Thinking outside of the (pill) box: alternative approaches to combating lipodystrophy.

HIV-associated lipodystrophy is a significant problem affecting those living with HIV disease and encompasses both morphologic (body shape) changes and metabolic abnormalities (such as dyslipidemia). Currently, a number of components of dyslipidemia are managed pharmacologically: statins to treat high cholesterol, fibrates for high triglycerides, and various medications to treat insulin resistance (a related metabolic disturbance). While these agents have had some success, they can potentially interact with antiretroviral medications. (1,2) But not all agents can successfully treat disturbances related to HIV-associated lipodystrophy. For example, data on the use of the glitazones (eg, troglitazone, rosiglitazone, pioglitazone) to treat HIV-associated lipodystrophy have been conflicting and somewhat disappointing. (2) Consequently, lifestyle changes such as modifying diet and exercise habits may be one way to ameliorate HIV-associated lipodystrophy.

Regarding diet, dramatic differences exist between HIV-positive people with lipodystrophy and HIV-positive patients who do not have lipodystrophy. An almost universal finding has been that dietary fiber prevents (or reverses) dyslipidemia, central fat accumulation, and insulin resistance in HIV-positive individuals. (3-5) Though the American Dietetic Association recommends that adults consume 20 to 35 grams of dietary fiber daily from a variety of plant foods, many Americans (regardless of HIV status) do not meet this requirement. (6) In one study cohort, the average fiber intake among HIV-positive patients with lipodystrophy was 7 grams a day. (3) Likewise, another group reported that 53% of their study participants consumed less than 20 grams of fiber daily. (5) Increased intake of soluble fiber is also associated with lower levels of total cholesterol and non-high density lipoprotein (non-HDL) cholesterol. (3) In one particular study, a 1-gram increase in total dietary fiber was associated with a 7% reduction in the risk of developing central fat deposition. (4) On the other hand, low dietary fiber intake, in addition to a high polyunsaturated fat:saturated fat ratio, is a strong predictor of hyperinsulinemia, (5) though other studies have reported no relationship between fat or dietary fiber intake and insulin resistance. (7)

Data also indicate that fat intake, and particularly the type of fat ingested, may have an effect on the development of HIV-associated lipodystrophy. A large, multicenter study analyzed the short-term effects of a Mediterranean-style diet rich in unsaturated fats versus a low-fat diet in HIV-negative adults at high risk for cardiovascular disease. (8) Adults who consumed a Mediterranean-style diet (see Table) improved their lipid profile and lowered their insulin resistance, blood pressure, and concentrations of inflammatory markers compared with adults who consumed the low-fat diet. Along these lines, a pilot study conducted in HIV-positive patients with lipodystrophy assessing the combination of dietary and exercise counseling with or without fish oil (omega-3 fatty acid) supplementation reported a significant decline in triglyceride levels at week 4 in patients receiving fish oil, that was no longer significant at week 16. (9) Treatment was well tolerated, but patients receiving fish oil did experience an increase in low-density lipoprotein (LDL) cholesterol at both time points. While these values are higher than expected, fish oil has been reported to increase LDL cholesterol levels. (10)

Not surprisingly, the data are conflicting and some studies have failed to observe any differences in fat intake between HIV-positive patients with and without lipodystrophy, specifically with regard to total or saturated fat intake. (3,4,11) Gavrilla and colleagues (7) reported no significant associations between any dietary component and levels of triglycerides, LDL, HDL, or total cholesterol in their study of HIV-positive patients. Interestingly, in this study, total intake of vitamin E was negatively associated with body fat percentage and subcutaneous abdominal fat. Shah and colleagues (3) observed that in their study cohort, patients with HIV-associated lipodystrophy consumed higher than recommended amounts of saturated fat and trans fat, and lower than recommended amounts of unsaturated fats. Levels of total cholesterol, triglycerides, and non-HDL cholesterol were positively associated with increased daily intake of total protein and animal protein; triglyceride level was positively correlated with increased daily intake of trans fats. However, daily intake of total fat, saturated fat, dietary cholesterol, and various unsaturated fats were not related to any metabolic parameter. Hendricks et al (4) reported no differences in intake of carbohydrates, fats, cholesterol, or any specific micronutrient between HIV-positive patients with fat deposition and HIV-positive patients without fat deposition, but did find that patients with fat deposition consumed less total protein than those subjects without fat deposition.

