The use of raltegravir (Isentress) plus ritonavir (Norvir)-boosted darunavir (Prezista) as first-line antiretroviral therapy was associated with significantly less bone mineral density (BMD) loss in the hip and lumbar spine than was the use of a regimen containing tenofovir/emtricitabine (Truvada) plus ritonavir-boosted darunavir at weeks 48 and 96 following initiation of treatment, according to results presented at ICAAC 2014 in Washington, D.C.
The multicenter randomized European trial found that at 48 weeks, being on the tenofovir/emtricitabine-containing regimen and having a high viral load at baseline were significantly associated with a percentage change in lumbar spine and total hip BMD -- and the factors seem to remain significant at 96 weeks, although the number of patients who reached 96 weeks of follow-up was small.
According to lead author Jose Bernardino, M.D., there was no significant difference in osteopenia; however, osteoporosis diagnoses or fractures were observed over the course of 96 weeks. Whether or when the reduction in BMD might lead to differences in the actual bone disorders is uncertain. However, as Bernardino pointed out, BMD is a well-validated surrogate risk factor for fractures in the general population.
The natural history and pathogenesis of bone disease and fractures in people living with HIV differs considerably from the general population, as both disease-related factors and treatment-related factors seem to contribute to the loss of BMD and changes in bone architecture, according to previous research. Even in the absence of treatment, there is a high prevalence of osteopenia and osteoporosis in people living with HIV (15%/30%) compared to HIV-negative controls. Fragility fractures are also more common.
Declines in BMD (by around 2%-6%) have also been a constant finding following the initiation of antiretroviral therapy, in past studies, regardless of the regimen. However, tenofovir/emtricitabine use is consistently associated with BMD loss in various studies. At least one other study observed that a nucleoside-sparing regimen was associated with less loss in total body BMD than a tenofovir/emtricitabine-containing regimen.
There was a need to more thoroughly explore what the impact of a nucleoside-sparing regimen versus a tenofovir/emtricitabine-containing regimen might be on BMD changes at different anatomical sites (total hip, femoral neck bone and the lumbar spine) in treatment-naive individuals, and whether this would be associated with more diagnoses of osteopenia, osteoporosis and fractures.
The NEAT 001/ANRS 143 study, a phase 3 randomized, open-label trial, conducted at over 78 sites in 15 European countries, provided an opportunity to do this. Results of the trial, showing the non-inferiority of boosted darunavir plus raltegravir versus boosted darunavir plus tenofovir/emtricitabine, were presented earlier this year at CROI, and were recently published in The Lancet.
NEAT 001/ANRS 143 included a nested bone sub-study. Participants were randomized at the same time as the main study. Whole body dual-energy X-ray absorptiometry (DXA) scans were performed at baseline, 48 weeks and 96 weeks assessing BMD at three sites: total hip, lumbar spine and femoral neck. Hologic and Lunar devices were locally calibrated and no central reading was planned.
The primary objective was to compare changes between treatment arms and to evaluate clinical factors associated with BMD loss.
One hundred forty-six participants were included in the bone sub-study. The baseline characteristics were well matched between arms. The population was mainly young Caucasian males with a median age of 40 and a normal body mass index (23 kg/m2). Of note, only 2% were coinfected with hepatitis C and 41% were current smokers.
The baseline median CD4 cell count was 338, and the viral load was 4.7 log/mL. Both CD4 and viral load values were equally distributed in both arms. Around 20% of the participants had a baseline viral load above 100,000 copies/mL, and roughly 9% had CD4 cell counts below 200.
Bone parameters at baseline:
There was no difference in the number of previous fractures or family history of fractures.
There was no difference in the number of patients taking calcium or vitamin supplements.
There was no difference in baseline median BMD in lumbar spine or the femoral neck.
There was a slightly lower baseline median BMD in the total hip on the raltegravir arm.
There was no difference in osteopenia/osteoporosis diagnosis.
- Forty-five patients had osteopenia/osteoporosis diagnosed at baseline (24 in the raltegravir arm and 21 in the tenofovir/emtricitabine arm).
There was a decrease in lumbar spine BMD in both arms, however the decrease in the tenofovir/emtricitabine arm was significantly higher -- both at 48 weeks and at 96 weeks.
The decrease in femoral neck BMD was even steeper in the tenofovir/emtricitabine arm at 48 weeks and at 96 weeks.
There was also a decrease in total hip BMD on both regimens, but the decrease was again significantly greater in the tenofovir/emtricitabine arm at 48 weeks and at 96 weeks.
There was no difference in the number of new cases of osteoporosis, osteopenia or Z-score. There were four new fractures (one in the raltegravir arm and three in the tenofovir/emtricitabine arm) at 48 weeks and three more at 96 weeks (one in the raltegravir arm and two in the tenofovir/emtricitabine arm).
A multivariate analysis adjusting for age, gender, ethnicity, baseline BMD, CD4 count and other variables (such as viral load, history of fractures, hours engaging in sports, etc.) that were significant in univariate analyses was performed. At 48 weeks, only being on the tenofovir/emtricitabine arm and baseline viral load (per log10 copies/mL higher) were significantly associated with the percentage change in BMD in each site except the femoral neck (where baseline viral load was not quite significant at P = .053).
Bernardino cautioned that findings at 96 weeks were preliminary, but being on the tenofovir/emtricitabine arm appeared to be significantly associated with percentage change in BMD in the lumbar spine and total hip.
During the discussion, it was noted that data had been presented earlier in the day suggesting that substitution of the new tenofovir-prodrug, tenofovir alafenamide fumarate, for tenofovir might have a similar effect on BMD as was reported for the raltegravir arm -- but in the meantime, the nucleoside-sparing regimen is clearly an option for individuals at risk of fractures and other bone disorders.
Theo Smart is an HIV activist and medical writer with more than 20 years of experience. You can follow him on Twitter @theosmart.