HTB

4th International Conference on Nutrition and HIV Infection and the 2nd European Workshop on Lipodystrophy – pt 2

By Ellen S. Engelson, EdD for HIV and Hepatitis.com

Dr. Engelson is Associate Research Scientist, St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons. She works closely with Donald Kotler, MD, Professor of Medicine at Columbia University College of Physicians and Surgeons

Impaired glucose metabolism

Impaired glucose metabolism, especially insulin resistance, has been associated with HAART and included as an aspect of lipodystrophy, but the role of immune reconstitution or viral suppression has not been ruled out. For example, Mulligan et al found that glucose and insulin increased more in a PI-treated group than in a 3TC (lamivudine)-treated group or controls on a stable regimen without a PI or 3TC. However, more of the PI group also achieved undetectable viral loads.

In an earlier attempt to separate the effects of drug from immune effects, Purnell previously published the results of a study in HIV-uninfected people which showed impaired lipid metabolism (e.g., elevated triglycerides and VLDL cholesterol, and lower HDL cholesterol) with ritonavir treatment.

At this conference, Mustafa Noor from San Francisco reported results of a trial of indinavir in 10 HIV-negative people. Each spent 5 days as an in-patient in a clinical research centre before and after 4 weeks of indinavir at 800 mg 3x/day. After treatment, fasting glucose and insulin, and 2-hour glucose tolerance test plasma glucose were all significantly elevated compared to baseline.

In contrast with ritonavir, there were no significant changes in lipid levels except in one person who also developed diabetes. There was also another individual who developed impaired glucose tolerance. There were no changes in body weight or visceral adipose tissue by CT scan, but total body fat by DXA decreased a mean of 0.6 kg. These results confirm an effect of drug, but the changes were not as large as those seen in the Mulligan study (Table 1). It is uncertain if the difference in magnitude is due to duration of treatment or an independent effect of HIV or the body’s response to it. In either case, these results underline that there are drug-specific vs class-specific effects of antiretrovirals.

Table: indinavir response

in HIV-ve in HIV+ve
Noor Mulligan
Glucose 105% 111%
Insulin 134% 195%
HOMA 147% 249%

Marc van der Valk from the Netherlands described updated results of a sub-study from the Atlantic trial of different initial HAART regimens: two NRTIs (d4T + ddI) plus a third NRTI (3TC) or indinavir (a PI) or nevirapine (an NNRTI). From 298 people who initiated therapy, frozen blood specimens of 114 representative subjects who completed 24 weeks were analysed to determine effects of therapy on lipid metabolism. There were no significant group differences in changes in total and LDL cholesterol or triglycerides. However, HDL cholesterol levels increased quite significantly by 49% in the nevirapine group vs 18% in the indinavir and 3TC groups. There were also significantly greater increases in HDL particle size, and levels of apolipoprotein A1 and lipoprotein A1.

The mechanism by which HDL is increased by NVP is only speculative. Two possibilities that were investigated, reduced cholesterol ester transfer protein (CETP), important for clearance of HDL by the liver, and response to immune restoration were not positive. CETP was not reduced in the NVP group but was increased in the indinavir group. And the increase in HDL with NVP remained significant when controlled for baseline levels and changes in CD4 and viral load. This effect gives NVP an antiatherogenic profile that is potentially greater than accomplished with statins.

Cardiovascular disease risk?

Despite comparisons with the metabolic Syndrome X and growing numbers of case reports of myocardial infarctions in young HIV+ men, it remains uncertain if the risk of vascular disease is increased with HAART and lipodystrophy.

Carl Grunfeld from the San Francisco VA Medical Centre reminds us that the short-term risk of death from HIV was higher (14.8% in his clinic) than any possible current risk from MI or stroke. However, he has strengthened his recommendation that treatment decisions include a thorough assessment of an individual patient’s risk factors for vascular disease. These factors have been identified by the multigenerational Framingham study. Included are HDL cholesterol below 25 mg/dl, elevated total and LDL cholesterol, and diabetes mellitus, all of which are now seen in HIV-infected patients. Dr. Grunfeld entered data from multiple antiretroviral studies into the Framingham equation to determine the increased risk.