Many of these same studies that have analyzed patients' diets have also analyzed patients' exercise habits. As with diet, differences in exercise habits exist between HIV-positive individuals with and without lipodystrophy. One study observed that HIV-positive men without fat deposition tend to participate in resistance training types of exercise more frequently than men with fat deposition. (4) HIV-positive patients who regularly participated in aerobic exercise or a combination of resistance training and aerobic exercise had a higher percentage of lean body mass. (7) Moreover, these patients had significantly reduced triglyceride levels and insulin resistance, though the latter was not statistically significant. However, exercise did not seem to affect levels of LDL, HDL, or total cholesterol. Likewise, Shah et al (3) observed that only aerobic exercise of a moderate or heavy intensity was associated with higher values of HDL cholesterol, though this association was not statistically significant.

In contrast to the observational studies discussed above, numerous studies have examined the effect of prescribing specific dietary changes or exercise regimens in people with HIV-associated lipodystrophy. Prescribed exercise regimens have included either aerobic or resistance training, or a combination of both. (12) Though there is some variability, aerobic exercise regimens typically have consisted of stationary cycling or treadmill walking for 20 to 60 minutes per session, 3 times a week. Resistance training usually has been performed 3 times a week with each session comprising 3 sets of 8 repetitions for each exercise. Studies that combined aerobic and resistance training usually involved 20 minutes of aerobic activity, followed by 35 to 40 minutes of resistance training, and then stretching.

A consistent regimen of aerobic exercise is beneficial in treating many of the symptoms of HIV-associated lipodystrophy. HIV-positive patients who exercised 3 times a week for 12 weeks improved their exercise capacity and experienced a significant reduction in body weight, body mass index (BMI), subcutaneous fat, and waist circumference compared with HIV-positive patients who continued their normal level of activity during the study. (13) Patients in the exercise group did reduce their percentage intake of dietary fat from 35% to almost 30%, although reducing fat intake was only a recommendation and not a planned intervention. In contrast, another study found that all subjects experienced similar decreases in body weight, body fat, and waist-to-hip ratio, regardless of whether they participated in an aerobic exercise regimen. (14) HIV-positive patients with lipodystrophy received nutritional counseling, but one group participated in a 45-minute routine of light stretching and relaxation exercises 3 times a week while the other group participated in 60 minutes of aerobic exercise 3 times a week. No significant changes in serum lipid levels were observed in either group, though patients in the aerobic exercise group showed a significant improvement in exercise capacity. The researchers speculated that morphologic changes were probably caused by dietary changes (ie, reducing total fat and saturated fat and increasing unsaturated fat) and questioned if a more intensive or long-term exercise program would have led to more dramatic changes in terms of dyslipidemia.

Resistance training may also offer a non-pharmacologic way to treat HIV-associated lipodystrophy. Following 16 weeks of progressive resistance training, HIV-positive men had a reduction in serum triglyceride levels, but no effect was seen on levels of relevant markers including total cholesterol, HDL cholesterol, LDL cholesterol, insulin, C-peptide, proinsulin, or glucagon. (15) Nonetheless, the regimen led to increased strength, body weight, and lean mass in the whole body, trunk, and arms, though no reduction in whole-body adiposity or trunk, arm, or leg adiposity was observed. The authors speculated that the absence of aerobic exercise was a likely explanation. In another small study, patients followed a highly intensive and progressive resistance training regimen for 8 weeks in conjunction with nutritional counseling. (16) To monitor any changes in strength and body composition, the subsequent 8 weeks were self-directed and patients were not required to exercise but permitted to do so. After the initial 8 weeks, both male and female patients had a significant increase in strength and lean body mass and a decrease in body fat. At 16 weeks, most patients still retained increased strength for most of the exercises and lean body mass was maintained, though the decrease in fat mass was no longer significant. For those who continued to exercise for the study duration, lean body mass continued to increase and body fat continued to decrease.

