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Inflammation and HIV at CROI 2013:
Focus on the Monocyte/Macrophage Axis and Innate Immunity
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David H. Shepp, MD
Associate Professor of Medicine
Hofstra North Shore-LIJ School of Medicine
North Shore University Hospital - Manhasset, NY
Untreated HIV induces a state of immune activation and chronic inflammation that is directly involved in AIDS pathogenesis. T-cell depletion and cellular immune dysfunction, the hallmark features of AIDS, result more from T-cell exhaustion and apoptosis than from direct viral cytopathic effects. Early studies focused on markers of T-cell activation and demonstrated a strong correlation with progression to AIDS and death. However, inflammation results from activation of both the adaptive and innate immune systems. In the general population, inflammation also contributes to the pathogenesis of many chronic medical illnesses, including cardiovascular and cerebrovascular disease (CVD), diabetes, chronic kidney disease, osteoporosis and cancer. These same illnesses, termed non-AIDS comorbidities (NACoMs) now account for most morbidity and mortality in people with HIV receiving virologically suppressive antiretroviral therapy (ART). Soluble plasma markers of innate immune activation correlate strongly with subsequent risk of NACoMs and death. More recent studies suggest activation of innate immunity may be more important than T-cell activation in predicting clinical events in ART-treated patients. At CROI 2013, new studies were presented that consolidate that view and highlight the importance of activation of the monocyte/macrophage axis in cardiovascular disease pathogenesis and all-cause mortality. Further gains in health and life expectancy in HIV-infected individuals with good virologic suppression on ART may require new treatments to control residual immune activation. Reports of possible treatments to reduce immune activation also appeared at this year's CROI.
Monocyte/Macrophage Activation in CVD and other NACoMs. Baker et al. studied coronary artery calcium (CAC) progression in participants in the SUN study, a prospective HIV-natural history cohort composed largely of patients responding well to contemporary ART [1]. Four-hundred thirty-six individuals had CAC scores assessed by CT scanning at baseline and two years later. Cellular markers of monocyte and T-cell activation also were measured. The prevalence of traditional cardiovascular disease (CVD) risk factors was fairly low except for cigarette smoking. Incident CAC or significant worsening of baseline CAC occurred in 55 individuals. In a multivariable analysis adjusting for multiple HIV-related characteristics and CVD risk factors, baseline monocyte expression of CD16, (with or without CD14, referred to as intermediate and non-classic monocyte phenotypes) were independently associated with CAC progression at two years. No correlation was seen with expression of the activation markers HLA-DR and CD38 or the senescence marker CD57 on either CD4 or CD8 T-cells.
Coronary heart disease in HIV-infected individuals may have more high-risk anatomic features and pathogenesis may be driven by monocyte activation, as suggested in an abstract presented by Zanni et al. [2]. In the general population, several angiographic features have been identified as correlates of increased risk of plaque rupture, leading to acute coronary syndrome, MI and sudden coronary death. Eccentric remodeling of the artery wall, low-attenuation plaque (LAP) and spotty microcalcification identify vulnerable plaque that is at increased risk for rupture. Using CT angiography, these investigators looked for vulnerable plaque features in 106 HIV-positive men, predominantly on ART, and 41 matched HIV-negative controls. None had known coronary heart disease. They found vulnerable plaque features (LAP and eccentric remodeling, but not microcalcification) were more common in HIV-positives. Vulnerable plaque with all 3 features were seen in 8% of HIV-positives and no controls. In univariate analysis, the presence of LAP correlated with both traditional CVD risk factors and inflammatory markers, but only plasma levels of soluble CD163, a marker of monocyte activation, remained independently associated with LAP in multivariate analysis. Similar data was described in women in a late-breaker poster [3]. This study suggests that CVD in HIV-positive individuals may be a more aggressive disease with more features that lead to serious events, and that systemic inflammation, particularly involving innate immunity and the monocyte/macrophage axis is central to the pathogenesis.
