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Abacavir Substitution for Nucleoside Analogs in Patients With HIV Lipoatrophy
A Randomized Trial
Andrew Carr, MD;
Cassy Workman, MBBS;
Don E. Smith, MD;
Jennifer Hoy, MBBS;
Jeff Hudson, RN;
Nicholas Doong, MBBS, MPH;
Allison Martin, MSc;
Janaki Amin, MPH;
Judith Freund, MBBS;
Matthew Law, PhD;
David A. Cooper, MD, DSc;
for the Mitochondrial Toxicity (MITOX) Study Group
JAMA. 2002;288:207-215.
ABSTRACT
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Context Peripheral lipoatrophy may complicate antiretroviral therapy of human
immunodeficiency virus (HIV) infection, often related to duration and type
of nucleoside analog therapy, and may have a mitochondrial pathogenesis. No
proven therapy exists for lipoatrophy, but abacavir is a nucleoside analog
that may be less toxic to mitochondria.
Objective To determine if substitution of stavudine or zidovudine with abacavir
improves HIV lipoatrophy without affecting control of HIV replication.
Design Randomized, open-label 24-week study.
Setting Seventeen hospital HIV outpatient clinics and primary care centers in
Australia and England, with randomization from June 2000 through January 2001.
Participants A total of 111 adults (109 men) with moderate or severe lipoatrophy
who were receiving stavudine (n = 85) or zidovudine (n = 26) and had stable
plasma HIV RNA levels below 400 copies/mL and no prior abacavir therapy.
Intervention Patients were randomly assigned to switch from stavudine or zidovudine
to abacavir, 300 mg twice per day, while continuing all other antiretroviral
therapy (n = 54) or to continue all antiretroviral therapy (n = 57).
Main Outcome Measures The primary end point was limb fat mass, measured by dual-energy x-ray
absorptiometry; key secondary end points were plasma HIV RNA levels, adverse
events, physician-assessed (via subjective measures) lipodystrophy severity,
total and central fat mass, and fasting metabolic (lipid, glycemic, and lactate)
levels.
Results There was a significant increase in limb fat in the abacavir group relative
to the stavudine/zidovudine group (0.39 vs 0.08 kg; mean difference, 0.31;
95% confidence interval [CI], 0.06-0.57 kg), as well as significant relative
increases in subcutaneous thigh (P = .01), arm (P<.001), and abdominal (P =
.001) fat areas on computed tomography. Switching had no significant effect
on secondary end points, including plasma HIV RNA (for unadjusted comparison
between groups at week 24, odds ratio, 1.38; 95% CI, 0.48-3.96). Change in
limb fat mass at week 24 did not correlate with change in subjectively determined
perceived lipoatrophy severity (r = -0.06; P = .53 by Spearman correlation). Hypersensitivity to abacavir
was seen in 5 patients (10%).
Conclusions In this sample of lipoatrophic HIV-infected adults, switching from stavudine
or zidovudine to abacavir for 24 weeks led to significant, albeit modest,
objectively measured increases in limb fat. Clinical lipoatrophy, as assessed
subjectively, did not resolve, however, and at the rate of increase observed
may take years to resolve with use of this strategy. Longer-term follow-up
is needed.
INTRODUCTION
Lipodystrophy (peripheral lipoatrophy, central fat accumulation, and
lipomata) is common in human immunodeficiency virus (HIV)–infected adults
receiving antiretroviral therapy and is significantly associated with dyslipidemia,
insulin resistance, and lactic acidemia.1-7
Lipoatrophy in HIV-infected adults is disfiguring and potentially stigmatizing
and has been associated with poorer adherence to antiretroviral therapy.8 Lipodystrophy was initially attributed to protease
inhibitor therapy on the basis of cohort studies, a finding confirmed by in
vitro adipocyte studies.9-11
The type and duration of nucleoside reverse transcriptase inhibitor (NRTI)
therapy were subsequently linked to lipoatrophy,12-16
with these findings also confirmed in vitro.17
The NRTI-related lipoatrophy may be a result of mitochondrial toxicity: lipoatrophy
is associated with lactic acidemia15; lipoatrophy
may develop more rapidly in adults with asymptomatic, low-level lactic acidemia18; and mitochondrial DNA depletion has been found in
atrophic peripheral adipocytes of recipients of NRTIs, most commonly stavudine
and zidovudine.19
No proven treatment exists for HIV lipoatrophy, and no study has found
that limb fat increases spontaneously over time in patients with lipoatrophy.
