New Options in the Treatment of Lipid Disorders in HIV-Infected Patients

Abstract

Since the introduction of HAART, there was a remarkably change in the natural history of HIV disease, leading to a notable extension of life expectancy, although prolonged metabolic imbalances could significantly act on the longterm prognosis and outcome of HIV-infected persons, and there is an increasing concern about the cardiovascular risk in this population. Current recommendations suggest that HIV-infected perons undergo evaluation and treatment on the basis of the Third National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) guidelines for dyslipidemia, with particular attention to potential drug interactions with antiretroviral agents and maintenance of virologic control of HIV infection. While a hypolipidemic diet and physical activity may certainly improve dyslipidemia, pharmacological treatment becomes indispensable when serum lipid are excessively high for a long time or the patient has a high cardiovascular risk, since the suspension or change of an effective antiretroviral therapy is not recommended. Moreover, the choice of a hypolipidemic drug is often a reason of concern, since expected drug-drug interactions (especially with antiretroviral agents), toxicity, intolerance, effects on concurrent HIV-related disease and decrease patient adherence to multiple pharmacological regimens must be carefully evaluated. Often the lipid goals of patients in this group are not achieved by the therapy recommended in the current lipid guidelines and in this article we describe other possibilities to treat lipid disorders in HIV-infected persons, like rosuvastatin, ezetimibe and fish oil.

Full text

The Open AIDS Journal, 2009, 3, 31-37 31
1874-6136/09 2009 Bentham Open
Open Access
New Options in the Treatment of Lipid Disorders in HIV-Infected Patients
Erika Ferrari Rafael da Silva*,1 and Giuseppe Bárbaro2
1Federal University of São Paulo, R Loefgren, 1588, Zip Code04040 002, São Paulo, Brazil
2Cardiology Unit, Department of Medical Pathophysiology, University La sapienza, Rome, Italy
Abstract: Since the introduction of HAART, there was a remarkably change in the natural history of HIV disease, leading
to a notable extension of life expectancy, although prolonged metabolic imbalances could significantly act on the long-
term prognosis and outcome of HIV-infected persons, and there is an increasing concern about the cardiovascular risk in
this population. Current recommendations suggest that HIV-infected perons undergo evaluation and treatment on the basis
of the Third National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood
Cholesterol in Adults (NCEP ATP III) guidelines for dyslipidemia, with particular attention to potential drug interactions
with antiretroviral agents and maintenance of virologic control of HIV infection. While a hypolipidemic diet and physical
activity may certainly improve dyslipidemia, pharmacological treatment becomes indispensable when serum lipid are
excessively high for a long time or the patient has a high cardiovascular risk, since the suspension or change of an
effective antiretroviral therapy is not recommended. Moreover, the choice of a hypolipidemic drug is often a reason of
concern, since expected drug-drug interactions (especially with antiretroviral agents), toxicity, intolerance, effects on
concurrent HIV-related disease and decrease patient adherence to multiple pharmacological regimen s must be carefully
evaluated. Often the lipid goals of patients in this group are not achieved by the therapy recommended in the current lipid
guidelin es and in this article we describe other possibilities to treat lipid disorders in HIV-in fected persons, like
rosuvastatin, ezetimibe and fish oil.
Keywords: Human immunodefciency virus, acquired immunodeficiency syndrome, highly active antiretroviral therapy,
dyslipidemia, statins, fish oil, ezetimibe.
INTRODUCTION
Disorders of lipid metabolism have been described in
patients with HIV infection before the introduction of highly
active antiretroviral therapy (HAART), includ ing increased
serum triglyceride (TG) levels and decreased cholesterol
levels observed in advanced stages of HIV infection [1-3].
