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Managing Metabolic Syndrome
   Last updated: 25.08.04
Can changing your lifestyle or switching antiretrovirals help lower your cardiovascular risk? by Edwin J Bernard
Since we last reported on metabolic abnormalities and HIV (ATU 123), evidence continues to accumulate that HIV does indeed increase the likelihood of coronary heart disease (CHD) and stroke, with HAART 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 (over 5 mmol/l)


  • 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, or lipid; over 4.4 mmol/l )


  • hyperglycaemia (high blood sugar, or glucose; over 5 mmol/l)


  • 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 (1), HAART’s uncanny ability to keep us alive means that as an increasingly ageing 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). Back in 1985, the British Regional Heart Study identified the relative risk of factors associated with CHD in middle-aged men drawn from general practices in 24 British towns [see TABLE 2 (2)].

HIV disease now means that CHD is no longer simply a problem that comes with middle age. A recent impressive study from California (3) found that, compared with their HIV-negative peers, CHD incidence more than doubled in HIV-positive men aged 25 - 34 years and was a staggering six-times higher in HIV-positive men aged between 18-25.

HIV-positive women were also found to have a significantly increased risk of heart disease, more than double the risk for women aged 18 - 24, and about one-and-a-half times the risk for women aged 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 ageing.”

Interestingly, when the investigators looked for evidence of a link between HAART and heart disease they found that 18 - 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 ageing) overshadowed HAART’s risks.

First change your lifestyle?
In August, the Infectious Disease Society of America published guidelines (4) 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 US guidelines prioritise 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 and this month's accompanying article explores these options in more detail.

However, given the UK’s penchant for fried and sugary foods, high smoking rates and perversely proud coach-potato status, can we afford to be as conservative with lipid interventions on this side of Atlantic?

In June, the Royal Society of Medicine organised a round table meeting on the subject of lipid management that will be turned into a booklet later this year. Whilst smoking, diet and exercise interventions were discussed, and considered to be equally, if not more important than medical interventions, there did appear to be a consensus amongst the experienced clinicians that it was up to doctors to make the most heart-friendly choices in terms of drug therapy - and to monitor the correct metabolic parameters regularly - since many patients are simply not motivated enough to make lifestyle changes until it is too late.

Assessing the risks
The US 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 (5).

However, this may not be sensitive enough for CHD risk assessment in people with HIV, according to Dr Devi Nair, the Royal Free’s lipid specialist who manages many HIV patients with metabolic disorders, and one of the round table participants. “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 weights age as an important factor. In HIV patients, because risk factors cluster at a very 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 insulin resistance, I take it a little more 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 US guidelines focus on cholesterol and triglycerides, there is a growing concern amongst UK clinicians that hyperglycaemia, insulin resistance and diabetes (increasingly severe stages of the same disease process - an inability to metabolise blood sugar or glucose) are more risky than increased lipids in terms of CHD risk. “It is important to realise that insulin resistance is not a 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.”

Dr. Nair takes elevated glucose levels very seriously in terms of CHD risk, since fasting glucose levels above 5 mmol/l signifies insulin resistance. “The clock starts ticking for cardiovascular disease before people become hyperglycaemic,” she says. “The quality of LDL is also different in the presence of insulin resistance: the LDL particles are small, dense and more atherogenic.”

“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 risk to people who have suffered a heart attack in the past eight years. “In addition,” notes Dr. Nair, “the inflammation which is part of insulin resistance adds to their risk further because the cytokines produced contributes to atherogenity.”

The latest US Guidelines don’t shy away from the issue, but see it as secondary to high lipids. The latest British HIV Association (BHIVA) Guidelines (6) take it more seriously, however, and include the recommendation that “insulin resistance should be treated with metformin”, as the first of only four conclusions in their section on lipodystrophy.

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 atazanavir, all currently available PIs do appear to elevate risk factors for heart disease (7). The US guidelines note that “lipid abnormalities tend to be most marked with ritonavir and lopinavir/ritonavir (Kaletra). Amprenavir and nelfinavir tend to have intermediate effects, whereas indinavir and saquinavir tend to have the fewest effects.” Preliminary reports suggest that atazanavir, the latest PI, currently only available in the UK to a limited number of people through an expanded access scheme, “appears to have little, if any, effect on lipid concentrations.”

The NNRTIs efavirenz and nevirapine also cause alterations in lipid levels, “although generally to a lesser degree than has been observed with PIs,” according to the US guidelines. However, the recent 2NN study appeared to favour nevirapine over efavirenz regarding cholesterol and triglyceride levels (8) although many clinicians still have concerns about the potency of nevirapine compared with efavirenz as well as nevirapine’s liver toxicities.

The recently completed NEFA study compared the effects of switching from a protease inhibitor to abacavir, nevirapine or efavirenz (9). Although this study found a trend towards a higher virological rebound rate in those who switched to abacavir, failures were almost entirely confined to people who had received dual nucleoside analogue treatment in the past. Abacavir-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.

