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Metabolic and Body Shape Abnormalities

Second International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
Toronto, Canada, September 13-15, 2000

Autumn 2000

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!


Does Gender Matter?

The Second International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV attracted 373 delegates, compared with 230 at last year’s meeting in San Diego. Twenty-two countries were represented, up from 16 last year, and 133 abstracts submitted, compared with 67 last year -- all reflections of the increasing concern with the emerging metabolic and body fat syndrome(s), usually referred to as "lipodystrophy."

The Toronto meeting was primarily devoted to current and ongoing research at the basic science level, where many questions remain about the causes and development of the disorders. Several posters that pertained to women with HIV and treatment issues are summarized below. The specific poster abstract number appears in brackets at the end of each report. In-depth coverage of the overall meeting will appear in the upcoming Winter issue of BETA.


Terms and Definitions

"Lipodystrophy" is a syndrome or set of syndromes comprised of multiple signs and symptoms. Since the first report in 1997, this new disorder has riveted attention in the scientific and treatment communities. An increasing number of case and anecdotal reports as well as scientific studies and presentations have offered insights into the phenomenon. Most commonly referred to as "lipodystrophy" in both the scientific and lay communities (which is reflected throughout this paper), the more cumbersome terms HIV-associated adipose redistribution syndrome (HARS) and central obesity, peripheral lipoatrophy, metabolic abnormalities (COLM) also have been proposed. Another term in common usage, body fat redistribution, is inappropriate because it implies a removal of fat from one area of the body to another -- a "redistribution" that simply is not seen in changes such as increased abdominal girth and lower limb wasting. Unfortunately, lipodystrophy is also a misnomer because, strictly speaking, it refers to a type of fat loss.

The lack of a definition and agreement upon what constitutes lipodystrophy has hampered research and made it difficult to make comparisons across studies. Prevalence estimates have varied enormously, from 2 to 84%. Any given study’s results and conclusions have to be evaluated carefully and individually with respect to the specific cohort studied and the operational definitions used.


Lipids

Lipoproteins are a group of substances that contain both lipids (fats) and proteins. In the blood, lipoproteins’ main role is to transport cholesterol, triglycerides, and other fats into peripheral tissues for storage. Once cholesterol is synthesized in the liver, lipoproteins carry it to the body’s cells as well as back to the liver for excretion.

Triglycerides are a type of lipid, which refers to a family of compounds that includes the phospholipid and sterol subcategories. Triglycerides are transported through the body by low-density lipoproteins (LDLs) and very-LDLs (VLDLs). Triglycerides act as energy stores. They are produced in the liver from glycerol and other fatty acids; when blood levels become too high, triglycerides go into more permanent storage in fatty tissues. Dietary or food lipids are 95% triglycerides and 5% phospholipids and sterols. Stored fat in the body is 99% triglycerides.

Cholesterol is a type of sterol and the main lipid associated with risk for the most common type of heart disease. Despite the association with risk for heart disease, cholesterol is essential for many beneficial bodily functions, such as producing endogenous (made in the body) steroids, bile acids, and cellular membranes. A lipid profile is a laboratory blood test that reports an individual’s levels of triglycerides and total cholesterol. The profile also includes amounts of cholesterol in the various lipoproteins (lipid/protein clusters that transport lipids in the body). To produce the lipid profile, a fasting sample of blood (blood drawn after not eating for 12 hours) is placed in a test tube and spun in a centrifuge. This causes the subtypes of lipoproteins or cholesterol components to separate so that they can be quantified.

Lipoproteins with a higher percentage of lipids, i.e., those fatty ones that rise to the top of the test tube, have a lower density and are called low-density lipoproteins (LDLs), commonly referred to as "bad" cholesterol because high LDL levels are associated with an increased risk of heart disease. LDLs carry primarily cholesterol, which can be deposited into tissues; nearly 75% of cholesterol is bound to LDLs. LDL-bound cholesterol is the type implicated in the buildup of fat on blood vessel walls (atherosclerosis).

Lipoproteins with a higher percentage of proteins have a higher density, and therefore migrate towards the bottom of the spinning test tube. These are called high-density lipoproteins (HDLs), commonly referred to as "good" or healthy cholesterol because normal or high HDL levels are associated with a reduced risk of heart disease. HDLs are believed to remove cholesterol from peripheral tissues and shepherd it into the liver for processing and removal. Compared with the high level bound to LDLs, just 25% of cholesterol is bound to HDLs.


