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Infectious Diseases

Glucose Disorders Associated with HIV and Its Drug Therapy


Hlne Hardy, Lori D Esch, and Gene D Morse

OBJECTIVE:

To review the impact that factors such as HIV infection, antiretrovirals, and other commonly used drug therapies have
on glucose metabolism in HIV-infected patients.

DATA SOURCES: Pertinent literature was identified via a MEDLINE search from 1980 to April 2000 and through secondary sources
(abstracts presented at recent scientific meetings, manufacturers package inserts). The key words used were antiretroviral therapy,
HIV infection, insulin resistance, and metabolic abnormalities. All information deemed relevant to evaluate the impact that HIV
infection and drug therapy have on glucose metabolism in HIV-infected patients was included.
DATA SYNTHESIS: The viral burden and stress that are present in HIV-infected patients elicit a complex hormonal and immunologic
response that may alter various biochemical pathways, including glucose metabolism. Although rare before the era of potent
antiretroviral therapy, insulin resistance has now been described as an important component of the lipodystrophy syndrome. The
complex and multifactorial nature of glucose metabolism dysregulation makes management of hyperglycemia or diabetes mellitus
challenging in HIV-infected patients. In such a context, a set of recommendations was developed to guide practitioners in assessing,
treating, and monitoring hyperglycemia or diabetes mellitus in HIV-infected patients.
CONCLUSIONS:

Alterations of glucose metabolism observed in HIV-infected patients are more frequent since the introduction of
potent antiretroviral therapy. Although the etiology of such abnormalities remains unknown, protease inhibitors and, to a lesser
extent, nucleoside reverse transcriptase inhibitors are believed to participate in their pathogenic mechanisms. Because of
similarities to the pathogenesis of diabetes mellitus, management of antiretroviral-induced hyperglycemia could follow that the
recommendations of the American Diabetes Association, with special considerations for monitoring patients with HIV infection.
Future studies of altered glucose metabolism in HIV-infected patients should focus on understanding the precise mechanism or
causes of this complication so that preventive and therapeutic guidelines can be further evaluated.

KEY WORDS: antiretroviral therapy, human immunodeficiency virus, hyperglycemia.

Ann Pharmacother 2001;35:343-51.

etabolic and endocrine abnormalities have been noted


M
in patients infected with HIV, whether they were or
were not taking antiretroviral therapy. These abnormali1-4

ties include, but are not limited to, lipid and glucose homeostasis abnormalities and gonadal dysfunction. Most investigations preceding the institution of potent antiretroviral
therapy focused on the AIDS-associated wasting syndrome and its relationship to altered metabolism, as it represented an identifying characteristic of advancing HIV infection.5,6 The introduction of potent antiretroviral therapy
enabled clinicians to treat HIV-infected patients with drug
regimens capable of decreasing viral burden below the level
of assay quantification, enabling them to live longer, more
productive lives.7-9 However, as we progress into the era of
HIV as a chronic disease, additional clinical complications
Author information provided at the end of the text.

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such as diabetes mellitus and changes in fat distribution


have appeared.10 The pathogenesis of these abnormalities
is unknown and, although a direct effect of potent antiretroviral therapy is suspected, a primary metabolic effect
secondary to HIV infection, but which is intensified by antiretroviral therapy, remains under evaluation.
This article illustrates how alterations in glucose metabolism fit into the spectrum of metabolic abnormalities encountered in HIV-infected patients receiving, as well as
those not receiving, potent antiretroviral therapy. To do so,
pertinent information was derived from a review of the English-language medical literature with regard to the metabolic abnormalities associated with the lipodystrophy syndrome. This article also provides the reader with recommendations for the clinical management of hyperglycemia/
diabetes mellitus in HIV-infected patients undergoing potent antiretroviral therapy.

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Abnormalities in Glucose Metabolism Prior to


Potent Antiretroviral Therapy

to activate the hypothalamicpituitaryadrenal (HPA) axis


during inflammatory states and lead to the secretion of glucocorticoids (Table 1).15-17,19-32 The latter, in turn, down-regulates the secretion of these cytokines. In HIV-infected patients, the expression and production of several cytokines
including IL-1, TNF-, IL-6, and IFN-, are dysregulated,
potentially contributing to the metabolic disturbances observed in this population.19 Although the influence each
cytokine may have on lipid and glucose metabolism is not
clearly defined, it has been suggested that TNF-, IL-1,
and IFN- mediate the higher rate of fat oxidation and
FFA turnover observed in HIV-infected patients, and therefore contribute to the decreased glucose turnover observed
in this population.33,34
Although the above mentioned cytokines can activate
the HPA axis and lead to the release of cortisol, an insulin
antagonist hormone, the plasma concentrations of cortisol
are often only modestly elevated in HIV-infected patients,
even in the early stages of the disease.35,36 Interestingly, despite this mild hypercortisolism, the glucose concentrations
observed in HIV-infected patients have been reported to be
normal or low in the absence of potent antiretroviral thera-

Relatively few perturbations in glucose metabolism were


observed in HIV-infected patients before the era of potent
antiretroviral therapy.2 In general, most patients were found
to have normal or decreased glucose concentrations with
true increased insulin sensitivity.11,12
In contrast, a wide variety of abnormalities in lipid metabolism had been noted, including hypertriglyceridemia,
increased de novo hepatic lipogenesis, decreased lipoprotein
lipase (LPL) activity, and decreased low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol
concentrations.13-15 These lipid abnormalities were found to
be mostly a consequence of overproduction of very-lowdensity lipoproteins along with a tendency toward decreased triglycerides clearance, and were often reported,
although not exclusively, in wasted patients with uncontrolled HIV.13,14
To better understand glucose homeostasis in HIV-infected patients, the effects of prolonged fasting (16 and 22 h of
overnight fasting) on glucose and lipid metabolism were
evaluated in eight clinically stable HIV-infected patients and compared with seven healthy
volunteers.16 While plasma glucose concentrations decreased in both groups, fasting induced
Table 1. Cytokine-Mediated Alterations in Glucose Metabolism
a significantly greater decline in glucose turnEffect on Glucose Metabolism
over (i.e., glucose uptake and/or oxidation) and
Cytokine
Direct
Indirecta
significantly increased fat oxidation in HIV-inTNF-b substrates for hepatic
plasma triglyceride concentration
fected patients when compared with the congluconeogenesis secondary
by stimulating hepatic lipogenesis,
trol subjects (both p = 0.01). Interestingly, the
to flux of glycerol to liver,
stimulating the production of VLDL,
concentrations of insulin and its counter-regu hepatic amino acid uptake
and rapidly mobilizing FFA
serum lactate15
secondary to stimulation of
latory hormones (glucagon, catecholamines)
activates HPA axis and thereperipheral lipolysis21,22
were not different among patients, suggesting
fore increases secretion of
that the greater decline in glucose turnover obglucocorticoids19,20
served in HIV-infected patients is related to inIL-1
stimulation of glucocorticoids
LPL activity and production of
release by stimulating hypolipolysis24,25
creased free fatty acid (FFA) oxidation. In light
thalamic CRF secretion19,20,23
of such findings, it appears that HIV infection
enhancement of hepatic
affects glucose metabolism in a clearly differgluconeogenesis15,17
ent way than other catabolic diseases (e.g., sepIL-6
important mediator of the
LPL activity in vitro and in vivo28
acute
phase
response
promotion of fatty acid synthesis28
sis), in which increased glucose turnover, hyperactivation of HPA axis; thereglycemia, and insulin resistance can be found.
fore, increased secretion of
glucocorticoids17,19,20,26,27
IFN-

