Protease inhibitors associated with increased risk of cardiovascular disease

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HIV-positive patients who take a protease inhibitor as part of their HAART regimen have a significantly increased risk of cardiovascular events, according to research published in the January edition of HIV Medicine.

There has been a dramatic fall in the incidence of HIV-related illness and death in HIV-positive individuals since HAART became available. However, cardiovascular illness has been seen with increasing frequency in HIV-positive patients since effective antiretroviral drugs became available. It has been suggested that anti-HIV drugs, particularly protease inhibitors which can cause metabolic complications, are at least partly responsible for the increasing amount of cardiovascular illness seen in HIV-positive patients. However, other possible causes have also been suggested. It has also been noted that HIV-positive individuals appear to have a higher prevalence of traditional cardiovascular risk factors, such as smoking. In addition, thanks to the success of anti-HIV therapy, many people taking HAART are now living to an age when they might become vulnerable to cardiovascular disease.

Investigators from the pharmaceutical company, Bristol Myers Squibb, the US Centers for Disease Control, and Johns Hopkins University obtained data from a large longitudinal database to answer the question: “does protease inhibitor exposure increase the risk of cardiovascular disease in HIV-infected patients after adjusting for known cardiovascular disease risk factors?”



Relating to the heart and blood vessels.

cardiovascular disease

Disease of the heart or blood vessels, such as heart attack (myocardial infarction) and stroke.


Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.

multivariate analysis

An extension of multivariable analysis that is used to model two or more outcomes at the same time.

traditional risk factors

Risk factors for a disease which are well established from studies in the general population. For example, traditional risk factors for heart disease include older age, smoking, high blood pressure, cholesterol and diabetes. ‘Traditional’ risk factors may be contrasted with novel or HIV-related risk factors.

The study population was provided by HIV InsightTM, a prospective observational database. Patients aged over 18 years who attended for at least two medical consultations between 1996 and 2003 were eligible for inclusion in the investigators’ anaylsis. Demographic and cardiovascular risk data were extracted and information was obtained on the date when a protease inhibitor-containing HAART regimen was first started, or (for non-protease inhibitor-treated patients), the date when antiretroviral therapy was first initiated.

For the purpose of the study, cardiovascular events included acute myocardial infarction, angina pectoris, coronary artery disease, angioplasty, coronary bypass, cerebrovascular accident, and peripheral vascular disease.

Risk factors for cardiovascular disease included high blood lipids, use of lipid lowering therapy, high blood pressure, diabetes, and smoking. Data were also obtained on injecting drug use, cocaine use, and weight. Family history of cardiovascular disease was not included in the investigators’ analysis as this information was not recorded in the database.

A total of 7542 patients were included. The median duration of follow-up was significantly longer for patients who were treated with a protease inhibitor (3.5 years versus 2 years, p

In total, 127 events of cardiovascular disease occurred. The overwhelming majority of these, 112, occurred amongst patients taking a protease inhibitor. The adjusted incidence of cardiovascular disease was 9.8 per 1,000 patient years for patients taking a protease inhibitor compared to 6.5 per 1,000 patient years for HIV-positive patients not prescribed a protease inhibitor (p = 0.008). When the investigators restricted their analysis to the subset of patients aged 35 – 65 they still found that cardiovascular events were significantly more likely to occur in patients taking a protease inhibitor than in patients who were not (11.5 per 1,000 patient years versus 8 per 1,0000 patient years, p = 0.01).

In multivariate analysis, the investigators established that more than 60 days cumulative therapy with a protease inhibitor was associated with a statistically significant increase in the risk of cardiovascular disease (p = 0.03).

However, they also found that many of the traditional risk factors for cardiovascular disease were also significant, including current smoking (p

In further sensitivity analyses, over a year of treatment with a protease inhibitor was shown to increase the risk of cardiovascular disease for patients in the 35 – 65 age group (adjusted hazard ratio, 1.6).

“The results of this analysis suggest an increased cardiovascular disease event rate in HIV-infected patients exposed to protease inhibitor therapies”, write the investigators. They conclude that doctors should evaluate the cardiovascular disease risk of patients currently taking, or about to initiate HAART.


Iloeje UH et al. Protease inhibitor exposure and the increased risk of cardiovascular disease in HIV-infected patients. HIV Medicine 6: 37 - 44, 2005.