| Cardiac Risk Assessment|
Cardiovascular disease is the leading cause of death in the United States. The factors associated with increased cardiac risk are well known and are underrecognized and undertreated in the general population (see Table 1).(2) In the developed world, before the availability of ART, most HIV-associated mortality was caused by opportunistic infections, malignancies, and the wasting syndrome. In patients whose lives have been extended through antiretroviral medications, we expect to see more cardiac mortality, and we must now aggressively try to reduce all known cardiac risks.
Modifiable and nonmodifiable risk factors for cardiovascular disease have been described by the National Cholesterol Education Program (NCEP) of the U.S. Department of Health and Human Services (3) and are available on the Internet.(4) Nonmodifiable risk factors include age, sex, and family history of premature CHD. Modifiable risk factors include hypertension, cigarette smoking, obesity, physical inactivity, hyperlipidemia, the metabolic syndrome, diabetes, chronic kidney disease with glomerular filtration rate <60 mL/min or microalbuminuria, and thrombogenic/hemostatic state. Diabetes is now considered to be a CHD equivalent in the sense that people with diabetes are considered to have the same risk of CHD as persons with known CHD (3) and are subject to the same lipid threshold guidelines as those with known coronary artery disease. The metabolic syndrome is a constellation of metabolic and physical measures that increase the risk of cardiovascular disease. It is characterized by central obesity, dyslipidemia, elevated blood pressure, and higher than normal levels of fasting blood glucose and will be discussed in detail below. Hypertension and hypercholesterolemia are continuous risk variables (5) for which average values in the population are not optimal values. The 7th Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) report defines normal blood pressure as a systolic measurement of <120 mm Hg and a diastolic measurement of <80 mm Hg.(2) The NCEP Adult Treatment Panel III defines the optimal lipid levels as a low-density lipoprotein (LDL) level of <100 mg/dL, a total cholesterol level of <200 mg/dL, and a high-density lipoprotein (HDL) level of >=60 mg/dL.(3) In general, the lower the LDL, the lower the risk.(5) This is especially important in those with other cardiac risk factors. There are a number of other markers that are associated with increased coronary artery disease (CAD), but are not yet in widespread use. These include C-reactive protein and coronary artery calcification score.
| HIV and Cardiac Risk Factors|
HIV-infected individuals, especially those on ART, appear to have increased rates of dyslipidemia, smoking, insulin resistance, and the metabolic syndrome, all of which are direct or indirect cardiac risk factors. How these risk factors will influence long-term cardiovascular mortality and morbidity rates is not yet known. In patients with advanced HIV disease, it is clear that the immediate benefits of ART far outweigh the risks of future cardiac disease.(6,7,8) However, the multiple metabolic changes that may occur in those receiving ART, along with increasing age and other known cardiac risks such as smoking, have heightened our awareness of potential cardiac disease and have made the reduction of risk factors an important goal.
| Diabetes Mellitus|
Rates of insulin resistance appear to be increased in individuals with HIV, and a number of cohort studies also report higher rates of diabetes mellitus, although the magnitude of this increase is unclear. The Women's Interagency HIV Study followed 1,785 nonpregnant women with no prior history of diabetes from 1994 to 1998 and found a 3-fold increase in the risk of newly diagnosed diabetes in women on protease inhibitor (PI) medications.(9) A large cohort study of Medicaid patients examined 7,219 HIV-infected subjects and 2,792,971 uninfected controls over 7 million patient years of follow-up.(10) This study found an overall incidence rate of diabetes of 10.68 per 100 patient years for those with HIV infection and 2.91 per 100 patient years for uninfected controls, with a 3.32 relative risk of diabetes in the HIV-positive subjects. The increased risk was seen in men and women and in all age groups. The Multicenter AIDS Cohort Study found that HIV-infected men on ART had approximately a 5-fold increase in risk of diabetes compared with HIV-negative controls, and that ART conferred a 2-fold to 3-fold increased risk of hyperglycemia compared with HIV-infected, untreated controls.(11) Hepatitis C coinfection, which is common in HIV infection, is an independent risk factor for developing diabetes.(12,13) In HIV-uninfected patients with increased abdominal fat or obesity, there is an increased risk of developing diabetes,(14-18) suggesting that HIV-associated central fat accumulation may carry a similar risk.
Lipid abnormalities are common in HIV-infected individuals and are seen in both untreated individuals and those on ART. Low HDL cholesterol and elevated triglycerides were reported in patients prior to treatment with ART and appear to be directly linked to HIV infection.(19,20) More recently, rates of severe hyperlipidemia, hypertriglyceridemia in particular, have increased in patients taking PIs, especially ritonavir-containing regimens. There is considerable variation in the effect on lipids from the various antiretroviral medications. Previously untreated patients on lopinavir/ritonavir, stavudine, and lamivudine for 48 weeks experienced an average increase in total cholesterol level of 49 mg/dL and trigylceride level of 111 mg/dL.(21) Atazanavir, a more recently approved PI, does not appear to induce lipid abnormalities by 48 weeks of treatment.(22)
Cohort studies usually report high rates of cigarette smoking among HIV-infected individuals. Data collected from HIV outpatient clinics in New England showed that >70% of patients smoked.(23) A medically indigent and ethnically diverse HIV clinic in Houston had a prevalence of current cigarette smoking of 47%.(24) The multinational D:A:D study reported 56.2% of the subjects were current or former smokers.(7) At the outpatient HIV clinic at San Francisco General Hospital, 54% of the 228 patients surveyed reported smoking.(25) Interestingly, 63% reported that they were currently thinking about quitting. A cohort study of women also reported a smoking rate of 42%.(26) Before the development of effective ART, smoking cessation was a low priority in the medical care of HIV-infected patients. Now, as people with HIV live longer and have multiple other risk factors for cardiovascular disease, smoking cessation has become a high priority.
Before the development of effective ART, hypertension was uncommon in individuals with HIV infection. There have been recent reports of increased rates of hypertension, especially in patients on ART. The Women's Interagency HIV Study reported that HIV-infected women at baseline had a prevalence of hypertension of 25.8%, which was identical to the prevalence among demographically matched HIV-negative women.(27) At up to 8 years of follow-up, hypertension was present in about 46% of both groups. The factors that were associated with incident hypertension were increasing age, African American ethnicity, smoking, lower educational levels, and obesity (body mass index >30 kg/m2). A case control study compared HIV-infected patients with abnormal body fat distribution (lipodystrophy) and abnormal serum lipids to HIV-infected controls without lipodystrophy and to HIV negative controls.(28) Over a 21-month period, 74% of the cohort, compared with 48% of the controls, had elevated blood pressure on 3 or more occasions. Systolic blood pressure correlated with waist-to-hip ratio, which is increased in abdominal obesity, is part of the metabolic syndrome, and is associated with ART use, especially PI-containing regimens.