However, laboratory and clinical abnormalities of lipid
metabolism have also been increasingly recognized after the
advent of HAART. Significant increases in plasma TG and
total cholesterol (TC) concentrations, often associated with
abnormal body fat distribution and glucose metabolism
alterations (such as peripheral insulin resistance,
hyperinsulinemia, hyperglycemia and diabetes mellitus),
have been reported specially in protease inhibitors (PI)-
treated patients [4-6]. For details see Table 1. Since the
introduction of HAART, there was a remarkably change in
the natural history of HIV disease, leading to a notable
extension of life expectancy, although prolonged metabolic
imbalances could significantly act on the long-term
prognosis and outcome of HIV-infected persons, and there is
an increasing concern about the cardiovascular risk in this
population [4,7,8]. While a hypolipidemic diet and physical
activity may certainly improve dyslipidemia,
pharmacological treatment becomes indispensable when
*Address correspondence to this author at the Federal University of São
Paulo, R Loefgren, 1588, Zip Code04040 002, São Paulo, Brazil; Tel: 55 11
5081 8972; Fax: 55 11 5081 8972;
E-mails: erikaferrari @uol.com.br, ferrarierika76@hotmail.com
serum lipid are excessively high for a long time or the
patient has a high cardiovascular risk, since the suspension
or change of an effective antiretroviral therapy is not
recommended [9]. Moreover, the choice of a hypolipidemic
drug is often a reason of concern, since expected drug-drug
interactions (especially with antiretroviral agents), toxicity,
intolerance, effects on concurrent HIV-related disease and
decrease patient adherence to multiple pharmacological
regimens must be carefully ev aluated [8,10]. HIV infected
person have an increase risk of coronary artery d isease
(CAD) [11]. Part of this risk may be due to the
hyperlipidemia associated with antiretroviral treatment
[11,12]. Often the lipid goals of patients in this group are not
achieved by the therapy recommended in the current lipid
guidelines [3] and in this article we describe others
possibilities to treat lipid disorders in HIV-infected persons.
PATHOGENESIS FOR DYSLIPIDEMIA
PIs- Associated Metabolic Alterations
PIs target the catalytic region of HIV-1 protease. This
region is homologous with regions of two human proteins
that regulate lipid metabolism: cytoplasmic retinoic-acid
binding protein-1 (CRABP-1) and low density lipoprotein-
receptor-related protein (LRP) [13,14]. It is hypothesized
that PIs inhibit CRABP-1-modified and cytrochrome P450
3- mediated synthesis of cis-9 retinoic acid and peroxisome
proliferator activated receptor (PPAR ) heterodimer. The
inhibition increases the rate of apoptosis of adipocytes and
reduces the rate at which pre-adipocytes differentiate into

32 The Open AIDS Journal, 2009, Volume 3 da Silva and Bárbaro
adipocytes, with the final effect of reducing TG storage and
increasing lipid release. PIs-binding to LRP would impair
hepatic chylomicron uptake and endothelial TG clearance,
resulting in hyperlipidemia and insulin resistance [13,14].
Table 1. Changes in Lipid Metabolism in HIV Infection
HIV-Infected Naïve Patients
 Triglyceride
 VLDL
 VLDL triglyceride production rates
Small, dense LDL
HIV Patients Treated with IP Based Regimen
 Triglyceride
Total Cholesterol
 VLDL, IDL, LDL-c, cholesterol Postprandial delipidation
 Apo B-100 VLDL to IDL/LDL transfer
 Apo E VLDL and LDL catabolic rates
 ApoC-III Hepatic lipase activity
 VLDL production Lipoprotein lipase activity
VLDL - very low-density lipoprotein (LDL), HDL – high density lipoprotein, IDL –
intermediate-density lipoprotein, Apo – apolipoprotein.
