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Research Alert: Study Casts Doubt on "Shock and Kill" Cure Strategy

Cardiovascular Risk Factors With HIV Infection: A Long and Motley List

Summer 2013

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Obesity Compounds Cardiovascular Risk With HIV

One reason HIV-positive people in the United States have high rates of hypertension and diabetes (see preceding section) is the growing girth of the populace at large. Besides causing or contributing to hypertension and diabetes, obesity heightens the risk of wanton lipids, coronary heart disease, and stroke.53 The CDC figures more than one third of US adults and 17% of children are obese. In 2000, the CDC reports, no state had an obesity prevalence topping 30%; in 2010, 12 states had crossed that line.54

In fact, a recent CDC analysis found a higher obesity prevalence in the general US population than in a nationally representative sample of people with HIV.55 This study focused on 4040 HIV-positive adults in 23 health departments across the United States, comparing them with people in the 2009-2010 National Health and Nutrition Examination Survey (NHANES). Obesity (body mass index above 30 kg/m2) affected 35.7% of NHANES participants and 22.8% of people with HIV. Age-adjusted obesity prevalence in HIV-positive women exceeded the general population rate (40% versus 36%), but HIV-positive men had an obesity rate less than half that of general-population men (17% versus 36%). Nearly half of HIV-positive women under 40 years old (45%) were obese.

Obesity prevalence fell with age in women with HIV and rose with age in the general population (Figure 5).55 Women with HIV ran a twice higher risk of obesity than HIV-positive men (adjusted prevalence ratio 2.12, 95% CI 1.87 to 2.41). Less education and less advanced HIV infection also made obesity more likely.


Figure 5. Obesity Prevalence by Age in US Women

Obesity Prevalence by Age in US Women

CDC analysis of a nationally representative sample of people with HIV found that obesity prevalence dwindled with age in HIV-positive women but rose with age in women in the general population (NHANES).55 Linear trend for age P < 0.01 for both groups.


Cohort studies verify the savage impact of high weight and visceral fat on cardiovascular risk in people with HIV. FRAM study investigators compared 586 HIV-positive men and women with 280 HIV-negative controls, calculating regional body fat by whole-body magnetic resonance imaging and figuring heart risk with the Framingham Risk Score.56 Splitting visceral adipose tissue (VAT) levels into four quartiles, they found that the median Framingham score rose with higher VAT quartiles in people with and without HIV. But in each VAT quartile the Framingham score was significantly or nearly significantly higher in the HIV group than in the HIV-negative group. "Increased VAT is associated with cardiovascular disease risk" with or without HIV infection, the FRAM team concluded, "but the risk is higher in HIV-infected individuals relative to controls at every level of VAT."56

Overweight and obese people with HIV also heft a heavier burden of other morbidities familiar to HIV clinicians, according to a 1833-person study at the University of Alabama at Birmingham.57 Earlier work by this team uncovered a 45% prevalence of overweight and obesity (>25 kg/m2) among HIV-positive men and women before they began cART in this clinic.58 The newer study classified participants as underweight, normal weight, overweight, or obese and grouped 15 common non-HIV conditions into three clusters -- metabolic, behavioral, and substance use. While 35% of participants were underweight or normal weight, 36% were overweight and 29% obese. Obesity independently predicted having one or more conditions in at least two of the disease clusters (adjusted odds ratio 1.52, 95% CI 1.15 to 2.00). The University of Alabama team urged colleagues to "embrace HIV care as complex chronic disease management of multiple overlapping conditions within the context of primary care."57

