Strategies For Management Of Antiretroviral Therapy Research Articles

Deciphering the association between HIV-specific immunity and immune reconstitution.

Numerous observational studies have reported elevated risk of cardiovascular disease, chronic lung disease, infections and cancers among people living with HIV (PLWH) compared to non-HIV infected individuals [1,2]. The association between HIV infection and increased risk of these non-AIDS related comorbidities is strongest for viraemic individuals as highlighted by two pivotal randomized trials, the Strategies for Management of Antiretroviral Therapy (SMART) study and Strategic Timing of Antiretroviral Treatment START study [3,4].

The association of human leukocyte antigen alleles with clinical disease progression in HIV-positive cohorts with varied treatment strategies.

The Strategic Timing of AntiRetroviral Treatment (START) and Strategies for Management of Antiretroviral Therapy (SMART) trials demonstrated that ART can partly reverse clinically defined immune dysfunction induced by HIV replication. As control of HIV replication is influenced by the HLA region, we explored whether HLA alleles independently influence the risk of clinical events in HIV+ individuals. Cohort study. In START and SMART participants, associations between imputed HLA alleles and AIDS, infection-related cancer, herpes virus-related AIDS events, chronic inflammation-related conditions, and bacterial pneumonia were assessed. Cox regression was used to estimate hazard ratios for the risk of events among allele carriers versus noncarriers. Models were adjusted for sex, age, geography, race, time-updated CD4+ T-cell counts and HIV viral load and stratified by treatment group within trials. HLA class I and II alleles were analyzed separately. The Benjamini--Hochberg procedure was used to limit the false discovery rate to less than 5% (i.e. q value <0.05). Among 4829 participants, there were 132 AIDS events, 136 chronic inflammation-related conditions, 167 bacterial pneumonias, 45 infection-related cancers, and 49 herpes virus-related AIDS events. Several associations with q value less than 0.05 were found: HLA-DQB1∗06:04 and HLA-DRB1∗13:02 with AIDS (adjusted HR [95% CI] 2.63 [1.5-4.6] and 2.25 [1.4-3.7], respectively), HLA-B∗15:17 and HLA-DPB1∗15:01 with bacterial pneumonia (4.93 [2.3-10.7] and 4.33 [2.0-9.3], respectively), and HLA-A∗69:01 with infection-related cancer (15.26 [3.5-66.7]). The carriage frequencies of these alleles were 10% or less. This hypothesis-generating study suggests that certain HLA alleles may influence the risk of immune dysfunction-related events irrespective of viral load and CD4+ T-cell count.

Health Utility Estimates and Their Application to HIV Prevention in the United States: Implications for Cost-Effectiveness Modeling and Future Research Needs.

Objectives. Health utility estimates from the current era of HIV treatment, critical for cost-effectiveness analyses (CEA) informing HIV health policy, are limited. We examined peer-reviewed literature to assess the appropriateness of commonly referenced utilities, present previously unreported quality-of-life data from two studies, and discuss future implications for HIV-related CEA. Methods. We searched a database of cost-effectiveness analyses specific to HIV prevention efforts from 1999 to 2016 to identify the most commonly referenced sources for health utilities and to examine practices around using and reporting health utility data. Additionally, we present new utility estimates from the Centers of Disease Control and Prevention’s Medical Monitoring Project (MMP) and the INSIGHT Strategies for Management of Anti-Retroviral Therapy (SMART) trial. We compare data collection time frames, sample characteristics, assessment methods, and key estimates. Results. Data collection for the most frequently cited utility estimates ranged from 1985 to 1997, predating modern HIV treatment. Reporting practices around utility weights are poor and lack details on participant characteristics, which may be important stratifying factors for CEA. More recent utility estimates derived from MMP and SMART were similar across CD4+ count strata and had a narrower range than pre–antiretroviral therapy (ART) utilities. Conclusions. Despite the widespread use of ART, cost-effectiveness analysis of HIV prevention interventions frequently apply pre-ART health utility weights. Use of utility weights reflecting the current state of the US epidemic are needed to best inform HIV research and public policy decisions. Improved practices around the selection, application, and reporting of health utility data used in HIV prevention CEA are needed to improve transparency.

