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Association of Suboptimal Antiretroviral Therapy Adherence With Inflammation in Virologically Suppressed Individuals Enrolled in the SMART Study

Association of Suboptimal Antiretroviral Therapy Adherence With Inflammation in Virologically... Open Forum Infectious Diseases BRIEF REPORT immune activation, and coagulopathy that, on average, does not Association of Suboptimal revert to the levels observed in their HIV-negative counterparts Antiretroviral Therapy Adherence [1]. This residual inflammation has been associated with the With Inflammation in Virologically development of serious non-AIDS adverse events (SNAEs) such as cardiovascular disease, cancer, and death [2, 3]. To date, the Suppressed Individuals Enrolled in the mechanisms behind this immune dysregulation remain poorly SMART Study understood, which has limited the efforts to identify interven- 1 2 3 Jose R. Castillo-Mancilla, Andrew N. Phillips, James D. Neaton, tions that can successfully reverse it. Thus, it remains imperative 3 4 5 6,7 Jacqueline Neuhaus, Simon Collins, Sharon Mannheimer, Sarah Pett, 8 7 9 to identify new and effective strategies to achieve this goal. Veronique Touzeau-Römer, Mark N. Polizzotto, Jens D. Lundgren, and Edward M. Gardner ; for the INSIGHT SMART Study Group Recently, suboptimal ART adherence has emerged as a poten- 1 2 University of Colorado-AMC, Medicine/Infectious Diseases, Aurora, Colorado; Institute tial contributor to residual inflammation in PLWH, even if it is for Global Health, University College London, London, UK; University of Minnesota, School sufficient to achieve and sustain plasma viral suppression through 4 5 of Public Health, Minneapolis, Minnesota; HIV i-Base, London, UK; Columbia University Medical Center, Harlem Hospital Center, New York, New York; University College London, conventional assays [4, 5]. Cohort-derived data suggest that sub- 7 8 London, UK; Kirby Institute, University of New South Wales, Sydney, Australia; University optimal (ie, less than 100%) adherence is associated with higher of Vienna Medical School, AKH, Division of Immunology, Allergy and Infectious Diseases, levels of residual inflammation, immune activation, and activation Vienna, Austria; CHIP, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark; Denver Health Medical Center, Denver, Colorado of coagulation in PLWH who have virologic suppression while on ART [4, 5]. These observations have emphasized the potential bio- Suboptimal (ie, <100%) antiretroviral therapy (ART) adher- logical differences that could exist between complete and subopti- ence has been associated with heightened inflammation in mal ART adherence in order to maximize the therapeutic benefit cohort studies, even among people with virologic suppression. of ART. Whether these associations can also be identified in a large, We aimed to evaluate this association among participants in the multinational diverse population remains unknown. To evaluate Strategies for Management of Antiretroviral Therapy (SMART) this, we aimed to study the association of ART adherence with study who had virologic suppression (HIV-1 VL < 200 copies/ inflammation and activation of coagulation in virologically sup- mL) at enrollment. Based on self-reported adherence (7-day pressed PLWH on chronic ART who were enrolled in the Strategies recall), plasma concentrations of interleukin 6 and D-dimer were 9% (95% confidence interval [CI], 1%–18%; P  = .02) and for Management of Antiretroviral Therapy (SMART) study. 11% (95% CI, 1%–22%; P  =  .03) higher in participants who METHODS reported suboptimal vs 100% adherence, respectively. These findings confirm previous observations and support the hypoth- Participants esis that suboptimal ART adherence, even in the context of viro- The SMART study (NCT00027352) was a multinational, ran- logic suppression, may have significant biological consequences. domized clinical trial performed in 5472 PLWH (women and ClinicalTrials.gov number NCT00027352 men older than 13 years) between 2002 and 2006; SMART study Keywords. adherence; antiretroviral therapy; inflamma- details and main results were previously published [6]. The trial tion; SMART study. included PLWH who were or were not on ART upon enrollment without restriction according to viral load (VL) [6]. In this ret- While suppressive antiretroviral therapy (ART) has allowed for rospective analysis, we evaluated participants who at enrollment: improved survival in people living with HIV (PLWH), these (1) were on ART, (2) had completed an adherence questionnaire, individuals exhibit a state of chronic residual inflammation, and (3) had an HIV-1 VL measurement available. Given our goal of evaluating the association between adherence and resid- ual inflammation and coagulopathy beyond virologic suppres- Received 13 November 2017; editorial decision 13 December 2017; accepted 19 December sion, we focused our study population to individuals who were virologically suppressed to at least <200 copies/mL (and to <50 Correspondence: J. R. Castillo-Mancilla, MD, Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus. 12700 E 19th Ave., B168, Aurora, copies/mL if this lower threshold was available) and limited our CO 80045 (jose.castillo-mancilla@ucdenver.edu). analysis to the enrollment visit only. All study procedures were Open Forum Infectious Diseases reviewed and approved by the local institutional review boards, © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative and all participants provided written informed consent. Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any Adherence Assessment medium, provided the original work is not altered or transformed in any way, and that the work Adherence was measured (within 45 days of randomization) is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofx275 by participant self-report using the Terry Beirn Community BRIEF REPORT • OFID • 1 Programs for Clinical Research on AIDS (CPCRA) RESULTS Antiretroviral Medication Self-Report Form 065-BAS-2, Study Participants which uses a 7-day global recall in which participants can At the baseline visit, a total of 3963 participants were tak- respond whether they took “all,” “most,” “about one-half,” ing ART and had both a completed adherence questionnaire “very few,” or “none” of their pills for each specific pill in and an HIV-1 RNA VL measurement. Of these, 3056 partici- their ART regimen. This is a validated adherence measure pants (77%) were virologically suppressed to <200 copies/mL that predicted the development of viral rebound in people and were included in the analysis (Supplementary Figure). with viral suppression in the SMART study [7, 8]. Adherence Additional demographic and baseline characteristics of the was labeled “suboptimal” if a participant reported any option study participants are shown in Table 1. other than taking “all of my pills” for at least 1 antiretroviral ART Adherence and Biomarkers of Inflammation and Activation of medication (calculated adherence < 100%), and “100%” if a Coagulation participant reported taking “all of my pills” for all ART med- Of the 3056 virologically suppressed participants analyzed, ications [8]. 404 (13%) reported suboptimal adherence at the baseline Biomarkers of Inflammation and Activation of Coagulation visit (Table  1). The distribution of time between HIV VL Plasma levels of interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer were measured in plasma sam- Table 1. Demographic Characteristics of Study Participants ples collected at enrollment using EDTA tubes (and stored/ shipped frozen) in a subset of the enrolled and randomized Characteristic (n = 3056) No. (%) or Median (IQR) participants, as previously reported [3]. These biomarkers were Demographics measured by the Laboratory for Clinical Biochemistry Research Age, median (IQR), y 44 (38–51) at the University of Vermont. IL-6 was measured by ultrasensi- Women 827 (27%) tive enzyme-linked immunosorbent assay (ELISA; Quantikine Race White 1519 (50%) HS Human IL-6 Immunoassay; R&D Systems), with a lower Black 696 (23%) limit of detection (LLOD) of 0.16 pg/mL. hsCRP was measured Hispanic 570 (19%) using the BNII nephelometer (N High Sensitivity CRP; Siemens Asian 200 (7%) Healthcare Diagnostics), with an LLOD of 0.16 µg/mL. D-dimer Other 71 (2%) was measured using immunoturbidimetric assay (Liatest D-DI; Country of origin Diagnostica Stago), with an LLOD of 0.01 µg/mL, as previously Non-US 1859 (61%) US 1197 (39%) described [3]. HIV exposure group Statistical Analysis MSM 1498 (49%) Participant demographic and baseline cohort characteristics Heterosexual 1156 (38%) IDU 239 (8%) were summarized using the appropriate statistical measures. Other 163 (5%) Adherence was dichotomized as 100% and suboptimal (<100%). BMI, median (IQR), kg/m 24.5 (22.1–27.4) Biomarker plasma concentrations were log-transformed before Smoking (current) 1138 (37%) analysis to address skewing of data. Initially, the relationship HBV infection 69 (2%) between ART adherence and the baseline concentrations of HCV infection 130 (4%) Time since start of ART, y the biomarkers was graphically analyzed using scatterplots. <1 72 (2%) We then utilized univariate and multivariable linear regression 1–5 1082 (35%) analysis to evaluate the association between adherence and >5 1895 (62%) the log-transformed concentrations of biomarkers at baseline, Antiretroviral regimen adjusting for covariates that have previously been associated NNRTI-based 1388 (45%) with biomarkers of inflammation and coagulopathy in SMART PI-based 1164 (38%) Other 504 (16%) and other cohorts [9–13], including age, race, gender, body + 3 Baseline CD4 T-cells, median (IQR), cells/mm 649 (496–842) mass index, time since start of ART, HIV exposure group, base- + 3 Nadir CD4 T-cells, median (IQR), cells/mm 230 (136–329) line viral load, baseline and nadir CD4 T-cells, co-infection HIV VL <50 copies/mL 2371 (78%) with hepatitis B or C, smoking, and ART regimen type based Adherence (7-d) on anchor drug. Data are presented as fold differences (95% CI) 100% adherence 2652 (87%) in biomarker concentrations in participants who were subopti- Suboptimal adherence 404 (13%) mally vs 100% adherent. All statistical analyses were performed Abbreviations: ART, antiretroviral therapy; BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; IDU, injection drug users; IQR, interquartile range; MSM, men who using SAS version 9.4. A  P value  <.05 was considered statisti- have sex with men; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease cally significant. inhibitor. 2 • OFID • BRIEF REPORT measurement and biomarker measurement was (min, percen- Our study reaffirms previous cohort findings in which sub- tiles, and max): min –69 days, 1st –43 days, 5th –36 days, 10th optimal adherence, measured by self-report [4] and Medication –30 days, 25th –16 days, 50th 0 days, 75th 0 days, 90th 0 days, Event Monitoring System [5], was associated with a similar 95th 0 days, and 99th 14 days, max 40 days. IL-6, D-dimer, and degree of increased residual inflammation and coagulopathy, hsCRP baseline biomarker data were available in 2763, 2776, and supporting the hypothesis that ART adherence has signifi- 2793 participants who fulfilled the other criteria, respectively. cant repercussions that extend beyond virologic suppression. The distribution of biomarker concentrations in suboptimally However, our findings are contrary to recent studies in which vs 100% adherent participants who had available biomarker short cycle ART interruptions (4 or 5 days on, 3 or 2 days off ) data at the baseline visit is shown in Table  2. In a univariate maintained viral suppression in PLWH, and where no differ - model, baseline IL-6, D-dimer, and hsCRP were 16% (95% CI, ences in inflammatory biomarkers were identified [14, 15]. 1.06–1.26; P  =  .0005), 17% (95% CI, 1.05–1.29; P  =  .002), and es Th e discrepancies could be due to differences in study pop- 7% (95% CI, 0.94–1.23; P = .31) fold higher in participants who ulations (ie, short cycle studies generally recruited preselected reported suboptimal adherence in comparison with those with participants with long-standing suppression), the small sample who reported 100% adherence, respectively (Table 2). This asso- size, and the nonrandomized nature of most of these studies. ciation remained significant for both IL-6 and D-dimer in an While this therapeutic forgiveness of modern ART has usu- adjusted model, where IL-6 was 9% (95% CI, 1.01–1.18; P = .02) ally been regarded as advantageous in clinical practice, it has and D-dimer was 11% (95% CI, 1.01–1.22; P = .03) higher in sub- de-emphasized the focus on achieving optimal adherence. It has optimally adherent participants (Table  2). Similar results were also allowed permissiveness to missed doses, as long as virologic observed in a sensitivity analysis restricted to participants with suppression is maintained. Further studies to better understand HIV-1 VL <50 copies/mL (n = 2371) (Supplementary Table). the role of this “suppressive adherence gap” on the pathogen- esis of chronic residual inflammation in treated HIV disease DISCUSSION are required, including additional studies evaluating treatment In this analysis, we identified a significant inverse association interruptions and studies focused on long-acting ART. between ART adherence and systemic inflammation and activa- In regards to potential explanatory mechanisms behind tion of coagulation in virologically suppressed (<200 copies/mL) our findings, suboptimal ART adherence could contribute to PLWH at the time of their enrollment in SMART. The magnitude residual inflammation and coagulopathy in a variety of possi- of this association ranged between 9% and 11% higher for levels ble ways, which include (1) residual viral replication below the of IL-6 and D-dimer, respectively, in participants reporting sub- limit of detection of clinically available assays (which may lead optimal vs 100% adherence after adjusting for multiple potential to persistently enhanced inflammation and immune activa- confounders such as smoking, body mass index, baseline and tion) [16, 17], (2) ongoing viral replication at sanctuary sites (ie, nadir CD4 T-cell count, time since start of ART, and drug reg- lymph node), where antiretroviral drug concentrations are low imen. In addition, these findings also remained significant after as a result of limited tissue penetration and/or low adherence restricting our analysis to participants who were suppressed (leading to