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.
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."
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.
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.
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."
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.
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.
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.
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 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-naive, and appeared to continue to sustain low viral load without the need for boosting. A Bristol-Myers 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.
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).
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.