The 3rd International Conference on Nutrition and HIV Infection, held on April 22-25 in Cannes, France, marked a break from the previous two conferences. Its emphasis on lipodystrophy and the metabolic complications of highly active antiretroviral therapy (HAART) rather than AIDS-related wasting reflects the changing face of HIV infection and its treatment, at least in rich countries. The new puzzle posed by the body's reaction to HAART is highly perplexing and only slowing approaching solution. The discussions at Cannes, largely a continuance of those at the 6th Conference on Retroviruses and Opportunistic Infections in Chicago last February, marked another step in this process.
Several presentations disputed the notion that protease inhibitors alone account for lipodystrophy. Spanish researchers reported striking differences in the occurrence of lipodystrophy, depending on the nucleoside analogs used in the HAART combo (poster 10). In 150 patients followed prospectively for two years there was a high incidence (40.6%) of lipodystrophy occurring within a mean of eight months following initiation of protease inhibitor (PI) therapy. However, the incidence varied greatly, ranging from only 2.2% in those on AZT/3TC/PI to 88.2% in those on ddI/d4T/PI. Those on d4T/3TC/PI were in the middle at 51.7%. The use of different protease inhibitors was evenly distributed between the groups and did not appear to account for any differences.
A study by French researcher Thierry Saint-Marc also appeared to point to d4T as a problem child, particularly in terms of fat depletion from arms, legs, face and buttocks. Saint-Marc hypothesized that d4T might cause apoptosis of fat cells (session 2, presentation 04).
The news on NNRTIs as a way out of lipodystrophy was a mixed bag. On the pro side, London's Brian Gazzard, M.D., reported the findings of a retrospective analysis covering five studies and 1,878 patients who had taken delavirdine for periods of 32 to 44 weeks. No relationship was seen between fat redistribution abnormalities and the drug. Another Gazzard study looked at the results of substituting efavirenz for indinavir in HAART combos (poster 25). It found that changes in body composition varied greatly among individuals and were not consistent for different regions of the body. And, alas, both fasting triglycerides and cholesterol actually increased after the NNRTI substitution. Most patients did sense an improvement in appetite and well-being, and there was a significant increase in mean weight at week 12 after the switch.
One report made it appear that doing better immunologically may actually be tied to worse lipodystrophy. French researchers found that greater clinical severity of lipodystrophy symptoms was correlated with larger CD4 increases on HAART (poster 8). The increased severity was not tied to viral load changes.
Gender Differences in Lipodystrophy Norma Muurahainen, M.D., Ph.D., presented the findings of the multicenter SALSA (Self-Ascertained Lipodystrophy Syndrome Assessment) Investigators Group on gender differences in lipodystrophy syndrome (session 3, presentation 03). Of the 208 patients willing to fill out a 19-page questionnaire on body characteristics, 85% reported fat accumulation, 73% fat depletion, and 60% a combination of the two. However, the location and type of fat redistribution changes varied significantly between men and women: * Fat around the abdomen was reported by 93% of women and 76% of men.
* Fat increases in the breasts were reported by 74% of women and 31% of men.
* A loss of fat in the limbs was reported by 53% of women and 69% of men.
* A loss of fat in the buttocks was reported by 45% of women and 60% of men.
* Buffalo humps were reported by 10% of women and 20% of men.
In addition, men's blood lipid levels rose considerably more often than did women's. Elevated triglycerides were seen in 63% of men, but only 26% of women, while cholesterol was high in 50% of men and 26% of women.
Julian Falutz, M.D., also reported sex differences in the signs of lipodystrophy among 17 women and 25 men at the HIV Clinic of Montreal General Hospital (session 3, presentation 04). Compared to men, women were more likely to have only central fat accumulation. On the other hand, none of the women studied had just subcutaneous fat loss in the limbs, whereas about 35% of the men did. Two-thirds of the women -- but none of the men -- had normal blood lipid levels. Men were far more likely to have both higher triglycerides and lower levels of HDL, the "good" cholesterol that protects against cardiovascular disease. Falutz hypothesized that hormonal activity might be responsible for these differences.