Some data indicate that PI-associated dyslipidemia may
be caused, at least in part, by PI-mediated inhibition of
proteasome activity and accumulation of the active portion
of sterol regulatory element-binding protein (SREBP)-1c in
liver cells and adipocytes or by apoliprotein (apo) CIII
polymorphisms in HIV-infected persons [15]. The observed
excess of apo CIII in lipoprotein might be a major
determin ant of a slower catabolism of triglyceride-rich
lipoproteins because apo CIII is an inhibitor of lipoprotein
lipase activity and also impairs the interaction of apo B and
apo E with LDL receptor and LRP. This will result in an
increased level of remnant lipoprotein returning to the liver
[15,16]. Sequence homologies have been described between
HIV-1 protease and human site-1 protease (S1P), which
activates SREBP-1c and SREBP-2 pathways. A
polymorphism in the S1P/SREBP-1c genes confers a
difference in risk for development of an increase in TC with
PI therapy, suggesting a possible genetic predisposition to
hyperlipoproteinemia in PI-treated patients [17]. Caron et al.
[17] reported that some PIs may impair the nuclear location
of SREBP-1 and alter the structure and stability of the
nuclear lamina possibly by impairing the maturation of
prelamin A to lamin A. Lamin A and lamin C are encoded
by the same gene and can combine with lamin B to form a
network of filamentous proteins located at the inner face of
the nuclear membrane called lamina [17]. Lamina interacts
with the nuclear membrane and with chromatin. In
particular, the C-terminal globular domain of lamin A/C can
bind DNA and also SERBP-1 [17]. Cells from these patients
have nuclear alterations and altered lamina stability, similar
to the alterations induced in cultured adipocytes by some PIs
[17]. It is possible to hypothesize that some PIs may alter the
lamina structure and thereby alter the normal location of
SREBP-1 inside the nucleus [17]. This could impair
adipocyte differentiation and induce insulin resistance.
Moreover, some PIs may alter the expression of
adipocytokines in cultured adipocytes [18], increasing the
expression of proinflammatory cytokines TNF- and IL-6,
which are known to play a pathogenetic role in adipose
tissue apoptosis and decreasing the expression of
adiponectin, which is associated with the development of
insulin resistance [18].
Treatment Considerations
The studies published until now show that dyslipidemia
in HIV-infected persons carries the same degree of
cardiovascular risk as in HIV-negative population [19].
Nowadays the benefits of lipid-lowering interventions have
been extended to HIV-infected persons. Further, there is
currently no basis for a more aggressive intervention among
HIV-infected persons than what is currently recommended
for the general population. Because there is a significant
possibility for drug interaction of some lipid-lowering agents
with antiretroviral drugs (in particular statins are metabolized
through the cytochrome (CYP) P450 system), care should be
given to the choice of lipid-lowering agents. Current
recommendations suggest that HIV-infected persons undergo
evaluation and treatment on the basis of the Third National
Cholesterol Education Program Expert Panel on Detection,
Evaluation and Treatment of High Blood Cholesterol in
Adults (NCEP ATP III) guidelines for dyslipidemia, with
particular attention to potential drug interactions with
antiretroviral agents and maintenance of virologic control of
HIV infection. Nonpharmacologic measures remain the basis
for intervention. The initial choice for hypertriglyceridemia
is fibrate, and for elevated LDL-c, statins [20].
According to the US-based Adult AIDS Clinical Trial
Group (AACTG) Cardiovascular Disease Focus Group,
treatment with pravastatin, fluvastatin or atorvastatin is
recommended for antiretroviral-linked hypercholesterolemia,
while lovastatin and simvastatin should be avoided due to
interactions with PIs or non-nucleoside reverse transcriptase
inhibitors (NNRTI) [21] and the risk of skeletal muscle
toxicity. Many studies that evaluate the effect of statins for
the treatment of antiretroviral-associated dyslipidemia have
shown only partial responses to such therapy, with total and
LDL-c values being reduced by just 25% [22].
