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Suboptimal cART Adherence is Associated with
Higher Levels of Inflammation Despite HIV Suppression
 
 
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"Summary: We observed higher serum levels of biomarkers of inflammation and immune activation in HIV-infected individuals who reported less than 100% antiretroviral adherence, even though they were virally suppressed (<50 HIV RNA copies/mL) at the time of biomarker measurement. .....cART adherence variations could have significant biological consequences despite apparent HIV suppression, since persistent inflammation and immune activation are associated with increased morbidity and mortality among HIV-infected persons ......The state of persistent inflammation and immune activation has been linked to the development of non-AIDS adverse events including cardiovascular disease (CVD), end-stage renal disease, cognitive decline, frailty and cancer
 
In this study, we identified a positive association between suboptimal cART adherence and higher levels of inflammation among HIV RNA-suppressed, HIV-infected men receiving cART. We initially found that <100% adherence was associated with higher levels of TNF-α, IFN-γ, CRP, IL-2, IL-6, and IL- 10. Further analysis revealed that these associations were largely driven by adherence levels below 85%.
 
Imperfect adherence was associated with higher concentrations of 21 out of the 24 biomarkers, and significantly associated with higher concentrations of CRP (21%, p=0.006), IFN-γ (15%, p=0.008), IL-2 (14%, p=0.022), IL-6 (12%, p=0.014), TNF-a (11%, p<0.001), and IL-10 (11%, p=0.023) relative to 100% adherence (Figure 1, Supplementary Table 2). After adjustment for multiple comparisons, <100% adherence was significantly associated with higher concentrations of TNF-alfa.
 
Adherence between 85% and 99% was not significantly associated with concentrations of any biomarker relative to 100% adherence, with the exception of TNF-a (10% increase, p=0.019). By contrast, adherence below 85% was significantly associated with higher concentrations of six biomarkers relative to 100% adherence (same biomarkers found in the 6-month analysis): CRP (22%, p=0.019), IL-2 (20%, p=0.011), IFN-γ (17%, p=0.012), IL-6 (16%, p=0.010), IL-10 (13%, p=0.035), and TNF-a (10%,
 
Systemic ART exposure is directly related to host factors including age, gender, weight, diet, genetics and drug-drug interactions; however, the dominant factor impacting long-term drug exposure is adherence .....adherence remains the main predictor of HIV outcomes among cART-treated persons
 
Initiation of cART and achievement of viral suppression has been associated with reductions in systemic inflammation and immune activation in HIV-infected individuals [5-7]. However, cART-induced viral suppression does not reduce inflammation to levels observed in HIV-uninfected persons, even in the setting of sustained viral suppression
 
The state of persistent inflammation and immune activation has been linked to the development of non-AIDS adverse events including cardiovascular disease (CVD), end-stage renal disease, cognitive decline, frailty and cancer “
 
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Suboptimal cART Adherence is Associated with Higher Levels of Inflammation Despite HIV Suppression
 
Clinical Infectious Diseases Advance Access published September 22, 2016
 
Jose R. Castillo-Mancilla1, Todd T. Brown2, Kristine M. Erlandson1, Frank J. Palella Jr.3, Edward M. Gardner1, Bernard J.C. Macatangay4, Elizabeth C. Breen5, Lisa P. Jacobson6, Peter L. Anderson7, Nikolas I. Wada
 
1Division of Infectious Diseases, School of Medicine, University of Colorado-AMC, Aurora, Colorado 2Division of Endocrinology, Diabetes & Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland 3Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois 4Division of Infectious Diseases/HIV/AIDS Unit, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 5Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California 6Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 7Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-AMC
 
Abstract
 
Background.
HIV-infected individuals exhibit residual inflammation regardless of virologic suppression. We evaluated whether suboptimal adherence to combination antiretroviral therapy (cART) is associated with greater residual inflammation compared to optimal adherence despite virologic suppression.
 
Methods. Longitudinal self-reported cART adherence data and serum concentrations of 24 biomarkers of inflammation and immune activation were measured at the same study visit in HIV RNA-suppressed (<50 copies/mL) HIV-infected men in the Multicenter AIDS Cohort Study from 1998 to 2009. Associations between dichotomized 6-month (<100% vs. 100%) and categorized 4-day (<85%, 85-99% and 100%) cART adherence with biomarker concentrations were evaluated.
 
Results. A total of 912 men provided 2816 person-visits with documented plasma HIV RNA suppression. In adjusted models, person-visits at which <100% cART 6-month adherence was reported had higher concentrations of interleukin (IL)-2, IL-6, IL-10, interferon-γ, tumor necrosis factor-α (TNF-α) and C-reactive protein compared to person-visits at which 100% cART adherence (p<0.05) was reported. These same differences were observed in person-visits reporting <85% vs. 100% 4-day cART adherence, but not in visits reporting 85-99% vs. 100% cART adherence. After adjusting for multiple comparisons, TNF-α remained significantly higher (11%, p<0.001) in person-visits at which <100% adherence was reported.
 
Conclusions. Higher concentrations of inflammatory biomarkers were observed among HIV RNA-suppressed men who reported <100% cART adherence compared to more adherent men. Residual HIV replication (i.e., below the limit of detection), more likely among men with suboptimal adherence, is a plausible mechanism. Whether improving cART adherence could impact residual inflammation and associated morbidity and mortality should be investigated.
 
Imperfect (<100%) and 100% 6-month adherence were reported in 362 (13%) and 2454 (87%) person-visits, respectively. Based on the 4-day adherence only, 100% adherence was reported in 2491 person-visits (88%), 85-99% adherence was reported in 112 person-visits (4%), and <85% adherence was reported in 213 person-visits (8%). Discordant adherence across ART drug types was reported in 180 (6%) person-visits (lowest level utilized). Distributions of biomarker concentrations are reported in Supplementary Table 1. Eight biomarkers had ≥1% of measurements below the LLD at the time of study visit. The proportions of LLD measurements in these biomarkers were: IL-1β (43%), IFN-γ (42%), GM-CSF (38%), IL-2 (28%), IL- 12p70 (13%), CRP (4%), IL-10 (2%), and IL-6 (1%).
 
Figure 1. Percent shifts in distribution of biomarker concentrations associated with <100% 6-month cART adherence, compared to 100% adherence.

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