Concerns and Culprits

Two of the most pressing, distinct areas of concern are body shape or fat changes (symptoms such as increased abdominal girth and depletion of subcutaneous fat from the buttocks and lower limbs) and metabolic disturbances (symptoms such as increased blood fats and glucose disturbances). Other, less frequently observed symptoms under investigation for their putative associations with lipodystrophy include osteopenia/osteoporosis (loss of bone minerals), avascular necrosis (bone death resulting from poor blood supply), and toenail paronychia (ingrown toenails). In addition, various combinations of symptoms have been observed, in patterns that vary widely. For instance, one person may only have high trigylcerides and cholesterol while another also may have increased abdominal girth; yet another may have all these symptoms plus lower limb wasting. The etiology of these patterns, as well as conditions in isolation, also remains unclear.

Many people experiencing lipid and metabolic disorders are particularly concerned about the risk for cardiovascular disease (including "heart attack"). In people without HIV, cardiovascular risk has been associated with central obesity (of the trunk and abdomen), insulin (hormone that regulates sugar) resistance, and lipid (fat) abnormalities. As people with HIV live longer, due in large part to HAART, age, another risk factor, comes into play.

While the exact causes of each distinct condition in people with HIV remain unknown, research to date has implicated two likely factors in both body fat and metabolic changes: 1) mitochondrial (related to the mitochondria, an "organelle" or sub-unit of a cell that produces energy) toxicity and 2) the use of certain antiretroviral drugs. It is also likely that host (individual characteristics of a particular person with HIV) and viral parameters play some role in metabolic and body fat changes.

For more information, see "Body Fat Changes: More than Lipodystrophy" and "HAART Attack: Metabolic Disorders during Long-Term Antiretroviral Therapy" in the January and April 1999 issues of BETA, respectively.


Gender Differences in Fat Disorders

Many factors influence body fat content and distribution in both HIV positive and negative people. Body composition -- the size and distribution of various body compartments, such as fat, bone, and muscle -- differs in women and men. In people with HIV, previous studies have demonstrated a sexual dimorphism (distinction) in patterns of HIV-related malnutrition and wasting. Three different groups presented posters on their findings on gender factors in aspects of lipodystrophy.

Serono’s SALSA Studies

At the Second International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, Norma Muurahainen of Serono Laboratories in Norwell, MA, updated findings from a multicenter assessment at 50 sites in North America and Australia. Serono is one manufacturer of recombinant human growth hormone (HGH); their brand is called Serostim. Muurahainen first reported differences in fat redistribution patterns between men and women at the 7th Conference on Retroviruses and Opportunistic Infections (CROI), held in San Francisco this past January. (See the Spring 2000 issue of BETA for a full report on the proceedings at the 7th CROI.) This presentation focussed on factors associated with abnormal fat accumulation and fat depletion in women and men with HIV. Fifteen percent of the 526 participants were women, of whom significantly more were non-White (28.4%) than men (9.9%).

All participants had been referred from clinical centers after presenting with body fat accumulation and/or depletion. Physician examination was used to diagnose actual cases. Research data were collected through an international study called SALSA, devised to evaluate as well as define various proposed aspects of what these investigators call HARS (or, as mentioned earlier, HIV-associated adipose redistribution syndrome). The study name was derived from their "self-ascertained lipodystrophy syndrome assessment" (SALSA) questionnaire.

When results were analyzed for the group overall, abnormal fat accumulation in all cases was significantly associated with female gender, low viral load, and high body mass index (BMI), which is a measure of body composition (weight divided by height squared). Generally speaking, the higher ones BMI, the more likely one is to be overweight and the greater the risk of coronary heart disease, some types of diabetes, and high blood pressure. BMI values apply to men and women, regardless of frame size or muscle mass, which means that BMI will have less relevance for certain people, e.g., heavily muscled people like body builders or professional athletes and people younger than 18 years old. (More information and a BMI "calculator" are available online at www.thriveonline.com.)