A combination of aerobic exercise and resistance training may provide the best strategy for treating HIV-associated lipodystrophy. (17) Several small pilot studies have assessed this strategy. For instance, following 16 weeks of combined aerobic exercise and resistance training, HIV-positive men experienced a significant reduction in total body and trunk fat. (18) Nevertheless, body weight, BMI, and lean mass were not affected. Another study performed in 6 HIV-positive patients (5 men and 1 woman) reported that after 10 weeks of combination exercise, total cholesterol and triglycerides decreased significantly, along with a slight (but not statistically significant) increase in HDL cholesterol. (19) This exercise regimen was associated with a significant increase in muscle strength, exercise capacity, and body mass, in conjunction with a decline in body fat.

A case report of a 44-year-old, HIV-positive man with lipodystrophy described such dramatic results after modifying his diet (eg, increasing dietary fiber consumption, as well as lowering consumption of saturated fat and simple sugars) and exercise habits, the authors recommended that these types of lifestyle changes be considered standard treatment for HIV-associated lipodystrophy. (20) Though it is not feasible to tease out the effect of diet versus exercise, this patient experienced significant reductions in abdominal fat, BMI, waist-to-hip ratio, and body fat percentage while increasing exercise capacity and lean body mass (though there was no effect on peripheral fat atrophy). In addition, levels of total and LDL cholesterol were reduced, though HDL cholesterol levels also decreased. Insulin resistance and levels of fasting insulin in this patient decreased.

Along the same lines, a recent randomized study examined the effects of a 6-month "lifestyle modification" program. (21) Patients in the lifestyle modification group attended weekly counseling sessions on improving their diet and participating in at least 3 hours of moderate exercise a week. These patients experienced a significant decrease in blood pressure, waist circumference, and various markers of cardiovascular disease. Exercise capacity increased, but (like several of the studies discussed) there was no effect on total, HDL, or LDL cholesterol.

Overall, these data strongly suggest that diet and exercise have a great impact on the morphologic and metabolic changes that characterize HIV-associated lipodystrophy. Though the published reports all differ somewhat in terms of patient populations, parameters examined, and the specific dietary or exercise recommendations, a common theme is the importance of "healthy living"--eating a balanced diet rich in plant-derived foods and fiber as well as participating in aerobic and strength-training exercises. This research emphasizes the importance of patient education for making these lifestyle changes. Teaching patients that healthy behaviors can have dramatic effects, not only in controlling HIV disease and limiting risk of cardiovascular disease, but on physical appearance as well, is essential to help them succeed in making these lifestyle changes.

But evidence also suggests that certain other habits may predispose HIV-positive patients to developing lipodystrophy. For example, Hendricks et al (4) reported that cigarette smoking was more prevalent in HIV-positive patients with fat deposition compared with patients without fat deposition. However, another study observed no relationship between smoking and dyslipidemia, though the sample size was limited. (3) Alcohol consumption also has been shown to be a positive predictor of increased LDL and HDL cholesterol levels and insulin resistance in HIV-positive patients with lipodystrophy. (5) Still, other studies have failed to show differences in terms of alcohol intake between HIV-positive men with fat deposition and without fat deposition. (4)

