Dyslipidemia With HIV: High Prevalence, Multiple Risks

April 20, 2017

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Abstract: Cholesterol first came to attention in gallstones, but it earned its notoriety by forming plaques in artery walls. Before an HIV-positive person starts antiretroviral therapy, infection with the virus profoundly upsets lipid metabolism. Starting antiretrovirals changes the balance again, sometimes for the better, sometimes for the worse. Estimates of dyslipidemia prevalence in HIV populations range from 23% to 80%, with differences in methods, metrics, and study groups explaining the wide gap. But abnormal lipid rates in HIV groups almost always exceed those in the general population. An array of clinical conditions, behaviors, demographics, and genetic factors may contribute to heightened dyslipidemia risk in people with and without HIV. Prominent risk factors include HIV infection itself, diabetes, chronic kidney disease, weight-related variables, family history, and older age.

"Cholesterol is the most highly decorated small molecule in biology," according to two people who should know, Michael Brown and Joseph Goldstein.1 Thirteen scientists who devoted big chunks of their careers to cholesterol picked up Nobel Prizes, including Brown and Goldstein, who snagged the medal for discovering the low-density lipoprotein (LDL) receptor and tracing its strong link to HMG-CoA reductase activity.1,2 Everyone knows that led to development of HMG-CoA reductase inhibitors -- statins -- among the most potent, most used, and most studied drug classes ever dispensed.

Since its discovery, Brown and Goldstein observed, "cholesterol has exerted a hypnotic fascination for scientists from the most diverse domains of science and medicine."1 Clinicians who began caring for people with a lethal immunodeficiency in the 1980s never suspected that they, too, would perforce join the army of cholesterol experts. A PubMed search for "dyslipidemia" and "HIV" now returns 1460 articles, jumping from 27 in 1998 to 93 in 2003 and staying around that level ever since. High cholesterol affects up to two thirds of women with HIV and 80% of men3 and could explain more than 40% of myocardial infarctions (MIs) in people with HIV.4 Yet by one estimate more than half of HIV-positive North Americans eligible for statins by current guidelines don't get them.5


Trouble With a White Greasy Mass

Cholesterol gets its name from the Greek khole, meaning bile, plus steros, meaning solid. That etymology is not as fanciful as it first seems when you learn that François Poulletier de la Salle, a French physician and chemist, discovered cholesterol in a solid form in gallstones. This happened in 1784, almost exactly 200 years before Brown and Goldstein flew to Stockholm to pick up their prize. Soon after Poulletier's discovery, Michel Eugène Chevreul, another French chemist, isolated and purified cholesterol. In 1843 pathologist Julius Vogel spotted "a yellowish-white greasy mass" in the aorta of an autopsied 84-year-old man.6 Soon that irrepressible polymath, Rudolf Virchow, reasoned that lipid buildup in artery walls caused atherosclerosis, a surmise confirmed 100 years ago by Russian pathologist Nikolai Anitschkow, who fed rabbits a lipid-dripping diet and gave them all hard arteries.7

When cardiovascular disease became the number one killer in the United States and elsewhere, cholesterol got a bad reputation it has yet to shirk. Of course cholesterol is not inherently malign. Without cholesterol, the body could not build healthy cells and could not produce essential hormones and vitamin D.8

But the waxy molecule has two faces, Brown and Goldstein noted in their Nobel talk. "The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal,"1 they explained. When cholesterol piles up in the wrong place -- between artery walls, for example -- body fluids can't dissolve it, and eventually the waxy buildup molds a life-threatening plaque (Figure 1). "If cholesterol is to be transported safely in blood," the Nobelists warned, " its concentration must be kept low, and its tendency to escape from the bloodstream [into cell membranes] must be controlled."1

Figure 1. Cholesterol, fat, calcium and other constituents can build up to form plaque between artery walls.

Figure 1. Cholesterol, fat, calcium and other constituents can build up to form plaque between artery walls.

(Illustration from Servier PowerPoint Image Bank.)

That formula for good heart health sounds simple because it is simple. The body churns out all the cholesterol we need to make healthy cells. But we add to the tally by overeating lipid-laden food, by getting diseases that promote cholesterol build-ups, by taking drugs that do the same thing, and sometimes by inheriting genes that favor atherosclerosis.

Cholesterol makes its way through the circulation in the small packets we call lipoproteins -- with lipids (fats) on the inside and protein on the outside. Low-density lipoprotein cholesterol (LDL-C) earns its "bad cholesterol" repute because too much LDL-C leads to plaque formation. High-density lipoprotein cholesterol (HDL-C) (Figure 2) claims the tag "good cholesterol" because it carries cholesterol from depots throughout the body (including arteries) to the liver, which eliminates it. HDL-C plus LDL-C plus about one fifth of triglycerides (the main fat constituent in humans) make up total cholesterol.9

Figure 2. Lipoproteins can be arranged from the smallest, most dense particle, HDL-C, through LDL-C, intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL), to chylomicrons, the largest and least dense particle.