Because almost all of the women (77 of 81) reported abnormal fat accumulation, there were not enough women (i.e., without fat accumulation) to compare and contrast, or to do multivariate analyses. Multivariate analysis is a statistical technique in which multiple variables are analyzed separately in order to determine the contribution made by each variable to an observed result. In the group as a whole, fat depletion was associated with d4T (Zerit) use. [Ed. note: associations do not necessarily describe cause and effect.]

Overall, more men than women reported fat depletion in limbs, face, and buttocks, and more women than men reported fat accumulation in the belly and breasts. Abnormal fat accumulation and depletion occurred concurrently in a majority of the subjects overall (about 60%). "Buffalo hump" (or, more technically, dorsocervical fat pad, a fatty deposit at the base of the neck) was the least frequently reported abnormality.

Results were also analyzed separately by gender. Of the 445 men, fat accumulation was significantly associated with high BMI (greater than 28.5 kg/m2) and low viral load (fewer than 500 copies/mL). In women, however, there were no statistically significant associations between fat accumulation and any detectable factor.

Among the men, fat depletion was significantly associated with d4T use on univariate (looking at a single variable) analysis. On multivariate analysis, fat depletion in men was less strongly associated to indinavir (Crixivan) use and being older than 40 years of age, and inversely associated with African-American ethnicity (meaning less likely in African-American men). In men, fat depletion was not associated with low BMI (defined as less than 28.5 kg/m2).

Fat depletion in women, on the other hand, was significantly associated with a low BMI and with physician-diagnosed dyslipidemia (abnormal blood fat levels), and somewhat associated with 3TC (Epivir) use on univariate analysis. On multivariate analysis, fat depletion in women was also borderline associated with being African-American.

These findings strongly support the hypothesis that gender (but not necessarily ethnic/racial) differences exist in the various manifestations of lipodystrophy overall. The definition of normal/abnormal BMI used in this study was a stringent one -- a high BMI was one greater than 28.5; anything lower was simply considered "not high" -- so those findings are less generalizable, or less applicable to "the real world." This study also suggests that other factors associated with body fat changes include baseline body composition, race-ethnicity, baseline metabolism, and antiretroviral exposure. This and other studies show that variables associated with fat accumulation differ from those associated with fat depletion, which lends support to the idea that more than one type of HIV-associated fat disorder may exist.

The St. Luke’s-Roosevelt Hospital Center Group

A group from St. Luke’s-Roosevelt Hospital Center in New York presented their retrospective case-control study of gender differences in lipodystrophy. They compared the size of visceral (intra-abdominal), subcutaneous (under the skin), and total adipose tissue (VAT, SAT, and TAT), using whole body magnetic resonance imaging (MRI). Of 85 HIV positive participants, 48 (56%) self-reported changes in body shape: 45 men (53%) and 40 women (47%). All were matched by gender, race, age (within five years), and height (within 10 cm) with one to six HIV negative controls.

Overall, fat content by body region differed by gender in people with HIV, regardless of whether or not they had reported any physical changes. Compared with HIV negative women, HIV positive women without changes had much lower amounts of SAT and TAT. Both men and women with fat redistribution (FR) had significantly higher VAT than did controls. Men with FR and women without FR had significant depletion of SAT. Women with FR and higher VAT did not seem to have the loss of SAT that men with FR did, however.

In conclusion, both men and women with self-reported changes in body shape showed increased VAT. Depletion of SAT was found in men with and women without self-reported changes in body shape. Investigators proposed this hypothesis: that the predominant phenotype (body manifestations) of lipodystrophy, i.e., fat accumulation or fat depletion, is related to changes in total body fat (which again differs by gender).

The COLM Study Group: Metabolic and Body Fat Changes and Anabolic Therapies

This multicenter study was sponsored by Bio-Technology General Corp., the manufacturer of oxandrolone (Oxandrin), an anabolic or tissue-building steroid. The study was designed in part as a cross-sectional evaluation of the type and distribution of body composition and metabolic abnormalities in people taking highly active antiretroviral therapy (HAART) and anabolic agents, including growth hormone. The study incorporated retrospective (looking back at data collected previously for some other reason) and prospective (collecting data by design on specific measures) data. "Central obesity, peripheral lipoatrophy, metabolic abnormalities" or COLM is the term preferred to lipodystrophy by the investigators.