Italian and Canadian researchers proposed one step toward that daunting goal. They devised a simple tool combining triglycerides (TG) and waist circumference (WC) that predicted a higher Framingham Risk Score -- as well as higher VAT and rates of metabolic syndrome and type 2 diabetes -- in 1481 men and 841 women with HIV in an Italian study group (Figure 6).59 Researchers divided people into four groups: low WC/low TG, low WC/high TG, high WC/low TG, and high WC/high TG using cutoffs of ≥90 cm and ≥2.0 mmol/L (177 mg/dL) for men and ≥85 cm and ≥1.5 mmol/L (133 mg/dL) for women. Men in the high TG/high WC group had the most VAT (208 cm2), the highest Framingham score (10.3), and the highest prevalence of metabolic syndrome and type 2 diabetes, when compared with other groups of men. Women in the high TG/high WC box also had elevated VAT (average 150 cm2) as well as the highest Framingham score (2.9) and the highest rates of metabolic syndrome, hypertension, and type 2 diabetes, when compared with other groups of women.


Figure 6. A Four-Box Tool to Predict CVD Risk

A Four-Box Tool to Predict CVD Risk

A foursquare tool dividing HIV-positive men (M) and women (W) into four groups according to high or low triglycerides (TG) plus high or low waist circumference (WC) predicted Framingham Risk Score, type 2 diabetes, hypertension, metabolic syndrome, and visceral adipose tissue in a 2322-person study.59 (Waist circumference in cm; triglycerides in mmol/L; 2 mmol/L = 177 mg/dL; 1.5 mmol/L = 133 mg/dL).


A North Carolina comparison of 92 HIV-positive adults and 92 age-matched HIV-negative people found that overweight/obesity prevalence in the HIV group climbed from 52% to 66% during the first 12 months of cART, a relative increase of 27% (P = 0.002).60 HIV-positive women gained significantly more weight than men, and people starting a protease inhibitor regimen gained significantly more than those starting other regimens. People who began cART with fewer than 200 CD4 cells/mm3 added significantly more pounds than those starting at higher CD4 counts. Nearly everyone in the HIV-negative group, 93%, was overweight or obese at the start of follow-up, and that rate did not change during the study.


Time for an Extended Mediterranean Vacation?

Diet and exercise -- or at least supplanting a sedentary lifestyle with some vigorous pursuits -- offers the surest path to weight reduction while often tempering cardiovascular risk. Research shows that structured exercise programs can cut fat and build lean body mass. But because most exercise studies in people with HIV are small and completion rates often modest, this article focuses on diet and its impact on heart disease.

Whether obese, overweight, or normal weight, many American have bad diets, a failing glaringly reflected in a study of 265 men and 56 women with HIV in Boston and Providence.61 About 3 in 10 women and 1 in 10 men were obese, while one third of women and 40% of men were overweight. Figuring dietary intake by 3-day food records, the researchers found that total fat and saturated fat intakes exceeded US recommendations for both men and women in all body mass index categories.

Heavier people did not eat more than normal-weight people, but they ate worse, wresting less energy from every kilocalorie (kcal) gulped: average energy intake per kilogram waned significantly from normal weight to overweight to obese in women (33 to 25 to 19 kcal) and in men (40 to 33 to 28 kcal) (Figure 7).61 Diets of overweight and obese people contained significantly less fiber than diets of normal-weight people among both women (11.3 to 9.3 to 6.9 g for normal, overweight, and obese women) and men (13.2 to 12.8 to 11.7 g) (Figure 7). A low-fiber diet bespeaks a lack of whole grains, fruits, vegetables, nuts, and seeds.


Figure 7. Dietary Energy and Fiber by BMI in US Adults With HIV

Dietary Energy and Fiber by BMI in US Adults With HIV

As body mass index (BMI) category rose from normal, to overweight, to obese in a study of 265 men (M) and 56 women (W) with HIV, (1) average energy intake per kilogram fell significantly, and (2) median fiber content dipped significantly.61 (See text for exact values.)


