Changes in bone mineral density
The percentage increase in total hip BMD measured by areal density from baseline to Week 48 was significantly greater in participants who switched to dolutegravir with rilpivirine (1.34%) compared with current ART (0.05%; difference in adjusted percentage change, +1.29%; 95% CI 0.27–2.31; P = 0.014; Fig. 2). The percentage increase in lumbar spine BMD from baseline to Week 48 (1.46%) was also significantly greater in the dolutegravir with rilpivirine group compared with the current ART group (0.15%; difference in adjusted percentage change, 1.32; 95% CI 0.07–2.57; P = 0.039; Fig. 2). The significant total hip result was also supported by a significant difference between treatment arms in the adjusted change from baseline to Week 48 in the total hip T score (difference in adjusted percentage change: 0.09; 95% CI 0.02–0.16; P = 0.016). A similar observation was made for the mean difference in adjusted change from baseline to Week 48 in the lumbar spine T score (difference in adjusted percentage change: 0.12; 95% CI 0.00–0.23; P = 0.049). A significantly greater increase from baseline to Week 48 was also observed in total hip and lumbar spine Z scores for the dolutegravir with rilpivirine group compared with the current ART group (P
= 0.026 and P = 0.013, respectively).
The change from baseline to Week 48 in total hip and lumbar spine BMD, expressed as areal density, was evaluated across demographic subgroups (age and sex) and baseline BMI. These results supported the primary analysis because a greater change from baseline was observed in the dolutegravir with rilpivirine group compared with the current ART group across all demographic subgroups; however, statistical comparisons were limited by the small sample size within each category (Fig. 3). Demographic groups at greater risk for BMD loss (e.g. ≥50 years of age, women, and BMI <25 kg/m2) exhibited greater increases in adjusted percentage change from baseline to Week 48 in total hip BMD in the dolutegravir with rilpivirine group compared with the current ART group (Fig. 3). Additionally, greater increases in point estimates of mean adjusted change from baseline in total hip and lumbar spine BMD were observed in participants in the dolutegravir with rilpivirine group compared with the current ART group regardless of baseline third-agent class (INSTI, NNRTI, or protease inhibitor; Fig. 3). Differences between groups within each baseline third-agent class were not significant, but this may be attributed to the small sample size within each class.
There was little change from baseline to Week 48 for participants in the dolutegravir with rilpivirine or current ART groups in the 10-year probability of hip fracture (−0.08 and 0.03%, respectively) and osteoporotic fracture (−0.12 and −0.04%, respectively) as assessed by FRAX score .
A post hoc analysis from baseline to Week 48 showed that participants in the dolutegravir with rilpivirine group had a similar mean change in BMI (0.84 kg/m2) compared with the current ART group (0.62 kg/m2). Vitamin D supplementation was reported for 20 of the 102 participants at baseline and did not change markedly through Week 48, with discontinuation of vitamin D reported for three participants (dolutegravir with rilpivirine, two; current ART, one).
Changes in bone biomarkers
Participants in the dolutegravir with rilpivirine group experienced significantly greater reductions from baseline to Week 48 in bone-specific alkaline phosphatase, osteocalcin, procollagen type 1 N-propeptide, and type 1 collagen cross-linked C-telopeptide compared with the current ART group (P value range from <0.001 to 0.029 across markers; Table 2). These results were consistent with those for concentrations of the same bone turnover biomarkers following analysis of pooled data from the SWORD-1 and SWORD-2 studies (N = 991) .
No adverse events were attributable to the DXA scan procedure. Clinically significant loss of BMD (defined as ≥5%) at Week 48 was reported in one 31-year-old male participant (dolutegravir with rilpivirine group). This participant's BMI was 21.8 kg/m2 at baseline and dropped to 20.5 kg/m2 at Week 48. The participant was a current smoker, had vitamin D levels within the normal range, and did not receive vitamin D or calcium supplementation during the study period. The investigator concluded that pharmacological intervention was not required. One 61-year-old postmenopausal female participant experienced a nontraumatic fracture of the right fibula (current ART group). This was considered an adverse event of moderate intensity but was not related to study treatment. This participant's BMI remained stable in the normal range during the study period; her vitamin D level was 80 nmol/mm3 at baseline, and the level had decreased to 50 nmol/mm3 at Week 48. However, she was osteopenic at baseline, with a T score of −2.01 which further decreased to −2.33 at Week 48.