viral escape and subsequent inflammation) [18], or to <50 copies/mL. To our knowledge, this is the first study to (3) intermittent episodes of viremia that are not captured at the demonstrate an association between adherence to ART and bio- time of viral load assessment in a clinical or research setting markers of inflammation and coagulopathy in a virologically (ie, missed viremia resulting in intermittent bursts of inflam- suppressed diverse international population on chronic ART. mation and immune activation). Given the limited impact that Table 2. Distribution of Biomarker Concentrations in Participants With Available Baseline Data According to Adherence Category and Fold Difference in Available Baseline Inflammatory and Coagulopathy Biomarker Plasma Concentrations in Suboptimally Adherent, Virologically Suppressed PLWH on ART Enrolled in SMART Unadjusted Analysis Adjusted Analysis Suboptimal Fold Higher Level Fold Higher Level 100% Adherence Adherence Compared With Compared With 100% b b Biomarker No. Mean (SD) No. Mean (SD) 100% Adherence 95% CI P Value Adherence 95% CI P Value IL-6, pg/mL 2372 2.60 (6.93) 391 2.93 (4.53) 1.16 1.06–1.26 .0005 1.09 1.01–1.18 .02 2382 0.30 (0.59) 394 0.38 (1.06) 1.17 1.05–1.29 .002 1.11 1.01–1.22 .03 D-dimer, μg/mL hsCRP, μg/mL 2397 3.72 (7.08) 396 4.27 (7.51) 1.07 0.94–1.23 .31 1.04 0.91–1.17 .58 Abbreviations: ART, antiretroviral therapy; CI, confidence interval; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; PLWH, people living with HIV. a + Models were adjusted for covariates including age, race, gender, body mass index, time on ART, HIV exposure group, baseline viral load, baseline and nadir CD4 T-cells, hepatitis B or C co-infection, smoking, and regimen type.  100% adherence defined as no report of any missed doses for any drug in the preceding 7-day period. BRIEF REPORT • OFID • 3 most interventions to date have had in reducing chronic resid- inflammation and activation of coagulation in PLWH on chronic ual inflammation in treated HIV infection, further research to ART. These findings replicate previous cohort observations and understand the pathogenesis of residual inflammation that can highlight the importance of optimal and durable ART adher- lead to new approaches aimed at achieving this goal is needed. ence as a potential factor to improve morbidity and mortality In this context, whether ART adherence optimization could in HIV disease. reduce residual chronic inflammation in individuals who have Supplementary Data achieved virologic suppression, or whether it could have a syn- Supplementary materials are available at Open Forum Infectious Diseases ergistic effect in conjunction with current and future ART strat- online. Consisting of data provided by the authors to benefit the reader, egies, remains unknown and should be evaluated in prospective the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corre- studies. sponding author. While the association between suboptimal adherence and enhanced residual inflammation is novel and provocative, its Acknowledgments clinical translation remains unclear, in particular as it relates We would like to thank the study participants for volunteering to partic- to the development of SNAEs in the virologically suppressed ipate in this study. Prior presentation. es Th e data were partially presented at the 9th IAS population. As chronic residual inflammation has been asso- Conference on HIV Science, July 23–26, 2017, Paris, France, Abstract num- ciated with the development of SNAEs [2, 3], it is plausible ber WEPEB0543. See N Engl J Med 2006; 355:2283–96 for the complete list that suboptimal adherence could also be responsible, at least of SMART investigators. Financial support. This work was supported by National Institute of in part, for the increased morbidity and mortality observed Health grants: U01AI068641, U01AI042170 and U01AI46362 (SMART) in treated PLWH who remain virally suppressed. To answer and K23AI104315 (JCM) and R21AI124859 (JCM). this question, future analyses evaluating the association of Potential coni fl cts of interest. A.P. received speaker fees for 2 presenta- SNAEs with ART adherence in the virally suppressed popula- tions in 2015. The other authors reported no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of tion should be performed in large clinical cohorts. This could Interest. Conflicts that the editors consider relevant to the content of the be coupled with a systematic evaluation of ART adherence in manuscript have been disclosed. current and future studies aimed at reducing chronic resid- References ual inflammation in HIV, and with studies in which persistent 1. Neuhaus J, Jacobs DR Jr, Baker JV, et al. Markers of inflammation, coagulation, inflammation could lead to further evaluation of adherence and renal function are elevated in adults with HIV infection. J Infect Dis 2010; practices. 201:1788–95. 2. Borges ÁH, Silverberg MJ, Wentworth D, et  al; INSIGHT SMART; ESPRIT; e Th main strengths of our study include a large and diverse SILCAAT Study Groups. Predicting risk of cancer during HIV infection: the role population of PLWH obtained within the context of a multina- of inflammatory and coagulation biomarkers. AIDS 2013; 27:1433–41. 3. 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Association of Suboptimal Antiretroviral Therapy Adherence With Inflammation in Virologically Suppressed Individuals Enrolled in the SMART Study