A randomized protease inhibitor switch study found a reduction in intra-abdominal
fat accumulation but no improvement in lipoatrophy.20
In 2 small studies, lipoatrophy improved after switching or ceasing nucleoside
analog therapy. In the first, switching stavudine to zidovudine or abacavir
led to increased limb fat on computed tomography (CT), but this study was
not randomized.21 In a randomized study, ceasing
stavudine or zidovudine without drug substitution resulted in increased limb
fat on dual-energy x-ray absorptiometry (DXA) but also frequently led to increased
plasma HIV RNA level (viral load).22 Given
these data, and because abacavir appears less toxic to mitochondria in vitro,23 we undertook a randomized, multicenter, 24-week study
to evaluate the hypothesis that switching from either stavudine or zidovudine
to abacavir would improve peripheral lipoatrophy without affecting control
of HIV replication. Further analyses were performed to explore whether any
patient subgroup derived more or less benefit from this strategy.
METHODS
Study Sample
Participants were recruited at 17 HIV hospital outpatient or community-based
primary care sites. Study eligibility criteria included documented HIV infection,
age older than 18 years, moderate or severe peripheral lipoatrophy5 in at least 1 region (face, arms, legs, or buttocks)
on physical examination, no prior abacavir therapy, viral load below 400 copies/mL
for at least the preceding 3 months, and stable well-tolerated antiretroviral
therapy including stavudine or zidovudine for at least the preceding 8 weeks.
The last 2 criteria were chosen because switching 1 drug of an antiretroviral
regimen in a patient without fully suppressed HIV replication would not be
ethical because resistance to the new drug would be likely.24
The NRTIs stavudine and zidovudine were chosen as the control NRTIs because
these drugs form part of almost all antiretroviral regimens24-25
and because the total duration of NRTI therapy is linked to lipoatrophy (often
zidovudine is followed by stavudine), as is current NRTI type (particularly
current use of stavudine).15-16
Other entry criteria were absence of an active acquired immunodeficiency syndrome
(AIDS)–defining condition in the preceding 3 months; use of standard-of-care
opportunistic infection prophylaxis; plasma venous lactate level of less than
45 mg/dL (5 mmol/L); serum hepatic transaminase levels of less than 5 times
the upper limit of normal; negative pregnancy test result in women of childbearing
age; no use of chemotherapy, radiotherapy, or immune modulators (except hydroxyurea);
and no ongoing alcohol or substance abuse. All patients provided written informed
consent after study approval by each site's research ethics committee.
Definitions
In the absence of a validated case definition, lipodystrophy was defined
subjectively by the presence of peripheral lipoatrophy (face, arms, buttocks,
or legs) and/or central fat accumulation (abdomen, dorsocervical fat pad)
using a standardized physical examination procedure.1, 4-5
Lipodystrophy intensity (mild, moderate, or severe) has been found to significantly
(P = .003) correlate with DXA measurement of peripheral
fat mass.4 Virologic failure was defined as
viral load above 400 copies/mL on 2 occasions more than 14 days apart in the
absence of intercurrent illness or an isolated value above 5000 copies/mL.20, 24, 26 Abacavir hypersensitivity
was defined according to criteria developed by the manufacturer.27
Interventions
The study was designed to equally randomize 100 eligible patients. Patients
either ceased stavudine or zidovudine and commenced open-label abacavir, 300
mg twice per day, or continued all current NRTI therapy including stavudine
or zidovudine (with an option to switch to abacavir at week 24). All patients
continued all other concomitant antiretroviral therapy (Figure 1).
Randomization was performed centrally at the National Centre in HIV
Epidemiology and Clinical Research, Sydney, Australia, after confirmation
of eligibility and stratified by factors previously associated with lipoatrophy
presence and severity5-6,14-16:
current use of stavudine (n = 85) or zidovudine (n = 26), current use of protease
inhibitors (n = 59) and/or nonnucleoside reverse transcriptase inhibitors,
and presence or absence of lactic acidemia (>18 mg/dL [2 mmol/L]) (n = 24).
