Suboptimal Adherence to Combination Antiretroviral Therapy Is Associated With Higher Levels of Inflammation Despite HIV Suppression

Abstract

Background: Human immunodeficiency virus (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 than 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 2, 6, and 10, interferon γ, tumor necrosis factor α, and C-reactive protein than person-visits at which 100% cART adherence (P < .05) was reported. These same differences were observed in person-visits reporting <85% versus 100% 4-day cART adherence, but not in visits reporting 85%-99% versus 100% cART adherence. After adjustment for multiple comparisons, tumor necrosis factor α remained significantly higher (11% increase; P < .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 than among more adherent men. Residual HIV replication (ie, below the limit of detection), more likely among men with suboptimal adherence, is a plausible mechanism. Whether improving cART adherence could affect residual inflammation and associated morbidity and mortality rates should be investigated.

Keywords: adherence; antiretroviral therapy; inflammation.

Figure 1.

Percentage shifts in distribution of biomarker concentrations associated with <100% 6-month adherence to combination antiretroviral therapy (cART), compared with 100% adherence. Biomarker data were analyzed at person-visits where human immunodeficiency virus (HIV)–infected men reported taking cART and had plasma HIV RNA levels <50 copies/mL. Generalized gamma models were adjusted for age, race, hepatitis C virus infection, smoking, depressive symptoms, diabetes mellitus, anemia, hypertension, and CD4⁺ T-lymphocyte cell count. Error bars represent 95% confidence intervals; orange squares, hazard ratios that are statistically significant (P <.05); and red square, hazard ratio that is statistically significant after adjustment for multiple tests, using the Benjamini-Hochberg procedure to control the false discovery rate at 5% [26]. Abbreviations: BAFF, B-cell activating factor; CCL, chemokine CC motif ligand; CRP, C-reactive protein; CXCL, chemokine CXC motif ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL-1β, interleukin 1β; IL-2, interleukin 2; IL-6, interleukin 6; IL-8, interleukin 8; IL-10, interleukin 10; IL-12p70, interleukin 12p70; sCD14, soluble CD14; sCD27, soluble CD27; sGP130, soluble glycoprotein 130; sIL-2Rα, soluble IL-2 receptor α; sIL-6R, soluble IL-6 receptor; sTNF-R2, soluble tumor necrosis factor receptor 2; TNF-α, tumor necrosis factor α.

Figure 2.

Percentage shifts in distribution of biomarker concentrations associated with 85%–99% and <85% 4-day adherence to combination antiretroviral therapy (cART), compared with 100% adherence. Biomarker data were analyzed at person-visits where human immunodeficiency virus (HIV)–infected men reported taking cART and had plasma HIV RNA levels <50 copies/mL. Generalized gamma models were adjusted for age, race, hepatitis C virus infection, smoking, depressive symptoms, diabetes mellitus, anemia, hypertension, and CD4⁺ T-lymphocyte cell count. Error bars represent 95% confidence intervals; squares and triangles, <85% and 85%–99% 4-day adherence, respectively; orange symbols, hazard ratios that are statistically significant (P <.05); and red symbol, hazard ratio that is statistically significant after adjustment for multiple tests, using the Benjamini-Hochberg procedure to control the false discovery rate at 5% [26]. Abbreviations: BAFF, B-cell activating factor; CCL, chemokine CC motif ligand; CRP, C-reactive protein CXCL, chemokine CXC motif ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL-1β, interleukin 1β; IL-2, interleukin 2; IL-6, interleukin 6; IL-8, interleukin 8; IL-10, interleukin 10; IL-12p70, interleukin 12p70; sCD14, soluble CD14; sCD27, soluble CD27; sGP130, soluble glycoprotein 130; sIL-2Rα, soluble IL-2 receptor α; sIL-6R, soluble IL-6 receptor; sTNF-R2, soluble tumor necrosis factor receptor 2; TNF-α, tumor necrosis factor α.