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Chapter
6
Metabolic Complications Of Antiretroviral Therapy
David H.
Spach, MD
Overview
TOP
What is
meant by metabolic complications of antiretroviral therapy (ART)?
Metabolic complications
refers to a group of adverse drug reactions that have been associated
with long-term use of antiretroviral drugs, which include:
- Lipid abnormalities
- Lipodystrophy
- Lactic acidosis
- Hyperglycemia
- Decreased
bone mineral density
Each adverse
reaction is more commonly associated with a specific class of antiretroviral
drugs, and the agents within the class that cause the reactions
do so with variable frequencies. In most cases, the pathophysiologic
mechanism of the changes is unknown. The classes of drugs associated
with each major adverse reaction are listed in Table 6-1.
Table
6-1. Adverse Reactions of Classes of Antiretroviral Drugs
Adverse
Reaction |
Lactic
Acidosis |
++
|
|
|
Lipid
Changes |
|
|
|
|
|
(+)
|
++
|
|
Elevated
LDL cholesterol |
|
+
|
++
|
Insulin
resistance |
|
|
++
|
Fat
redistribution |
|
|
|
|
Fat
atrophy |
+
|
|
|
|
Fat
accumulation |
|
|
++
|
**NNRTIs |
= |
Non-nucleoside
reverse transcriptase inhibitors |
***PIs |
= |
Protease
inhibitors |
(+) |
= |
possible
causes adverse reaction |
+ |
= |
sometimes
causes adverse reaction |
++ |
= |
frequently
causes adverse reaction |
What metabolic
toxicities should you monitor for in patients taking ART?
Recommendations
for monitoring patients for ART-related metabolic complications,
listed in Table 6-2, are discussed in detail in the sections below.
Table
6-2. Recommendations for Assessment and Monitoring of Metabolic
Complications of Antiretroviral Therapy for HIV Infection
Body
fat distribution abnormalities |
- No
specific technique can be recommended at the present time
for routine assessment and monitoring of body fat distribution
changes.
|
Lactic
acidemia |
- Routine
measurement of lactic acid levels is not recommended.
- Lactic
acid levels should be monitored in those receiving NRTIs
who have clinical signs or symptoms of lactic acidemia,
and in pregnant women receiving NRTIs.
- If
alternative NRTIs are resumed in those who have interrupted
antiretroviral therapy for lactic acidemia, lactate levels
should be monitored every 4 weeks for at least 3 months.
|
Osteopenia,
osteoporosis, and osteonecrosis |
- Routine
screening for osteoporosis or osteonecrosis is not recommended.
- Radiographic
examination of involved bone is recommended for those with
symptoms of bone or joint pain; the contralateral joint
should also be assessed.
|
DEXA |
= |
Dual-energy
x-ray absorption |
HDL |
= |
High-density
lipoprotein |
LDL |
= |
Low-density
lipoprotein |
NCEP |
= |
National
Cholesterol Education Program |
NNRTI |
= |
non-nucleoside
reverse transcriptase inhibitor |
NRTI |
= |
nucleoside
reverse transcriptase inhibitor |
Source: Schambelan
M, Benson CA, Andrew Carr A, et al. "Management of metabolic
complications associated with antiretroviral therapy for HIV-1 infection:
Recommendations of an International AIDS Society-USA Panel."
J Acquir Immune Defic Syndr. 2002;31:269. Reprinted with permission
of Lippincott Williams and Wilkins.
Lipid
Abnormalities
TOP
What antiretroviral
medications adversely affect lipid levels?
Available data
suggest that drugs in the protease inhibitor (PI) class have the
greatest adverse effect on triglycerides, total cholesterol, and
low-density lipoprotein (LDL) cholesterol levels. The mechanism
remains unclear. Among the PIs, ritonavir (RTV) and ritonavir-boosted
regimens appear to have the greatest impact on triglycerides and
total cholesterol levels. Because some patients who receive ritonavir
had no significant changes whereas others have dramatic increases,
genetic predisposition may play a major role. The PI atazanavir
(ATV) does not significantly affect lipid levels. The impact of
nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside
reverse transcriptase inhibitors (NNRTIs) on lipid levels has not
been well defined, but the impact appears much less than changes
associated with PIs. In 96-week data from a trial that compared
stavudine (d4T) plus lamivudine (3TC) plus efavirenz (EFV) with
tenofovir (TDF) plus lamivudine plus efavirenz, those patients in
the stavudine arm had significantly higher cholesterol and triglyceride
levels. The NNRTI nevirapine (NVP) has no adverse affect on lipids,
and the changes with efavirenz are variable. Patients receiving
PIs should undergo regular monitoring of lipid levels (see Table
6-2).