Figure 2. Lipoproteins can be arranged from the smallest, most dense particle, HDL-C, through LDL-C, intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL), to chylomicrons, the largest and least dense particle.

(Illustrations from Servier PowerPoint Image Bank.)

What HIV Does to Lipids

HIV infection changes everything. Before someone swallows an antiretroviral, infection with HIV profoundly upsets lipid metabolism. Comparing untreated HIV-positive people with HIV-negative heterosexuals and gays, Carl Grunfeld and colleagues found higher triglycerides, lower HDL-C, and lower LDL-C in the HIV groups.10,11 Drops in HDL-C and LDL-C are consistent with chronic inflammatory disease. Effective antiretroviral therapy (ART) returns total cholesterol and LDL-C to pre-HIV levels, but HDL-C stays low.12 Yet the impact of ART can't be stated so simply, metabolics experts Todd Brown and Marshall Glesby write,13 because individual antiretrovirals have differing effects and people take more than one antiretroviral at a time.

One thing is certain. HIV populations everywhere end up with high rates of dyslipidemia, however it's measured. The Centers for Disease Control and Prevention (CDC) estimates that prevalence of high total cholesterol in the general population dropped from 18% in 1999 to 13% in 2012.14 Prevalence in people with HIV is much higher, sometimes even in perinatally infected children under 10 years old (Tables 1 and 2). And incidence estimates in adults and children are daunting (Table 3).

Table 1. Prevalence of Dyslipidemia in Adult and Pediatric HIV Populations
Glass15Switzerland, SHCS; 2000-20068033TC ≥240 mg/dL; HDL-C <40 mg/dL; TG >177 mg/dL37.2% low HDL-C; 35.7% high TG; percent with high TC fell from 21.1% in 2000 to 12.3% in 2006 but percent with high TG or low HDL-C hardly changed
Buchacz3USA, HOPS; 2006-20103166Dyslipidemia, HDL-C*Women: 67.3% dyslipidemic, 27.3% low HDL-C; men: 81.2% dyslipidemic, 41.4% low HDL-C
Oh16CDC MMP, Oregon; 2007-2008539HDL-C <40 mg/dL; TG ≥200 mg/dL55% low HDL-C; 42% high TG
Mothe178 Barcelona HIV clinics; 2008179, all ≥70 years oldDyslipidemia*54% with dyslipidemia
Myerson18New York City hospital; 2010-20114278LDL-C, from ≥130 to ≥190 mg/dL according to CVD risk35% dyslipidemic
Carter19U.S. perinatally infected cohort; 1999-2004178 childrenHigh TC ≥200 mg/dL; high TG ≥150 mg/dL47% with high TC at least once; 67% with high TG at least once; 93% younger than 10 y
Jacobson20U.S. PACTG 219C cohort; 2000-20072581 childrenHigh TC ≥220 mg/dL13% with high TC, median age 8.7 y

CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; HOPS, HIV Outpatient Study; LDL-C, low-density lipoprotein cholesterol; MMP, Medical Monitoring Project; PACTG, Pediatric AIDS Clinical Trials Group; SHCS, Swiss HIV Cohort Study; TC, total cholesterol; TG, triglycerides.

* Further definition not available.

Table 2. Prevalence of Dyslipidemia in HIV-Positive vs Negative Populations
Triant21Two Boston hospitals; 1996-20043851 HIV+ vs 1.04 million HIV-Dyslipidemia defined by ICD-9 code23.3% dyslipidemia with HIV vs 17.6% without HIV (P < 0.0001)
Currier22USA, WIHS; 2002248 HIV+ vs 129 HIV-Adjusted analysis comparing TG and HDL-CCompared with HIV- women, HIV+ women had 21% lower HDL-C and 40% higher TG
Farley23US PACTG 219C cohort; 2000-20031812 HIV+ children vs 187 HIV-High TC >95th percentile in U.S. age group13.0% HIV+ with high TC vs 4.8% HIV-; current PI use strongest predictor
Onen24Clinics in St. Louis and Philadelphia; 2006-2007122 HIV+ vs 122 HIV-; all 50+ years oldTG >150 mg/dL51% HIV+ with high TG vs 33% HIV- (P < 0.05)

HDL-C, high-density lipoprotein cholesterol; PACTG, Pediatric AIDS Clinical Trials Group; PI, protease inhibitor; TC, total cholesterol; TG, triglycerides; WIHS, Women's Interagency HIV Study.

Table 3. Incidence of Dyslipidemia in Adult and Pediatric HIV Populations
Tripathi25South Carolina Medicaid database; 1994-201113,632 adultsDyslipidemia, indicated by ICD-9 codes for lipid abnormalities2.45 per 100 p-y in HIV+ on ART, 1.43 in HIV+ ART-naive, 2.32 in HIV-
Tassiopoulos26PACTG 219C cohort; 2000-20072122 perinatally infected childrenTC ≥220 mg/dL on consecutive visits13% developed high TC,3.4 per 100 p-y

ART, antiretroviral therapy; PACTG, Pediatric AIDS Clinical Trials Group; p-y, person years; TC, total cholesterol.