Based on 5 studies that quantified increases in total and LDL cholesterol with PI therapy, he arrived at a figure of 6 cases of MI per 100 patients over 10 years, an increase of 1.32 cases. His figures are consistent with those reported at the 8th Annual Retrovirus Conference in Chicago this year, including from the 4,541 member Kaiser HIV cohort, where there were 5.8 cardiac events in patients on PIs vs 5.2 without PIs and 2.8 in HIV- controls per 1000 person-years of follow-up (Klein). In a French study (Mary-Krause), the MI rate increased with increased exposure to PIs. However, the additional risks of low HDL, hypertriglyceridaemia, diabetes, hypertension, insulin resistance, cigarette smoking, sex hormone status, and family history must also be taken into account in a multivariate analysis of an individual’s risk.

Judith Currier, a cardiologist from UCLA, agreed in her oral presentation that the risk of vascular disease in HIV and with PI therapy is ‘worrisome’ based on the number of risk factors present in many people with HIV, but uncertain based on the conflicting conclusions of eight studies previously published or presented. The 8 studies include the two mentioned above from Klein, in which the effect of HIV on incidence of MI was significant but results in those taking and not taking PIs were similar, and Mary-Krause, in which increased length of time on PI therapy was associated with increased risk. Pre-event assessment of arterial health has also been inconclusive.

Ultrasound measurements of femoral and/or carotid intima medial thickness (an indicator of atherogenic plaques in the main artery in the leg or neck which is associated with future risk of stroke or MI) showed increased risk in those on PIs in one study (Maggi), but risk associated only with classic risk factors (e.g., serum cholesterol and triglycerides) in two others (Depairon; Currier). Two additional measures of arterial disease risk in HIV have been presented at prior conferences. Electron beam CT scans showed no increased coronary calcification with PI therapy but brachial reactivity showed more endothelial dysfunction in people on PIs than not.

Results of the Depairon study underline the importance of multivariate analysis in trying to determine cardiovascular risk. Although potential risk was higher in the HIV-infected group than in HIV-negative controls, so was the prevalence of cigarette smoking and hyperlipidaemia. Dr. Currier emphasized that many risk factors for vascular disease cannot be modified, such as age and gender. Others remain uncertain, such as chronic infection with HIV and antiretroviral therapy. But still others can and should be modified despite the lack of data in people with HIV to prove that the results will be the same in HIV as in the general population. These include cessation of cigarette smoking and reduction of lipid levels and blood pressure using diet, exercise and lipid-lowering agents such as the fibrates and statins. The National Cholesterol Education Program (NCEP) guidelines (1993) can be followed to decide when to begin treatment with medications based on fasting cholesterol levels, which should be measured as standard of care.

Plastic surgery?

The pros and cons of plastic surgery treatment for fat redistribution were presented by Dr. Patrick Amard from Paris. The excision of fat from buffalo humps by liposuction is problematic because although the fat is easily accessible, it grows back quickly. Removal of the entire mass by surgical excision may improve results, but no long-term follow-up exists to validate this alternative. There is also no appropriate surgical treatment for excess visceral fat. Liposuction is totally inappropriate because the fat is contained within the peritoneal cavity and not subcutaneously.

