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For several years now there
has been debate and confusion over whether coronary heart
disease is a real phenomenon for people with HIV. In the HIV
community, heart attacks are most certainly on the rise at
least anecdotally. Increased levels of cholesterol and triglycerides
that result from treatment may or may not be contributing
to heart disease. So the important questions are: do HIV drugs
cause an increase in heart complications, or are people with
AIDS becoming more susceptible as they age while continuing
to survive? Or is it both?
Several past HIV conferences
have presented controversial studies disputing the actual
incidence of heart disease in HIV. At the 10th Conference
on Retroviruses and Opportunistic Infections in Boston in
February there was an entire session devoted to heart disease.
But the session generated much controversy and debate based
on the conflicting reports. As in the past, each study seemed
to contradict the others.
One conundrum in figuring
out if there is a problem is just trying to count heart disease
cases through different retrospective or “look back” studies
of people with HIV. In order for the studies to be accurate
you have to consider all the other factors that may influence
heart disease such as age, smoking, previous heart disease,
body weight, diabetes and hypertension, all symptoms that
are very common in the general population. The best way to
see if heart disease is actually happening as a result of
HIV therapy, or long-term HIV disease is to design a study
following similar matched groups of people, one group taking
the drugs, the other not taking them and using a control group
as a comparison.
The other problem in discerning
what is going on with heart disease is asking what to look
for. Do you look for signs of heart disease, or actual disease,
symptoms or risks? A long-term prospective matched study that
is well controlled and looking for actual heart disease would
be the most definitive. But that kind of study won’t help
anyone right now. Since heart disease takes many years to
take hold, it’s going to take a lot more time to see that
anything is happening through a prospective study.
In the Boston conference,
the D:A:D study, one very large retrospective analysis by
Dr. Friis-Møller and colleagues, looked at 23,490 people in
11 cohorts (groups) on three continents. Data collected were
risk of heart attack (specifically myocardial infarction or
MI), incidence of MI, and HIV disease.
The investigators showed
that HAART use (highly active antiretroviral therapy) was
associated with a 27% relative increase in the rate of MI
per year of exposure over the first seven years of data collection.
Interestingly, they also saw that lipodystrophy was found
to be protective against heart disease, but it was defined
by subjective analysis, so that may not be accurate. Overall,
despite those results, and the shortcomings of the study,
the investigators concluded that the benefits of HAART outweigh
concerns over cardiovascular disease. One of the researchers
noted that the actual risk was small—there were only 129 MIs
among the nearly 24,000 people, of which 36 were fatal.
There are significant questions
about the analysis and measurements used in this study. There
were limitations to collecting the information retrospectively,
then conducting prospective follow-up. However, the researchers
plan to follow the cohort over time. They can then analyze
people who enter the study not on HAART and then start medications,
and begin to sort out factors contributing to heart disease
from HIV and its therapies versus the traditional risk factors
such as smoking, age, sex and previous cardiovascular heart
disease. Longer term prospective information will give important
information in this large cohort.
Another sizeable cohort came
from Johns Hopkins University. As with the Friis-Møller analysis,
there were many confounding factors here. Bottom line is that
incidence of heart disease is higher in this study than a
matched population based survey used as a comparison. But
comparing historic controls to a current database is not accurate
and does not account for smoking, metabolic complications
and HIV disease. With this cohort there is no indication if
HIV therapy has anything to do with the slightly higher incidence
of heart disease.
Two other studies were presented
in the Complications of HIV session in Boston through prospective
studies looking at carotid artery intima-medial thickness
(IMT), a measurement of the thickness of the heart wall that
is predictive of clinical cardiac disease. The AIDS Clinical
Trials Group (ACTG) designed a prospective study without the
confounding issues seen in the large cohorts above and was
the first study looking at the relation of HIV therapies and
HIV to heart disease. Forty-five “triads” consisting of one
person with HIV on a protease inhibitor, one person with HIV
not on a protease inhibitor, and one HIV uninfected individual
(the control group) were compared at seven sites and analyzed
at 96 weeks.
When the study was complete
there was an increase in waist to hip measurement (one of
several measurements of fat redistribution) and elevated triglycerides
and total cholesterol in the people on protease inhibitors.
However, there was no significant difference in the IMT between
all three groups. Even though it takes decades to develop
cardiovascular heart disease, this well matched controlled
study is the right design to find out if the increased IMT
translates into actual heart disease in people using protease
inhibitors. It will just take longer than 96 weeks to see
if something shows up. The study is continuing.
A San Francisco study looked
at IMT in 106 patients on HIV therapy. At one year the study
showed a small increase in IMT matched to previous general
population studies. In contrast to the ACTG study mentioned
above, the investigators concluded that HIV and its therapy
in addition to traditional risk factors may contribute to
the development of heart disease. The differences between
the outcome of these two studies may be because of the location
of the measurement of heart wall thickness. Also, there was
no control group to use as a comparison in this study. Again,
more time and the addition of a control group would help support
the findings of this study. This information would seem to
be common sense and leads to the preventative message that
anyone on a protease inhibitor should not smoke if they want
to help prevent any heart disease.
So, one can see through these
reported studies the complexity and confusion over just what
exactly is happening with heart disease in HIV. It has become
a major area of AIDS research due to the concern over the
life-threatening implications of heart disease and the growing
concern about drug toxicity. Certainly, heart disease is much
more life threatening than body fat redistribution. But we
still don’t know if the two complications are related.
Clearly, there is a great
need for better analysis, controlled comparative studies,
and a look at all the confounding risk factors in long-term
prospective studies if we are going to find any true answers
and stop all the wondering. But the conflicting results in
these studies may just be what it takes to persuade researchers
into designing the best, most appropriate studies to give
us an answer. Meanwhile, we wait in hope and anticipation.
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