Of 1,900 people with HIV screened at 11 clinical sites in the U.S., 757 gave informed consent for the retrospective chart review portion of the study and agreed to be screened for participation in the prospective part, provided they met the criteria after chart review. Ultimately, 339 men and 82 women (19% of the whole cohort) met all of the criteria, including sole anabolic agent use. All participants had currently or previously used protease inhibitors (PIs) for a minimum of six months within the past year. The majority of women had never used an anabolic agent but they were included for the analysis of gender differences in COLM.

Nineteen percent of the participants were women, 23 of whom were White and 59 (72%) non-White. Mean data for women were: 38 years of age, 83 kg (185 pounds), BMI of 30.4 kg/m2, and HIV duration of six years.

Investigators looked at several laboratory parameters (including insulin resistance, insulin to glucose ratio, lipid parameters, immunologic parameters, i.e., CD4 and CD8 cell count, viral load, and hormone parameters) and body composition by dual energy X-ray absorptiometry (DEXA), a method of determining the composition of body tissues. Extensive information about changes in body shape, knowledge of COLM, family history, quality of life, and risk factors was also collected through a participant questionnaire. All participants received physical examinations as well.

Analysis of the retrospective portion of the study, designed to identify predictors of COLM, was not presented at the meeting. Preliminary analysis of the questionnaire produced two noteworthy observations: first, 46% of the women reported body shape changes. Second, of those women who reported changes, 74% reported some lipoatrophy in the face, buttocks, or legs. The reason these are noteworthy relates to the fact that most of the women were overweight; even so, they perceived changes in their bodies including an abnormal sort of fat loss, changes that were confirmed upon subsequent examination yet which might have been overlooked or dismissed by providers. These data underscore how important it is both for health-care providers to listen to their patients’ perceptions, and to follow-up with a physical exam and measurements. At the time of the conference, DEXA measurements had not been completely analyzed.

Investigators reported that the most significant laboratory findings were in those women who used the anabolic agents growth hormone and oxandrolone, along with HAART. These women had large changes in levels of Lp(a), a lipoprotein that is associated with atherogenic (ability to cause arterial plaques or disease) risk. A subset of total cholesterol, Lp(a) measurements were included in the lipid profiles evaluated here because, according to investigators, the importance of Lp(a) as an independent predictor of heart disease in the general population is increasingly recognized.

Specifically, those women taking oxandrolone with HAART experienced a decrease in Lp(a), while those taking growth hormone with HAART experienced an increase. These changes were relative to HIV positive antiretroviral-naive controls and to HAART-experienced women not using any anabolic agent. Median levels of Lp(a) for those four groups, respectively, were 15.1, 41.9, 15.7, and 29.1. The elevation in the HAART-positive, anabolic-negative women is consistent with findings from other studies showing that use of HAART is associated with an increase in Lp(a).

Unfortunately, while investigators note that "most women were categorized as AA [i.e., anabolic agent] negative and had no history of AA use," they fail to disclose the actual number of women taking HAART and oxandrolone or HAART and growth hormone. Whatever the number, investigators indicate that it is "very small," a fact that limits the generalizability of the lipid and anabolic results.

In terms of other lipid parameters, median cholesterol values in mg/dl for the four groups of women were reported as follows: HIV positive, antiretroviral-naive women (172); women taking HAART but no anabolic agent (205); women taking HAART and oxandrolone (173); and women taking HAART and growth hormone (245). While normal cholesterol values vary somewhat with age, a normal value for adults is less than 200 mg/dl. Thus, women taking GH had undesirably high levels of total cholesterol, and women taking HAART alone also had mildly elevated total cholesterol.

For the same four groups, median HDL levels in mg/dl were 52, 47, 34, and 57.5; a normal level for adult women is greater than 55 mg/dl. Therefore, results were best in women taking GH and worst in women taking oxandrolone, although again, the applicability to other women is limited, given the small numbers of women taking anabolic agents. Women taking HAART alone however had lower than normal levels of HDL as well. LDL measurements were in the normal range for all four groups of women, as were measures of insulin resistance.


All-Women Survey of Symptoms

R. Colebunders, MD, and others from the Institute of Tropical Medicine in Antwerp, Belgium, organized a survey of HIV positive women receiving anti-HIV treatment at centers in ten European countries. They used an anonymous questionnaire to determine the prevalence of symptoms of lipodystrophy and its possible associations with different antiretroviral treatment(s), as well as to collect basic demographic data. The main question(s) asked were, "Have any of the following occurred since you started your current anti-retroviral regimen: increase of abdominal girth? Breast enlargement? Decrease in fat over the buttocks? Decrease in facial fat?"

