By Ronald Baker, PhD

The widespread use of highly active antiretroviral therapy (HAART) since the mid-1990s has led to a dramatic decrease in disease complications and death rates in HIV positive individuals in the U.S. and Europe.

However, the use of certain antiretroviral drugs has been shown to increase blood lipid levels and to contribute to the onset of insulin resistance and visceral fat accumulation. In the general (non-HIV-infected) population, these characteristics reflect metabolic syndrome and are risk factors for diabetes and cardiovascular disease.

It is especially noteworthy that protease inhibitors (PIs) have been associated with an increased risk of cardiovascular disease, in part because of their negative effect on blood lipids (cholesterol and triglycerides). A number of recent studies have demonstrated a high prevalence of metabolic syndrome in HIV positive patients on HAART. Interestingly, however, these prevalence rates are equal to or even less than the 22%-24% prevalence rate of metabolic syndrome seen in the general population.

There are also data suggesting that the increased prevalence of metabolic syndrome in HIV positive individuals may reflect the growing epidemic of obesity in the U.S. more than the adverse effects of HAART. Nonetheless, regardless of causality, current U.S. treatment guidelines recommend screening HIV positive patients for metabolic complications and providing treatment (Aberg et al. Clinical Infectious Diseases 2004; Dube et al. Clinical Infectious Diseases 2003).

The Current Study

The association between the use of HAART and increased risk of metabolic syndrome and cardiovascular disease remains unclear. In the present retrospective study, published in the March 1, 2007 issue of Clinical Infectious Diseases, Kristin Mondy, MD, and colleagues examined the medical records of HIV-infected patients for evidence of risk factors for cardiovascular disease. They used data collected at the Washington University HIV Clinic in St. Louis between January and July 2005.

The objectives of the study were:

(1) to determine the prevalence of metabolic syndrome among a diverse, urban HIV positive outpatient population;

(2) to compare the prevalence of metabolic syndrome and diabetes in HIV positive patients with that of a contemporary U.S. cohort of HIV negative individuals matched for age, sex, race, and tobacco use;

(3) to determine the risk factors for the development of metabolic syndrome that are unique to HIV-infected patients.

Results

• 471 HIV positive patients completed the study protocol.

• The overall prevalence of metabolic syndrome was similar in HIV positive patients and HIV negative individuals (25.5% vs 26.5%, respectively).

• However, the HIV positive patients had a significantly smaller waist circumference, lower body mass index, lower high-density lipoprotein (HDL) cholesterol levels, higher triglyceride levels, and lower glucose levels compared with the HIV negative subjects.

• Framingham 10-year cardiovascular risk scores were similar in the 2 groups.

• HIV negative individuals in the control group with metabolic syndrome were more likely to be diabetic, older, and white, and to have high CD4 cell counts and high body mass index compared to patients without metabolic syndrome (P < 0.05 for all).

• The type or duration of antiretroviral therapy was not an independent risk factor for metabolic syndrome.

Based on these findings, the authors concluded, "The prevalence of metabolic syndrome is high among HIV-infected persons, but not higher than the prevalence among HIV-uninfected persons."

"Traditional risk factors play a more significant role in the development of metabolic syndrome than do HIV treatment-associated factors," they added.

Discussion

The study authors posed 2 interesting questions regarding their study results:

• Do the results of this study make a difference in how we should implement recommendations for screening for cardiovascular risk factors, which has been suggested as a standard of HIV clinical care?

• Should we be more concerned about looking for metabolic syndrome in patients receiving HAART?

In an editorial published in the same issue of Clinical Infectious Diseases, Clara Jones, MD, of Tufts University Medical School pointed out that Mondy and colleagues found no significant difference in the percentage of persons receiving HAART between those with and without metabolic syndrome. Additionally, they found that the type of HAART was not a significant predictor of metabolic syndrome [Emphasis added-Ed].

Although HIV positive patients with metabolic syndrome "were more likely to be white (47%) than HIV-infected subjects without metabolic syndrome (34%)," the majority of HIV-infected individuals with metabolic syndrome in this study were African American, according to Dr. Jones.

Mondy and colleagues could not determine whether there was a difference in race and sex demographics between HIV-infected patients with metabolic syndrome and the HIV negative control subjects with metabolic syndrome because they matched subjects for race and sex.