Cutting to the Bone San Francisco's Mary Romeyn, M.D., reported the frightening findings of her study of bone mineral density. A large majority of men with CD4 counts under 100 cells/mm3 showed bone mineral loss, with frank osteoporosis diagnosed in 40%. In her preliminary study of men with higher CD4 counts, all those tested so far have bone mineral loss, too. These findings parallel those on reduced bone mineral density presented last winter at the 6th Conference on Retroviruses and Related Infections by Argentine researchers (N. Luna et al., Conf Retroviruses Opportunistic Infect 1999 Jan 31-Feb 4; 6th:195 (abstract no. 679).
Impact of Dietary Fat There was seemingly conflicting evidence on the influence of dietary fat on development of elevated blood lipids. Australian researchers found no relationship between dietary fat intake and serum cholesterol or triglycerides (session 3, presentation 01). However, Parisian researchers who counseled patients on reducing fats and sugars in the diet found that triglyceride levels had dropped considerably after six months (session 13, latebreaker 5). At baseline, the 20 patients had average triglyceride levels of 20 mmol/l, (4 mmol/l is considered normal and 10 mmol/l is the level considered the threshold for risk of pancreatitis). Eighty-five percent of the patients dropped below the 10 mmol/l level, with a decrease in the mean level of triglycerides from 20.3 at baseline to 7.5.
Brazilian researchers also reported success in lowering triglycerides with a combination of low-fat diet and high exercise levels (poster 19). In a cohort of 57 men and 29 women with 11 months or more of protease inhibitors, high triglycerides were seen in 35.6%, with a median level of 410.4 mg/dl. Four months after being counseled on the need for a low-fat diet and beginning a serious exercise program (a minimum of 40 minutes, three times per week), the median had dropped to 312.6 mg/dl, and a fifth of those with previously elevated triglycerides had reached a normal level.
Drugs to Lower Sugar and Lipids Although the connection between insulin resistance and antiretroviral therapy remains a mystery, treating lack of response to insulin appears to hold some promise for reversing fat redistribution problems. Thierry Saint-Marc, M.D., of the Hôpital Edouard Herriot in Lyon, France, reported that treatment with metformin, an insulin sensitizing agent, resulted in decreases in waist-to-hip ratios and in abdominal fat when compared to placebo (session 9, presentation 21). Although the decrease in abdominal fat plateaued after two months, the improvement remained at the end of the six-month study. Since lipodystrophy usually continues to progress, the lack of worsening during the study might be considered a victory in and of itself.
The fear of future heart disease has stimulated interest in the use of lipid-lowering agents to decrease blood fats in those on HAART. However, the possibility of serious interactions with protease inhibitors makes their use problematic. David Zucman, M.D., of the Hôpital Foch in Saresnes, France, showed that two months of atorvastatin resulted in blood serum cholesterol reductions from a baseline average of 336 mg/dl to 223 mg/dl, a significant reduction. Unfortunately, in those on a ritonavir/saquinavir combo, there was also a significant reduction in the protease inhibitor levels in the blood.
More Studies on Growth Hormone A number of presentations supported the use of human growth hormone (Serono Laboratories' Serostim) for reversing fat redistribution problems. Tufts University's Christine Wahnke, M.D., followed 28 patients with fat redistribution and observed that without therapy the condition progressed, while daily therapy with growth hormone improved body composition. Using CT scans of the abdomen taken before and after growth hormone therapy was given to a man with truncal obesity, German gastroenterologist Stefan Mauss, M.D., illustrated how growth hormone resulted in disappearance of visceral fat and the appearance of increased lean muscle. Manhattan's Danielle Milano, M.D., reported on the successful use of growth hormone to treat a large lipoma on a man's head. His truncal obesity also decreased. Jill Cadman provided information on ten growth hormone-treated patients in New York (session 13, latebreaker 8). One patient was lost to followup, but eight of the other nine experienced improvement or complete resolution of truncal obesity, while five of six with buffalo humps also saw improvement or disappearance of the humps.
And finally, back to AIDS: Singapore's Nick Paton, M.D., reported that use of growth hormone within 48 hours of beginning treatment of opportunistic infections significantly improved quality of life. Patients given growth hormone had significantly better functional status compared to those given placebo, and the overall outcome was improved in those given the hormone. Wilbert Jordan, M.D., of the OASIS Clinic in Los Angeles, reported that two of four patients undergoing kidney dialysis for HIV-associated nephropathy were able to come off dialysis after treatment with growth hormone. A third person was also improving and producing urine. This uncommon kidney condition is rarely reversible in the normal course of events.