The Body Covers: The 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy
Overview of Metabolic Complications in HIV Disease
September 16, 2003
Chris Wanke from Tufts and Peter Weiss from the University of Amsterdam were given the challenging task of summarizing and synthesizing the state of knowledge on the subject of metabolic abnormalities as seen in the setting of HIV infection and its treatment.
Dr. Wanke began her talk by reviewing the history of HIV-associated metabolic complications and presenting a general overview. She reminded the audience that wasting and elevated triglycerides (3Gs) were reported early in the epidemic prior to any HIV treatment. The issue of whether the syndromes of wasting, fat distribution changes, lipid abnormalities and glucose dysregulation overlapped or represented separate problems was highlighted.
Several studies, including the U.S. Centers for Disease Control (CDC)-sponsored HIV Outpatient Study (HOPS), have identified patient factors (such as age, gender, hepatitis C infection, diet/exercise), disease severity factors (i.e., duration of HIV infection, low nadir CD4 T-cell count, response to antiretroviral therapy [ART]) and antiretroviral therapy factors (specific drugs and duration) as impacting some metabolic parameters.
In addition, even the definition of lipodystrophy has lacked precision, although Andrew Carr et al. have proposed a definition for research purposes recently in the Journal of AIDS. Clinical data such as patient and doctor evaluation, photography, waist/hip ratios, mid-arm circumference and clothing size are available to demonstrate the presence of lipodystrophy. Diagnostic tests such as DEXA, CT and MRI scans are likely to remain mostly research tools.
However, the management of metabolic complications in HIV-positive patients remains a huge challenge. The bottom line is that there is no established, consistent therapy for established lipodystrophy, with lipoatrophy emerging as the biggest concern for patients.
Management with exercise/diet, growth hormone, insulin-sensitizing agents, lipid lowering drugs, plastic surgery and ART switches were discussed. Although Dr. Wanke wasn't enthusiastic about ART switches, I personally try to aggressively switch medications to find the most fat-friendly regimen that still fits a patient's HIV needs in order to prevent/minimize lipodystrophy from developing.
Dr. Weiss' discussion focused on the role of specific HIV drugs in causing lipodystrophy. He pointed out that lipodystrophy seems to be worse when NRTIs and protease inhibitors (PIs) are combined and that studies which utilized PI-only regimens had a lower risk for lipodystrophy (such as the often-cited combination of ritonavir [RTV or r, Norvir]/saquinavir [SQV, Invirase or Fortovase] +/- d4T [stavudine, Zerit]).
There are a number of possible mechanisms, Dr. Weiss noted, for the metabolic effects of PIs (including insulin resistance, decreased lipogenesis, increased lipolysis and increased apoptosis) and NRTIs (focusing on mitochondrial issues). Not all drugs within a class are the same. For instance, unlike most PIs, indinavir (IDV, Crixivan) has been shown to induce insulin resistance but not have much effect on lipids. The effect of lopinavir/ritonavir (LPV/r, Kaletra) has been more on the lipid levels. Dr. Weiss pointed out that the risk for lipoatrophy in some studies (such as ACTG 384 [click here for a summary of this study]) is higher for d4T combined with ddI (didanosine, Videx) than for AZT (zidovudine, Retrovir) combined with 3TC (lamivudine, Epivir).
Dr. Weiss suggested that perhaps a selective autonomic neuropathy could be an explanation for regional effects on fat (i.e., fat gain in some areas and fat loss in others), but there is only some animal data on this and little human data.
And then, of course, Dr. Weiss discussed one of the hotter issues of our time -- the risk for coronary artery disease (CAD). There is concern that chronic HIV infection itself could be a risk factor (atherosclerosis is now viewed as a chronic inflammatory process). Data from the D:A:D study (presented at the Boston CROI meeting and in the New England Journal of Medicine) found a 26 percent increase in risk for CAD for each year patients were on potent ART. Standard risk factors for CAD still dominate (smoking is number one). This issue was highlighted in the case used for discussion in which the approach to ART was influenced by the CAD risk factors for the patient. Dr. Weiss nicely stated that once significant fat changes have occurred, the underlying problems are further aggravated, therefore making prevention crucial.
Options for preventing coronary artery disease include:
In the discussion period, Dr. Wanke cautioned against the use of alternative medications or supplements (such as antioxidants) due to concern about their effect on efficacy and possible other drug interactions. The point was made by an audience member that co-infection with hepatitis C can significantly aggravate metabolic problems.
There was also much discussion about plastic surgery options (i.e., New-Fill for facial wasting) and a plea for more studies addressing lipoatrophy. On the subject of lipoatrophy, data from Andrew Carr's study (six-month results published in JAMA 2002 with 12-24 month data recently discussed at the Lipodystrophy meeting) showed that a switch from d4T to abacavir (ABC, Ziagen) can result in slow increases in peripheral fat (imperceptible to patients but picked up on DEXA scans).
Many of these issues are currently being addressed in an AIDS Clinical Trials Group (ACTG) study (i.e., ACTG 5142, a clinical trial focusing on an initial NRTI-sparing regimen) and other studies. Although there is much concern about lipodystrophy, this hasn't translated into heightened interest among doctors or patients in clinical studies. Without results from well-designed clinical studies, it seems unlikely that the etiologies of these problems will be elicited or that effective targeted treatments will be developed.
Later that morning, during session 142 ("Management of the Patient With HIV Infection"), Andrew Carr also addressed the issue of the management of the metabolic complications of ART. He presented a case in which he applied the recent data from the ART Collaboration Group (two recent Lancet papers), which looked at the risk for AIDS progression for a patient if untreated or after six months of potent ART.
He plugged the coronary artery risk factors into the Framingham risk calculator and juxtaposed the risk for HIV progression versus CAD risks. He then looked at typical interventions for CAD (i.e., smoking cessation or statin treatment for elevated cholesterol) and showed that smoking cessation and switching the HIV regimen to a more lipid friendly regimen could significantly impact the CAD risk. Thus some useful tools to help sort out what to do for individual patients are becoming available.
Authored by: Christine Wanke, M.D. and Peter Reiss, M.D.
Affiliations: Tufts Univ. Sch. of Med., Boston, MA; Univ. of Amsterdam, Amsterdam, Netherlands
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