Statins are considered the current first-line therapy for
primary hypercholesterolemia and showed beneficial effects
in both reducing total and LDL-c cholesterol levels in the
HIV-negative persons [23]. Because of the variable
metabolism through CYP 3A4, significant interactions have
been documented with potent CYP 3A4 inhibitors (such as
itraconazole, cyclosporine, oral anticoagulants, PIs and
delaverdine), which cause elevated levels of statins, leading
to a significantly increase of liver and skeletal muscle
toxicity [23]. Lovastatin and simvasatin are administered as
inactive lactone prodrugs that are avidly metabolized by
intestinal and hepatic CYP 3A4. On the other hand,
pravastatin, atorvastatin and fluvastatin are administered
directly as the active hydroxyl-acid. Pravastatin is eliminated
mostly by glucoronidation, fluvastatin by CYP 2C9 isoform,
and CYP 3A4 has no role in their metabolism [24]. On the
basis on the clinical and experimental data, simvastin and
lovastatin should not be used in patients taking PIs or

Treatment of Lipid Disorders in HIV-Infected People The Open AIDS Journal, 2009, Volume 3 33
NNRTIs, atorvastatin can be used with caution (at low initial
doses) and pravastatin and fluvastatin appear to be safe for
use in association with HAART [19]. Table 2 has a summary
of the lipid lowering therapy in HIV infected persons.
Rosuvastatin
Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA) inhibitor that showed the highest dose-to-
dose potency in lowering total and LDL-c levels, compared
with other currently available statins. It works also to reduce
TG and increase HDL-c. Moreover, pharmacokinetic studies
have demonstrated that its metabolism is not dependent on
the CYP 450 3A4 isoenzyme and its use could be considered
in PI-treated individuals as the result of the low risk of drug-
drug interactions [25]. Only 10% of the administered dose is
metabolized by CYP 2C9 isoenzyme into N-desmethyl
rosuvastatin and its metabolite are 90% eliminated by the
fecal route [24-26]. The usual recommended starting dose of
rosuvastatin is 10 mg daily, but initiation at 5 mg daily may
be considered for patients who have predisposing factors for
myopathy or are taking cysclosporine. In subjects with
severe renal impairment or taking fibrates, therapy with
rosuvastatin should only be used with great caution, daily
dose should be initiated at 5 mg and not exceed 10 mg [26].
In the research of Bottero et a l. [27], the use of
rosuvastatin (10 mg/day) was retrospective evaluated during
16 weeks in HAART-treated HIV-infected persons with
dyslipidemia. Seventy eight patients started on rosuvastatin,
sixty as monotherapy. After 16 weeks of treatment, a
significant decrease was seen in both LDL-c and non-HDL
(31,3% and 29,9% reduction respectively). The decrease in
triglyceride was also significant (34,1%). Rosuvastatin was
safe and effective in the treatment of dyslipidemia in
HAART-treated HIV-infected persons. The results showed
above are similar to the HIV-uninfected population. Calza et
al. [28] in an open label, randomized, prospective study
evaluated the role of rosuvastatin (10 mg once daily),
pravastatin (20 mg once daily) and atorvastatin (10 mg once
daily) in the treatment of hypercholesterolemia (TC > 250
mg/dL) in HIV-infected persons at least 3 month duration
and unresponsive to a hypolipidemic diet and physical
exercise. Eighty five subjects completed the study and the
mean reduction after one year follow up was 21,2% and
23,6% versus baseline TC and LDL-c levels, respectively
(p=0.002). Mean decrease in TC concentration was
significantly greater with rosuvastatin (25,2%) than with
pravastatin (17,6% p = 0.01) and atorvastatin (19,8% p =
0.03). All the statins showed a favourable tolerability profile,
but rosuvastatin was found to be more effective. Van der Lee
et al. [29] evaluated the pharmacokinectics and
pharmacodynamics of combined use of lopinavir/ritonavir
and rosuvastatin (10 mg, 20 mg and 40 mg) in HV-infected
persons and found that the levels of this PI were not affected
by the administration of rosuvastatin, but the rosuvastin
levels unexpectedly appeared to be 1.6 fold compared with
healthy volunteers. Larger studies are necessary to confirm
these findings, until there, the combination of rosuvastin and
lopinavir/ritonavir should be used with caution.
