Download Management of Metabolic Side Effects of Antiretoviral Drugs

Advances in Biology, Bioengineering and Environment
Management of Metabolic Side Effects of Antiretoviral Drugs in Patients
Infected with Human Immunodeficiency Virus
DANOIU SUZANA1, BIZDOACA NICU GEORGE2, DANOIU MIRCEA3, DANCIULESCU MIULESCU
RUCSANDRA4
Department: 1Patophysiology; 2Mechatronics; 3Physiology; 4 Endocrinology.
1
University: University of Medicine and Pharmacy of Craiova; 2,3 University of Craiova; 4University of
Medicine and Pharmacy, Bucharest.
1
Address: Petru Rares Street No 4, Craiova; 2,3A.I Cuza Street No 13, Craiova; 4 Dionisie Lupu Street No 37
Bucharest.
COUNTRY: ROMANIA
e-mail: [email protected]; 2 [email protected]; [email protected];
4
[email protected]
Abstract: - Acquired immunodeficiency syndrome (AIDS) is a human immune systemic disease caused by the human
immunodeficiency virus (HIV). This condition reduces progressively the effectiveness of the immune system and
leaves individuals susceptible to infection and tumors. Antiretroviral treatment reduces the mortality and the morbidity
of HIV infection but the treatment is associated with increasing reports of metabolic abnormalities such as body fat
abnormalities, impaired glucose metabolism and insulin resistance, and dyslipidemia. All these metabolic side effects
of antiretroviral therapy combined with effect of HIV infection seem to play a key role in the increased cardiovascular
risk of these patients. The modification of cardiovascular risk factors has become an important aspect of HIV
management. All treatment strategies should emphasize cardiovascular risk reduction, focusing particularly on
hypertension control and correction of glycemic parameters, and dyslipidemia. Switching antiretrovirals may result in
improvements of cardiovascular risk factors, but special care must be taken to avoid virologic failure with such
substitutions. The treatment of cardiovascular risk factors in HIV often involves polypharmacy, which increases the
risk of suboptimal adherence and may compromise the benefit of antiretroviral drugs.
Key-Words: - Acquired immunodeficiency syndrome, Antiretroviral treatment, Cardiovascular risk factors
•
Protease inhibitors inhibit the activity of
protease, enzyme used by HIV to cleave nascent
proteins for final assembly of new virons.
•
Integrase inhibitors inhibit the integrase, which
is responsible for integration of viral DNA into the
DNA of the infected cell.
•
Fusion inhibitors which interfere with binding,
fusion and entry of HIV-1 to the host cell by
blocking one of several targets.
•
CCR5 inhibitors. C-C chemokine receptor type
5 known as CCR5 is a protein. HIV uses CCR5 or
another protein, as a co-receptor to enter its target
cells. A number of new HIV drugs have been
designed to interfere with the interaction between
CCR5 and HIV.
Combinations of antiretroviral drugs create
multiple obstacles to HIV replication to keep the
number of offspring low and reduce the possibility
of a superior mutation. If a mutation that conveys
resistance to one of the drugs being taken arises, the
other drugs continue to suppress reproduction of that
mutation. Most current highly active antiretroviral
therapy regimens consist of three drugs: 2
1 Introduction
Acquired immunodeficiency syndrome (AIDS) is
a disease of the human immune system caused by
the human immunodeficiency virus (HIV). This
condition progressively reduces the effectiveness of
the immune system and leaves individuals
susceptible to infection and tumors [1]. AIDS is now
a pandemic. In 2008, 33.400.000 people lived with
the disease worldwide, and that AIDS killed 2
million people [2]. Antiretroviral treatment reduces
the mortality and the morbidity of HIV infection.
Antiretroviral drugs are classified by the phase of
the retrovirus life-cycle that the drug inhibits [3].
Nucleoside and nucleotide reverse transcriptase
inhibitors inhibit reverse transcription by being
incorporated into the newly synthesized viral
deoxyribonucleic acid (DNA) and preventing its
further elongation.
•
Non-nucleoside reverse transcriptase inhibitors
inhibit reverse transcriptase directly by binding to
the enzyme and interfering with its function.
•
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Advances in Biology, Bioengineering and Environment
nucleoside and nucleotide reverse transcriptase
inhibitors + a protease inhibitor or a non-nucleoside
reverse transcriptase inhibitors [4].
