HIV infection and cardiovascular disease

Hemkens LG, Bucher HC
Eur Heart J. 2014 Jan 9. [Epub ahead of print]

Background

The downside of the success of antiretroviral therapy (ART) to reduce AIDS-related morbidity and mortality and human immunodeficiency virus (HIV)-infection is that a parallel increase in morbidity and death not directly related to HIV was noted. Cardiovascular diseases (CVD) are a particular concern due to antiviral-drug-induced metabolic changes, the high prevalence of CV risk factors in HIV-infected individuals, and growing evidence on HIV-accelerated inflammatory processes known to promote atherosclerosis. We here summarise the review on the complex association of HIV infection and CVD.

Cardiovascular disease risk in HIV-infected compared to HIV-uninfected individuals
Various studies have found an increased risk of CVD in HIV-infected individuals as compared to HIV-uninfected individuals, although some, but not all, studies may not have adequately corrected for confounding by traditional CV risk factors.

Cardiovascular risk factors in human immunodeficiency virus-infected individuals

HIV-infected individuals have been found to exhibit more CV risk factors, including higher prevalence of smoking and dyslipidaemia, than non-infected individuals. The D:A:D study (Data Collection of Adverse events of Anti-HIV Drugs) is a large database on CV risk factors in over 30000 HIV-infected patients. The 10-year observation period confirmed high smoking rates and dyslipidaemia in age groups that generally have low CVD risk.

While a difference in total cholesterol (TC) levels, HDL-c and LDL-c and an increase in triglycerides (TGs) is seen following an untreated HIV-infection, after ART initiation marked increases in TC, LDL-c and TGs are observed, while HDL-c remains low. Antiretroviral drugs and different drug classes yield distinct lipid changes patterns. In HIV-infected patients, basal lipolysis and hepatic de novo lipogenesis are increased, while the ability of insulin to suppress lipolysis in adipocytes is reduced, as well as peripheral fatty acid trapping.
Change in body fat composition are often seen after exposure to ART; lipoatrophy may develop in the face and limbs, while lipohypertrophy can occur in other body parts, both as central visceral fat gain and ectopic fat deposition. Lipohypertrophy and visceral fat deposits after ART use are commonly associated with metabolic changes similar to those in HIV-uninfected people with metabolic syndrome. Although the complex mechanisms underlying lipohypertrophy remain partly unclear, inflammatory cytokines, high levels of circulating TGs and free fatty acid storage in visceral fat and the liver are thought to play a role. Individuals with peripheral lipoatrophy and/or central lipohypertrophy have an increased CVD risk. Unfortunately, changes in body composition cannot be reverted to a clinically relevant extent in most patients, and are typically common in patients who have taken first-generation antiretroviral drugs.
Newer antiretroviral drugs do not appear to be associated with an increased risk of diabetes, as opposed to older drugs. Thymidine-containing analogues reverse transcriptase inhibitors have known mitochondrial toxicity, which could impair insulin sensitivity

Chronic inflammation

Evidence is accumulating that HIV-related inflammation and immunologic processes contribute to CV risk in HIV-positive patients. The SMART trial showed that HIV-infected patients who interrupted ART, the rationale of the study being to limit ART-toxicity, showed not only a higher hazard of AIDS and death, but also more CVD events than patients who continued ART. The inflammatory biomarkers IL-6, C-reactive protein and D-dimer were increased after ART interruption, and these levels were associated with increased all-cause mortality and were modestly but independently predictive of CVD.
Soluble factor CD163 is associated with macrophages in atherosclerotic plaques and correlates with arterial inflammation. ART-users with well-suppressed viral load showed arterial inflammation of similar magnitude as HIV-negative individuals with atherosclerosis. Endothelial inflammation in HIV-infection may persist independently of ART. Inflamed or injured endothelial cells express chemokines that subsequently attract inflammatory cells. ART has been shown to reduce this process in randomised clinical trials. Similar inflammatory mechanisms have been described to occur in adipose tissue, which is relevant in light of the changes in body fat mass seen in HIV infection.