The prevalence of hypertension has been reported to be higher in patients who take indinavir compared with those who take nelfinavir. In contrast, a large cohort study of 16,000 patients found no correlation between ART and hypertension when traditional risk factors for hypertension were taken into account.(29)
| C-Reactive Protein|
C-reactive protein (CRP) is an inflammatory marker whose concentration increases with acute or chronic inflammation. It is produced by the liver in response to stimulation by cytokines such as interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha.(30) High-sensitivity measurement of CRP has been shown to add prognostic information at all levels of Framingham risk,(31) but CRP has not been consistently shown to be an independent risk factor across all studies.(32) Patients with HIV infection have significantly higher rates of high-risk CRP levels than does the general population. CRP may increase further in the setting of an opportunistic infection. Higher CRP levels tended to be associated with some features of the metabolic syndrome and with other CAD risk factors. A recent study reported that patients with HIV levels durably suppressed on an indinavir-containing regimen had stable or decreased values of CRP over 73 months, but >50% remained in the moderate-to-high risk category.(33,34) Further study is needed to determine whether CRP is a useful independent marker for future cardiac disease in HIV-infected individuals.
| Key Points|
Measure all cardiac risk factors; they are often undetected otherwise.
Expect metabolic abnormalities in patients who are overweight or obese.
Use quantifiable risk calculators based on Framingham data to determine 5- and 10-year risk of myocardial infarction or coronary death.
Aggressively treat all modifiable risk factors; they are often undertreated.
Encourage weight loss (if overweight) and exercise.
Encourage smoking cessation and refer to the cessation resources. Patients may call 1-800-NO BUTTS to find local resources or to obtain counseling by telephone.
| The Metabolic Syndrome|
The metabolic syndrome is a constellation of metabolic disorders that increases the risk of cardiovascular disease. It is characterized primarily by central obesity, dyslipidemia, hypertension, and insulin resistance. The NCEP Adult Treatment Panel III (3,4) suggests that clinical identification of the metabolic syndrome should be based on any 3 of the following criteria (see Table 13):
Abdominal obesity--waist circumference >102 cm (>40 inches) in men or >88 cm (>35 inches) in women
Elevated fasting triglycerides (>=150 mg/dL)
Low HDL (<40 mg/dL in men or <50 mg/dL in women)
Hypertension (systolic blood pressure >=130 mm Hg, or diastolic blood pressure >=90 mm Hg)
Hyperglycemia (fasting glucose >=110 mg/dL)
Data from the Third National Health and Nutritional Examination Survey (NHANES III), which examined a representative sample of 18,162 noninstitutionalized U.S. residents from 1988 through 1994, showed a 25% prevalence of the metabolic syndrome.(35) Prevalence rose with increasing age and was highest in Mexican American women above age 50, who had a prevalence of >50%. The metabolic syndrome was present in 50% of obese women and in 60% of obese men.
The causes of the metabolic syndrome are not well understood, but appear to involve multiple metabolic abnormalities associated with obesity, inactivity, and genetic factors. Visceral adiposity induces insulin resistance. Insulin resistance is associated with diabetes, hypertension, obesity, hypercholesterolemia, high levels of small, dense LDL, low HDL, and hypercoagulability. These are in turn associated with increased atherosclerosis and endothelial dysfunction.(14)
In non-HIV-infected persons, the metabolic syndrome has been shown to be associated with CHD, increased CHD mortality, and the development of diabetes and hypertension. It is also associated with inflammation and increased CRP. A study of 1,005 Finnish men showed that the presence of the metabolic syndrome increased the relative risk of developing diabetes over a 4-year period by 7-fold to 9-fold.(15) Another study of 5,000 subjects followed for 7 years showed a 3-fold relative risk increase in CHD events and a 2-fold increase in cardiovascular mortality for those with the metabolic syndrome.(16) A third Finnish cohort study showed a greater than 3-fold increase in relative risk of CHD mortality and a 2.5 increase in relative risk of all-cause mortality in those with the metabolic syndrome.(17) In a recent study of 668 U.S. veterans with known CHD, 570 (75%) met the criteria for the metabolic syndrome.(18)
The prevalence of the metabolic syndrome is highly correlated with exercise level. In the landmark Diabetes Prevention Trial, 3,224 subjects with impaired glucose tolerance were randomized to lifestyle intervention, metformin treatment, or a control group.(36) The primary endpoint of the study was the development of diabetes. After 3 years, the lifestyle intervention group had lost 12 pounds on average, exercised more, and had markedly reduced rates of new diabetes: 4.8 per 100 patient years in the lifestyle group compared with 7.8 in the metformin group and 11 in the control group. This study showed that the onset of diabetes could be prevented by diet, weight loss, and exercise.
HIV infection and its treatments are associated with most of the features of the metabolic syndrome. Given the similarity of the morphologic and biochemical changes seen in HIV patients on ART with the features of the metabolic syndrome, especially the lipid abnormalities and abdominal obesity, there is much interest in studying whether HIV and antiretroviral medications are associated with increased risk of CHD and diabetes.
| Key Points|
The metabolic syndrome is common.
The metabolic syndrome is associated with increased CHD and cardiac mortality and with the development of diabetes and hypertension.
Suspect the metabolic syndrome in those who are overweight, obese, or have central obesity (apple-shaped body as opposed to pear-shaped body).
Moderate exercise and weight loss can prevent the onset of diabetes and decrease the prevalence of the metabolic syndrome.
Waist circumference should be measured and tracked; weight loss should be encouraged.
All traditional cardiac risk factors should be measured and risk reduction should be aggressively pursued.
Hypertension is the most common diagnosis for office visits in the United States. Approximately 50 million Americans have hypertension. Although rates of hypertension awareness have improved to about 70%, only 34% of individuals with hypertension have controlled blood pressure, defined as systolic blood pressure (SBP) <140 mm Hg and diastolic blood pressure (DBP) <90 mm Hg.(2) Hypertension is more common in older individuals, occurring in two thirds of those >65 years of age. Hypertension is more common and more severe in African Americans than in Caucasians.
Cardiovascular disease risk is directly related to blood pressure. The risk of myocardial infarction, heart failure, stroke, and kidney disease increase consistently at blood pressures >115/75 mm Hg. The JNC 7 has recently revised its classification of blood pressures in adults (see Table 2).(2) It defines normal blood pressure as <120/80 mm Hg and hypertension as SBP >=140 mm Hg or DBP >=90 mm Hg. It identifies a new category of prehypertension as SBP 120-139 mm Hg or DBP 80-89 mm Hg. Patients with blood pressures in this range have twice the risk of developing hypertension as those with normal blood pressure. These prehypertensive patients are candidates for lifestyle modifications that may prevent the development of hypertension.
