Longitudinal changes in weight, lean body mass and bone mineral density in first-line combinations: ACTG 5205 substudy

1 October 2013. Related: Side effects.

Matt Sharp, HIV I-Base

As treatment guidelines shift and more people initiate ART for life-long therapy, it is critical to understand various regimens impact on the body. A new analysis reports the impact of different regimens on lean body mass and bone mineral density after starting treatment.

The large ACTG 5202 study randomised 1857 ART naïve individuals starting therapy to tenofovir/FTC or abacavir/3TC with either efavirenz (EFV) or atazanavir/ritonavir (ATV/r) and included a metabolic substudy, which has a new analysis published in 13 August 2013 edition of AIDS. [1] Previous metabolic analyses have focused on BMD, peripheral fat and visceral fat. [2, 3]

This paper was a post-hoc analysis to compare weight and lean body mass (LBM) between pooled and randomised NRTI components from baseline to week 96. Whole body dual energy absorptiometry (DXA) and hip and lumbar spine measurements at 24, 48 and 96 weeks and every 48 weeks until the end of follow-up, and single-slice CT scans at baseline and week 96 were administered. LBM was defined as fat-free, bone-free mass defined by DXA. Initially, an intent-to-treat analysis was performed but after the DSMB recommended unblinding the NRTI component of the study due to virologic failures with ABC/3TC, a second as-treated analysis was done.

This substudy (A5224s) included results from 269 participants from 37 ACTG trial sites in the US and Puerto Rico. Baseline demographics included mean (+/- SD) age 37 (+/-10), weight 78.0 kg (15.5); median (IQR) BMI 24.9 lg/m2 (21.8 – 28.2). Mean CD4 count was 236 cells/mm3 (+/- 185) and median (IQR) viral load was 4.6 log copies/mL (4.2–4.9). The majority of participants were men (85%) with 15% women. All participants regardless of their ART regimen gained a mean average of 4.8 kg at week 96 (p<0.001) although those in the ATV/r arm gained statistically significant greater weight than those in the EFV arm regardless of analysis. BMI also increased in all participants by a mean 1.5 kg/m2 at week 96 and this was greater in the ATV/r arm (by 0.88 kg/m2 in the ITT analysis) compared to the EFV arm. Change in LBM increased significantly in all treatment arms by a mean of 1.4 kg at week 96. Interestingly, those who screened with at least 100,000 HIV-RNA copies m/L and were randomised to receive ATV/r had significantly greater mean gain in LMB, compared to EFV. Overall, lower CD4 count and higher viral load at baseline levels were both associated with greater gain in total body mass, BMI and LBM at week 96 after adjusting for treatment arm, suggesting a return to health effect.

When looking at hip and lumbar spine BMD in a multivariate linear regression analyses, ABC/3TC was associated with less percentage hip BMD between baseline and week 96 (mean change 1.35; 95% CI 0.18, 2.35; p=0.02) The regimen was also associated with less percentage loss in lumbar spine mean percentage BMD from week 0 to 96. (mean change: 2.00; 95% CI 0.66, 3.33; p=0.004) Compared to EFV, ATV/r was associated with greater mean percentage loss in lumbar spine. (mean change: -1.46; -2.82; -0.10; p=0.035)

As expected, lower baseline CD4 count, lower baseline weight, higher HIV RNA, less increase in LBM over 96 weeks, and higher increase in CD4 count over 96 weeks, and history of fracture were associated with loss in BMD in both measurements.

According to the authors, this is the first study to look longitudinally at changes in LBM, assessment of body and visceral fat, and LBM on the change of bone mineral density after initiation of current first-line therapy, and they also suggested that weight, BMI and LBM changes may mediate some of the change in BDM. Limitations include that long-term follow up was not of duration to adequately assess bone endpoints and that the study population was relatively young.

Comment

The is a complex study to interpret and differences between groups even when statistically significant may not have a clinical relevance, especially without considering individual results and lifestyle factors. The authors also note the large number of analyses that were performed without appropriate adjustment increasing the probability of Type-1 errors.

However, the dataset is still important for highlighting the broad directions of changes when starting treatment with combinations that are still commonly used.

References:

1. Erlandson, Kristine M. et al. Weight and lean body mass change with antiretroviral initiation and impact on bone mineral density. AIDS 2013, 27(13):2069–2079. DOI:10.1097/QAD.0b013e328361d25d.
   http://journals.lww.com/aidsonline/Fulltext/2013/08240/Weight_and_lean_body_mass_change_with.7.aspx
2. McComsey GA et al. Peripheral and central fat changes in subjects randomized to abacavir-lamivudine or tenofovir-emtricitabine with atazanavir-ritonavir or efavirenz: ACTG Study A5224s. Clin Infect Dis. (2011) 53 (2): 185-196. doi: 10.1093/cid/cir324.
   http://cid.oxfordjournals.org/content/53/2/185.full
3. McComsey GA 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): 1791-1801. doi: 10.1093/infdis/jir188.
   http://jid.oxfordjournals.org/content/203/12/1791.full