Cardiovascular Disease in People with HIV - Part II

What Does It All Mean?

Practical Implications

What are the implications of the disparate and sometimes conflicting data on HIV disease, antiretroviral therapy, and cardiovascular disease? Will elevated blood fat levels, abdominal fat accumulation, diabetes, and high blood pressure in people taking HAART lead to an increased incidence of cardiovascular events, as is the case among those in the general population with similar risk factors? All evidence to date indicates that it is still too soon to know.

On the one hand, in the words of Pablo Tebas, MD, "there is not a very good biological reason to think that these elevations are not going to be associated with an increased risk of cardiovascular disease." According to the Adult AIDS Clinical Trial Group (AACTG) Cardiovascular Disease Focus Group, "On the basis of precedent in other disease states, there is reason to believe that HIV treatment-associated changes in lipid levels are likely to result in some degree of increased cardiovascular risk. It appears likely that the chronic presence of traditional cardiovascular risk factors increases risk regardless of the etiology, and this same potential certainly exists during the long-term management of HIV-infected subjects." As AACTG focus group members Oluwatoyin Falusi, MD, and Judith Aberg, MD, point out, "Even if [HIV positive] patients are not at increased risk for cardiovascular disease, they are at least at the same risk as HIV negative, age-matched persons with similar risk factors."

Beyond studying risk factors, some researchers have looked for actual evidence of early cardiovascular disease in people with HIV. In the November 10, 2000 issue of AIDS, Paolo Maggi, MD, of the University of Bari in Italy and colleagues reported that 29 of 55 study participants (nearly 58%) taking PIs showed evidence of carotid artery dysfunction compared with 7 of 47 PI-naive participants (15%) and 7 of 104 HIV negative participants (7%). The carotid arteries in the neck supply blood to the brain, and plaques in these vessels are associated with strokes. In contrast, Michèle Depairon, MD, of CHUV University Hospital in Lausanne, Switzerland, and colleagues found that while carotid and femoral (leg) artery plaques were significantly more common in HIV positive people (93 of 168, or 55%) compared with HIV negative people (26 of 68, or 38%), there was no independent association with PI use.

On the other hand, lipid level elevations in people taking HAART may not be quite as similar as many have assumed to hyperlipidemia in the general population. Stefan Mauss, MD, of the Center for HIV and Hepatogastro-enterology in Düsseldorf, Germany, and colleagues presented results at the February Retrovirus conference suggesting that a closer look at cholesterol may be indicated. The researchers analyzed fasting blood samples from 187 HIV positive participants receiving different types of antiretroviral treatment. Overall, 45% had high total cholesterol levels; of these, 14% had elevated LDL levels, 16% had elevated LDL plus elevated very low-density lipoprotein (VLDL) levels, and 66% had elevated VLDL levels only. The rate of elevated LDL -- about 30% -- was comparable to that in the population at large. The other participants with elevated total cholesterol had only high VLDL, which is believed to be less atherogenic (likely to lead to cardiovascular disease) because the particles are too large to deposit cholesterol in artery walls.

HAART has only been in use for six years, and cardiovascular disease generally takes years or decades to develop. The long-term impact of HIV infection and antiretroviral therapy on the heart and blood vessels is only beginning to be revealed. A majority of people receiving treatment for HIV still are relatively young. The complete picture may only emerge when larger numbers of people who have taken anti-HIV drugs for many years reach their fifties, the age at which cardiovascular problems typically begin to occur. Large, longitudinal cohort studies spanning many years will be needed to uncover definitive answers to the question of whether HIV infection and/or antiretroviral therapy increases the incidence of cardiovascular events in people with HIV.

Risk vs. Benefit

Some researchers have attempted to quantify the increased risk of heart disease due to blood lipid elevations related to HAART, and to weigh this against the benefits of antiretroviral therapy. Using data from the Framingham Heart Study, Carl Grunfeld, MD, of the San Francisco Veterans Affairs Medical Center calculated that cholesterol and triglyceride increases in people using PIs could be expected to lead to a small average increase in coronary heart disease -- one case per 100 people over 10 years -- but that this risk was outweighed by the benefits of HAART. However, in people with additional risk factors such as smoking, high blood pressure, male sex, age over 50 years, and/or family history of heart disease, the additional increase in cardiovascular events may be as high as 27 cases per 100 people over 10 years.

Matthias Egger, MD, of the University of Bristol in the UK also has attempted to predict the impact of HAART-related metabolic changes on heart disease risk. Dr. Egger applied relative risk figures from the Caerphilly Heart Disease Study to a cohort of 113 HIV positive people who had used PI-based regimens. After calculating absolute five-year cardiovascular risk for individuals with and without lipodystrophy, Dr. Egger estimated that anywhere between 10 and 200 people would have to be treated with HAART to produce a single additional case of coronary heart disease. He then compared this increase in relative risk to the benefits of HAART. In people with low CD4 cell counts and high viral loads, antretroviral therapy greatly decreases rates of HIV disease progression and death. But in those with higher CD4 cell counts (over 350 cells/mm³) and lower viral loads (less than 5,000 copies/mL), the risk of HIV disease progression is already low, and HAART has less of an impact. Among the latter group, 100-200 people would need to receive treatment for three years in order for one person to benefit.