Worse diets in heavier people in this study probably contributed to three factors intimately linked to cardiovascular risk -- significantly worse insulin resistance in both men and women (Figure 8), and significantly higher triglycerides and total cholesterol in men.61


Figure 8. Insulin Resistance by BMI in US Adults With HIV

Insulin Resistance by BMI in US Adults With HIV

HIV-positive women and men in each higher body mass index (BMI) category had a higher prevalence of insulin resistance (HOMA IR >3.5).61


A study comparing 356 HIV-positive adults with 162 HIV-negative people in the same community determined that, despite consuming similar shares of calories, the HIV group ate significantly more total fat, saturated fat, and cholesterol.62 Using 4-day food records or 24-hour recall, this Boston study of 197 men and 159 women with HIV also found that the HIV group derived a significantly higher percentage of calories from saturated fat and trans fat than the 73 men and 89 women in the HIV-negative group. Triglycerides rose 8.7 mg/dL for each gram of fat an HIV-positive person swallowed (P = 0.005).

People who improve their diets reap health benefits, plentiful research attests. Anyone who had occasion to browse the internet or scan a newspaper in the past few months will know results of the randomized clinical-endpoint PREDIMED trial pitting a Mediterranean diet against advice to eat a low-fat diet: People in the two Mediterranean diet groups (supplemented by extra-virgin olive oil or additional nuts) had a 30% lower risk of myocardial infarction, stroke, or death from cardiovascular disease than the low-fat group after only 4.8 years of follow-up.63

Adherence to the Mediterranean diet prescribed in this trial (Table 3) was good. The PREDIMED researchers believe their striking results "are particularly relevant given the challenges of achieving and maintaining weight loss."63 Earlier, a systematic review rated a Mediterranean diet the type of diet most likely to ward off coronary heart disease in the general population.64


Table 3. Mediterranean Diet Prescribed in the Spanish PREDIMED Trial63
RecommendedDiscouraged
Olive oilSoda drinks
Tree nuts and peanutsCommercial bakery goods, sweets, pastries
Fresh fruitsSpread fats
Fish (especially fatty fish), seafoodRed and processed meats
Legumes 
Sofrito (tomato and onion sauce) 
White meat 
Wine with meals (only for habitual drinkers) 


This widely lauded study may have special pertinence for people with HIV because study participants had a high risk of heart disease but a clean cardiovascular slate when they entered the trial. A comparison of risk factors shows, though, that PREDIMED participants were a whole lot closer to a heart attack than 33,308 antiretroviral-treated DAD Study participants in 2010:5 The PREDIMED contingent ran a higher heart risk by age (67 versus 39 in DAD), body mass index (29 versus 23 kg/m2), hypertension prevalence (82% versus 14%), and diabetes prevalence (48% versus 3%). The DAD cohort had a twice higher proportion of current smokers (35% versus 14%). More than half of PREDIMED study participants, 57%, were women, and 97% were white Europeans. In the DAD study 26% were women and 54% white. So whether the profound cardiovascular benefit seen with a Mediterranean diet in PREDIMED would hold true in contemporary HIV populations -- at least over the short term -- remains an open question.

A few studies have appraised Mediterranean fare in people with HIV. A pilot randomized trial in HIV-positive Hong Kong patients found pluses and minuses with a 12-month Mediterranean diet versus a low-fat, low-cholesterol diet.65 Of the 48 people randomized to one diet or the other, 36 (75%) completed 12 months of follow-up, which included regular dietary consultation. Dietary adherence was good, and use of specific nucleosides and protease inhibitors was similar between study arms. People in the low-fat/cholesterol crew had unfavorable body fat changes in triceps skinfold, hip circumference, and waist-to-hip ratio. Triglycerides rose in the low-fat/cholesterol group while remaining unchanged in the Mediterranean group. The Mediterranean arm had significant jumps in total cholesterol at 9 months (P = 0.03) and 12 months (P = 0.01), whereas the low-fat group did not. Because of missing data, the researchers did not analyze HDL and LDL cholesterol, so the total cholesterol findings are hard to interpret.

