HAART patients can face greater risk of developing heart disease — studies
Study shows connection with myocardial infarction
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Some of the strongest evidence to date suggesting that patients on highly active antiretroviral therapy (HAART) are at greater risk for developing cardiovascular disease was presented at the 39th Annual Meeting of the Infectious Diseases Society of America (IDSA), held Oct. 25-28, 2001, in San Francisco. While a large focus of the IDSA meeting was on anthrax and bioterrorism, which were a national obsession in the fall, the research presented about the connection between HIV and cardiovascular disease is something HIV clinicians will want to keep in mind when starting new patients on HAART or making adjustments to existing HIV treatments.
"HAART therapy is associated with a variety of changes that go under the umbrella of lipodystrophy and hypercholesterolemia," says John Bartlett, MD, chief of the Division of Infectious Diseases at Johns Hopkins University School of Medicine in Baltimore. "And increases in cholesterol and triglycerides are like it is for other populations without HIV infection — it confers risk for heart disease."
Investigators from the HIV Outpatient Study (HOPS) group, which is located at 10 sites in the United States, found that after a few years of taking protease inhibitors, HIV patients were beginning to show a significantly increased rate of myocardial infarctions, says Scott D. Holmberg, MD, MPH, senior epidemiologist in the Division of HIV/ AIDS Prevention at the Centers for Disease Control and Prevention in Atlanta. "When we looked at the rate of myocardial infarction in the HOPS cohort overall, the rates start significantly increasing after 1996, the time the protease inhibitor drugs were introduced," Holmberg says.
The main argument of the research, which was presented at the IDSA conference, was that the HIV patients who were on PI-containing regimens were several times more likely to have a myocardial infarction, even after controlling for traditional cardiovascular risk.1 This increased risk also appears when HIV patients on PI regimens are compared with HIV patients on non-PI regimens, including those that contain nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors, Holmberg adds. "Also, it’s consistent and biologically plausible that PI drugs increase lipid and glucose levels in the blood and perhaps increase hypertension, as well," Holmberg says.
Diagnoses verified against clinical records
The HOPS data came from two groups of 3,000 HIV patients. One group had taken protease inhibitors, and the other had not. The study’s findings are particularly noteworthy because researchers looked specifically at myocardial infarctions and verified hospital discharge diagnoses against clinical records.
"We found a couple of MIs that were actually angina, and some angina that were not angina," Holmberg says. This is what makes the HOPS outcomes unique. "Some other cohorts have been limited in their ability to look at actual drugs patients have taken and at the patients’ cardiovascular risk factors," Holmberg adds. "Some previous studies may not have followed patients long enough." Still, the HOPS patients will need to be followed even longer to verify what CDC researchers have seen thus far, Holmberg notes.
The HOPS findings confirm what HIV clinicians and researchers have suspected for the past few years, but it’s too soon to base clinical decisions solely on the risk of cardiovascular disease, experts say. "It’s way too early to say that PIs by themselves are going to automatically guarantee serious cardiovascular problems," says Kenneth Mayer, MD, professor of medicine and community health at Brown University and Miriam Hospital in Providence, RI, and medical research director of Fenway Community Health in Boston.
However, it is time for clinicians to consider assessing HIV patients’ risk factors for cardiovascular disease and to make recommendations for prevention programs, such as smoking cessation programs, increased exercise, and weight loss, in the event an HIV patient is taking protease inhibitors and also has other risk factors, Mayer says. "Ten years ago, patients may not have lived long enough to be concerned about heart disease, but now they are," Mayer adds.
A second study that assessed coronary heart disease (CHD) among HIV patients also suggested that young men ages 18-34 with HIV infection were more likely than non-HIV men to have coronary heart disease.2 The study, conducted on behalf of Bristol-Myers Squibb of Plainsboro, NJ, looked at claims codes and data from the California Medicaid (MediCal) population, which has a large HIV-infected population, says Sally Lynn Hodder, MD, director of clinical analysis for Bristol-Myers Squibb Virology. HIV patients who were not receiving therapy were excluded from the study, Hodder says. "It appeared that young men with HIV had an increased incidence of coronary heart disease as opposed to their non-infected counterparts," Hodder says. "Older individuals with HIV had a lower incidence of coronary heart disease."
The study had some limitations, including that the claims databases did not have information on smoking and some other coronary heart disease risk factors, but it at least suggests that there is an acceleration of atherosclerosis in young HIV-infected people receiving HAART, Hodder says. "In the study design, people had to be continuously medically eligible for three years to be included, and the first year was a wash-out period in which the individual had to be free of any coronary heart disease diagnoses," Hodder explains. "We were looking at incidence, not at prevalence."
The bottom line is that clinicians caring for HIV-infected patients should give important consideration to modifying a patient’s risk for coronary heart disease. "While it’s unclear whether HIV infection, antiretroviral agents, or both are affecting the incidence of coronary heart disease, you clearly want to minimize an individual’s risk factors for CHD," Hodder adds.
A third IDSA study looked at the characteristics of HIV-infected patients who had a myocardial infarction. It concluded that these patients were predominately middle-aged African-Americans with relatively preserved immune function, and 80% were on HAART.3 Yet, it would be a mistake if clinicians concluded that they should not be giving patients PI drugs because of the increased cardiovascular risk, Bartlett notes.