There were 1,161 respondents, 904 of whom had taken antiretrovirals at some point. Of 177 total participants currently using combination antiretroviral regimens, 102 reported heterosexual acquisition of HIV; 20 also reported intravenous drug use (IVDU) and 41 reported both IVDU and heterosexual exposure to HIV as their means of contracting the virus. The mean age was 37 and the mean duration of HIV seropositivity was reported to be eight years. Of 168 (95%) of women reporting current antiretroviral use, 116 (66%) were on a protease-containing regimen; 52 (29%) were on a non-PI-containing regimen consisting of all nucleoside analogs, or NRTIs (27), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus NRTIs (25).

Although the results were not statistically significant, increase of abdominal girth was reported by far more of the women on a protease-containing regimen (60, or 52%) compared with only 22 (42%) of women on a non-PI-containing regimen. Breast enlargement was reported by 45 (39%) of those taking a PI and 11 (21%) of those not taking a PI. That finding was statistically significant, as was the difference between women taking a PI who reported loss of subcutaneous fat in the buttocks (43, or 37%), compared with 8 (15%) of those not taking a PI. Decrease in facial fat was reported by 34 (29%) of those on a PI-containing regimen compared with 12 (23%) of those on a non-PI-containing regimen, but the difference was not statistically significant.

In conclusion, women using combination regimens commonly reported signs of lipodystrophy, especially women whose regimens included a PI. Investigators also noted that d4T use in these women seemed to be more associated with an increase in visceral and breast fat than with lipoatrophy, or fat depletion.


Body Shape and Lipid Abnormalities: A Follow-Up Study

In another presentation, A. Mahajan and other Brown University researchers described a 3.5-year follow-up of women who were found to have body shape and lipid changes in an earlier observational study. In the earlier study, conducted from May 1997 to February 1998, 21 HIV positive women taking HAART who reported body shape changes and serum lipid abnormalities were compared with a control group of 21 women taking HAART but not experiencing any lipodystrophy-type abnormalities. At that point, women with changes had been on their current regimens for about one year, and women without changes for a year and a quarter (15 months).

Investigators evaluated the same women, who by then had been on HAART for a mean of 41.8 months, or roughly three and one-half years, to see if their conditions were bet-ter, worse, or the same. For comparison, they used the same methods as in the earlier study: interview, physical examination, chart review, body measurements, serum lipid analyses, CD4 count, and viral load.

Of the original 21 in the group with changes, 12 remained. Of these 12 women, only one had had progressive body shape changes; the others seemed to have had "stable abnormalities." Six of the 12 had switched from a PI to an NNRTI, and had been on this newer regimen for a mean of 14 months. Three of these six had had mild improvement in body shape changes within two months of starting the NNRTI-containing regimen. However, "mild improvement" was not defined nor were the women’s drug regimens specified.

Ten women remained in the original control group of women on HAART without body shape changes. Two of these women had developed changes since the original study, and reported noticing these changes after approximately 21.5 months on a PI. Lipid profiles, which were similar between both groups at the time of the original study, were unchanged.

The authors concluded that body shape changes developing within one year after initiating HAART were more or less stable, at least for two and one-half years. Only "modest and inconsistent" (again, not further defined) improvement seemed to result from switching drugs. Bearing in mind the extremely small number of participants in the follow-up study, it would appear that a minority of women taking HAART go on to develop changes after one year on a HAART regimen.


Increased Breast Size, Lower Limb Thinning, and Cytokine Dysregulation

C. Gervasoni and others from the University of Milan, Italy, followed up earlier work regarding increased breast size in women on antiretroviral therapy, this time examining the possible role of cytokine dysregulation. Cytokines are intercellular chemical messenger proteins released by white blood cells such as CD4 and CD8 cells. Cytokines facilitate communication among immune system cells and with the rest of the body. In this way they coordinate several aspects of the immune response by stimulating antibody production, dispatching phagocytes (a scavenger white blood cell that engulfs and destroys dead cells, bacteria and other debris) to the site of an infection, and activating cytotoxic (cell-killing) T-lymphocytes.