Ezetimibe
Ezetimibe is the first lipid-lowering drug that inhibits
intestinal uptake of dietary and biliary cholesterol at the
brush border of the intestine, resulting in a reduction of
hepatic cholesterol stores and an increase in clearance of
cholesterol form in the blood [30]. It doesn’t affect the
absorption of fat-soluble nutrients and is an attractiv e option
for HIV-infected persons because it lacks CYP P450
metabolism and therefore is not expected to interact with
antiretroviral [30,31]. It reduces cholesterol absorption in the
duodenum by approximately 50%, thereby attaining
reductions in LDL-c of 20% [32]. This benefit is
significantly greater when it is given with any of the statins,
achieving reductions in LDL-c of up to 50% [32,33]. This
synergistic effect of the two drugs in combination results
from the inhibition of duodenal cholesterol absorption by
ezetimibe, together with the reduction of hepatic cholesterol
production by the statins [30]. Following oral administration,
Table 2. Lipid Lowering Therapy for HIV-Infected People
Lipid Alteration Therapy Caution
Elevated LDL-c or
non-HDL
cholesterol with
triglycerides level of
200-500 mg/dL
Statins:
- Pravastatin: 20-40 mg daily
- Atorvastatin: 10-20 mg/daily
- Fluvastatin: 20-40 mg/daily
- Rosuvastatin
- Lovastatin
- Simvastatin
- Ezetimibe: 10 mg daily
Less drug interaction potential
Used with caution in lower doses when combined with PIs and NNRTIs
Minimal drug interaction potential. Not widely used due to low potency
Most potent statin. May be used safely with antiretroviral
Avoid in patients taking PIs
Avoid in patients taking PIs or delaverdine
Can be used with statin or in monotherapy
triglycerides level >
500 mg/dL
Fibrates and Fish Oil:
- Gemfibrozil: 1200 mg daily
- Fenofibrate: 200 mg daily
- Bezafibrate: 400 mg daily
- Omega-3 polyunsaturated fatty
acids/fish oil: 3-5g
Caution wh en used with statins in mixed dyslipid emia
Caution wh en used with statins in mixed dyslipid emia
First line therapy for hypertriglyceridemia
Evidence suggest fish oil may decrease triglycerides and increase HDL-c,
however can also increase LDL-c
Adapted from Bennet M [38], Stebbing J [39], Calza L [53], Soler A [54], Bader MS [55].

34 The Open AIDS Journal, 2009, Volume 3 da Silva and Bárbaro
ezetimibe is rapidly absorbed and extensively metabolized
(>80%) to the pharmacolog ically active ezetimibe-
glucuronide [30]. The recommended dose is 10 mg/day, and
can be administered in the morning or evening without
regard to food [30]. The major metabolic pathway for
Ezetimibe consists of glucuronidation of 4-hydroxyphenyl
group by uridine 5’-diphosphate-glucuronosyltransferase
isoenzymes to form ezetimibe-glucuronide in the intestine
and liver [30]. It has a favourable drug-drug interaction
profile. Ezetimibe does not have significant effects on
plasma levels of HMG-CoA reductase inhibitors known as
statins (atorvastatin, fluvastatin, lovastatin, pitavastatin,
pravastatin, rosuvastatin, simvastatin), fibric acid derivatives
(gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and
triphasic oral contraceptives (ethinylestradiol an d
levonorgestrel). Concomitant administration of food,
antiacids, cimetidine or statins had no significant effect on
ezetimibe bioavailability [34].
Ezetimibe has been effective in optimizing lipid levels
when added to traditional therapy in non-HIV infected
persons [34-36]. In HIV positive population some studies
have assessed the efficacy of this drug and are described as
follow. Coll et al. [37] showed that ezetimibe monotherapy
decreases LDL-c as effectively as fluvastatin monotherapy.