A third study also highlighted the importance of elevated levels of soluble markers of innate immune activation. Tenorio et al. analyzed the ACTG cohort of ART trials participants in long-term follow-up to determine the relationship between soluble plasma markers of inflammation, cellular markers of T-cell activation and clinical events, defined here as MI, stroke, serious non-AIDS bacterial infections and non-accidental death [4]. Cases (n=143) who experienced an event were matched to 315 controls who did not. In multivariable analysis adjusted for multiple potential confounding characteristics, levels of IL-6, soluble TNF receptors I & II, soluble CD14 ( sCD14, a marker of monocyte activation) were significantly associated with clinical events, while markers of T-cell activation and senescence were not. This relationship was found at baseline (pre-ART) but also held at one year after initiating ART and in a time-updated analysis that used the last pre-event value. Although markers of T-cell activation were not correlated with clinical events, CD4+ T-cell immune reconstitution was. Compared to controls, cases had poorer CD4+ reconstitution and every 100 cell/uL increase in CD4 conferred a 19% reduction in risk of clinical events.
Using Inflammatory Markers to Predict Risk. Previous studies have shown IL-6 and d-dimer levels to be among the most powerful predictors of future occurrence of NACoMs and death. Baseline levels correlate with risk as much as 5 years later. Grund et al. combined data on baseline levels of these markers from 3 large clinical outcome trials (SMART, ESPRIT, SILCAAT) to develop a prediction equation using both that was more strongly correlated with clinical events and deaths [5]. The authors proposed this equation could be used in clinical trials design to estimate the impact of candidate interventions to reduce chronic inflammation and potentially could serve as a surrogate marker for clinical outcomes, although prospective validation of this concept would be required.
Interventions to Reduce Chronic Inflammation. Statins are effective for primary and secondary CVD prevention in the general population, but their effectiveness in HIV is not certain. Statins are an attractive option in HIV because, in addition to cholesterol-lowering properties, they have anti-inflammatory effects that may further reduce CVD, other NACoMs and all cause mortality. A previously published cohort analysis identified a significant survival benefit for HIV-infected statin users who were virologically controlled on ART. Two abstracts at CROI 2013 further examined the benefits of statin use in HIV. Using a national registry, Rasmussen et al. examined all-cause mortality among all HIV-positive individuals in Denmark, comparing statin users and non-statin users [6]. In a multivariable model adjusted for multiple HIV-related parameters know to affect survival, the presence of certain co-morbidities and censored for failure of viral suppression, these investigators found a trend toward reduced mortality in statin users that did not achieve statistical significance. Due to size, this study may have lacked statistical power to detect an effect. A much larger study from the VACS found, surprisingly, that statin use was significantly associated with a reduced risk of cancer, but not CVD or all-cause mortality [7]. An analysis limited to users of only the potent statins atorvastatin and rosuvastatin suggested greater reductions in cancer, CVD and mortality, but again achieved statistical significance only for cancer. These two studies tend to support a favorable effect of statin, but like other cohort studies, are limited by possible confounding of unmeasured risk factors and by indication for statin use. The results of randomized trials would help clarify the benefits of statins in HIV.
Preliminary results of a randomized, controlled trial of the anti-inflammatory effects of statin therapy were reported in a late breaker poster [8]. One hundred forty seven patients receiving ART with good virologic control, without hypercholesterolemia (LDL <130) and either baseline evidence of T-cell activation (CD8+/HLA-DR+/CD38+ >19%) or hsCRP ≥2 mg/L were randomized to rosuvastatin 10 mg daily or placebo. At 24 weeks, three markers indicative of monocyte/macrophage activation, sCD14, LP-PLA2 and CD14dim/CD16+ monocytes were significantly reduced in the rosuvastatin arm. Markers of CD4+ and CD8+ T-cell activation and various other soluble markers of inflammation and coagulation were not affected. This encouraging result suggests statins may in have anti-inflammatory effects on the monocyte/macrophage axis which is emerging as the most powerful indicator of risk for CVD and other NACoMs. Correlation with clinical outcome is needed.