Cessation of abacavir was mandatory for related grade 3 or 4 adverse
events, including hypersensitivity; dose reduction or rechallenge was not
permitted. Patients ceasing abacavir could start alternative antiretroviral
therapy at investigators' discretion. Grade 1 or 2 adverse events (other than
abacavir hypersensitivity) were managed according to treating physicians'
assessments. Substitution of antiretroviral drugs other than abacavir was
mandatory for recurrent grade 3 or 4 drug-related adverse events and was optional
for persistent drug-related grade 1 or 2 adverse events and for virologic
failure.
Assessments
Demographic data and details of all prior antiretroviral therapy were
recorded at screening. (Screening indicates confirmation of eligibility after
signing consent form. All screened patients were eligible. Patients were not
referred but were under routine care. Eligibility was confirmed centrally.)
After the 2-week screening period, patients were seen at baseline and weeks
4, 12, and 24, including those ceasing therapy but agreeing to follow-up (n
= 10), and at weeks 2 and 6 in the abacavir group for additional safety assessments.
Adverse events, concomitant medication, weight, waist and hip circumference,
physical examination, safety assessments involving blood testing (measures
of complete blood cell count, electrolytes, liver enzymes, urea, creatinine,
creatine kinase, phosphate, and amylase), quality of life (as assessed by
patients and physicians using the EuroQol technique, a visual analog scale
[0-100] based on perceived overall quality of life on day of assessment),28 CD4 cell counts, and plasma HIV RNA (lower limit
of detection for screening, 400 copies/mL; for analysis, 50 copies/mL batch
tested), fasting total and high-density lipoprotein cholesterol, triglyceride,
glucose, insulin, and C-peptide measurements were assessed as described.1, 4, 15 Adherence was estimated
clinically by counts of remaining pills in each month's supply of study drugs.
For collection of venous lactate, patients were advised not to vigorously
exercise for 24 hours beforehand and to be well hydrated. Blood was collected
after patients rested for at least 5 minutes, without fist clenching or stasis,
into a prechilled fluoride-oxalate tube, transported immediately on ice, and
processed within 4 hours of collection.
Body composition was quantified at screening and at weeks 12 and 24
by DXA (Lunar DPXL, Madison, Wis) and single-cut CT.1-2,4, 15
The DXA studies were used to measure total and regional body fat and lean
tissue, and CT to quantify fat areas at the L4 vertebral level (intra-abdominal
and extra-abdominal [ie, subcutaneous]), right mid humerus, and right mid
thigh. We did not perform CT of the face because of lack of validated landmarks
for this measurement, and we did not assess facial skin folds because of concern
about high intraobserver variability (A.C., unpublished data, February 2002).
Quality assurance programs were instituted for both scanning techniques prior
to study commencement. For DXA data acquisition, the scan was deferred in
patients having had recent radionuclide or barium tests until the material
was cleared; in addition, jewelry was removed, arms were separated from the
body sides, use of sandbags or pillows was avoided, and care was taken to
ensure that the whole body was included. The DXA analysis required display
of soft tissue and bone for appropriate allocation of soft tissue, use of
extended research mode analysis, and detailed Lunar-defined localization of
the arm, rib, central, pelvic, lumbar, dorsal, and neck cuts; the regions
analyzed were arms, legs, and trunk as previously described.1, 4
Daily quality control and calibration procedures were performed at all sites.
A Lunar soft tissue phantom (composite blocks used for calibration) was measured
regularly at the central site and the same phantom measurement was taken once
at all other sites. All patient and phantom scans were read centrally every
month. For CT, each patient underwent imaging using a conventional helical
or nonhelical system, with each site using only 1 CT scanner and constant
soft-tissue imaging parameters. Patients lay supine with the head straight,
shoulders relaxed, and arms raised above the head; patient motion was kept
at a minimum. All soft tissue was included in the CT field of view. Using
a mid–L4 vertebral scout film as a guide, a single 10-mm axial slice
of the abdomen through the point of the marker was performed on a normal setting.