Do antiretroviral
drugs cause an increase in cardiovascular disease?
Several isolated
case reports initially suggested ART could lead to cardiovascular
disease, including death from myocardial infarction, in HIV-infected
patients. More recent aggregate data from over 20,000 patients in
cohort studies indicate the risk related to ART is low and substantially
lower than the risk of smoking (Friss-Moller, et al, 2003). In addition,
in a large study that involved more than 36,000 veterans, investigators
found the benefit of these drugs far outweighed the risks. Because
cardiovascular disease may take 10-15 years to manifest, investigators
will need long-term followup of individuals who have received ART
to determine the long-term impact.
Should you
treat abnormal lipid levels in HIV-infected persons?
Although prospective
studies have not clearly defined the long-term adverse cardiovascular
effects associated with hyperlipidemia in HIV-infected persons,
abnormal lipid levels appear to pose the same long-term risks as
have been well established in persons who do not have HIV infection
and thus need to be managed appropriately (see Table 6-3). Accordingly,
clinicians should address abnormal lipid levels and the individual
patient risks, including prior cardiovascular events, smoking, hypertension,
diabetes, family history, obesity, and baseline lipid levels. The
potential interventions include 1) switching to a regimen less likely
to cause abnormal lipids (if possible without sacrificing antiviral
effectiveness), 2) implementing dietary changes, 3) using a lipid-lowering
agent according to recommendations in Table
6-4, and 4) addressing other lifestyle habits that affect cardiovascular
risk, such as smoking and exercise.
Table
6-3. Recommendations
for Treatment of Metabolic Complications
of Antiretroviral Therapy for HIV Infection
Glucose
intolerance and diabetes mellitus |
- Weight
loss for overweight subjects is recommended.
- Follow
established guidelines for treating diabetes in the general
population, with preference given to insulin sensitizing
agents such as metformin (except for those with renal disease
or history of lactic acidemia) or thiazolidinediones (except
for those with prexisting liver disease).
- Avoid
use of a PI as initial therapy in patients with preexisting
glucose intolerance or diabetes mellitus.s.
|
Lipid
and lipoprotein abnormalities |
- Follow
NCEP III guidelines for assessment of risk factors for cardiovascular
disease, and dietary and lifestyle alterations for lowering
cholesterol and triglyceride levels.
- Avoid
use of PIs, if possible, in those with preexisting cardiovascular
risk factors, family history of hyperlipidemia, or elevated
lipid levels.
- Follow
NCEP guideline thresholds for lipid-lowering therapy.
- Fibrates
are recommended as initial therapy for those with isolated
fasting hypertriglyceridemia.
- Pravastatin
or atorvastatin are preferred statin agents for those with
isolated fasting hypercholesterolemia requiring treatment
in the setting of PI or other CYP 3A4 inhibitor therapy.
- If
combination therapy for hypercholesterolemia and hypertriglyceridemia
is indicated, therapy should begin with a statin, followed
by the addition of a fibrate if there is insufficient response
after 3 to 4 months of treatment.
|
Body
fat distribution abnormalities |
- No
therapies for fat distribution abnormalities in the absence
of other metabolic complications can be routinely recommended.
|
Lactic
acidemia |
- ART
should be withheld for all patients with confirmed lactate
levels >10 mmol/L (90 mg/dL) or those with confirmed
lactate levels >5 mmol/L (45 mg/dL) who are symptomatic.
- No
intervention apart from NRTI cessation is recommended.
- Restart
combination NNRTI and PI therapy after lactate levels return
to normal and symptoms resolve.
|
Osteopenia,
osteoporosis, and osteonecrosis |
- Surgical
resection of involved bone is the only effective therapy
for symptomatic osteonecrosis.