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

Suboptimal (ie, <100%) antiretroviral therapy (ART) adherence has been associated with heightened inflammation in cohort studies, even among people with virologic suppression. We aimed to evaluate this association among participants in the Strategies for Management of Antiretroviral Therapy (SMART) study who had virologic suppression (HIV-1 VL < 200 copies/mL) at enrollment. Based on self-reported adherence (7-day recall), plasma concentrations of interleukin 6 and D-dimer were 9% (95% confidence interval [CI], 1%–18%; P = .02) and 11% (95% CI, 1%–22%; P = .03) higher in participants who reported suboptimal vs 100% adherence, respectively. These findings confirm previous observations and support the hypothesis that suboptimal ART adherence, even in the context of virologic suppression, may have significant biological consequences.ClinicalTrials.gov number NCT00027352

Anti-HIV-1 ADCC Antibodies following Latency Reversal and Treatment Interruption.

There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRAs) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC. We found that treatment with the LRA panobinostat or a short analytical treatment interruption (ATI), 21 to 59 days, was not sufficient to stimulate an increase in ADCC-competent antibodies, despite viral rebound in all subjects who underwent the short ATI. In contrast, a longer ATI, 2 to 12 months, among subjects enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial robustly boosted HIV-1 gp120-specific Fc receptor-binding antibodies and ADCC against HIV-1-infected cells in vitro These results show that there is a lag between viral recrudescence and the boosting of ADCC antibodies, which has implications for strategies toward eliminating latently infected cells.IMPORTANCE The "shock and kill" HIV-1 cure strategy aims to reactivate HIV-1 expression in latently infected cells and subsequently eliminate the reactivated cells through immune-mediated killing. Several latency reversing agents (LRAs) have been examined in vivo, but LRAs alone have not been able to achieve HIV-1 remission and prevent viral rebound following analytical treatment interruption (ATI). In this study, we examined whether LRA treatment or ATI can provide sufficient antigenic stimulus to boost HIV-1-specific functional antibodies that can eliminate HIV-1-infected cells. Our study has implications for the antigenic stimulus required for antilatency strategies and/or therapeutic vaccines to boost functional antibodies and assist in eliminating the latent reservoir.

START or SMART? Timing of Antiretroviral Therapy Initiation and Cardiovascular Risk for People With Human Immunodeficiency Virus Infection.

The Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection (START) study has reinforced the benefits of early initiation of antiretroviral therapy (ART). However, a notable secondary finding from that study was that immediate initiation of ART did not prevent cardiovascular disease (CVD) events (0.17 vs 0.20 events/1000 person-years, P = .65). This result appears to contradict a body of evidence, most notably from the Strategies for Management of Antiretroviral Therapy (SMART) study, which reported a 70% increased hazard of cardiovascular events for those deferring or interrupting treatment. Thus, an important unresolved question is whether the timing of ART impacts CVD risk. In this review, published data on relationships between timing of ART and CVD risk are reviewed. The data support a role for ART in mitigating CVD risk at lower CD4 counts, but data also suggests that, among those initiating therapy early, ART alone appears to suboptimally mitigate CVD risk. Additional interventions to address CVD risk among human immunodeficiency virus-infected populations are likely to be needed.

A simple self-reported adherence tool as a predictor of viral rebound in people with viral suppression on antiretroviral therapy.

The aim of the study was to investigate the relationship between self-reported antiretroviral therapy (ART) adherence and virological outcomes in the multinational Strategies for Management of Antiretroviral Therapy (SMART) study. Eligible participants were from the continuous ART arm and had at least one viral load (VL) ≤ 50 HIV-1 RNA copies/mL and a subsequent VL value (VL pair). Self-reported adherence was measured at each visit using a five-point Likert scale which employed a 7-day recall. High adherence was defined as taking 'all pills every day' (level 1) for every regimen component; all others had suboptimal adherence (levels 2 - 5). In individuals with VL suppression (≤ 50 copies/mL), the association between adherence (at the time of VL suppression) and VL rebound (> 200 copies/mL at next visit) was assessed using multivariable logistic regression with generalized estimating equations. A total of 10 761 sets of VL pairs from 1986 participants were included in the study. For 1220 (11%) VL pairs, adherence was suboptimal. For 507 VL pairs (5%), VL rebound occurred. The risk of rebound generally increased as adherence decreased: 4.2% for level 1, 7.7% for level 2, 16.3% for level 3, 9.4% for level 4 and 12.9% for level 5. In multivariable analysis, suboptimal adherence at the time of suppression was associated with a 50% increased odds of experiencing subsequent VL rebound [odds ratio (OR) 1.51; 95% confidence interval (CI) 1.19-1.92; P = 0.0023], compared with high adherence. Self-reported suboptimal adherence in people with VL suppression is associated with an increased risk of VL rebound. Our findings highlight the importance of continued adherence counselling, even in people with VL suppression, and to ensure that people with HIV infection maintain excellent adherence in order to minimize the risk of VL rebound.