CYTOKINE AND HORMONAL INVOLVEMENT IN


METABOLIC DYSREGULATION

Although the mechanisms underlying these


metabolic abnormalities remain unclear, a complex interaction of cytokines and/or hormonal
factors is believed to actively participate in
mediating them.17-19 The neuroendocrine system and the immune system appear to be interrelated via a bidirectional network through
which immune responses influence hormone
responses and, in turn, hormones modulate immune responses.20 Tumor necrosis factor alfa
(TNF-), interleukin-1 (IL-1), interleukin-6 (IL6), and interferon-alfa (IFN-) have been shown
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plasma glucose29
glucagon concentration29
insulin concentration
participation in insulin
resistance29

hypertriglyceridemia strongly correlated with IFN- concentrations30,31

CRF = corticotropin-releasing factor; FFA = free fatty acids; HPA axis = hypothalamicpituitaryadrenal axis; IFN- = interferon alfa; IL-1 = interleukin-1; IL-6 = interleukin-6; LPL = lipoprotein lipase; TNF- = tumor necrosis factor alfa; VLDL =
very-low-density lipoprotein.
a
The indirect effect of cytokines on glucose metabolism mainly consists of alteration of lipid metabolism. Increased lipogenesis can prevent hepatic oxidation of
fatty acids and increase re-esterification of triglycerides, leading to hypertriglyceridemia, which results in the development of glucose intolerance and, in some patients, insulin resistance.
b
During inflammatory states, TNF- is secreted first and promotes the cellular secretion of IL-1. The release of both cytokines leads to the secretion of IL-6, which in
turn acts in conjunction with glucocorticoids to elicit the production of many mediators of the acute-phase response by the liver.16,32

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Hyperglycemia and HIV

py.11 A reduced peripheral sensitivity to cortisol may be


partially responsible for this lack of metabolic response,
simulating a glucocorticoid-deficient state.37 Few data are
available on how, in the absence of potent antiretroviral
therapy, HIV infection impacts the regulation of the other
insulin antagonist hormones, glucagon and catecholamines.
The regulation of glucagon and catecholamines in stable,
symptomatic HIV-infected patients may not be different
than in healthy individuals in a fasting state, but their impact
on the regulation of glucose metabolism is likely to differ.16
DRUG-INDUCED GLUCOSE ALTERATIONS IN HIV

Although HIV-induced metabolic alterations appear responsible for some cases of hyperglycemia before the antiretroviral era, most of the cases were related to medications commonly taken by HIV-infected patients.
Glucocorticoids are known to cause hyperglycemia
through the promotion of gluconeogenesis in the liver and
decreased use of glucose in muscle, adipose tissue, and
lymphatic tissues. The development of glucose intolerance
associated with the use of glucocorticoids is likely due to
peripheral insulin resistance secondary to a reduction of
the number and affinity of insulin receptors, and its intensity is dependent on the dosage and duration of therapy.38,39
When the use of glucocorticoids is required, the dose should
be tapered to the smallest effective dose, and diet modification with or without the use of oral hypoglycemic agents
or insulin therapy should be considered. Patients should be
monitored closely for manifestations of pancreatitis.
Megestrol acetate, used for appetite stimulation, has structural similarities to glucocorticoids, and therefore its mechanism for causing peripheral insulin resistance is likely
secondary to a reduction of the number and affinity of insulin receptors, similar to the proposed mechanism for glucocorticoids.40-43 The majority of hyperglycemic episodes
are reversible on discontinuation of megestrol acetate, and
dronabinol can be substituted if necessary. If megestrol acetate must be continued, insulin can be added to the regimen for as long as megestrol acetate is required.44,45
Pentamidine, a drug used for prevention and treatment
of Pneumocystis carinii pneumonia, can be directly toxic to
the pancreas, inducing extensive islet necrosis. Consequently, its use can be initially associated with hypoglycemia
due to extensive insulin release and later associated with
hyperglycemia due to the loss of pancreatic function.46,47
Most cases of hyperglycemia have been reported with the
injectable rather than the aerosolized formulation of pentamidine.48 If hyperglycemia is mild, diet modification with
possible insulin therapy can be considered; however, if severe hyperglycemia occurs, discontinuation of pentamidine and initiation of insulin therapy are usually required.49
Alterations in Glucose Metabolism
Associated with Potent Antiretroviral Therapy
Since the introduction of potent antiretroviral therapy,
the frequency of metabolic abnormalities has significantly
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increased in HIV-infected patients.10 Fat redistribution,


changes in serum lipid profiles, insulin resistance, and diabetes mellitus, collectively termed the HIV-associated lipodystrophy syndrome, have been reported most often in patients taking protease inhibitors (PIs) as part of their combination antiretroviral therapy.10,50,51
The prevalence of HIV-associated lipodystrophy syndrome is estimated to be between 2% and 83% in patients
taking PIs; however, difficulties exist in estimating prevalence due to lack of standardized case definition of the syndrome. Recently, the reverse transcriptase inhibitors have
also been implicated in the development of the lipodystrophy syndrome, although lipid and glycemic parameters, as
well as insulin concentrations, appear to be altered minimally in comparison with PI-associated lipodystrophy syndrome.50,51 The large variation in the clinical presentation
of this syndrome emphasizes the complexity of its pathogenesis.
PROTEASE INHIBITORASSOCIATED ALTERATIONS IN
GLUCOSE METABOLISM

The alterations of glucose metabolism associated with


the lipodystrophy syndrome vary largely in the severity of
their presentation, ranging from mild glucose intolerance
to frank diabetes mellitus.52-56 The incidence of diabetes
mellitus reported in the presence of the PI-associated lipodystrophy syndrome ranges from 2% to 10%, compared
with 6% in the general population, and is characterized by
a delayed onset after initiation of PI therapy (average 710
mo).55,57,58 All PIs currently available have been implicated
in the development of diabetes mellitus.52,53,56,59-62 Interestingly, no causal relationship has yet been confirmed between the use of PIs and the development of hyperglycemia or diabetes mellitus because most studies evaluating
their relationship have been cross-sectional in nature or of
small sample size.
A recent longitudinal study63 in a group of 20 HIV-infected patients evaluated the effect that initiation of PI therapy had on glucose and lipid metabolism, as well as fat
distribution. Twenty patients initiating a PI-containing regimen were compared with nine patients starting lamivudine and 12 control patients who were continuing on stable
regimens or were nave to antiretroviral therapy. Significant increases in glucose, insulin, triglycerides, total
cholesterol, and LDL cholesterol concentrations were noted in patients beginning PI therapy after a follow-up period
of 3.4 0.5 (mean SD) months, whereas no such increases were noted in patients beginning therapy with
lamivudine or in patients in the control group.
The study was unable to evaluate whether changes in
glucose and lipid metabolism were a direct effect of PI
therapy. Since a greater proportion of patients in the PI
group achieved undetectable concentrations of HIV at the
end of the follow-up period, it is possible that an indirect
effect of PI therapy (i.e., virologic suppression and subsequent immune reconstitution) confounded these results and
contributed to the development of metabolic abnormalities