- If
osteoporosis is demonstrated by radiography or regional
DEXA scanning, or if a pathological fracture occurs in the
setting of osteoporosis, therapy with a bisphosphonate should
be considered.
|
DEXA |
= |
Dual-energy
x-ray absorption |
HDL |
= |
High-density
lipoprotein |
LDL |
= |
Low-density
lipoprotein |
NCEP |
= |
National
Cholesterol Education Program |
NNRTI |
= |
non-nucleoside
reverse transcriptase inhibitor |
NRTI |
= |
nucleoside
reverse transcriptase inhibitor |
Source: Schambelan
M, Benson CA, Andrew Carr A, et al. "Management of metabolic
complications associated with antiretroviral therapy for HIV-1 infection:
Recommendations of an International AIDS Society-USA Panel."
J Acquir Immune Defic Syndr. 2002;31:269. Reprinted with permission
of Lippincott Williams and Wilkins.
Table
6-4. Summary of National Cholesterol Education Program Treatment
Recommendations Based on LDL Cholesterol*
With
CHD or CHD** risk equivalent (10-year risk >20%, noncoronary
atheroslerotic vascular disease, or type 2 diabetes mellitus) |
100
mg/dL
( 2.6 mmol/L) |
130
mg/dL
( 3.4 mmol/L)
100¨C129 mg/dL (2.6¨C3.3 mmol/L):
therapy optional |
<100
mg/dL
(<2.6 mmol/L) |
<130
mg/dL
(<3.4 mmol/L) |
2
or more risk factors (10-year risk <20%) |
130
mg/dL
( 3.4 mmol/L) |
10-year
risk of
10%¨C20%:
130 mg/dL
( 3.4 mmol/L)
10-year risk of <10%:
( 160 mg/dL
( 4.1 mmol/L) |
<130
mg/dL
(<3.4 mmol/L) |
<160
mg/dL
(<4.1 mmol/L) |
0
or 1 risk factor |
160
mg/dL
( 4.1 mmol/L) |
190
mg/dL
( 4.9 mmol/L)
160¨C189 mg/dL
(4.1¨C4.9 mmol/L):
therapy optional |
<160
mg/dL
(<4.1 mmol/L) |
<190
mg/dL
(<4.9 mmol/L) |
† |
Risk
factors include cigarette smoking; hypertension (blood pressure
140/90 mm Hg or taking antihypertension drugs);
HDL cholesterol level below 40 mg/dL (1.0 mmol/L); family history
of premature CHD (in first-degree male relatives <55 years
and first-degree female relatives <65 years); age (>45
years for men and >55 years for women). Risk factor equivalent:
diabetes. If HDL cholesterol is over 60 mg/dL (1.6 mmol/L),
subtract 1 risk factor from the total. |
‡ |
Therapeutic
lifestyle changes refer to reducing saturated fat and cholesterol
intake; enhancing the reduction in LDL cholesterol level by
the use of plant stanols/sterols and increased soluble fiber;
weight reduction; and increased physical activity. |
** |
CHD,
coronary heart disease; HDL, high-density lipoprotein; LDL,
low-density lipoprotein; VLDL, very low-density lipoprotein. |
Source: Schambelan
M, Benson CA, Carr A, et al. "Management of Metabolic Complications
Associated with Antiretroviral Therapy for HIV-1 Infection: Recommendations
of an International AIDS Society--USA Panel." J Acquir Immune
defic Syndr. 31:262. Nov 1, 2002. Adapted from Executive Summary
of the "Third Report of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel III)." JAMA
2001;285:24862497. Reprinted with permission of Lippincott
Williams and Wilkins.
What statins
are recommended for treating patients on PIs?
