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Bone & Limb Fat Outcomes in ACTG5202-
More Bone Loss With TDF/FTC Than ABC/3TC
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17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco
Mark Mascolini
"All regimens appeared to produce an initial bone loss with subsequent stabilization after 48 weeks." Study authors said. – from Jules
People taking tenofovir/emtricitabine (TDF/FTC) lost more bone mineral density than those taking abacavir/lamivudine (ABC/3TC) after 96 weeks in ACTG study A5224 [1]. Limb fat gains were similar with TDF/FTC and ABC/3TC. People randomized to atazanavir/ritonavir lost more lumbar spine bone density than those randomized to efavirenz but loss of hip bone density was similar in both the efavrirenz & atazanavir/r groups, but the atazanavir group gained more limb fat. Slides of this presentation are linked in the References below.
In a report on the parent trial, ACTG A5202 (summarized separately by NATAP and linked below), Eric Daar reported similar 96-week virologic response rates with atazanavir/ritonavir and efavirenz [2]. Among people starting treatment with fewer than 100,000 HIV RNA copies, virologic responses were also similar TDF/FTC and ABC/3TC. Among people starting with more than 100,000 copies, time to virologic failure proved significantly shorter with ABC/3TC [3].
ACTG A5224, the metabolic substudy, randomized 69 antiretroviral-naive adults to TDF/FTC plus efavirenz, 65 to TDF/FTC plus atazanavir, 70 to ABC/3TC plus efavirenz, and 65 to ABC/3TC plus atazanavir. The study group had a median age of 38 years (interquartile range [IQR] 31 to 44), a median viral load of 4.62 log (about 40,000 copies, IQR 4.24 to 4.90), a median CD4 count of 233 (IQR 106 to 334), a median body mass index of 24.9 kg/m(2) (IQR 21.8 to 28.2), and median limb fat of 7.4 kg (IQR 4.7 to 10.1). One third of study participants entered the trial with a lumbar spine t score at or below -1, and 23% had a hip t score that low. (from Jules: so there was bone loss before starting HAART in naives).
In intention-to-treat analyses, lumbar spine bone mineral density fell in both nucleoside groups but fell significantly more with TDF/FTC than with ABC/3TC at 96 weeks (about -3.5 versus -1.5, P = 0.004). Hip density also fell significantly more with TDF/FTC (about -4 versus -2.5, P = 0.025). Spine density decreased significantly more with atazanavir/ritonavir than with efavirenz at 96 weeks (about -3 versus -2, P = 0.035), but the groups did not differ in hip density through 96 weeks.
The between-group differences in bone mineral density did not result in significantly different fracture rates either in ACTG A5224 or in the parent trial, ACTG A5202. Overall fracture rates were 5.6% in A5224 (all traumatic fractures) and 4.3% in A5202 (12.7% of those atraumatic fractures). Fracture incidence was 1.7 per 100 person years across the four treatment arms.
Grace McComsey and ACTG A5224 colleagues found no significant differences between the nucleosides or between atazanavir/ritonavir and efavirenz in proportion of people with at least a 10% limb fat loss or at least a 20% loss through 96 weeks. But there was a trend to better absolute limb fat gains with ABC/3TC than with TDF/FTC through 96 weeks (about 1.5 kg versus 1.0 kg, P = 0.12) in an intention-to-treat analysis. In an as-treated analysis, people taking ABC/3TC gained significantly more limb fat through 96 weeks (about 2.0 kg versus 1.0 kg with TDF/FTC, P = 0.023). Limb fat percent change improved significantly more with atazanavir/ritonavir than with efavirenz at 96 weeks in the intention-to-treat analysis (about 30% versus 15%, P = 0.010), as did absolute limb fat (about 2.0 kg versus 1.0 kg, P = 0.008).
Subclinical, protocol-defined lipoatrophy occurred in 16% of study participants, with no significant differences between TDF/FTC and ABC/3TC or between efavirenz and atazanavir/ritonavir.
The findings confirm concerns about tenofovir's impact on bone mineral density and indicate that long-term toxicities differ between atazanavir and efavirenz.
References
1. 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. http://www.natap.org/2010/CROI/croi_20.htm.
2. Daar E, Tierney C, Mischl, et al. ACTG 5202: Final results of ABC/3TC or TDF/FTC with either EFV or ATV/r in treatment-naive HIV-infected patients. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 59LB. http://www.natap.org/2010/CROI/croi_08.htm.
3. Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009;361:2230-2240.
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