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in this group.63 Indeed, it has been suggested1,63,64 that, by


favoring immune reconstitution, PI therapy may induce elevation of specific cytokines, such as TNF- and IL-1, capable of enhancing de novo lipogenesis and consequently
participating in the progressive development of insulin resistance.
Proposed Mechanisms of
PI-Associated Metabolic Dysregulation

Although the mechanism responsible for the development of insulin resistance in patients on PI therapy remains
unknown, two potential mechanisms have been described.65,66
The first hypothesized that due to a 60% homology between
the HIV-1 catalytic site and lipoprotein receptorrelated
protein (LRP), PIs could bind to the LRP-LPL complex on
vascular endothelium, impairing chylomicron uptake and
triglyceride clearance.65 The resulting hyperlipidemia would
participate in the development of insulin resistance by allowing a competition between glucose and lipid oxidation
pathways in skeletal muscles, interference of lipids with
post-receptor signaling insulin, or inhibition of glycogen
synthase. However, since low LPL activity has been described in HIV-infected patients well before the introduction of PIs, PI therapy would be expected only to worsen
preexisting lipid abnormalities rather than induce them.4
Since the constellation of metabolic abnormalities observed in the lipodystrophy syndrome resembles that in
type 2 diabetes mellitus, the mechanism responsible for the
development of insulin resistance may mimic the pathogenesis in type 2 diabetes mellitus.66 Several mechanisms
are known to lead to peripheral insulin resistance in type 2
diabetes mellitus, including reduced binding of insulin to
its receptors, alterations in intracellular pathways, and defective cellular uptake of glucose.66,67 In such a context, the
initial decrease in insulin sensitivity would most likely be
compensated by an increased secretion of insulin by the cells of the pancreas, resulting in a hyperinsulinemic state
and normal glucose tolerance. The inability of the pancreas
to maintain hyperinsulinemia would result in severe hyperglycemia and hyperlipidemia secondary to the inability of
insulin to maintain FFA concentration within a normal
range.68 As an extension to this proposed mechanism,
some authors have suggested that, as in extreme cases of
type 2 diabetes, the greater demand placed on pancreatic
-cells by insulin resistance may lead to a progressive loss
of -cell function in the pancreas and, therefore, progression from impaired glucose tolerance to diabetes mellitus.69,70 This finding remains controversial, and further direct measurement of -cell dysfunction is required to support this hypothesis.58,71
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR
ASSOCIATED GLUCOSE METABOLISM ALTERATIONS:
MITOCHONDRIAL TOXICITY

Although the lipodystrophy syndrome has been described in patients on nucleoside reverse transcriptase in346

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hibitor (NRTI)containing regimens, its presentation appears


to be different than in patients taking PIs.72-74 Generally,
lipid and glucose metabolism, as well as insulin regulation,
are often minimally altered, whereas increased lactate concentrations and altered hepatic function are more common.
Fat redistribution appears to be seen as frequently as in patients on PI therapy; however, it is mostly characterized by
lipoatrophy, in particular with stavudine.72,75,76
Mitochondrial toxicity is believed to be responsible for
the development of metabolic abnormalities seen in patients on NRTI therapy.77 Once phosphorylated to their active form, NRTIs can specifically bind to the DNA polymerase gamma, the only human polymerase involved in
mitochondrial DNA synthesis. By binding with various
degrees of affinity to this enzyme, NRTIs inhibit mitochondrial DNA synthesis and therefore alter mitochondrial
functioning, in particular mitochondrial oxidative phosphorylation, leading to decreased production of adenosine
triphosphate production, a crucial substrate for energy-requiring reactions within cells. Although very little data are
available on NRTI-associated impaired glucose tolerance,
NRTI-induced mitochondrial toxicity may induce an increased apoptosis of peripheral adipocytes, resulting in
lipoatrophy and hypertriglyceridemia.78 In such a context,
insulin resistance could develop secondary to reduced uptake of fat and glucose in the affected adipocytes.
Future Perspectives
Further research is needed to fully understand the effect
of potent antiretroviral therapy on alterations of glucose
metabolism observed in HIV-infected patients. Indeed, no
single mechanism has been found to clearly account for
the development of glucose intolerance, hyperglycemia, or
diabetes mellitus in this population. Insulin resistance appears to be a fundamental metabolic abnormality of this
syndrome as it is in Syndrome X, which is characterized
by fat redistribution (central/visceral obesity) and metabolic abnormalities (hyperlipidemia, insulin resistance). This
resemblance to Syndrome X is worrisome since this syndrome is associated with an increased risk for coronary
artery disease.
To strengthen the external validity of future studies and
assist in the development of a standardized case definition,
a number of factors should be considered. First, large, longitudinal, controlled multicenter studies would assist in
overcoming the limitations of small sample-size, crosssectional studies. Complete medication histories are essential in order to rule out hyperglycemia induced by drugs
other than antiretrovirals. Other potential contributing factors such as time since HIV diagnosis, time on antiretroviral therapy, age, weight, and family history of diabetes
should always be included. Further studies should also
evaluate the impact that immune reconstitution or decreased HIV replication associated with successful antiretroviral therapy may have on metabolic abnormalities.
Finally, in light of the complex multifactorial process responsible for the lipodystrophy syndrome and its glucose

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Hyperglycemia and HIV

abnormalities, it is critical that multivariate analyses be included in all study designs.


