BOSTON — Switching antiretroviral medications can reduce the incidence and severity of drug-induced lipoatrophy in some HIV patients, according to three studies presented at a conference on retroviruses and opportunistic infections.
Subcutaneous fat loss, particularly from the face and limbs, is a frequent adverse effect of current combination antiretroviral therapy (ART) regimens. Although the effect has been associated with both nucleoside analogue reverse transcriptase inhibitors (NRTI) and protease inhibitors, not all of the drugs in both classes are equal in this regard, prompting investigators to consider new combinations that might have more favorable effects on fat distribution.
Switching to Abacavir or Tenofovir
In one study—a 48-week randomized, open-label trial—Graeme Moyle, M.D., of the Royal Free Hospital, London, and colleagues tested the hypothesis that removing a thymidine analogue from a highly active ART (HAART) regimen may improve associated lipoatrophy.
The investigators studied changes in limb fat as measured by dual energy x-ray absorptiometry (DXA) and visceral fat as measured by computed tomography in 105 HIV-infected adults in whom zidovudine (AZT, Retrovir) or stavudine (d4T, Zerit) therapy was replaced with either the nucleoside analogue abacavir (Ziagen) or the NRTI tenofovir (Viread).
Of the 71 stavudine and 34 zidovudine patients, 53 were randomly assigned to abacavir, and 52 were assigned to tenofovir. At 48 months, patients in both groups had similarly significant increases in leg and visceral fat from baseline, Dr. Moyle reported in an abstract presentation at the conference sponsored by the Foundation for Retrovirology and Human Health.
Among patients switched to abacavir, limb fat had increased at the end of the study by an average of 0.5 kg from a baseline average of 3.7 kg. In the tenofovir group, limb fat increased 0.3 kg from a baseline average of 3.9 kg. “Similar changes were observed in visceral and subcutaneous abdominal fat,” Dr. Moyle said.
Both treatment groups maintained similar virologic suppression with the change in their regimens, although more patients in the abacavir group than in the tenofovir group discontinued therapy. Of the patients switched to abacavir, eight discontinued treatment, including three who developed hypersensitivity reactions. Three patients in the tenofovir arm dropped out of the study.
There were no statistically significant differences between treatment groups with respect to changes in bone mineral density scores, but measurements of mean changes in total cholesterol, LDL cholesterol, and triglycerides through week 48 significantly favored tenofovir.
Nucleoside-Sparing Regimens I
Mirroring these findings were the results from a prospective, randomized trial presented by Robert Murphy, M.D., of Northwestern University, Chicago on behalf of the AACTG 5110 Study Team.
In the first study to detect an improvement in lipoatrophy after only 24 weeks of treatment modification, 101 patients on zidovudine-inclusive or stavudine-inclusive regimens were randomized to either change their nucleoside to abacavir, switch to a nucleoside-sparing cocktail of ritonavir (Norvir)-boosted lopinavir (Kaletra) plus nevirapine (Viramune), or delay any switch until 24 weeks followed by randomization into one of the two treatment groups.
At 24 weeks, CT-measured limb fat among patients on the nucleoside-sparing regimen had increased 8%, while no change was observed in the abacavir group and a 3% increase was found in the treatment-delay group. Both treatment groups had significant increases in subcutaneous abdominal fat—17% for the nucleoside-sparing group and 9% for the abacavir group—compared with a decrease in the treatment-delay group. Visceral abdominal fat decreased in all three groups, with a smaller decrease in the nucleoside-sparing group than in the abacavir group (9% vs. 12%).
Virologic suppression was maintained in both treatment groups. “The [nucleoside-sparing] regimen led to a significant increase in CD4 cell count at 24 weeks,” Dr. Murphy said, compared with a nonsignificant decrease with abacavir. Similar proportions of both treatment groups maintained undetectable viral loads.
Although statistically significant, “the 8% increase in limb fat from a very low baseline [median 18.9 cm
Nucleoside-Sparing Regimens II
Similar results were reported from a longer-term study in which 62 patients who had been on indinavir (Crixivan)/efavirenz (Sustiva) regimens for at least 18 months were randomly switched to either efavirenz and two nucleosides or to ritonavir-boosted lopinavir and efavirenz.
At baseline, median total limb fat for all patients, measured by DXA, was 6 kg. At 48 weeks, limb fat of patients in the non-nucleoside arm had increased significantly by a median of 562 g, compared with a 246-g loss in the nucleoside arm, reported lead investigator Pablo Tebas, M.D., of the University of Pennsylvania, Philadelphia.
At 48 weeks, there were no differences in amount of trunk fat, bone mineral density, or glucose metabolism between the treatment groups. However, total cholesterol and triglyceride levels increased significantly in the nonnucleoside group.