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Can changing your lifestyle or switching
antiretrovirals help lower your cardiovascular risk?
Evidence continues to accumulate that
HIV does indeed increase the likelihood of coronary heart
disease (CHD) and stroke, with HAART (highly active antiretroviral
therapy) a contributing, but not sole, factor.
Today, HIV clinicians are increasingly
concerned with managing lipodystrophy’s metabolic syndrome,
since it can be life-threatening, particularly in regards
to the risk of cardiovascular disease.
These include:
- High total cholesterol
- Increased LDL
(low density lipoprotein, the so-called ‘bad’
cholesterol)
- Reduced HDL
(high density lipoprotein, the so-called ‘good’
cholesterol)
- High triglycerides (another type of
blood fat)
- Hyperglycemia (high blood sugar, or
glucose)
- Insulin resistance (when more insulin
is needed to control blood sugar)
- Diabetes (when the pancreas can no longer
make enough insulin)
The logic behind their concern is this:
even if HAART doesn’t actually increase the risk of heart
attack by 26% for each year of exposure to antiretroviral
therapy, as was estimated by the authors of the DAD study,
HAART’S uncanny ability to keep us alive means that as
an increasingly aging population living with HIV we are, at
the very least, subject to the same cardiovascular risks as
everyone else.
Who is at risk?
Several factors contribute to the risk
of coronary heart disease (CHD) in HIV-negative populations,
some of which can be modified (like smoking) and some of which
cannot (like gender and age).
HIV disease now means that CHD is no longer
simply a problem that comes with middle age. A recent impressive
study from California found that, compared with their HIV-negative
peers, CHD incidence more than doubled in HIV-positive men
aged 25-35 years and was a staggering six-times higher in
HIV positive men between ages 18-25.
HIV-positive women were also found to
have a significantly increased risk of heart disease, more
than double the risk for women age 18-24, and about one-and-a-half
times the risk for women between 25-44. This, concluded the
study’s authors, put younger HIV-positive people at a
risk of CHD “comparable in magnitude with the increase
associated with aging.”
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Clinicians will need to weigh the risks
of new treatment-related toxicities and possibility of virological
relapse when switching antiretroviral drugs…
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Interestingly, when the investigators looked
for evidence of a link between HAART and heart disease they
found that 18 to 33 year-olds on HAART had double the risk
compared to their peers who did not receive antiretroviral
therapy, but that once they reached 34, other factors (like
smoking and age) overshadowed HAART’S risks.
First change your lifestyle
In August, the Infectious Disease Society
of America published guidelines (www.idsociety.org) recommending
that all adults with HIV be evaluated and treated to reduce
their risk of heart disease and stroke, and included detailed
discussion of how to do just that.
“Clinicians will need to weigh
the risks of new treatment-related toxicities and possibility
of virological relapse when switching antiretroviral drugs
to the risks of potential drug interactions and new treatment-related
toxicities from lipid-lowering agents that are added to existing
regimens,” the guidelines’ authors warned.
Consequently, these U.S. guidelines prioritize
lifestyle changes over drug switching or lipid lowering therapy.
Surprisingly, however, stopping smoking was only mentioned
in passing despite the fact that smoking is the single most
significant modifiable lifestyle choice in the prevention
of CHD. Diet and exercise were given most space in the guidelines.
Assessing the risks
The U.S. guidelines review the latest
information on the prevalence and incidence of high total,
lowered HDL and increased LDL cholesterol, and high triglycerides,
and their relationship with cardiovascular disease in people
with HIV on HAART, AND recommend that antiretroviral drug
switching and/or lipid lowering therapy should be initiated,
depending on an individual’s 10 year-risk of CHD, which
they base on the Framingham Heart Study risk assessment tool.
However, this may not be sensitive enough
for CHD risk assessment in people with HIV, according to Dr.
Devi Nair, the U.K.’s Royal Free Hospital’s lipid
specialist who manages many HIV patients with metabolic disorders.
“One of the problems with assessing cardiovascular risk
in patients with HIV is that because they are mostly young,
even though they might have high cholesterol, low HDL and
high blood pressure and smoke, they would not be considered
at risk according to the Framingham calculation, which weighs
age as an important factor. In HIV patients, because risk
factors cluster at a vary young age, we have to be more proactive,”
she argues. “I do not use the Framingham calculator;
if a patient has a lipid problem, I count up the risk factors.
