The Metabolic Syndrome: News From the 4th International AIDS Society Conference

The 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention was held in Sydney, Australia, July 22 to 25, 2007. This biennial conference drew more than 5000 attendees from more than 130 countries. Among the 1835 presentations were a number that discussed the metabolic syndrome associated with HIV infection. Notable among them were those that talked about the changing face of metabolic disorders seen in HIV-infected patients.

Lipodystrophy: Not What It Used to Be
Nguyen and associates¹ summed up these changes in their poster discussion titled “Lipodystrophy Is Not What It Used to Be: Data From the Swiss HIV Cohort Study.” The Swiss HIV Cohort included more than 14,000 patients, approximately 4000 of whom were treated with potent antiretroviral therapy and then observed at 6-month intervals.

The researchers reported that antiretroviral treatments are changing, and that these changes may affect lipodystrophy. For instance, the decreased use of stavudine was expected to reduce the incidence of lipoatrophy, while lipohypertrophy, thought to be associated with protease inhibitors, might cause weight gain in the cohort.

They tracked the frequency of physician-diagnosed lipodystrophy and weight changes between 2003 and 2006 in relation to the use of specific drugs. Treatments and reasons for regimen changes were recorded, and at each visit, patients were given scores for fat accumulation, fat loss, or neither. The researchers selected patients with a body mass index greater than 20 for men and greater than 18 for women, identified those who gained more than 5 kg over 6 months (cases), and compared them with those who had not gained more than 5 kg (controls).

From 2003 to 2006, the percentage of patients taking stavudine decreased from 14.2% to 3.6%; indinavir, from 3.4% to 0.7%; and nelfinavir, from 15.8% to 5.5%. The percentage of patients taking lopinavir remained stable (22%) and increased for atazanavir (from 2.9% to 21.5%). The annual prevalence of weight gain greater than 5 kg remained stable at about 7%, but the relative frequency of treatment change related to lipodystrophy decreased from 2.25% to 1.0% of visits. In each year from 2003 to 2006, case patients (weight gain of more than 5 kg) were more likely than controls to take lopinavir or atazanavir (P < .001). In multivariate logistic regression analysis, atazanavir and lopinavir were associated with weight gain of more than 5 kg. With the same analysis, exposures to atazanavir, indinavir, nelfinavir, efavirenz, nevirapine, and abacavir were associated with fat accumulation, while stavudine, ritonavir, abacavir, and efavirenz were associated with fat loss (all results, P < .01).

The researchers concluded that treatment changes because of lipodystrophy became less frequent from 2003 to 2006 and that weight gain of more than 5 kg was associated with use of atazanavir and lopinavir.

In another poster presentation, Aboud and coworkers² summarized the results of the CREATE 1 trial (Cardiovascular Risk Evaluation and Antiretroviral Therapy). They concluded that as the long-term prognosis for patients with HIV infection improves, it becomes more important to assess each patient’s risk of cardiovascular disease and other health problems.

They reminded us that HIV infection and antiretroviral therapy are associated with an abnormal metabolic profile and an increase in cardiovascular risk (CVR) and observed cardiac events. In this large, prospective, cross-sectional, multicenter study, they assessed risk factors (including ethnicity and antiretroviral use) that might have an independent effect on 10-year CVR. They also measured the prevalence of the metabolic syndrome and abnormal metabolic parameters and investigated a potential association between statin use and surrogate markers of HIV progression.

The cohort consisted of 1012 randomly selected patients from 2 HIV referral centers who underwent a 10-year assessment of CVR and the occurrence of the metabolic syndrome using the National Cholesterol Education Program-Adult Panel III guidelines.³ Data on patient demographics, cardiovascular and metabolic syndrome risk factors, individual metabolic parameters, and statin use were collected.

The mean 10-year CVR was 3.5%. Mean 10-year CVR was greater for whites than for “black Africans” (5.41% vs 2.36%; P < .001), and for those receiving potent antiretroviral therapy than for those who were treatment-naive (4.55% vs 3.28%; P = .0004). There was no difference between those taking a protease inhibitor (PI) and those taking a non-PI regimen at the time of assessment (P = .74). The prevalence of the metabolic syndrome was 13.7%. The metabolic syndrome was associated with male sex, advanced age, and higher CVR. Patients taking statins presented with higher CD4 counts and more sustained virological control than those who were not, even when the data were controlled for antiretroviral use.

The researchers concluded that: (1) white ethnicity and potent antiretroviral use were positively and independently correlated with an increased 10-year CVR, although being on a PI versus a non-PI regimen at the time of assessment was not; (2) the metabolic syndrome was associated with male sex, advanced age, and increased CVR; and (3) the use of statins, usually with lifestyle modification, has an association (possibly causal) with improvements in surrogate markers for HIV progression.

Finally, they injected a note of caution for those of us who provide HIV care: although long-term cardiovascular disease risks are a concern in patients with HIV disease, the primary objective still requires control of HIV. In other words, CVR and the metabolic syndrome are important considerations when selecting antiretrovirals and in the continued monitoring of our patients.

Today's Approach to Treatment and Monitoring: Assessing CVR
An industry-sponsored satellite presentation, “HIV and Cardiovascular Disease-Minimizing the Risk of HIV and HAART,” went on to look at the bigger picture of CVR.⁴ Not unexpected, the presenters at this symposium came to the same conclusions as the researchers discussed above.