Numerous clinical studies in HIV-negative individuals show the benefit of lowering blood pressure in those with hypertension. Hypertension therapy lowers stroke rates by 35% to 40%, myocardial infarction rates by 20% to 25%, and heart failure rates by >50%. Individuals with cardiovascular risk factors (see Table 1), known CAD or CHD equivalents, or target organ disease (see Table 3) are at increased risk of cardiovascular events and will gain the greatest benefit from blood pressure control. CHD equivalents are factors that place the person at a similar risk of a CHD event as a person who has a history of CHD itself, such as a previous myocardial infarction. The CHD equivalents are: diabetes, symptomatic carotid artery disease, peripheral arterial disease, and multiple risk factors that confer a 10-year risk of CHD of >20%.
| Diagnosis of Hypertension|
In order to diagnose hypertension, blood pressure must be measured accurately. The patient should be seated comfortably on a chair for 5 minutes, wearing a shirt with an appropriate cuff size. Cuffs that are too tight for the person's wrist can contribute to falsely high readings. At least 2 readings should be performed on 2 or more office visits. The patient should try to obtain additional readings in nonmedical settings and report those values during subsequent visits; normal readings may alert providers to the possibility of white-coat hypertension.
| Evaluation of a Person with Hypertension|
The goals of the evaluation of the patient with documented hypertension are to identify other cardiovascular risk factors or concomitant disorders and to assess lifestyle factors that may affect prognosis and guide treatment, to reveal identifiable causes of high blood pressure, and to assess the presence or absence of target organ disease and cardiovascular disease.(2) The evaluation begins with documentation of family history of cardiac and renal disease, followed by a physical examination to search for signs and symptoms of secondary causes of hypertension and target organ disease. It is important to document the complete list of medications and supplements that are used, as well as health-related habits, alcohol use, tobacco use, and other substance use. Key aspects of the physical examination include correct measurement of blood pressure in both arms; funduscopy; auscultation for bruits in neck, abdomen, and femoral areas; palpation of the thyroid; complete examination of the heart, lungs, and abdomen; examination of pulses and abdominal pulsations; neurological examination; and calculation of the body mass index (BMI) (BMI: wt in kg/height in meters squared) and waist circumference. Extensive laboratory work is not recommended unless the history or the physical examination suggests secondary causes of hypertension. Recommended tests prior to starting treatment include: an electrocardiogram; urine analysis; measurement of blood glucose, hemoglobin, creatinine, electrolyte, and calcium levels; and a lipid profile. Urine albumin-to-creatinine ratio is an optional test.
| Treatment of Hypertension|
The goal of therapy is to reduce cardiovascular and renal mortality and morbidity while avoiding possible adverse effects of antihypertensive medications. The blood pressure goal is <140/90 mm Hg, or <130/80 mm Hg in patients with diabetes, congestive heart failure (CHF), CAD, or renal disease.
Therapy should include lifestyle modifications to help lower blood pressure and decrease the amount of medication required to achieve the goal. Lifestyle modifications include dietary changes, weight reduction, salt restriction, exercise, and moderation of alcohol consumption (see Table 4).(2) For stage 1 hypertension without target organ disease, it is acceptable to try lifestyle modifications for several months; if these are effective, it may be possible to forgo pharmacologic treatment.
For patients with stage 1 hypertension who have incomplete blood pressure control with lifestyle changes, as well as for those with stage 1 hypertension with target organ disease or stage 2 hypertension, antihypertensive medication is indicated. A recent meta-analysis of 42 clinical trials that included 192,478 patients randomized to 7 major treatment strategies, including placebo, showed that low-dose thiazide diuretics (hydrochlorothiazide 12.5 mg per day) were the most effective first-line treatment for preventing cardiovascular morbidity and mortality.(37) Diuretics enhance the efficacy of multidrug regimens, and are the least costly of hypertension medications. Despite the evidence of their efficacy, they are underused. Many patients with stage 1 hypertension and most patients with stage 2 hypertension will require 2 or more drugs to control their blood pressure.
There are situations in which alternatives to thiazides are indicated for initial therapy. For example, patients with hypertension and certain comorbidities may benefit from particular therapies. There is compelling evidence that patients with heart failure and hypertension have decreased mortality and morbidity from therapy with angiotensin-converting enzyme inhibitors (ACEIs), beta blockers, and angiotensin receptor blockers (ARBs).(38,39) Part of this mortality and morbidity benefit is independent of blood pressure lowering. Patients with stable angina benefit from beta blockers, and patients with acute coronary syndrome benefit from beta blockers and ACEIs.(40) In post-myocardial infarction patients, ACEIs, beta blockers, and ARBs have proved effective in reducing recurrence of myocardial infarction and angina, and in reducing mortality.(40)
Persons with diabetes commonly develop hypertension during the course of their illness. In terms of cardiovascular risk assessment, diabetes is considered equivalent to known coronary disease. For diabetic patients, the blood pressure goal is <130/80 mm Hg. Diabetic patients often require 2 or more drugs for blood pressure control. Thiazides, beta blockers, ACEIs, ARBs, and calcium channel blockers are beneficial in reducing cardiovascular disease and stroke in patients with diabetes. ACEI- and ARB-based treatments have the additional benefits of decreasing the rate of diabetic nephropathy and reducing microalbuminuria.
In patients with existing renal disease, aggressive lowering of blood pressure to <130/80 mm Hg will slow the rate of deterioration of renal function. ACEIs and ARBs have shown favorable effects on diabetic and nondiabetic renal disease. These patients have to be carefully monitored for hyperkalemia and worsening of renal function.(41)
| Resistant Hypertension|
Resistant hypertension has been defined as blood pressure that remains above goal in patients who are adhering to full doses of an appropriate 3-drug regimen that includes a diuretic.(2) Clinicians need to explore the reasons for failure to achieve the blood pressure goals. Nonadherence, improper measurement of blood pressure, and failure to use a diuretic are common causes. Consideration of the causes (listed in Table 5) and a workup of secondary causes or referral to a hypertension specialist may be appropriate. Even after a thorough workup, resistant hypertension is most often attributable to severe primary hypertension. Potent vasodilators such as minoxidil and hydralazine may need to be added to the treatment regimen.
| Miscellaneous Hypertension Considerations|
ACEIs and ARBs should not be used during pregnancy because of potential teratogenicity. Methyldopa, beta blockers, and hydralazine are considered safe for the fetus. Abrupt discontinuation of beta blockers or clonidine may lead to rebound hypertension. Thiazides may elevate uric acid levels and exacerbate gout. Thiazides are not contraindicated in gout, but patients should be stable and receiving prophylactic medication when thiazides are initiated.
Data from the U.S. National Health and Nutrition Examination Surveys show that, while 70% of patients with hypertension are aware of their condition, and treatment rates have risen to 59%, control of hypertension has remained low at 34%.(2) The phenomenon of knowing that patients are not at their target blood pressures and accepting those values without making further attempts to lower their blood pressure measurements is sometimes referred to as clinical inertia. These situations can be remedied by setting specific blood pressure goals, using flow sheets, and involving nurses and pharmacists in the care of patients.(42)
| The Interaction between HIV and Hypertension|
There is no evidence that HIV infection itself causes hypertension. However, certain coinfections, comorbidities, and antiretroviral medications have been associated with hypertension in persons with HIV. Hypertension may be directly related to hepatitis B or C when these infections cause chronic kidney disease. HIV-associated nephropathy does not usually cause hypertension directly, but it can lead to end-stage renal disease.(43)
Hypertension may be present at the time of diagnosis of the metabolic syndrome. It often develops in patients who are followed for 3 to 5 years after having normal blood pressure at baseline. Abdominal obesity and other features of the metabolic syndrome, including hypertension and insulin resistance, may be seen in patients on certain antiretroviral medications.
There is no evidence that HIV infection causes hypertension. However, hypertension is expected to be as common, if not more so, in patients on ART as it is in the general population. The Women's Interagency HIV Study recently reported on a cohort of HIV-positive women and demographically similar HIV-negative women.(27) At baseline, both groups had a 19% prevalence of hypertension. Through 8 years of follow-up, the overall incidence of hypertension was about 46% for both groups. The factors associated with incident hypertension were increasing age, African American ethnicity, smoking, lower educational levels, and obesity.