Dr. Jones added that the findings of this study "do not support the restriction of screening for metabolic syndrome for any demographic group of patients, nor for patients receiving any particular HIV medication regimens."

Another recent study (Jacobson and colleagues. JAIDS 43 2006.) found that HAART use was not significantly associated with an increased risk of developing metabolic syndrome. However, when the researchers looked at specific medications, lopinavir/ritonavir (Kaletra) and ddI (didanosine; Videx) were associated with an increased risk of metabolic syndrome.

Dr. Jones wrote in the conclusion of her editorial, "This study [by Mondy and colleagues] did not controvert the evidence that metabolic complications increase in persons after initiating HAART or with effective maintenance of weight and reduction of opportunistic infections during the post-HAART era, but showed that the estimated level of increased risk of metabolic syndrome in HIV-infected persons (diagnosed by NCEP criteria or Framingham 10-year risk score) is not significantly greater than the risk in HIV-uninfected persons of the same age, race, sex, and smoking status."

In closing, she wrote, "The findings do not diminish the potential importance of addressing the risk factors in individual patients to decrease the risk of cardiovascular disease or type II diabetes."

02/09/07

References

K Mondy, E Turner Overton, J Grubb, and others. Metabolic Syndrome in HIV-Infected Patients from an Urban, Midwestern US Outpatient Population. Clinical Infectious Diseases 44(5): 726-734. March 1, 2007.

C Y Jones. Metabolic Syndrome in HIV-Infected Patients: No Different than the General Population? (Editorial). Clinical Infectious Diseases 44(5): 735-736. March 1, 2007.

Suggested Reading

J A Aberg, J E Gallant, J Anderson, and others. Primary care guidelines for the management of persons infected with human immunodeficiency virus: recommendations of the HIV Medicine Association of the Infectious Disease Society of America. Clin Infect Dis 39: 609-629. 2004.

V Amorosa, M Synnestvedt, R Gross, and others. A tale of 2 epidemics: the intersection between obesity and HIV infection in Philadelphia. J Acquir Immune Defic Syndr 39: 557-561. 2005.

A Carr, K Samaras, S Burton, and others. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 12: F51-F58. 1998.

M P Dubé, J Stein, J Aberg, and others. Guidelines for the evaluation and management of dyslipidemia in HIV-infected adults receiving antiretroviral therapy: recommendations of the HIV Medicine Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 37: 613-627. 2003.

E S Ford, W H Gilles and W H Dietz. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287: 356-359. 2002.

N Friis-Moller, P Reiss, W M El-Sadr, and others. Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group. Exposure to PI and NNRTI and risk of myocardial infarction: results from the D:A:D study. 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO, February 5-8, 2006. Abstract 144.

N Friis-Moller, C A Sabin, R Weber, and others. Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 349: 1993-2003. 2003.

C Hadigan, J B Meigs, C Corcoran, and others. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 32: 130-139. 2001.

S D Holmberg, T C Tong, D J Ward, and others. HIV Outpatient Study (HOPS) Investigators. Protease inhibitor drug use and adverse cardiovascular outcomes in ambulatory HIV-infected persons. Lancet 360: 1747-1748. 2002.

B Isomaa, P Almgren, T Tuomi, and others. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24: 683-689. 2001.

D Jacobson, A Tang, D Spiegelman, and others. Incidence of metabolic syndrome in a cohort of HIV-infected adults and prevalence relative to the US population (National Health and Nutrition Examination Survey). J Acquir Immune Defic Syndr 43: 458-466. 2006.

C Jerico, H Knobel, M Montero, and others. Metabolic syndrome among HIV-infected patients: prevalence, characteristics, and related factors. Diabetes Care 28: 144-149. 2005.

K D Miller, E Jones, J A Yanovski, and others. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 351: 871-875. 1998.

F Palella, Z Wang, H Chu, et al. Correlates and prevalence of the metabolic syndrome over time in the Multicenter AIDS Cohort Study (MACS). 3rd IAS Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil, July 24-27, 2005. Abstract TuPe2.2B18.

K E Yarasheski, P Tebas, C Sigmund, and others. Insulin resistance in HIV protease inhibitor-associated diabetes. J Acquir Immune Defic Syndr 21: 209-216. 1999.