Recommendations for the Management of
Altered Glucose Metabolism

ASSESSMENT OF GLUCOSE METABOLISM

Although the frequency of hyperglycemia and/or diabetes mellitus has significantly increased in HIV-infected
patients since the introduction of potent antiretroviral therapy, this metabolic complication remains rare.55 The paucity of data regarding definitive factors for hyperglycemia
and optimal treatment options has made the development
of management guidelines difficult and has led most physicians to treat cases of severe hyperglycemia or frank diabetes mellitus independently, based on personal clinical experience. In this context, it is crucial to develop treatment
and monitoring recommendations for management of hyperglycemia in HIV-infected patients. A set of recommendations for assessment, treatment, and monitoring of glucose metabolism abnormalities encountered in HIV-infected patients on potent antiretroviral therapy is proposed
here based on the American Diabetes Association Guidelines.79,80
BASELINE EVALUATION

Risk Factors

In attempts to evaluate the association between antiretroviral therapy and abnormalities in glucose metabolism, baseline parameters must be obtained. Age, duration
of antiretroviral therapy, stage of HIV infection, and gender have been associated with an increased risk of development of the lipodystrophy syndrome; however, the subpopulation of HIV-infected patients on antiretroviral therapy at risk for developing altered glucose metabolism has
yet to be identified. In type 2 diabetics, central obesity, age,
sedentary lifestyle, hypertension, dyslipidemia, and specific medications (glucocorticoids, valproate, fluoxetine, progestin) have been identified as risk factors for the development of insulin resistance in the general population.80 By
homology with the general population, the subpopulation
of HIV-infected patients at risk for developing insulin resistance can be defined using the same risk factors, with
additional factors being PI therapy, family history of diabetes, as well as medications such as megestrol acetate and
pentamidine.
Baseline Glucose Monitoring

A baseline fasting plasma glucose (FPG) concentration


should be obtained in all patients at risk for developing insulin resistance. Patients with an FPG concentration <126
mg/dL should be monitored every three to six months with
random plasma glucose concentration tests once protease
inhibitor therapy is initiated. If the random plasma glucose
concentration is <200 mg/dL, it is recommended to continue monitoring plasma glucose every three to six months. If
the random plasma glucose concentration is >200 mg/dL,
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the patient should be assessed and treated with a steppedcare approach similar to patients with a baseline FPG of
126200 mg/dL.

ABNORMALITIES

Potent antiretroviral therapy can be extremely complex,


often requiring adherence to regimens with considerable
pill burden, adverse effects, and drug interactions. Consequently, it is crucial to establish a differential diagnosis and
assess the role of other contributing factors in inducing abnormalities in glucose metabolism before further complicating a patients regimen with hypoglycemic agents.
As reviewed earlier, a number of medications other than
antiretroviral agents have been associated with the development of hyperglycemia. Such abnormalities can sometimes be managed by withdrawal of the causative agent
and diet modification, and may not require the introduction
of hypoglycemic agents.56 It is also important to assess patients adherence to antiretroviral therapy when establishing a differential diagnosis since, if a patient is grossly
nonadherent to antiretroviral therapy, the likelihood of PIassociated hyperglycemia is unlikely. Family history of diabetes, as well as the patients risk factors for diabetes mellitus (age, central obesity while off antiretroviral therapy,
sedentary lifestyle, hypertension, hyperlipidemia) should
also be considered when establishing a differential diagnosis. Finally, if all other causes of glucose metabolism abnormalities have been ruled out, antiretroviral therapy may
be considered as a potential cause. In this context, we recommend that therapeutic interventions be based on a
stepped-care approach.
TREATMENT OF GLUCOSE METABOLISM ABNORMALITIES

Since insulin resistance plays such a central role in the


glucose metabolism abnormalities encountered in HIV-infected patients on potent antiretroviral therapy, drug therapy should aim at improving insulin sensitivity.
Diet and Exercise

The initial management approach applies to all HIV-infected patients with hyperglycemia or diabetes mellitus
who are receiving antiretroviral therapy regardless of their
virologic and immunologic status. It is recommended that
aerobic physical activity be increased, since it favors the
development of lean muscle mass, reduces triglyceride
concentrations, and is particularly effective in reducing abdominal fat.81 Diabetic HIV-infected patients with dyslipidemia should also follow the dietary recommendations of
the National Cholesterol Education Program.82 If glucose
control has been achieved after eight weeks, it is recommended to monitor FPG every three to six months. If diet
and exercise fail to achieve the desired level of glucose
control after eight weeks, pharmacologic intervention
should be considered.

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Pharmacologic Interventions

Since abnormalities in glucose metabolism encountered


in HIV-infected patients on antiretroviral therapy resemble
those seen in type 2 diabetes mellitus, it is reasonable to
apply the recommendations from the American Diabetes
Association standard of medical care for patients with diabetes mellitus to HIV patients.
Because viral suppression remains the primary objective
of the medical care for HIV patients, discontinuing antiretroviral therapy to achieve glucose control is not usually
desirable. Recent data83,84 suggest that switching from a PIbased regimen to a simplified triple NRTI combination
containing abacavir maintains viral suppression, tends to
lower triglycerides and cholesterol concentrations, and improves insulin sensitivity; however, longer follow-up periods are needed before this can be recommended in patients
who develop insulin resistance. Switching patients to a
non-NRTI-based regimen has also been attempted with
some success.83,84 However, HIV-infected patients with
mild to moderate hyperglycemia (FPG 126 200 mg/dL)
should be started on monotherapy with an oral hypoglycemic agent.
Metformin. Recent data85,86 in HIV-infected patients suggest that metformin holds the greatest short-term promise
among the insulin-sensitizing agents because it is effective
in controlling hyperglycemia and can favorably influence
the metabolic abnormalities frequently associated with insulin resistance. Although preliminary, these results are interesting because they are similar to those described on
metformin use in non-HIVinfected patients with type 2
diabetes mellitus. In this population, metformin has been
shown85 to improve peripheral and hepatic sensitivity to insulin by decreasing hepatic glucose production and increasing peripheral glucose disposal. In addition, it shows
a modest beneficial effect on lipid profile (decreased triglyceride and LDL cholesterol concentrations, increased
HDL cholesterol concentrations) and is associated with a
modest weight loss.
Since metformin is not metabolized by the liver, no
risks of drug interactions with PIs exist. Most drugs with
which metformin may interact are cationic drugs (cimetidine, ranitidine, vancomycin, trimethoprim, morphine),
which can lead to an increased plasma concentration of
metformin.87 A concern with using metformin in the HIV
population is that its gastrointestinal adverse effects can
add to those associated with antiretroviral therapy. In addition, although rare, lactic acidosis is an adverse effect of
metformin that might be exacerbated in patients taking
NRTIs, since the mitochondrial toxicity of these agents
and lactic acidosis are clearly linked.88 Finally, metformin
is contraindicated in patients with congestive heart failure
or renal dysfunction (serum creatinine >1.4 mg/dL in
women; >1.5 mg/dL in men) because of the increased risk
of lactic acidosis in these patients.
Thiazolidinediones. The thiazolidinediones, rosiglitazone and pioglitazone, also referred to as insulin sensitizers, have been shown to improve glucose and lipid home348