Dr Judith Currier (University of California, Los Angeles) said that the current management of HIV infection needs to include screening and interventions to reduce morbidity and mortality from other chronic diseases, such as cardiovascular disease. She reviewed a series of clinical studies that attempted to address whether HIV infection itself is responsible for increased risk of cardiovascular disease, whether the problem is rooted in the treatment of HIV disease with potent antiretroviral therapy, and which of the components of antiretroviral therapy might be associated with increased risk of heart disease.

She said that one of the surprising results of the Strategies for Management of Antiretroviral Therapy (SMART) study was that patients with HIV infection who were assigned to a regimen in which treatment was guided by levels of CD4⁺ cells and who were able to take less medication actually had worse cardiovascular disease outcomes than did patients who never stopped taking the antiretroviral regimen.^5,6 The 5472-patient study was halted in January 2006 when it became clear that there was an excess of opportunistic infections and other morbidities in the treatment-interruption arm. Patients whose treatment was interrupted had significantly greater risk of both fatal and nonfatal myocardial infarction, stroke, coronary artery disease requiring surgery, renal disease, and liver disease per 100 years of follow-up (P = .02) compared with those in the continuous-therapy group.

On the other hand, she noted, data from the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study indicated that use of PIs increased HIV patients' risk of myocardial infarction by about 16% per year.⁷ However, the absolute risk of myocardial infarction was low and must be balanced against the marked benefits of antiretroviral treatment.

Currier also noted that treatment of cardiovascular disease requires that the physician be aware of interactions between statins and PIs. For example, fluvastatin and pravastatin appear safe for use in HIV-infected patients, but lovastatin and simvastatin are contraindicated. The other statins have to be used with caution, she said.

In clinical settings, it is important to consider the CVR profile of a patient with HIV infection, Currier noted. However, she explained, “The absolute risk of cardiovascular disease in the HIV population remains low, at about 2%.” Modification of coronary heart disease risk and use of antiretroviral agents less likely to cause metabolic disturbances may be warranted when patients have many options, but “the fear of coronary heart disease should not preclude the use of effective potent antiretrovirals,” she said.

In the same symposium, Dr Peter Reiss (Academic Medical Centre, Amsterdam), illustrated how the treatment choices fit into selection of therapy, noting that a patient’s risk of heart disease might be reduced by a more intelligent selection of HIV drugs.⁴

While NNRTIs are not the only answer, one small study shed some light on their role in lipid metabolism. The NILE (Nevirapine Intensive Lipid Evaluation) study was a small pilot study (N = 13) that showed that nevirapine increased high-density lipoprotein (HDL) cholesterol (ie, “good cholesterol”) levels by 19% through a 14% increase of apolipoprotein A-I levels without an increase in HDL cholesterol catabolism.⁸ However, he said, the best way for patients to dramatically reduce Framingham Heart scores is to quit smoking.

Summary: A Multifactorial Approach
“Cardiovascular risk assessment has become an integral component of the care for persons with HIV infection,” Reiss said. “Careful choice of antiretroviral regimens may contribute to optimization of lipid profiles. Cardiovascular disease risk reduction, however, involves much more than just paying attention to lipids.”

In other words, managing CVR is a multifactorial effort in clinical settings. Antiretroviral selection; treatment of lipid disorders; and lifestyle changes, especially diet and smoking cessation, all play a role.

The metabolic disorders in HIV/AIDS include more than just the fat redistribution of lipoatrophy and lipohypertrophy. CVR is an important, emerging cause of morbidity and mortality in patients with HIV/AIDS. However, potent antiretroviral therapy remains pivotal in improving patient outcomes, and the goal of therapy remains full suppression of HIV RNA level for all patients. For those of us who provide patient care, the message is clear: we need to incorporate strategies to manage CVR when selecting antiretroviral regimens for and monitoring our patients.

References:

References1. Nguyen A, Bernasconi E, Battegay M. "Lipodystrophy" is not what it used to be: data from the Swiss HIV cohort study. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPEB084. Available at: http://www.ias2007.org/pag/Abstracts.aspx?SID=154&AID=1583. Accessed August 6, 2007.
2. Aboud M, Elgalib A, Pomeroy L. A large prospective cohort study of cardiovascular risk and associated metabolic changes in HIV infection: CREATE 1 (cardiovascular risk evaluation and antiretroviral therapy). 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPEB068. Available at: http://www.ias2007.org/pag/Abstracts.aspx?AID=3672. Accessed August 6, 2007.
3. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement [published correction appears in Circulation. 2005;112:e297-298]. Circulation. 2005;112:2735-2752.
4. Satellite Conference: HIV and cardiovascular disease-minimizing the risk. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 22-25, 2007; Sydney, Australia. Session MOSA1.
5. El-Sadr WM, Lundgren JD, Neaton JD, et al. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4⁺ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296.
6. Currier JS, Baden LR. Getting smarter-the toxicity of undertreated HIV Infection. N Engl J Med. 2006;355:2359-2361.
7. Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356:1723-1735.
8. Sankatsing R, Franssen R, Hassink E, et al. Nevirapine increases high density lipoprotein-cholesterol by stimulation of apolipoprotein AI synthesis. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEB120LB. Available at: http://www.ias2007.org/pag/PosterExhibition.aspx?presType=PE&day=25&Track=All&absCat=Lipodystrophy%2c+metabolic+abnormalities%2c+cardiovascular+disease. Accessed August 6, 2007.

Other Resources
The 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. Web site. Available at: http://www.ias2007.org. Accessed August 6, 2007.

The 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. Programme at a Glance. Available at: http://www.ias2007.org/pag. Accessed August 6, 2007.