Compared with the 13% to 18% estimated high total cholesterol prevalence in the U.S. adult general population, dyslipidemia prevalence in HIV-positive adults in the United States, Switzerland, and Spain ranges from 23% in a large study at two Boston hospitals (Table 2)21 to 67% among women and 81% among men in the U.S. HIV Outpatient Study (HOPS) (Table 1).3 Notably, high cholesterol levels dropped during the last decade in the Swiss HIV Cohort Study.15 Tracking 8033 cohort members from February 2000 to February 2006, the researchers found that the proportion of cohort members with total cholesterol at or above 240 mg/dL fell from 21.1% to 12.3%. But the proportion with high triglycerides dipped only from 37.4% to 34.6% and with low HDL-C from 34.9% to 30.9%.

Differences in how researchers calculate dyslipidemia partly explain the wide range in prevalence estimates. The 1996-2004 Boston study used a strict definition, counting only people who had a dyslipidemia diagnosis on their charts (Table 2).21 The HIV group in this analysis had significantly higher dyslipidemia prevalence than a comparison group of more than 1 million people without HIV (23.3% versus 17.6%, P < 0.0001), and the 17.6% for the negative group matches the 1999 CDC estimate of high total cholesterol for the general U.S. population.14 The lofty dyslipidemia prevalence in a 2006-2010 eight-city U.S. HOPS analysis relies on a much broader definition of dyslipidemia, as the HOPS team culled cases from medical records of diagnoses plus lab measures and treatments.3

Older age boosts risk of out-of-line lipids. A study in two urban U.S. clinics compared 122 HIV-positive people 50 or older with 122 HIV-negative people that age.24 Half of the HIV group, 51%, had high triglycerides, compared with 33% of the HIV-negative group, a significant difference (P < 0.05). Researchers at 8 Barcelona HIV clinics found a dyslipidemia rate not much higher, 54%, in HIV-positive people 70 or older,17 probably reflecting the different metrics but also perhaps indicating pre-70 deaths of people with high lipids -- or a more lipid-friendly Mediterranean lifestyle in Barcelona than in the United States.

On the other end of the age spectrum, askew lipids threaten children infected with HIV at birth or later. In a Pediatric AIDS Clinical Trials Group (PACTG) cohort, 13% of 2581 children had conservatively defined high total cholesterol (>220 mg/dL) at a median age of 8.7 years (Table 1).20 Almost all of them had begun treatment with a protease inhibitor (PI). In a much smaller cohort of 187 perinatally infected U.S. children, 47% had high total cholesterol (>200 mg/dL) at least once, and 67% had high triglycerides (>150 mg/dL) at least once.19 Most of these children, 93%, were 10 years old or younger, and 56% began therapy with a PI.

Dyslipidemia incidence is high in both adults and children taking antiretroviral therapy (Table 3). Analysis of 13,632 adults in the South Carolina Medicaid database charted a dyslipidemia incidence of 2.45 per 100 person-years in people on ART (71% black and all relying on public health insurance).25 That means lipids got high in more than 2 of every 100 people every year. Incidence proved lower in HIV-negative Medicaid users, at 2.32 per 100, and lower still in HIV-positive people who had not begun ART, at 1.43 per 100. Cox proportional hazard analysis determined that, compared with the HIV-negative group, HIV-positive antiretroviral-treated people had a higher risk of incident dyslipidemia (adjusted hazard ratio [aHR] 1.18, 95% confidence interval [CI] 1.07 to 1.30), while HIV-positive antiretroviral-naive people had a lower risk (aHR 0.66, 95% CI 0.53 to 0.82). Longer time taking a protease inhibitor or a nonnucleoside raised chances of incident dyslipidemia.

The researchers observe that the lower dyslipidemia rate in antiretroviral-naive people with HIV reflects the previously observed drop in total cholesterol after HIV seroconversion and the return to pretreatment levels when ART begins.10-12 The authors also caution that results in this poor Medicaid population may not apply to other HIV groups.

A study of 2122 perinatally infected children found an even higher incidence of high total cholesterol (≥220 mg/dL), 3.4 per 100 person-years.26 Taking a ritonavir-boosted PI raised the risk of high cholesterol 14 times in the pediatric study. About 80% of these children were younger than 13 at their baseline visit, and 56% were younger than 10. Another analysis of this same cohort found that 81 of 240 children with incident hypercholesterolemia (34%) returned to a normal cholesterol reading in a median follow-up of 1.9 years.20 Two factors independently predicted reversion to normal cholesterol: switching antiretroviral regimens (aHR 2.37, 95% CI 1.45 to 3.88) and being 13 or older (aHR 2.39, 95% CI 1.33 to 4.27).

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This article was provided by The Center for AIDS Information & Advocacy. 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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