The Annals of Pharmacotherapy

ostasis in patients with type 2 diabetes.88 They act by


restoring the ability of insulin to suppress hepatic glucose
output, increasing peripheral glucose disposal, and reducing plasma triglycerides and FFA concentrations. Although
the thiazolidinediones are effective in the treatment of type
2 diabetes, no data are yet available on their efficacy in
HIV-infected patients, especially in light of their potential
liver toxicity. Troglitazone, the first marketed thiazolidinedione for the treatment of type 2 diabetes, was withdrawn
from the market by the Food and Drug Administration secondary to severe liver toxicity reported in non-HIVinfected diabetic patients.89 Although rosiglitazone and pioglitazone are considered less toxic to the liver, two recent case
reports90,91 describe episodes of hepatic failure and hepatocellular injury in patients taking rosiglitazone. In light of
these reports, caution should be taken when these agents
are being used in HIV-infected patients.
Another concern with using these agents in HIV-infected patients is the risk of potential drug interactions. The
major cytochrome P450 isoenzymes involved in the hepatic metabolism of pioglitazone are CYP2C8 and CYP3A4.
Specific pharmacokinetic studies have not been conducted
with pioglitazone and most other drugs metabolized by
CYP3A4. However, in vitro studies92 suggest that pioglitazone is likely to interact with drugs metabolized by CYP3A4,
such as the PIs. Rosiglitazone, in contrast, is predominantly metabolized by CYP2C8; therefore, the risk for interaction with PIs is minimal.93 Further studies are needed to
evaluate the role that thiazolidinediones may play in the
treatment of hyperglycemia in HIV-infected patients. A
study in development by the AIDS clinical trials group
plans to evaluate rosiglitazone in patients with elevated insulin concentrations and abdominal obesity. Patients will
be randomized to receive rosiglitazone, metformin, or a
combination of both.
Combination Hypoglycemic Agents. If FPG targets of
<150 mg/dL are not achieved with monotherapy or if FPG
ranges between 200 and 300 mg/dL are not achieved despite exercise and diet, oral combination therapy consisting
of a sulfonylurea with metformin or a thiazolidinedione
should be considered. The second-generation sulfonylureas, such as glipizide and glimepiride, may have an advantage, as their duration of action permits once-daily dosing and may potentially improve patient adherence.
However, as with thiazolidinediones, caution should be
exercised when sulfonylureas are used in addition to a PIcontaining regimen because of the potential risk of drug interactions since they are metabolized hepatically. Ritonavir
as well as nelfinavir have moderate inhibitory effects on
CYP2C9; therefore, they may be responsible for increasing plasma concentrations of glyburide, glipizide, and tolbutamide, which are substrates of CYP2C9.
Insulin Therapy. Finally, in patients who are severely
hyperglycemic at baseline (baseline FPG concentration
>300 mg/dL) and who are either symptomatic or have ketonuria or ketonemia, insulin therapy alone or in combination with an oral hypoglycemic agent such as metformin
should be used if the insulin regimen is not working suffi-

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Hyperglycemia and HIV

ciently. Thiazolidinediones can be used with insulin as


well; however, close monitoring for hypoglycemia as well
as significant weight gain is advised.
MONITORING OF GLUCOSE METABOLISM ABNORMALITIES

HIV-infected patients treated for hyperglycemia or diabetes mellitus should be monitored in a similar manner as
non-HIVinfected patients with hyperglycemia or diabetes
mellitus once glucose control is achieved. FPG concentrations as well as glycosylated hemoglobin (HbA1c) should
be incorporated into patients routine care. HbA1c should
be obtained two to four times a year for tracking long-term
glucose control with the goal of preventing micro- and
macrovascular complications. FPG concentrations should
be measured every three to six months. In addition, home
glucose monitoring should be considered to guide pharmacotherapeutic changes. Home glucose monitoring should
be performed once a day in patients with well-controlled
glucose concentrations, varying the time from fasting, to
postprandial, to bedtime. In other patients, home glucose
monitoring should be done before each meal, postprandially, and at bedtime.
Summary
Although the pathogenic mechanisms responsible for
abnormalities in glucose metabolism in HIV-infected patients are not fully elucidated, potent antiretroviral therapy
is believed to play a central role in their development. Insulin resistance appears to be a fundamental abnormality
of these metabolic alterations, and its degree of severity
can vary widely among patients. Because of similarities to
the pathogenesis of diabetes mellitus, management of antiretroviral-induced hyperglycemia could follow those
guidelines recommended by the American Diabetes Association, with special considerations for monitoring patients
with HIV infection. Larger, multicenter, controlled trials
are needed to better understand the mechanism of altered
glucose metabolism in HIV patients and to define the subpopulation of HIV-infected patients at risk for hyperglycemia or diabetes mellitus.
Hlne Hardy PharmD, Clinical Pharmacist Specialist, Infectious
Diseases, New England Medical Center, Boston, MA
Lori D Esch PharmD, Clinical Assistant Professor, Department of
Pharmacy Practice, University at Buffalo, Buffalo, NY; Antiviral Clinical Pharmacology Unit, Immunodeficiency Services, HIV Pharmaceutical Care Specialist, Erie County Medical Center, Buffalo
Gene D Morse PharmD, Professor and Chairman, Associate Dean,
Clinical Education and Research, Department of Pharmacy Practice, University at Buffalo
Reprints: Lori D Esch PharmD, BB110 SUNY Clinical Center, Erie
County Medical Center, 462 Grider St., Buffalo, NY 14215, FAX
716/898-3187, E-mail lswick@acsu.buffalo.edu

References
1. Kotler DP, Rosenbaum K, Wang J, Pierson RN. Studies of body composition and fat distribution in HIV-infected and control subjects. J Acquir
Immune Syndr Human Retrovirol 1998;20:228-37.