The primary analysis of the 202094 sub-study of the pooled SWORD-1 and SWORD-2 study populations demonstrated that participants who received dolutegravir with rilpivirine had an increase from baseline to Week 48 in total hip (1.34%) and lumbar spine BMD (1.46%), which differed significantly (P
= 0.014 and P = 0.039, respectively) from participants who continued to receive ART containing tenofovir disoproxil fumarate. We selected total hip BMD as the primary measurement of interest because hip is composed of more compact cortical bone and less trabecular bone compared with lumbar spine ; therefore, change in total hip BMD is the more conservative endpoint because it changes less readily in comparison with lumbar spine BMD. The significant changes in total hip BMD demonstrated a marked positive effect on bone health after switching from tenofovir disoproxil fumarate-containing three-drug regimens to the NRTI-sparing 2DR, dolutegravir with rilpivirine.
Although a limited number of switch studies that replaced tenofovir disoproxil fumarate with other NRTIs like abacavir or tenofovir alafenamide showed a beneficial effect on BMD [8,23], this is the first randomized study to show that a switch from a tenofovir disoproxil fumarate-based regimen to an NRTI-sparing regimen led to a beneficial effect on BMD and bone turnover markers. A small study (n = 37) replaced tenofovir disoproxil fumarate with raltegravir, but this was a nonrandomized study, and many participants remained on an NRTI, often emtricitabine .
Data for other secondary endpoints, including evaluation of change in BMD expressed as T and Z scores and evaluation of change in BMD over 48 weeks by baseline third-agent class, supported the primary endpoint analysis. Despite the limited number of participants in some subgroup categories, data from subgroup analyses were consistent with and supportive of the primary endpoint analysis. The beneficial effect seems consistent in high-risk populations such as older participants, women, and smokers.
In a post hoc analysis, participants in the dolutegravir with rilpivirine and current ART groups had similar mean BMI values at baseline. We observed small but similar changes from baseline in BMI in both groups at Week 48. As there was no significant treatment effect on BMI at Week 48, the effect of dolutegravir with rilpivirine on total hip BMD at Week 48 is unlikely to be confounded by concurrent changes in BMI.
In addition to the consistent effect on BMD, we observed significant decreases in bone turnover markers after the switch. Bone undergoes constant remodelling, with osteoclasts resorbing older bone and osteoblasts laying down new bone, and the actions of osteoclasts and osteoblasts can be assessed in vivo using bone turnover markers . These processes are normally tightly coupled, but in HIV, especially whenever initiating tenofovir disoproxil fumarate-containing ART, accelerated bone resorption results in net bone loss. In our study, among participants receiving dolutegravir with rilpivirine, the decreases from baseline to Week 48 in levels of bone formation markers (bone-specific alkaline phosphatase, procollagen type 1 N-propeptide, and osteocalcin) and the bone resorption marker type-1 collagen cross-linked C-telopeptide were significantly greater than the decreases in all bone turnover biomarkers in participants who continued current ART. Taken together, these data indicate a lower rate of bone turnover in participants who received dolutegravir with rilpivirine compared with those who continued current ART.
This sub-study did not demonstrate any significant effect of dolutegravir with rilpivirine on FRAX scores. This was not surprising because many of the 12 input parameters (e.g. age, BMI, alcohol intake, smoking status, medical history) needed to calculate FRAX scores did not change in this relatively short 48-week study.
The protocol attempted to limit the effect of factors that affect bone density by permitting only stable testosterone or female hormone replacement therapy given for at least 6 months before baseline with no intention to stop during the study; excluding participants with male hypogonadism, uncontrolled thyroid disease, vitamin D deficiency, or severe osteoporosis at baseline; and prohibiting osteoporosis medications (e.g. bisphosphonates). These eligibility criteria prohibited recruitment of some SWORD study participants to the sub-study. We acknowledge the limitations of this bone sub-study. Enrolment of 102 participants provided adequate statistical power for the comparison of change in total hip BMD (as areal density) but not for all categories in the various subgroup analyses. Further, the sub-study was limited by the use of only one time point after baseline (Week 48). Additional assessments may have provided a more detailed analysis of the treatment differences. However, both parent studies and this sub-study are ongoing, with subsequent analyses at weeks 100 and 148 after all participants have been switched to dolutegravir with rilpivirine. Participants in the parent studies randomized to current ART at baseline switched to dolutegravir with rilpivirine at Week 52 if virologically suppressed at Week 48.