Significant
drug interactions may occur with PIs and lipid-lowering statins;
for patients on PI-based ART, most experts consider pravastatin
and atorvastatin as preferred statins and avoid using lovastatin
or simvastatin. Initial therapy should consist of a low dose of
either pravastatin (20 mg po qd) or atorvastatin (10 mg po qd),
with monitoring of response to therapy and, if required, gradual
and cautious increases in doses of the statin. Triglyceride levels
in excess of 1000 mg/dL place the patient at risk for developing
pancreatitis. Most experts recommend intervening when triglyceride
levels exceed 500 mg/dL. Although dietary changes can improve triglyceride
levels, most patients with PI-associated hypertriglyceridemia will
require pharmacologic intervention. Patients with isolated hypertriglyceridemia
should receive a fibric acid derivative, either gemfibrozil (600
mg po bid) or fenofibrate (200 mg po qd). For those who have high
triglyceride and LDL cholesterol levels, a statin drug should be
used first with the plan of adding a fibric acid derivative after
4 months if the response to the statin is suboptimal. Because both
the statin drugs and the fibric acid derivatives can cause rhabdomyolysis,
caution should be used if these medications are given concurrently.
In patients with severe hypertriglyceridemia refractory to a fibric
acid derivative, some experts would recommend a trial of adding
fish oil supplements to the lipid-lowering regimen.
Does switching
ART improve lipid abnormalities?
Although some
antiretroviral medications clearly have a greater adverse impact
than others on lipids, modifying the regimen in an attempt to improve
the lipid profile is sometimes difficult, mainly because of the
need to maintain antiretroviral efficacy. Examples of possible changes
likely to improve lipid abnormalities include switching a PI to
either nevirapine (NVP) or using the alternative PI atazanavir (ATV).
Changing from a PI to efavirenz (EFV) has not produced consistent
results. Preliminary data from one study has shown that patients
who switched from stavudine (d4T) to tenofovir (TDF) had a significant
improvement in cholesterol and triglyceride levels. Future work
will better determine whether changes from one nucleoside to another
will affect lipid levels.
Lypodystrophy
TOP
What is
lipodystrophy?
Although lipodystrophy
was first reported in the mid-1990's, investigators have not agreed
on a standardized, objective definition for this disorder. Most
researchers and clinicians loosely define lipodystrophy as any significant
change in body morphology that does not result from either weight
gain or weight loss. The general term lipodystrophy now typically
includes 3 subsets of morphologic changes: generalized fat accumulation,
focal fat accumulation, and fat atrophy. Fat accumulation most often
occurs in the abdominal, breast, or dorsocervical region. Fat atrophy
most often occurs as buccal fat pad atrophy (facial wasting) or
subcutaneous fat wasting in the buttocks or extremities. Because
a standardized definition for lipodystrophy is lacking, the incidence
varies depending on the exact criteria investigators use to define
lipodystrophy in their specific study. Tests for abnormalities in
body fat distribution have included computed tomography (CT) scanning,
magnetic resonance imaging (MRI), bioelectrical impedance analysis
(BIA), DEXA (dual energy x-ray absorptiometry) scans, and anthropometric
measurements. The CT and MRI tests are generally considered the
most accurate, but not practical for routine screening purposes,
primarily because of their high cost. Anthropometric measurements
can estimate visceral adipose tissue and subcutaneous adipose tissue
and can easily be performed in the clinic without major costs. Despite
the many options available for measuring abnormalities in fat distribution,
no technique has shown adequate sensitivity and specificity to recommend
performing routinely.
What causes
lipodystrophy in HIV-infected persons?
Despite intense
investigation, the exact pathogenesis of lipodystrophy remains unclear.
Initial reports linked PI use with lipodystrophy, but subsequent
reports have identified lipodystrophy in patients who had never
received a PI. Several studies have shown that the most important
risk factors for development of lipodystrophy are a history of severe
immune suppression (nadir CD4 count <100 cells/mm3), older age,
prolonged use of antiretroviral drugs, and highly active antiretroviral
therapy. Investigators have found that patients with lipodystrophy
often have high insulin levels and evidence of insulin resistance,
a finding that suggests insulin resistance is associated with lipodystrophy,
but does not prove that insulin resistance causes lipodystrophy.
Many clinicians have observed that fat accumulation is more often
associated with PI-based therapy, whereas fat wasting has been most
closely linked to NRTIs, particularly stavudine (d4T). In 96-week
data from a trial that compared stavudine plus lamivudine (3TC)
plus efavirenz (EFV) with tenofovir (TDF) plus lamivudine plus efavirenz,
those patients in the stavudine arm had substantially higher rates
of lipodystrophy.
Can fat
redistribution be reversed?