Less is known about the differing effects of PIs on insulin resistance: a 2000 review found that indinavir appeared to have more of an effect on insulin levels than nelfinavir or saquinavir, but pointed out that the statistical standards of the study were weak. (10) The NEFA study found that after switching from a protease inhibitor, glucose levels fell in nevirapine and abacavir-treated patients, but not in the efavirenz 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-naive? 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 tenofovir with stavudine, alongside lamivudine and efavirenz, the only significant differences between the two arms of the study appear to be higher fasting cholesterol and triglyceride levels in the stavudine-treated patients. (11) Given efavirenz’s tendency to increase lipids, and a lack of previous evidence that stavudine raises lipid levels (12) these results suggest that efavirenz could be the agent affecting lipids, and tenofovir may actually be exerting a moderating effect, rather than stavudine 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 nelfinavir to (unboosted) atazanavir, 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 nelfinavir, however, the study population were drug-naive, and appeared to continue to sustain low viral load without the need for boosting. (13) A Bristol Myers Squibb (BMS)-sponsored Phase IIIB study is currently recruiting in the US looking at the effect of serum LDL cholesterol when switching from other protease inhibitor regimens to atazanavir.

Professor Brian Gazzard suggests that given current evidence switching from a PI-based regimen to atazanavir- rather than nevirapine or abacavir - may well be the best option, because “even if resistance testing does not suggest NNRTI or nucleoside analogue resistance, the possibility of resistance must be relatively high. I would usually opt for atazanavir in the majority of patients who had previously failed an NRTI/NNRTI-containing regime but have not failed a PI.”

It is still a little early to come to any firm conclusions, but atazanavir (at least when boosted with ritonavir) may also help reduce lipids in the PI-experienced, whilst keeping viral load under control. The 045 study found that ritonavir-boosted atazanavir was equal to lopinavir/ritonavir in terms of anti-HIV potency and still reduced total cholesterol significantly, whilst keeping fasting triglycerides stable. The same study found that combining atazanavir with saquinavir also appears to be lipid friendly, but is not as potent in terms of sustained viral load compared with atazanavir/ritonavir or lopinavir/ritonavir. (14)

It should be noted, however, that atazanavir and tenofovir should not be combined without ritonavir-boosting, according to an August 2003 ‘Dear Doctor’ letter from BMS, since this may risk treatment failure, due to an interaction that reduces atazanavir levels by up to 40%. They suggest that doctors consider boosting atazanavir levels with ritonavir, using the 300/100 mg dose, if atazanavir and tenofovir 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 round table clinicians right about our lack of motivation to take better care of ourselves? Do you want to prove them wrong?

Key Conclusions
Metabolic abnormalities are part of lipodystrophy syndrome and are a cause for concern, since the greater the metabolic changes, the higher the risk of heart disease and stroke.

Both HIV, and some HIV drugs, particularly protease inhibitors, increase these risks, along with certain lifestyle choices and some unchangeable factors like how old you are, what gender and ethnicity you are, and whether cardiovascular problems run in the family.

It is possible to change some aspects of your lifestyle to reduce these risks. The most important of these is stopping smoking, but also eating a heart-healthier diet and exercising regularly can make a difference.

Being unable to metabolise blood sugar - known as insulin resistance - or getting diabetes, is probably more of a cardiovascular risk than having high blood fats alone. Medication, diet and exercise can help reduce these risks.

If you are starting on anti-HIV medication for the first time, or want to change from your first combination, it should be relatively easy to find HAART that packs a powerful anti-HIV punch without adding significantly to your cardiovascular risk.

If you have been on several HAART combinations and you or your doctor are concerned it may be adding to your cardiovascular risk, there are lipid-lowering drugs that may help reduce the risk. Additionally, a new protease inhibitor, atazanavir, is now available that may reduce the risk if you switch from another protease inhibitor, although more studies are needed to know how successful this will be in the long-term.

References
1. Law M. HIV Med 4:1-10, 2003.
2. Shaper AG. J Epi & Com Health 39: 197-209, 1985.
3. Currier J. JAIDS 33: 506 - 512, 2003.
4. Dubé MP. CID 37: 613-27, 2003.
5. see http://hin.nhlbi.nih.gov/atpii/calculator.asp
6. see http://www.bhiva.org/guidelines/2003/hiv/index.html
7. Rhew DC. CID 37: 959-72, 2003.
8. van Leth F. 10th CROI, Boston, abs 752, 2003.
9. Martinez E. NEJM 349: 1036-46, 2003.
10. Dubé MP. CID 31:1467-75, 2000.
11. Staszewski S. 10th CROI, Boston, abs 564b, 2003.
12. Matthews GV. JAIDS 24: 310-5, 2000.
13. Murphy R. 10th CROI, Boston, abs P555, 2003.
14. Badaro R. 2nd IAS Conf, Paris, abs 118, 2003.