[pronut-hiv] More data on role of antiretrovirals, interventions, HCV, in cardiovascular disease risk

["ProNut-HIV" <pronut-hiv@healthnet.org>]

AIDSMAP
CROI: More data on role of antiretrovirals, interventions, HCV, in
cardiovascular disease risk

Although the biggest news regarding cardiovascular disease risk at last
month's Thirteenth Conference on Retroviruses and Opportunistic
Infections (CROI) came from the Data Collection on Adverse Events of
Anti-HIV Drugs (D:A:D) study, reported here, several other important
studies presented in Denver provided additional data on the role of
antiretrovirals, interventions, and hepatitis C virus (HCV) in
cardiovascular disease risk in both adults and children. 

Could aggressive interventions be reducing the long-term risk of
PI-induced cardiovascular disease? 
Kaiser Permanente of Northern California is a private health insurance
organisation looking after more than three million people in their own
medical facilities, with more than 5000 HIV-positive patients. Utilising
medical records they systematically identified rates of cardiovascular
disease, including heart attack, or myocardial infarction, and compared
the risk in HIV-positive males aged 35-64 with men aged 35-64 not
diagnosed HIV-positive. (Klein) 

Out of 5430 HIV-positive men, 140 experienced a cardiovascular disease
event - of which 86 were heart attacks - over the nine-and-a-half years
of observation. The other cardiovascular disease events consisted of
atherosclerosis (hardening and narrowing of the arteries) which can lead
to coronary artery disease and angina. Compared with the HIV-negative
men of the same age, the HIV-positive men were found to have
significantly higher rates of both cardiovascular disease (2.9 vs. 6.0
events per 1000 patient-years; p<0.001) and heart attacks (2.2 vs. 3.6
events per 1000 patient-years; p=0.002). 

When the rates of cardiovascular disease - and heart attacks,
specifically - were compared between the HIV-positive men who had
received protease inhibitors (PIs), for a mean of 4.5 years (resulting
in 15,527 person-years of follow-up) with those had never received PIs
(for a mean of 2.3 years, and 11,390 person-years of follow-up), the
investigators found that there was a trend towards an increased risk
with PI exposure. They found that the age-adjusted relative risk of a
heart attack was increased by 16% for each year of PI exposure, roughly
equivalent to a doubling of the risk every six years. 

Although 16% is exactly the same increased relative heart attack risk
for yearly PI exposure reported by the D:A:D study, in this case the
investigators found that there was only a trend for this 16% increased
risk (p=0.112) and that the risk was not necessarily cumulative. Rather,
the relative risk for heart attacks on PIs appeared to have peaked at
between four and six years of PI exposure, and was actually reduced
after six years. 

This may well have been due to the introduction of interventions that
seek to modify traditional cardiovascular disease risks - like stopping
smoking and using lipid- and blood pressure-reducing medication - as
well as the availability of atazanavir (Reyataz), a newer PI that
appears to have a neutral effect on lipids. 

The investigators found that: 


between 2001 and 2005, the percentage of PI-treated patients on
atazanavir rose from 6% to 35%


between 1997 and 2005 the percentage of PI-treated patients on lipid
lowering therapy increased from 1% to 27%


and the percentage of current smokers fell from 21.1% in 2002-3 to
17.9% in 2004-5.

Together, these interventions appeared to offset the increased risk of
both cumulative PI exposure and of ageing: the investigators found
significantly improved mean total cholesterol, HDL and systolic blood
pressure levels between 2000-1 and 2004-5 (p<0.001) and a steady overall
ten-year cardiovascular disease risk (as measured by Framingham risk
scores) between 2000-1 and 2004-5 (8.6% vs. 8.3%) despite a significant
rise in the mean age of the cohort. 