First, it is
important to evaluate the severity of the lipodystrophy, the degree
to which the patient is bothered by the body changes, and how strongly
the patient wants to try to reverse the lipodystrophy. Although
fat redistribution does not appear to directly alter health outcome,
many patients experience notable unfavorable changes in their phyical
appearance that may affect their quality of life. Morever, these
changes in body appearance may broadcast their HIV diagnosis. That
lipodystrophy changes thus may even lead some to stop their antiretroviral
medications. If lipodystrophy develops, there are 3 treatment options:
1) Switch therapy, meaning a substitution for the implicated drug.
This usually involves a substitute for stavudine (d4T) if lipoatrophy
has developed or a change to a non-PI-based regimen if fat accumulation
has occurred. Initial results with switches showed limited success,
and when there was a response it took a long time. More promising
results were seen in a recent study in which replacing stavudine
(d4T) with abacavir (ABC) or zidovudine (AZT) resulted in significant
improvement after 48 weeks in patients with stavudine-induced lipoatrophy
(McComsey, et al, 2004). 2) Drug therapy is another option. Metformin,
thiazolidinediones, testosterone, other anabolic steroids, and growth
hormone have been used with partial success with fat accumulation,
but all have drawbacks and do not address the underlying lipoatrophy.
3) The third option is plastic surgery, which may be particularly
useful for buccal fat atrophy or dorsothoracic fat accumulations;
however, results have been highly variable, and these procedures
are usually regarded as cosmetic surgery and not covered by insurance
companies.
Lactic
Acidosis
TOP
What are
ART-related hyperlactatemia and lactic acidosis?
ART-related
abnormalities of serum lactate levels (hyperlactatemia) range from
asymptomatic hyperlactatemia to symptomatic hyperlactatemia with
mild acidosis, to fulminant lactic acidosis, liver failure, and
death. In addition, some patients develop hepatic steatosis. The
development of fulminant lactic acidosis, although very rare, has
clearly emerged as one of the most dreaded adverse effects associated
with ART.
What antiretroviral
drugs cause hyperlactatemia?
Hyperlactatemia
and lactic acidosis result from abnormal mitochondrial toxicity
caused by NRTIs that inhibit the critical enzyme mitochondrial DNA
polymerase gamma. There is no evidence that NNRTIs or PIs cause
mitochondrial toxicity or abnormalities in serum lactate levels.
In vitro data and retrospective clinical data show that stavudine
(d4T) and didanosine (ddI) are the most likely medications in the
NRTI class to cause this complication, especially if used together.
Zidovudine poses some risk but significantly less than either stavudine
or didanosine. Tenofovir (TDF), abacavir (ABC), emtricitabine (FTC),
and lamivudine (3TC) appear to pose the least risk of causing lactic
acidosis. Identified risk factors, in addition to the use of NRTIs,
include pregnancy, female gender, obesity, or concurrent treatment
with ribavirin, hydroxyurea, or metformin.
How do you
collect and interpret a serum lactate test?
The normal
serum lactate level is <2 mmol/dL. Proper blood collection and
appropriate transport are essential for obtaining an accurate result.
The patient should not exercise for 24 hours prior to the test and
should be well hydrated, and should rest for at least 5 minutes
prior to the blood draw. The blood should be drawn without tourniquet
and the patient should be instructed not to clench his or her fist.
The sample should be submitted promptly for processing using a pre-chilled
fluoride-oxalate tube transported on ice. The specimen should be
processed within 4 hours after being drawn.
For interpretation, levels of 2-5 mmol/dL are often associated with
no symptoms, levels of 5-10 mmol/dL are usually associated with
symptoms that require discontinuation of NRTIs, and levels of >10
mmol/dL are associated with a fatality of >30% and require immediate
intervention. Abnormal levels should usually be confirmed.
How do you
diagnose lactic acidosis?
Routine monitoring
of serum lactate levels in asymptomatic patients is not recommended
(see Table 6-2), but obtaining a
serum lactate level is critical if hyperlactatemia is suspected
(see previous question for correct technique). Patients with mild
increases in serum lactate levels generally do not have significant
symptoms, and if symptoms are present, they are most likely nonspecific.