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Abstract

Open Forum Infectious Diseases BRIEF REPORT immune activation, and coagulopathy that, on average, does not Association of Suboptimal revert to the levels observed in their HIV-negative counterparts Antiretroviral Therapy Adherence [1]. This residual inflammation has been associated with the With Inflammation in Virologically development of serious non-AIDS adverse events (SNAEs) such as cardiovascular disease, cancer, and death [2, 3]. To date, the Suppressed Individuals Enrolled in the mechanisms behind this immune dysregulation remain poorly SMART Study understood, which has limited the efforts to identify interven- 1 2 3 Jose R. Castillo-Mancilla, Andrew N. Phillips, James D. Neaton, tions that can successfully reverse it. Thus, it remains imperative 3 4 5 6,7 Jacqueline Neuhaus, Simon Collins, Sharon Mannheimer, Sarah Pett, 8 7 9 to identify new and effective strategies to achieve this goal. Veronique Touzeau-Römer, Mark N. Polizzotto, Jens D. Lundgren, and Edward M. Gardner ; for the INSIGHT SMART Study Group Recently, suboptimal ART adherence has emerged as a poten- 1 2 University of Colorado-AMC, Medicine/Infectious Diseases, Aurora, Colorado; Institute tial contributor to residual inflammation in PLWH, even if it is for Global Health, University College London, London, UK; University of Minnesota, School sufficient to achieve and sustain plasma viral suppression through 4 5 of Public Health, Minneapolis, Minnesota; HIV i-Base, London, UK; Columbia University Medical Center, Harlem Hospital Center, New York, New York; University College London, conventional assays [4, 5]. Cohort-derived data suggest that sub- 7 8 London, UK; Kirby Institute, University of New South Wales, Sydney, Australia; University optimal (ie, less than 100%) adherence is associated with higher of Vienna Medical School, AKH, Division of Immunology, Allergy and Infectious Diseases, levels of residual inflammation, immune activation, and activation Vienna, Austria; CHIP, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark; Denver Health Medical Center, Denver, Colorado of coagulation in PLWH who have virologic suppression while on ART [4, 5]. These observations have emphasized the potential bio- Suboptimal (ie, <100%) antiretroviral therapy (ART) adher- logical differences that could exist between complete and subopti- ence has been associated with heightened inflammation in mal ART adherence in order to maximize the therapeutic benefit cohort studies, even among people with virologic suppression. of ART. Whether these associations can also be identified in a large, We aimed to evaluate this association among participants in the multinational diverse population remains unknown. To evaluate Strategies for Management of Antiretroviral Therapy (SMART) this, we aimed to study the association of ART adherence with study who had virologic suppression (HIV-1 VL < 200 copies/ inflammation and activation of coagulation in virologically sup- mL) at enrollment. Based on self-reported adherence (7-day pressed PLWH on chronic ART who were enrolled in the Strategies recall), plasma concentrations of interleukin 6 and D-dimer were 9% (95% confidence interval [CI], 1%–18%; P  = .02) and for Management of Antiretroviral Therapy (SMART) study. 11% (95% CI, 1%–22%; P  =  .03) higher in participants who METHODS reported suboptimal vs 100% adherence, respectively. These findings confirm previous observations and support the hypoth- Participants esis that suboptimal ART adherence, even in the context of viro- The SMART study (NCT00027352) was a multinational, ran- logic suppression, may have significant biological consequences. domized clinical trial performed in 5472 PLWH (women and ClinicalTrials.gov number NCT00027352 men older than 13 years) between 2002 and 2006; SMART study Keywords. adherence; antiretroviral therapy; inflamma- details and main results were previously published [6]. The trial tion; SMART study. included PLWH who were or were not on ART upon enrollment without restriction according to viral load (VL) [6]. In this ret- While suppressive antiretroviral therapy (ART) has allowed for rospective analysis, we evaluated participants who at enrollment: improved survival in