Twenty HIV-infected persons were randomly assigned to
receive ezetimibe (10 mg/day) or fluvastatin (80 mg/day).
Patients receiving ezetimibe experienced a statistically
significant (p=0,003) 20% reduction in the concentration of
LDL-c, similar to that observed with fluvastatin (24%, p
between groups 0.70). Negredo et al. [30] conducted a
prospective study and Ezetimibe was added when the statin
(pravastatin monotherapy) has poor response. During 24
weeks, nineteen patients received ezetimibe (10mg/day) and
pravastatin (20 mg/day), while the patients maintained the
same antiretroviral regimen. At week 24, 61,5% of patients
achieved the endpoint of the study (LDL-c < 130 mg/dL).
Significant declines in total and LDL-c levels were observed
between baseline and weeks 6, 12, 24, irrespective of
antiretroviral regimen (IP or ITRNN) and mean HDL-c
increased significantly. No patients discontinued therapy due
to intolerance or toxicity. The addition of ezetimibe to
ongoing pravastin was effective and a safe option for HIV-
infected persons not achieving the NCEP ATP III LDL-c
goals despite receiving a statin alone. Bennet et al. [38],
added ezetimibe to maximally tolerated lipid lowering
therapy (statins or fenofibrate) in 33 HIV infected persons.
The mean TC and LDL-c were reduced 21% and 35%
respectively (p <0.001) and HDL-c increased 8% (p=0.038).
No adverse events occurred. Stebbin et a l. [39] analyzed
twenty nine HIV-infected persons with ezetimibe alone or
associated with statins. Of these individuals, 16 and 11
respectively were receiving PI-based and NNRTI-based
regimen. During 12 weeks, it was observed a significant
reduction of 18% in TC (p<0.01) and 28,9% in TG (p<0.05)
regardless of whether patients received statins or not, or the
type of antiretroviral therapy. In the end of study, 40% of the
patients had normalized serum TC, but the same didn’t occur
with TG. There were no significant differences in reduction
of either serum TC or TG in those receiving ezetimibe alone
(n =12) or combined with statins (n= 17). The limitations of
this study included small sample size and lack of
measurement of LDL-c level. Van den Berg-Wolf et al. [40]
in a prospective, non controlled study, evaluated twenty
HIV-infected persons who were on treatment with statins
and didn’t reach the LDL-c goal during 18 weeks. These
patients were on HAART that included ritonavir-boosted PIs
in 17 (85%) and 3 (15%) on nelfinavir. Mean percentage of
changes from baseline in LDL-c were: - 10,9%, - 12,2% and
– 9,1% at weeks 6,12,18, respectively (p<0.05 at each time
period vs baseline). No significant changes in TG and HDL-c
were seen. In a subgroup of patients on lopinavir/ritonavir
(LPV/r), the concentrations of the drug were obtained before
and after the introduction of Ezetimibe and no significant
changes were observed in the concentration of this PI.
Ezetimibe could be recommended as a second line
therapy to HAART induced dyslipidemia if hypercholesterolemia
is refractory to th e statins or if the patient does not tolerate
these drugs. Its high tolerability and the lack of interactions
with the CYP 3A4 indicate that ezetimibe will not increase
the risk of toxicity or pharmacokinetic interactions with
antiretroviral.
