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  4th Intl Lipodystrophy Workshop
San Diego at Coronado Beach, Sept 22-25, 2002
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Lipodystrophy Workshop: Lipids and Cardiovascular Risk
Michael Dube, MD, Indiana University School of Medicine, ACTG researcher
  Agrawal (abstract #12) reported on the effects of different antiretroviral agents and combinations in an in vitro model, using cultured human aortic endothelial cells (HAECs). These cells that line the aorta and other arteries respond to different stimuli and facilitate blood vessel relaxation under normal conditions. In PI-treated patients, the endothelium appears to be dysfunctional, resulting in impaired dilation of blood vessels. This "endothelial dysfunction" is known to be an inciting cause of atherosclerosis and helps to promote myocardial infarctions. Both HIV itself and the therapies we use may affect endothelial dysfunction. Agrawal used a variety of techniques and drug combinations. Bottom lines included: HAART that included indinavir+NRTI increased expression of ICAM and VCAM (these are "adhesion molecules" that encourage thrombosis), reduced eNOS expression and nitric oxide production (eNOS is the enzyme that produces nitric oxide, which dilates blood vessels), and reduced the endothelial cells' response to insulin (a form of insulin resistance). The lab data support the findings reported by Dube et al at Retrovirus earlier this year, who found that indinavir given alone to normal men resulted in endothelial dysfunction, which may be mediated by insulin resistance. What needs to be clarified is what precisely are nucleosides contributing to endothelial dysfunction, how much the different PIs differ in their effects on blood vessels, and if PI-sparing regimens will result in improved endothelial function. This lab model can also be used to examine the effects of insulin sensitizers such as rosiglitazone and metformin on blood vessels.
In a study of healthy men (Kurowski), low-dose ritonavir (100 mg) plus saquinavir (1000 mg, both bid) resulted in no increases in cholesterol or triglycerides over 20 days. These results are in marked contrast with what has been reported with higher doses of ritonavir. My overall impression of studies that use low-dose ritonavir has been that there are minimal lipid changes from the ritonavir itself, and that whatever lipid changes are seen are probably due to the boosted PI. Data that definitively prove this are difficult to come by however.
Lipid effects of atazanavir were discussed in my earlier report on insulin and glucose metabolism and are repeated here. Several clinical studies have now reported lesser or no lipid effects with atazanavir. In contrast to nelfinavir, naive subjects initiating atazanavir-based ART did not develop elevations in total cholesterol, LDL-cholesterol, or triglycerides. Murphy (abstract #15) reported a follow-up study where subjects initially assigned to nelfinavir treatment were switched to atazanavir. Elevated lipid levels among these subjects tended to normalize upon switching to nelfinavir. A poster from Sension (abstract 36) reported the effects of atazanavir-AZT-3TC and efavirenz-AZT-3TC on ~800 ART-naive subjects. Atazanavir appeared to have lesser effects on total and LDL-cholesterol and triglycerides, efavirenz appeared to have greater effects on increasing HDL-cholesterol. Statistical comparisons of the lipid results was not provided in this BMS-sponsored study.
d4T-containing regimens appeared to result in greater increases in cholesterol and triglycerides than non-d4T-containing regimens in the FOCUS trial (Walmsley). While subjects were randomized to receive either efavirenz or once-daily saquinavir-ritonavir in this trial, the nucleosides given in combination with them did not appear to be randomized. This lack of randomization makes any conclusions about "d4T being worse than other nukes" somewhat questionable as it pertains to lipid changes, but they are consistent with what has been reported by Kumar in a randomized study earlier this year at Retrovirus (ESS40002). Because NRTI effects on lipids appear to be less rapid in onset than PI or NNRTI effects, it will be interesting to see if NRTI-associated lipid changes correlate with body fat changes when prospective, randomized studies that measure both over a period of time are reported.
