Controversy over the risk of heart disease in people on HAART continued at the Third International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV Infection last week, with competing views on the significance of cholesterol elevations on HAART.
Dr Vincent Mooser of the University of Lausanne in Switzerland, a cardiovascular specialist who has been working with the Swiss HIV Cohort to look at the risk of heart disease, warned that an epidemic of atherosclerosis in people on HAART was a possibility. Although PI therapy may not be a direct cause of atherosclerosis, it could substantially increase the risk in people with other risk factors, especially those under 40 years old.
What is atherosclerosis?
Atherosclerosis - or `furring ‘ of the arteries - is a consequence of oxidated LDL cholesterol particles being deposited on the walls of arteries, where they are absorbed into the walls of the artery (the intima media) in an accumulation called a plaque. Eventually the plaque may become unstable, and may rupture, leading to what is called thrombosis.
This process is accelerated by smoking, by oxidative stress, by diabetes, and by low levels of HDL cholesterol. Chronic inflammatory conditions and hypertension also affect the rate at which plaques develop.
High LDL cholesterol levels are a surrogate marker for subclinical atherosclerosis. Direct damage can be measured by high resolution ultrasound imaging of the intima media.Thickening of the intima media is associated with a higher risk of cardiovascular events such as heart attack.
An analysis by Vincent Mooser’s group recently published in AIDS showed that HIV-positive individuals were significantly more likely to have plaques and carotid artery intima media thickening, but this was not associated with protease inhibitor therapy. Instead, the classic cardiovascular risk factors – high LDL cholesterol (> 4.0mmol/L), smoking and age – were associated with an increased risk of plaques, as was HIV infection.
People with HIV may be more predisposed to thickening of the intima media because of concomitant lifestyle factors such as smoking, although the inflammatory effect of HIV infection itself is unclear.
An analysis of 120 cases of premature coronary artery disease in Switzerland found that 35% of individuals who developed coronary artery disease before the age of 50 had only one risk factor, whilst a further 35% had just two risk factors. The most common risk factors were: smoking, which was practiced by 85% of the premature CAD cases compared to 30% of an age matched reference group from the Swiss population, and hyperlipidemia (40% in the CAD group vs 35% in the general Swiss population).
In a major analysis of studies carried out in the United States looking at 366,559 individuals, smoking, high blood pressure and cholesterol levels above 5.17mmol/l together increased an individual’s risk of coronary heart disease or death due to cardiovascular disease seven fold (Stamler).
Should cholesterol increases be treated?
However, clinicians disagree about the implications of relatively short term lipid elevations in people on HAART.
Dr Stefan Mauss, one of Germany’s leading HIV clinicians, recently looked at the make up of the cholesterol in the bloodstreams of 172 of his patients, and found that it may not be as atherogenic as first thought. He looked at the proportion of VLDL to LDL cholesterol particles, and found that the ratio of VLDL cholesterol to total cholesterol was much higher than in people with elevated cholesterol in the general population. When VLDL cholesterol is elevated in this way, the risk of heart disease is lowered. Less than one third of patients with a high total cholesterol had elevated LDL cholesterol.
“I used to treat very aggressively but now I would treat [cholesterol elevations] in patients with multiple risk factors and elevated LDL cholesterol” he told aidsmap.
Dr Jonathan Cartledge of London’s University College Medical School is also skeptical.
“I’m not convinced that just because we are seeing intima media thickening in people on HAART, that this translates into a long term increase in risk – if people stop or switch therapy, we know that the cholesterol goes down. Also, people may typically only be on protease inhibitors for a few years and other therapies in the future may not have the same effect [on lipids]. I'm not sure that short-term elevations will have the same effect on long-term risk as lifestyle factors which may go on for years and years, such as smoking.”
Dr Graeme Moyle of the Chelsea and Westminster Hospital pointed out that it may be far too early to tell whether treatment of lipid elevations will have an effect on clinical outcomes – and in the meantime, it may be expensive and may carry more risks than benefits.