With more severe increases in serum lactate levels, patients may
have marked fatigue, nausea, anorexia, vomiting, abdominal pain,
dyspnea, and hyperventilation. Although a chemistry panel may show
a decreased serum bicarbonate level or increased anion gap level,
some reports have documented patients with severe lactic acidosis
who do not have abnormal serum bicarbonate or increased anion gap
measurements. CT scan of the liver may show enlargement and fatty
infiltration.
How do you
manage severe hyperlactatemia or lactic acidosis?
Patients with
severe hyperlactatemia or lactic acidosis should immediately discontinue
ART (see Table 6-3). Seriously ill
patients may require IV bicarbonate, mechanical ventilation, or
dialysis. Most respond to drug withdrawal. Case reports have suggested
improvement in lactic acidosis with use of compounds such as riboflavin,
thiamine, L-carnitine, or co-enzyme Q, with the benefit hypothetically
resulting from improvement in mitochondrial function; however, the
use of these agents to prevent hyperlactatemia and lactic acidosis
has not been studied. Unfortunately, even after discontinuing ART,
recovery from lactic acidosis typically takes about 8 weeks, since
regeneration of severely damaged mitochondria is a prolonged process.
Once a lactic
acidosis episode is resolved, can a patient resume ART?
For those patients
who recover from an episode of lactic acidosis, the optimal management
of their subsequent ART remains unclear. For those patients who
clearly need ART, the safest option would be to use a regimen that
does not contain an NRTI, such as lopinavir plus ritonavir plus
efavirenz (LPV/r + EFV), saquinavir plus ritonavir (SQV + RTV),
or indinavir plus ritonavir plus efavirenz (IDV + RTV + EFV). Available
data suggest tenofovir (TDF), lamivudine (3TC), emtricitabine (FTC),
and abacavir (ABC) are the NRTIs least likely to cause severe hyperlactatemia
or lactic acidosis. In a report of 17 patients who developed symptomatic
hyperlactatemia while receiving stavudine (d4T), the patients were
rechallenged with abacavir or zidovudine; none of the 17 had a recurrence
of symptomatic hyperlactatemia. Nevertheless, providers should obtain
expert consultation and also observe the patient closely when restarting
a new regimen that includes one or more NRTIs in any patient with
a history of lactic acidosis.
Other
Metabolic Complications
TOP
Does ART
cause hyperglycemia and diabetes?
Although several
studies have shown that PIs can have a direct effect on glucose
metabolism, predominantly by increasing insulin resistance, it remains
unclear whether ART significantly increases the risk for developing
diabetes mellitus. Available data would suggest that ART, particularly
with PIs, likely causes a slightly increased risk of developing
overt diabetes mellitus. Routine monitoring for hyperglycemia is
recommended for any patient on a PI-based regimen (see Table
6-3). Studies of patients with hyperglycemia and insulin resistance
have consistently shown that switching from a PI to either nevirapine
(NVP), efavirenz (EFV), or abacavir (ABC) will significantly improve
the hyperglycemia and insulin resistance. Nevertheless, further
study is needed to better clarify the risk of a patient's developing
diabetes mellitus while taking a PI and the long-term clinical benefit
of switching from a PI to a regimen that causes less insulin resistance.
Does ART
cause abnormalities in bone density?
Several retrospective
reports have suggested that ART may cause decreases in bone mineral
density and, rarely, avascular necrosis. Recently, the relationship
between ART and decreases in bone mineral density has become very
controversial and prospective studies are needed to resolve the
issue. From a clinical perspective, avascular necrosis should be
suspected when a patient complains of focal bone pain; either CT
or MRI can confirm the diagnosis. Avascular necrosis most often
involves the femoral or humeral head, can consist of necrosis at
a single or multiple sites, does not respond to medical therapy,
and typically requires surgical intervention (see Table
6-3). There are no data regarding modifying an ART regimen either
to prevent avascular necrosis or to improve the condition once it
has already developed.
- Metabolic
complications include the long-term consequences of antiretroviral
agents: lactic acidosis (due to NRTIs [nucleosides]), dyslipidemia
(usually due to PIs), insulin resistance (usually due to PIs),
fat redistribution (usually due to NRTIs and PIs).