Aspirin is also effective in both primary and secondary CVD prevention in the general population. Like statins, aspirin has multiple modes of action, working as both an anti-platelet agent and an anti-inflammatory. Little is know about aspirin use or its efficacy in HIV-infected individuals. Suchindran et al. investigated non-episodic aspirin use in a large database of HIV-positive and HIV-negative individuals receiving care from a large academic health system in Boston [9]. Aspirin was utilized less in HIV-positive men, but not women. The difference became greater among those with two or more CVD risk factors, where aspirin was used about twice as often in HIV-negative men and women. After adjustment for conventional risk factors, MI rates were significantly reduced among HIV-negative aspirin users, but there did not appear to be any beneficial effect among HIV-positive men or women at low or high risk for CVD. This study, like other cohort studies, is limited by possible confounding, but it is provocative and shows it cannot be assumed that inventions that work in the general population will be effective in HIV. CVD may behave differently in HIV-infected populations, due in part to different pathogenesis. Randomized trials of aspirin therapy in HIV, or greater inclusion of HIV-infected patients in CVD prevention trials in the general population are needed.
Using an animal model of AIDS, Walker et al. explored the ability of an investigational compound PA 300 to inhibit activated macrophages in the heart [10]. CD8+ T-cell depleted, SIV-infected rhesus macaques, develop a rapidly progressive AIDS-like illness with high rates of encephalitis and myocarditis, both conditions characterized CD163+ macrophages infiltrating the target tissues. PA 300 is an orally bioavailable form of the anti-tumor agent MGBG which inhibits polyamine synthesis. Polyamine compounds are necessary for the activation and trafficking of macrophages to tissues. PA 300 treated SIV-infected animals showed a dose-related decrease in CD163+ macrophages in cardiac tissue. Functional and histologic improvement were not demonstrated, and it is unclear if this animal model is relevant to human HIV infection, or if PA 300 would be safe for human trials. Further studies are needed.
Adjunctive therapies to reduce inflammation in patients receiving ART would be welcome if they decrease the risk of NACoMs, but would give up some of the recent gains made in ART regimen simplification. Antiretrovirals (ARVs) with useful immunomodulatory properties could get around this problem. Cenicriviroc (CVC) is an antiretroviral that blocks CCR5 to inhibit HIV entry, but also blocks CCR-2, an important receptor on the surface of monocytes that mediates activation. Gathe et al. reported interim 24 week data from a phase 2, randomized, double-blind, double dummy study comparing cenicriviroc 100 mg or 200 mg once daily to efavirenz (EFV), both given with tenofovir DF and emtricitabine [11]. The study enrolled 143 treatment-naive participants with HIV that was sensitive to all study drugs. Both doses of CVC and EFV produced similar rates of suppression of HIV RNA to <50 copies/mL (71-76%) although the study was not powered to demonstrate non-inferiority. The CVC arms tended to have more viral failures and the EFV arm more discontinuations for adverse events, but overall efficacy may have been hampered by use of a cumbersome early phase formulation of CVC and the double-dummy design, leading to a high pill burden. Levels of MCP-1, a ligand for CCR-2 increased in those receiving CVC, suggesting CCR-2 blockade was occurring, but were unchanged with EFV. Soluble CD14, a macrophage activation marker that is another strong correlate of mortality in HIV-infected populations declined, while it rose slightly in the EFV arm. Although this study was not powered to generate robust results, it does suggest there may differences in anti-inflammatory effects among antiretroviral agents. Further studies to better define these effects is warranted.
CROI: Week 24 Primary Analysis of Cenicriviroc vs Efavirenz, in Combination with FTC/TDF, in Treatment-naïve HIV-1 Infected Adults with CCR5-tropic virus - (03/08/13)
CROI: CCR5/CCR2 Antagonist Cenicriviroc: 24-Week Data vs Efavirenz in ART-Naive - written by Mark Mascolini - (03/08/13)
ART has been shown to reduce to a varying degree the elevated levels of immune activation and inflammation markers present in HIV-infected individuals. However little is known about the relative anti-inflammatory effects of commonly used ARVs. A previously published study suggested switching from a ritonavir-boosted HIV protease inhibitor to raltegravir resulted in greater improvement in inflammatory marker than did remaining on a protease inhibitor (PI). Lake et al. reported changes in inflammatory markers in a small trial that randomized women with central adiposity to switch from either a PI or NNRTI to raltegravir or remain on their baseline regimen [12]. After 24 weeks, sCD14 decreased in women switching to raltegravir while those remaining their baseline regimen had no change. Significant changes were not seen in sCD163 or in I-FABP, a marker of intestinal integrity and microbial translocation. This is the second study to suggest raltegravir may have a more favorable effect on inflammatory markers than certain other ARVs. Further confirmation of this potential effect is needed.