Putting it all together, Dr. Egger estimated, "For 30-year-old men who don't smoke and have metabolic complications associated with lipodystrophy, 71 need to continue [antiretroviral] treatment for five years and only one of them will have a cardiac event. This will be an acceptable risk for most patients on HAART." However, for older people with additional risk factors, the picture changes. For example, a 50-year-old HIV positive man who smokes and has a high CD4 cell count and a low viral load may be more likely to develop coronary heart disease than to benefit from HAART. "While it's clear that the benefits of HAART outweigh the risks of [coronary heart disease] for many patients, there are definitely some patients for whom the reverse may be true."

While Dr. Egger concluded that, "the potential risk of long-term adverse effects, in particular coronary heart disease, cannot be ignored when making decisions on starting or delaying [antiretroviral] treatment," others are more hesitant to consider forgoing HAART. According to Dr. Bozzette, "We don't think fear of vascular complications should inhibit prescribing of antiretroviral medicines." Although Dr. Holmberg believes that his findings in the HOPS study may reflect an early indication of a growing problem, he agrees that PIs should not be discarded due to worry about cardiovascular complications.

Prevention Is Key

As Dr. Egger's estimates reveal, many factors besides drug-related metabolic abnormalities contribute to a person's aggregate risk for cardiovascular disease. Studies in the general population have shown that elevated blood fat levels alone do not always lead to heart disease in people without other risk factors, and that people with several other risk factors may develop cardiovascular disease even in the absence of elevated blood lipids. And hyperlipidemia itself is much more likely to lead to cardiovascular disease in people with other risk factors such as older age, smoking, family history of heart disease, obesity, and sedentary lifestyle. In fact, several researchers including Drs. Depairon, Duong, and Fichtenbaum have concluded from their data that heart disease in people with HIV is more closely correlated with these traditional risk factors than with antiretroviral therapy. The more risk factors a person has, the more likely he or she is to experience cardiovascular problems -- and the more likely to benefit from risk reduction measures (see sidebar).

Based on what is known to date, it appears that for many people using HAART the short-term risk of developing cardiovascular disease is relatively low. But as effective antiretroviral treatment extends the life expectancy of people with HIV, preventive measures become increasingly important. In the words of Marshall Glesby, MD, PhD, of Cornell University's Weill Medical College, "With the prolongation of survival associated with potent antiretroviral therapy, clinicians and patients now have the luxury of worrying about longer-term complications and comorbidities associated with HIV infection, such as chronic hepatitis and cardiovascular disease."

Although much remains to be learned about heart disease in people with HIV, experts agree that there are several steps that can be taken to decrease the likelihood of cardiovascular problems. Health-care providers should carefully monitor their patients' cholesterol, triglyceride, and blood glucose levels; regularly check blood pressure; and be on the lookout for manifestations that signal increased cardiovascular risk. People with HIV should make every effort to quit smoking, eat a healthy diet, lose excess weight, and exercise regularly. When appropriate, medications should be used to control elevated blood lipids, diabetes, and high blood pressure. If these measures are inadequate, people with HIV and their health-care providers may consider switching to a protease-sparing regimen or a newer PI that is less likely to cause metabolic abnormalities.

As Dr. Depairon notes, addressing modifiable risk factors has led to a significant decline in the incidence of heart disease among the general population, and "there is no evidence that HIV-infected individuals may benefit less from these interventions."

Selected Sources

1. Bozzette, S.A. and others. Cardio- and cerebrovascular outcomes with changing process of anti-HIV therapy in 36,766 U.S. veterans. 9th Conference on Retroviruses and Opportunistic Infections. Seattle, WA. February 24-28, 2002. Abstract LB9.
2. David, M.H. and others. Ischemic cardiovascular disease in persons with human immunodeficiency virus infection. Clinical Infectious Diseases 34(1): 98-102. January 1, 2002.
3. Depairon, M. and others. Premature atherosclerosis in HIV-infected individuals -- focus on protease inhibitor therapy. AIDS 15(3): 329-334. February 16, 2001.
4. Dubé, M.P. and others. Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group. Clinical Infectious Diseases 31(5): 1216-1224. November 2000.
5. Egger, M. Cardiovascular epidemiology in the context of HIV disease. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Ontario. September 17-20, 2000. Abstract 1374.
6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Journal of the American Medical Association 285(19): 2486-2497. May 16, 2001.
7. Falusi, O.M. and Aberg, J.A. HIV and cardiovascular risk factors. The AIDS Reader 11(5): 263-268. 2001.
8. Henry, K. and others. Severe premature coronary artery disease with protease inhibitors. The Lancet 351(9112). May 2, 1998.
9. Holmberg, S. and others. Protease inhibitor use and adverse cardiovascular outcomes in ambulatory HIV patients. 9th CROI. Abstract 698-T.
10. Klein, D. and Hurley, L. Hospitalizations for coronary heart disease and myocardial infarction among HIV+ patients in the HAART era. 9th CROI. Abstract 696-T.
11. Maggi, P. Premature lesions of the carotid vessels in HIV-1-infected patients treated with protease inhibitors. AIDS 14(16): FT123-128. November 10, 2000.
12. Martinez, E. and others. Switching protease inhibitors to nevirapine, efavirenz or abacavir: a randomized, multicenter, open-label, simplification trial. 9th CROI. Abstract LB17.
13. Passalaris, J.D. and others. Coronary artery disease and human immunodeficiency virus infection. Clinical Infectious Diseases 31(3): 787-797. September 2001.
14. Piliero, P. and others. Atazanavir: a once-daily protease inhibitor with a superior lipid profile: results of clinical trials beyond week 48. 9th CROI. Abstract 760-T.
15. Weber, R. and others. Risks for cardiovascular disease associated with antiretroviral therapy (ART). 41st ICAAC. Chicago. December 16-19, 2001. Abstract 1326.