- All PIs
except atazanavir (ATV) are associated with variable increases
in the LDL cholesterol and/or triglycerides.
- Cardiovascular
risks of dyslipidemia associated with PI therapy are assumed to
be the same as for persons without HIV infection; they are usually
managed with lifestyle changes (smoking cessation, diet modifications,
and exercise) and, if necessary, lipid-lowering drugs; if statins
are used, pravastatin or atorvastatin are preferred to avoid drug
interactions with the PIs.
- Patients
receiving PIs should have blood lipids and glucose monitored at
baseline, at 3-6 months and then at least annually, and more frequently
depending on other risks and severity of abnormalities.
- ART is associated
with fat redistribution, both fat accumulation (abdomen, breasts,
dorsocervical) and fat wasting (buccal fat with face thinning,
buttocks, and extremities). These changes can result in major
unfavorable changes in physical appearance and can have a significant
impact on quality of life.
- There are
no effective treatments for reversing fat redistribution. Discontinuing
or switching therapy has moderate effect at best and improvement
requires a very long time; with face thinning the best results
are with discontinuing stavudine (d4T) early.
- Lactic acidosis
is a result of mitochondrial toxicity caused by prolonged use
of NRTIs, primarily stavudine (d4T), didanosine (ddI) and to a
lesser degree zidovudine (AZT).
- The usual
symptoms of lactic acidosis are fatigue, abdominal pain, nausea,
and weight loss; the usual laboratory finding is a serum lactate
exceeding 5 mmol/dL. The main treatment is to discontinue the
implicated drugs or switch to NRTIs that are less likely to cause
this.
- Type 2 diabetes
is an occasional complication of PI therapy due to insulin resistance.
Monitoring should include fasting blood glucose at baseline and
at 5-8 months with subsequent measurements depending on risk and
prior results.
Suggested
Resources
TOP
Bozzette SA,
Ake CF, Tam HK, Chang SW, Louis TA. "Cardiovascular and cerebrovascular
events in patients treated for human immunodeficiency virus infection."
N Engl J Med. 2003;348:702-710.
Carr A, Cooper
DA. "Adverse effects of antiretroviral therapy." Lancet.
2000;356:1423-1430.
Dube MP. "Disorders
of glucose metabolism in patients infected with human immunodeficiency
virus". Clin Infect Dis. 2000;31:1467-1475.
Dube MP, Stein
JH, Aberg JA, Fichtenbaum CJ, et al: "Guidelines for the evaluation
and management of dyslipidemia in human immunodeficiency virus-infected
adults receiving antiretroviral therapy: Recommendations of the
HIV Medicine Association of the Infectious Disease Society of America
and the Adult AIDS Clinical Trials Group." Clin Infect Dis.
2003;37:613-627.
Moyle G, Carr
A. "HIV-associated lipodystrophy, metabolic complications,
and antiretroviral toxicities." HIV Clin Trials. 2002;3:89-98.
Moyle GJ, Datta
D, Mandalia S, Morlese J, Asboe D, Gazzard BG. "Hyperlactataemia
and lactic acidosis during antiretroviral therapy: relevance, reproducibility
and possible risk factors." AIDS. 2002;16:1341-1349.
Orenstein R.
"Presenting syndromes of human immunodeficiency virus."
Mayo Clin Proc. 2002;77:1093-1102.
Smith KY. "Selected
metabolic and morphologic complications associated with highly active
antiretroviral therapy." J Infect Dis. 2002;185 Suppl
2:S123-127.
References
TOP
Friis-Moller
N, Sabin CA, Weber R, et al. "Combination antiretroviral therapy
and the risk of myocardial infarction". N Engl J Med.
2003;349:1993-2003.
McComsey GA,
Ward DJ, Hessenthaler SM, et al. "Improvement in lipoatrophy
associated with highly active antiretroviral therapy in human immunodeficiency
virus-infected patients switched from stavudine to abacavir or zidovudine:
the results of the TARHEEL study." Clin Infect Dis.
2004;38:263-270.
Schambelan
M, Benson CA, Andrew Carr A, et al. "Management of metabolic
complications associated with antiretroviral therapy for HIV-1 infection:
Recommendations of an International AIDS Society-USA Panel."
