SUMMARY: A body composition sub-study of the large ACTG 5202 trial found that different antiretroviral regimens are associated with different types of changes in bone mineral density and body fat, according to a report presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) last month in San Francisco. Tenofovir/emtricitabine (Truvada) led to greater bone loss than abacavir/lamivudine (Epzicom), and ritonavir-boosted atazanavir (Reyataz) led to both more bone loss and greater limb and trunk fat gain than efavirenz (Sustiva). But compared with some past regimens, the overall rate of lipoatrophy (peripheral fat loss) in this study was low.

By Liz Highleyman

Grace McComsey (Photo by Liz Highleyman)

ACTG 5224s, a sub-study of the larger ACTG 5202 trial, looked at 2 types of body composition changes associated with antiretroviral therapy, bone loss and body fat changes.

ACTG 5202 was a randomized Phase 3b clinical trial comparing the effectiveness of commonly used ART components. Two nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) "backbones" -- abacavir/lamivudine (the drugs in the Epzicom coformulation) and tenofovir/emtricitabine (the drugs in the Truvada coformulation) -- were studied in combination with both the non-nucleotide reverse transcriptase inhibitor (NNRTI) efavirenz and the boosted protease inhibitor atazanavir.

Participants were enrolled during 2005-2007. The high viral load group was unblinded early after an interim analysis showed that abacavir/lamivudine did not suppress HIV as well as tenofovir/emtricitabine in patients with high viral load. The low viral load group continued follow-up through September 2009, or 96 weeks after the last enrollment, so some patients were followed for nearly 4 years.

Final ACTG 5202 data were also presented at CROI. Overall, there were no significant differences among the regimens with regard to virological suppression, though there were differences in side effects, including cholesterol changes.

Grace McComsey presented the sub-study data on behalf of the A5224 team. The investigators used dual energy X-ray absorptiometry (DEXA) scans to measure bone mineral density changes in the lumbar spine (lower back) and hip bone, as well as the rate of bone fractures.

They also looked changes in limb fat and trunk (abdominal or central) fat and the percentage of patients who developed lipoatrophy (defined as >10% or greater loss of limb fat from baseline, a change that might not be visually evident). Among people with HIV, fat gain in the arms and legs is generally considered good (relative to the lipoatrophy seen with older NRTIs) while abdominal fat gain is unfavorable; however, some degree of weight gain may be due to a return to health among people with AIDS-related wasting.

The sub-study included 269 participants, with similar numbers taking each of the 4 combination regimens. Most participants (85%) were men, about half were white, the median age was 38 years, and the median body mass index (BMI) was 24.9 (the top of the "normal" category). They had a relatively low median CD4 cell count of about 230 cells/mm3 and about 41% had a high viral load (>100,000 copies/mL). None had diabetes or other conditions associated with bone or body fat changes.

Results

	Bone density dropped steeply with all regimens during the first 24 weeks after starting therapy.
	Bone density then began to rise, but did not reach baseline levels.
	At week 96, participants using tenofovir/emtricitabine experienced significantly larger bone density decreases from baseline compared with abacavir/lamivudine recipients:
	Lumbar spine: -1.3% vs -3.0%; Hip bone: -2.6% vs -3.9% for hip.
	Looking at the other 2 drugs, atazanavir/ritonavir was associated with more bone loss than efavirenz at both sites:
	Lumbar spine: -1.7% vs -3.2%; Hip bone: -3.1% vs -3.4% for hip (not significant).
	Among patients followed through week 192 (about 45%), lumbar spine bone density began to decrease at about 144 weeks in people taking tenofovir/emtricitabine or atazanavir/ritonavir; this pattern was not seen with hip bone density.
	5.6% of participants in the sub-study had 1 or more bone fractures, all of them traumatic (due to injury).
	4.3% of participants in the larger parent study had 1 or more fractures, of which 12.7% were non-traumatic (spontaneous).
	There were no significant differences in fracture rates between the NRTI backbones or between atazanavir/ritonavir and efavirenz.
	16% of participants overall had 10% limb fat loss at week 96, with no statistically significant differences between the regimens:
	Abacavir/lamivudine + efavirenz: 18.9%; Abacavir/lamivudine + atazanavir/ritonavir: 16.3%; Tenofovir/emtricitabine + efavirenz: 14.3%; Tenofovir/emtricitabine + atazanavir/ritonavir: 15.6%.
	In a post hoc analysis of >20% or greater limb fat loss, there was more variation:
	Abacavir/lamivudine + efavirenz: 3.8%; Abacavir/lamivudine + atazanavir/ritonavir: 6.1%; Tenofovir/emtricitabine + efavirenz: 8.9%; Tenofovir/emtricitabine + atazanavir/ritonavir: 0%.
	In an intent-to-treat analysis at 96 weeks, absolute amountand percentage change of limb fat increased to a similar extent with both NRTI backbones (1.1 with tenofovir/emtricitabine vs 1.7 kg with abacavir/lamivudine).
	After 96 weeks, limb fat continued to rise with both backbones, but more steeply with abacavir/lamivudine, so the difference between them widened by week 192.
	In a 96-week intent-to-treat analysis, the absolute amount of limb fat rose significantly more with atazanavir/ritonavir than with efavirenz (1.9 vs 1.0 kg, respectively), and the percentage increase was twice as large with atazanavir/ritonavir (about 15% vs 30%).
	With longer follow-up, limb fat declined among atazanavir/ritonavir recipients starting about week 96, but then rose again after week 144; efavirenz recipients experienced a continued rise, so changes were similar by week 192.
	In an ad hoc analysis of trunk fat, absolute amounts gained (1.5-2.0 kg) and percentage changes (about 25%) were similar with tenofovir/emtricitabine and abacavir/lamivudine.
	Trunk fat rose significantly more with atazanavir/ritonavir than with efavirenz in absolute amount (about 1.2 vs 2.5 kg) and percentage (about 20% vs nearly 40%, respectively).

The researchers concluded that, "All regimens appeared to produce an initial bone loss with subsequent stabilization after week 48. [Tenofovir/emtricitabine] led to greater bone mineral density loss in hip and lumbar spine than [abacavir/lamivudine]. Atazanavir/ritonavir led to greater bone mineral density loss in lumbar spine (but not hip) than efavirenz. Fractures were similarly distributed among study arms."

With regard to fat, they concluded, "Regimens containing [tenofovir/emtricitabine] or [abacavir/lamivudine] increased limb fat and trunk fat and were not significantly different (by intent-to-treat). Atazanavir/ritonavir led to great gain in limb fat and trunk fat than efavirenz."

Finally, they noted, "Lipoatrophy, even the mild protocol-defined form, occurred in 16% of the participants and was not significantly different between [tenofovir/emtricitabine] and [abacavir/lamivudine] or between efavirenz and atazanavir/ritonavir."

Speaking at an accompanying press conference, McComsey said these lipoatrophy rates were "very low," which offers "very encouraging news" that modern ART regimens do not cause some of the problems seen with certain older drugs.

Case Western Reserve Univ, Cleveland, OH; Harvard Sch of Publ Hlth, Boston, MA; Los Angeles Biomed Res Inst at Harbor-UCLA, Torrance, CA; Social & Sci Systems, Inc, Silver Spring, MD; Univ of Pennsylvania, Philadelphia, PA; Frontier Sci and Tech Res Fndn, Amherst, NY; Brigham and Women`s Hosp, Harvard Med Sch, Boston, MA.

3/2/10

Reference
G McComsey, D Kitch, E Daar, and others. 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 & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 106LB.