Factors Associated With Plasma IL-6 Levels During HIV Infection

Elevated interleukin 6 (IL-6) levels have been linked to cardiovascular disease, cancer and death. Persons with human immunodeficiency virus (HIV) infection receiving treatment have higher IL-6 levels, but few data are available on factors associated with circulating IL-6. Participants in 3 trials with IL-6 measured at baseline were included (N = 9864). Factors associated with IL-6 were identified by linear regression. Demographic and HIV variables (nadir/entry CD4(+) cell count, HIV RNA level, antiretroviral therapy regimen) were investigated in all 3 trials. In the SMART (Strategies for Management of Anti-Retroviral Therapy) trial, CD4/CD8 ratio, smoking, comorbid conditions, serum lipids, renal function (estimated glomerular filtration rate [eGFR]), and educational level were assessed. Demographics associated with higher IL-6 levels were older age and lower education, whereas black race was associated with lower IL-6. Higher HIV RNA levels were associated with higher IL-6 levels, and higher nadir CD4(+) cell counts with lower IL-6 levels. Compared with efavirenz, protease inhibitors were associated with higher and nevirapine with lower IL-6 levels. Smoking and all comorbid conditions were related to higher IL-6. IL-6 levels increased with decreasing eGFR and decreasing serum lipids. Higher levels of IL-6 were associated with older age, nonblack race, higher body mass index, lower serum lipid levels, HIV replication, low nadir CD4(+) cell count, protease inhibitor use, comorbid conditions, and decreased eGFR. Multiple factors affect inflammation in HIV and should be considered in studies of IL-6 as a biomarker of clinical outcomes.

Abstract 14731: Glyc A, a Novel Marker of Inflammation, Predicts Cardiovascular Events in HIV-Positive Patients: Results of SMART Study

Background: Cardiovascular disease (CVD) is increasing in HIV-infected patients. Glyc A is a novel nuclear magnetic resonance (NMR) spectroscopy signal in plasma arising from the glycosylation of circulating acute phase proteins. The acute phase proteins have been independently associated with CVD in HIV patients, but the association of Glyc A and CVD has not been studied. We aimed to quantify the risk of CVD associated with Glyc A at baseline in HIV-positive patients enrolled in the Strategies for Management of Anti-Retroviral Therapy (SMART) study. Methods: In a nested case-control study, Glyc A was measured using NMR at baseline in 246 HIV positive patients [median age, interquartile range (IQR): 49 (44,56) years, 81 % male], who experienced a CVD event (defined as coronary heart disease (CHD), myocardial infarction, coronary artery disease requiring revascularization, atherosclerotic non-CHD (stroke and peripheral arterial disease), congestive heart failure and CVD or unwitnessed death) over an average of 2.8 years of follow-up and 472 matched controls. Odds ratios (ORs) associated with baseline levels of Glyc A for CVD were estimated using conditional logistic regression unadjusted and after adjustment for BMI, race, HIV-RNA and antiretroviral therapy status, smoking, prior CVD, diabetes, total/high-density lipoprotein cholesterol ratio, use of blood pressure and lipid-lowering drugs, hepatitis co-infection, CD4+ and major baseline ECG abnormalities. Results: At baseline median Glyc A (IQR) was 383 (333, 442) μmol/L in patients who developed a CVD event and 368 (322, 419) μmol/L in controls (P &lt; 0.001 for difference). The unadjusted OR for CVD (highest versus lowest quartile) was 2.18 (with 95% confidence interval (CI) 1.38-3.44, P &lt; 0.001). After adjustment for baseline covariates and CVD risk factors, OR was 2.20 (95% CI, 1.29-3.76, P = 0.004). Conclusion: Higher levels of Glyc A are associated with increased risk of CVD in HIV patients after considering established CVD risk factors.

HIV Replication Alters the Composition of Extrinsic Pathway Coagulation Factors and Increases Thrombin Generation