Effects of antiretroviral drugs on clinical cardiovascular disease endpoints

A meta-analysis of observational data suggested an increased risk of myocardial infarction (MI) with exposure to different ARTs, both reverse transcriptase inhibitors and protease inhibitors, although some studies were of limited quality, thus these findings have to be interpreted with caution. Another meta-analysis studying the reverse transcriptase inhibitor abacavir did not find an increased risk of MI, thus it remains unclear whether such an effect exists. In any case a potential absolute risk increase is likely to be moderate and needs to be regarded in the context of the benefit of ART.

Managing human immunodeficiency virus and risk factors for cardiovascular disease

Since HIV suppression and improved immune function is associated with reductions in systemic inflammation and CV risk, sustained and lifelong viral suppression is the first priority in HIV treatment. Guidelines therefore recommend initiation of ART irrespective of CD4 cell count in patients over 50 years old. Considering that potential long-term side effects from many ARTs are largely unknown, choice of the regimen must be based on a balancing the risk for CVD and other comorbidity, psychosocial conditions and patient preferences and commitment to lifelong drug adherence.
Based on the D:A:D study, a specific CV risk calculator has been developed that takes into account exposure to antiretroviral drugs with known increased risk of coronary heart disease and/or CVD. This instrument predicted the individual CVD risk better than the established Framingham risk score. Even though this specific risk calculator for HIV-infected patients does not yet include inflammatory or immunologic markers, it currently appears to be the best tool to assess individual CV risk.

Management of CV risk factors such as dyslipidaemia, hypertension and counselling for behaviour changes should be given priority. Overall, this can be done according to guidelines established for non-HIV-infected individuals. Reducing the prevalence of smoking would give the largest reduction in CVD events, but this goal appears the most difficult to achieve.
When dyslipidaemia is treated in HIV-infected individuals on ART, possible drug interactions need to be considered. Newer antiretroviral medication seems to induce fewer lipid changes, thus using less atherogenic drugs could be a good option. However, all modifications of successful antiretroviral drug combinations should be decided on by the specialist.
Different lipid-lowering drugs have been shown to be effective in HIV-infected individuals, including reduction of ART-induced TG increases. However, some of these compounds did not give positive outcomes in HIV-negative patients, thus they are not routinely recommended. Dietary intervention and statins are therefore the preferred options for management of dyslipidaemia in HIV-infected individuals at moderate risk for CHD.
Certain statins may interact with protease inhibitors and/or non-nucleoside reverse transcriptase inhibitors (NNRTI), depending on  by which enzyme they are metabolised. Drug interactions with antiretroviral drugs can be checked at www.HIV-druginteractions.org.
HIV-infected patients with elevated and uncontrolled blood pressure are also at increased CV risk, and they may develop end-stage renal failure. Blood pressure management in HIV-patients do not differ from recommendations for HIV-negative individuals, although potential drug interactions need to be considered.
In light of the JUPITER trial that showed that rosuvastatin in patients with normal LDL-c reduces C-reactive protein and CV events, it is under current investigation whether rosuvastatin may reduce systemic and endothelial inflammation markers in patients on ART. Also other anti-inflammatory agents deserve evaluation for their possible additional benefit in HIV-positive individuals.

Conclusion

HIV-infected patients are at increased risk to develop CVD due to the high prevalence of CVD risk factors, ART-related metabolic changes, and systemic immune activation that promotes endothelial inflammation and atherosclerosis. ART is the first priority to suppress viral load, and it also has survival benefits. At the same time, a sustained virological response is associated with a reduction of the inflammatory response and reduced CVD events. These benefits need to be considered in relation to ART-induced metabolic changes.
CVD risk should be routinely assessed and dyslipidaemia and hypertension should be treated to reduce CVD risk. Smokers should be strongly encouraged to quit.
Optimally coordinated care between CV and HIV specialists is crucial for the chronic disease management of HIV and to further improve prognosis of HIV-infected patients.

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