HIV medications have been associated with hypertension.(27,28) A subgroup univariate analysis of the Women's Interagency HIV Study showed a time-dependent relationship between the duration of ART and the development of hypertension.(27) It is not clear whether this trend toward hypertension in patients receiving ART is true or whether it can be explained by confounding factors. Another study followed 181 Italian patients with HIV and normal baseline blood pressures for a mean of 34 months.(44) One hundred four were taking indinavir and 77 were receiving other PIs. Thirty-one patients, all of whom were taking indinavir, developed hypertension. Half of those 31 patients had a family history of hypertension. The authors concluded that hypertension was associated with indinavir use and that blood pressure should be monitored carefully, especially in patients with a family history of hypertension.
PIs inhibit cytochrome P450 CYP3A4 and should potentiate the effect of calcium channel blockers used to treat hypertension. Losartan, an ARB, may have its effect potentiated by CYP2C9 induction, which leads to active metabolites. Starting these antihypertensive medications at low doses and monitoring effects carefully are important in treating patients on PIs.
As with ART, patient education and adherence are of utmost importance to the success of hypertension treatment, as medications must be taken consistently over a long period of time to achieve the maximum benefits.
| Key Points|
Hypertension is a common disease.
For accurate diagnosis, it is important to measure blood pressure correctly, using the appropriate technique and making sure that patients' shirtsleeve cuffs are not too tight.
Hypertension is a component of the metabolic syndrome. If hypertension is present, check for other components.
Treatment will prevent cardiovascular complications.
All cardiac risk factors should be assessed and treated.
Patients at highest risk will benefit most from treatment.
Lifestyle modifications are important and effective.
Low-dose thiazides (eg, 12.5 mg of hydrochlorothiazide) are generally the first-line medications.
Comorbidities indicating the use of other medications as first-line treatment may be present.
Blood pressure goals should be set and efforts should be made to achieve them.
Patient education and long-term adherence are important.
| Diabetes Mellitus|
Diabetes mellitus is a common disease that is increasing in prevalence as the population of the United States grows more obese. Approximately 17 million Americans, or 8% of the population, have diabetes and about one third of them are not aware of it.(45) Approximately 900,000 people in the United States are infected with the HIV virus. The chance for overlap between these two diseases is high. As people with HIV live longer, their risk of acquiring diabetes increases with advancing age.
HIV infection and HIV medications have been associated with increased insulin resistance and clinical diabetes.(9,10,11,27) Diabetes and HIV feature some of the same metabolic and morphologic changes. Both diseases are associated with multiple complications of various organ systems. Diabetic patients commonly have characteristics of the metabolic syndrome, as do patients with HIV disease. Whether HIV is associated with the increased cardiovascular morbidity and mortality being attributed to diabetes is an area of active research.
Treatment for both conditions usually requires a polypharmacy of potentially toxic and interacting medications. Neither is curable at present and both require long-term management and special considerations to prevent complications. Both are leading causes of death in the United States.
| New Diagnostic Criteria for Diabetes|
The American Diabetes Association (ADA) has recently revised the diagnostic criteria for diabetes.(46)
A confirmed fasting plasma glucose value of >=126 mg/dL indicates a diagnosis of diabetes. Previously, a value of >=140 mg/dL had been required for diagnosis.
In the presence of symptoms of diabetes, a confirmed nonfasting plasma glucose value of >=200 mg/dL indicates a diagnosis of diabetes.
Currently, there are no criteria based on hemoglobin A1C (HbA1C) testing, but this measurement may provide useful information in interpreting an isolated elevated blood glucose value.
In the absence of hyperglycemia with acute metabolic decompensation, the diagnosis should be confirmed by repeat testing. An oral glucose tolerance test is not routinely recommended for the diagnosis of diabetes.
Between 90% and 95% of all cases are type 2 diabetes, which is characterized by both insulin resistance and impaired insulin secretion. Type 2 diabetes is more common in African Americans, Latinos, and Native Americans than in Caucasians. Its prevalence increases with age. The relative risk of acquiring type 2 diabetes rises with increasing BMI. The ADA recommends screening all adults aged 45 or older every 3 years, and the U.S. Preventive Services Task Force recommends screening for younger persons who are at higher risk for diabetes, including those with obesity, a family history of diabetes, hypertension, dyslipidemia, previous elevated blood glucose levels, or African American, Latino, or Native American ethnicity. The rationale for screening is that early detection may prevent the development of diabetes. Detection of blood glucose elevation to levels below the threshold for the diagnosis of diabetes may allow the prevention of diabetes through diet and lifestyle modification. In addition, long-term complications of diabetes are often present at the time of diagnosis, and other cardiac risk factors are often found in those with elevated blood glucose levels. Early intervention for those patients can begin before sequelae of cardiovascular disease are present.
| Treatment of Diabetes|
The goals of therapy for diabetes are the prevention of morbidity and mortality associated with the macrovascular and microvascular complications of diabetes, as well as control of the symptoms associated with suboptimal control of diabetes.
Eighty percent of mortality in diabetics is caused by cardiovascular disease. Most of this is due to CAD. A person with diabetes and no known CAD has the same chance of developing a fatal or nonfatal myocardial infarction as a nondiabetic with a history of myocardial infarction. When diabetes is present with other risk factors such as hypertension, smoking, or increased cholesterol levels, the risk of cardiovascular disease progresses stepwise as each risk factor is added.(2) Diabetes is now the leading cause of adult blindness and end-stage kidney disease requiring dialysis. The major diabetes complications and possible interventions to decrease the rate of each complication are listed in Table 6.
Treatment of diabetes involves the reduction of cardiac risk factors. While treatment includes the control of hyperglycemia, it also encompasses control of hypertension and hyperlipidemia and the cessation of smoking. In fact, a synergistic cardiovascular benefit is achieved by reducing other risk factors in addition to lowering blood glucose concentrations.(47,48) In 2 large studies, the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study (UKPDS), tight control of blood glucose levels in patients with type 2 diabetes was shown to decrease the rate of microvascular complications.(49) There also was a trend toward decreasing macrovascular complications, but this did not reach statistical significance. In the subset of diabetic patients treated with metformin in the UKPDS, the rates of any diabetic outcome, diabetes-related mortality, all-cause mortality, and myocardial infarction were decreased significantly.(50) Metformin reduced serum insulin levels, reduced weight gain, and improved lipid profiles. Metformin has become the drug of choice in treating obese patients with type 2 diabetes who are able to take it safely. Table 7 lists the different classes of medications used to control diabetes, their site of action, and brief comments on each class.
Diet modifications and exercise that promote weight loss can be effective in treating diabetes. Both can reduce insulin resistance and both have beneficial cardiovascular effects. In some cases, diabetes can resolve with weight loss. In the UKPDS, that required a mean weight loss of 18 kg. Diet modifications and exercise should continue in patients on medication and may allow for glucose control with fewer medications or lower doses of medication. For patients with type 2 diabetes who require medication, therapy is begun with a single agent, usually metformin, unless there are contraindications to its use. Metformin decreases hepatic glucose production, increases muscular uptake of glucose, decreases insulin levels, and mitigates weight gain. Its adverse effects include lactic acidosis in patients with abnormal renal function, congestive heart failure, liver disease, and other risks for metabolic acidosis such as severe illness in which acidosis is likely.