Fish O il
The metabolic effects of N-polyunsaturated fatty acids
(PUFAs) derived from marine sources (so-called “fish oils”)
have been demonstrated to reduce fasting and postprandial
TG levels in subjects without HIV infection [41]. Omega-3
is considered an alternative treatment in non-HIV infected
persons. Interest in the triglyceride-lowering effect of
omega-3 fatty acids first came from studies in Greenlandic
Eskimos, which showed that, despite high intake of animal
fats, there was low incidence of CAD. A contributing factor
was the type of fats being consumed, which were rich in
omega-3 fatty acids [42,43] however the exact mechanism
whereby these fats decrease the risk of CAD is unclear. It
has been demonstrated that 3-5 g per day of omega-3 fatty
acids can reduce triglycerides by 30-50%, thereby potentially
minimizing the risk of coronary heart disease (CHD) and
pancreatitis [44]. Intake of small amounts of fish has also
been shown to affect mortality [44]. One research showed
that, in addition to significantly lowering plasma levels of
TC, LDL-c and VLDL-c, salmon oil and other omega-3-
enriched fish oils can have a potentially therap eutic role in
the treatment of very high plasma TG levels [45-48]. Few
data are available on the effect of PUFAs on metabolic
abnormalities in HIV persons [49] however recent studies
suggest possible efficacy and safety of fish oil
supplementation in the treatment of antiretroviral therapy-
associated hypertriglyceridemia [50].
Whol et al. [50] conducted an open-label, randomized
trial with 52 patients receiv ing HAART with fasting TG
levels of > 200 mg/dL to receive nutritionist-administered
dietary and exercise counseling with or without fish oil
supplementation for 16 weeks. Patients assigned to receive
fish oil had a 25% decline in fasting TG levels at week 4
(95%CI, - 34.6% to - 15.7% change), compared with a 2.8%
mean increase among patients assigned to receive counseling
alone (95% CI, - 17.5% to + 23.1% change p = .007). By

Treatment of Lipid Disorders in HIV-Infected People The Open AIDS Journal, 2009, Volume 3 35
week 16, the mean reduction in TG levels in the fish oil arm
remained significant at 19.5% (95% CI, - 34.9% to – 4.0 %
change), whereas the mean decrease in the diet and exercise
only arm was 5.7% (95% CI – 24.6% to + 13.2% change);
however, the difference between study arms was no longer
statistically significant (p=.12). Low density lipoprotein
cholesterol levels had increased by 15.6% (95% CI, + 4.8%
to + 26.4 % change), at week 4 and by 22.4% (95% CI, +
7.91% to + 36.8 % change) at week 16 in the fish oil arm but
did not change in the other group. Carter et al. [51]
compared the effectiveness of omega-3 fatty acid
supplementations and placebo in lowering TG levels in HIV-
infected persons on HAART. It was a placebo-controlled,
randomized, double-blind trial in participants with stable
HAART with fasting TG > 312 mg/dL* to 890 mg/dL*
using 9 g of omega-3 fatty acids versus placebo (olive oil)
after 6 week lead in on dietary therapy. Eleven HIV-infected
males were enrolled. The mean TG level decreased from 447
mg/dL* at baseline to 395 mg/dL* (- 11.6%) after dietary
intervention and to 300 mg/dL* (-32.9%) after 8-week
treatment period. In the omega-3 fatty acid arm, TG fell from
475 mg/dL to 447mg/dL* (- 6%) after dietary intervention
and to 210 mg/dL* (- 56.9%) after treatment period. In the
placebo arm, TG fell from 425 mg/dL to 361 mg/dL*
(- 15.1%) after dietary intervention and to 363 mg/dL*
(- 14.5%) after the treatment period. The difference between
the groups was significant (p=0.0487). The estimated
difference between groups for change in mean TG over 8-
weeks was - 207 mg/dL* (CI 95% - 402 to - 11 mg/dL). De
Truchis et al. [52] evaluated the TG levels in HIV-infected
persons receiving stable antiretroviral therapy treated with
PUFAs in a prospective double-blind randomized design.
One hundred twenty two patients with TG > 200 mg/dL* and
 1000 mg/dL* after 4-week diet were randomized for 8-
weeks to N-3 PUFAs (2 capsules containing 1g of fish oil 3
times daily, n=60) or placebo (1g of paraffin oil capsules,
n=62). An 8-week open-label phase of N-3 PUFAs followed.
