# The Effects of Thiazolidinediones on Metabolic Complications and Lipodystrophy in HIV-Infected Patients

Authors: Jussi Sutinen
Journal: PPAR Research
 (2009)

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## Abstract

Highly active antiretroviral therapy (HAART)-associated metabolic complications include lipoatrophy (loss of subcutaneous adipose tissue (SAT)) and insulin resistance. Thiazolidinediones are insulin-sensitizing antidiabetic agents which—as an untoward side effect in obese diabetic patients—increase SAT. Furthermore, troglitazone has improved lipoatrophy and glycemic control in non-HIV patients with various forms of lipodystrophy. These data have led to 14 clinical trials to examine whether thiazolidinediones could be useful in the treatment of HAART-associated metabolic complications. The results of these studies indicate very modest, if any, effect on lipoatrophic SAT, probably due to ongoing HAART negating the beneficial effect. The benefit might be more prominent in patients not taking thymidine analoges. Despite the poor effect on lipoatrophy, thiazolidin-ediones improved insulin sensitivity. However, especially rosiglitazone induced harmful effects on blood lipids. Current data do not provide evidence for the use of thiazolidinediones in the treatment of HAART-associated lipoatrophy, but treatment of lipoatrophy-associated diabetes may be warranted. The role of thiazolidinediones for novel indications, such as hepatosteatosis, should be studied in these patients.


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## Body

## 1. Introduction

The  prognosis of HIV-infection has
drastically changed after the introduction of combination antiretroviral
therapy [1] often referred to as highly active antiretroviral therapy (HAART). Since the eradication of the virus is
impossible with current medicines [2] and since periodic treatment with
HAART can be harmful when compared to continuous therapy [3], patients need to continue therapy uninterruptedly
and permanently.Lifelong exposure to HAART puts patients
at a significant risk for long-term metabolic adverse effects including lipodystrophy,
insulin resistance, hyperlipidemia, and increased cardiovascular morbidity [4, 5]. The most characteristic component
of HAART-associated lipodystrophy is the loss of subcutaneous adipose tissue [6] which has proven to be very difficult
to treat (Figure 1).Abdominal magnetic resonance image (MRI) of a HAART-treated patient with normal fat distribution (a) and a patient with severe HAART-associated lipodystrophy with complete loss of subcutaneous fat and accumulation of intra-abdominal fat (b). Fat is shown white in these MRI images.
(a)(b)Thiazolidinediones (glitazones) are
oral insulin-sensitizing antidiabetic agents. As an untoward side effect, glitazones
increase subcutaneous fat mass in
patients with type 2 diabetes [7–9]. Additionally, in non-HIV infected
patients with various forms of lipodystrophy, troglitazone has improved metabolic
control and subcutaneous lipoatrophy [10]. These insulin-sensitizing and fat-inducing
effects of glitazones have lead to several clinical trials examining whether these
drugs  could reverse lipoatrophy and
insulin resistance in patients with HAART-associated lipodystrophy.The ensuing review is focused on summarizing
the currently available clinical data on the use of glitazones in patients with
HAART-associated lipodystrophy


## 2. Thiazolidinediones

Thiazolidinediones are synthetic ligands
for peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is a nuclear
receptor which alters expression of multiple genes including those regulating lipid
and glucose metabolism [11]. PPARγ is expressed mainly in
adipose tissue and is also found
in pancreatic beta cells,  vascular endothelium, and macrophages, and in low
quantities in other tissues such as the liver, skeletal muscle, and the heart [12, 13]. The activation of PPARγ is critical
in adipocyte differentiation, fatty acid uptake, and storage in the adipocytes [14, 15].Glitazone-induced activation of
PPARγ in adipose tissue may improve the whole body insulin
sensitivity by keeping fatty acids within adipocytes and hence protecting other
tissues (liver, skeletal muscle, and pancreatic beta cells) from the “toxic”
effects of the high-circulating concentration of free fatty acids [12]. Alternatively or additionally,
glitazones may affect whole body insulin sensitivity by altering adipokine
release from adipose tissue [12].The potential role of PPARγ in the
pathogenesis of some human lipodystrophies has been demonstrated in recent
studies finding dominant negative and loss-of-function mutations to affect the
ligand-binding domain of PPARγ in non-HIV patients with partial lipodystrophy,
hepatic steatosis, dyslipidemia, and insulin resistance [13]. Furthermore, trogilitazone was
shown to improve subcutaneous lipoatrophy in HIV-negative patients with various
forms of lipodystrophic/lipoatrophic syndromes [10]. Taken together, the available data
make glitazones an interesting therapy option for HAART-associated lipodystrophy.


## 3. HAART-Associated Lipodystrophy

The prevalence of HAART-associated
lipodystrophy has varied from as low as 2% [16] up to 83% [17] in HAART-treated patients. This
huge variation is explained by the lack of uniformly accepted definition of
lipodystrophy, and the variable combination and duration of HAART in different studies.
Estimates from large surveys indicate a prevalence of 50% of at least one
physical abnormality after 12–18 months of
therapy [18, 19]. Most of these prevalence data arise
from patients taking mainly the older and metabolically more toxic antiretroviral
regimens. Although there are accumulating data demonstrating a significantly decreased
risk for lipodystrophy in patients taking newer antiretroviral agents [20, 21], lipodystrophy still remains a
significant clinical problem.Lipoatrophy, that is, a decrease in
subcutaneous adipose tissue (SAT) mass, has mainly been attributed to the use
of nucleoside reverse transcriptase inhibitors (NRTIs) and thymidine analoges (tNRTI)
in particular [22–25]. The tNRTIs stavudine and more
recently zidovudine gradually decrease SAT mass. Typically, SAT initially
increases during the first 4–8 months of
therapy, but thereafter, a 19% decrease in limb fat per year has been described
with stavudine and didanosine containing regimens as compared to a decrease of
1.7% per year with zidovudine and lamivudine [26]. Further evidence demonstrating the
deleterious effects of tNRTIs on SAT arises from the so called “switch” studies.
Replacing tNRTI by abacavir or tenofovir has in several studies lead to an increase
of 300–500 g of limb fat
during the first 6–12 months after
the switch [27–29]. Although most data indicate a
major role of tNRTIs in the development of lipoatrophy, other drug classes may
be involved. Irrespective of the NRTI backbone, nelfinavir (a protease
inhibitor) was associated with more severe fat loss than efavirenz
(nonnucleoside reverse transcriptase inhibitor) [30], whereas in another study efavirenz
caused more fat loss than lopinavir/ritonavir (protease inhibitor) [31]. The less significant role of protease
inhibitors (PIs) for lipoatrophy is demonstrated in the switch studies. In contrast
to the beneficial effects of switching away from tNRTIs,  the effects of switching away from PIs have
been disappointing regarding lipoatrophy [32].The potential pathophysiological mechanisms
leading to lipoatrophy include NRTI-induced inhibition of mitochondrial (mt)
DNA polymerase gamma through several different mechanisms [33, 34]. This inhibition would lead to decreased
mtDNA content which consequently would result in depletion of proteins encoded
by mtDNA and dysfunctional mitochondria. Additionally, also genes encoded by
nuclear DNA are affected by NRTIs, and these drugs promote apoptosis in adipocyte
cell modes in vitro [35].In keeping with these in vitro data, human studies have
shown decreased mtDNA content in adipose tissue of patients with
HAART-associated lipodystrophy when compared to HIV-negative subjects,
HIV-infected patients not taking HAART, or to HAART-treated patients without
lipodystrophy [36–39]. However, studies in healthy
subjects have shown that a 2-week exposure to NRTIs leads to a decrease in
mtRNA and alters expression of several nuclear genes without a significant
change in the mtDNA content [40]. Various studies have shown
multiple alterations in gene expression in lipoatrophic adipose tissue such as
decreased expression of several transcription factors (PPARγ, SREBP-1c (sterol
regulatory element-binding protein), PPARδ, C/EBPα, and β
(CCAAT/enhancer-binding protein)) [41, 42]. Alterations have also been
described in the expression of several genes involved in lipogenesis, fatty
acid, and glucose metabolism, for example, the expressions of acyl coenzyme A synthase,
lipoprotein lipase, and glucose transport protein 4 are decreased in patients
with HAART-associated lipodystrophy [42]. Several markers of inflammation such
as interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα), CD45, and CD68
have been shown to be increased in lipoatrophic adipose tissue [41–44]. Of the adipokines, the expression of
adiponectin in adipose tissue and its circulating concentration have been shown
to be decreased in several studies [44–47], whereas serum concentrations of
leptin have been either decreased [48, 49], unchanged [46, 50, 51], or increased [52] in lipoatrophic patients. In
addition to these findings implying severe adipose tissue dysfunction,
increased rate of apoptosis has also been described in the SAT of these patients
[43, 53].Although multiple alterations have
been described in lipoatrophic adipose tissue, the role and sequence of each critical
abnormality eventually leading to loss of SAT still remain elusive. It also
remains unknown which critical abnormalities should be counteracted in order to
reverse HAART-associated abnormalities in adipose tissue of these patients, and
whether thiazolidinediones would have this potential.