For loss of subcutaneous fat in the gluteal region, Dr. Amard suggests performing a ‘lift’ of the buttocks, filling the area with a solid silicone implant at the same time through a single incision. He commented that this procedure is simple, well described and has been used for years. He has also had good results in lipoatrophic cheeks with fat grafting or transplants. He considers this a natural treatment because fat is being replaced with the individual’s own adipose tissue and a small amount of collagen. The finished result appears very normal and diminishes relatively slowly over time. There is some minor soreness and swelling which may last for a few weeks and varies between patients. Unfortunately, the fat graft donor site is usually the buttocks, and in approximately 15% of his HIV+ patients, lipoatrophy is so severe that the donor site is difficult to isolate. It is also unknown if over time the fat tissue which survived at the donor site will succumb to lipoatrophy at the new site. Another option for some is a face lift with fibrous and fat tissue from another patient. One advantage is shorter recovery than fat transfer but the cost is higher. There is also significant pain and oedema at the site. Even though the cosmetic result from these transplants is good, the fat may be absorbed by the body and move into the jaws. Such side effects require additional procedures and time.

As an alternative to fat tissue, two broad classes of injectable materials exist: biodegradable injectable implants (bovine collagen or hyaluronic gel) and synthetic nonbiological implants (silicone gel or oil). The major risk of collagen is a slight chance of an allergic reaction because of the animal origin of the collagen. The results are short-term; there are decreasing lengths of benefit with repeated uses, and use is limited to lower face and cheeks. Silicone gel is banned in many countries but is still used because of its low price. Injection into the face creates dramatic improvement in appearance initially, but because it is not fixed in position, it may shift over time. There also may be a recurring inflammatory reaction that produces oedema, redness and granuloma formation which can result in fibrosis and unnatural looking and feeling skin. There are other synthetics in the same family adopted for use in the correction of facial wasting. Some intradermal implants, including polylactic acid (PLA), induce the formation of collagen, increasing dermal thickness. Week 24 results from 26 subjects in an ongoing PLA evaluation study were previously reported in Toronto (Amard 2000), showing a mean increase in dermal thickness of 5.3 mm (196%). Thirty-three patients with facial lipoatrophy have now been treated with PLA (0.3 cc/cheek) every 2 weeks for 8 weeks. They have been followed for a median of 64 months, and increased dermal thickness appears to last for 3-4 yrs.

References:

Mulligan K, Grunfeld C, Tai VW, Algren H, Pang M, Chernoff DN, Lo JC, Schambelan M. Hyperlipidaemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Defic Syndr 2000; 23:35-43.

Purnell JQ, Zambon A, Knopp RH, Pizzuti DJ, Achari R, Leonard JM, Locke C, Brunzell JD. Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS 2000; 14:51-7.

Klein D, Hurley L, Sorel M, Sidney S. Do protease inhibitors increase the risk for coronary heart disease among HIV positive patients – follow-up. 8th Conference on Retroviruses and Opportunistic Infections 2001; abstr 655.

Mary-Krause M, Cotte L, Partisani M, Simon A, Costagliola D. Impact of treatment with protease inhibitor (PI) on myocardial infarction (MI) occurrence in HIV-infected men. 8th Conference on Retroviruses and Opportunistic Infections 2001; abstr 657.

Currier J, Johnson DL, Dube M, Hodis H. A pilot study of carotid intima media thickness in HIV-infected women treated with protease inhibitors. 7th Conference on Retroviruses and Opportunistic Infections 2000; abstr 32.

Maggi P, Serio G, Epifani G, Fiorentino G, Saracino A, Fico C, Perilli F, Lillo A, Ferraro S, Gargiulo M, Chirianni A, Angarano G, Regina G, Pastore G. Premature lesions of the carotid vessels in HIV-1-infected patients treated with protease inhibitors. AIDS 2000; 14:F123-8

Depairon M, Chessex S, Sudre P, Rodondi N, Doser N, Chave JP, Riesen W, Nicod P, Darioli R, Telenti A, Mooser V. Premature atherosclerosis in HIV-infected individuals-focus on protease inhibitor therapy. Swiss HIV Cohort Study. AIDS 2001;15:329-34.

Amard P, Saint-Marc T, Katz P. the effects of polylactic acid as therapy for lipoatrophy of the face. Antiviral Therapy 2000; 5(Supplement): 79.

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