www.theannals.com

2. Grinspoon SK, Bilezikian JP. HIV disease and the endocrine system. N
Engl J Med 1992;327:1360-5.
3. Grinspoon SK. Metabolic complications of ARVT. Topics HIV Med
1999;(Oct):14-9.
4. Sellmeyer DE, Grunfeld C. Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocrine Rev 1996;17:518-32.
5. Mhiri C, Belec L, Di Costanza B, Georges A, Gherardi R. The slim disease in African patients with AIDS. Trans R Soc Trop Med Hyg 1992;
86:303-6.
6. Kotler DP, Wang J, Pierson RN. Body composition studies in patients
with AIDS. Am J Clin Nutr 1985;42:1255-65.
7. Perelson AS, Essunger P, Cao Y. Decay characteristics of HIV-1 components during combination therapy. Nature 1997;387:188-91.
8. Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE,
Kalams SA, et al. Vigorous HIV-1 specific CD4 T-cell responses associated with control of viremia. Science 1997;278:1447-50.
9. Patella FJ, Delanney KM, Moorman AC, Loveless MO, Fuhrer J, Satten
GA, et al. Declining morbidity and mortality among patients with advanced HIV infection. N Engl J Med 1998;338:853-60.
10. Safrin S, Grunfeld C. Fat distribution and metabolic changes in patients
with HIV infection. AIDS 1999;13:2493-505.
11. Hommes MJT, Ramijn JA, Endert E, Sauerwein HP, Eeftinck Schattenkerk JK. Insulin sensitivity and insulin clearance in human immunodeficiency virusinfected men. Metabolism 1991;40:651-6.
12. Heylingenber R, Romijn JA, Hommes MJT, Endert E, Eeftinck Schattenkerk JKM, Sauerwein HP. Non-insulin mediated glucose uptake in
human immunodeficiency virusinfected men. Clin Sci 1993;84:209-16.
13. Hellerstein MK, Grunfeld C, Wu K, Christiansen M, Kaempfer S, Kletke
C, et al. Increased de novo hepatic lipogenesis in HIV infection. J Clin
Endocrinol Metab 1993;76:559-65.
14. Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR.
Lipids, lipoproteins, triglycerides clearance and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992;74:1045-52.
15. Grunfeld C, Kotler DP, Hamadeh R, Tierney A, Wang J, Pierson RN.
Hypertriglyceridemia in the acquired immunodeficiency syndrome. Am
J Med 1989;86:27-31.
16. Hommes MJT, Romijn JA, Endert E, Eeftinck Schattenkerk JKM,
Sauerwein HP. Basal fuel homeostasis in symptomatic human immunodeficiency virus infection. Clin Sci 1991;80:359-65.
17. Grunfeld C, Feingold KR. The metabolic effects of tumor necrosis factor
and other cytokines. Biotherapy 1991;3:143-58.
18. Chang HR, Dulloo AG, Bistrian BR. Role of cytokines in AIDS wasting.
Nutrition 1998;14:853-63.
19. Poli G, Fauci AS. The role of monocyte/macrophages and cytokines in
the pathogenesis of HIV infection. Pathophysiology 1992;60:246-51.
20. Gaillard RC. Cytokines in the neuroendocrine system. Intern Rev Immunol 1998;17:181-216.
21. Feingold KR, Grunfeld C. Tumor necrosis factor alpha stimulates hepatic lipogenesis in the rat in vivo. J Clin Invest 1987;80:184-90.
22. Semb H, Peterson J, Tavernier J, Olivecrona T. Multiple effects of tumor
necrosis factors on the lipoprotein lipase in vivo. J Biol Chem 1987;62:
8390- 4.
23. Savastano S, Tommaselli AP, Valentino R, Scarpitta MT, Damore G,
Luciano A, et al. Hypothalamicpituitaryadrenal axis and immune system. Acta Neurologica 1994;16:206-13.
24. Gaillard RC. Pituitaryimmune system interactions. In: Melmed S, ed.
Molecular and clinical advances in pituitary disorders. A basic and clinical update. Beverly Hills: Endocrine Research and Education, 1993:8792.
25. Besedovosky H, Del Rey A, Sorkin E, Dinarello CA. Immuno-regulatory feedback between interleukin-1 and glucocorticoid hormones. Science
1986;233:652- 4.
26. Grunfeld C, Feingold KR. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med 1992;327:329-37.
27. Feingold KR, Soued M, Serio MK. Multiple cytokines stimulate hepatic
synthesis in vivo. Endocrinology 1989;125:267-74.
28. Feingold KR, Grunfeld C. Role of cytokines in inducing hyperlipidemia.
Diabetes 1992;41(suppl 2):97-101.
29. Van Snick J. Interleukin-6: an overview. Ann Rev Immunol 1990;8:25378.
30. Martinez-Maza O. IL6 and AIDS. Res Immunol 1992;143:764-9.

The Annals of Pharmacotherapy


Downloaded from aop.sagepub.com by Fernanda MIreles on August 20, 2016

2001 March, Volume 35

349

H Hardy et al.
31. Koivisto VA, Pelkonen R, Cantell K. Effect of interferon on glucose tolerance and insulin sensitivity. Diabetes 1989;38:641-7.
32. Grunfeld C, Shigenaga JK, Doerrler W, Tierney A, Wang J, Pierson RN,
et al. Circulating interferon-alpha level and hypertriglyceridemia in the
acquired immunodeficiency syndrome. Am J Med 1991;90:154-62.
33. Evans RD, Argiles JM, Williamson DH. Metabolic effects of tumor
necrosis factor-alpha (cachectin) and interleukin-1. Clin Sci 1989;77:
357-64.
34. Patton JS, Shepard HM, Wilking H. Interferons and tumor necrosis factor have similar catabolic effects on 3TC-L1 cells. Proc Natl Acad Sci
1986;83:8313-7.
35. Miller KK, Daly PA, Sentochnik D, Doweiko J, Samore M, Basgoz NO,
et al. Pseudo-Cushing syndrome in human immunodeficiency virus
infected patients. Clin Infect Dis 1998;27:68-72.
36. Azar S, Melby J. Hypothalamicpituitaryadrenal function in non-AIDS
patients with advanced HIV infection. Am J Med Sci 1993;305:321-5.
37. Norbiato G, Bevilacqua M, Vago T, Baldi E, Chebat P, Bertora M, et al.
Cortisol resistance in acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992;74:608-13.
38. Chang JC, Cockran CS. Drug-induced disturbances of carbohydrate metabolism. Adverse Drug React Toxicol Rev 1991;10:1-29.
39. Seale JP, Compton MR. Side-effects of corticosteroid agents. Med J Aust
1986;144:139- 42.
40. Gonzalez Del Valle L, Ambrosio AH, Hernandez PM, Diaz BG, Caballero EJ. Hyperglycemia induced by megestrol acetate in a patient with
AIDS. Ann Pharmacother 1996;30:1113- 4.
41. Siminoski K, Drucker DJ, Goss P. The Cushing syndrome induced by
medroxyprogesterone acetate. Ann Intern Med 1989;111:758-60.
42. Pandit MK, Burke J, Gustafon AB, Minochu A. Drug-induced disorders
of glucose intolerance. Ann Intern Med 1993;118:529-39.
43. Henry K, Rathgaber S, Sullivan C, McCabe K. Diabetes mellitus induced by megestrol acetate in a patient with AIDS and cachexia. Ann Intern Med 1992;116:53- 4.
44. Schwartz MS, Brandt LJ. The spectrum of pancreatic disorders in patients with AIDS. Am J Gastroenterol 1989;84:459-62.
45. Kilby JM, Tabereaux PB. Severe hyperglycemia in an HIV clinic: preexisting versus drug-associated diabetes mellitus. J Acquir Immune Syndr
Human Retrovirol 1998;17:46-50.
46. Chen JP, Braham RL, Squires KE. Diabetes after aerosolized pentamidine. Ann Intern Med 1991;114:913- 4.
47. Shen M, Orwell ES, Cohn SE, Prince MJ. Pentamidine-induced pancreatic beta-cell dysfunction. Am J Med 1989;86:726-8.
48. Monk JP, Benfield P. Inhaled pentamidine: an overview of its pharmacological properties and a review of its use in PCP. Drugs 1990;39:741-56.
49. Ravaux I, Rihet P, Quinson AM, Mars ME, Sellier P, Gallais H. Relapse
of pentamidine-induced diabetes in AIDS patients (abstract Mo.B.1189).
In: Program and abstracts of the 11th World AIDS Conference, Vancouver, June 28July 31, 1996.
50. Vigouroux C, Gharakhanian S, Salhi Y, Nguyen TH, Adda N, Rozenbaum W, et al. Adverse metabolic disorders during highly active antiretroviral treatments of HIV disease. Diabetes Metab 1999;25:383-92.
51. Qaqish RB, Fisher E, Rubbein J, Wohl DA. HIV-associated lipodystrophy syndrome. Pharmacotherapy 2000;20:13-22.
52. Visnegarwala F, Frause KL, Musher DM. Severe diabetes associated
with protease inhibitor therapy (letter). Ann Intern Med 1997;127:947.
53. Eastone JA, Derker CF. New-onset diabetes mellitus associated with use
of protease inhibitors (letter). Ann Intern Med 1997;127:948.
54. Dong BJ, Gruta CI, Legg JJ. Diabetes and use of protease inhibitors (abstract). In: Program and abstracts of the 12th World AIDS Conference,
Geneva, June 28July 31, 1998.
55. Carr A, Samaras K, Thorisdottir A, Kaufman GR, Chisholm DJ, Cooper
DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitorassociated lipodystrophy, hyperlipidemia, and diabetes mellitus:
a cohort study. Lancet 1999;353:2093-9.
56. Dube MP, Johnson DL, Currier JS, Leedom JM. Protease inhibitorassociated hyperglycemia (letter). Lancet 1997;350:713- 4.
57. Gharakhanian S, Salhi Y, Nguyen H, Adda N, Catrix S, Vigouroux C, et
al. Frequency of lipodystrophy and factors associated with glucose/lipid
abnormalities in a cohort of 650 patients treated by protease inhibitors
(abstract 642). 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31February 4, 1999.
58. Martinez E, Garcia MA, Conget I, Buira E, Blanco JL, Mallolas J, et al.
Incidence, characteristics, and prognosis of diabetes mellitus associated
with protease inhibitors. 7th Conference on Retroviruses and Oppor-