## 4. Thiazolidinediones for HAART-Induced Metabolic Adverse Effects

Thiazolidinediones have been used in
14 clinical trials in HIV-infected, HAART-treated patients [54–67]. The basic characteristics of these
trials are given in Table 1. In total, 281 patients have used rosiglitazone, 82
patients pioglitazone, and 6 patients troglitazone in these trials. Four of
these trials were open label-uncontrolled studies [54, 59, 64, 67], 6 were randomized placebo-controlled
studies [55–57, 61, 62, 66], and 4 had a comparison arm with
another active agent (metformin or fenofibrate) [58, 60, 63, 65]. Followup times varied from 6 weeks
to 12 months.Table 1
The basic characteristics of the studies with thiazolidinediones
in HIV-infected, HAART-treated patients. HAART = highly active antiretroviral therapy, IR = insulin resistance,
LA = lipoatrophy, OGTT = oral glucose tolerance test, LD = lipodystrophy.
Number of subjectsStudy designStudy groupsDurationInclusion criteriaReferenceRosiglitazone studies8Open label, uncontrolledRosiglitazone 8 mg/d6–12 weeksIR (defined by clamp)Gelato et al. [54]30Randomized, double blindRosiglitazone 8 mg/d, or placebo24 weeksLA (clinical definition)Sutinen et al. [55]108Randomized, double blindRosiglitazone 8 mg/d, or placebo48 weeksLA (limb fat%<20%, or limb
fat% at least 10% less than truncal fat%)Carr et al. [56]28Randomized, double blindRosiglitazone 4 mg/d, or placebo3 monthsLA (clinical definition) and IR
(fasting insulin>15 μIU/ml, or 2 h insulin [OGTT] >75 μIU/ml)Hadigan et al. [57]39Randomized, open labelRosiglitazone 8 mg/d, or metformin 2 g/d26 weeksLA (clinical definition)van Wijk et al. [58]20Open label, uncontrolledRosiglitazone 4 mg/d24 weeksNo LD or IR requirementsFeldt et al. [59]105Randomized, double blindRosiglitazone 4 mg/d, or metformin 2 g/d, or rosiglitazone + metformin, or placebo16 weeksIR (fasting insulin>15 μIU/ml, or 2 h insulin [OGTT] >75 μIU/ml, or 2 h glucose [OGTT] >7.7 mmol/L and fasting insulin >10 μIU/ml) and
self-reported changes in body fat (including increased waist-to-hip ratio or
waist circumference)Mulligan et al. [60]37Randomized, double blindRosiglitazone 8 mg/d, or placebo6 monthsBody mass index 19–24 kg/m2, no requirements on LD or IRHaider et al. [61]96Randomized, double blindRosiglitazone 4 mg/d, or placebo24 weeksLD (clinical definition)Cavalcanti et al. [62]90Randomized, open labelRosiglitazone 4 mg/d, or metformin 1 g/d, or no treatment48 weeksIR (impaired fasting glucose or
impaired glucose tolerance [OGTT], with fasting insulin>20 μIU/ml)Silič et al. [63]Pioglitazone studies11Open label, uncontrolledPioglitazone 45 mg/d6 monthsLA (clinical definition)Calmy et al. [64]14Randomized, double blind (2×2 factorial)Pioglitazone 30–45 mg/d, or fenofibrate
200 mg/d, or pioglitazone + fenofibrate, or placebo12 monthsIR (impaired glucose tolerance
[OGTT], or diabetes, or fasting insulin>20 μIU/ml) and dyslipidemiaGavrila et al. [65]130Randomized, double blindPioglitazone 30 mg/d, or placebo48 weeksLA (clinical definition)Slama et al. [66]Troglitazone study6Open label, uncontrolledTroglitazone 400 mg/d3 monthsLD and newly diagnosed diabetesWalli et al. [67]The presence of lipoatrophy without
reference to insulin resistance was the inclusion criteria in five studies [55, 56, 58, 64, 66], one additional study required the
presence of at least one feature of lipodystrophy (but not necessarily lipoatrophy)
without reference to insulin resistance [62]. Insulin resistance (defined by
fasting insulin concentration, oral glucose tolerance test, or clamp studies)
without reference to lipodystrophy was the inclusion criteria in three studies [54, 63, 65]. One study required the presence of
both lipoatrophy and insulin resistance [57], and another study included
patients with changes in body fat (but not necessarily lipoatrophy) together
with insulin resistance [60]. The troglitazone study included
patients with newly diagnosed diabetes with lipodystrophy and dyslipidemia [67], and two studies did not specify
any metabolic abnormalities in the inclusion criteria [59, 61]. The exclusion criteria were variable,
but often included liver function tests >2-3 times upper
limit of normal, serum creatinine >1-2 times upper
limit of normal, haemoglobin <90–95 g/L, serum
triglycerides >10–15 mmol/L,
presence of heart failure, and pregnancy.


### 4.1. Effects on Body Composition

Body composition data from the eight
studies which included a control arm and an objective measurement of subcutaneous
fat (dual-energy X-ray absorptiometry [DEXA], computed tomography [CT], magnetic
resonance imaging [MRI]) are included in Table2. No significant changes in the
amount of subcutaneous fat could be detected in four studies: two of these
studies used a single method to measure adipose tissue volume (one with MRI [55], one with DEXA [62]), and the other two studies measured
fat volume using both DEXA and CT [56, 65]. In contrast to these four studies,
three other studies reported statistically significant increases in SAT in
patients taking either rosiglitazone [57, 60] or pioglitazone [66] as compared to placebo. SAT was quantified
by both DEXA and CT scan in all these three studies, but none of the studies
could confirm the statistically significant increase in SAT versus placebo by
the second method in the same study. The absolute changes in SAT in the thiazolidinedione
arm were reported in two studies: an increase of 50 g in leg fat mass after 12-week
treatment with rosiglitazone [57], and 380 g increase in limb fat
mass in the pioglitazone arm after 48 weeks of therapy [66]. In the study by van Wijk et al.
rosiglitazone was compared to metformin without a placebo arm [58]. In this study, there was a
statistically significant increase in SAT measured by CT scan in the
rosiglitazone arm versus baseline, and also relative to metformin. DEXA
scanning was not performed in this study.Table 2
Body composition data from thiazolidinedione
studies which included a control arm and an objective measurement of body
composition in HIV-infected, HAART-treated patients. HAART = highly active antiretroviral therapy, SAT
= subcutaneous adipose tissue, NS = nonsignificant, MRI = magnetic resonance
imaging, DEXA = dual-energy X-ray absorptiometry, CT = computed tomography,
s.c. = subcutaneous, ND = not done, CI = confidence interval.
NDrugDurationSubcutaneous adipose tissueVisceral adipose tissueBody mass index (kg/m2)ReferenceNo change in SAT30Rosi versus placebo24 weeksMRI: NSMRI: NSNSSutinen et al. [55]108Rosi versus placebo48 weeksDEXA  limb  fat:  NS CT  thigh:  NS CT  s.c.  abdomen:  NSCT: NSNSCarr et al. [56]14Pio versus feno versus pio + feno versus placebo12 monthsDEXA  upper  limb  fat:  NS DEXA  lower  limb  fat:  NS CT  s.c.  abdomen:  NSCT: NSNSGavrila et al. [65]96Rosi versus placebo24 weeksDEXA limb fat: NS