This line of inquiry was prompted by observations that modified immune system functions, particularly changes in the amount of the cytokine tumor necrosis factor (TNF)-alpha produced by white blood CD8 cells, may contribute to body fat and metabolic changes. TNF-alpha is produced by activated monocytes and macrophages and is known to be a co-factor in the destruction of tumors. However, when chronically elevated (as may occur in HIV disease), TNF-alpha may lead to fever, anorexia, hypermetabolism, and wasting. TNF-alpha also may block the production of enzymes that digest fats, leading to the breakdown of muscle tissue. In laboratory tests TNF-alpha has been shown to stimulate HIV replication.

The researchers evaluated the possible association of cytokine (TNF-alpha) production and immune function with body shape and metabolic changes in a group of women. All women had significant breast enlargement (defined as equal to or greater than two bra sizes) and lower limb thinning, defined as a decrease of subcutaneous fat in the buttocks and legs and confirmed by DEXA. This case-control study involved 22 HIV positive women with FR and a control group of 20 HIV positive women without FR. Participants were matched for age, BMI, CD4 cell count, viral load, HIV disease stage (as defined by the U.S. Centers for Disease Control and Prevention, or CDC), and current and past antiretroviral use. Blood cells taken from the women were studied in the laboratory to evaluate the production of several cytokines including interferon (IFN)-gamma, interleukin (IL)-2, IL-4, IL-10, TNF-alpha, and IL-12, and other immunologic functions (e.g., responsiveness to simulation with an influenza antigen) were studied in a subset of women.

The demographic and laboratory characteristics were similar in the case and control women. Fifteen of the women with FR were taking 3TC plus d4T plus AZT (Retrovir); three were taking 3TC plus d4T plus ritonavir (Norvir); two were taking 3TC plus AZT plus saquinavir (Fortovase) -- the same combinations were used by the control women. Duration of current therapy was similar as well.

Despite the stringent matching criteria used and the good virologic responses to antiretroviral therapy and CD4 cell count increases in both groups, studies of blood cells and cytokines in the FR group showed a trend toward more efficient proliferative responses (to influenza antigen) compared with the control group. Also, the profile of cytokine production was significantly different between the two groups, with "a polarization to IL-12 in the FR group and to IL-10 synthesis in the control group."

These data suggest that a particular pattern of immune reconstitution may be involved in causing breast fat tissue accumulation, when accompanied by lower limb wasting as seen in some women. However, this study did not find that TNF-alpha production appeared to be involved in causing at least this manifestation of lipodystrophy.


The Interleukin Family of Cytokines

The interleukins are a family of cytokines (chemical messengers) that include IL-1, IL-2 (sometimes called T-cell growth factor), IL-10 and IL-12. IL-1 activates CD4 cells, mediates acute systemic immune symptoms (e.g., fever), and acts on the hypothalamus (a gland in the brain that helps regulate metabolic rate) to decrease appetite.

  • IL-2 promotes the proliferation and activity of CD4 cells, cytotoxic T-lymphocytes, and natural killer cells. IL-2 is associated with cell-mediated immune response. Recombinant IL-2 (aldesleukin, Proleukin) is used for cancer therapy and continues to be studied as an immunomodulatory treatment for Kaposi’s sarcoma and HIV disease. Side effects include flu-like symptoms (fever, chills), decreased blood pressure, and anorexia.

  • IL-3 is a hematopoietic (blood growth) factor that promotes the growth and differentiation of several types of blood cells (red, white, and platelets).

  • IL-4 is released by a subset of CD4 cells, and helps stimulate antibody production.

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  • IL-6 is produced by macrophages and mediates acute systemic immune responses (e.g., fever).

  • IL-8 stimulates the growth of new blood vessels.

  • IL-10 stimulates the proliferation and activity of B-cells (which produce antibodies), modulates macrophage function, and enhances humoral (TH2) immunity, while suppressing cell-mediated immune function.

  • IL-12 is produced by various immune cells (e.g., monocytes, macrophages, dendritic cells, and neutrophils), and activates natural killer cells and cytotoxic T-lymphocytes and induces the production of interferon-gamma. IL-12 is associated with the cell-mediated immune response.


