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Trunk and Visceral Fat Gains With Atazanavir & Efavirenz in ACTG A5224s
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18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
CROI: Central Fat Accumulation in ART-naïve Subjects Randomized to ABC/3TC or TDF/FTC with ATV/r or EFV: ACTG A5224s, a Substudy of ACTG A5202 - (03/7/11)
Mark Mascolini
Previously untreated people randomized to atazanavir/ritonavir gained more trunk fat and visceral fat through 96 weeks than people randomized to efavirenz in ACTG A5224s, a metabolic substudy of study A5202 [1]. Changes in the ratio of visceral adipose tissue to total adipose tissue (VAT/TAT) were similar in the two arms. Trunk and visceral fat changes did not differ significantly between people randomized to tenofovir/emtricitabine (TDF/FTC) versus abacavir/lamivudine (ABC/3TC).
ACTG A5202 randomized antiretroviral-naive people to double-blinded TDF/FTC or ABC/3TC and to open-label atazanavir/ritonavir or efavirenz [2]. Virologic response was similar in people who took atazanavir/ritonavir and efavirenz with TDF/FTC or ABC/3TC, and time to safety (P = 0.048) and tolerability (P < 0.001) events in people taking atazanavir/ritonavir were longer than in those taking efavirenz with ABC/3TC but not with TDF/FTC. (See link for complete article in references.)
Metabolic substudy investigators reported earlier that mild lipoatrophy (more than 10% subcutaneous fat loss) affected 16% of study participants and did not differ between treatment arms [3]. Both TDF/FTC and ABC/3TC increased limb fat, and atazanavir/ritonavir led to greater limb fat gains than efavirenz.
The visceral and trunk fat substudy analysis involved 269 people (85% men) with a median age of 38 years, a median pretreatment viral load of 4.62 log (about 43,000 copies), and a median CD4 count of 233. Median pretreatment body mass index was 24.9 kg/m(2), median trunk fat 9.4 kg, and median visceral fat 84.1 cm(2). About half of these people (47%) were non-Hispanic white.
When the investigators combined the nucleoside arms, estimated average percentage gain in trunk fat through 96 weeks was significantly higher with atazanavir/ritonavir than with efavirenz in an intention-to-treat analysis (36.5% versus 21.1%, P = 0.028) and an as-treated analysis (38.9% versus 21.7%, P = 0.028). On average, people taking atazanavir/ritonavir gained 1.1 kg more trunk fat than people taking efavirenz.
There was a trend toward a higher estimated average percentage change in VAT with atazanavir/ritonavir than with efavirenz at week 96, but that difference did not reach statistical significance (26.6% versus 12.4%, P = 0.09, in an intention-to-treat analysis and 30.0% versus 14.5%, P = 0.10, in the as-treated analysis). Estimated average percentage changes in the VAT/TAT ratio at week 96 were statistically similar with atazanavir/ritonavir and efavirenz (-2.24% versus -1.00%, P = 0.67, in an intention-to-treat analysis and -0.43% versus -0.40%, P = 0.99, in the as-treated analysis).
When the ACTG team combined the atazanavir/ritonavir and efavirenz arms, they saw no significant differences in 96-week trunk fat, VAT, or VAT/TAT ratio between TDF/FTC and ABC/3TC in intention-to-treat or on-treatment analyses.
Overall, 96-week changes in VAT correlated positively with changes in limb fat (the more VAT added, the more limb fat added, r = 0.48, P < 0.001). Absolute or percentage VAT change at week 96 did not correlate with age, gender, race/ethnicity, or pretreatment viral load, CD4 count, or body mass index. Changes in VAT correlated positively with changes in trunk fat (r = 0.58, P < 0.001), and changes in SAT correlated positively with limb fat changes (r = 0.88, P < 0.001).
Principal investigator Grace McComsey noted that the clinical significance of the trunk and visceral fat gains with atazanavir/ritonavir versus efavirenz remains uncertain (from Jules: the question came up at the oral session- is the fat gain a return to health or something else? And McComsey did not have answer except that further analyses are planned). Visceral fat is a cardiovascular risk factor, but the visceral fat difference between the two study arms fell short of statistical significance. Also, visceral fat gains correlated positively with limb fat gains, and the body-image tradeoff probably varies from one person to the next.
References
1. McComsey G, Kitch D, Sax P, et al. Central Fat Accumulation in ART-naive subjects randomized to ABC/3TC or TDF/FTC with ATV/r or EFV: ACTG A5224s, a substudy of ACTG A5202, 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 77.
2. Daar ES, Tierney C, Fischl MA, et al. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV type-1: a randomized trial. Ann Intern Med. 2011; Feb 14. Epub ahead of print. Online at http://www.annals.org/content/early/2011/02/11/0003-4819-154-7-201104050-00316.long.
3. McComsey G, Kitch D, Daar E, et al. Bone and limb fat outcomes of ACTG A5224s, a substudy of ACTG A5202: a prospective, randomized, partially blinded phase iii trial of ABC/3TC or TDF/FTC with EFV or ATV/r for initial treatment of HIV-1 infection. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 106LB. Study abstract online at http://www.retroconference.org/2010/Abstracts/39788.htm.
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