DEXA arm fat: NS DEXA leg fat: NSNDNSCavalcanti et al. [62]Increase in SAT28Rosi versus
placebo3 monthsCT thigh(cm2): rosi: + 2.3 versus pla −0.9, Δ rosi versus pla, P=.002
CT s.c. abdomen: NS DEXA leg: NS (rosi +50 g versus pla −80g,
Δ rosi versus pla P=.08)CT: NSNSHadigan et al. [57]105Rosi versus metformin versus rosi + met versus placebo16 weeksDEXA leg fat (%): rosi: +4.8,NS*; met: −3.6, NS*; rosi + met: −0.5, NS*; pla: −8.3%,
NS*Δ rosi vs pla P=.03, other groups versus pla, NS
DEXA arm fat: NS DEXA limb fat: NS CT  s.c.  abdomen:  NSCT (%): rosi: 0.0,NS*; met: −0.6,NS*; rosi + met:
−7.9, NS*; pla: −7.2, NS*Δ rosi versus pla, P=.08, other groups versus pla, NSBody mass index ND, body weight (kg): rosi: 0.0,NS*; met: −2.0, P*<.001; rosi + met: −1.5, P*<.01; pla:
−0.05, NS*Δ met versus
pla, P=.03;  Δ met + rosi versus
pla, P=.06Mulligan et al. [60]130Pio versus placebo48 weeksDEXA limb fat (g): pio: +380 g; pla: +50 gΔ pio versus pla P=.051 CT s.c. abdomen: NSCT: NSPio: +0.9; pla: +0.3Δ pio versus pla P=.07Slama et al. [66]39Rosi versus metformin26 weeksCT s.c. abdomen (cm2) rosi: +16, P*<.05; met: −11, P*<.05Δ rosi versus met 27cm2(95% CI, 7 to 46)CT (cm2)
rosi: −1, NS*; met: −25, P*<.05Δ rosi versus met 24 cm2 (95% CI, 6 to 51)Rosi: +0.4,P*<.05; met: −0.4, P*<.05Δ rosi versus
met 0.7 (95% CI, 0.5 to 1.6)van Wijk et al. [58]* denotes
significance within the study group compared to baseline value,Δ denotes
comparison of the change between respective study groups.One study found a statistically
almost significant increase in visceral adipose tissue (VAT) in the
rosiglitazone group when compared to placebo [60], while there were no significant
changes in VAT between the glitazone and placebo arms in the other studies.
None of the placebo-controlled trials reported significant changes in BMI
either within the glitazone arm or between the placebo and glitazone group,
although the difference approached statistical significance in the pioglitazone
trial by Slama et al. [66]. In the study comparing
rosiglitazone and metformin, there was a significant increase in body mass
index (BMI) within the rosiglitazone arm from baseline, and also the change between
the rosiglitazone and metformin arm was statistically significant [58]. The studies finding no significant
increase in SAT reported changes in body weight ranging from a loss of 3.0 kg
to the gain of 3.8 kg in the thiazolidine arm [55, 56, 62, 65]. In contrast to variable effects
seen on body weight with glitazones, all three studies having a metformin arm [58, 60, 63] reported a decrease in body weight from
1.2 to 2.2 kg in patients using metformin.The effects of thiazolidinediones on
body composition in HAART-treated patients contrast data from HIV-negative
diabetic patients. In these patients, thiazolidinediones have increased body
weight constantly by 2–4 kg after 16–26 weeks of
therapy [12]. This increase has been attributed mainly
to an increase in the fat mass and in some patients to edema [12].  The increase in total fat mass has
been in the order of 1.5–4 kg after 3-4 months of rosiglitazone
therapy [9, 68, 69], and it consists almost exclusively
of the increase in the subcutaneous fat depot [7, 8, 69, 70]. Similar effects on body fat have
also been described in nondiabetic patients treated with pioglitazone for
insulin resistance [71] or nonalcoholic steatohepatitis [72].Table3 lists  some confounding
factors that possibly could explain the conflicting results of thiazolidinediones
on SAT in different trials with HIV-infected, HAART-treated patients. The drug
dose, study duration, inclusion criteria and baseline BMI appeared to be
similar between studies showing a statistically significant increase versus
those not showing a change in SAT. The prevalence of concomitant use of stavudine,
the NRTI most strongly associated with fat loss, may explain some of the discrepancies,
since the studies reporting an increase in SAT were those with least frequent
use of stavudine [57, 58, 66]. Also in the study by Carr et al.,
after 24 weeks of treatment with rosiglitazone, there was a statistically
almost significant increase in SAT in those patients not taking stavudine or zidovudine
when compared to the placebo group (+480 g versus 190 g, P=.06), but this
difference was not maintained at week 48 [56]. Similarly, in the study by Slama
et al., patients not taking stavudine at baseline had a mean increase of limb
fat mass of 450 g in the pioglitazone group versus 40 g increase in the placebo
group (P=.013) [66]. Based on these data one can hypothesize
that thiazolidinediones may have a fat-inducing effect in lipoatrophic SAT, but
the ongoing stavudine (and zidovudine) treatment may negate this beneficial effect.Table 3
Comparison of the baseline characteristics of the thiazolidinedione
arms of the studies showing versus not showing an increase in subcutaneous fat mass
in HIV-infected HAART-treated patients. HAART =
highly active antiretroviral therapy, SAT = subcutaneous adipose tissue, NR =
not reported.
Drug (dose/d)DurationInclusion criteriaBMI (kg/m2)% taking stavudineReferenceNo change in SATRosi 8 mg24 weeksLipoatrophy2467Sutinen et al. [55]Rosi 8 mg48 weeksLipoatrophy2349Carr et al. [56]Pio 30–45 mg12 monthsInsulin resistance and dyslipidemia26NRGavrila et al. [65]Rosi 4 mg24 weeksLipodystrophy25NRCavalcanti et al. [62]Increase in SATRosi 4 mg3 monthsLipoatrophy and insulin resistance2644Hadigan et al. [57]Rosi 4 mg16 weeksLipodystrophy and insulin resistanceBody weight 80 kgNRMulligan et al. [60]Pio 30 mg48 weeksLipoatrophy2225Slama et al. [66]Rosi 8 mg26 weeksLipoatrophy2421van Wijk et al. [58]In addition to quantifying adipose
tissue compartments, liver fat content was measured in one study [55]. Liver fat decreased with
rosiglitazone and increased with placebo (−2.1% versus +2.1% in the
rosiglitazone versus placebo, P<.05) [55]. Serum alanine aminotransferase (ALT)
concentrations were reported in 5 rosiglitazone studies [55–58, 60]. In three of these studies, there
was a statistically significant decrease in ALT concentration in the rosiglitazone
arm compared either to the baseline value or to the placebo arm possibly suggesting
a decrease in liver fat content [55, 56, 58].Outside these trials, a single case
report describes development of several dozen lipomas in a patient with HAART-associated
lipoatrophy during 3-month therapy with rosiglitazone. After rosiglitazone was
discontinued, all but 5 lipomas resolved completely [73].