“Are we really treating a blood test result, or are we doing something that’s going to beneficial in our patients, given the numbers needed to treat in order to show benefit?” he asked during a discussion on the effects of statin therapy on cardiovascular risk. A major study of pravastatin in Scotland found that 45 men with hypercholesterolemia must be treated for five years to prevent one non-fatal heart attack or death from cardiovascular causes, and 143 men must be treated to prevent one death from a cardiac cause (Shepherd).
In other studies, statins have only been shown to affect survival after at least eighteen months of treatment, suggesting that short term reductions in lipid levels have no effect on the risk of cardiovascular disease.
This means that long-term data from studies of switching therapy will be needed in order to show that any trends are sustained. At the Lipodystrophy Workshop Allain Lafeuillade presented 48 week results of the Trizal study, which looked at the effects of switching from stable PI-containing therapy to Trizivir.
This study showed that after 48 weeks, there was no difference in the percentage with viral load below 50 copies, but cholesterol and triglyceride levels fell significantly in the Trizivir group (median cholesterol reduction –0.80 mmol/L). However, cholesterol also fell by 0.44mmol/L in the continued HAART group (individuals with 24 months prior HAART and a median baseline cholesterol of 5.6mmol/L). This reduction was also statistically significant, despite the fact that cholesterol elevations worsened in 29% of the PI recipients.
A study from Houston, Texas, showed that in patients with high lipid levels, lipid lowering therapy was only partially successful. Sixty three consecutive patients were analysed. A mean cholesterol reduction of 19% was reported on the first lipid-lowering regimen (predominantly fibrates), and LDL cholesterol levels fell by just 5%. Only 16% of patients who continued protease inhibitor therapy achieved target levels of LDL and total cholesterol after more than one year of lipid-lowering treatment. Presenting the study, Dr Fahmida Visnegarwala said that management of dyslipidemia alone without correcting the underlying metabolic disturbances may not be effective, but Dr Michael Dube of the University of Indiana pointed out that a disappointingly small proportion of non-HIV patients (typically less than 40%) ever reach the lipid goals set out at the beginning of lipid-lowering therapy.
Another issue relevant to the use of lipid lowering drugs is the impact of diet on the success of lipid lowering drugs. Dr Carl Grunfeld noted that in patients with high triglyceride levels, adherence to a diet designed to lower triglyceride levels has improved the effects of lipid-lowering drugs. On its own, dietary adjustment in HIV-positive patients with lipid elevations did not result in significant cholesterol reductions in a study carried out by Dr Graeme Moyle at the Chelsea and Westminster Hospital, and when patients received pravastatin plus dietary advice in an open label study, adherence to dietary advice was poorer than in the dietary advice arm of the study.
Depairon M et al. Premature atherosclerosis in HIV-infected individuals – focus on protease inhibitor therapy. AIDS 15: 239-334, 2001.
Lafeuillade A et al. Trizal: Comparison of the metabolic disorders and clinical lipodystrophy 48 weeks after switching from HAART to Trizivir versus continued HAART (AZL30002). Antiviral Therapy 6 (supp 4): 20, 2001.
Mauss S et al. Hypercholesterolemia and HIV – time to reconsider a dogma? Antiviral Therapy 6 (supp 4): 58, 2001.
Moyle GJ et al. Dietary advice with or without pravastatin for the management of hypercholesterolemia associated with protease inhibitor therapy. AIDS 15: 1503-1508, 2001.
Rogers S et al. Prevention of coronary heart disease with pravastatin. New England Journal of Medicine 334:1333-1335, 1996.
Shepherd J et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. New England Journal of Medicine 333: 1301-1308, 1996.
Stamler J et al. Low risk factor profile and long term cardiovascular and non-cardiovascular mortality and life expectancy: findings for five large cohorts of young adult and middle-aged men and women. Journal of the American Medical Association 282 (21): 2012-2018, 1999.
Visnegarwala F et al. Inconsistent effects of lipid lowering drugs in the management of HIV-associated dyslipidemias. Antiviral Therapy 6 (supp 4): 21, 2001.