Visceral adipose tissue and subcutaneous adipose tissue were traced manually.
Both DXA and CT scans were read centrally by technicians unaware of patient
assignment.
Subjective measures of lipodystrophy presence and severity in the periphery
(lipoatrophy in the face, arms, legs, and buttocks), centrally (fat accumulation
in the abdomen and dorsocervical spine region), and overall were assessed
using a case record form by a physician every 12 weeks. Each patient was evaluated
by the same physician each time. Use of this form and method of assessment
have been found to correlate (P value for trend =
.003) with DXA measurement of peripheral fat mass.4
All study physicians received prestudy training to ensure physical examination
standardization for assessment of lipodystrophy at each site, in particular
for rating lipodystrophy severity. The physicians all used the same form (available
from the authors on request) for assessing patients and received training
regarding use of the form (previously used4).
Physicians were aware of patient assignment. In each region, a score of 0
for nil, 1 for mild, 2 for moderate, or 3 for severe was assigned, for a maximum
possible score of 12 peripherally, 6 centrally, and 18 overall using a previously
described scoring system.4
Statistics
The primary study end point was the mean change in limb (arm and leg)
fat mass measured by DXA at week 24. Secondary end points were adverse events;
anthropometry; total and central fat mass; biochemical, lipid, and glycemic
measurements; viral load; CD4 cell count; and quality of life.
The sample size of 100 patients was chosen to have an 80% power to detect
a 0.5-kg difference in mean limb fat between the 2 groups and assumed that
up to 10% of the abacavir group would cease taking abacavir because of intolerance
or virologic failure. These calculations were based on estimates of variability
derived from the Protease Inhibitor Induced Lipodystrophy Reversal (PIILR)
study.20
All analyses were by intention to treat (except they excluded 5 patients
withdrawing prior to baseline) and included all follow-up data on all patients
receiving stavudine/zidovudine or commencing abacavir at day 0, regardless
of any subsequent treatment changes. No interim analysis was performed. In
summarizing changes from baseline by nominal study week, a last-value-carried-forward
approach was adopted for patients with any missing data for the remainder
of the follow-up period (sensitivity analyses on available data only gave
qualitatively very similar results and are not presented [A.C., unpublished
data, February 2002]). The percentage of patients with detectable HIV RNA
( 50 copies/mL) was analyzed using odds ratios (ORs) generated by logistic
regression models; 2 patients with no week 24 viral load measurements were
assigned a status of virologic failure.29 Changes
from baseline were compared between treatment groups using 2-sample t tests. The Spearman correlation was used to assess the
correlation between change in limb fat mass and change in subjectively assessed
lipoatrophy severity. The  2 test was used to compare the frequency
of dorsocervical lipomata at week 24. All hypothesis tests were 2-sided, with
statistical significance at the .05 level. There was no adjustment of P values for multiple comparisons because these adjustments,
with many correlated variables, are overly conservative, both in terms of
the type 1 error rate and reductions in power. Analyses were performed using
SAS statistical software, version 8 (SAS Inc, Cary, NC).
RESULTS
Participants
One hundred eleven patients were screened and randomized between June
2000 and January 2001 (Figure 1).
Five randomized patients withdrew from the study prior to baseline visits
(1 after becoming aware of randomization to abacavir therapy) and were excluded
from analyses. Baseline patient characteristics of the remaining 106 patients,
who completed all scheduled visits through week 24 (except 1 patient who died),
were similar between groups (Table 1).
The number of patients with lactic acidemia (>18 mg/dL [2 mmol/L]) was 13
(26%) in the abacavir group and 11 (20%) in the stavudine/zidovudine group,
but lactic acidemia was asymptomatic in all patients and did not require intervention.
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Table 1. Baseline Patient Characteristics*
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Treatment Outcomes, Safety, HIV RNA Levels, and Quality of Life
Overall, 45 (90%) of 50 abacavir patients and 50 (89%) of 56 patients
in the stavudine/zidovudine group completed 24 weeks of randomized therapy.
Five patients (10%) ceased taking abacavir before week 24 because of hypersensitivity
occurring after 1 to 3 weeks of abacavir which resolved a mean of 8 days after
abacavir was ceased (Table 2).