Are traditional risk factors the most important driver of
cardiovascular disease? 
Interestingly, data from the 8000-strong HIV Outpatient Study (HOPS)
cohort both supports and contrasts with the Kaiser Permanente study.
Although they found that lipid-lowering medications reduced the risk of
cardiovascular disease, they found that switching to atazanavir, or a
non-nucleoside (NNRTI) had no effect on cardiovascular disease risk.
(Lichtenstein) 

HOPS is an ongoing multicentre study of HIV-positive individuals in
seven US cities. Between 1993-2005, out of 8024 cohort members, there
were 209 cardiovascular disease events, including 57 heart attacks, 44
strokes and 86 coronary artery disease events. Although incidence of
heart attacks peaked between 2000-2 (at 3.5 events per 1000
patient-years) and was around 1.1 events per 1000 patient-years in 2005,
incidence of strokes (2.8 events per 1000 patient-years) and coronary
artery disease (11.5 events per 1000 patient-years) were highest in
2005. 

When the investigators analysed the relative risk factors associated
with cardiovascular disease events (restricted to the 1807 patients
diagnosed with hyperlipidaemia, or high blood fats) they found that the
risk of cardiovascular disease was associated only with traditional risk
factors: age over 40 (Adjusted Odds Ratio, AOR, 3.31; p<0.001); diabetes
(AOR, 3.24; p<0.001); hyperlipidaemia (AOR, 1.95; p=0.024); and
hypertension, or high blood pressure (AOR, 1.73; p=0.059). In addition,
the nadir, or lowest ever level of high density lipoprotein (HDL, "bad")
cholesterol was slightly protective of cardiovascular disease (AOR,
0.97; p=0.004). 

Although the investigators found that use of lipid-lowering drugs
reduced the risk of cardiovascular disease by two-thirds (Hazard Ratio
0.34; 95% CI, 0.14-0.85; p=0.021), no link was found with a specific
antiretroviral agent. In addition, no reduction in risk was found with a
switch to atazanavir (p=1.0) or to any NNRTI (p=0.27) from a PI.
However, even the much larger D:A:D study does not include enough
patients to allow detection of the role of individual protease
inhibitors on the risk of cardiovascular disease. 

A smaller study from Boston (Gerrior) which examined coronary
calcification - a marker of subclinical atherosclerosis - in 129
HIV-positive individuals over three years, which found that those with
calcification at baseline were more likely to have calcification after
three years, also concluded that it was traditional risk factors that
were the main driver of cardiovascular disease in their cohort. 

Prematurely 'ageing' arteries in adults and children 
A study from Frankfurt, Germany (Stephan) suggests that HIV-positive
individuals have the equivalent artery health of HIV-negative
individuals who are up to five years older, and that this means a higher
risk of cardiovascular disease. 

Investigators from Frankfurt's Goethe University compared artery wall,
or intima-media, thickness in 292 HIV-positive individuals diagnosed
HIV-positive a median 10.6 years ago, with 1168 individuals enrolled in
a cardiovascular risk study who had not tested positive for HIV.
Previous studies have shown that increased artery wall thickness is
linked to an increased risk of heart attack. 

They found that the HIV-positive individuals (95.5% of whom had taken,
or were currently taking, antiretroviral therapy) were significantly
more likely to have increased wall thickness at several artery
locations. The investigators found no correlation between any individual
drug or class of antiretrovirals. 

However, the HIV-positive individuals were much more likely to smoke
than the HIV-negative controls (27 vs. 13.4 pack-years; p<0.0001), which
could also have contributed to these 'ageing' arteries. 

They concluded that HIV-positive individuals have artery health similar
to HIV-negative people that are four or five years older, and that these
'ageing' arteries means an increase in cardiovascular risk of between
4-14% over five years. 

Something similar appears to be happening in HIV-positive children on
antiretroviral therapy, according to a small study from the United
States. (McComsey) 

Investigators measured intima-media thickness and other cardiovascular
risk factors in 27 HIV-positive children with a median age of ten with
17 age-matched HIV-negative controls. The HIV-positive children had been
on antiretroviral therapy for a median of 79 months, and on PIs for a
median of 29 months. 