No adverse events were considered attributable to the DXA scan procedure; however, there were treatment-related adverse events reported in the parent SWORD-1 and SWORD-2 studies . Over 70% of participants in each treatment group reported adverse events (dolutegravir with rilpivirine, 77%; current ART, 71%); however, adverse events leading to withdrawal were low for both treatment groups (dolutegravir with rilpivirine, 3%; current ART, <1%), indicating that the regimens were well tolerated. Other studies involving switches to regimens containing rilpivirine (GS-US-366–1160  and SPIRIT ) or dolutegravir (STRIIVING ) have also reported that patients in the current ART groups experienced fewer overall adverse events or discontinuations because of adverse events compared with the switch groups. However, there may be an inherent bias toward the current ART group in switch studies because of the number of years of experience participants had with the previous regimen (GS-US-366–1160, not reported; SPIRIT, 2.8 years; STRIIVING, >4 years; SWORD-1 and SWORD-2, ∼4 years). In these trials, patients in the current ART groups experienced fewer adverse events compared with the switch groups (GS-US-366–1160, 74 versus 80%; SPIRIT, only reported percentages for grades 3 and 4 adverse events; STRIIVING, 47 versus 66%; SWORD-1 and SWORD-2, 71 versus 77%; respectively) and fewer discontinuations because of adverse events (GS-US-366–1160, 2 versus 3%; SPIRIT, 0 versus <1%; STRIIVING, 0 versus 4%; SWORD-1 and SWORD-2, < 1 versus 3%; respectively). Overall, discontinuations because of adverse events were low in the switch groups, which is consistent with increases in treatment satisfaction in the switch group compared with the current ART group in both the STRIIVING and SWORD-1 and SWORD-2 trials.
The little change observed in hip and lumbar spine BMD in participants in the current ART group was expected because the detrimental effect of certain ART regimens on BMD has been reported to slightly decrease [24,27] and stabilize after 1 or 2 years . Participants in the current ART group were receiving tenofovir-containing regimens for at least 6 months before randomization and then another 48 weeks before being switched to dolutegravir with rilpivirine. The observed changes from baseline to Week 48 in total hip and lumbar spine BMD (expressed as areal density, T scores, and Z scores), together with the reduction in bone turnover markers, provide evidence that the switch from a three-drug or four-drug ART regimen containing tenofovir disoproxil fumarate to dolutegravir with rilpivirine was associated with bone health maintenance at minimum, and possibly an improvement through 48 weeks. Together, the BMD and bone marker data from the sub-study indicate that switching to the NRTI-sparing 2DR, dolutegravir with rilpivirine, limits the deleterious effect of ART on BMD and improves markers of bone health, while maintaining viral suppression in patients living with HIV-1 infection.
ViiV Healthcare was the financial and regulatory sponsor and participated in designing the trial, collecting data, conducting the analysis, and interpreting data. Janssen participated as a partner in the development of the dolutegravir with rilpivirine two-drug regimen. All authors had full access to the data and are responsible for the veracity and completeness of the reported data. The corresponding author had final responsibility for the decision to submit for publication.
We thank the study participants, their families, and caregivers for participation in the study. We also acknowledge and thank all investigators and site staff who participated in this sub-study (see Appendix for list of investigators, http://links.lww.com/QAD/B206). Editorial assistance was provided under the direction of the authors by Jeffrey Stumpf, Julie Stimmel, and Diane Neer, MedThink SciCom, and was funded by ViiV Healthcare.
Contributors: G.M., L.K., K.A., B.W., K.V., M.C., M.A., and M.G. participated in the design and conduct of the SWORD sub-study and analysis of study data. S.L., D.P., M.C.P., J.D., L.K., K.A., B.W., K.V., M.G., M.C., and M.A. were study investigators and participated in the conduct of the study, including the recruitment and follow-up of participants. All authors participated in the collection and interpretation of study data and the drafting and review of the manuscript. Jeffrey Stumpf, Julie Stimmel, and Diane Neer provided editorial assistance with development of the manuscript.
Conflicts of interest
G.M. has served as a consultant for Gilead and Merck. S.L., D.P., and M.C.P. have nothing to disclose. J.D. has served on advisory boards for ViiV Healthcare, Gilead, and Merck; has been a speaker for ViiV Healthcare and Merck; and has been a part-time consultant for Gilead Marketing and AbbVie Canada. L.K., B.W., M.G., and M.A. are employees of ViiV Healthcare and GlaxoSmithKline shareholders. K.A. and M.C. are employees and shareholders of GlaxoSmithKline. K.V. is an employee of Janssen.
Study registration with ClinicalTrials.gov: 202094 Sub-Study, NCT02478632; SWORD-1, NCT02429791; SWORD-2, NCT02422797.
