significance of this strategy will also depend on the underlying absolute risk for fracture, which for the HIV population and the general population alike, increases with age.
J.H. and A.C. produced the concept and designed the study. R.R. and A.C. were responsible for the overall conduct of the study. N.P. reviewed and calibrated all DXA scans as the Central Reading centre. S.K. performed the statistical analysis. J.H. wrote the first draft of the manuscript, and all authors contributed to the manuscript and reviewed and approved the final version.
We would like to thank all study participants and members of the ZEST study team. Investigators: Mark Bloch (Holdsworth House Medical Practice), David Baker, Marilyn McMurchie (East Sydney Doctors), Robert Finlayson (Taylor Square Private Clinic), James McMahon, Margaret Hellard (Alfred Hospital), Norman Roth, Beng Eu (Prahran Market Clinic), Richard Moore, Cate Sheppard (Northside Clinic), Timothy Read, Stephen Kent, Tina Schmidt (Melbourne Sexual Health Centre), Ban Kiem Tee, Nanette Presswell (Centre Clinic).
Site coordinators: Shikha Agrawal (Holdsworth House), Katherine Ognenovska, Lesley Williams (East Sydney Doctors), Shruti Gupta, David Ninham (Taylor Square Private clinic), Nicola McKenzie (St Vincent's Hospital), Cath Downs, Janine Roney (Alfred Hospital), Susan Boyd, Sian Edwards (Northside Clinic) Julie Silvers, Helen Kent (Melbourne Sexual Health Centre), Helen Lau (Prahran Market Clinic, Centre Clinic), Pilar Callau, Isabel Montano (Hospital Clinic, Barcelona).
Imaging staff: Sherala Gunasekara (St Vincent's Hospital), Marita Huynh (Alfred Hospital), Amparo Tricas y Ana Rodríguez (Barcelona).
Pharmacists: Linda Hotong (St Vincent's Hospital), Ivette Aguirre (Melbourne Sexual Health Centre), Anne Mak (Alfred Hospital), Elisabet Farré (Barcelona).
Conflicts of interest
A.C. received research funding from Gilead Sciences and ViiV Healthcare; lecture and travel sponsorships from Bristol-Myers Squibb, Gilead Sciences, and ViiV Healthcare; and has served on advisory boards for Gilead Sciences and ViiV Healthcare. P.R.E.'s institution has received research funding from Novartis and honoraria from Gilead Sciences. J.F.H.'s institution receives reimbursement for her participation in Advisory Boards for Gilead Sciences, Merck, Sharp & Dohme, and ViiV Healthcare. E.M. received research funding from Merck, Sharp & Dohme; lecture and travel sponsorships from Gilead Sciences, Janssen, Merck, Sharp & Dohme, and ViiV Healthcare; and has served on advisory boards for Janssen, Merck, Sharp & Dohme, and ViiV Healthcare. R.R., N.P., J.R., and S.J.K. report no conflicts of interest.
Source of funding: National Health and Medical Research Council of Australia, Project Grant APP1022660; Balnaves Foundation, Sydney, NSW, Australia.
Novartis provided zoledronic acid for the study participants in Australia and Spain.
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