Hormones, Blood Lipids, and Race

HAART has been associated with abnormal body changes, hyperlipidemia (elevated blood fats), and glucose dysregulation. Adrenal hormones (hormones secreted by the adrenal glands, organs located above each kidney) are also known to affect body fat and metabolism. In other studies, the adrenal hormones cortisol and dihydroepian-drosterone (DHEA) have been associated with lipid dysregulation in men taking HAART. Levels of DHEA are often decreased in people with HIV disease. Cortisol is secreted as part of the body’s response to stress. Cortisol promotes the breakdown of body tissues to provide energy and raw materials; high cortisol levels are associated with reduced immune function.

In a report by L.L. Bausserman and other Brown University investigators, levels of cortisol, DHEA, and aldosterone (another steroid hormone produced by the adrenal gland; aldosterone regulates potassium/sodium exchange in the kidneys) were scrutinized in a cohort of 39 women. Twenty-six of the women were Caucasian and 13 (33%) were African-American. Investigators also looked at blood levels of glucose and lipids and body fat.

Levels of adrenal hormones, measured in the morning, were essentially the same in both race-ethnic groups. Moreover, adrenal hormones were not correlated with body measurements (body-mass index or BMI), waist-hip ratio (WHR), or glucose or insulin in either group. However, a strong correlation was detected between adrenal hormones and lipid levels, with striking differences between the two ethnic groups. In Caucasian women, cortisol was associated with LDL and aldosterone was related to triglycerides. In African-American women, cortisol, DHEA, and aldosterone were related to measures of HDL. Overall, adrenal hormones were correlated serum lipids in both groups of women, but in different ways.


Switching Drugs May Reduce Risk for Heart Disease

K.T. Tashima and a team from Brown University reported some observations from women with lipodystrophic changes who switched from a PI to an NNRTI drug. This cohort included 116 women who had been taking HAART that included a PI for a year and one-half or longer; 30% had changes in body fat.

Ten of the women with documented body fat changes that occurred while successfully taking a PI (i.e., eight had an undetectable viral load) switched to an efavirenz (Sustiva)-based HAART regimen. After the switch, nine had undetectable viral loads for a median of nearly 8 months. Mean CD4 cell count increased by about 70 cells/mm3 (from approximately 530 to 600 cells/mm3).

After the switch to NNRTI-based HAART, HDL ("healthy" or "good" cholesterol) significantly increased; total cholesterol decreased significantly (from 252 to 233 mg/dl), and there was a trend toward a decrease in LDL ("bad" cholesterol) and triglycerides. Although three of the ten women self-reported a reduction in abdominal girth after the switch, there were no significant mean changes (i.e., in the group as a whole) in total body weight or waist or hip circumference.

From this small study, it would appear that switching from a PI-based to an efavirenz-based HAART regimen has some potential benefits. Beyond an equal or modest improvement in virologic control and immune parameters, these women showed changes that are associated with reduced risk for heart disease, including increases in HDL cholesterol and decreases in LDL and total cholesterol.


Psychosocial Impact of Body Shape Changes

In preparation for a larger study at the University of Toronto, a small pilot study by E. Collins and colleagues surveyed 33 women and men with HIV about their feelings regarding self-reported body changes. In the group as a whole, people commonly reported eroded self-images and self-esteem, problems in social and sexual relationships, anxiety about unintended HIV disclosure as a result of noticeable body changes, and frustration with healthcare providers who trivialized the importance of body changes for the individual. Participants also reported greater discouragement and depression.

While researchers did not specifically look at gender differences at this stage of inquiry, they indicated a need to do so in further study. There is a body of knowledge available in the literature as to differential feelings by gender about body shape and their changes, both in the general population and from earlier research about HIV-related wasting. A more informed understanding of the real psychosocial impact of body shape changes may elucidate appropriate treatment directions and coping strategies.


Gender, Hepatitis C, and Lipid Profiles

C.B. Hsiao and a team of researchers from the State University of New York at Buffalo explored the relationship between coinfection with hepatitis C virus (HCV), gender, and use of antiretroviral therapy on changes in lipid profiles.

In this retrospective analysis of lipid profiles of persons treated between December 1998 and June 2000, two groups were distinguished, based on type of regimen. People in both groups were taking triple-combination regimens with a backbone of two nucleoside analogs (not identified specifically), but Group 1 used a PI and Group 2 used an NNRTI. Group 1 consisted of 84 people taking nelfinavir (Viracept) plus two nucleoside analogs; 46 were men and 38 women, 40% of whom were HCV positive. Group 2 consisted of 33 people (21 men and 12 women, 63% HCV positive) taking an NNRTI plus two nucleoside analogs; specifically, seven men and six women were taking nevirapine (Viramune) and 14 men and six women were taking efavirenz.