If a single agent fails, a second oral agent is added, usually a sulfonylurea. Sulfonylureas increase insulin secretion by the pancreatic islet cells. They can cause hypoglycemia and weight gain, and have a high long-term failure rate as monotherapy. It is important to remember that these are sulfa drugs and patients with allergies to sulfas may not be able to tolerate them. As with sulfonylureas, meglitinides such as repaglinide and nateglinide increase insulin secretion, but they are not sulfa drugs. They have short durations of action and are usually administered 3 times per day, just before meals.
If 2 oral agents fail to control glucose adequately, a third may be added. The third-line agent is usually a thiazolidinedione, or "glitazone" (eg, rosiglitazone or pioglitazone), which increases insulin sensitivity by decreasing hepatic glucose production and increasing muscular uptake of glucose. Thiazolidinediones can be used in renal failure. They can cause edema and occasionally even lead to congestive heart failure in patients who use both insulin and a thiazolidinedione. Troglitazone, the first approved agent in this class, caused a number of cases of severe liver toxicity and death and was taken off the market. Currently available agents appear safer, but liver enzymes should be monitored and these drugs should not be used in patients with moderate to severe liver disease. Two medications, acarbose and miglitol, decrease alpha-glucosidase in the gut and decrease glucose absorption in the intestines. They are less potent than the previously mentioned agents and are limited by gastrointestinal side effects of flatulence, bloating, and increased bowel movement.
If oral agents fail, insulin may be added, dosed either 1 time per day at bedtime or 2 or more times per day. Insulin is potent, but can cause hypoglycemia and weight gain. In addition, patients often dislike the injections required for its administration.
| Additional Treatment and Monitoring Considerations|
Patients' levels of understanding of diabetes management should be reviewed on a regular basis. Referral to a diabetes educator and a nutritionist can help them improve control of blood glucose concentrations. Home glucose monitoring is a helpful tool for self-management and should be available to all diabetics who wish to use it.(51) Glucose control can be improved by stating a specific HbA1C goal.(52) The general target is <7%. If that is unattainable, an intermediate goal should be a reduction of 1 to 2 percentage points in HbA1C; this has been shown to decrease retinopathy. Patients should be referred yearly for ophthalmologic evaluations. A fasting lipid profile should be checked around the time of diagnosis and yearly thereafter. The LDL goal for diabetic patients is <100 mg/dL; this should be pursued aggressively. The Scandinavian Simvastatin Survival Study of patients with CHD showed that diabetic patients achieved twice the degree of cardiovascular risk reduction as nondiabetics by LDL reduction through therapy with statins.(53)
In patients with diabetes, blood pressure should be controlled to a systolic measurement of <130 mm Hg and a diastolic measurement of <80 mm Hg. The antihypertensives that have been shown to reduce cardiovascular events in diabetics are ACEIs, thiazides, beta blockers, certain calcium channel blockers, and ARBs. Most diabetic patients with hypertension will require 2 or more agents to control their blood pressure.
A random urine albumin-to-creatinine ratio should be checked at baseline and yearly thereafter. Diabetic patients with a ratio >30 mg/g should be treated with an ACEI or an ARB to slow the progression of nephropathy and should be evaluated for other factors causing nephropathy. Small elevations in creatinine concentrations, for example an increase from 0.8 to 1.2, may represent a substantial loss of glomerular filtration rate. It maybe helpful to calculate the glomerular filtration rate by the Cockcroft-Gault formula (see Table 8) to quantify the decline in renal function. Once the patient has a creatinine concentration of >1.5 mg/dL, a plot of 1/creatinine vs time should be graphed. Most patients progress toward end-stage renal disease in a linear fashion. If the creatinine measurement falls off the anticipated graph, a thorough investigation of the prerenal, renal, and postrenal causes of this decline should be performed. An early referral to a nephrologist is important to investigate reversible causes of renal failure and to prepare the patient for dialysis when this becomes appropriate.
| The Interaction between HIV and Diabetes|
HIV infection has been associated with insulin resistance, which is often a precursor of type 2 diabetes mellitus. A study of the California Medicaid database for the period from 1994 to 2000 examined 7,219 HIV-infected subjects and 2,792,971 noninfected controls.(54) This study, which had more than 7 million patient years of follow-up, showed an overall incidence of diabetes of 10.68/100 patient years in the HIV-infected subjects and 2.91/100 in the noninfected controls. The overall relative risk of diabetes in HIV patients compared with non-HIV patients was 3.32. There was no information about HIV therapy or important risk factors for the development of diabetes. The Multicenter AIDS Cohort Study found that HIV-infected men on ART had approximately a 5-fold increase in risk of diabetes compared with HIV-negative controls, and that ART conferred a 2- to 3-fold increased risk of hyperglycemia compared with HIV-infected, untreated controls.(11) HIV medications also may cause insulin resistance. For example, a study has shown that indinavir can cause insulin resistance, with this effect sometimes seen after administration of a single dose.(55) Studies have estimated that the risk of developing diabetes while on PI-based therapy ranges from 1% to 7%.(56,57) Hepatitis C coinfection, which is common in patients who have a history of injection drug use, has been shown in other cohort studies to increase the risk of diabetes.(12,13)
HIV-infected patients with lipodystrophy may be more likely than matched healthy non-HIV-infected controls or HIV-infected patients without fat redistribution to have impaired glucose tolerance, diabetes, hypertriglyceridemia, and reduced levels of HDL cholesterol. In one study, 71 HIV-infected subjects (49 men and 22 women) with self-reported recent changes in body fat distribution (verified by a single investigator) were compared with 3 age-, gender-, and BMI-matched controls from the Framingham Offspring study and with 30 HIV-infected subjects without lipodystrophy.(57) In the lipodystrophy patients, diabetes was detected in 7% and impaired glucose tolerance was detected in 35.2%, while the rates among controls were 0.5% and 5.2%, respectively. There was no difference between Framingham controls and HIV-infected without lipodystrophy controls.
Medications commonly used to treat HIV-related conditions can cause diabetes. Medications that can cause diabetes include pentamidine, prednisone, nicotinic acid (niacin), anabolic steroids, human growth hormone, and megestrol. Pentamidine, which is used as an alternative treatment for Pneumocystis jiroveci pneumonia (PCP), is toxic to pancreatic islet cells and can cause severe acute hypoglycemia as well as type 1 and type 2 diabetes at variable time intervals either during or after the course of its administration.
Medications used to treat diabetes also may be problematic in patients with HIV. The sulfonylureas contain sulfa and may trigger allergic reactions in those patients who have been intolerant of sulfa-containing antibiotics such as trimethoprim-sulfamethoxazole. Metformin is the drug of choice for obese type 2 diabetic patients who have failed diet and exercise therapy. However, metformin should not be given to patients with renal dysfunction or creatinine concentrations >1.4 mg/dL, due to increased risk of lactic acidosis. It should be stopped prior to X-ray contrast studies and not restarted until 48 hours afterward (and after confirmation that the postcontrast creatinine measurement is normal). Metformin is contraindicated in other conditions known to cause acidosis, for example severe CHF, hypoxia, sepsis, and liver failure. Metformin should be stopped during hospitalizations for surgery and conditions that may cause acidosis, such as CHF, chronic obstructive pulmonary disease (COPD) exacerbation, and pneumonia. It is unknown whether metformin is associated with an increased risk of lactic acidosis induced by mitochondrial damage from nucleoside analogues. Medical providers should have a low threshold for checking a lactic acid level and stopping metformin promptly if the lactate level is elevated. Ritonavir may increase serum levels of sulfonylureas and potentiate their effect. Other PIs may cause lesser increases in sulfonylurea levels. In a patient taking ritonavir or another PI, the starting dosage of a sulfonylurea should be low.