Like every drug, it has risks’
"PI therapy has been the miracle of the decade in terms of medical treatment and has had an astonishing record of success in every parameter," Bartlett says. "But like every drug, it has risks." Still, there are three potential strategies clinicians might consider, Bartlett says:
- They could refrain from making changes because the risk of cardiovascular disease isn’t very high.
- They could treat according to current medical guidelines and give HIV patients with increased cholesterol and cardiovascular disease risk factors a statin drug.
- They could try to switch certain patients to HAART regimens.
"I think switching is a reasonable thing to consider, but you wouldn’t switch if the person didn’t have hyperlipidemia," Mayer says. "Clinical judgment says you don’t have a one-size-fits-all strategy." On the other hand, keeping patients on PI regimens and then adding a statin drug to their daily pill-taking routine means HIV patients will have one more medicine and its side effects to contend with, and that could pose adherence problems, Mayer says.
"Unfortunately, because we don’t have a cure, we’re still in the realm of learning more about this phase of HIV disease and the interaction of people living long periods of time and being on chronic medications that potentially have significant side effects," Mayer explains. "It’s a set of interactions that we can’t predict."
The actual risk of cardiovascular disease to any particular HIV patient on PI drugs appears to be very small, Holmberg says.
Still, there’s the potential for the complications and risk to increase as HIV patients age, Mayer says.
If a patient and clinician are uncomfortable with the risk, consider these questions:
- What are the patient’s modifiable cardiovascular risk factors?
- How long has the patient been on PI drugs?
- How well is the patient doing on PI drugs?
"All of these factors need to be weighed before the physician starts immediately swapping patients out," Holmberg says. "But the patient’s wishes are always something to consider."
If a clinician and patient decide that switching off PI therapy would be the most desirable strategy, then there are a few suitable options. One strategy would be to replace PIs with abacavir, efavirenz, or nevirapine regimens. For instance, the triple-drug pill Trizivir, which contains abacavir, lamivudine (3TC), and ATC, appears to work well, Bartlett says.
In another study presented at the IDSA conference, investigators found that HIV patients randomly assigned to be switched from a PI regimen to an abacavir substitute retained viral load suppression at 24 weeks, says Joseph J. Pulvirenti, MD, director of inpatient HIV services for Cook County Hospital in Chicago. "There was an improvement as far as cholesterol was concerned at 24 weeks, and it was considered to be significantly improved in the abacavir arm," Pulvirenti says. "We also saw a difference in triglycerides, with people who swapped out to abacavir having a significant improvement as far as lipid studies."
Investigators looked at the issue of swapping HIV therapies because of the problems patients have experienced in recent years with PI therapies, including resistance, adherence, adverse events, and chronic problems, Pulvirenti says. (See "Easier abacavir regimen has promising results" in this issue.)
Also, two studies presented at the 8th European Conference on Clinical Aspects and Treatment of HIV Infection, held in October 2001 in Athens, Greece, showed that HIV patients taking a nevirapine-based therapy had an improved lipoprotein profile. The 96-week data showed that patients treated with nevirapine, ddI, and d4T demonstrated a 40% increase from baseline in HDL cholesterol and a decrease in the total cholesterol/HDL cholesterol ratio. By comparison, patients receiving the protease inhibitor indinavir showed significant increases in total and LDL-cholesterol and an increase in the total/HDL cholesterol ratio. The study has not produced results evaluating the effectiveness of nevirapine in a combination therapy to treat HIV-1 infection.4
"The data are getting stronger and stronger to say [non-PI regimens] will work, but we have to take the individual patient into account," Bartlett adds. "So if this patient has no risk for heart disease, elevated cholesterol for a few years is quite acceptable." Alternatively, if the patient has previous heart problems or diabetes, hypertension, or a bad family history, a clinician may say that’s too great a risk, Bartlett says.
References
1. Holmberg S, Moorman AC, Tong T, et al. Protease inhibitor drug use and myocardial infarction in ambulatory HIV-infected patients. Presented at the 39th Annual Meeting of the Infectious Diseases Society of America. San Francisco: Oct. 25-28, 2001. Abstract 941.
2. Hodder S, Burtcel B, Kawabata H, et al. Coronary heart disease in patients with human immunodeficiency virus infection. Presented at the 39th Annual Meeting of the Infectious Diseases Society of America. San Francisco: Oct. 25-28, 2001. Abstract 18.
3. Castro JG, Fischl M. Characteristics of HIV-infected patients who had a myocardial infarction. Presented at the 39th Annual Meeting of the Infectious Diseases Society of America. San Francisco: Oct. 25-28, 2001. Abstract 730.
4. van der Valk M, Kastelein J, Murphy R, et al. Nevirapine-containing potent antiretroviral therapy results in a sustained anti-atherogenic plasma lipid profile: 96 weeks results from the Atlantic Study. Presented at the 8th European Conference on the Clinical Aspects and Treatment for HIV Infection. Athens: Oct. 29, 2001. Abstract 126.
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