Novel mechanism, potential treatment strategies for CVD in patients with HIV

Issue: July 2015

BySteven K. Grinspoon, MD

Epidemiological studies suggest CVD events, including MI and stroke, are increased 50% to 100% among patients with HIV compared with patients without HIV. Moreover, data suggest CVD rates remain high in this population, even as rates of morbidity and mortality from HIV-related infections continue to improve with more effective antiretroviral therapies.

A novel paradigm of CVD in HIV

Recent studies indicate that both traditional and nontraditional risk factors contribute to increased CVD risk in HIV. Traditional risk factors, including smoking, dyslipidemia and diabetes, are more common in the HIV population, but contribute only partially to the increased CVD risk in the HIV population.

Steven K. Grinspoon

For example, Triant and colleagues have shown that hypertension, diabetes and dyslipidemia accounted for 25% of the excess CVD risk in this population. In addition, recent imaging studies using advanced CT angiography demonstrate unique differences in CAD in the HIV population. First, coronary lesions are more prevalent, even among HIV patients with low traditional risk factors who were carefully matched with non-HIV patients with similar risk factors, seen in 59% of HIV patients vs. 34% of non-HIV patients in one recent study. Coronary artery lesions among HIV patients are not only more prevalent, but they are often noncalcified and more frequently demonstrate high-risk morphology. That includes positive remodeling and low-attenuation plaque — features that are associated with more vulnerable, rupture-prone plaque. Of note, molecular imaging studies using fluorodeoxyglucose-positron emission tomography to assess arterial inflammation also demonstrated increased uptake, consistent with more metabolically active plaque in the arterial surface. Both altered plaque morphology and increased arterial inflammation related most strongly to markers of immune activation, including sCD163, rather than traditional risk markers or even markers of generalized inflammation, such as high-sensitivity C-reactive protein (hs-CRP).

Taken together, these studies suggest a novel paradigm of CVD in HIV, marked by increased immune activation, which may contribute in part to increased plaque inflammation among HIV patients. Immune activation occurs even among HIV patients on chronic ART with good immunological control as well as among elite controllers without measurable viremia who have never received ART. The mechanisms of increased immune activation are not entirely understood, but may in part relate to depletion of T cells in the gut, resulting in increased microbial translocation and increased lipopolysaccharide and subsequent immune activation. Cytomegalovirus and other chronic infections also may contribute to increased immune activation. Indeed, strategies to decrease immune activation related to microbial translocation in the gut may be useful against CVD and are being tested in current studies.

Appropriate therapy

What do the unique data regarding CVD in HIV tell us about appropriate therapy for this group, and who should we target? Primary prevention is a critical but untested strategy for CVD among HIV patients. This strategy is important because CVD among HIV patients often is seen among asymptomatic patients, with minimal CVD risk factors. In addition, this disease often is marked by sudden cardiac death without prodrome, suggesting acute plaque rupture as a mechanism. A number of primary prevention strategies may be considered. Minimization of traditional risk factors (ie, lifestyle modification, counseling for smoking cessation and treatments for hypertension and diabetes) are critical, but are they enough?

Figure 1: Regression of noncalcified plaque in the proximal left anterior descending coronary artery in an HIV patient on statin therapy for 12 months. Adapted from Lo J, et al. Abstract 136. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 23-26, 2015; Seattle.

Images: Lo J, et al./Massachusetts General Hospital

Recent studies suggest treatment with HMG-CoA reductase inhibitors, or “statins,” may prevent CVD even among patients without increases in LDL cholesterol. For example, in the JUPITER trial among non-HIV patients with low LDL but increased CRP, statins reduced CV events. Of note, this increase was much larger than predicted by the size of LDL reduction alone, suggesting additional effects on inflammatory and other pathways may have contributed to the overall beneficial effects.

Studies conducted among HIV patients show the significant potential of statins to lower LDL. In addition, statins have been shown to have positive effects on inflammatory and immune activation markers among HIV patients. Recently, Lo and colleagues demonstrated that 12 months of statin therapy among HIV patients with coronary plaque but without significant symptoms or traditional risk factors significantly reduced high-risk plaque morphology and plaque volume, while reducing blood markers of arterial inflammation (Figure 1). These data suggest the potential utility of statins in the HIV population. Significant effects on glucose were not seen in this study, but they were seen in the HIV SATURN study and in some non-HIV studies. Newer statins, such as Livalo (pitavastatin, Kowa Pharmaceuticals) may be better tolerated and beneficial in this regard as they have no known effects on glucose or interactions with ART.

Landmark study underway

Is the time right to recommend statins for HIV patients? The answer is no, not yet. However, the data are promising enough to suggest the need for a large definitive trial.

Recently, the National Heart, Lung and Blood Institute, in collaboration with the National Institute of Allergy and Infectious Diseases and Kowa Pharmaceuticals, funded a landmark study, REPRIEVE, to determine the efficacy of statins for the primary prevention of CVD in HIV patients. REPRIEVE will assess whether use of a statin results in reduced rates of MI, stroke and other CVD events in asymptomatic HIV patients. Participants are eligible for the study if they do not meet criteria for statin therapy according to the new American College of Cardiology guidelines. In this way, the study is testing whether statins should be used for CVD prevention among HIV patients without significant symptoms or traditional risk factors. If this proves true, it will change practice and save lives. Of note, REPRIEVE will collect information on non-CVD events, including HIV events, cancer, diabetes and liver and kidney disease. In addition, the study will collect critical safety information as to the tolerability of statins in the HIV group. Pitavastatin will be utilized to minimize any effects on glucose and the need for dose alterations. Importantly, REPRIEVE will include a mechanistic substudy to assess effects on coronary plaque and detailed markers of immune activation. REPRIEVE will enroll 6,500 participants from approximately 100 sites, and will utilize the AIDS Clinical Trials Group network as well as other NIAID network sites (see www.REPRIEVEtrial.org for more information).

Acknowledgements: Janet Lo, MD; Markella V. Zanni, MD; Kathleen V. Fitch, BSN, NP; and Chloe O. Zimmerman, BA.

References:

Lo J, et al. AIDS. 2010;doi:10.1097/QAD.0b013e328333ea9e.
Lo J, et al. Lancet HIV. 2015;doi:10.1016/S2352-3018(14)00032-0.
McComsey GA, et al. Oral abstract 134. Presented at: Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston.
Ridker PM, et al. N Engl J Med. 2008;doi:10.1056/NEJMoa0807646.
Triant VA, et al. J Clin Endocrinol Metab. 2007;doi:10.1210/jc.2006-2190.

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Steven K. Grinspoon, MD, is a professor of medicine, Harvard Medical School and director of Massachusetts General Hospital’s Program in Nutritional Metabolism.

Disclosure: Grinspoon reports receiving research support through his institution from Kowa Pharmaceuticals relevant to this article.