### 4.2. Effects on Insulin Resistance and Blood Lipids

The effects of thiazolidinediones on
glycemic indeces in the ten comparative studies reporting data on glucose and
insulin are shown in Table4. In contrast to the very modest effects on SAT described
above, eight [55–58, 60, 61, 63, 65] out of 10 studies showed improvements
in insulin resistance in the thiazolidinedione arm when compared to the
baseline value or to the placebo arm. One study reported a significant positive
correlation between the change in fasting insulin concentration and the change
in liver fat content [55]. Only two studies did not show
significant improvements in insulin sensitivity [62, 66]. Of note, insulin resistance was an
inclusion criteria in only four [57, 60, 63, 65] out of these 10 studies.Table 4
The effects of thiazolidinediones on glycemic indeces in controlled trials with HIV infected, HAART-treated patients. HAART = highly active antiretroviral therapy, HOMA
= homeostasis model assessment (fasting insulin [μIU/ml] × fasting glucose [mmol/L]/22.5), OGTT = oral glucose tolerance test, NS = nonsignificant, NR = not
reported, AUC = area under the curve.
NDrugDurationInsulin (μIU/ml)HOMAOGTTFasting glucose (mmol/L)Reference30Rosi versus placebo24 weeksRosi: −3.3,P<.05*; pla: +6.7, NS*Δ
rosi versus pla P<.05NRNRNSSutinen et al. [55]108Rosi versus placebo48 weeksRosi: −3.5; pla: +0.7Δ rosi versus pla P=.02Rosi: −1.0; pla: +0.04Δ rosi versus pla P=.032 h glucose: NS
2 h insulin: rosi −13.6; pla +3.9Δ rosi versus pla P=.09NSCarr et al. [56]14Pio versus feno versus pio + feno versus placebo12 monthsNSPio: −3.8,P<.05*; pla: −1.3, NS*NRNSGavrila et al. [65]96Rosi versus placebo24 weeksNSNSNSNSCavalcanti et al. [62]28Rosi versus
placebo3 monthsNSNR2
h glucose: rosi: −0.3; pla:
+0.1Δ rosi versus pla P=.06 2h insulin AUC: rosi: −2.3; pla: +1.8
Δ rosi versus pla P=.003NSHadigan et al. [57]105Rosi versus metformin versus rosi + met versus placebo16 weeksRosi: −4,P=.08*; met: −2, P=.07*NRInsulin AUC: rosi: −26,P=.012*; met: −11, P=.06*; rosi + met: −18, P=.002*Δ  rosi + met versus placebo P=.03; Δ rosi versus pla P=.07NSMulligan et al. [60]130Pio versus placebo48 weeksNSNSNSNSSlama et al. [66]37Rosi versus placebo6 monthsNSRosi: −0.1,NS*; pla: +1.3, P<.05* At 6 months: rosi versus pla P<.05NRNSHaider et al. [61]90Rosi versus metformin versus No-treatment48 weeksRosi: −19.3,P<.001*; met: −11.1, P<.001*; No-Tx: +0.7, NS* At 48 weeks: rosi versus No-Tx P<.001;
met versus No-Tx P<.001; met versus rosi P<.001Rosi: −7.3,P<.001*; met: −6.2, P<.001*; No-Tx: +0.3, NS* At 48 weeks: rosi versus No-Tx P<.001; met versus No-Tx P<.001; rosi versus met P<.001NRRosi: −1.9,P<.001*;
met: −2.2, P<.001*; No-Tx: 0.0, NS*
At 48 weeks: Rosi versus No-Tx P<.001; met versus No-Tx P<.001; rosi versus met P=.015Silič et al. [63]39Rosi versus metformin26NRNRGlucose AUC: rosi: −1.9,P=.04*; met: −1.1, P=.05*Δ
rosi versus met NS Insulin AUC:
rosi: −37, P=.01*; met −33, P=.01*Δ rosi versus met NSNRvan Wijk et al. [58]*denotes significance within the study group compared to baseline
value, Δ denotes comparison of the change between respective study groups.Since none of the comparative
studies recruited patients with type 2 diabetes, it is difficult to compare these
effects on glycemic indeces in HAART-treated patients to those in HIV-negative diabetic
patients treated with glitazones. The average decrease in haemoglobinA1c has been 1–1.5% in non-HIV patients with type 2 diabetes
treated with glitazones [12].The effects of thiazolidinediones on
blood lipids in the nine comparative studies reporting data on cholesterol and
triglycerides are shown in Table5. Five [55–58, 60] out of seven studies with rosiglitazone
reported a statistically significant increase in total cholesterol concentration
in the rosiglitazone arm when compared either to the baseline value or to the comparative
arm. The absolute increases in total cholesterol concentration in the rosiglitazone
arms varied from 0.4 to 1.4 mmol/L. Neither of the two pioglitazone studies
reported significant changes in total cholesterol concentrations [65, 66]. HDL (high-density lipoprotein) cholesterol
concentration increased statistically significantly in both studies with pioglitazone
(increases of 0.09 and 0.15 mmol/L) [65, 66], but decreased significantly in two
out of the seven rosiglitazone studies with absolute decreases of 0.1 and 0.15 mmol/L [58, 60]. LDL (low-density lipoprotein)
cholesterol was measured in five rosiglitazone studies [56–58, 60, 62]. Four of these studies reported
significant increases in LDL cholesterol concentrations when compared to the
baseline value (absolute increases between 0.2–0.8 mmol/L) or to the comparative arm [56–58, 60]. The increase of 1.7 mmol/L in LDL
cholesterol was statistically almost significant in one of the two pioglitazone
studies [65]. Statistically significant
increases in triglyceride concentrations were reported in three out of seven rosiglitazone
studies (versus baseline or versus the comparative arm) [55, 56, 58]. The absolute increases were between
0.5–3.0 mmol/l. There were no significant changes
in triglyceride concentrations in the two pioglitazone studies. A proatherogenic
effect of rosiglitazone on blood lipids was further described by Hadigan et al.
[74]. Rosiglitazone treatment increased
significantly the concentration of small dense LDL cholesterol, and decreased
the concentration of large HDL cholesterol and also of HDL particle size [74]. In contrast, pioglitazone
treatment was associated with an increase in the LDL particle size (from 19.9
at baseline to 20.6 nm at 12 months, P=.06) [65].Table 5
The effects of thiazolidinediones
on blood lipids in comparative studies with HIV infected, HAART-treated
patients. HDL
= high-density lipoprotein, LDL = low-density lipoprotein, NS = nonsignificant,
NR = not reported, CI = confidence interval.
NDrugDurationTotal cholesterol (mmol/L)HDL cholesterol (mmol/L)LDL cholesterol (mmol/L)Triglycerides (mmol/L)Reference30Rosi versus placebo24 weeksRosi: +1.4,P*<.01; pla: 0.0, NS*Δ rosi versus pla NSNSNRNS
At 12 weeks: rosi: +3.0,P*<.05; pla: NSSutinen et al. [55]108Rosi versus placebo48 weeksRosi: +0.9; pla: 0.0Δ Rosi versus pla P<.001NSRosi: +0.8; pla: +0.4Δ rosi versus pla P=.04Rosi: +1.5; pla: +1.3Δ rosi versus pla P=.04Carr et al. [56]14Pio versus feno versus pio + feno versus placebo12 monthsNSpio: +0.15,NS*; pla: −0.20, NS*Δ pio versus pla P=.01Pio: +1.7,P*=.07; pla: −0.6, NS*NSGavrila et al. [65]96Rosi versus placebo24 weeksNSNSNSNSCavalcanti et al. [62]28Rosi versus
placebo3 monthsRosi: +0.6; pla:−0.4Δ rosi versus pla P=.007NSRosi: +0.4; pla:−0.4Δ rosi versus pla P=.01NSHadigan et al [57]105Rosi versus metformin versus rosi + met versus placebo16 weeksRosi: +0.4,P*<.05; all other groups NS*Rosi:−0.1, P*<.001; all other groups NS*Δ rosi versus pla P=.005; Δ rosi versus rosi + met P=.006Rosi: +0.2,P*<.05; all other groups NS*Δ rosi versus pla P=.048NSMulligan et al. [60]130Pio versus placebo48 weeksNSPio: +0.09; pla:−0.08Δ pio versus pla P=.005NSNSSlama et al. [66]37Rosi versus placebo6 monthsNSNRNRNSHaider et al. [61]39Rosi versus metformin26 weeksRosi: +0.4,NS*; met: −0.4, P*<.05Δ rosi versus met 0.8 (95% CI, 0.3
to 1.3)Rosi:−0.15, P*<.05; met:
+0.01, NS*Δ rosi versus met 0.16 (95% CI,
−0.35 to −0.02)Rosi: +0.2,NS*: met: −0.4, P*<.05Δ rosi versus met 0.6 (95% CI, 0.2
to 1.1)Rosi: +0.5,*versus <0.05; met: −0.6, P*<.05Δ rosi versus met 1.1 (95% CI, 0.4
to 2.6)van Wijk et al. [58]*denotes significance within the study group
compared to baseline value, Δ denotes comparison of the change between respective
study groups.The results of these studies with
HAART-treated patients suggest pioglitazone to have a more favorable lipid
profile than rosiglitazone as has been observed in patients with type 2
diabetes [12]. A striking difference in HAART-treated
patients relative to HIV-negative diabetic patients was the significant increase
in triglyceride concentration by 1.5 to 2.3 mmol/L in the rosiglitazone arm in
some studies [55, 56]. One may hypothesize that the
increases in serum triglycerides were possibly aggravated by the high
prevalence of stavudine use in these studies. The ongoing stavudine treatment may
have prevented the storage of circulating lipids within the adipocytes. In the
study by Sutinen et al., one patient had to discontinue rosiglitazone treatment
due to serum triglyceride increase up to 32.5 mmol/L [55] and another patient using
rosiglitazone in the study by Cavalcanti et al. discontinued due to abnormal
lipid values [62]. Carr et al. reported grade 3-4 increases in
triglyceride concentrations in 57% of the participants in the rosiglitazone arm
compared to 36% in the placebo arm [56]. The large study by Cavalcanti et
al. did not report any deleterious effects on blood lipid concentrations by
rosiglitazone, but in the same study 15% of patients in the rosiglitazone arm
started lipid-lowering therapy during the study compared to 5% in the placebo
arm [62]. In addition to these prospective
clinical trials, a small retrospective study reported effects of fenofibrate
alone versus fenofibrate in combination with rosiglitazone in HIV-infected
patients [75]. When fenofibrate was given alone,
triglyceride concentrations decreased by 27% and HDL cholesterol increased by
19%. In contrast, when fenofibrate was combined with rosiglitazone, triglycerides
increased by 48% and HDL cholesterol decreased by 33% [75].Three of the rosiglitazone studies [57, 60, 76] also reported the effects of
rosiglitazone on free fatty acid (FFA) concentrations. In two of these studies,
a statistically significant decrease in FFA concentration was found in the
rosiglitazone arm when compared to baseline value or to placebo [57, 76].Serum adiponectin concentration was
measured in six rosiglitazone studies [56–58, 60, 61, 76]. All these studies showed a statistically
significant increase of 0.8–4.1 μg/ml in the
rosiglitazone arms. One study found an inverse correlation between the change
in adiponectin concentration and the change in fasting insulin concentration
and liver fat content [76].Additional findings from these
clinical trials with HAART-treated patients include either a decline [77] or no change [55, 78] in leptin concentration with
rosiglitazone. Circulating concentrations of inflammatory markers (TNFα,
C-reactive protein, or IL-6) did not change in any study reporting these
measurements [78–80]. Plasma concentrations of PAI-1
(plasminogen activator inhibitor-1) and tPA (tissue plasminogen activator) were
reported to either decline [79] or remain unchanged [78] with rosiglitazone therapy. Plasma
resistin concentration decreased with rosiglitazone in one study [78]. Rosiglitazone decreased systolic
blood pressure, but had a nonsignificant effect on flow-mediated arterial
dilatation compared to placebo in one study [77].


### 4.3. Thiazolidinedione-Induced Gene Expression in Sat in HAART-Treated Patients

Two studies have evaluated the
effects of rosiglitazone on gene expression in SAT in HAART-treated patients [76, 81]. Sutinen et al. reported
statistically significant increases in the expression of adiponectin and PPARγ coactivator 1 (PGC-1), and a
decrease in IL-6 expression with rosiglitazone treatment [76]. In addition, there was a significant
increase in PPARγ expression in the rosiglitazone arm relative to the placebo
arm [76]. Mallon et al. studied gene
expression in SAT two and 48 weeks after rosiglitazone or placebo treatment,
and compared patients taking tNRTIs at baseline to those without tNRTI treatment
[81]. After two weeks, only those
randomized to rosiglitazone in the no-tNRTI group experienced a significant
rise in PPARγ and PGC-1 expression. At 48 weeks, PPARγ expression was increased
in the no-tNRTI groups when compared to tNRTI groups, but there was no
difference between the rosiglitazone and placebo arms [81].The increase in the expression of
adiponectin, PPARγ (albeit limited), and that of PGC-1 are consistent with data
from type 2 diabetic patients treated with glitazones [82, 83]. There are,
however, also some differences in these two patient populations. In non-HIV
patients, the expression of lipoprotein lipase (LPL) [82, 84] and adipocyte fatty
acid binding protein (aP2) [83] increased with glitazone
treatment. The expression of these genes remained unchanged in HAART-treated patients
[76].Taken together, it seems plausible
that thiazolidinedione treatment had a functional effect in lipoatrophic SAT by
increasing the production of adiponectin and decreasing IL-6 expression. Both
of these changes may have been involved in the improvement of whole body
insulin sensitivity. The correlation between the change in adiponectin
concentration and the change in liver fat content implies a possibility for
adiponectin to have mediated this beneficial effect on liver fat [76]. These functional changes in
adipose tissue occurred despite the lack of a significant increase in fat mass.
One may also hypothesize that the blunted increase in PPARγ expression, especially in patients
receiving tNRTI therapy, as well as the lack of an increase in LPL and aP2 expression
may all have contributed to the nonsignificant effect on SAT mass and to high-serum
triglyceride concentration in these patients.