people living with HIV (PLWH), these (1) were on ART, (2) had completed an adherence questionnaire, individuals exhibit a state of chronic residual inflammation, and (3) had an HIV-1 VL measurement available. Given our goal of evaluating the association between adherence and resid- ual inflammation and coagulopathy beyond virologic suppres- Received 13 November 2017; editorial decision 13 December 2017; accepted 19 December sion, we focused our study population to individuals who were virologically suppressed to at least <200 copies/mL (and to <50 Correspondence: J. R. Castillo-Mancilla, MD, Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus. 12700 E 19th Ave., B168, Aurora, copies/mL if this lower threshold was available) and limited our CO 80045 (jose.castillo-mancilla@ucdenver.edu). analysis to the enrollment visit only. All study procedures were Open Forum Infectious Diseases reviewed and approved by the local institutional review boards, © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative and all participants provided written informed consent. Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any Adherence Assessment medium, provided the original work is not altered or transformed in any way, and that the work Adherence was measured (within 45 days of randomization) is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofx275 by participant self-report using the Terry Beirn Community BRIEF REPORT • OFID • 1 Programs for Clinical Research on AIDS (CPCRA) RESULTS Antiretroviral Medication Self-Report Form 065-BAS-2, Study Participants which uses a 7-day global recall in which participants can At the baseline visit, a total of 3963 participants were tak- respond whether they took “all,” “most,” “about one-half,” ing ART and had both a completed adherence questionnaire “very few,” or “none” of their pills for each specific pill in and an HIV-1 RNA VL measurement. Of these, 3056 partici- their ART regimen. This is a validated adherence measure pants (77%) were virologically suppressed to <200 copies/mL that predicted the development of viral rebound in people and were included in the analysis (Supplementary Figure). with viral suppression in the SMART study [7, 8]. Adherence Additional demographic and baseline characteristics of the was labeled “suboptimal” if a participant reported any option study participants are shown in Table 1. other than taking “all of my pills” for at least 1 antiretroviral ART Adherence and Biomarkers of Inflammation and Activation of medication (calculated adherence < 100%), and “100%” if a Coagulation participant reported taking “all of my pills” for all ART med- Of the 3056 virologically suppressed participants analyzed, ications [8]. 404 (13%) reported suboptimal adherence at the baseline Biomarkers of Inflammation and Activation of Coagulation visit (Table  1). The distribution of time between HIV VL Plasma levels of interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer were measured in plasma sam- Table 1. Demographic Characteristics of Study Participants ples collected at enrollment using EDTA tubes (and stored/ shipped frozen) in a subset of the enrolled and randomized Characteristic (n = 3056) No. (%) or Median (IQR) participants, as previously reported [3]. These biomarkers were Demographics measured by the Laboratory for Clinical Biochemistry Research Age, median (IQR), y 44 (38–51) at the University of Vermont. IL-6 was measured by ultrasensi- Women 827 (27%) tive enzyme-linked immunosorbent assay (ELISA; Quantikine Race White 1519 (50%) HS Human IL-6 Immunoassay; R&D Systems), with a lower Black 696 (23%) limit of detection (LLOD) of 0.16 pg/mL. hsCRP was measured Hispanic 570 (19%) using the BNII nephelometer (N High Sensitivity CRP; Siemens Asian 200 (7%) Healthcare Diagnostics), with an LLOD of 0.16 µg/mL. D-dimer Other 71 (2%) was measured using immunoturbidimetric assay (Liatest D-DI; Country of origin Diagnostica Stago), with an LLOD of 0.01 µg/mL, as previously Non-US 1859 (61%) US 1197 (39%) described [3]. HIV exposure group Statistical Analysis MSM 1498 (49%) Participant demographic and baseline cohort characteristics Heterosexual 1156 (38%) IDU 239 (8%) were summarized using the appropriate statistical measures. Other 163 (5%) Adherence was dichotomized as 100% and suboptimal (<100%). BMI, median (IQR), kg/m 24.5 (22.1–27.4) Biomarker plasma concentrations were log-transformed before Smoking (current) 1138 (37%) analysis to address skewing of data. Initially, the relationship HBV infection 69 (2%) between ART adherence and the baseline concentrations of HCV infection 130 (4%) Time since start of ART, y the biomarkers was graphically analyzed using scatterplots. <1 72 (2%) We then utilized univariate and multivariable linear regression 1–5 1082 (35%) analysis to evaluate the association between adherence and >5 1895 (62%) the log-transformed concentrations of biomarkers at baseline, Antiretroviral regimen adjusting for covariates that have previously been associated NNRTI-based 1388 (45%) with biomarkers of inflammation and coagulopathy in SMART PI-based 1164 (38%) Other 504 (16%) and other cohorts [9–13], including age, race, gender, body + 3 Baseline CD4 T-cells, median (IQR), cells/mm 649 (496–842) mass index, time since start of ART, HIV exposure group, base- + 3 Nadir CD4 T-cells, median (IQR), cells/mm 230 (136–329) line viral load, baseline and nadir CD4 T-cells, co-infection HIV VL <50 copies/mL 2371 (78%) with hepatitis B or C, smoking, and ART regimen type based Adherence (7-d) on anchor drug. Data are presented as fold differences (95% CI) 100% adherence 2652 (87%) in biomarker concentrations in participants who were subopti- Suboptimal adherence 404 (13%) mally vs 100% adherent. All statistical analyses were performed Abbreviations: ART, antiretroviral therapy; BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; IDU, injection drug users; IQR, interquartile range; MSM, men who using SAS version 9.4. A  P value  <.05 was considered statisti- have sex with men; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease cally significant. inhibitor. 2 • OFID • BRIEF REPORT measurement and biomarker measurement was (min, percen- Our study reaffirms previous cohort findings in which sub- tiles, and max): min –69 days, 1st –43 days, 5th –36 days, 10th optimal adherence, measured by self-report [4] and Medication –30 days, 25th –16 days, 50th 0 days, 75th 0 days, 90th 0 days, Event Monitoring System [5], was associated with a similar 95th 0 days, and 99th 14 days, max 40 days. IL-6, D-dimer, and degree of increased residual inflammation and coagulopathy, hsCRP baseline biomarker data were available in 2763, 2776, and supporting the hypothesis that ART adherence has signifi- 2793 participants who fulfilled the other criteria, respectively. cant repercussions that extend beyond virologic suppression. The distribution of biomarker concentrations in suboptimally However, our findings are contrary to recent studies in which vs 100% adherent participants who had available biomarker short cycle ART interruptions (4 or 5 days on, 3 or 2 days off ) data at the baseline visit is shown in Table  2. In a univariate maintained viral suppression in PLWH, and where no differ - model, baseline IL-6, D-dimer, and hsCRP were 16% (95% CI, ences in inflammatory biomarkers were identified [14, 15]. 1.06–1.26; P  =  .0005), 17% (95% CI, 1.05–1.29; P  =  .002), and es Th e discrepancies could be due to differences in study pop- 7% (95% CI, 0.94–1.23; P = .31) fold higher in participants who ulations (ie, short cycle studies generally recruited preselected reported suboptimal adherence in comparison with those with participants with long-standing suppression), the small sample who reported 100% adherence, respectively (Table 2). This asso- size, and the nonrandomized nature of most of these studies. ciation remained significant for both IL-6 and D-dimer in an While this therapeutic forgiveness of modern ART has usu- adjusted model, where IL-6 was 9% (95% CI, 1.01–1.18; P = .02) ally been regarded as advantageous in clinical practice, it has and D-dimer was 11% (95% CI, 1.01–1.22; P = .03) higher in sub- de-emphasized the focus on achieving optimal adherence. It has optimally adherent participants (Table  2). Similar results were also allowed permissiveness to missed doses, as long as virologic observed in a sensitivity analysis restricted to participants with suppression is maintained. Further studies to better understand HIV-1 VL <50 copies/mL (n = 2371) (Supplementary Table). the role of this “suppressive adherence gap” on the pathogen- esis of chronic residual inflammation in treated HIV disease DISCUSSION are required, including additional studies evaluating treatment In this analysis, we identified a significant inverse association interruptions and studies focused on long-acting ART. between ART adherence and systemic inflammation and activa- In regards to potential explanatory mechanisms behind tion of coagulation in virologically suppressed (<200 copies/mL) our findings, suboptimal ART adherence could contribute to PLWH at the time of their enrollment in SMART. The magnitude residual inflammation and coagulopathy in a variety of possi- of this association ranged between 9% and 11% higher for levels ble ways, which include (1) residual viral replication below the of IL-6 and D-dimer, respectively, in participants reporting sub- limit of detection of clinically available assays (which may lead optimal vs 100% adherence after adjusting for multiple potential to persistently enhanced inflammation and immune activa- confounders such as smoking, body mass index, baseline and tion) [16, 17], (2) ongoing viral