A larger cross-sectional US study linked Mediterranean eating habits to improvements in three heart disease indicators -- insulin resistance, triglycerides, and HDL cholesterol.66 This study involved 247 HIV-positive people with abnormal fat distribution seen at a Boston center, all of whom had complete metabolic profiles available. Researchers figured how closely their diet fit a Mediterranean plan by calculating a Mediterranean Diet Score (MedDietScore).67 A higher MedDietScore meant (1) a lower rate of insulin resistance (standardized beta -0.15, P = 0.03), (2) marginally lower triglycerides (standardized beta -0.16, P = 0.13), and (3) higher "good" HDL cholesterol (standardized beta 0.15, P = 0.01).

Two studies in Croatia gauged the impact of a Mediterranean diet and other variables on lipids and body fat in the first year of cART.68,69 Both studies relied on a 150-item questionnaire to rank people in a low Mediterranean adherence group (below 4 points on a 0-to-9 scale) or a moderate to high adherence group (4 to 9 points). Analysis of 117 people interviewed between May 2004 and June 2005 discerned no link between Mediterranean diet and serum lipids.68 Notably, people in this study were still taking lipid-malefic antiretrovirals such as indinavir and stavudine, both of which were associated with higher total cholesterol.

A similar questionnaire-based dietary analysis of 136 Croatians in the first year of cART during the same period focused on lipoatrophy and lipohypertrophy assessed by self-report and physical exam.69 Compared with nonsmoking participants with a moderate to high Mediterranean diet score, nonsmokers with a low diet score had nonsignificantly higher odds of lipoatrophy (adjusted odds ratio 4.53, 95% CI 0.86 to 23.92, P = 0.076), while smokers with a low diet score had significantly higher lipoatrophy odds (adjusted OR 3.42, 95% CI 1.21 to 9.67, P = 0.014), as did smokers with a moderate to high diet score (adjusted OR 4.39, 95% CI 1.35 to 14.26, P = 0.021). People with a moderate to high Mediterranean diet score had 70% lower odds of lipohypertrophy (adjusted OR 0.3, 95% CI 0.1 to 0.7, P = 0.012).

Although these small studies65,6668,69 hint that Mediterranean meal planning can score cardiovascular pluses for people with HIV, hints are all they provide (Table 4). Results of the randomized PREDIMED trial63 strongly suggest that HIV-positive people with a heart risk as high as people in this trial can ward off ischemic heart disease by eating more olive oil, nuts, fish, and fresh produce.


Table 4. Impact of Mediterranean Diet on Heart Risk Factors in HIV Studies
Body FatTriglyceridesCholesterolInsulin Resistance
  • No body fat changes (RCT)
  • Less lipoatrophy (in nonsmokers) (XC Cr)
  • Less lipohypertrophy (XC Cr)
  • Triglycerides unchanged (RCT, XC Cr)
  • Lower triglycerides (XC US)
  • Total cholesterol up (RCT)
  • Cholesterol unchanged (XC Cr)
  • Higher HDL cholesterol (XC US)
  • Less insulin resistance (XC US)

RCT, 12-month randomized controlled trial in Hong Kong65; XC US, cross-sectional study in United States66; XC Cr, cross-sectional studies in Croatia.68,69 See text for study details.


But will other healthy diets, leavened with a little exercise, do as well? A small randomized US trial found heart marker benefits with a 6-month low-fat/high-fiber diet plus 3 hours of physical activity weekly.70 This trial randomized 34 HIV-positive adults with metabolic syndrome to physical activity plus counseling that emphasized a diet low in saturated, polyunsaturated, and trans fat and high in omega 3 fatty acids and fiber or to a control group whose members got monthly counseling sessions on healthy eating. After 6 months the intervention group did significantly better on measures of waist circumference, systolic blood pressure, hemoglobin A1C, lipodystrophy score, and activity measured by the Modifiable Activity Questionnaire. Lipids did not improve significantly in the intervention group compared with the control group. And as in many studies of diet and/or exercise, getting people to stick to the program was not easy. Four people dropped out of the intervention arm and 2 left the control arm for an overall 6-month dropout rate of 18%.

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This article was provided by The Center for AIDS. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.
 

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