### 4.4. Safety

Since in vitro and animal models, as well as clinical
studies clearly indicate that thiazolidinediones correct endothelial
dysfunction, suppress chronic inflammatory processes, reduce fatty streak formation,
and enhance plaque stabilization and regression [85], one would expect favorable effects
on cardiovascular endpoints also in human studies. In contrast, the meta analysis by Nissen and Wolski [86] demonstrated that rosiglitazone as compared to the control group significantly
increased (and not decreased) the odds ratio for myocardial infarction (OR 1.43;
95% confidence interval [CI], 1.03 to 1.98; P=.03), and the odds ratio
for death from cardiovascular causes (OR 1.64; 95% CI, 0.98 to 2.74; P=.06).
A more recent meta analysis confirmed the increased risk of myocardial
infarction (RR 1.42; 95% CI, 1.06 to 1.91; P=.02) and heart failure (RR
2.09; 95% CI, 1.52 to 2.88; P<.001) with rosiglitazone, but found no
significant increase in the risk of cardiovascular mortality (RR 0.90; 95% CI,
0.63 to 1.26; P=.53) [87]. In contrast to findings with rosiglitazone, a
meta-analysis of pioglitazone found a decreased hazard ratio for death,
myocardial infarction, or stroke in patients receiving pioglitazone when
compared to those receiving control therapy (HR 0.82; 95% CI, 0.72 to 0.94; P=.005)
[88]. However, the hazard ratio for serious heart
failure was increased in patients receiving pioglitazone versus the control
patients (HR, 1.41; 95% CI, 1.14 to 1.76; P=.002) [88].  Whether
these deleterious effects of glitazones on cardiovascular morbidity would be
diminished in patients receiving HAART, since patients are usually younger,
fewer have diabetes, and so forth, or enhanced since HAART by itself increases
risk for myocardial infarction [4], remains to be studied. None of the studies
with HAART-treated patients using glitazones so far have reported any
significant cardiovascular events.In general, both rosiglitazone and
pioglitazone were well tolerated in all trials with HAART-treated patients. However,
the total number of HAART-treated patients taking rosiglitazone and pioglitazone
was only 281 and 82, respectively, and none of the studies had followup beyond
one year. Furthermore, it is important to keep in mind that due to exclusion
criteria of these trials there are basically no data on glitazones in HIV-infected
patients with significantly increased liver function tests, high creatinine or triglyceride
concentrations, or low hemoglobin at baseline; all these laboratory
abnormalities are relatively common in HAART-treated patients.Regarding the known adverse effect
profile of thiazolidinediones in non-HIV infected patients, it was reassuring
that no cases of clinically significant oedema, heart failure or other
cardiovascular events were reported. A decrease in haemoglobin concentration is
another known side effect with all glitazones, which is not explained by
hemodilution but possibly caused by mild suppressive effect on bone marrow [89, 90]. This might be of significance in HAART-treated
patients, since both HIV per se
and antiretroviral agents may cause bone marrow suppression [91]. A statistically, but not
clinically significant decrease in haemoglobin concentration in the rosiglitazone
arm was reported in one study, possibly also reflecting good adherence to study
medication [55]. A single case with a decrease of
haemoglobin concentration to less than 110 g/L was reported by Hadigan et al. [57]. Given the concerns for severe
liver toxicity induced by troglitazone [92], liver function tests were carefully
monitored in these patients receiving polypharmacy. A single participant in a
pioglitazone trial discontinued the study due to an increase in liver function
tests >3 times upper limit of normal [65]. In contrast, three studies
observed significant decreases in ALT concentrations either within the
rosiglitazone arm or when compared to placebo [55, 56, 58]. Adverse effects on blood lipids
were already discussed earlier; two patients had to discontinue rosiglitazone
due to abnormal lipid values [55, 62].Harmful effects of thiazolidinediones
on bone metabolism have recently been discussed in patients with type 2 diabetes.
A recent analysis of the data from five glitazone studies suggests that treatment with
thiazolidinediones, primarily rosiglitazone, contributes to bone loss [93]. This effect appears to be most prominent in
postmenopausal women [93]. The effect on bone density may have special
relevance in HAART-treated patients, since both HIV-infection as such and also
antiretroviral therapy have been associated with decreased bone mineral density
[94]. None of the studies using glitazones in HAART-treated
patients have reported effects on bone density.Potential for drug-drug interactions
must always be considered, when new medications are combined with HAART. Most
PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are not only metabolized
by CYP450 3A4 but are also either inhibitors (PIs, ritonavir in particular) or
inducers (NNRTIs) of the same enzyme and to lesser extent of other isoforms of
CYP450 [95]. Both rosiglitazone and
pioglitazone are predominantly metabolized by CYP450 2C8 (http://www.emea.europa.eu/). Rosiglitazone is not an inducer of any
tested human CYP450 isoforms,  but has shown moderate inhibition of 2C8 and low
inhibition of 2C9  (http://www.emea.europa.eu/). There is no in vitro evidence that pioglitazone
would either inhibit or induce any of the human CYP450 isoforms (http://www.emea.europa.eu/). Interaction studies have not shown
clinically significant interactions with rosiglitazone and substrates for
CYP450 3A4. These interactions are not expected with pioglitazone either (http://www.emea.europa.eu/).There are currently very limited
pharmacological data on the concomitant use of thiazolidinediones and
antiretroviral drugs. Data from a limited number of patients by Oette et al.
suggest that rosiglitazone could be safely administered together with either
lopinavir or efavirenz [96]. Rosiglitazone, however, seemed to decrease
nevirapine concentrations and the authors recommend to monitor nevirapine serum
concentrations if these drugs are used concomitantly [96]. Serum PI concentrations were
measured in one study with rosiglitazone [55] and both PI and NNRTI
concentrations were measured in one pioglitazone study [66].  Neither study observed any
significant change in the serum concentrations of these antiretroviral drugs during the
study period. None of the studies reported any statistically significant
changes in either HIV viral load or CD4 count within the glitazone arm or
between different study arms. Nevertheless, six patients in the pioglitazone
arm versus two in the placebo arm (P=.1) experienced viral breakthrough
(>400 copies/ml) during a pioglitazone trial [66]. It is not reported if these patients
were possibly taking nevirapine-based HAART (potential interaction between
nevirapine and rosiglitazone, see above). Interestingly, in vitro both PPARγ (rosiglitazone, ciglitazone,
troglitazone) and PPARα (fenofibrate) agonists have been shown to inhibit
HIV replication [97, 98].