replication at sanctuary sites (ie, nadir CD4 T-cell count, time since start of ART, and drug reg- lymph node), where antiretroviral drug concentrations are low imen. In addition, these findings also remained significant after as a result of limited tissue penetration and/or low adherence restricting our analysis to participants who were suppressed (leading to viral escape and subsequent inflammation) [18], or to <50 copies/mL. To our knowledge, this is the first study to (3) intermittent episodes of viremia that are not captured at the demonstrate an association between adherence to ART and bio- time of viral load assessment in a clinical or research setting markers of inflammation and coagulopathy in a virologically (ie, missed viremia resulting in intermittent bursts of inflam- suppressed diverse international population on chronic ART. mation and immune activation). Given the limited impact that Table 2. Distribution of Biomarker Concentrations in Participants With Available Baseline Data According to Adherence Category and Fold Difference in Available Baseline Inflammatory and Coagulopathy Biomarker Plasma Concentrations in Suboptimally Adherent, Virologically Suppressed PLWH on ART Enrolled in SMART Unadjusted Analysis Adjusted Analysis Suboptimal Fold Higher Level Fold Higher Level 100% Adherence Adherence Compared With Compared With 100% b b Biomarker No. Mean (SD) No. Mean (SD) 100% Adherence 95% CI P Value Adherence 95% CI P Value IL-6, pg/mL 2372 2.60 (6.93) 391 2.93 (4.53) 1.16 1.06–1.26 .0005 1.09 1.01–1.18 .02 2382 0.30 (0.59) 394 0.38 (1.06) 1.17 1.05–1.29 .002 1.11 1.01–1.22 .03 D-dimer, μg/mL hsCRP, μg/mL 2397 3.72 (7.08) 396 4.27 (7.51) 1.07 0.94–1.23 .31 1.04 0.91–1.17 .58 Abbreviations: ART, antiretroviral therapy; CI, confidence interval; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; PLWH, people living with HIV. a + Models were adjusted for covariates including age, race, gender, body mass index, time on ART, HIV exposure group, baseline viral load, baseline and nadir CD4 T-cells, hepatitis B or C co-infection, smoking, and regimen type.  100% adherence defined as no report of any missed doses for any drug in the preceding 7-day period. BRIEF REPORT • OFID • 3 most interventions to date have had in reducing chronic resid- inflammation and activation of coagulation in PLWH on chronic ual inflammation in treated HIV infection, further research to ART. These findings replicate previous cohort observations and understand the pathogenesis of residual inflammation that can highlight the importance of optimal and durable ART adher- lead to new approaches aimed at achieving this goal is needed. ence as a potential factor to improve morbidity and mortality In this context, whether ART adherence optimization could in HIV disease. reduce residual chronic inflammation in individuals who have Supplementary Data achieved virologic suppression, or whether it could have a syn- Supplementary materials are available at Open Forum Infectious Diseases ergistic effect in conjunction with current and future ART strat- online. Consisting of data provided by the authors to benefit the reader, egies, remains unknown and should be evaluated in prospective the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corre- studies. sponding author. While the association between suboptimal adherence and enhanced residual inflammation is novel and provocative, its Acknowledgments clinical translation remains unclear, in particular as it relates We would like to thank the study participants for volunteering to partic- to the development of SNAEs in the virologically suppressed ipate in this study. Prior presentation. es Th e data were partially presented at the 9th IAS population. As chronic residual inflammation has been asso- Conference on HIV Science, July 23–26, 2017, Paris, France, Abstract num- ciated with the development of SNAEs [2, 3], it is plausible ber WEPEB0543. See N Engl J Med 2006; 355:2283–96 for the complete list that suboptimal adherence could also be responsible, at least of SMART investigators. Financial support. This work was supported by National Institute of in part, for the increased morbidity and mortality observed Health grants: U01AI068641, U01AI042170 and U01AI46362 (SMART) in treated PLWH who remain virally suppressed. To answer and K23AI104315 (JCM) and R21AI124859 (JCM). this question, future analyses evaluating the association of Potential coni fl cts of interest. A.P. received speaker fees for 2 presenta- SNAEs with ART adherence in the virally suppressed popula- tions in 2015. The other authors reported no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of tion should be performed in large clinical cohorts. This could Interest. 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Published: Dec 22, 2017

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