A study of 6 subjects (Souza) with mean triglycerides of ~700 mg/dl, reported that 1500 mg/d of the extended-release niacin product Niaspan (Kos Pharmaceuticals) resulted in a significant decrease in triglyceride levels. Significant changes in other lipid parameter did not occur, but the study's power was limited due to its small size. Of note, no safety problems were identified. There is concern that niacin, which can cause insulin resistance, may be poorly tolerated among patients who already have a tendency for insulin resistance. However, this was not found in this small study. The ACTG currently has a larger pilot trial using Niaspan (A5148) with careful evaluation of glucose metabolism using oral glucose tolerance tests. Subjects are eligible if triglycerides exceed 200 mg/dl and non-HDL cholesterol (total cholesterol - HDL cholesterol = non-HDL cholesterol) exceed 180 mg/dl. If niacin is safe in HIV-infected subjects, it may be particularly useful because it combines HDL-raising capability with LDL-lowering and triglycerides-lowering capability. Currently, the major option available where a statin (eg pravastatin, atorvastatin) or a fibrate (eg gemfibrozil or fenofibrate) does not result in sufficient lipid-lowering by itself, is to combine a statin plus a fibrate. However, this can increase the risk of muscle toxicity, so niacin may turn out to be an excellent option as an "add-on" to incompletely effective treatment. All these require further study.
While fasting levels of different lipoproteins predict cardiovascular risk, excesses in lipid levels following a meal also independently contribute to CV risk. Merwood (abstract 51) reported that PI recipients had elevated levels of triglycerides and IDL (intermediate-density lipoprotein, an atherogenic particle) as compared to those subjects not taking PI and controls after ingesting a high-fat shake. This slower clearance adds one more factor to be concerned about when considering lipid risks of medications, but whether or not fasting levels are adequate predictors of which PI's impair lipoprotein clearance remains to be seen; in other words, for clinical care purposes and for purposes of comparing between the PI's, evaluating fasting levels may be sufficient.
Little was presented regarding risk of cardiovascular disease from epidemiologic studies. Currier (abstract 34) updated her retrospective review of Medi-Cal claims submitted in California from 1995-2000. After excluding those with <30 days of antiretroviral therapy and an evidence of cocaine abuse, an increase in CHD was found only for the group 18-33 years old who received ART. This group had a relative risk of about 2 times of the group who were not receiving ART, after adjusting for increased lipids, hypertension, diabetes and kidney disease (apparently smoking was not considered). Thus, for those at greatest risk of CHD in the first place, ie older patients, did not appear to have an increased risk due to ART. While this is somewhat reassuring that treatment of HIV does not necessarily increase cardiovascular risk, it does not address regimen-specific risks, such as has been reported for PI's. Furthermore, since treatment has the potential to cause increases in lipids, hypertension, diabetes and kidney disease, you could easily wipe out any effect of treatment-induced co-morbidities by "controlling" for these diseases. For example if treatment A caused your blood pressure to increase from 120/70 to 250/140 and you then had a heart attack, you might conclude treatment A may have caused the heart attack. But if you "controlled" for blood pressure, you would consider the person with a treatment-induced increase in blood pressure to 250/140 the same as someone with a blood pressure of 250/140 to begin with, leading to the conclusion that it was the blood pressure that caused the MI and not treatment A. Thus, if you "control" for the mediators of CV disease, but these mediators are adversely influenced by treatment, you could come to the erroneous conclusion that it is not the treatment that is at fault. This aspect needs to always be considered when evaluating epidemiologic studies.
It is always easy to say "more work is needed" but clearly this is the case here. Certainly, we need more data about the effects of antiretroviral treatment on blood vessel functioning, and begin to sort out which drugs/regimens have the least effects on lipids and cardiovascular risk factors such as endothelial dysfunction and insulin resistance. The role of PI's needs further clarification, and whether non-PI regimens really do affect the bottom line of heart attack and stroke. The search for the kinder/gentler regimen continues. While this search continues, expanded data on interventions, which may include agents such as niacin and fish oils, and the role of diet and exercise, will add to our armamentarium to deal with the issues raised by prolonged HIV disease-free survival.