BackgroundHIV infection leads to activation of coagulation, which may increase the risk for atherosclerosis and venous thromboembolic disease. We hypothesized that HIV replication increases coagulation potentially through alterations in extrinsic pathway factors.Methods and ResultsExtrinsic pathway factors were measured among a subset of HIV participants from the Strategies for Management of Anti‐Retroviral Therapy (SMART) trial. Thrombin generation was estimated using validated computational modeling based on factor composition. We characterized the effect of antiretroviral therapy (ART) treatment versus the untreated state (HIV replication) via 3 separate analyses: (1) a cross‐sectional comparison of those on and off ART (n=717); (2) a randomized comparison of deferring versus starting ART (n=217); and (3) a randomized comparison of stopping versus continuing ART (n=500). Compared with viral suppression, HIV replication consistently showed short‐term increases in some procoagulants (eg, 15% to 23% higher FVIII; P<0.001) and decreases in key anticoagulants (eg, 5% to 9% lower antithrombin [AT] and 6% to 10% lower protein C; P<0.01). The net effect of HIV replication was to increase coagulation potential (eg, 24% to 48% greater thrombin generation from computational models; P<0.01 for all). The pattern of changes from HIV replication was reversed with ART treatment and consistent across all 3 independent comparisons.ConclusionsHIV replication leads to complex changes in extrinsic pathway factors, with the net effect of increasing coagulation potential to a degree that may be clinically relevant. The key influence of changes in FVIII and AT suggests that HIV‐related coagulation abnormalities may involve changes in hepatocyte function in the context of systemic inflammation.Clinical Trial RegistrationURL: ClinicalTrials.gov. Unique identifier: NCT00027352.

Editorial Commentary: Universal Antiretroviral Therapy for HIV Infection?

Human immunodeficiency virus (HIV) still infects more people per year than existing health systems are able to initiate and maintain on antiretroviral therapy. Therefore, the development of effective HIV population prevention strategies remains a high priority. There is no immediate promise for an effective HIV vaccine, risk behavior change has been difficult to implement, and biomedical prevention measures lack effectiveness due to inconsistent use. In contrast, antiretroviral therapy (ART) can benefit the infected individual and under clinical trial conditions has been shown to reduce transmission [1]. The use of ART as both treatment and prevention is now a well-established concept, which has been widely welcomed as the “missing link” that will curb HIV incidence [2]. However, a disconnect exists between the individual and transmission benefits of ART. Persons with advanced HIV disease (reflected by having a CD4 lymphocyte count <250 cells/μL), have clear benefit, documented by several randomized controlled trials (reviewed in [3]). Conversely, the target populations for transmission benefit are those with high CD4 counts, in whom observational studies have shown inconsistent or no clinical benefit (reviewed in [4]). Additional biological plausibility for early treatment has been the observation that untreated HIV infection activates host inflammatory processes associated with organ disease and cancers and that ART partly (but not completely) reverts immune activation. However, no specific anti-inflammatory intervention has been demonstrated to reduce the risk of these adverse outcomes, and changes in inflammatory biomarker levels have not been validated surrogates for clinical benefits of ART. Therefore, whether inflammation is causally involved in the pathogenesis of these events or merely an epiphenomena to the underlying pathology remains to be identified in HIV as it does in the general population. The uncertainties relating to net benefit of early ART are reflected in disparities between treatment guidelines. Guidelines based on consensus “expert opinion” recommend that all HIV-positive persons, as a matter of principle, should be started on ART [5, 6], and those based on available direct evidence [7–9] (including the 2010 World Health Organization guidelines) are more conservative. Unfortunately, consensus among experts can be prescient or subsequently shown to be incorrect. For example, 10 years ago, expert opinion was that ART could be used intermittently, but the SMART (Strategies for Management of Antiretroviral Therapy) trial demonstrated definitively that this view was wrong [10]. Gallant et al, in this issue of Clinical Infectious Diseases [11], highlight reasons why the recommendations of the US guidelines are not necessarily generalizable to other settings. They highlight a fundamental ethical obligation of clinicians to benefit patients while not causing harm. They note that although the individual benefits of early ART remain undefined in resource-limited settings, the risks associated with early ART may be higher. Cost constraints in resourcelimited settings limit the available ART repertoire, resulting in frequent use of older, cheaper drugs with poor adverse event profiles. In a setting where only stavudine-based ART regimens are available, for example, starting ART at a high CD4 count of 650 cells/μL would less likely maintain health than deferring to a more conservative threshold of 250–350 cells/μL. Lack of laboratory monitoring may also potentially increase risk by delayed recognition of toxicity. Tenofovir, which is included in most currently recommended ART regimens, may adversely affect kidney and bone physiology [12, 13]. Emerging reports of more severe renal diseases in settings without access to laboratory monitoring raise Received 30 May 2013; accepted 1 June 2013; electronically published 11 June 2013. Correspondence: Jens D. Lundgren, MD, DMSc, Department of Infectious Diseases (5112), Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen O, Denmark (jdl@cphiv.dk). Clinical Infectious Diseases 2013;57(6):888–90 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cit381

HIV: An underrecognized secondary cause of osteoporosis?

HIV: An underrecognized secondary cause of osteoporosis?