The importance of building strength and muscle mass cannot be underestimated as a means of staying healthy and avoiding injury or disabling events, and there is some suggestion that working with an exercise trainer may be even more beneficial to patients. (16) An encouraging finding was that for people with HIV in otherwise good overall health, regular exercise had no negative impact on a patient's immune system, as shown by stable CD4 cell counts and percentages and HIV viral load levels. (13,14,16,17,21) Unfortunately, in the midst of these positive data, another common theme in many of these studies was that the resultant dyslipidemia in those living with HIV may be too much to overcome with lifestyle changes. Many researchers speculate that diet and exercise are not enough for treating HIV-associated lipodystrophy, particularly in the presence of HIV antiretrovirals. (14,21) Thus, pharmacologic treatment may need to be combined with these interventions to achieve desirable measures that fall within general guideline recommendations for cardiovascular health.

References

(1.) Dube MP, Stein JH, Aberg JA, et al. Clin Infect Dis. 2003;37(5):613-627.

(2.) Wanke CA, Falutz JM, Shevitz A, Phair JP, Kotler DP. Clin Infect Dis. 2002;34:248-259.

(3.) Shah M, Tierney K, Adams-Huet B, et al. HIV Med. 2005;6:291-298.

(4.) Hendricks KM, Dong KR, Tang AM, et al. Am J Clin Nutr. 2003;78(4):790-795.

(5.) Hadigan C, Jeste s, Anderson EJ, Tsay R, Cyr H, Grinspoon S. Clin Infect Dis. 2001;33:710-717.

(6.) Marlett JA, McBurney MI, Slavin JL; American Dietetic Association. J Am Diet Assoc. 2002;102(7):993-1000.

(7.) Gavrila A, Tsiodras S, Doweiko J, et al. Clin Infect Dis. 2003;36:1593-1601.

(8.) Estruch R, Martinez-Gonzalez MA, Corella D, et al. Ann Intern Med. 2006;145(1): 1-11.

(9.) Wohl DA, Tien HC, Busby M, et al. Clin Infect Dis. 2005;41(10):1498-1504.

(10.) Grunfeld C. Clin Infect Dis. 2005;41:1505-1506.

(11.) Batterham MJ, Garsia R, Greenop PA. AIDS. 2000;14(12):1839-1843.

(12.) Dudgeon WD, Phillips KD, Bopp CM, Hand GA. AIDS Patient Care STDS. 2004;18(2):81-98.

(13.) Smith BA, Neidig JL, Nickel JT, Mitchell GL, Para MF, Fass RJ. AIDS. 2001;15(6):693-701.

(14.) Terry L, Sprinz E, Stein R, Medeiros NB, Oliveira J, Ribeiro JP. Med Sci Sports Exerc. 2006;38:411-417.

(15.) Yarasheski KE, Tebas P, Stanerson B, et al. J Appl Physiol. 2001;90:133-138.

(16.) Roubenoff R, McDermott A, Weiss L, et al. AIDS. 1999;13(2):231-239.

(17.) Yarasheski KE, Roubenoff R. Exerc Sport Sci Rev. 2001;29(4): 170-174.

(18.) Roubenoff R, Weiss L, McDermott A, et al. AIDS. 1999;13(11):1373-1375.

(19.) Jones SP, Doran DA, Leatt PB, Maher B, Pirmohamed M. AIDS. 2001;15(15):2049-2051.

(20.) Roubenoff R, Schmitz H, Bairos L, et al. Clin Infect Dis. 2002;34(3):390-393.

(21.) Fitch KV, Anderson EJ, Hubbard JL, et al. AIDS. 2006;20(14):1843-1850.

By Jennifer Newcomb-Fernandez, PhD

TABLE: Examples of foods included in a Mediterranean-style diet

High intake of:

Virgin olive oil
Vegetables
Fruits
Tree nuts (eg, wallnuts, hazelnuts, almonds)
Whole grains
Legumes
Fish and shellfish
Wine (in moderation)

Low intake of:

Meat or meat products
Poultry
High-fat dairy products
Desserts (cakes, pastries, or other sweets)

[ILLUSTRATIONS OMITTED]