If they have more than one risk factor, I take the problem
seriously. If they have three or four risk factors, I treat
them.”
Are high sugar levels more of a concern
than high fat levels?
Although the U.S. guidelines focus on
cholesterol and triglycerides, there is a growing concern
amongst U.K. clinicians that hyperglycemia, insulin resistance
and diabetes (increasingly severe stages of the same disease
process—an inability to metabolize blood sugar or glucose)
are more risk than increased lipids in terms of CHD risk.
“It is important to realize that insulin resistance is
not sugar disease; rather it is a cardiac problem,” says
Dr. Nair. “Lipid metabolism is linked with insulin resistance
and both go hand-in-hand with HAART.
“The prevalence of insulin
resistance is much higher in HIV patients who take HAART,”
adds Dr Nair. “Infection with HIV itself does not make
people insulin resistant, in fact insulin sensitivity is better
if the patient is not treated and has infection with HIV that
is not controlled. Only when patients start taking drugs and
get better does insulin resistance develop.” Insulin
resistance will eventually lead to diabetes, which adds considerably
to the risk of CHD: people diagnosed with diabetes have a
similar level of heart attack in the past eight years.
Is switching from PIs the best option?
A recent systematic review of both the
published literature and conference abstracts on the relationship
between protease inhibitor (PI) use and cardiovascular risk
has found that with the exception of Reyataz (atazanavir),
all currently available PIs do appear to elevate risk factors
for heart disease. The U.S. guidelines note “lipid abnormalities
tend to be most marked with Norvir (ritonavir) and (Kaletra
lopinavir/ritonavir). Agenerase (Amprenavir) and Viracept
(nelfinavir) tend to have intermediate effects, whereas Crixivan
(indinavir) and Invirase (saquinavir hard-gel) tend to have
the fewest effects.” Preliminary reports suggest that
Reyataz, the latest PI, “appears to have little, if any,
effect on lipid concentrations.”
The NNRTIs Sustiva (efavirenz) and Viramune
(nevirapine) also cause alterations in lipid levels, “although
generally to a lesser degree than has been observed with PIs,”
according to the U.S. guidelines. However, the recent 2NN
study appeared to favor Viramune over Sustiva regarding cholesterol
and triglyceride levels although many clinicians still have
concerns about the potency of Viramune compared with Sustiva
as well as Viramune’s liver toxicities.
The recently completed NEFA study compared
the effects of switching from a protease inhibitor to Ziagen
(abacavir sulfate), Viramune or Sustiva. Although this study
found a trend toward a higher virological rebound rate in
those who switched to Ziagen, failures were almost entirely
confined to people who had received dual nucleoside analogue
treatment in the past. Ziagen-treated patients were significantly
less likely to require lipid-lowering medication by the end
of the study and had significantly lower total cholesterol
after 48 weeks.
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The news that HIV alone can increase cardiovascular
risk needs to be taken, if you pardon the pun, to heart
by everyone living with HIV.
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Less is known about the differing effects of PIs on insulin
resistance: a 2000 review found that Crixivan appeared to
have more of an effect on insulin levels than Viracept or
Invirase, but pointed out that the statistical standards of
the study were weak. The NEFA study found that after switching
from a protease inhibitor, glucose levels fell in Viramune
and Ziagen treated patients, but not in the Sustiva group.
Heart-friendlier HAART
Are some antiretrovirals less atherogenic? Is it possible
to switch to these and/or use them as first-line therapy in
the treatment-naïve? Preliminary data suggest that both
tenofovir and atazanavir may permit the use of more atherogenic
agents as part of HAART, on the assumption that either drug
exerts a benign effect.
Two years into a three-year study comparing Viread (tenofovir)
with Zerit (d4T, stavudine), alongside Epivir (3TC, lamivudine)
and Sustiva, the only significant differences between the
two arms of the study appear to be higher fasting cholesterol
and triglyceride levels in the Zerit-treated patients. Given
Sustiva’s tendency to increase lipids, and a lack of
previous evidence that Zerit raises lipid levels these results
suggest that Sustiva could be the agent affecting lipids,
and Viread may actually be exerting a moderating effect, rather
than Zerit a negative effect. More data is needed before this
theory is proved, or disproved, however.
