INTRODUCTION

The medical management of HIV has been revolutionized by the use of highly active antiretroviral therapy (HAART). In the pre-HAART era, HIV typically led to death within ten years. Treatment of HIV with HAART can extend the lifespan of HIV-infected persons by several decades.¹ A major challenge that has arisen out of this success is the management of the side effects of antiretroviral therapy. Antiretroviral therapy (ART) commonly causes various complications, some of which may be life threatening.

This article focuses on some of the more common metabolic complications associated with the treatment of HIV-infected persons, such as dyslipidemia, insulin resistance states, and lipodystrophy syndromes. These abnormalities may eventually lead to an epidemic of cardiovascular disease and diabetes among HIV-infected patients. Management of these complications has therefore become an integral component of HIV care.

HIV causes lipid changes even in the absence of HAART. Low total cholesterol, low high-density lipoprotein cholesterol (HDL), low LDL (low-density lipoprotein), and high triglycerides were commonly seen in the pre-HAART era. Initiation of HAART reverses some of these effects. HDL rises to levels lower than that of the general population. Total cholesterol (including LDL and very-low-density lipoprotein (VLDL)) and triglycerides are all increased by ART. HAART causes an increase of the atherogenic small, dense LDL-2 particle. Of concern is that elevated triglycerides, low HDL, along with small LDL size, comprise the atherogenic dyslipidemia phenotype that is associated with premature atherosclerosis.²

A comprehensive approach to the management of HIV-infected patients must take into consideration cardiac and metabolic consequences. A large prospective cohort study demonstrated that HIV-infected patients on HAART suffer cardiac events at an increased rate. The Data Collection of Adverse Events of Anti-HIV Drugs (D:A:D) Study Group has followed more than 23,000 HIV-infected individuals to assess whether exposure to antiretroviral therapy increases the incidence of myocardial infarction and other cardiovascular events. Of note, the incidence of traditional risk factors in this relatively young cohort was substantial – 56% had a smoking history, 2.8% were diabetic, 7.2% had high blood pressure, and 45.9% had dyslipidemia. In their initial reporting, 126 patients had had a myocardial infarction (MI) (incidence of 3.5 events per 1000 person-years), 38 patients had a stroke, and 39 patients required cardiac intervention. The incidence of cardiac and cerebrovascular events, including myocardial infarction, increased with increasing exposure to HAART. After adjustment, the relative risk for MI was 1.16%. This leads to a doubling of cardiac risk after five years of exposure to HAART. Overall, the absolute risk of MI remained low, and HAART contributed only partially to the apparent excess risk.^4,5

The use of HAART is only one of several factors that contribute to cardiovascular disease in HIV-infected individuals. The following modifiable risk factors for coronary heart disease are targets for risk modification: dyslipidemia, hypertension, cigarette use, diabetes, overweight/ obesity (BMI >25/30 kg/m2), inactivity, and atherogenic diet. Older age, male sex, and family history of premature CHD (<55 years old in a first degree male relative or <65 years old in a first degree female relative) are nonmodifiable risk factors.⁶ Other authors have suggested that HIV-infected individuals utilize elicit substances like cocaine and methamphetamine that increase cardiac stress, though this is unproven.⁷ Additionally, interactions between drugs, host, and virus means that metabolic complications are often not the sole consequence of medication.

The D:A:D Study demonstrated that despite the frequent use of lipid lowering agents like statins and fibrates, the risk factor profile among their HIV-infected cohort worsened from 1999 to 2006. This detrimental change in risk factors was partly caused by the aging of the HIV-infected population; as people aged, they also developed diseases like hypertension and diabetes. Over that period of time the incidence of MI remained stable, suggesting that worsening risk factors may have negated the benefits of risk reduction.⁸ Interestingly, the Framingham Cardiac Risk Calculator consistently underestimates the number of events predicted in the D:A:D cohort. This suggests that a lower threshold for intervention (diet, switch, or lipid lowering drugs) should be considered in HIV-infected persons.³

Management of Dyslipidemia

The National Cholesterol Education Program has produced guidelines, which should be used to guide therapy for dyslipidemia in HIV-infected patients.6 The NCEP guidelines were updated in 2004 to provide an option for more aggressive lipid lowering therapy in high risk individuals.⁹ These reports can be accessed at: http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.

• LDL is the main target of intervention to decrease the risk of CHD. LDL can be calculated as: LDL = total cholesterol - (HDL – [triglycerides/5]).
  
  
• Determination of an individual's ten-year risk for developing coronary heart disease is an integral first step set forth in the NCEP guidelines. Three strata based on a ten-year risk guide target LDL levels.
  
  – CHD or CHD equivalents have a >20% risk of experiencing a cardiac event within 10 years. The target LDL is <100 (with an optional target of <70 in very high-risk patients).
  
  – CHD equivalents are: other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease); diabetes; and multiple risk factors that confer a 10-year risk for CHD >20%.
  
  
• The second category includes patients with 2+ risk factors but a ten-year risk of <20%. The target LDL is <130.
  
  – In this instance, only age, family history of CHD, smoking history, hypertension, and low HDL cholesterol are applicable.
  
  – The Framingham Tool is used to calculate 10 year CHD risk. It can be accessed online at http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof
  
  – Ten-year Framingham risk is based on age, total cholesterol, HDL cholesterol, gender, smoking history, and systolic blood pressure.
  
  
• The third category includes patients with 0-1 risk factors. They generally have a 10-year risk of <10%. The target LDL is <160. Framingham scoring is not necessary.