Raltegravir body composition study: 48-week DEXA results
31 December 2009. Related: Conference reports, Side effects, Lipodystrophy and metabolic complications, ICAAC 49th San Fransisco 2009.
Simon Collins, HIV i-Base
While some aspects of the lipodystrophy syndrome are better understood and managed, fat accumulation (lipohypertrophy), principally central visceral adipose tissue (VAT), remains unexplained and is still associated with all families of antiretrovirals.
While this mechanism is unknown, it appears to have little relationship to the atherogenic lipid and glucose changes that appear to be a separate set of lipodystrophy symptoms.
The DEXA results reported here are from a sub-set of 76/563 naive patients from the double-blind placebo-controlled STARTMRK trial, randomised to either raltegravir or efavirenz, each with tenofovir/FTC. This analysis compared baseline to week 48, with follow-up planned to week 96. Metabolic parameters included fasting lipid and glucose changes and relationship to NCEP goals.
Baseline characteristics for patients in the sub study were similar to the larger group and are summarised in Table 1. Median CD4 count and viral load (in the substudy) was approximately 200 cells/mm3 and 5 log copies/mL.
At 48 weeks there were few overall changes and no significant differences between the two arms. Total fat increased in both groups by around 16-20% in both limbs and trunk (see Table 2). Investigator reported observational changes were two cases of mild fat accumulation in the blinded efavirenz arm. No patients reported lipodystrophy.
Lipid changes were significantly great in the efavirenz group: TC +33 vs +10; HDL +10 vs + 4; LDL +16 vs +6; and TG +37 vs –3 mg/dL (all p<0.001). The change in the TC:HDL ratio was –0.1 vs –0.3 in the efavirenz and raltegravir groups (p=0.292).
Table 1: Baseline Characteristics in the DEXA Sub-Study
| raltegravir (n=54) | efavirenz (n=57) | |
| Male, n (%) | 50 (92.6) | 48 (84.2) |
| Female, n (%) | 4 (7.4) | 9 (15.8) |
| White | 33 (61.1) | 33 (57.9) |
| Black | 14 (25.9) | 9 (15.8) |
| Median CD4 (range) | 230 (1 to 573) | 202 (6 to 567) |
| Median viral load, log (range) | 4.9 (4 to 6) | 5.0 (4 to 6) |
| B/line CD4 <50 | 8 (14.8) | 9 (15.8) |
| B/line VL >100K | 24 (44.4) | 30 (52.6) |
Table 2: Body composition changes in STARTMRK at 48 weeks
| Region | raltegravir 400 mg bid | efavirenz 600 mg qd | ||||
| n | Baseline mean (gm) | Mean % change (95% CI) | n | Baseline mean (gm) | Mean % change (95% CI) | |
| Arms | 35 | 1873.08 | 23.33 (5.95, 40.72) |
41 | 1724.23 | 18.94 (11.80, 26.07) |
| Legs | 35 | 7055.66 | 16.31 (3.85, 28.77) |
41 | 6305.59 | 15.63 (9.59, 21.67) |
| Appendicular | 35 | 8928.73 | 17.38 (4.34, 30.42) |
41 | 8029.83 | 16.09 (10.15, 22.03) |
| Trunk | 35 | 11683.73 | 17.01 (2.87, 31.15) |
41 | 10142.54 | 20.46 (11.72, 29.19) |
| Total | 35 | 20612.46 | 16.92 (3.52, 30.32) |
41 | 18172.37 | 17.98 (10.89, 25.07) |
N = # of patients in the treatment group. Mean % changes from baseline are based on the measurements of the pts who were measured at baseline and the time point assessed.
COMMENT
The lipohypertrophy profile of each new drug should be included routinely in all Phase 3 antiretroviral trials.
While raltegravir was originally approved over two years ago (October 2007 in the US), the first information on fat accumulation was only presented at ICAAC this year (September 2009). It is unfortunate that this is based on DEXA rather than CT scans: while DEXA can provide information about limb fat loss, it is not able to separate visceral fat from subcutaneous fat.
While no signal of early problems is reassuring, 48 weeks is probably too early to see significant changes. Also, as efavirenz has previously been linked to fat accumulation, similar results at this timepoint should be interpreted cautiously.
References
Berger D et al. Metabolic profiles and body composition changes in treatment-naive HIV-infected patients treated with raltegravir (RAL)-based vs. efavirenz (EFV)-based combination therapy: 48-week data. 49th ICAAC, 12-15 September 2009, San Francisco. Poster abstract H-1571.
http://www.posters2view.com/icaac/view.php?nu=H-1571