In Group 1, men had statistically significant higher cholesterol (greater than or equal to 200 mg/dl) or higher triglycerides (greater than or equal to 320 mg/dl) than women. In Group 2, more men had statistically significant higher triglycerides and lower HDL (less than 40 mg/dl) than women.

In both groups, people who were HCV positive had a trend toward lower cholesterol. More Group 2 women had higher HDL (greater than 40 mg/dl) than in Group 1, a finding that was statistically significant (p=0.013).


Trends and Cofactors

It is now clear that when women and men with metabolic and body shape changes are surveyed using the same methods, different patterns emerge. Therefore, gender must be considered in the development of a case definition for this still new HIV-related syndrome(s).

As mentioned earlier, one of the problems to date with these new findings is the lack of agreement and understanding of what exactly constitutes "lipodystrophy." The methods used to measure body fat changes also are inconsistent; e.g., some studies rely on patient or physician perceptions while other use anthropometric measurements. Since the field is still very young, even when studies are similar enough to allow comparisons, contradictory results are not uncommon. At the Toronto Workshop, for example, one study concluded that fat accumulation in women was associated with d4T use, while another reported an association between fat loss and d4T. Additional studies with larger numbers of subjects, especially women, people of various ethnicities, and control participants without fat and metabolic disorders will be needed to expand on the findings of studies reported on here. Some prospective studies already have been planned or are underway.

Not surprisingly, effective treatments have yet to be established. In the meantime, since environmental factors also play a role in metabolic and body fat disorders, they may be worth evaluating. For women with HIV, especially those taking HAART, knowledge of family history, genetic predispositions to, and risk factors for heart disease is useful information. Obesity, a sedentary lifestyle, a high-fat and high-cholesterol diet, and cigarette smoking clearly increase the risk of heart disease or diabetes for a person with both HIV and metabolic disorders. As with HIV negative people, exercise, while not curative, has been shown to mitigate genetic predispositions toward obesity and heart disease, loss of lean body mass, as well as high blood fats. Hopefully, future research will lead to a better understanding of the etiology of and to treatments for body fat changes and associated metabolic disorders in both women and men with HIV.

Leslie Hanna is Editor of BETA.


Sources

Note: all sources are from Antiviral Therapy 2000; 5 (supplement 5):39, an official publication of the International Society for Antiviral Research for the 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, September 13-15, 2000, Toronto, Canada.

Bausserman, L.L. and others. Relationships among adrenal hormones and serum lipids differ in Caucasian and African-American HIV-positive women treated with combination antiretroviral therapy. Abstract P35.

Berger, D. and others. Fat redistribution syndrome/lipodystrophy in women: sub-analysis of a multicenter U.S. study. Abstract P53.

Colebunders, R. and others. Lipodystrophy in women taking antiretroviral treatment. Abstract P57.

Collins, E. and others. Psychosocial impact of body changes in lipodystrophy. Abstract P36.

Gervasoni, C. and others. Adipomasty and lower limb wasting in women under ART are not associated with an increase of TNF-alpha production. Abstract P27.

Hsiao, C.B. and others. The impact of gender and hepatitis C (HCV) co-infection on lipid profiles in HIV-infected patients on nelfinavir and NNRTI (nevirapine or efavirenz)-containing antiretroviral therapy. Abstract P39.

Lopes, J. and others. Interactions among sex, HIV infection, and fat redistribution. Abstract P29.

Mahajan, A. and others. Changes in body habitus and serum lipid abnormalities in HIV-positive women on HAART: a 3.5-year follow-up study. Abstract P65.

Muurahainen, N. and others. Different factors are associated with abnormal fat accumulation and fat depletion in men and women with HIV. Abstract P71.

Tashima, K.T. and others. Significantly improved cardiovascular risk profile in women who switch from a protease inhibitor to efavirenz. Abstract P91.


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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
 
See Also
An HIVer's Guide to Metabolic Complications
More Research on Lipodystrophy and Other Metabolic Complications

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