Coronary heart disease in people infected with HIV
ABSTRACTPeople infected with human immunodeficiency virus (HIV) are living longer thanks to effective antiretroviral therapy. As this population ages, cardiovascular disease is becoming an important cause of morbidity and death. The authors of this review discuss the magnitude and likely mechanisms of the risk and strategies for managing it.
KEY POINTS
- Traditional risk factors are the main contributors to cardiovascular disease in this population, although HIV infection is independently associated with increased cardiovascular risk.
- Antiretroviral therapy contributes modestly to the risk of coronary heart disease. Antiretroviral combinations that include protease inhibitors cause the most substantial deleterious changes in lipid levels.
- Most changes in lipids and insulin resistance can be managed by adding lipid-lowering and antiglycemic agents and may not require changes to the antiretroviral regimen.
- Close attention to drug interactions is important when selecting lipid-lowering medications for patients on antiretroviral therapy to avoid dangerous increases in the levels of certain statins.
- Addressing modifiable risk factors such as smoking, obesity, and sedentary lifestyle can have a far greater impact on cardiovascular risk than changes in antiretroviral therapy.
EFFECT OF ANTIRETROVIRAL THERAPY ON CORONARY RISK
Antiretroviral therapy is associated with a small but significant increase in coronary risk.
Medi-Cal,15 a retrospective study of 28,513 patients, found antiretroviral therapy to be associated with coronary heart disease among patients 18 to 33 years of age (relative risk 2.06, P < .001).
The Data Collection on Adverse Events of Anti-HIV Drugs study16 prospectively followed 23,437 patients for 94,469 person-years. Adjusted for exposure to nonnucleoside reverse transcriptase inhibitors and for hypertension and diabetes, the relative risk of myocardial infarction per year of protease inhibitor exposure was 1.16 (95% confidence interval [CI] 1.10–1.23). The relative risk was lower after adjusting for serum lipid levels but remained significant at 1.10 (95% CI 1.04–1.18).
Reports have been mixed regarding a possible association between myocardial infarction and the nucleoside reverse transcriptase inhibitor abacavir (Ziagen): several studies found a statistically significant association,17–20 and others did not.21–23 Differences in study design (observational cohort studies vs prospective randomized clinical trials), populations studied (differing in age, cardiovascular risk factor prevalence, and whether the patients had already been exposed to treatment), and outcome definition probably contributed to the different conclusions.
On the other hand, several studies have shown that suppression of HIV with antiretroviral therapy actually improves some of the surrogate markers of cardiovascular disease. For example:
- Markers of endothelial function such as flow-mediated vasodilation improve significantly within 4 weeks of a patient’s starting antiretroviral therapy, regardless of the class of antiretroviral drug used.24
- After viral suppression is achieved, levels of the markers of endothelial activation VCAM-1 and P-selectin decline significantly, as do levels of the adipocyte activation marker leptin and the coagulation marker D-dimer.25,26
- Levels of the anti-inflammatory markers adiponectin and interleukin 10 increase. 25,26
Interrupting antiretroviral therapy may increase coronary risk
Not only is uncontrolled viral replication in untreated HIV infection associated with cardiovascular disease, but interrupting antiretroviral therapy may result in a supplementary increase in coronary risk.
In the 5,472-patient Strategies for Management of Antiretroviral Therapy (SMART) trial, the rate of cardiovascular disease events was higher if treatment was interrupted than with continuous treatment, with a hazard ratio of 1.57 (95% CI 1.0–2.46, P = .05).27
This association between treatment interruption and coronary events does not appear to be related to the level of viremia.28 Rather, development of cardiovascular disease in HIV-infected patients who interrupt antiretroviral therapy may be mediated, to a large extent, by chronic inflammation in the setting of viral replication. In the treatment-interruption group, levels of the inflammatory cytokine interleukin 6 (IL-6) and the coagulation marker D-dimer were significantly elevated 1 month after randomization, and these differences were strongly associated with death (odds ratio [OR] 12.6, P < .0001 for IL-6; OR 13.1, P < .0001 for D-dimer). Elevated IL-6 levels were also significantly associated with the development of cardiovascular disease (OR 2.8, P = .03).29
METABOLIC COMPLICATIONS OF ANTIRETROVIRAL THERAPY
Persons with HIV infection may experience metabolic complications that are due to HIV itself or to its treatment.
Cross-sectional studies that included HIV-negative patients as controls have demonstrated changes in lipid processing that are known to promote atherosclerosis. For example, persons with HIV infection have smaller LDL-C particles30 and higher levels of circulating oxidized LDL-C.31
In the Multicenter AIDS Cohort Study (MACS), after HIV seroconversion, nonfasting total cholesterol, LDL-C, and HDL-C levels declined, which is consistent with a chronic inflammatory state. After antiretroviral therapy was started, lipid levels returned to baseline levels or slightly higher except for HDL-C, which remained low.9 These changes may be due to a general “return to health,” or they may be direct medication effects.
Similar patterns were seen in the SMART study.28 Participants randomized to receive intermittent antiretroviral therapy had overall decreases in all lipid levels, with a marked reduction in HDL-C, while those randomized to receive continuous therapy had increased levels of all lipids, including HDL-C, at 12 months. Overall, the ratio of total cholesterol to HDL-C actually increased for participants on episodic therapy, while it decreased in the continuous-treatment group. Along with continued vascular inflammation, the low HDL-C may have contributed to the worse cardiovascular outcomes in patients who received intermittent antiretroviral therapy.
Some lipid changes associated with antiretroviral therapy may actually be beneficial. For example, nonnucleoside reverse transcriptase inhibitors may raise HDL-C levels. However, such increases alone do not necessarily offset the other lipid changes or translate to an observed improvement in coronary risk.32
The degree of dyslipidemia and specific lipid changes differ among the different classes of antiretroviral drugs and even among the individual drugs within each class. Furthermore, the magnitude of the observed lipid changes varies widely among patients on the same antiretroviral regimen, reflecting the likely important role of host genomics.
While the protease inhibitors and nonnucleoside reverse transcriptase inhibitors have well-described effects on lipids (described in greater detail in the following sections), there have been no reported significant changes in lipid profiles or cardiovascular risk associated with the newest classes, ie, fusion inhibitors such as enfuvirtide (Fuzeon), CC chemokine receptor type 5 (CCR5) receptor inhibitors such as maraviroc (Selzentry), or integrase inhibitors such as raltegravir (Isentress).