No other adverse event was attributed to abacavir therapy. Of these 5 patients,
2 restarted stavudine and 1, zidovudine. Five patients (9%) in the stavudine/zidovudine
group ceased stavudine or zidovudine by week 24 (stavudine in 4 patients;
zidovudine in 1 patient). Overall adherence to assigned therapy in the abacavir
group was 90% at weeks 12 and 24 and was 93% and 96% in the stavudine/zidovudine
group at weeks 12 and 24.
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Table 2. Treatment Outcomes*
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There was no AIDS-defining (Centers for Disease Control and Prevention
category C) illness in either group, but 2 patients in the stavudine/zidovudine
group had myocardial infarctions; 1 was fatal at week 7 and another (nonfatal)
occurred at week 12. Quality of life, as assessed by both patients and their
physicians, was similar at baseline between the groups and did not change
significantly over 24 weeks (Table 3).
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Table 3. Changes in Secondary End Points*
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The proportions of patients with viral load of at least 50 copies/mL
did not differ significantly between the groups (18% and 23%, respectively,
in the abacavir and stavudine/zidovudine groups at week 24; (OR, 1.38; 95%
confidence interval [CI], 0.48-3.96; P = .26). After
adjustment for baseline differences in viral load, there was a nonsignificant
trend toward greater control of HIV replication to below 50 copies/mL in the
abacavir group than in the stavudine/zidovudine group at week 24 (OR, 2.66;
95% CI, 0.80-8.85; P = .08).
There was no significant change in hematologic or biochemical safety
assessments, both between groups at week 24 and between baseline and week
24 within each group (A.C., unpublished data, February 2002), except for a
modest relative decline in hemoglobin in the abacavir group (0.3 g/dL; 95%
CI, 0.0-0.6 g/dL; P = .03 by 2-sample t test).
Body Composition
All objective measures of peripheral fat mass showed significant increases
by week 24 in the abacavir group relative to the stavudine/zidovudine group
(Figure 2). Limb fat mass on DXA
increased by 0.39 kg in the abacavir group vs 0.08 kg in the stavudine/zidovudine
group (mean difference, 0.31 kg; 95% CI, 0.06-0.57 kg; P = .02 by 2-sample t test). This represents
an increase of 11% in limb fat mass in the abacavir group over 24 weeks (and
2% in the stavudine/zidovudine group). Subcutaneous right mid-thigh fat area
increased by 3.3 cm2 in the abacavir group vs a decline of 1.2
cm2 in the stavudine/zidovudine group (mean difference, 4.5 cm2; 95% CI, 1.1-7.9 cm2; P = .01
by 2-sample t test). Subcutaneous right mid-humeral
fat area increased by 3.5 cm2 in the abacavir group and did not
change in the stavudine/zidovudine group (mean difference, 3.5 cm2;
95% CI, 1.8-5.1 cm2; P<.001 by 2-sample t test). Subcutaneous L4 abdominal fat increased by 13.9
cm2 in the abacavir group and declined by 1.2 cm2 in
the stavudine/zidovudine group (mean difference, 15.1 cm2; 95%
CI, 6.0-24.2 cm2; P = .001).
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Figure 2. Changes in Body Composition
P values are for comparisons at week 24
using the 2-sample t test.
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Overall lipoatrophy severity was not perceived by physicians (assessing
patients at screening and weeks 12 and 24) as having improved significantly
in the abacavir group relative to the stavudine/zidovudine group; all but
3 patients had lipodystrophy assessed at weeks 12 and 24. Change in limb fat
mass at week 24 did not correlate with change in perceived lipoatrophy severity
(r = -0.06; P = .53
by Spearman correlation). No baseline variable was found to be significantly
associated with greater increases in peripheral fat as measured by DXA (Table 4) or CT (A.C., unpublished data,
February 2002).
