Several
studies have shown that people with HIV have
an elevated risk of cardiovascular disease. This may be related to chronic HIV
infection itself or use of antiretroviral
therapy -- in particular protease
inhibitors (PIs) -- but the specific underlying mechanisms remain poorly understood.
One
possible contributing factor may be fibrinogen, an inflammatory factor associated
with blood clotting that appears to play a role in atherosclerosis, or "hardening
of the arteries."
As described in the March 30, 2008 issue of AIDS,
researchers measured plasma fibrinogen levels of 1131 HIV positive participants
in the Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM)
recruited in 2000 and 2001, as well as 281 HIV negative control subjects from
the population-based Coronary Artery Risk Development in Young Adults (CARDIA)
study. Multivariable linear regression was used to identify factors associated
with fibrinogen levels. FRAM participants also received MRI scans to measure adipose
(fat) tissue.
Results
•
HIV positive
men and women had lower levels of subcutaneous fat compared with HIV negative
subjects.
•
Visceral fat
was reduced in HIV positive men relative to control subjects, but elevated in
HIV positive women.
•
HIV positive
individuals had higher fibrinogen levels compared with uninfected controls:
•
8% (25 mg/dl)
higher for HIV positive men (P = 0.006); •
6% (21 mg/dl)
higher for HIV positive women (P = 0.39).
•
After adjusting
for other cardiovascular risk factors such as smoking, age, and body fat, HIV
positive men still had a significantly higher fibrinogen level compared with controls,
but the difference did not reach statistical significance for HIV positive women.
•
Among the HIV
positive individuals, median fibrinogen levels were 11% (39 mg/dl) higher in patients
currently taking any protease inhibitor compared with those not using a PI (P
< 0.0001).
•
Patients taking
ritonavir-boosted indinavir had a median fibrinogen level 8% higher than those
taking indinavir alone (P = 0.049).
•
Individuals
taking lopinavir/ritonavir (Kaletra)
had a median 12% higher fibrinogen level than those not taking the drug.
•
Fibrinogen levels
were lower by 9% (32 mg/dl) in HIV positive patients taking a non-nucleoside reverse
transcriptase inhibitor (NNRTI) compared with those not using a NNRTI:
•
The associations
between ritonavir, indinavir, nevirapine, and efavirenz use and fibrinogen levels
persisted in a multivariate analysis, and were independent of other antiretroviral
agents.
•
Besides antiretroviral
therapy, other factors significantly associated with higher fibrinogen levels
in HIV positive patients included older age, black race/ethnicity, smoking, elevated
visceral and subcutaneous fat, higher HIV viral load, and elevated C-reactive
protein.
•
However, the
association between antiretroviral drugs and fibrinogen levels persisted after
adjusting for these other cardiovascular risk factors.
Conclusion
Based
on these findings, the study authors concluded, "Protease inhibitor use is
associated with elevated fibrinogen levels which may contribute to increased risk
of atherosclerosis in HIV-infected patients."
Conversely, they added,
"NNRTI use is associated with lower fibrinogen levels which may decrease
risk of atherosclerosis."
In their discussion, the investigators acknowledged
that this study did not include more recently approved PIs including atazanavir
(which does not raise blood fat levels as much as other drugs in its class), darunavir,
and tipranavir. However, they
noted that even the small dose of ritonavir used to boost levels of other PIs
was associated with higher fibrinogen levels.
They
added that the fact that PI use remained associated with elevated fibrinogen even
after controlling for C-reactive protein suggests that mechanisms besides inflammation
are likely involved.
04/15/08
Reference E
Madden, G Lee, DP Kotler, and others. Association of antiretroviral therapy with
fibrinogen levels in HIV-infection. AIDS 22(6): 707-715. March 30, 2008.
One
possible contributing factor may be fibrinogen, an inflammatory factor associated
with blood clotting that appears to play a role in atherosclerosis, or "hardening
of the arteries."