350

The Annals of Pharmacotherapy

59.
60.

61.
62.

63.

64.

65.

66.

67.

68.
69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

tunistic Infections (abstract 16). San Francisco, January 30February 2,


2000.
Paterson DL. Exacerbated hyperglycemia associated with nelfinavir.
Ann Pharmacother 1998;32:609-10.
Dube MP, Johnson DLJ, Currier JSC, Leedom JML. Protease inhibitor
associated hyperglycemia: results of switching from indinavir to nelfinavir (abstract 32172). 12th World AIDS Conference, Geneva, June
28July 3, 1998.
Data on file, GlaxoWellcome Inc. (RM 1998/00318/00 integrated summary of safety).
Pedneault L, Hanson C, Nacci P. Amprenavir: a new protease inhibitor
with a favorable metabolic profile (abstract 34). 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Diego,
June 2628, 1999.
Mulligan K, Grunfeld C, Tai VW, Algren H, Pang M, Chernoff DN. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Syndr Human Retrovirol 2000;23:35- 43.
Al-Harthi L, Roebuck KA, Kessler H, Landay A. Inhibition of cytokinedriven human immunodeficiency virus type I replication by protease inhibitor. J Infect Dis 1997;176:1175-9.
Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of HIV-1protease inhibitorassociated peripheral lipodystrophy, hyperlipidemia,
and insulin resistance. Lancet 1998;351:1881-3.
Walli R, Herfort O, Michl GM, Demant T, Jager H, Dieterle C, et al.
Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients.
AIDS 1998;12:F167-73.
Goebel FD, Walli R. Antiretroviral therapy-associated insulin resistance:
frequency, potential causes and possible therapeutic interventions. 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in
HIV (abstract 005). San Diego, June 2628, 1999.
Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;
37:1595-607.
Behrens G, Dejam A, Schmidt H, Balks HJ, Brabant G, Korner T. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV
patients under treatment with protease inhibitors. AIDS 1999;13:F63-70.
Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Charles MA, Bennet PH.
A two-step model for the development of non-insulin dependent diabetes. Am J Med 1991;90:229-35.
Yarasheski KE, Tebas P, Sigmund C, Dagogo-Jack S, Bohrer A, Turk J,
et al. Insulin resistance in HIV protease inhibitorassociated diabetes. J
Acquir Immune Syndr Human Retrovirol 1999;21:209-16.
Saint-Marc T, Poizot-Martin I, Partisani M, Fabre J, Touraine J, Bruno F.
A syndrome of lipodystrophy in patients receiving long-term nucleoside
analogue therapy. AIDS 1999;13:1659-67.
Madge S, Kinloch-De Loes S, Tyrer M, Jonhson M. Lipodystrophy syndrome in patients on reverse transcriptase inhibitors (abstract 654). 6th
Conference on Retroviruses and Opportunistic Infections, Chicago, January 31February 4, 1999.
Carr A, Miller J, Law M, Cooper DA. A syndrome of lipodystrophy, lactic acidemia and liver dysfunction associated with HIV nucleoside reverse transcriptase inhibitor therapy: contribution to protease inhibitor
related lipodystrophy syndrome (abstract 011). 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Diego,
June 2628, 1999.
Goujard C, Lescaux AS, Dulioust A, Boue F, Delfraissy JF, Sobel A, et
al. Lipodystrophy in protease inhibitornave patients treated with reverse transcriptase inhibitor combinations: frequency and risk factors
(abstract 20). 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, January 30February 2, 2000.
Modina JM, Angelini E, Cotte L, Lang JM, Morlat P, Rancinan C, et al.
Prevalence of lipodystrophy in the long-term follow-up of a clinical trial
comparing various combinations of nucleoside reverse transcriptase inhibitors, ALBI trial (ANRS070) (abstract 19). 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, January 30-February 2, 2000.
Brinkman K, Burger D, Smeitink JAM, Koopmans PP, Ter Hofstede
HJM. Adverse effects of reverse transcriptase inhibitors: mitochondrial
toxicity as common pathway. AIDS 1998;12:1735- 44.
Kakuda TN, Brundage RC, Anderson RL, Fletcher CV. Nucleoside reverse transcriptase inhibitorinduced mitochondrial toxicity as an etiology for fat redistribution syndrome (abstract 041). 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Diego,
June 2628, 1999.