1. Biver E, Calmy A, Rizzoli R. Bone health in HIV and hepatitis B or C infections
. Ther Adv Musculoskelet Dis
2. Rivas P, Gorgolas M, Garcia-Delgado R, Diaz-Curiel M, Goyenechea A, Fernandez-Guerrero ML. Evolution of bone mineral density in AIDS patients on treatment with zidovudine/lamivudine plus abacavir or lopinavir/ritonavir
. HIV Med
3. Zhao H, Goetz MB. Complications of HIV infection in an ageing population: challenges in managing older patients on long-term combination antiretroviral therapy
. J Antimicrob Chemother
4. Hoy J, Young B. Do people with HIV infection have a higher risk of fracture compared with those without HIV infection?
. Curr Opin HIV AIDS
5. Ofotokun I, Weitzmann MN. HIV and bone metabolism
. Discov Med
6. 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
7. Woodward CL, Hall AM, Williams IG, Madge S, Copas A, Nair D, et al. Tenofovir-associated renal and bone toxicity
. HIV Med
8. Negredo E, Domingo P, Perez-Alvarez N, Gutierrez M, Mateo G, Puig J, et al. Improvement in bone mineral density after switching from tenofovir to abacavir in HIV-1-infected patients with low bone mineral density: two-centre randomized pilot study (OsteoTDF study)
. J Antimicrob Chemother
9. Bloch M, Tong WW, Hoy J, Baker D, Lee FJ, Richardson R, et al. TROP (switch from tenofovir to raltegravir for low bone density) Study Team. Switch from tenofovir to raltegravir increases low bone mineral density and decreases markers of bone turnover over 48 weeks
. HIV Med
10. Baril JG, Angel JB, Gill MJ, Gathe J, Cahn P, van Wyk J, et al. Dual therapy treatment strategies for the management of patients infected with HIV: a systematic review of current evidence in ARV-naive or ARV-experienced, virologically suppressed patients
. PLoS One
11. Gantner P, Cuzin L, Allavena C, Cabie A, Pugliese P, Valantin MA, et al. Dat’AIDS study group. Efficacy and safety of dolutegravir and rilpivirine dual therapy as a simplification strategy: a cohort study
. HIV Med
12. Molina JM, Cahn P, Grinsztejn B, Lazzarin A, Mills A, Saaq M, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial
13. Cohen CJ, Andrade-Villanueva J, Clotet B, Fourie J, Johnson MA, Ruxrungtham K, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial
14. Castagna A, Maggiolo F, Penco G, Wright D, Mills A, Grossberg R, et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study
. J Infect Dis
15. Clotet B, Feinberg J, van Lunzen J, Khuong-Josses MA, Antinori A, Dumitru I, et al. NG114915 Study Team. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study
16. Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, et al. SPRING-2 Study Group. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study
17. Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, et al. Extended SAILING Study Team. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study
18. Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, et al. Short-term antiviral activity of TMC278--a novel NNRTI--in treatment-naive HIV-1-infected subjects
19. Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers
. Antimicrob Agents Chemother
20. Kanis JA, Oden A, Johansson H, Borgstrom F, Strom O, McCloskey E. FRAX and its applications to clinical practice
21. Llibre JM, Hung C-C, Brinson C, Castelli F, Girard PM, Kahl L, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. [published online January 5, 2018]. Lancet. doi: http://dx.doi.org/10.1016/S0140-6736(17)33095-7
22. Riggs BL, Melton LJ, Robb RA, Camp JJ, Atkinson EJ, McDaniel L, et al. A population-based assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men
. J Bone Miner Res
23. Gallant JE, Daar ES, Raffi F, Brinson C, Ruane P, DeJesus E, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial
. Lancet HIV
24. DeJesus E, Ramgopal M, Crofoot G, Ruane P, LaMarca A, Mills A, et al. Switching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study
. Lancet HIV
25. Palella FJ Jr, Fisher M, Tebas P, Gazzard B, Ruane P, Van Lunzen J, et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants
26. Trottier B, Lake JE, Logue K, Brinson C, Santiago L, Brennan C, et al. Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label, Phase IIIb study
. Antivir Ther
27. Orkin C, DeJesus E, Ramgopal M, Crofoot G, Ruane P, LaMarca A, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study
. Lancet HIV
bone mineral density; dual-energy X-ray absorptiometry; FRAX; lumbar spine; nucleoside reverse transcriptase inhibitor-sparing; total hip; two-drug regimen
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