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Table 4. Change in Limb Fat Mass at Week 24
in Relation to Baseline Variables
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There was no significant change in the abacavir group relative to the
stavudine/zidovudine group for total body fat, weight, total lean mass, or
waist or hip circumference. Intra-abdominal fat area decreased by 12.5 cm2 in the abacavir group and increased by 1.5 cm2 in the stavudine/zidovudine
group (mean difference, 14.0 cm2; 95% CI, -1.1 to 29.0 cm2; P = .07 by 2-sample t test) (Figure 2E). Intra-abdominal
fat did not improve significantly in patients with moderate or severe central
fat accumulation at baseline who switched to abacavir (A.C., unpublished data,
February 2002). The proportions of patients in the abacavir and stavudine/zidovudine
groups with dorsocervical lipomata at baseline were 14% and 13%, respectively,
and were 30% and 17%, respectively, at week 24 (for comparison at week 24, P = .16 by 2 test).
Metabolic Assessments
There was no significant difference between the 2 groups at week 24
for any metabolic measurement. This was also the case for patients with abnormal
baseline values (lactate >18 mg/dL [2 mmol/L], total cholesterol >193 mg/dL
[5 mmol/L], high-density lipoprotein cholesterol <39 mg/dL [1 mmol/L],
triglycerides >177 mg/dL [2 mmol/L], insulin >10 µU/mL, and C peptide
>2 ng/mL [A.C., unpublished data, February 2002]).
COMMENT
In lipoatrophic, HIV-infected adults with extensive prior antiretroviral
therapy, switching an NRTI (either stavudine or zidovudine) to abacavir for
24 weeks was safe and resulted in improvement in objectively defined peripheral
lipoatrophy. Suppression of HIV replication improved nonsignificantly with
the switch. Metabolic measures associated with lipoatrophy, such as lactic
acidemia, insulin resistance, and hyperlipidemia, did not change.
In objective assessments, lipoatrophy improved with switching to abacavir,
with consistent and significant effects seen with 2 imaging methods of several
affected regions. However, after 6 months, limb fat mass had only increased
by about 11% from baseline. If normal limb fat is about 7 or 8 kg in adult
men with normal body mass index,1 at the rate
observed, it might take 5 or more years for limb fat mass to return to normal.
This is not surprising since lipoatrophy may take years to develop (patients
had a mean 5.5 years of NRTI therapy prior to the study) and antiretroviral
toxic effects of slow onset may take as long to resolve or not be fully reversible.30 Longer follow-up of this population is needed to
determine if lipoatrophy can improve clinically or even resolve.
No factor was significantly associated with greater improvement in limb
fat mass, although there was a suggestion that it might be greater in those
who switched from stavudine rather than from zidovudine (Table 4). This suggests, but certainly does not prove, that stavudine
has a greater lipoatrophic effect than zidovudine. Larger populations will
need to be studied to identify patients most suitable for the switch strategy
used in this study.
It is possible but unlikely that some of the variation in body fat between
groups is a product of altered food intake in the abacavir group. However,
lean mass did not differ between groups at week 24 and did not change significantly
in either group over time. Also, no patient ceased either stavudine or zidovudine
because of nausea or diarrhea. Last, the dosing schedule was either unchanged
(for patients switching from stavudine) or more complex (for those switching
from the combined pill containing zidovudine and lamivudine), and abacavir,
stavudine, and zidovudine can all be taken with or without food.
There was a trend toward improved intra-abdominal fat area, but it did
not reach statistical significance. The study was not powered to address this
end point, however, and about 20% of patients did not have abnormal abdominal
fat accumulation identified by their treating physician at study entry. An
exploratory analysis of patients with moderate or severe intra-abdominal fat
accumulation at baseline found no evidence of benefit in this subgroup (A.C.,
unpublished data, February 2002).
A nonsignificant trend was noted for an increased likelihood of developing
dorsocervical fat accumulation in the abacavir group. This might reflect increased
fat accumulation in patients recovering from lipoatrophy or, less likely,
that abacavir causes lipomatosis. This finding should be interpreted cautiously
given the limited power of the study to evaluate this abnormality.
It has been hypothesized that lipodystrophy may be a consequence of
effective suppression of HIV replication.31
The improvement of lipoatrophy (as assessed by objective methods) in tandem
with stable or even slightly (although nonsignificantly) better HIV suppression
suggests, however, that lipoatrophy is not due to effective HIV suppression.