Total and LDL cholesterol and triglycerides were significantly higher
in the HIV-positive children (p=0.01 or greater for all three), and
carotid artery wall thickness was also found to be greater in the
HIV-positive children on the both the left (p=0.038) and right (p=0.08)
sides. 

The investigators concluded that these differences indicate that
HIV-positive children on antiretroviral therapy may be at an increased
risk of premature cardiovascular disease. They are following-up these
children for 144 weeks, and will report their results at a future
conference. 

Does HCV genotype 3 reduce cardiovascular disease risk? 
It has previously been reported by investigators from Spain and the
United States that hepatitis C virus (HCV) coinfection reduces levels of
certain blood fats. 

At this year's CROI, researchers from Italy compared 415 HIV
monoinfected and 307 HIV/HCV coinfected individuals on PI- or
NNRTI-based antiretroviral therapy between January 2001 and November
2004. They, too, found that HIV/HCV coinfection resulted in lower levels
of total cholesterol and triglycerides independently of antiretroviral
therapy (Lapadula). 

However, when they examined lipid levels by HCV genotype, they found
that HCV genotype 3 (HCV-3) reduced lipid levels even more than the
other HCV genotypes. 

In comparison to HIV monoinfected individuals, HCV-3 was associated
with a 45-fold lower risk of high (>200mg/dL) total cholesterol
(p<0.0001). In contrast, the other HCV genotypes (1, 2 and 4) were
associated with an 18-fold lower risk of high total cholesterol
(p<0.0001). 

Similarly, when the investigators compared triglyceride levels in HCV-3
coinfected individuals with HIV monoinfected individuals, HCV-3 was
associated with a 39-fold lower risk of high (>180mg/dL) triglycerides
(p=0.017). In contrast, the other HCV genotypes were associated with a
7-fold lower risk of high triglycerides, but this was not statistically
significant (p=0.558). 

The investigators concluded that hepatitis C virus (HCV) affected
elevations in total cholesterol and triglycerides independently of
antiretroviral therapy. Whilst HCV coinfection was associated with
protection from high total cholesterol, and HCV coinfection per se was
associated with a lower risk of high triglycerides on antiretroviral
therapy, it is HCV-3 that is the driving factor here. 

The exact reasons for HCV's protective effects - and HCV-3's in
particular - against lipid elevations is not known. It is also not yet
known whether these lower lipid levels translate into a lower
cardiovascular disease risk over the long-term. 

References 
Gerrior J et al. Predictors of abnormal coronary calcification scores
(CCS) at three years in the Nutrition for Healthy Living cohort .
Thirteenth Conference on Retroviruses and Opportunistic Infections,
Denver, abstract 739, 2006. 

Klein D et al. Hospitalization of CHD and MI among Northern California
HIV+ and HIV- men: additional follow-up, changes in practice and
Framingham risk scores. Thirteenth Conference on Retroviruses and
Opportunistic Infections, Denver, abstract 737, 2006. 

Lapadula G et al. Influence of hepatitis C genotype on lipid elevations
in HIV-positive patients during highly active antiretroviral therapy.
Thirteenth Conference on Retroviruses and Opportunistic Infections,
Denver, abstract 877, 2006. 

Lichtenstein KA et al. Analysis of cardiovascular risk factors in the
HIV Outpatient Study (HOPS) cohort. Thirteenth Conference on
Retroviruses and Opportunistic Infections, Denver, abstract 735, 2006. 

McComsey G et al. Carotid intima media thickness and cardiovascular
markers in HIV infected children. Thirteenth Conference on Retroviruses
and Opportunistic Infections, Denver, abstract 691, 2006. 

Stephan C et al. Long term HIV infection as an independent risk factor
for early atherosclerosis. Thirteenth Conference on Retroviruses and
Opportunistic Infections, Denver, abstract 738, 2006.