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03/06/2014

Inflammation and Comorbidities of HIV: CROI 2014


Cardiovascular disease:
In the general population, certain angiographic features have been identified as correlates of increased risk of coronary plaque rupture, leading to acute coronary syndrome, MI and sudden coronary death. Last year at CROI, HIV-infected individuals were shown by CT angiography (CTA) to have more high-risk plaque morphologies than HIV-negative individuals, including positively remodeled plaque (PRP) and low-attenuation plaque (LAP). This year, Tawakol et al [1] presented a follow-up study correlating CTA plaque morphology with arterial inflammation measured by aortic 18fluorodeoxyglucose (FDG) PET scanning. Previous studies have shown that FDG is avidly taken up by metabolically active cells, including activated macrophages, and FDG uptake correlates with pathologically proven inflammation in the aorta. Aortic inflammation is used as a surrogate for coronary inflammation because FDG PET technology cannot yet directly assess coronary inflammation. Forty-one HIV-infected individuals on stable suppressive ART with subclinical coronary artery plaque by CTA underwent aortic FDG PET. CTA features were then compared among those with measurements above and below the median on FDG PET. Compared to the low uptake group, significantly more individuals in the high uptake group had at least one LAP or at least one plaque with 2 features. There was a trend to more PRP in the high reading group that did not quite achieve statistical significance. In a multivariable analysis FDG PET reading and duration of HIV infection were independently associated with the presence of LAP.

The association between coronary artery abnormalities and inflammatory markers was reported in a cross-sectional study of 139 HIV-positive patients controlled on ART and 92 HIV-negative participants from the MACS cohort [2]. Higher levels of CD8 T-cell activation (CD38+/HLA-DR+) and monocyte activation (sCD14, sCD163) were present in the HIV-positive group. No significant difference in coronary artery abnormalities as assessed by CT angiography were found, although HIV-positives tended to have more non-calcified plaque and more stenoses of >50%. In an analysis adjusted for age, race and traditional CVD risk factors, both CD8 activation and sCD163 (but not sCD14) levels correlated with the presence of various types of coronary artery abnormalities among HIV-positive subjects only. No correlations were found in the HIV-negative group.



Diabetes (DM):

Elevated markers of chronic inflammation are associated with risk of DM in the general population. Betene et al [3] used data from the control arms of the ESPIRIT and SMART studies (n=3,965) to study the association between IL-6 and hsCRP levels and incident DM in HIV-infected patients on ART. Increasing baseline levels of both markers were associated with increasing risk of incident DM. In an analysis adjusted for multiple covariates, each doubling of IL-6 and hsCRP conferred a 30% and 24% increase in DM risk, respectively. Comparison to studies of these markers in the general population suggested the associated risk was similar or perhaps greater in HIV.



Lung Disease:

COPD is another co-morbidity common in HIV, largely because of increased rates of smoking. Other factors such as immune deficiency may contribute to the severity of COPD in HIV. The role of chronic inflammation is unknown. Crothers et al [4] analyzed lung function longitudinally in 168 HIV-infected and 147 HIV-uninfected patients with COPD in the VA Cohort Study. The two groups were matched for current smoking status. IL-6, d-dimer and sCD14 were measured at baseline. FEV1 was similar at baseline but the rate of decline was faster among HIV-infected than HIV-uninfected participants (-100 ml/year vs -68 ml/year; p=0.03). Among the HIV-infected group, after adjustment for differences in age, smoking pack-years and BMI, elevations of all 3 inflammatory markers were associated with lower FEV1 at baseline and higher sCD14 was associated with more rapid decline in FEV1. These associations with inflammatory markers were not seen in the HIV-uninfected group. The findings of this study suggest COPD in HIV may have a unique pathogenesis with chronic inflammation contributing to the severity and rate of progression.



Fraility:

Another important correlate of chronic inflammation is frailty, a syndrome defined by the presence of 3 of 5 of the following features: weight loss, low physical activity, exhaustion, low grip strength and slow gait. The correlation between frailty and inflammatory markers was assessed in the ALIVE cohort, comprised of current or former injection drug users in Baltimore, 29% of whom are HIV-infected [5]. After adjustment for other factors, elevated levels of IL-6, sTNFRI and HIV-infection were significantly associated with frailty (adjusted OR 1.79,1.34,1.56, respectively). Other factors associated with frailty included, age, low education status, prescription drug abuse, being unmarried, multiple co-morbid conditions and depression. After adjustment for multiple other risk factors, including frailty, an inflammatory index score derived from IL-6 and sTNFRI was strongly correlated with mortality in both HIV-positive and HIV-negative cohort participants.



Summary:

Chronic inflammation is a major driver of many non-AIDS co-morbidities in individuals with HIV-infected treated with ART, including cardiovascular disease, diabetes, COPD and fraility. While systemic inflammation is also important in the general population, the pathogenesis of these illnesses may be more dependent on inflammatory processes in HIV.



References:
1. Tawakol A, Zanni MV, Lo J, et al. Increased Arterial Inflammation Relates to High-Risk Coronary Plaque Morphology in HIV+ Patients. Abstract 130. CROI 2014, Boston, MA, March 3-6, 2014.
2. Daar ES, Post WS, Darilay AT, et al. Monocyte But Not Cellular Activation Is Associated With Coronary Atherosclerosis in the MACS. Abstract 730. CROI 2014, Boston, MA, March 3-6, 2014.
3. Béténé C, Dooko A, Neuhaus J, et al. IL-6, hsCRP, and the Development of Type 2 Diabetes Among HIV Positive Patients Taking ART. Abstract 768. CROI 2014, Boston, MA, March 3-6, 2014.
4. Crothers K, Rodriguez CV, Wongrakool C, et al. Association of HIV Infection and Immune Activation With Decline in Lung Function. Abstract 774. CROI 2014, Boston, MA, March 3-6, 2014.
5. Piggot DA, Varadhan R, Mehta SH, et al. Frailty, Inflammation and Mortality Among Aging HIV-Infected and At-Risk Injection Drug Users. Abstract 762. CROI 2014, Boston, MA, March 3-6, 2014.


Source: Reporting from Boston for PRN News: David H Shepp, MD