A similar lack of association was also observed previously in patients switching
from a protease inhibitor to a complex non–protease inhibitor antiretroviral
regimen in whom intra-abdominal fat accumulation improved but HIV viremia
did not change.20
Switching to abacavir was safe, and no unexpected adverse events were
reported or linked to abacavir use. Also, in these patients having extensive
prior antiretroviral therapy, control of HIV replication and CD4 cell count
preservation were not compromised.
No metabolic measure improved significantly, but the study was not designed
to show a significant benefit of switching for these measures.
There are limitations to our study. Only 2 women and no children were
studied, and only 7 of 106 patients were nonwhite. The study also was not
powered to assess the effect of switching from stavudine or zidovudine therapy.
The lipodystrophy severity assessment, the results of which correlated significantly
with DXA fat mass in 2 cross-sectional prevalence surveys,4, 15
was open to patient bias in a previous open-label prospective study20 and may not have been reliable in the present study;
it is almost certainly less reliable than the objective assessment.
In summary, HIV lipoatrophy can improve significantly after switching
from stavudine or zidovudine to abacavir without affecting control of HIV
replication, although clinically, this benefit on lipoatrophy was not apparent
after 24 weeks. This suggests this switching strategy may be a useful approach
over a longer period for a condition that is distressing, potentially stigmatizing,
and associated with poorer adherence to antiretroviral therapy. Whether this
strategy can lead to clinically apparent improvement or even complete reversal
of lipoatrophy may require several more years of follow-up (we are continuing
to follow up the study groups described herein), and will depend on no other
long-term safety or efficacy issues arising. Other strategies under investigation
include intermittent antiretroviral therapy and concurrent therapy with thiazolidinediones,
antidiabetic drugs that promote growth and differentiation of peripheral adipocytes
and that have been effective in congenital lipoatrophy states.32
AUTHOR INFORMATION
Author Contributions: As principal investigator
for the study, Dr Carr had full access to all of the data and takes responsibility
for the integrity of the data and the accuracy of the data analyses.
Study concept and design: Carr, Smith, Hoy,
Hudson, Cooper.
Acquisition of data: Carr, Workman, Smith,
Hoy, Hudson, Doong, Martin, Freund.
Analysis and interpretation of data: Carr,
Smith, Martin, Amin, Freund, Law, Cooper.
Drafting of the manuscript: Carr, Smith, Martin.
Critical revision of the manuscript for important
intellectual content: Carr, Workman, Smith, Hoy, Hudson, Doong, Amin,
Freund, Law, Cooper.
Statistical expertise: Amin, Law.
Obtained funding: Smith, Cooper.
Administrative, technical, or material support:
Carr, Workman, Smith, Hudson, Martin, Freund, Cooper.
Study supervision: Carr, Smith, Hudson, Doong,
Cooper.
Financial Disclosures: Dr Carr has research
grants/funding, honoraria, or lecture sponsorships from or is a consultant
or advisor to Abbott, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Bristol-Myers
Squibb/DuPont, GlaxoSmithKline, the National Institutes of Health (NIH); Pfizer-Agouron,
Roche, Schering-Plough, and the UK Medical Research Council; Dr Workman has
research grants/funding, honoraria, lecture sponsorships, assay kits/reagents
or government grants/research funding from or is a consultant or advisor to
Abbott, Boehringer Ingelheim, Chiron, Glaxo Wellcome, Merck, and the National
Health and Medical Research Council; Dr Smith has research grants/funding,
honoraria, lecture sponsorships, honoraria for continuing medical education
(CME) programs, or government grant/research funding from Abbott Australasia,
Australasian Society for HIV Medicine, Boehringer Ingelheim, Bristol Myers-Squibb,
Communicable Disease Branch of the Department of Health and Aging, Gilead
Sciences, GlaxoSmithKline, Merck Sharpe & Dohme, Roche Products LTD, and
The Albion Street Nursing Education Fund, and provided expert testimony for
Abbott Australasia; Dr Hoy has research grants/funding, honoraria (travel
sponsorship to conferences), or lecture sponsorships from or is an advisor
to Bristol Myers-Squibb, Gilead, GlaxoSmithKline, Merck Sharpe & Dohme,
and Roche; Dr Doong has honoraria for CME programs from Boehringer Ingelheim,
Bristol-Myers Squibb Pharmaceuticals, GlaxoSmithKline, and Merck Sharpe &
Dohme; Dr Cooper has research grants/funding, honoraria, or lecture sponsorships
from or is a consultant or advisor to Abbott, Boehringer Ingelheim, Bristol-Myers
Squibb, Chiron, Gilead, GlaxoSmithKline, Merck Sharpe & Dohme, NIH, Pfizer,
and Roche.