The use of antiretroviral therapy is associated with
increasing reports of metabolic abnormalities such
as body fat abnormalities, impaired glucose
metabolism and insulin resistance, and dyslipidemia.
reverse transcriptase inhibitors therapy. Decreases in
mitochondrial RNA coincided with simultaneous
up-regulation of nuclear genes involved in
transcriptional regulation of mitochondrial RNA and
oxidation of fatty acids, whereas peroxisome
proliferator-activated receptor gamma which is
important for fatty acid storage and glucose
metabolism differentiation of adipose tissue, was
down-regulated. Many nuclear changes correlated
with changes in peroxisome proliferator-activated
receptor-gamma coactivator-1 suggesting a central
role for peroxisome proliferator-activated receptorgamma coactivator-1 in nuclear responses to
mitochondrial
dysfunction
[11].
Genetic
predisposition, gender, and age may be associated
with increased lipodystrophy risk.
2 Body fat abnormalities
Body fat abnormalities in patients receiving
antiretroviral therapy, occurr in 30-50% in several
large, prospective studies [5]. Body fat
abnormalities include central fat accumulation,
development of a dorsocervical fat pad and breast
enlargement, as well as loss of peripheral
subcutaneous fat. The combination of these
morphologic changes and antiretroviral-associated
metabolic derangements has been referred to as the
lipodystrophy
syndrome.
Several
elements
contribute to lipodystrophy syndrome, supporting a
multifactorial etiology [6]. Different classes of
antiretroviral
drugs
are
implicated
both
independently and synergistically in this process.
Immune system dysfunction resulting from a
sustained elevation of proinflammatory cytokines,
mitochondrial toxicity caused by nucleoside reverse
transcriptase inhibitor and metabolic changes
induced by protease inhibitor are all involved in the
pathogenesis of lipodystrophy. Lipogenesis and
lipolysis can be influenced by proinflammatory
cytokines, such as tumour necrosis factor-alpha, that
inhibit the former and stimulate the latter process
[7,8]. There is now strong evidence that nucleoside
reverse
transcriptase
inhibitors-induced
mitochondrial toxicity plays a major role in the
development of the lipoatrophic component of HIVassociated
lipodystrophy
syndrome
[9,10].
Nucleoside analogues are effective in inhibiting HIV
replication due to their high affinity for the viral
enzyme reverse transcriptase (a viral DNA
polymerase). Nucleoside analogues can also bind to
other human DNA-polymerases, like DNA
polymerase beta (necessary for repair of nuclear
DNA) and mitochondrial DNA polymerase gamma,
which is exclusively responsible for the replication
of mitochondrial DNA. Lipodystrophy with
peripheral fat wasting is associated with a decrease
in subcutaneous adipose tissue mitochondrial DNA
content in patients with nucleoside reverse
transcriptase inhibitors therapy. Mallon et al. found
decreased transcription of mitochondrial ribonucleic
acid (RNA) without significant depletion of
mitochondrial DNA in patients in dual- nucleoside
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3 Insulin resistance
intolerance
and
glucose
Multiple mechanisms were involved to insulin
resistance and glucose intolerance in the HIVinfected individual taking antiretroviral therapy:
• impaired cellular glucose uptake due to
inhibition of the Glut4 glucose transporter and
glucose phosphorylation induced by protease
inhibitors [12].
• the elevated blood levels of free fatty acids
induced by both the fat accumulation and depletion
components of lipodystrophy may interfere with
cellular glucose transport through a reduction in the
phosphorylation of insulin receptor substrate-1associated phosphatidylinositol 3-kinase, which
results in impaired intracellular signaling and insulin
resistance, especially in muscle and hepatic [13].
• HIV infection and antiretroviral-mediated
disturbances in the quantity and distribution of fat
may disrupt the normal cytokine regulation of
glucose homeostasis. A correlation between low
adiponectin levels and decreased peripheral
subcutaneous fat has been reported [14].
4 Dyslipidemia
Abnormalities of lipid metabolism are common
complications of HIV disease and HIV therapy.
