Some people are genetically protected against the loss of subcutaneous fat when they take anti-HIV treatment, according to results from a US study published in the March 1st edition of the Journal of Infectious Diseases
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The research is being seen as the clearest sign yet that it is not just certain antiretrovirals that cause changes in body fat, but that genetics plays a role too.
Antiretrovirals were implicated as the sole cause of lipodystrophy when the problem was first identified in 1998. The loss of subcutaneous fat from the face and extremities – lipoatrophy – was also thought to be part of the same problem as the build up of fat in other areas – lipodystrophy.
Being male, white and having advanced HIV disease have all been identified as factors which make lipoatrophy more likely, although exactly why has not been clear.
The US researchers have now studied genetic factors in HIV-infected people who took part in the AIDS Clinical Trials Group 384 study. The trial randomised treatment naïve people to receive the nucleoside analogue drugs ddI (didanosine) /d4T (stavudine) or AZT (zidovudine)/3TC (lamivudine) combined with the non-nucleoside reverse transcriptase inhibitors efavirenz and/or nelfinavir.
The researchers carried out their genetic analyses in 96 patients who had taken part in a substudy of ACTG 384 designed to look at fat distribution, which involved them having dual-energy X-ray absorptiometry (DEXA) scanning to calculate the amount of fat in their limbs.
Overall the participants lost 8.8% of subcutaneous fat, 48 or 64 weeks after starting therapy.
But the researchers also studied the DNA of the participants, focussing on the hemochromatosis gene (HFE).
They chose this gene because antiretroviral-associated lipodystrophy is known to involve problems in the mitochondria – the subcellular structures involved in producing energy for the cell. Iron metabolism is known to impact on mitochondrial function and hemochromatosis is the most common form of iron overload disease.
In earlier studies HFE polymorphisms – or natural genetic variations - were found to influence antiretroviral-associated neuropathy, another mitochondrial problem.
They found that a specific mutation in the HFE gene – HFE 187C/G – was protective against fat loss.
The 23 people who had a copy of the HFE 187C/G variant (heterozygotes) gained a median of 6.1% limb fat, while 71 people with two HFE 187C/C gene variants (homozygotes) lost a median of 12.5% of limb fat, a statistically significant difference (p = 0.02).
They found another set of mitochondrial gene variants (haplogroup J) also had a protective effect in non-Hispanic white participants but the difference was not significant.
The authors say this is the first study to show a genetic polymorphism affecting iron transport may protect against lipoatrophy – meaning some people may be genetically predisposed to lipoatrophy while others might be protected against it. A previous study found that heterozygosity for the HFE 187C/G variant was also protective against the development of peripheral neuropathy.
More work is needed they say, but the hope is that genetic studies may help in the choice of antiretroviral therapy to avoid subcutaneous fat changes.
In an accompanying editorial Dr Kenneth Lichtenstein of National Jewish Research and Medical Center, Denver, notes that the findings "provide evidence for the use of medications we might otherwise avoid giving to patients who may be genetically protected from the development of lipoatrophy."
The drug most strongly asociated with fat loss is d4T (stavudine). Treatment guidelines in the UK have advised doctors to avoid prescribing d4T in a first-line regimen due to the risk of lipoatrophy since 2003.
Huldan T et al. Hemochromatosis gene polymorphisms, mitochondrial haplogroups and peripheral lipoatrophy during antiretroviral therapy. J Infect Dis 197: 858-866, 2008.