MITOX Study Group Investigators: Philip Cunningham,
Robert Fielden (St Vincent's Hospital, Sydney); John Chuah, Sally Jacobs,
Robyn James, Fiona Clark (Gold Coast Sexual Health Clinic, Miami); Anne Mijch,
Melissa Bryant, Claire McCormack (Alfred Hospital, Melbourne); David Baker,
Hugh McLeod, Janet Kidd, Robert McFarlane, Robyn Vale (407 Doctors, Sydney);
Mark Kelly, Harry Michelmore, Jega Sarangapany (Albion Street Centre, Sydney);
Norman Roth, Jenny Mitchell, Helen Wood (Prahran Market Clinic, Melbourne);
Robert Finlayson, Neil Bodsworth, David Wheatley, Robyn Richardson (Taylor
Square Private Clinic, Sydney); Mike Youle, Margaret Johnson, Zoe Cuthbertson,
Tony Drinkwater (Royal Free Hospital, London); Marilyn McMurchie (Darlinghurst,
Sydney); Peter Meese (deceased), Dennis Rhodes, Ian Chenoweth (Middle Park
Clinic, Melbourne); David Austin, Mark Bloch, Anthony Frater (Holdsworth House
General Practice, Sydney); Jonathon Anderson, Julie Patching (Carlton Clinic,
Melbourne); Gary Rogers, Michael Curry, Wendy Ferguson (Adelaide); Nick Medland,
Helen Wood, (Centre Clinic, Melbourne); Tuck Meng Soo, Philip Habel (Interchange
General Practice, Canberra); Sean Emery, Robyn Munro, Wendy Lee, Terry Sharkey
(National Centre in HIV Epidemiology and Clinical Research, University of
New South Wales, Sydney).
Funding/Support: The National Centre in HIV
Epidemiology and Clinical Research is funded by the Commonwealth Department
of Health and Aging through the Australian National Council on AIDS, Hepatitis
C and Related Diseases. The study was supported in part by a grant from GlaxoSmithKline.
Role of the Sponsor: The study was investigator
initiated, developed by a large team of HIV clinicians, statisticians, and
metabolic experts, and conducted independently by the National Centre in HIV
Epidemiology and Clinical Research (NCHECR), University of New South Wales,
Sydney. The NCHECR maintained the database and undertook all analyses, and
the investigators will prepare any conference presentations. GlaxoSmithKline
provided some funds to assist with the conduct of the study and reviewed the
protocol but did not attempt to change the study design or assessments or
influence data analysis and interpretation. The manuscript was forwarded to
GlaxoSmithKline as a courtesy but not with a view to modification.
Acknowledgment: We acknowledge the time and
commitment of the patients who participated in the study. We also acknowledge
the efforts of Nicole Culton and Sue Kalnins from the Nuclear Medicine department
of St Vincent's Hospital and John Branson, MD, Jennifer Raxworthy, and David
Joselyn, BSc, from Darlinghurst X-Ray for their work on body composition studies.
Corresponding Author and Reprints: Andrew
Carr, MD, HIV, Immunology and Infectious Diseases Clinical Services Unit,
St Vincent's Hospital, Sydney, 2010 Australia (e-mail: acarr{at}stvincents.com.au).
Author Affiliations: St Vincent's Hospital
(Drs Carr, Freund, and Cooper), AIDS Research Initiative (Dr Workman and Mr
Hudson), National Centre in HIV Epidemiology and Clinical Research, University
of New South Wales (Drs Smith, Law, and Cooper and Mss Martin and Amin), and
Burwood Road Medical Centre (Mr Hudson and Dr Doong), Sydney, Australia; and
Alfred Hospital and Monash University, Melbourne, Australia (Dr Hoy).
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