Diabetes and HIV share many complications. This makes monitoring for and prevention of diabetes very important. Shared complications include neuropathy, retinopathy, gastrointestinal dysfunction, cardiac disease, dermatological diseases, weight loss, increased susceptibility to certain infections, and pregnancy-related problems. It may be difficult to know with certainty which disease process has caused a particular complication.
| Key Points|
View diabetes as a metabolic and vascular disease with increased cardiac mortality and morbidity. Plan CAD risk reduction.
Reduce the risk of developing diabetes by diet, weight loss in overweight patients, and regular exercise.
Screen for diabetes with blood glucose testing and symptom review. Evidence points to increased rates of diabetes in people with HIV, especially those with lipodystrophy and those receiving treatment with PIs.
In patients with diabetes, control the blood glucose levels (including avoidance of hypoglycemia), lipids, and blood pressure.
Have an HbA1C goal in mind (7% is recommended). If this is not possible, try to lower the HbA1C measurement by 1 to 2 percentage points.
Control blood pressure to <130/80 mm Hg.
Control hyperlipidemia. LDL goal is <100 mg/dL; HDL goal is >45 mg/dL in men and >55 mg/dL in women.
Encourage smoking cessation for patients who smoke.
Refer patients to a diabetes educator or nutritionist, and yearly to an ophthalmologist.
Check drug interactions and avoid renal-toxic medications and tests (eg, intravenous radiocontrast).
When using metformin, monitor for the possibility of lactic acidosis. Do not use if the creatinine measurement is >1.4 mg/dL. Stop for 48 hrs after intravenous contrast and hold for serious illness or surgery.
Check for sensory loss (a 5.02 monofilament is recommended for evaluating the feet) and microalbuminuria.
Lipid abnormalities are common in the general population and among people infected with HIV. Hyperlipidemia is a major cardiac risk factor and is part of the metabolic syndrome. In addition, high levels of triglycerides can cause pancreatitis. Before the use of combination ART, men with HIV were reported to have hypocholesterolemia with low total cholesterol, HDL, and LDL with or without hypertriglyceridemia.(58) Current ART is associated with variable levels of hyperlipidemia. Updated U.S. guidelines for the evaluation and treatment of elevated lipids were published in 2002.(3,4) Key features of these guidelines are:
A more intensive approach to primary prevention in persons with multiple risk factors.
Patient risk is determined by counting cardiovascular risk factors and, if 2 or more risk factors are present, by calculating the 10-year Framingham CHD risk (see Table 9).
Optimal LDL is <100 mg/dL, desirable total cholesterol is <200 mg/dL, low HDL is <40 mg/dL, optimal HDL is >=60 mg/dL, normal triglycerides are <150 mg/dL.
LDL treatment goals have been intensified. LDL goals are <100 mg/dL for CHD or equivalent or a 10-year risk of >20%; <130 mg/dL for 2 or more risk factors or a 10-year risk of <=20%; and <160 mg/dL for 0 or 1 risk factor.
CHD equivalents include known CAD, diabetes, abdominal aortic aneurysm, carotid artery disease, peripheral artery disease, and absolute 10-year risk of >20%.
Discussion of establishing the LDL goal of therapy, determining the need for therapeutic lifestyle changes, determining the level to consider drug therapy (see Table 10 and Table 11).
Discussion of other aspects of the metabolic syndrome and indications for treatment (see Table 12 and Table 13).
Studies have shown cardiovascular morbidity and mortality benefit through lipid lowering both in subjects with known CAD (secondary prevention) and in those without known CAD (primary prevention). Secondary prevention trials show larger absolute risk reduction in CHD events than do primary prevention trials, reinforcing the point that those with higher risk benefit more from risk reduction.
The MRC/BHF Heart Protection Study, a 5-year randomized, placebo-controlled trial of 20,536 subjects, showed that treatment with a statin (simvastatin 40 mg per day) in subjects with high cardiac risk produced a substantial benefit in all-cause mortality, coronary death, vascular mortality, stroke, and first nonfatal myocardial infarction.(59) This effect was seen irrespective of the baseline cholesterol. There was no evidence for an LDL threshold below which no benefit was gained. Subjects with baseline LDL <97 mg/dL whose LDL dropped to <65 mg/dL experienced a risk reduction as great as that seen in subjects with a higher baseline LDL. This study suggests that LDL levels well below the current guideline of <100 mg/dL for high-risk patients will provide substantial benefit. The number of subjects needed to treat (NNT) for 5 years to prevent any major vascular event was 19, and 55 to prevent death from any cause.
All patients with lipid abnormalities should be counseled about therapeutic lifestyle changes, which include reduced saturated fat and cholesterol intake, increased fiber intake, weight reduction, and exercise (see NCEP Adult Treatment Panel III guidelines for specific diet recommendations).(3,4) A referral to a nutritionist is highly recommended.
Patients with hyperlipidemia should be evaluated for secondary causes. Diabetes, hypothryoidism, liver disease, chronic renal failure, and medications such as steroid hormones and PIs can cause secondary dyslipidemia.
| Drug Therapy|
There are several classes of lipid-lowering medications. They include HMG-CoA reductase inhibitors (statins), fibrinic acid derivatives (fibrates), bile acid sequestrants, nicotinic acid, and the newest agents, cholesterol absorption inhibitors (eg, ezetimibe). Probucol, an older, more toxic medication is still available, but is not widely used. Statins are usually the first-line medications for lipid abnormalities that include elevated LDL levels. These are the most potent agents in lowering LDL levels, and a large body of evidence shows decreased mortality and morbidity with their use. When both triglyceride and LDL levels are elevated, the LDL generally should be treated first, because reducing LDL levels with statins will lower triglyceride levels as well. If the triglycerides are very high (>500 mg/dL), they are usually treated initially with a fibrate or nicotinic acid to prevent pancreatitis. If the LDL is normal, treatment goals are based on the non-HDL cholesterol (total cholesterol minus HDL). The non-HDL goal is 30 mg/dL more than the LDL cholesterol goal. Elevated non-HDL can be treated with therapeutic lifestyle changes, followed by a statin, nicotinic acid, or a fibrate.