## 4.1. Effects on Body Composition

Body composition data from the eight
studies which included a control arm and an objective measurement of subcutaneous
fat (dual-energy X-ray absorptiometry [DEXA], computed tomography [CT], magnetic
resonance imaging [MRI]) are included in Table2. No significant changes in the
amount of subcutaneous fat could be detected in four studies: two of these
studies used a single method to measure adipose tissue volume (one with MRI [55], one with DEXA [62]), and the other two studies measured
fat volume using both DEXA and CT [56, 65]. In contrast to these four studies,
three other studies reported statistically significant increases in SAT in
patients taking either rosiglitazone [57, 60] or pioglitazone [66] as compared to placebo. SAT was quantified
by both DEXA and CT scan in all these three studies, but none of the studies
could confirm the statistically significant increase in SAT versus placebo by
the second method in the same study. The absolute changes in SAT in the thiazolidinedione
arm were reported in two studies: an increase of 50 g in leg fat mass after 12-week
treatment with rosiglitazone [57], and 380 g increase in limb fat
mass in the pioglitazone arm after 48 weeks of therapy [66]. In the study by van Wijk et al.
rosiglitazone was compared to metformin without a placebo arm [58]. In this study, there was a
statistically significant increase in SAT measured by CT scan in the
rosiglitazone arm versus baseline, and also relative to metformin. DEXA
scanning was not performed in this study.Table 2
Body composition data from thiazolidinedione
studies which included a control arm and an objective measurement of body
composition in HIV-infected, HAART-treated patients. HAART = highly active antiretroviral therapy, SAT
= subcutaneous adipose tissue, NS = nonsignificant, MRI = magnetic resonance
imaging, DEXA = dual-energy X-ray absorptiometry, CT = computed tomography,
s.c. = subcutaneous, ND = not done, CI = confidence interval.
NDrugDurationSubcutaneous adipose tissueVisceral adipose tissueBody mass index (kg/m2)ReferenceNo change in SAT30Rosi versus placebo24 weeksMRI: NSMRI: NSNSSutinen et al. [55]108Rosi versus placebo48 weeksDEXA  limb  fat:  NS CT  thigh:  NS CT  s.c.  abdomen:  NSCT: NSNSCarr et al. [56]14Pio versus feno versus pio + feno versus placebo12 monthsDEXA  upper  limb  fat:  NS DEXA  lower  limb  fat:  NS CT  s.c.  abdomen:  NSCT: NSNSGavrila et al. [65]96Rosi versus placebo24 weeksDEXA limb fat: NS
DEXA arm fat: NS DEXA leg fat: NSNDNSCavalcanti et al. [62]Increase in SAT28Rosi versus
placebo3 monthsCT thigh(cm2): rosi: + 2.3 versus pla −0.9, Δ rosi versus pla, P=.002
CT s.c. abdomen: NS DEXA leg: NS (rosi +50 g versus pla −80g,
Δ rosi versus pla P=.08)CT: NSNSHadigan et al. [57]105Rosi versus metformin versus rosi + met versus placebo16 weeksDEXA leg fat (%): rosi: +4.8,NS*; met: −3.6, NS*; rosi + met: −0.5, NS*; pla: −8.3%,
NS*Δ rosi vs pla P=.03, other groups versus pla, NS
DEXA arm fat: NS DEXA limb fat: NS CT  s.c.  abdomen:  NSCT (%): rosi: 0.0,NS*; met: −0.6,NS*; rosi + met:
−7.9, NS*; pla: −7.2, NS*Δ rosi versus pla, P=.08, other groups versus pla, NSBody mass index ND, body weight (kg): rosi: 0.0,NS*; met: −2.0, P*<.001; rosi + met: −1.5, P*<.01; pla:
−0.05, NS*Δ met versus
pla, P=.03;  Δ met + rosi versus
pla, P=.06Mulligan et al. [60]130Pio versus placebo48 weeksDEXA limb fat (g): pio: +380 g; pla: +50 gΔ pio versus pla P=.051 CT s.c. abdomen: NSCT: NSPio: +0.9; pla: +0.3Δ pio versus pla P=.07Slama et al. [66]39Rosi versus metformin26 weeksCT s.c. abdomen (cm2) rosi: +16, P*<.05; met: −11, P*<.05Δ rosi versus met 27cm2(95% CI, 7 to 46)CT (cm2)
rosi: −1, NS*; met: −25, P*<.05Δ rosi versus met 24 cm2 (95% CI, 6 to 51)Rosi: +0.4,P*<.05; met: −0.4, P*<.05Δ rosi versus
met 0.7 (95% CI, 0.5 to 1.6)van Wijk et al. [58]* denotes
significance within the study group compared to baseline value,Δ denotes
comparison of the change between respective study groups.One study found a statistically
almost significant increase in visceral adipose tissue (VAT) in the
rosiglitazone group when compared to placebo [60], while there were no significant
changes in VAT between the glitazone and placebo arms in the other studies.
None of the placebo-controlled trials reported significant changes in BMI
either within the glitazone arm or between the placebo and glitazone group,
although the difference approached statistical significance in the pioglitazone
trial by Slama et al. [66]. In the study comparing
rosiglitazone and metformin, there was a significant increase in body mass
index (BMI) within the rosiglitazone arm from baseline, and also the change between
the rosiglitazone and metformin arm was statistically significant [58]. The studies finding no significant
increase in SAT reported changes in body weight ranging from a loss of 3.0 kg
to the gain of 3.8 kg in the thiazolidine arm [55, 56, 62, 65]. In contrast to variable effects
seen on body weight with glitazones, all three studies having a metformin arm [58, 60, 63] reported a decrease in body weight from
1.2 to 2.2 kg in patients using metformin.The effects of thiazolidinediones on
body composition in HAART-treated patients contrast data from HIV-negative
diabetic patients. In these patients, thiazolidinediones have increased body
weight constantly by 2–4 kg after 16–26 weeks of
therapy [12]. This increase has been attributed mainly
to an increase in the fat mass and in some patients to edema [12].  The increase in total fat mass has
been in the order of 1.5–4 kg after 3-4 months of rosiglitazone
therapy [9, 68, 69], and it consists almost exclusively
of the increase in the subcutaneous fat depot [7, 8, 69, 70]. Similar effects on body fat have
also been described in nondiabetic patients treated with pioglitazone for
insulin resistance [71] or nonalcoholic steatohepatitis [72].Table3 lists  some confounding
factors that possibly could explain the conflicting results of thiazolidinediones
on SAT in different trials with HIV-infected, HAART-treated patients. The drug
dose, study duration, inclusion criteria and baseline BMI appeared to be
similar between studies showing a statistically significant increase versus
those not showing a change in SAT. The prevalence of concomitant use of stavudine,
the NRTI most strongly associated with fat loss, may explain some of the discrepancies,
since the studies reporting an increase in SAT were those with least frequent
use of stavudine [57, 58, 66]. Also in the study by Carr et al.,
after 24 weeks of treatment with rosiglitazone, there was a statistically
almost significant increase in SAT in those patients not taking stavudine or zidovudine
when compared to the placebo group (+480 g versus 190 g, P=.06), but this
difference was not maintained at week 48 [56]. Similarly, in the study by Slama
et al., patients not taking stavudine at baseline had a mean increase of limb
fat mass of 450 g in the pioglitazone group versus 40 g increase in the placebo
group (P=.013) [66]. Based on these data one can hypothesize
that thiazolidinediones may have a fat-inducing effect in lipoatrophic SAT, but
the ongoing stavudine (and zidovudine) treatment may negate this beneficial effect.Table 3
Comparison of the baseline characteristics of the thiazolidinedione
arms of the studies showing versus not showing an increase in subcutaneous fat mass
in HIV-infected HAART-treated patients. HAART =
highly active antiretroviral therapy, SAT = subcutaneous adipose tissue, NR =
not reported.
Drug (dose/d)DurationInclusion criteriaBMI (kg/m2)% taking stavudineReferenceNo change in SATRosi 8 mg24 weeksLipoatrophy2467Sutinen et al. [55]Rosi 8 mg48 weeksLipoatrophy2349Carr et al. [56]Pio 30–45 mg12 monthsInsulin resistance and dyslipidemia26NRGavrila et al. [65]Rosi 4 mg24 weeksLipodystrophy25NRCavalcanti et al. [62]Increase in SATRosi 4 mg3 monthsLipoatrophy and insulin resistance2644Hadigan et al. [57]Rosi 4 mg16 weeksLipodystrophy and insulin resistanceBody weight 80 kgNRMulligan et al. [60]Pio 30 mg48 weeksLipoatrophy2225Slama et al. [66]Rosi 8 mg26 weeksLipoatrophy2421van Wijk et al. [58]In addition to quantifying adipose
tissue compartments, liver fat content was measured in one study [55]. Liver fat decreased with
rosiglitazone and increased with placebo (−2.1% versus +2.1% in the
rosiglitazone versus placebo, P<.05) [55]. Serum alanine aminotransferase (ALT)
concentrations were reported in 5 rosiglitazone studies [55–58, 60]. In three of these studies, there
was a statistically significant decrease in ALT concentration in the rosiglitazone
arm compared either to the baseline value or to the placebo arm possibly suggesting
a decrease in liver fat content [55, 56, 58].Outside these trials, a single case
report describes development of several dozen lipomas in a patient with HAART-associated
lipoatrophy during 3-month therapy with rosiglitazone. After rosiglitazone was
discontinued, all but 5 lipomas resolved completely [73].