Prior to the availability of effective antiretroviral
therapy, proatherogenic lipid profiles characterized
by reduced levels of high-density lipoprotein (HDL)
and low-density lipoprotein (LDL) cholesterol, but
with appearance of small dense LDL (small dense
LDL is proatherogenic because it is susceptible to
oxidation particularly and can penetrate the
endothelium and bind to intima proteoglycans more
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Advances in Biology, Bioengineering and Environment
any age is associated with improvements in health
[4]. Dietary intervention. The guidelines of
European AIDS Clinical Society included the
following recommendations: dietary intervention
should not interfere with the absorption of
antiretroviral therapy, limit intake of fat (<30%),
dietary cholesterol (<300 mg/day), but should
emphasize intake of vegetables, high fibre fruits and
grain products, emphasize consumption of fish and
lean meat, intake of alcohol should be restricted (<
20-40 g/day) [4]. Exercise promotion. The
guidelines of European AIDS Clinical Society
included the following recommendations: promote
active lifestyle to prevent and treat obesity,
hypertension and diabetes, encourage self-directed
moderate physical activity (take the stairs, cycle or
walk to work, cycling, swimming etc), emphasize
regular moderate-intensity rather than vigorous
exercise, achieve cardiovascular fitness (30 minutes
brisk walking > 5 days a week, maintain muscular
strength and joint flexibility [4]. Among non-HIVinfected patients the Finnish Diabetes Prevention
study [23], in which individualized counseling
aimed at reducing weight, the total intake of fat, and
saturated fat, and increasing the intake of fiber and
physical activity, the risk of diabetes was decreased
58% among overweight patients with impaired
glucose tolerance. Among HIV-infected patients,
Roubenoff et al demonstrated a decrease in total
abdominal fat, waist-to-hip ratio, body mass index,
total cholesterol, and increased fitness and muscle
strength with progressive cardiovascular and
resistance training for one hour and 15 min three
times a week, and a diet with total fat intake less
than or equal to 30% of total calories, a saturated fat
intake less than or equal to 10% of total calories, and
a fiber intake greater than 25 g per day [24]. In
contrast, a study of home-based progressive
resistance training among HIV-infected women
without dietary intervention improved waist
circumference and cardiorespiratory fitness, but no
effect was seen on blood pressure or lipids [25].
Another study of HIV-infected patients with
dyslipidemia receiving a lipid-lowering diet
followed 161 patients for 3 months and 70 patients
for 6 months, and showed a significant decrease in
total cholesterol and triglyceride levels in subjects
with compliance [26].
effectively than large LDL, resulting in retention in
the arterial wall) and increased triglyceride levels
were reported [15]. Since the initiation of
antiretroviral therapy, particularly with the use of
protease inhibitors, elevations in triglycerides, LDL,
and total cholesterol are seen commonly in practice.
Protease inhibitors have been implicated as a major
cause of the lipid abnormalities seen with
antiretroviral therapy. Protease inhibitors inhibit the
degradation
of
apolipoprotein
B
[16].
Apolipoprotein B is the primary apolipoprotein of
LDL and there is considerable evidence that levels
of apolipoprotein B are a better indicator of heart
disease risk than total cholesterol or LDL. [17].
Medications with nucleoside reverse transcriptase
inhibitors appear to have less of a tendency than
protease inhibitors to cause dyslipidemia,
particularly on a short-term basis bat lipoatrophy
epidemiologically linked to the use of nucleoside
reverse transcriptase inhibitors has been associated
with increases in free fatty acid production and
triglyceride levels [18]. Non-nucleoside reverse
transcriptase inhibitors have effects on lipid levels,
although not to the same degree as protease
inhibitors and comperd with protease inhibitors, use
of non-nucleoside reverse transcriptase class has
been noted to result in generally higher HDL
cholesterol levels [19,20].
All these metabolic side effects of antiretroviral
therapy combined with effect of HIV infection
seems to play a key role in the increased
cardiovascular risk of these patients [21]. A
prospective assessment of 23.490 patients from 11
cohorts on 3 continents (DAD Study) found that
combination antiretroviral therapy was associated
with a increase in the rate of myocardial infarction
[22]. The modification of cardiovascular risk factors
has become an important aspect of HIV
management.
The guidelines of clinical management of treatment
of HIV infected adults in Europe elaborated by The
European AIDS Clinical Society in 2009 included:
life style intervention, prevention and management
of lipodystrophy, diagnosis and management of type
2 diabetes, management of dyslipidemia [4].
5 Life style intervention
Smoking cessation. Much of the prior work
documenting the impact of smoking on health. The
high prevalence of smoking among HIV-infected
patients and the particular health risks make
interventions to promote smoking cessation
imperative in this population. Quitting smoking at
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6. Prevention and management of
lipodystrophy
Because their pathogenic mechanisms differ, fat
accumulation and fat depletion require different
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Advances in Biology, Bioengineering and Environment
glucose 73-110 mg/dl (4-6 mmol/l) according to The
Guidelines of Clinical Management of Treatment of
HIV Infected Adults of The European AIDS Clinical
Society [4], Diet has an important role in the
management of glycemia in diabetic patients [29].
therapeutic
interventions.The
prevention
of
lipoatrophy by switching antiretroviral drugs from
nucleoside reverse transcriptase inhibitors to
anothers regimens has been demonstrated to result in
some improvement in subcutaneous adipose
tissue.The management of lipoatrophy. Switching
antiretrovirals therefore may result in modest
improvements, but care must be exercised to avoid
virologic
failure
with such
substitutions.