A meta-analysis of medication adherence evaluations in different settings showed poor adherence to lipid-lowering drugs.(60) Pharmacy databases revealed a statin discontinuation rate of about 50%. A review of a database at a veterans' hospital in the state of Washington showed that 31% of patients had stopped taking their statin by 1 year. Clinical trials show a 30% discontinuation rate within 5 years of starting a statin, while lipid clinics have lower rates (<13%) of discontinuation. Discontinuation rates were higher for bile acid resins and gemfibrozil than for statins. Rates of taking less than the prescribed dose are even higher. It is important to assess patients' adherence to lipid medications and educate them about the important cardiovascular benefits provided by controlling lipid levels.
| Hyperlipidemia in Persons with HIV|
Lipid abnormalities are common, especially in patients on PI medications. Individual PIs cause dyslipidemia to variable degrees, with large elevations in patients taking lopinavir/ritonavir and small changes in those taking atazanavir.(22)
There are significant drug interactions between some statins and PIs. Simvastatin and lovastatin are metabolized by intestinal and hepatic CPY3A4. When CPY3A4 is inhibited by PIs, the area under the curve (AUC) of these drugs can increase dramatically. In a study of 56 seronegative subjects given saquinavir + ritonavir with a statin, the AUC of simvastatin increased 3,059%, the AUC of atorvastatin increased 347%, and the AUC of pravastain decreased 50%.(61) Simvastatin and lovastatin should not be used with PIs.(19) Fatal rhabdomyolysis has occurred in a patient taking both a PI and simvastatin (personal observation). Pravastatin is the PI least affected by drug interactions and should be the initial statin used. If the lipid goal is not met, low-dose atorvastatin may be used instead and carefully titrated up, but large increases in the AUC may occur. Fibrates have a low potential for interaction with PIs. If statins and fibrates are combined, the risk of rhabdomyolsis is increased.
| Key Points|
Screen patients with fasting lipid panels.
Determine whether they have CHD-equivalent disease.
Count the number of major CHD risk factors.
If 2 or more risk factors are present, use the Framingham table to calculate the10-year CHD event risk.
From Table 9, determine risk category and treatment goals.
Significant drug interactions exist between certain antiretrovirals and lipid-lowering medications. Simvastatin and lovastatin AUCs are greatly increased when these drugs are used with PIs; these statins are contraindicated in patients taking PIs. Atorvastatin AUC is increased to a lesser degree. Pravastatin AUC is either mildly elevated or decreased, making pravastatin the first-line statin for patients who are taking PIs. A useful Internet resource on medication interactions is the HIV InSiteDatabase of Antiretroviral Drug Interactions. It is regularly updated as new information becomes available.
For patients with dyslipidemia, a referral to a nutritionist is highly recommended.
| Cardiac Studies in Individuals with HIV Infection|
Given the metabolic derangements and increased inflammatory states associated with HIV and ART, along with an aging population that may have significant cardiac risk factors, there is concern that cardiovascular morbidity and mortality in persons with HIV may rise.
Studies of cardiovascular disease in HIV-infected individuals thus far have shown mixed results. A retrospective study of cardiovascular and cerebrovascular disease showed that overall mortality among HIV-infected U.S. military veterans decreased by 75% during the study period.(6) The rates for cardiovascular or cerebrovascular disease-related hospital admissions decreased from 1.7 to 0.9 per 100 patient years during the study period. There was no relationship between use of nucleoside analogues, PIs, or nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the hazard of cardiovascular or cerebrovascular disease. The use of antiretroviral drugs was associated with a decreased hazard of death from any cause. While this study did not show an increase in cardiovascular disease, it had several shortcomings, including the possibility that the study period may not have been long enough to detect the development of atherosclerotic heart disease and that high-risk patients and lower-risk patients may have been treated differently.
In a case-control study of rates of hospitalization for CHD among HIV-infected male patients in the Northern California Kaiser Permanente HMO, 4,762 men with HIV infection (cases) and 42,526 HIV-negative male patients (controls) were followed for up to 8 years.(62) The patients' ages ranged from 35 to 64. At baseline, the HIV-positive group had a higher percentage of smokers (24% vs 13%) but a lower prevalence of hypertension (27% vs 34%). Age-adjusted rates of hospitalization for CHD and myocardial infarction were higher in the HIV-positive patients than in the HIV-negative patients. CHD event rates were 6.3/1,000 patient years in HIV-positive patients and 3/1,000 patient years in HIV-negative patients. Myocardial infarction rates were 3.7/1,000 patient years and 2.2/1,000 patient years, respectively, in the 2 groups. These differences were statistically significant. Further analysis in HIV-positive men showed a trend toward more CHD events in the PI-exposed patients than in those not exposed to PIs (7/1,000 patient years vs 5.5/1,000 patient years), but this was not statistically significant. While the rate of events in HIV-positive patients was higher than in the HIV-negative controls, the absolute difference per year was small (0.17%); for every 588 HIV-positive patients followed for 1 year, there may be 1 excess cardiac event compared with age-matched HIV-negative patients.
The Data Collection of Adverse Events of Anti-HIV Drugs (DAD) study was a prospective observational study that analyzed myocardial infarction events in 23,468 HIV-infected patients from 11 international cohorts.(7) The DAD cohort was comprised largely of men (76%), and had a mean age of 39. At baseline, 45.9% had dyslipidemia, 56.2% were current or former smokers, 7.2% had hypertension, 2.8% had diabetes, and 4.8% had a BMI >30 kg/m2. The cohort was followed from December 1999 to February 2002. Data were collected on cardiovascular risk factors and the incidence of myocardial infarction in patients on ART, which included a PI or an NNRTI, and in patients not on ART. There were 126 myocardial infarctions in 36,500 person years of follow-up. After adjustments for traditional risk factors were made, ART was associated with a steadily increasing risk of myocardial infarction over 7 years of exposure. The relative risk of myocardial infarction was 1.26 per year of exposure to ART. Other factors that predicted myocardial infarction were increasing age, current or past smoking, previous cardiovascular disease, and male gender. Lipoatrophy was associated with a decreased risk of myocardial infarction. Annual rates of myocardial infarction were low, even in those exposed to ART (<0.6%), and only a portion of the excess risk could be attributed to ART. For every 571 HIV-positive patients treated with ART for 1 year, there would be 1 excess case of myocardial infarction.
In a subsequent analysis, the DAD study group found that cardiovascular and cerebrovascular events increased at similar rates in patients treated with ART.(8) The relative rate of these events was 1.26 per year of exposure to ART. The absolute differences between patients on ART and those not on ART were small. The analysis also compared the predicted number of events with the observed number of events. Using the Framingham risk equation to predict the rate of myocardial infarction that would have been expected in the DAD study, the study compared the predicted rate of myocardial infarction with the observed rate. In subjects not receiving ART, the observed rate was less than the predicted rate. In subjects receiving ART, the observed rate was higher than the predicted rate but was within the 95% confidence intervals. Both the predicted and observed rates of myocardial infarction increased in a parallel fashion with increased ART exposure, suggesting that the increase in myocardial infarction may be due to ART-induced conventional cardiovascular risk factors. Predicted rates were based on Framingham risk factors and increased as the subjects aged and their levels of lipids changed. Only a portion of the observed increased risk was attributable to ART. While there appears to be a trend of increased events, it is very small and is far outweighed by the decreased mortality from ART.
