Incomplete ART adherence is associated with higher inflammation in individuals who achieved virologic suppression in the START study

Abstract

Introduction Suboptimal ART adherence, despite HIV viral suppression, has been associated with chronic residual inflammation. Whether this association extends to individuals who initiate ART during early HIV infection remains unknown, which was the objective of this study. Methods Plasma levels of interleukin‐6 (IL‐6), high‐sensitivity C‐reactive protein, serum amyloid A protein (SAA), IL‐27, soluble intercellular adhesion molecule‐1, soluble vascular adhesion molecule‐1, D‐dimer and the CD4+/CD8+ T‐cell ratio, were analysed at baseline and eight months after ART initiation in treatment‐naïve participants with HIV and CD4+ T‐cells >500 cells/mm 3 enrolled in the immediate arm of START. Adherence was assessed by seven‐day self‐report. Multivariable linear regression was utilized to analyse the association between ART adherence and each biomarker at the eight‐month visit in participants who achieved virologic suppression (<50 copies/mL). Results We evaluated 1627 participants (422 female) who achieved virologic suppression at the eight‐month visit in the period between 2009 and 2013. Median (IQR) CD4+ T‐cell count before ART was 651 (585, 769) cells/mm 3 . Incomplete adherence was reported in 109 (7%) participants at the eight month visit. After adjusting for covariates, plasma IL‐6 was 1.12 (95% CI, 1.00 to 1.26; p = 0.047) fold higher in participants reporting incomplete versus 100% adherence. A similar association for SAA was observed in an exploratory analysis (1.29 (95% CI 1.04 to 1.60); p = 0.02). No significant differences in other biomarkers were observed. Conclusions Incomplete ART adherence was associated with higher IL‐6 levels in individuals who achieved virologic suppression early after ART initiation in START. A potential similar association for SAA requires confirmation. These findings suggest a role for identifying strategies to maximize ART adherence even during virologic suppression. ClinicalTrials.gov number: NCT00867048.

Association of Incomplete Adherence to Antiretroviral Therapy With Cardiovascular Events and Mortality in Virologically Suppressed Persons With HIV: The Swiss HIV Cohort Study

“…As has been previously proposed [ 4 , 6 , 7 , 46 ], several potential mechanisms could explain our findings. These include intermittent viral replication below the limit of detection in plasma [ 10 , 12 ] or tissue (ie, lymphoid and/or gut tissue) [ 47 ] where drug penetration is suboptimal [ 48 ], resulting in enhanced residual inflammation exacerbated by incomplete adherence.…”

Long-Term Changes of Inflammatory Biomarkers in Individuals on Suppressive Three-Drug or Two-Drug Antiretroviral Regimens

“…In addition, because inflammatory biomarkers change slowly in ART-suppressed individuals ( 16 ), the comparison of ART strategies on inflammation may need long follow-up to detect slight differences between treatment groups. Conceptually, the most likely mechanism by which a suppressive 2DR could yield an increase of plasma inflammatory biomarkers is related to the magnitude of HIV RNA expression and translation in locations where drugs are poorly distributed, mainly lymphoid tissue, which would then trigger the inflammatory response ( 11 – 13 , 15 ). However, no studies have directly assessed this hypothesis.…”

“…Non-virologic parameters associated with excess risk of mortality, such as increased bacterial translocation or inflammation (9,10), are often assumed to be a consequence of the immune damage elicited by acute HIV infection, but no longer affected by HIV replication in individuals on ART. However, even during HIV RNA suppression in PWH, a lower ART adherence to 3-drug regimens (3DR) is associated with increased levels of inflammatory biomarkers, suggesting that a decrease in drug concentrations results in virologic phenomena in tissues, not detected in plasma, that elicit immune activation (11)(12)(13). Mounting evidence generated in SIV-infected macaques, HIVinfected humanized mice, and humans indicates that antiretrovirals are distributed very heterogeneously within lymphoid tissues (14,15).…”

Immunotherapy in People With HIV and Cancer

“…The likelihood of full immune recovery improves with earlier diagnosis and a younger age at ART initiation (26), although immune recovery is often incomplete (27). The heightened pro-inflammatory state associated with both untreated and treated HIV contributes to long-term adverse outcomes (28, 29).…”