Two small pilot studies exploring anti-inflammatory interventions reported negative results. Twenty-four weeks of chloroquine given as adjunctive therapy to patients on suppressive ART failed to produce any reductions in a large number of cellular and soluble markers of inflammation [13]. This result contrasts the favorable changes in inflammatory markers previously reported in patients on suppressive ART receiving the related drug hydroxychloroquine. In a randomized, double-blinded placebo-controlled trial of the purported TNF-alpha inhibitor pentoxyfylline given for 8 weeks to patients not receiving ART, there was no improvement in arterial flow-mediated dilation, cellular activation markers, or any of a panel of soluble inflammatory and endothelial function markers [14].
References
1. Baker J, Huppler Hullsiek K, Singh A, et al. Monocyte Activation, but Not T Cell Activation, Predicts Progression of Coronary Artery Calcium in a Contemporary HIV Cohort. Abstract 66LB, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts/47865.htm
2. Zanni M, Lo J, Wai B, Shah B, et al. Increased Coronary Atherosclerotic Plaque Vulnerability Features on Computed Tomography Angiography among HIV+ Subjects vs Matched HIV- Controls. Abstract 63, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts/47634.htm
3. Fitch K, Abbara S, Burdo T, et al. Non-Calcified Coronary Plaque and Macrophage Activation Markers Are Increased in HIV+ Women. Abstract 185LB, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts8888/48048.htm
4. Tenorio A, Zheng E, Bosch R, et al. Soluble Markers of Inflammation and Coagulation, but Not T Cell Activation, Predict Non-AIDS-defining Events during Suppressive ART. Abstract 790, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts/47174.htm
5. Grund B, Baker J, Deeks S, et al. Combined Effect of Interleukin-6 and D-dimer on the Risk of Serious Non-AIDS Conditions: Data from 3 Prospective Cohorts. Abstract 60, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts/47309.htm
6. Rasmussen L, Kronborg G, Larsen C, et al. Statin Therapy and Mortality in HIV+ Individuals: A Danish Nationwide Population-based Cohort Study. Abstract 764, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/PDFs/764.pdf
7. Drechsler H, Zhang S, Maalouf N, et al. Impact of Statin Exposure on Mortality and Non-AIDS Complications in HIV Patients on HAART. Abstract 765, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/PDFs/765.pdf
8. McComsey G, Jiang Y, Debanne S, et al. Effect of Statins on Immune Activation and Inflammation in HIV+ Subjects on ART: A Randomized Placebo Controlled Trial. Abstract 186LB, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts8888/48072.htm
9. Suchindran S, Regan S, Meigs J, et al. Comparison of Aspirin Use and Incident Myocardial Infarction Rates in HIV+ and HIV- Patients in a Large US Healthcare System. Abstract 65, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts/45699.htm
10. Walker J, Burdo T, Miller A, et al. Elevated Numbers of CD163+ Macrophages in Hearts of SIV+ Rhesus Macaques with Cardiac Disease Are Decreased Using PA300. Abstract 64, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts/47395.htm
11. Gathe J, Cade J, DeJesus E, et al. Week-24 Primary Analysis of Cenicriviroc vs Efavirenz, in Combination with Emtricitabine/Tenofovir, in Treatment-naïve HIV-1+ Adults with CCR5-tropic Virus. Abstract 106LB, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts/48023.htm
12. Lake J, McComsey G, Hulgan T, et al. Soluble CD14 Declines in Virologically Suppressed Women Switching from Protease Inhibitor or NNRTI to Raltegravir: The Women, Integrase, and Fat Accumulation Trial. Abstract 794, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts/46835.htm
13. Jenabian M-A, Patel M, Kanagaratham C, et al. Evaluation of Chloroquine Administration on CD4 Recovery and Immune Activation in HIV+ Subjects Receiving ART. Abstract 565, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts8888/46089.htm
14. Gupta S, Mi D, Dube M, et al. Pentoxifylline neither Reduces Systemic Inflammation nor Improves Endothelial Function in HIV+ Persons Not Receiving ART. Abstract 565, 20th CROI, Atlanta, GA, March 3-6, 2013; http://www.retroconference.org/2013b/Abstracts/45579.htm
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