Two other studies have examined ultrasound measurements of carotid intima-media thickness, a marker of cardiovascular risk. These had differing results. One study showed that the progression of carotid intima-media thickening over 1 year was 10 times greater in PI-experienced subjects than in historical controls.(63,64) Multivariate analysis showed significant associations with nadir CD4 T-cell count <200 cells/µL, increasing age, high LDL cholesterol level, and hypertension. The duration of HIV infection, viral load, current CD4 T-cell count, lipodystrophy, and C-reactive protein were not predictive. A second study showed no significant differences in carotid intima-media thickening in 3 groups of subjects: HIV-infected persons on PIs for >2 years, those never on PIs, and uninfected controls.(65)
At this point in time, data from observational cohorts suggest a small absolute increase in cardiac events in HIV-infected patients treated with ART. These events may be mediated through conventional cardiovascular risk factors, such as hyperlipidemia, which may be induced or worsened by ART. The magnitude of the increased cardiovascular risk is small in comparison with the great decrease in mortality and AIDS-defining events seen in patients receiving ART. Careful cardiovascular risk assessment and reduction of all modifiable risk factors through lifestyle modification, pharmacologic methods, or both, are clearly indicated.
| Key Points|
Cardiovascular disease is the number one cause of death in the United States.
Traditional cardiac risk factors are highly predictive of future cardiac risk in HIV-infected and HIV-uninfected persons.
Cardiac risk factors are underevaluated and undertreated.
Hypertension, hyperlipidemia, and diabetes are often not treated at the levels recommended in national guidelines.
Given the metabolic derangements and inflammatory state associated with HIV and ART, along with an aging population that has significant cardiac risk factors, there may be an increase in cardiovascular morbidity and mortality in persons with HIV.
We do not have to wait for further data to begin evaluating our patients' risks and aggressively trying to reduce their modifiable risks.
Screening for hypertension, lipid abnormalities, diabetes, and the metabolic syndrome is simple and may detect early abnormalities that can be treated by nonpharmacologic methods or, if necessary, medication.
Rates of smoking, in most cohorts, are in excess of 40%. Smoking cessation should be encouraged.
Diet and exercise should be encouraged in all patients.
Significant drug interactions exist between certain lipid-lowering medications (statins) and PIs. Consult drug interaction databases when initiating or changing medications in patients who are on PIs, NNRTIs, or drugs that affect the hepatic cytochrome P450 system.
Monitor renal and liver function in patients who take potentially toxic medications or medications that need to be adjusted or stopped for abnormal renal or liver function.
|| || Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr., Jones DW, Materson BJ, Oparil S, Wright JT, Jr., Roccella EJ. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. Jama 2003; 289:2560-72.|
|| ||National Heart, Lung, and Blood Institute at the NIH Cholesterol Guidelines and online risk calculator. www.nhlbi.nih.gov/guidelines/cholesterol|
|| || Friis-Moller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, Reiss P, Thiebaut R, Morfeldt L, De Wit S, Pradier C, Calvo G, Law MG, Kirk O, Phillips AN, Lundgren JD. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993-2003.|
|| ||Law M, Monforte AD, Moller NF, et al. Cardio- and cerebrovascular events and predicated rates of myocardial infarction in the D:A:D study. Abstract 737. 11th Conference on Retroviruses and Opportunistic Infections; Feb 8-11, 2004; San Francisco, California. Poster Abstract 739.|
|| ||Currier JS, Boyd F, Kawabata H, et al. Diabetes mellitus in HIV-infected individuals. In: Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; Feb 24-28, 2002; Seattle, Washington. Abstract 677.|
|| ||Brown TT, Cole SR, Li X, et al. Prevalence and incidence of pre-diabetes and diabetes in the Multicenter AIDS Cohort Study. 11th Conference on Retroviruses and Opportunistic Infections; Feb 8-11, 2004; San Francisco, California. Abstract 73.|
|| ||Deedwania PC, Thomas NC, Brar K. Metabolic syndrome is highly prevalent in patients with coronary artery disease. American College of Cardiology Annual Meeting; March 31,2003; Chicago, Illinois. Abstract 1107-139.|
|| || Murphy RL, Brun S, Hicks C, Eron JJ, Gulick R, King M, White AC, Jr., Benson C, Thompson M, Kessler HA, Hammer S, Bertz R, Hsu A, Japour A, Sun E. ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results. Aids 2001; 15:F1-9.|
|| ||Khalsa A, Minkoff H, Cohen M, et al. Hypertension in HIV infected women. Relationship to HAART in the Women's Interagency HIV Study. In: Program and abstracts of the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment; July 7-11, 2001; Buenos Aires, Argentina. Abstract 512.|
|| ||Khalsa A, Karim R, Mack W, et al. Hypertension in HIV-infected women related to HAART: women's interagency HIV study. Poster Abstract 741. 11th Conference on Retroviruses and Opportunistic Infections; Feb 8-11, 2004; San Francisco, California.|
|| ||Thiébaut R, El-Sadr W, Chenuc G, et al. Predictors of hypertension and changes in blood pressure in the D:A:D study. 11th Conference on Retroviruses and Opportunistic Infections; Feb 8-11, 2004; San Francisco, California. Abstract 75.|
|| ||Henry K, Zackin R, Dube M, et al. C-reactive protein levels and cardiovascular risk status for a cohort of HIV-I infected persons durably surprised on indinavir containing regimen. 9th Conference on Retroviruses and Opportunistic Infections; Feb 24-28, 2002; Seattle, Washington. Abstract 694-T.|
|| ||Henry K, Kitch D, Currier J, et al. Trends in C-reactive protein levels in a cohort of HIV-1 infected persons durably suppressed on an indinavir based regimen (ACTG 5056). Poster Abstract 733. 11th Conference on Retroviruses and Opportuntistic Infections; Feb 8-11, 2004; San Francisco, California. Abstract 739.|
|| || Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, Noble RJ, Packer M, Silver MA, Stevenson LW, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Jacobs AK, Hiratzka LF, Russell RO, Smith SC, Jr. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001; 38:2101-13.|
|| || Mehta RH, Montoye CK, Gallogly M, Baker P, Blount A, Faul J, Roychoudhury C, Borzak S, Fox S, Franklin M, Freundl M, Kline-Rogers E, LaLonde T, Orza M, Parrish R, Satwicz M, Smith MJ, Sobotka P, Winston S, Riba AA, Eagle KA. Improving quality of care for acute myocardial infarction: The Guidelines Applied in Practice (GAP) Initiative. Jama 2002; 287:1269-76.|
|| ||American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2001;24:S5-S20.|
|| ||Currier JS, Boyd F, Kawabata H, et al. Diabetes in HIV-infected individuals. In: Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; Feb 24-28, 2002; Seattle, Washington. Abstract 677.|
|| || Hadigan C, Meigs JB, Corcoran C, Rietschel P, Piecuch S, Basgoz N, Davis B, Sax P, Stanley T, Wilson PW, D'Agostino RB, Grinspoon S. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001; 32:130-9.|
|| ||Klein D, Hurley L, Quesenberry CP, et al. Hospitalization for coronary heart disease and myocardial infarction among men with HIV-1 infection: follow-up through 12/31/03. 11th Conference on Retroviruses and Opportunistic Infections; Feb 8-11, 2004; San Francisco, California. Abstract 739.|
|| ||Hsue P, Lo J, Franklin A, et al. Increased atherosclerotic progression in patients with HIV: the role of traditional and immunologic risk factors. 10th Conference on Retroviruses and Opportunistic Infections; Feb 10-14, 2003; Boston, Massachusetts. Abstract 139b.|
|| ||Currier J, Kendall M, Henry K, et al. Carotid intima-media thickness in HIV infected and uninfected adults: ACTG 5078. 10th Conference on Retroviruses and Opportunistic Infections; Feb 10-14, 2003; Boston, Massachusetts. Abstract 131.|