2001 March, Volume 35

Downloaded from aop.sagepub.com by Fernanda MIreles on August 20, 2016

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Hyperglycemia and HIV


79. American Diabetes Association: clinical practice recommendations. Diabetes Care 1996;19(suppl 1):S1-118.
80. American Diabetes Association. Consensus Development Conference on
Insulin Resistance. Diabetes Care 1998;21:310- 4.
81. American Diabetes Association. Diabetes mellitus and exercise. Diabetes
Care 1999;22(suppl 1):S49-53.
82. Summary of the second report of the National Cholesterol Education
Program Expert Panel on detection, evaluation and treatment of high
blood cholesterol in adults. JAMA 1993;269:3015-23.
83. Martinez E, Conget I, Lozano L, Casamitjana R, Gatell JM. Reversion of
metabolic abnormalities after switching from HIV-1 protease inhibitors
to nevirapine. AIDS 1999;13:805-10.
84. Moyle G, Baldwin C, Dent N, Gazzard B. Management of indinavirassociated metabolic changes by substitution with efavirenz in virologically controlled HIV+ persons (abstract 669). 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31February 4,
1999.
85. Scheen AJ, Lefebvre PJ. Oral antidiabetic agents. A guide to selection.
Drugs 1998;55:225-36.
86. Saint-Marc T, Touraine JL. Effects of metformin on insulin resistance
and central adiposity in patients receiving effective protease inhibitor
therapy (abstract 672). 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31February 4, 1999.
87. Package insert. Glucophage (metformin hydrochloride). Princeton, NJ:
Bristol-Myers Squibb, January 1999.
88. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin
resistance and type 2 diabetes. Diabetes 1996;45:1661-9.
89. US Department of Health and Human Services. Food and Drug Administration. Rezulin to be withdrawn from the market. March 21, 2000.
90. Forman LM, Simmons DA, Diamond RH. Hepatic failure in a patient
taking rosiglitazone. Ann Intern Med 2000;132:118-21.
91. Al-Salman J, Arjomand H, Kemp DG, Mittal M. Hepatocellular injury in
a patient receiving rosiglitazone. Ann Intern Med 2000;132:121- 4.
92. Package insert. Actos (pioglitazone). Indianapolis, IN: Eli Lilly, July
1999.
93. Package insert. Avandia (rosiglitazone). Philadelphia: SmithKline Beecham
Pharmaceuticals, 1999.

EXTRACTO
OBJETIVO:

Describir el impacto de factores como el virus de


immunodeficiencia humana (VIH), el uso de antiretrovirales y de otros
medicamentos comnmente utilizados en pacientes infectados con VIH
en el metabolismo de glucosa. Adems se proveen recomendaciones
para el manejo de la hiperglucemia o de la diabetes mellitus que
presentan estos pacientes.
FUENTE DE DATOS: Se identific la literatura pertinente a travs de una
bsqueda en el sistema MEDLINE (19802000) y a travs de fuentes
secundarias como resmenes de trabajos presentados en reuniones
cientficas recientes y el inserto de informacin que provee la compaa
manufacturera del frmaco. Se incluy toda la informacin relevante
para evaluar el impacto de la infeccin con VIH y su farmacoterapia en
el metabolismo de glucosa.
SNTESIS: Antes de introducir al mercado los potentes medicamentos
antiretrovirales, los pacientes infectados con VIH presentaban pocas
alteraciones en el metabolismo de glucosa. Sin embargo, estos pacientes
manifestaban una gran variedad de anormalidades en el metabolismo de
lpidos. Se ha sugerido que estos desrdenes en glucosa y lpidos se
asocian con alteraciones en las citokinas. La carga viral y el estrs
producen una respuesta hormonal e immunolgica compleja que puede
alterar varias rutas metablicas, incluyendo el metabolismo de glucosa.
Un componente importante en el sndrome de lipodistrofia de los
pacientes infectados con VIH es la resistencia a insulina. El sndrome de
lipodistrofia se asocia a redistribucin de grasa, cambios en el perfil de
lpidos, y resistencia a insulina y a diabetes mellitus. Este sndrome tiene
una prevalencia estimada de 283% en los pacientes infectados con
VIH que utilizan inhibidores de proteasa, aunque la severidad de la
presentacin vara grandemente. Por otro lado, otros medicamentos que
se utilizan en pacientes infectados con VIH, tambin se asocian con
alteraciones en glucosa. Entre estos se encuentra pentamidina. La

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naturaleza compleja y multifactorial que incide en las alteraciones en el


metabolismo de glucosa hace difcil el manejo de la hiperglucemia y de
la diabetes mellitus en estos pacientes. Los autores presentan un grupo
de recomendaciones que han desarrollado para guar al proveedor de
salud en la evaluacin, tratamiento, y seguimiento de hiperglucemia y de
diabetes en pacientes infectados con VIH.
CONCLUSIONES: Las alteraciones en el metabolismo de glucosa en
pacientes infectados con VIH son ms frecuentes luego de la
introduccin al mercado de los antiretrovirales potentes. Aunque la
etiologa de estas alteraciones an continua desconocida, los inhibidores
de proteasa y en menor grado los inhibidores de nuclesido de
transcriptasa reversa se han asociado a mecanismos patognicos de
descontrol de glucosa. Estos mecanismos son similares a la patognesis
de diabetes mellitus. Los autores recomiendan que el manejo de la
hiperglucemia inducida por antiretrovirales se base en las guas
establecidas por la Asociacin Americana de Diabetes, teniendo
precauciones especiales en el seguimiento de estos pacientes. Estudios
futuros deben estar dirigidos a entender el mecanismo preciso o las
causas del desorden en el metabolismo de glucosa de manera que se
puedan evaluar las guas de prevencin y tratamiento establecidas.
Mirza Martnez
RSUM
OBJECTIF:

Revoir limpact que peuvent avoir sur le mtabolisme des


glucides chez les patients infects par le virus de limmunodficience
humaine (VIH) diffrents facteurs, tels linfection par le VIH, les
antirtroviraux, et dautres thrapies mdicamenteuses frquemment
utilises.
REVUE DE LITTRATURE: La documentation pertinente a t identifie
laide dune recherche sur MEDLINE de 19802000 et laide de
sources secondaires (rsums prsents des runions scientifiques
rcentes, renseignements fournis par les fabriquants). Toute information
juge pertinente pour valuer limpact de linfection par le VIH et de la
thrapie mdicamenteuse sur le mtabolisme des glucides chez les
patients infects par le VIH a t retenue.
RSUM: La charge virale et le stress prsents chez les patients infects
par le VIH provoquent une rponse immunologique et hormonale
complexe qui peut modifier diffrentes voies biochimiques incluant le
mtabolisme des glucides. Bien que rare avant lre de la puissante
thrapie antirtrovirale, la rsistance linsuline est maintenant dcrite
comme une composante importante du syndrome de lipodystrophie. La
nature complexe et les causes varies du drglement du mtabolisme
des glucides rendent le traitement de lhyperglycmie et du diabte
mellitus exigeants chez les patients infects par le VIH. Dans un tel
contexte, un ensemble de recommandations ont t dveloppes pour
aider les cliniciens valuer, traiter, et effectuer le suivi de
lhyperglycmie ou du diabte mellitus chez les patients infects par le
VIH.
CONCLUSIONS: Les altrations du mtabolisme des glucides observes
chez les patients infects par le VIH sont plus frquentes depuis
lintroduction de la puissante thrapie antirtrovirale. Bien que
ltiologie de telles anormalits demeure inconnue, on pense que les
inhibiteurs de la protase et, un moindre degr, les analogues
nuclosidiques inhibiteurs de la transcriptase inverse, jouent un rle dans
le dveloppement de ces anormalits. tant donn les ressemblances
avec la pathognse du diabte mellitus, le traitement de
lhyperglycmie associe la thrapie antirtrovirale pourrait suivre les
recommandations de lAmerican Diabetes Association en ce qui
concerne le suivi des patients infects par le VIH. Les tudes futures
devraient rechercher comprendre le mcanisme prcis ou les causes de
cette complication pour que des lignes de conduite thrapeutiques et
prventives puissent tre values.

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