The difference (PUFA versus placebo) in TG percent change
at week 8 was – 24.6% (range: -40.9% to – 8.4%; p =
0.0033), the median was - 25.5% in the PUFA group versus
1% in placebo group and mean TG levels at week 8 were
340 ±180 mg/dL* and 480 ± 310 mg/dL* respectively. The
TG levels were normalized in 22.4% (PUFA) versus 6.5%
(placebo) (p=0.013) with a  20% reduction in 58.6%
(PUFA) versus 33.9% (placebo) (p=0.007). Under the open-
label phase of N-3 PUFAs, the decrease in TG levels was
sustained at week 16 for patients in the PUFA group (mean
TG levels: 340 ± 170 mg/dL*, whereas a 21.2% decrease in
TG levels occurred in the placebo group (mean TG levels:
330 ± 140 mg/dL*. The median TG change at week 8 was -
43.6% (range Q1-Q3; 95% CI: - 66.5% to – 4.6%) for
patients with TG levels > 1000 mg/dL. Manfredi et al. [49]
in a prospective, open-label study, evaluated the efficacy and
safety profile of polyunsaturated ethyl esters of n-3 fatty
acids (PEEs) in the control of moderate hypertriglyceridemia
complicating antiretroviral-treated HIV disease, compared
with diet and exercise and with fibr ate. Patients with
moderate hypertriglyceridemia (200-500 mg/dL) while on
HAART, despite modified diet and increased physical
activity were selected. A total of 156 patients aged 36-62
years (97 men) were evaluated. Fifty four patients received
PEE at 1g twice daily; 53 subjects were treated with standard
doses of either: b ezafibrate (21 cases), fenofibrate (19 cases)
or gemfibrozil (13 cases); and the remaining 49 patients
continued a diet-exercise program and served as controls. An
analysis of 18 months showed that continued PEE
administration led to a significant decrease of mean TG of
5.6; 15.8, 13.3, 16; 15.3 and 11.6% after 3, 6, 9, 12, 15 and
18 months, respectively (P<0.0001 vs baseline levels), while
negligible changes occurred in serum cholesterolemia. Both
PEE and fibrate administration achieved a significant (p<
0.0001) amelioration of triglyceridemia compared with diet-
exercise only, although fibrates showed a better efficacy
profile vs PEE (p < 0.0001); these significance levels were
maintained throughout the entire 18-month observation
period. When comparing the efficacy of PEE with that of a
diet-exercise program, a significant difference was reached
at the 6th month (p=0.001) and was maintained until the 18th
month (p=0.005 – P< 0.0001). It showed that pharmaceutical
interventions for extreme hyperlipidaemia will continue to
be superior to dietary therapy alone and that omega-3 fatty
acid will be a useful additional intervention in HIV-infected
people with hypertriglyceridemia.
CONCLUSION
All HIV-infected persons should have their fasting
plasma lipid profile prior to starting HAART. These exams
should be repeated 2 to 3 months after starting or changing
antiretroviral therapy, every 2 to 3 months with the existing
of significant abnormalities and to assess response to lipid-
lowering therapy. It should be checked annually in the
absence of significant abnormalities or well-achieved targets
as a result of intervention. Efforts should be used including
lifestyle modification and lip id-lowering agents if it is
necessary, to achieve lipids goals. Special attention should
be given to drug interactions between lipid-lowering agents
and antiretroviral therapy. Neith er, lovastatin or simvastatin
should be used with PI and atorvastatin should be used with
caution. Rosuvastatin is a new statin with promising results
in HIV-infected people. Ezetimibe is the first lipid-lowering
drug that inhibits intestinal uptake of dietary and biliary
cholesterol at the brush border of the intestine and researches
showed that it could be used as monotherapy or combined
with statin. Omega-3 is considered an alternative treatment
in non-HIV infected populations and that this fish oil could
be used to treat high TG levels related to HAART.
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Received: March 11, 2009 Revised: May 15, 2009 Accepted: May 19, 2009
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