Pharmacological interventions to treat lipodistrophy
have not been proven to be effective and may
introduce new complications [4]. Plastic surgery has
gained increasing attention in the HIV-infected
community due to the limited efficacy of other
therapeutic
options.
The
prevention
of
lipohypertrophy has no proven strategy. Weight
reduction of avoidance of weight gain may decrease
visceral adiposity [4]. The management of
lipohypertrophy. Dietary intervention and exercise
may reduce visceral adiposity. Pharmacological
interventions to treat lipohypertrophy have not been
proven to be effective and may introduce new
complications [4].
8. Management of dyslipidemia
Target levels for lipids parameters are to be used
as guidance are not definitive. Guidelines of clinical
management of treatment of HIV infected adults of
European AIDS Clinical Society recomend the
optimal target for LDL cholesterol < 80 mg/dl (2
mmol/l) and standard ≤ 115mg/dl (3 mmol/l) and for
triglycerides, the optimal target is < 155 mg/dl (4
mmol/l) and standard ≤ 190 mg/dl (5 mmol/l) [4].
Higher LDL cholesterol levels increase the risk of
cardiovascular
diseases.
Conversely
the
cardiovascular risk implication from higher
hypertriglyceridaemia
is
less
clear;
hypertriglyceridaemia may increase the risk of
pancreatitis. According to the National Cholesterol
Education Program expert panel on detection,
evaluation, and treatment of high blood cholesterol
in adults (Adult Treatment Panel III) guidelines,
lifestyle modification is essential: smoking
cessation, dietary modification and regular exercise
should be promoted. Only after lifestyle
modification has proved ineffective or when lipid
levels are elevated severely are lipid-lowering
agents necessary [30]. For elevated LDL cholesterol,
hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitors (statins) have produced
favorable responses. Use of these drugs must be
taken with caution, as elevated levels of statins
resulting from the inhibitory effect of protease
inhibitors on cytochrome P450 may result in
myositis and rhabdomyolysis. The use of ezetimibe
in combination with antiretroviral therapy and statin
therapy
is
being
studied
[4].
For
hypertriglyceridemia fibric acid analogues have
produced favorable responses.
The treatment of cardiovascular risk factors in HIV
often involves polypharmacy, which increases the
risk of suboptimal adherence and may compromise
the continued benefit of antiretroviral drugs. The
possibility of drug-drug interactions with
antiretroviral drugs should be considered prior to
introducing any treatment [4].
7. Diagnosis and management of type 2
diabetes
Criteria for the diagnosis of diabetes mellitus,
impaired glucose tolerance and impaired fasting
glucose of experts of World Health Organization:
•
Diabetes: fasting plasma glucose (FPG): > 126
mg/dl (7.0 mmol/l) or two-hour postprandial plasma
glucose (2hrPPG) > 200 mg per dL (11.1 mmol/l)
after a 75-g glucose load
•
Impaired fasting glucose: FPG from 110 to <
126 (6.1 to 7.0 mmol/ l)
•
Impaired glucose tolerance: 2hrPPG from 140
to < 200 (7.75 to < 11.1 mmol/l) [27].
A joint panel of American Diabetes Association and
European Association for the Study of Diabetes
experts updated the treatment recommendations for
type 2 diabetes in a consensus statement which
provides guidance to health care providers. The first
step is comprised of lifestyle modifications and
metformin. If glycemic parameters are not met or
maintained, the algorithm proceeds to the second
step which provides for either the addition of basal
insulin or sulfonylurea, or
the addition of
pioglitazone or a glucagon-like peptide-1 (GLP-1)
receptor agonists. If the second step paradigm does
not meet or maintain glycemic goals, the third step
is a transition to intensive insulin therapy [28].
Target levels for glycemic parameters are: HbA1c <
6.5-7% without hypoglycaemia, fasting plasma
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9 Conclusion
Antiretroviral treatment reduces the mortality and
the morbidity of HIV infection. The use of
antiretroviral therapy is associated with increasing
149
Advances in Biology, Bioengineering and Environment
reports of metabolic abnormalities such as body fat
abnormalities, impaired glucose metabolism and
insulin resistance, and dyslipidemia.
The modification of cardiovascular risk factors has
become an important aspect of HIV management.
All treatment strategies should emphasize
cardiovascular risk reduction, focusing particularly
on hypertension control, smoking cessation,
correction
of
glycemic
parameters,
and
dyslipidemia.
The treatment of cardiovascular risk factors in HIV
often involves polypharmacy, which increases the
risk of suboptimal adherence and may compromise
on long term basis the benefit of antiretroviral drugs.
This work was supported by CNCSIS –UEFISCSU,
project number PNII – IDEI code 2177/2008
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