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Reversibility
of Lipoatrophy in HIV Patients 2 Years After Switching from a Thymidine
Analogue to Abacavir
The HIV-associated lipodystrophy syndrome affects approximately
50% of HIV-positive patients, particularly those receiving antiretroviral
therapy based on nucleoside reverse transcriptase inhibitors (NRTIs)
and protease inhibitors (PIs).
The selection of an optimal treatment regimen for HIV infection
is influenced by increasing evidence that particular antiretroviral
drugs may exacerbate lipoatrophy and associated metabolic abnormalities.
However, because of cross-resistance among antiretroviral drug
classes and other treatment toxicities, it is likely that, in a
lifetime, HIV patients will have to take drugs that are associated
with the development of the lipodystrophy syndrome.
A number of cohort studies have suggested that long-term exposure
to thymidine-based analogues results in lipoatrophy that is associated
with mitochondrial toxicity and lactic acidemia.
The PIILR extension study examined lipoatrophic patients on
a protease inhibitor-sparing antiretroviral regimen for a least
12 months, who then ceased stavudine/ d4T (Zerit)
or zidovudine/ ZDV (Retrovir).
This study resulted in significant improvements in lipoatrophy but
an unacceptable rate of HIV virological rebound.
More recently, replacement of d4T or ZDV with abacavir/ ABC
(Ziagen) in randomized
controlled trials has been shown to lead to modest improvements
in fat mass over a relatively short period of time.
The initial MITOX (mitochondrial toxicity) study reported a
significant increase of 0.4 kg (11%) in limb fat in the ABC-treated
subjects at 24 weeks, as well as significant relative increases
in subcutaneous thigh and abdominal fat mass. However, this difference
in limb fat was not apparent clinically.
The objective
of the current study was to determine if long-term improvement in
HIV lipoatrophy can be attained by substitution of the thymidine analogues
ZDV d4T with ABC. Long-term follow-up (104 weeks) of this randomized,
open-label study (MITOX) appears in the April 30 issue of AIDS.
Seventeen
HIV clinics in Australia and London enrolled 85 patients with HIV
lipodystrophy who were randomized to switch from a thymidine analogue
to ABC, while continuing all other antiretroviral therapy (ABC arm)
(n = 42) or continue current therapy (ZDV/d4T arm) (n = 43).
At week
24, all control patients could switch to ABC. Of the original 111
patients randomized, 85 had long-term follow-up data, with 77 having
imaging data available at 104 weeks.
The primary
endpoint was time-weighted change in limb fat mass, measured by dual-energy
X-ray absorptiometry (DEXA).
Results
At week 104, the mean increase in limb fat
for the ABC and ZDV/d4T group was 1.26 ± 2.02 kg and 0.49 ± 1.38
kg, respectively. The time-weighted change for limb fat was significantly
different between the two arms (0.43 kg; P = 0.008).
On-treatment analysis demonstrated a trend
for increased limb fat in patients in the ABC arm.
Interestingly,
visceral fat accumulation, buffalo hump, self-assessed lipodystrophy
or the lipodystrophy case definition score (LCDS) did not improve.
The authors conclude, “In patients with moderate-to-severe
lipodystrophy, significant improvements in subcutaneous fat continued
over 104 weeks after switching from a thymidine analogue to ABC.
Nevertheless, the lipodystrophy syndrome was still evident, indicating
additional strategies need evaluating.”
04/23/04
Reference
A Martin and others (for the Mitochondrial Toxicity (MITOX)
Study Group). Reversibility
of lipoatrophy in HIV-infected patients 2 years after switching
from a thymidine analogue to abacavir: the MITOX Extension Study.
AIDS
18(7):
1029-1036.
April
30, 2004.
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