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Switching to abacavir to reduce fat wasting

Report from the 9th annual Retrovirus Conference

Although highly active antiretroviral therapy (HAART) has many benefits, its use is associated with side effects, including body shape changes. In such cases, fat that lies under the skin — called subcutaneous fat — disappears from the face, arms and legs. In some cases fat gets deposited in the breasts, abdomen and back of the neck (buffalo hump). Precisely why these strange changes occur is not clear, but a research team in Australia has a theory. According to the team, a group of anti-HIV drugs called nukes (nucleoside analogues) can damage the energy-producing parts — called mitochondria — of fat cells. Unable to produce enough energy, fat cells malfunction and die. Certain nukes called “T” drugs (thymidine analogues) may have a closer link to fat wasting than other nukes. Examples of these “T” drugs are:

d4T (Zerit, stavudine)
AZT (Retrovir)

To try to remedy HAART-related fat wasting, the Australian researchers conducted a study in which some HIV positive subjects who were using d4T or AZT as part of their combination therapy could replace (or switch) either of these “T” drugs with another nuke — abacavir (ABC, Ziagen). Researchers monitored subjects for six months to assess if there were any changes in body shape.

Study details
Researchers enrolled 105 subjects with the following profile:

all were male
average age – 44 years
average CD4+ count – 577 cells
they had been using nukes for about 5� years
they had about three years’ exposure to AZT and another three years’ exposure to d4T
56% were using protease inhibitors
they had moderate-to-severe fat wasting
at least 80% of subjects had fat wasting in the face, arms, legs and buttocks
no subject had previously used abacavir

The team randomly assigned 50 subjects to substitute their “T” nuke for abacavir and the remaining 55 subjects to continue taking their existing regimen.

Results
After six months, there was an increase in the fat content of the arms and legs of subjects taking abacavir compared to subjects who continued to take their pre-study therapy. This difference was statistically significant; that is, not likely due to chance alone. However, the rise in fat levels was only about 10% — an increase so small that the untrained eye would have difficulty noticing. Indeed, this increase in subcutaneous fat in the limbs was detected using X-ray scans called DEXA. The rise in fat in abacavir-users occurred regardless of the following factors:

whether or not they used a protease inhibitor
how long they had previously used nukes
even if they had “profound” fat loss at the beginning of the study

Levels of abdominal fat in the abacavir group declined slightly. Levels of lactic acid in the blood — higher-than-normal levels suggest mitochondrial damage — declined slightly in the abacavir group, but did not decline in the other subjects. There were no significant changes in lipid levels — cholesterol and triglycerides — in the blood of subjects during the study.

On average, viral load remained suppressed in subjects who switched to abacavir.

Adverse events
Two subjects in the non-abacavir group had heart attacks and 10% of subjects receiving abacavir developed a hypersensitivity syndrome associated with the use of that drug.

Key issues
Readers ought to keep these results in perspective — the improvements in subcutaneous fat were small and needed to be confirmed with the use of X-rays. It is possible that it may take years, as the researchers theorize, for subcutaneous fat to reappear. The results from Australia were similar to those reported in other studies in which subjects were switched to abacavir to assess changes in fat wasting. This and other studies lay the groundwork for future research. For instance, should PHAs use combinations of nukes that avoid or minimize their exposure to “T”-containing ones such as AZT and d4T? Here are some possible combinations:

abacavir and tenofovir (Viread)
ddI (Videx) and 3TC (lamivudine, Epivir)
ddI and tenofovir
abacavir and ddI

The problem with this list is that there are only a few drugs from which to choose. Moreover, the listed drugs have other side effects. An alternative strategy may be to cycle the use of all nukes, using one combination for a fixed period of time, say six months to one year, and then switching to another combination for the next time period and so on. These are merely some possibilities of many that require investigation. Before rushing out to switch nukes, PHAs would be far better off to await the results of further studies that carefully weigh the risks (increased viral load, different side effects) and benefits (small, hard-to-notice increases in subcutaneous fat) of changing their regimens. Although nukes were among the first group of drugs to be approved for the treatment of HIV/AIDS, there is still a lot about them that needs to be understood.

—Sean R. Hosein

REFERENCE
Carr A, Smith D, Workman C, et al. Switching stavudine or zidovudine to abacavir for HIV lipoatrophy: a randomized, controlled, open-label, multicentre, 24-week study. Abstract 32.

Created on: 03/11/2002

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