## 4.2. Effects on Insulin Resistance and Blood Lipids

The effects of thiazolidinediones on
glycemic indeces in the ten comparative studies reporting data on glucose and
insulin are shown in Table4. In contrast to the very modest effects on SAT described
above, eight [55–58, 60, 61, 63, 65] out of 10 studies showed improvements
in insulin resistance in the thiazolidinedione arm when compared to the
baseline value or to the placebo arm. One study reported a significant positive
correlation between the change in fasting insulin concentration and the change
in liver fat content [55]. Only two studies did not show
significant improvements in insulin sensitivity [62, 66]. Of note, insulin resistance was an
inclusion criteria in only four [57, 60, 63, 65] out of these 10 studies.Table 4
The effects of thiazolidinediones on glycemic indeces in controlled trials with HIV infected, HAART-treated patients. HAART = highly active antiretroviral therapy, HOMA
= homeostasis model assessment (fasting insulin [μIU/ml] × fasting glucose [mmol/L]/22.5), OGTT = oral glucose tolerance test, NS = nonsignificant, NR = not
reported, AUC = area under the curve.
NDrugDurationInsulin (μIU/ml)HOMAOGTTFasting glucose (mmol/L)Reference30Rosi versus placebo24 weeksRosi: −3.3,P<.05*; pla: +6.7, NS*Δ
rosi versus pla P<.05NRNRNSSutinen et al. [55]108Rosi versus placebo48 weeksRosi: −3.5; pla: +0.7Δ rosi versus pla P=.02Rosi: −1.0; pla: +0.04Δ rosi versus pla P=.032 h glucose: NS
2 h insulin: rosi −13.6; pla +3.9Δ rosi versus pla P=.09NSCarr et al. [56]14Pio versus feno versus pio + feno versus placebo12 monthsNSPio: −3.8,P<.05*; pla: −1.3, NS*NRNSGavrila et al. [65]96Rosi versus placebo24 weeksNSNSNSNSCavalcanti et al. [62]28Rosi versus
placebo3 monthsNSNR2
h glucose: rosi: −0.3; pla:
+0.1Δ rosi versus pla P=.06 2h insulin AUC: rosi: −2.3; pla: +1.8
Δ rosi versus pla P=.003NSHadigan et al. [57]105Rosi versus metformin versus rosi + met versus placebo16 weeksRosi: −4,P=.08*; met: −2, P=.07*NRInsulin AUC: rosi: −26,P=.012*; met: −11, P=.06*; rosi + met: −18, P=.002*Δ  rosi + met versus placebo P=.03; Δ rosi versus pla P=.07NSMulligan et al. [60]130Pio versus placebo48 weeksNSNSNSNSSlama et al. [66]37Rosi versus placebo6 monthsNSRosi: −0.1,NS*; pla: +1.3, P<.05* At 6 months: rosi versus pla P<.05NRNSHaider et al. [61]90Rosi versus metformin versus No-treatment48 weeksRosi: −19.3,P<.001*; met: −11.1, P<.001*; No-Tx: +0.7, NS* At 48 weeks: rosi versus No-Tx P<.001;
met versus No-Tx P<.001; met versus rosi P<.001Rosi: −7.3,P<.001*; met: −6.2, P<.001*; No-Tx: +0.3, NS* At 48 weeks: rosi versus No-Tx P<.001; met versus No-Tx P<.001; rosi versus met P<.001NRRosi: −1.9,P<.001*;
met: −2.2, P<.001*; No-Tx: 0.0, NS*
At 48 weeks: Rosi versus No-Tx P<.001; met versus No-Tx P<.001; rosi versus met P=.015Silič et al. [63]39Rosi versus metformin26NRNRGlucose AUC: rosi: −1.9,P=.04*; met: −1.1, P=.05*Δ
rosi versus met NS Insulin AUC:
rosi: −37, P=.01*; met −33, P=.01*Δ rosi versus met NSNRvan Wijk et al. [58]*denotes significance within the study group compared to baseline
value, Δ denotes comparison of the change between respective study groups.Since none of the comparative
studies recruited patients with type 2 diabetes, it is difficult to compare these
effects on glycemic indeces in HAART-treated patients to those in HIV-negative diabetic
patients treated with glitazones. The average decrease in haemoglobinA1c has been 1–1.5% in non-HIV patients with type 2 diabetes
treated with glitazones [12].The effects of thiazolidinediones on
blood lipids in the nine comparative studies reporting data on cholesterol and
triglycerides are shown in Table5. Five [55–58, 60] out of seven studies with rosiglitazone
reported a statistically significant increase in total cholesterol concentration
in the rosiglitazone arm when compared either to the baseline value or to the comparative
arm. The absolute increases in total cholesterol concentration in the rosiglitazone
arms varied from 0.4 to 1.4 mmol/L. Neither of the two pioglitazone studies
reported significant changes in total cholesterol concentrations [65, 66]. HDL (high-density lipoprotein) cholesterol
concentration increased statistically significantly in both studies with pioglitazone
(increases of 0.09 and 0.15 mmol/L) [65, 66], but decreased significantly in two
out of the seven rosiglitazone studies with absolute decreases of 0.1 and 0.15 mmol/L [58, 60]. LDL (low-density lipoprotein)
cholesterol was measured in five rosiglitazone studies [56–58, 60, 62]. Four of these studies reported
significant increases in LDL cholesterol concentrations when compared to the
baseline value (absolute increases between 0.2–0.8 mmol/L) or to the comparative arm [56–58, 60]. The increase of 1.7 mmol/L in LDL
cholesterol was statistically almost significant in one of the two pioglitazone
studies [65]. Statistically significant
increases in triglyceride concentrations were reported in three out of seven rosiglitazone
studies (versus baseline or versus the comparative arm) [55, 56, 58]. The absolute increases were between
0.5–3.0 mmol/l. There were no significant changes
in triglyceride concentrations in the two pioglitazone studies. A proatherogenic
effect of rosiglitazone on blood lipids was further described by Hadigan et al.
[74]. Rosiglitazone treatment increased
significantly the concentration of small dense LDL cholesterol, and decreased
the concentration of large HDL cholesterol and also of HDL particle size [74]. In contrast, pioglitazone
treatment was associated with an increase in the LDL particle size (from 19.9
at baseline to 20.6 nm at 12 months, P=.06) [65].Table 5
The effects of thiazolidinediones
on blood lipids in comparative studies with HIV infected, HAART-treated
patients. HDL
= high-density lipoprotein, LDL = low-density lipoprotein, NS = nonsignificant,
NR = not reported, CI = confidence interval.
NDrugDurationTotal cholesterol (mmol/L)HDL cholesterol (mmol/L)LDL cholesterol (mmol/L)Triglycerides (mmol/L)Reference30Rosi versus placebo24 weeksRosi: +1.4,P*<.01; pla: 0.0, NS*Δ rosi versus pla NSNSNRNS
At 12 weeks: rosi: +3.0,P*<.05; pla: NSSutinen et al. [55]108Rosi versus placebo48 weeksRosi: +0.9; pla: 0.0Δ Rosi versus pla P<.001NSRosi: +0.8; pla: +0.4Δ rosi versus pla P=.04Rosi: +1.5; pla: +1.3Δ rosi versus pla P=.04Carr et al. [56]14Pio versus feno versus pio + feno versus placebo12 monthsNSpio: +0.15,NS*; pla: −0.20, NS*Δ pio versus pla P=.01Pio: +1.7,P*=.07; pla: −0.6, NS*NSGavrila et al. [65]96Rosi versus placebo24 weeksNSNSNSNSCavalcanti et al. [62]28Rosi versus
placebo3 monthsRosi: +0.6; pla:−0.4Δ rosi versus pla P=.007NSRosi: +0.4; pla:−0.4Δ rosi versus pla P=.01NSHadigan et al [57]105Rosi versus metformin versus rosi + met versus placebo16 weeksRosi: +0.4,P*<.05; all other groups NS*Rosi:−0.1, P*<.001; all other groups NS*Δ rosi versus pla P=.005; Δ rosi versus rosi + met P=.006Rosi: +0.2,P*<.05; all other groups NS*Δ rosi versus pla P=.048NSMulligan et al. [60]130Pio versus placebo48 weeksNSPio: +0.09; pla:−0.08Δ pio versus pla P=.005NSNSSlama et al. [66]37Rosi versus placebo6 monthsNSNRNRNSHaider et al. [61]39Rosi versus metformin26 weeksRosi: +0.4,NS*; met: −0.4, P*<.05Δ rosi versus met 0.8 (95% CI, 0.3
to 1.3)Rosi:−0.15, P*<.05; met:
+0.01, NS*Δ rosi versus met 0.16 (95% CI,
−0.35 to −0.02)Rosi: +0.2,NS*: met: −0.4, P*<.05Δ rosi versus met 0.6 (95% CI, 0.2
to 1.1)Rosi: +0.5,*versus <0.05; met: −0.6, P*<.05Δ rosi versus met 1.1 (95% CI, 0.4
to 2.6)van Wijk et al. [58]*denotes significance within the study group
compared to baseline value, Δ denotes comparison of the change between respective
study groups.The results of these studies with
HAART-treated patients suggest pioglitazone to have a more favorable lipid
profile than rosiglitazone as has been observed in patients with type 2
diabetes [12]. A striking difference in HAART-treated
patients relative to HIV-negative diabetic patients was the significant increase
in triglyceride concentration by 1.5 to 2.3 mmol/L in the rosiglitazone arm in
some studies [55, 56]. One may hypothesize that the
increases in serum triglycerides were possibly aggravated by the high
prevalence of stavudine use in these studies. The ongoing stavudine treatment may
have prevented the storage of circulating lipids within the adipocytes. In the
study by Sutinen et al., one patient had to discontinue rosiglitazone treatment
due to serum triglyceride increase up to 32.5 mmol/L [55] and another patient using
rosiglitazone in the study by Cavalcanti et al. discontinued due to abnormal
lipid values [62]. Carr et al. reported grade 3-4 increases in
triglyceride concentrations in 57% of the participants in the rosiglitazone arm
compared to 36% in the placebo arm [56]. The large study by Cavalcanti et
al. did not report any deleterious effects on blood lipid concentrations by
rosiglitazone, but in the same study 15% of patients in the rosiglitazone arm
started lipid-lowering therapy during the study compared to 5% in the placebo
arm [62]. In addition to these prospective
clinical trials, a small retrospective study reported effects of fenofibrate
alone versus fenofibrate in combination with rosiglitazone in HIV-infected
patients [75]. When fenofibrate was given alone,
triglyceride concentrations decreased by 27% and HDL cholesterol increased by
19%. In contrast, when fenofibrate was combined with rosiglitazone, triglycerides
increased by 48% and HDL cholesterol decreased by 33% [75].Three of the rosiglitazone studies [57, 60, 76] also reported the effects of
rosiglitazone on free fatty acid (FFA) concentrations. In two of these studies,
a statistically significant decrease in FFA concentration was found in the
rosiglitazone arm when compared to baseline value or to placebo [57, 76].Serum adiponectin concentration was
measured in six rosiglitazone studies [56–58, 60, 61, 76]. All these studies showed a statistically
significant increase of 0.8–4.1 μg/ml in the
rosiglitazone arms. One study found an inverse correlation between the change
in adiponectin concentration and the change in fasting insulin concentration
and liver fat content [76].Additional findings from these
clinical trials with HAART-treated patients include either a decline [77] or no change [55, 78] in leptin concentration with
rosiglitazone. Circulating concentrations of inflammatory markers (TNFα,
C-reactive protein, or IL-6) did not change in any study reporting these
measurements [78–80]. Plasma concentrations of PAI-1
(plasminogen activator inhibitor-1) and tPA (tissue plasminogen activator) were
reported to either decline [79] or remain unchanged [78] with rosiglitazone therapy. Plasma
resistin concentration decreased with rosiglitazone in one study [78]. Rosiglitazone decreased systolic
blood pressure, but had a nonsignificant effect on flow-mediated arterial
dilatation compared to placebo in one study [77].


## 4.3. Thiazolidinedione-Induced Gene Expression in Sat in HAART-Treated Patients

Two studies have evaluated the
effects of rosiglitazone on gene expression in SAT in HAART-treated patients [76, 81]. Sutinen et al. reported
statistically significant increases in the expression of adiponectin and PPARγ coactivator 1 (PGC-1), and a
decrease in IL-6 expression with rosiglitazone treatment [76]. In addition, there was a significant
increase in PPARγ expression in the rosiglitazone arm relative to the placebo
arm [76]. Mallon et al. studied gene
expression in SAT two and 48 weeks after rosiglitazone or placebo treatment,
and compared patients taking tNRTIs at baseline to those without tNRTI treatment
[81]. After two weeks, only those
randomized to rosiglitazone in the no-tNRTI group experienced a significant
rise in PPARγ and PGC-1 expression. At 48 weeks, PPARγ expression was increased
in the no-tNRTI groups when compared to tNRTI groups, but there was no
difference between the rosiglitazone and placebo arms [81].The increase in the expression of
adiponectin, PPARγ (albeit limited), and that of PGC-1 are consistent with data
from type 2 diabetic patients treated with glitazones [82, 83]. There are,
however, also some differences in these two patient populations. In non-HIV
patients, the expression of lipoprotein lipase (LPL) [82, 84] and adipocyte fatty
acid binding protein (aP2) [83] increased with glitazone
treatment. The expression of these genes remained unchanged in HAART-treated patients
[76].Taken together, it seems plausible
that thiazolidinedione treatment had a functional effect in lipoatrophic SAT by
increasing the production of adiponectin and decreasing IL-6 expression. Both
of these changes may have been involved in the improvement of whole body
insulin sensitivity. The correlation between the change in adiponectin
concentration and the change in liver fat content implies a possibility for
adiponectin to have mediated this beneficial effect on liver fat [76]. These functional changes in
adipose tissue occurred despite the lack of a significant increase in fat mass.
One may also hypothesize that the blunted increase in PPARγ expression, especially in patients
receiving tNRTI therapy, as well as the lack of an increase in LPL and aP2 expression
may all have contributed to the nonsignificant effect on SAT mass and to high-serum
triglyceride concentration in these patients.