J Acquir Immune Defic Syndr. 2002; 31:257-275.
Cases
TOP
1.
A 36-year-old HIV-infected man has received stavudine (d4T) plus
lamivudine (3TC) plus indinavir (IDV) for approximately 4 years.
This regimen was his first regimen and before starting therapy his
HIV RNA was 59,000 copies/mL and his CD4 count was 34 cells/mm3.
His antiviral and immunologic response has been excellent, with
HIV RNA levels persistently less than 50 copies/mL and a CD4 count
that has increased to 526 cells/mm3. In the past 9 months, however,
he has developed hyperlipidemia, hyperglycemia, and body fat changes,
most notably enlargement of his abdominal region and facial thinning.
He has been very hesitant to change his regimen but now comes into
the clinic to discuss this matter again.
Question:
If he changes his antiretroviral regimen, will he likely continue
to have excellent control of HIV?
Answer:
Since this patient has experienced excellent long-term viral suppression
and this was his first regimen, it is highly likely that a switch
from a PI to a NNRTI (efavirenz [EFV] or nevirapine [NVP]) would
maintain continued viral suppression. Similarly, a change from one
NRTI to another would likely have no adverse affect on HIV suppression.
In patients who have previously developed resistance and are currently
on a salvage regimen, changing a medication because of side effects
can pose a much greater risk of not maintaining excellent virologic
control.
Question:
What improvements would he likely expect if he makes a change?
Answer:
Among the problems this patient has developed as a complication
of ART, insulin resistance and hyperlipidemia are the most likely
to improve with a regimen change. In particular, several studies
have shown switching from a PI to either nevirapine, efavirenz,
or abacavir (ABC) typically leads to significant improvement in
hyperglycemia and insulin resistance. Improvements in lipids are
most likely to occur if the PI is switched to either nevirapine
or abacavir. Switching from one PI to the new PI atazanavir (ATV)
may provide significant improvement in lipid abnormalities. Unfortunately,
changing from a PI to an NNRTI has not produced reliable improvements
in lipodystrophy. Changing from stavudine to either abacavir or
tenofovir (TDF) may provide some improvement in lipodystrophy for
some patients. Although tenofovir causes less lipodystrophy than
stavudine, studies that examine the effect of changing stavudine
to tenofovir have not been performed.
2.
A 33-year-old woman on stavudine (d4T) plus didanosine (ddI)
plus efavirenz (EFV) presents with severe fatigue. No obvious cause
for the fatigue is discovered and 1 week later she returns with
even worse fatigue. Serum chemistries now are notable for a bicarbonate
of 17 mmol/L. A serum lactate level is drawn and a lactate level
of 6.3 mmol/L is reported from the laboratory. The patient is not
taking any other medications and is not taking any herbal preparations.
Question:
Is the serum lactate level of 6.3 mmol/L concerning in this patient?
Answer:
Experts have stratified serum lactate levels based on the risk of
developing complications from hyperlactatemia. Those with a serum
lactate level of 2.1-5.0 mmol/L are considered to have mild hyperlactatemia,
those with a serum lactate level of at least 5 mmol/L have serious
hyperlactatemia, and those with a lactate level at least 5 mmol/L
plus a bicarbonate level less than 20 mmol/L have lactic acidosis.
Accordingly, the patient's serum lactate of 6.3 mmol/L (along with
the serum bicarbonate of 17 mmol/L) is extremely concerning and
suggests lactic acidosis, a potentially life-threatening problem.
Question:
If lactic acidosis is suspected, how should the patient be managed?
Answer:
Because hyperlactatemia and lactic acidosis result from NRTI-induced
mitochondrial toxicity, the first step in managing this problem
is to immediately discontinue ART. Although several case reports
have suggested improvement in lactic acidosis by using compounds
such as riboflavin, thiamine, L-carnitine, or co-enzyme Q, supportive
care remains the mainstay of therapy. After discontinuing ART, regeneration
of severely damaged mitochondrial typically requires prolonged periods,
and recovery from lactic acidosis can take several months. Following
recovery, the optimal management of subsequent antiretroviral therapy
remains unclear. Preliminary reports suggest changing the NRTIs
(typically replacing stavudine) can safely be performed, but should
be done with expert consultation.
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