Update on Metabolic Complications

Hopkins HIV Report 2006 Sep; 18(5):9-10

Todd T. Brown, M.D.
Johns Hopkins

Several studies presented in Toronto provide further insight into the pathogenesis and treatment of metabolic problems in HIV-infected patients.

Role of Specific Antiretrovirals

The KLEAN study was a 46-week, randomized, open label study in which 878 antiretroviral-naive patients received either fosamprenavir/ritonavir (FPV/r) or lopinavir/ritonavir (LPV/r), with a backbone of abacavir/lamivudine in both arms [Eron J, et al. Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. THLB0205; also Lancet. 2006 Aug 5;368(9534):476-82]. As reviewed elsewhere in this issue, antiviral efficacy was similar in both arms. Somewhat surprisingly, both arms were also similar in the effect on lipids. Fasting triglycerides (TG) increased by 59% in the FPV/r arm and 66% in the LPV/r arm at 48 weeks, while the use of lipid lowering medications was similar in both groups (11%). HDL also increased similarly in both arms (40% vs. 41%). The important message is that FPV/r, which has been considered relatively “lipid friendly,” is also associated with significant increases in hypertriglyceridemia.

One explanation for these findings is that the increases in TGs are the result of the boosting doses of ritonavir. The impact of low-dose ritonavir on lipids was addressed in a switch study that compared lipid changes in those switched to atazanavir (ATV, n=559) or to ritonavir-boosted atazanavir (ATV/r, n=638) [Keiser P, et al. Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEPE0163]. While this study was not randomized and therefore may be subject to confounding, a switch to ATV was associated with a 27% decrease in TGs, compared to a somewhat attenuated decrease of 20% in those who switched to ATV/r.

Another switch study quantified the lipid improvements in 88 patients who substituted ATV/r for LPV/r [Guillemi S, et al. Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEPE0156]. After 6 months, there was an average 13% decrease in total cholesterol and a 30% decrease in triglycerides. When Framingham Scores [Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults - http://hp2010.nhlbihin.net/ atpiii/calculator.asp?usertype=prof ] were used to calculate cardiovascular risk, these changes corresponded to a decrease from 12% to 10% in the average 10-year risk of myocardial infarction or cardiovascular death, reminding us to place lipid changes into the larger perspective of cardiovascular risk reduction when contemplating interventions. Risk Factors for Cardiovascular Disease Several studies examined emerging cardiovascular risk factors in HIV-infected populations. High levels of lipoprotein a [Lp(a)] have been independently associated with cardiovascular disease in the general population, although the role of Lp(a) in HIV-infected patients and its interaction with antiretroviral therapy are unclear. In a cohort of 109 HIV-infected patients beginning antiretroviral therapy, Lp(a) increased significantly after treatment initiation, but only among the 30% who had high concentrations at baseline [Mauss S, et al. Abstract WEPE0159]. The impact of this change on cardiovascular risk requires further investigation. In addition to LDL-cholesterol, LDL phenotype may also play an independent role the pathogenesis of cardiovascular disease. Specifically, small dense LDL particles (so called, Pattern B) are thought to be more atherogenic than larger LDL particles in the general population. The prevalence of this phenotype has not been well described in HIV-infected patients. In one cohort of HIV-infected patients, hypertriglyceridemia (>300 mg/dL) was an important marker of small, dense LDL particles, with a prevalence of up to 50% in this group [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEPE0163]. These small, dense particles are thought to be more readily oxidizable, increasing their atherogenic potential. Another study showed that higher levels of oxidized LDL were found in HIV-infected patients on HAART, especially in those who had experienced body composition changes [Duong M, et al. WePE0168.html">Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEPE0168]. While these finding are interesting and deserve further investigation, their clinical utility has not been established, and it is premature to evaluate and treat based on these risk factors.

The metabolic syndrome (the constellation of high triglycerides, low HDL, central adiposity, hypertension, and hyperglycemia) is a cardiac risk factor that has attracted controversy in the general population in the past year, with some experts questioning its clinical utility. Several studies have examined the epidemiology in HIV-infected patients, but mostly in predominately male populations. In the first study reporting on metabolic syndrome in women, investigators from the WIHS observed a higher prevalence in HIV-infected women (33%) compared to HIVnegative women (22%) [Sobieszczyk ME, et al. Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEPE0147]. In a multivariable analysis, traditional risk factors, such as age and BMI as well as disease and treatment factors (HIV viral load and stavudine use) were associated with the presence of metabolic syndrome.

The Risk of Myocardial Infarction Compared to HIV-uninfected Patients

While data from cohorts of HIV-infected patients have demonstrated an increased risk of myocardial infarction that is in part related to antiretroviral therapy, there are few studies comparing the risk of myocardial infarction in HIV-infected and uninfected persons. In a large database study from two Boston hospitals, the rate of myocardial infarction in HIV-infected patients was 1.77-fold higher than that of HIV-negative patients, with a more pronounced effect in women, reinforcing the need for aggressive risk modification [Triant V, et al. Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEPEP0179].

Specific Interventions

The case for the use of omega-3 fatty acids in HIV-infected patients with hypertriglyceridemia was strengthened with the report of a randomized controlled trial of salmon oil (1 g three times daily) in 58 patients [Baril J, et al. Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEPE0138]. Over the 12 weeks of observation, there was a 20% decrease in TG levels in those randomized to salmon oil, compared to a 7% increase in those who did not receive any additional treatment. This effect was present but somewhat attenuated in those receiving other lipid-lowering agents. Omega-3 fatty acids do indeed provide additional benefits for HIV-associated hypertriglyceridemia, but it is not clear whether patients can reach their target using omega-3 fatty acids, either as an adjunctive or single therapy.

There are few effective treatments for fat accumulation in HIV-infected patients. In the late breaker session, results of a randomized trial were presented in which patients with evidence of body composition changes received either growth hormone (12-week induction of 4 mg qd) or placebo [Grunfeld C, et al. Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. THLB0212]. Those who received active drug were randomized to 2 mg every other day or placebo for a 24-week maintenance period. Statistically significant reductions in visceral adipose tissue were observed after the induction period (20% vs. 4% in placebo), which generally persisted during the maintenance phase. However, the clinical significance of these changes requires clarification, and at this point growth hormone should not be recommended for this purpose.

Body Composition Changes in the Developing World

Over the past decade, a substantial body of research has established the role of stavudine in the pathogenesis of glucose abnormalities, lipid alterations, and body composition changes, most notably lipoatrophy. There are few data reporting on the risk of these changes in patients in the developing world, where the use of stavudine is widespread. In a cohort of 226 HIV-infected patients in Rwanda, 25% had either lipoatrophy or lipohypertrophy after an average of 18 months on HAART, and these changes were seen more commonly in females [van Griensven J, et al. Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEPE0140]. Given our understanding of the consequences of stavudine therapy on metabolic and morphologic parameters, a commitment to finding less toxic, low cost alternatives is critical.

2006-09-10
HHR-2006-09-05

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