The only switching study using atazanavir reported so far,
found that after switching from Viracept to (unboosted) Reyataz,
significant reductions in total cholesterol (16%), LDL cholesterol
(21%) and triglycerides (28%) and a significant increase in
high density lipoprotein (HDL) “good” cholesterol
(5%) were seen. Prior to receiving Viracept, however, the
study populations were drug-naïve, and appeared to continue
to sustain low viral load without the need for boosting. A
BristolMyers Squibb (BMS)-sponsored Phase IIIB study is currently
recruiting in the U.S. looking at the effect of serum LDL
cholesterol when switching from other protease inhibitor regimens
to atazanavir.
It is still a little early to come to any firm conclusions,
but Reyataz (at least when boosted with ritonavir) may also
help reduce lipids in the PI-experienced, while keeping viral
load under control. The BMS 045 study found that Norvir-boosted
Reyataz was equal to Kaletra in terms of anti-HIV potency
and still reduced total cholesterol significantly, while keeping
fasting triglycerides stable. [The 045 results were from 48
weeks and study participants are not being followed for long-term
efficacy and potency.]
It should be noted, however, that Reyataz and Viread should
not be combined without Norvir-boosting, according to an August
2003 ‘Dear Doctor’ letter from BMS, since this may
risk treatment failure, due to an interaction that reduces
Reyataz levels by up to 40%. They suggest that doctors consider
boosting Reyataz levels with Norvir, using the 300/100 mg
dose, if Reyataz and Viread must be used together.
Do you want to prove them wrong?
The news that HIV alone can increase cardiovascular risk
needs to be taken, if you pardon the pun, to heart by everyone
living with HIV. Simply being young no longer appears to protect
people with HIV from diseases previously associated with middle
age. Can we afford to rely on only one head-in-the-sand strategy—let
the doctors deal with it—when it is becoming clear that
changing to lipid-friendlier HAART or adding lipid-lowering
medications is probably not enough to make up for this increased
risk? Are the clinicians right about our lack of motivation
to take better care of ourselves? Do you want to prove them
wrong?
This article was first published in AIDS Treatment Update
issue 130 and is reprinted with permission from NAM (www.aidsmap.com).
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Glossary
Atherogenic—Producing
the most degenerative changes in artery walls.
Buffalo hump—A mass
of fat and connective tissue on the back of the neck.
Cardiovascular—Relating
to the heart and blood vessels
Cardiovascular disease—Includes
CHD (about 50%), stroke (about 25%), and other circulatory
system diseases.
Cholesterol—A waxy
substance, mostly made by the body and used to produce steroid
hormones.
Coronary heart disease (CHD)—Occurs
when the walls of the coronary arteries become narrowed by
a gradual fatty build-up. Heart attack and angina are main
symptoms.
Diabetes—Raised concentration
of sugar in the blood, due to insulin production or action
productions (insulin resistance, or reduced insulin sensitivity,
are also known as pre-diabetes).
HAART—Highly Active
Antiretroviral Therapy: anti-HIV combination therapy with
3 or more drugs.
Hyperglycemia—High
blood glucose level.
Lipodystrophy—A disruption
to the way the body produces, uses and distributes fat.
Metabolism—The mechanisms
which sustain life, turning carbohydrates and fat into energy,
and protein into muscle.
Mitochondrial toxicity—Mitochondria
are structures in human cells responsible for energy production.
When damaged by anti-HIV drugs, this can cause a wide range
of side-effects, including possibly fat loss.
Myopathy—A disorder
of muscle tissue of muscles.
National Cholesterol Education
Program—U.S. program aimed at reducing high blood
cholesterol. www.nhlbi.nih.gov/about/ncep/index.htm
NNRTI—Non nucleoside
reverse transcriptase inhibitor.
PI—Protease inhibitor.
Triglycerides—The basic
‘building blocks’ from which fats are formed.
Viral Load—The amount
of virus, usually from a blood sample, indicating the extent
to which HIV is reproducing in the body.
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