Lipoatrophy, or loss of peripheral subcutaneous
fat in the face and limbs, is a side effect of certain antiretroviral drugs that
has been linked to mitochondrial toxicity, or damage to small energy-producing
structures within the cells.
Peripheral
fat loss has become less common in recent years as the so-called "d-drugs"
stavudine (d4T; Zerit) and didanosine (ddI; Videx) have fallen out of favor, at
least in industrialized countries. Yet it remains a concern for many people with
HIV.
As described in the March 15, 2008 Journal of Infectious Diseases,
the AIDS Clinical Trials Group (ACTG) 384 and A5005s study teams conducted an
analysis of genetic factors associated with antiretroviral therapy-associated
lipoatrophy.
As background, they noted that iron metabolism affects mitochondrial
function and oxidative stress. Specific mitochondrial haplogroups and hemochromatosis
gene (HFE) polymorphisms (natural genetic variations) have been associated with
antiretroviral-induced neuropathy, which is also linked to mitochondrial toxicity
caused by the same drugs.
Hemochromatosis, or iron overload disease, is
a hereditary condition that leads to the storage of excess iron, which over time
can lead to liver damage and other complications. People who have 2 matching copies
of specific HFE alleles (known as homozygotes), as well as those with certain
patterns of unmatched alleles (heterozygotes), are at risk for clinical hemochromatosis.
In
ACTG 384, treatment-naive individuals were randomly assigned to receive either
didanosine plus stavudine or zidovudine (AZT; Retrovir) plus lamivudine (3TC;
Epivir), in combination with either efavirenz (Sustiva), nelfinavir (Viracept),
or both. Substudy A5005s evaluated body fat distribution using DEXA scans. In
the present analysis, the investigators characterized HFE polymorphisms 845G>A
and 187C>G and European mitochondrial haplogroups in A5005s participants who
consented to genetic analysis.
Results
•
Among 96 participants
(58% white, 90% men) with baseline and 48 or 64 week DEXA data, the overall median
limb fat change was -8.8%.
•
The 23 patients
who were HFE 187C/G heterozygotes had less limb fat loss than the 71 who
were 187C/C homozygotes (+6.1% vs -12.5%; P = 0.02).
•
The heterozygotes
were also less likely to develop lipoatrophy after adjusting for age, sex, race,
and antiretroviral regimen (odds ratio 0.31; P = 0.04).
•
Among non-Hispanic
white participants, the median limb fat change was +26.1% among 5 patients with
mitochondrial haplogroup J, compared with -9.7% among 49 individuals with other
mitochondrial haplogroups (P = 0.07).
Conclusion
In
conclusion, the investigators wrote, "HFE 187C>G and, possibly,
mitochondrial haplogroup J gave relative protection against lipoatrophy during
antiretroviral therapy in A5005s."
In an accompanying editorial, Kenneth
Lichtenstein of the National Jewish Medical and Research Center in Denver suggested
that these findings might provide evidence that it is safe to offer implicated
drugs to specific patients "who may be genetically protected from the development
of lipoatrophy."
Vanderbilt University School
of Medicine, Nashville, TN; University of Pennsylvania, Philadelphia, PA; University
of California at San Francisco, San Francisco, CA; Indiana University School of
Medicine, Indianapolis, IN; Massachusetts General Hospital, Harvard University,
Boston, MA.
5/02/08
References
T Hulgan, P Tebas,
JA Canter, and others (AIDS Clinical Trials Group 384 and A5005s Study Teams).
Hemochromatosis Gene Polymorphisms, Mitochondrial Haplogroups, and Peripheral
Lipoatrophy during Antiretroviral Therapy. Journal of Infectious Diseases
197(6): 858-866. March 15, 2008.
KA Lichtenstein. Human Immunodeficiency
Virus-Associated Lipoatrophy: Letting the Genome Out of the Bottle. Journal
of Infectious Diseases 197(6): 784-786. March 15, 2008.
Results