## 4.4. Safety

Since in vitro and animal models, as well as clinical
studies clearly indicate that thiazolidinediones correct endothelial
dysfunction, suppress chronic inflammatory processes, reduce fatty streak formation,
and enhance plaque stabilization and regression [85], one would expect favorable effects
on cardiovascular endpoints also in human studies. In contrast, the meta analysis by Nissen and Wolski [86] demonstrated that rosiglitazone as compared to the control group significantly
increased (and not decreased) the odds ratio for myocardial infarction (OR 1.43;
95% confidence interval [CI], 1.03 to 1.98; P=.03), and the odds ratio
for death from cardiovascular causes (OR 1.64; 95% CI, 0.98 to 2.74; P=.06).
A more recent meta analysis confirmed the increased risk of myocardial
infarction (RR 1.42; 95% CI, 1.06 to 1.91; P=.02) and heart failure (RR
2.09; 95% CI, 1.52 to 2.88; P<.001) with rosiglitazone, but found no
significant increase in the risk of cardiovascular mortality (RR 0.90; 95% CI,
0.63 to 1.26; P=.53) [87]. In contrast to findings with rosiglitazone, a
meta-analysis of pioglitazone found a decreased hazard ratio for death,
myocardial infarction, or stroke in patients receiving pioglitazone when
compared to those receiving control therapy (HR 0.82; 95% CI, 0.72 to 0.94; P=.005)
[88]. However, the hazard ratio for serious heart
failure was increased in patients receiving pioglitazone versus the control
patients (HR, 1.41; 95% CI, 1.14 to 1.76; P=.002) [88].  Whether
these deleterious effects of glitazones on cardiovascular morbidity would be
diminished in patients receiving HAART, since patients are usually younger,
fewer have diabetes, and so forth, or enhanced since HAART by itself increases
risk for myocardial infarction [4], remains to be studied. None of the studies
with HAART-treated patients using glitazones so far have reported any
significant cardiovascular events.In general, both rosiglitazone and
pioglitazone were well tolerated in all trials with HAART-treated patients. However,
the total number of HAART-treated patients taking rosiglitazone and pioglitazone
was only 281 and 82, respectively, and none of the studies had followup beyond
one year. Furthermore, it is important to keep in mind that due to exclusion
criteria of these trials there are basically no data on glitazones in HIV-infected
patients with significantly increased liver function tests, high creatinine or triglyceride
concentrations, or low hemoglobin at baseline; all these laboratory
abnormalities are relatively common in HAART-treated patients.Regarding the known adverse effect
profile of thiazolidinediones in non-HIV infected patients, it was reassuring
that no cases of clinically significant oedema, heart failure or other
cardiovascular events were reported. A decrease in haemoglobin concentration is
another known side effect with all glitazones, which is not explained by
hemodilution but possibly caused by mild suppressive effect on bone marrow [89, 90]. This might be of significance in HAART-treated
patients, since both HIV per se
and antiretroviral agents may cause bone marrow suppression [91]. A statistically, but not
clinically significant decrease in haemoglobin concentration in the rosiglitazone
arm was reported in one study, possibly also reflecting good adherence to study
medication [55]. A single case with a decrease of
haemoglobin concentration to less than 110 g/L was reported by Hadigan et al. [57]. Given the concerns for severe
liver toxicity induced by troglitazone [92], liver function tests were carefully
monitored in these patients receiving polypharmacy. A single participant in a
pioglitazone trial discontinued the study due to an increase in liver function
tests >3 times upper limit of normal [65]. In contrast, three studies
observed significant decreases in ALT concentrations either within the
rosiglitazone arm or when compared to placebo [55, 56, 58]. Adverse effects on blood lipids
were already discussed earlier; two patients had to discontinue rosiglitazone
due to abnormal lipid values [55, 62].Harmful effects of thiazolidinediones
on bone metabolism have recently been discussed in patients with type 2 diabetes.
A recent analysis of the data from five glitazone studies suggests that treatment with
thiazolidinediones, primarily rosiglitazone, contributes to bone loss [93]. This effect appears to be most prominent in
postmenopausal women [93]. The effect on bone density may have special
relevance in HAART-treated patients, since both HIV-infection as such and also
antiretroviral therapy have been associated with decreased bone mineral density
[94]. None of the studies using glitazones in HAART-treated
patients have reported effects on bone density.Potential for drug-drug interactions
must always be considered, when new medications are combined with HAART. Most
PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are not only metabolized
by CYP450 3A4 but are also either inhibitors (PIs, ritonavir in particular) or
inducers (NNRTIs) of the same enzyme and to lesser extent of other isoforms of
CYP450 [95]. Both rosiglitazone and
pioglitazone are predominantly metabolized by CYP450 2C8 (http://www.emea.europa.eu/). Rosiglitazone is not an inducer of any
tested human CYP450 isoforms,  but has shown moderate inhibition of 2C8 and low
inhibition of 2C9  (http://www.emea.europa.eu/). There is no in vitro evidence that pioglitazone
would either inhibit or induce any of the human CYP450 isoforms (http://www.emea.europa.eu/). Interaction studies have not shown
clinically significant interactions with rosiglitazone and substrates for
CYP450 3A4. These interactions are not expected with pioglitazone either (http://www.emea.europa.eu/).There are currently very limited
pharmacological data on the concomitant use of thiazolidinediones and
antiretroviral drugs. Data from a limited number of patients by Oette et al.
suggest that rosiglitazone could be safely administered together with either
lopinavir or efavirenz [96]. Rosiglitazone, however, seemed to decrease
nevirapine concentrations and the authors recommend to monitor nevirapine serum
concentrations if these drugs are used concomitantly [96]. Serum PI concentrations were
measured in one study with rosiglitazone [55] and both PI and NNRTI
concentrations were measured in one pioglitazone study [66].  Neither study observed any
significant change in the serum concentrations of these antiretroviral drugs during the
study period. None of the studies reported any statistically significant
changes in either HIV viral load or CD4 count within the glitazone arm or
between different study arms. Nevertheless, six patients in the pioglitazone
arm versus two in the placebo arm (P=.1) experienced viral breakthrough
(>400 copies/ml) during a pioglitazone trial [66]. It is not reported if these patients
were possibly taking nevirapine-based HAART (potential interaction between
nevirapine and rosiglitazone, see above). Interestingly, in vitro both PPARγ (rosiglitazone, ciglitazone,
troglitazone) and PPARα (fenofibrate) agonists have been shown to inhibit
HIV replication [97, 98].


## 5. Conclusions Regarding the Role of Thiazolidinediones in the Treatment of HAART-Associated Metabolic Complications

The  available evidence does not support the use
of thiazolidinediones for HAART-associated lipoatrophy although they may
have beneficial effects in subgroups of patients such as those that do not receive
concomitant tNRTI therapy. The lack of effect may at least partially be
explained by the decreased expression of PPARγ which has been
demonstrated not only in SAT of lipoatrophic HAART-treated patients [41, 42],
but also in SAT of healthy volunteers after only a 2-week exposure to NRTIs
including a thymidine analog [40].
However, if a thiazolidinedione
is used for lipoatrophy, pioglitazone
should perhaps be preferred because of its more favorable effects on serum lipids.
Currently, the best treatment option for HAART-associated lipoatrophy is to
replace tNRTIs by abacavir or tenofovir [27–29] or possibly to avoid use of NRTI altogether [99]. However, if this causal treatment of
lipoatrophy is not feasible due to HIV resistance profile or intolerance to
other antiretroviral agents, one may consider using uridine, which showed a significant
increase in SAT in a small randomized, placebo-controlled trial in lipoatrophic
patients continuing tNRTI-based HAART [100]. Pravastatin has also been shown to increase
SAT in HAART-treated patients in a single small trial [101]. However, patients in this trial were not
recruited for lipoatrophy but hyperlipidemia and hence the effect of
pravastatin in severely lipoatrophic patients remains to be studied.  Finally and most importantly, one should aim
to prevent lipoatrophy altogether by avoiding the use of tNRTIs in the primary
combinations of HAART as has recently been suggested [102].Glitazones, pioglitazone in particular, could
however, be used for the treatment of HAART-associated diabetes, especially in
patients with reduced amount of SAT. The consistent data on the beneficial
effects on insulin sensitivity in HAART-treated patients support this, albeit
none of these studies recruited diabetic patients. The direct evidence of the
benefits in diabetic HAART-treated patients is therefore still lacking. When
using glitazones for diabetes in HAART-treated patients, one must keep in mind
the potential risk for heart failure associated with both glitazones and increased
risk for myocardial infarction with rosiglitazone. Nevertheless, glitazones
might be the preferred choice, since metformin has been associated with further
loss of SAT in HAART-treated lipodystrophic patients [58, 103] and there are no clinical data at all on other
oral antidiabetic agents in this patient population.Finally, the potential therapeutic role of thiazolidinediones on liver-related morbidity in HAART-treated
patients should be evaluated. Patients who are infected with both hepatitis C (HCV)
and HIV seem to have higher liver fat content than those having HCV
monoinfection [104, 105] although some controversy exists [106]. Among HIV-infected patients without chronic HCV
infection, those with lipodystrophy have increased liver fat content when
compared to age and BMI-matched HIV-negative subjects or HAART-treated
nonlipodystrophic patients [48]. It, therefore, appears that both prevalent
coinfection with HCV and HAART-induced metabolic complications put HIV-infected
patients at increased risk for liver steatosis.In HIV-negative patients with nonalcohol
hepatic steatosis, 6-month treatment with pioglitazone decreased liver fat
content, increased hepatic insulin sensitivity, and improved histologic
findings with regards to liver steatosis, ballooning necrosis and inflammation [107]. In the study by Sutinen et al., treatment
with rosiglitazone decreased significantly liver fat content when compared to
placebo in HAART-treated patients, although patients were not recruited for
increased liver fat but for the presence of lipoatrophy [55]. Two additional trials reported significant decreases
in liver function tests in the glitazone arms [56, 58]. Although promising, it remains unknown
whether glitazones would also improve inflammatory changes in the liver in
these patients, since no biopsy data are so far available.



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*Source: 373524-2008-12-01.xml*