Outcomes after reinitiating antiretroviral therapy in children randomized to planned treatment interruptions

Excess risks for death/opportunistic disease in adults randomized to CD4-driven planned treatment interruption (PTI) in the Strategies for Management of Antiretroviral Therapy (SMART) trial remained after antiretroviral therapy (ART) re-initiation. Risks for children following PTI were evaluated in long-term follow-up of children in the PENTA 11 trial. Children with HIV RNA below 50 copies/ml and CD4 at least 30% (2-6 years) or at least 500 cells/μl (7-15 years) were randomized to continuous ART (cART) or PTI in PENTA 11 (ISRCTN 36694210). After the end of the trial, all were recommended to resume ART. Data were collected annually and analysed up to the second year of visit. One hundred and one (51 cART, 50 PTI; median baseline age 9.2 years) children had median overall follow-up 4.6 (range 3.7-5.0) years. During 2-year post-trial period, there were no deaths or new Centers for Disease Control and Prevention (CDC) stage B/C events. Rate of clinical grade of at least two events was similar between PTI and cART [relative risk (RR) 1.03; 95% confidence interval (CI) 0.43, 2.50; P = 0.94]. At 2 years, difference in absolute CD4% between PTI and cART was -1.6% (-4.5%; 1.3%; P = 0.27), and proportions with HIV RNA below 50 copies/ml were 82 versus 86% (P = 0.57), respectively; no differences in growth or fasting lipids were observed. Key predictors of greater CD4% recovery after re-initiating ART were higher CD4% at baseline (P < 0.001) and longer time since ART re-initiation (P < 0.001). During overall follow-up, 4 (8%) PTI versus 5 (10%) CT children switched ART for failure (P = 0.75) and 9 (18%) versus 1 (2%) (P = 0.008) substituted ART for simplification. No adverse clinical, immunological or virological consequences of PTI were observed 2 years after the end of PENTA 11 trial. Although ART interruption is not generally recommended, it may be an acceptable option for children, particularly when there is high risk of unplanned treatment interruptions.

Interruption or deferral of antiretroviral therapy reduces markers of bone turnover compared with continuous therapy: The SMART body composition substudy

Bone mineral density (BMD) declines significantly in HIV patients on antiretroviral therapy (ART). We compared the effects of intermittent versus continuous ART on markers of bone turnover in the Body Composition substudy of the Strategies for Management of AntiRetroviral Therapy (SMART) trial and determined whether early changes in markers predicted subsequent change in BMD. For 202 participants (median age 44 years, 17% female, 74% on ART) randomized to continuous or intermittent ART, plasma markers of inflammation and bone turnover were evaluated at baseline and months 4 and 12; BMD at the spine (dual-energy X-ray absorptiometry [DXA] and computed tomography) and hip (DXA) was evaluated annually. Compared with the continuous ART group, mean bone-specific alkaline phosphatase (bALP), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), N-terminal cross-linking telopeptide of type 1 collagen (NTX), and C-terminal cross-linking telopeptide of type 1 collagen (βCTX) decreased significantly in the intermittent ART group, whereas RANKL and the RANKL:osteoprotegerin (OPG) ratio increased (all p ≤ 0.002 at month 4 and month 12). Increases in bALP, osteocalcin, P1NP, NTX, and βCTX at month 4 predicted decrease in hip BMD at month 12, whereas increases in RANKL and the RANKL:OPG ratio at month 4 predicted increase in hip and spine BMD at month 12. This study has shown that compared with continuous ART, interruption of ART results in a reduction in markers of bone turnover and increase in BMD at hip and spine, and that early changes in markers of bone turnover predict BMD changes at 12 months.

Platelet count kinetics following interruption of antiretroviral treatment

To investigate the mechanisms of platelet kinetics in the Strategies for Management of Antiretroviral Therapy (SMART) study that demonstrated excess mortality with CD4 guided episodic antiretroviral therapy (ART) drug conservation compared with continuous treatment viral suppression. Follow-up analyses of stored plasma samples demonstrated increased activation of both inflammatory and coagulation pathways after stopping ART. SMART patients from sites that determined platelets routinely. Platelet counts were retrospectively collected from 2206 patients from visits at study entry, and during follow-up. D-dimer levels were measured at study entry, month 1, and 2. Platelet levels decreased in the drug conservation group following randomization, but remained stable in the viral suppression group [median (IQR) decline from study entry to month 4: -24 000/μl (-54 000 to 4000) vs. 3000 (-22 000 to 24 000), respectively, P < 0.0001)] and the rate of developing thrombocytopenia (<100 000/μl) was significantly higher in the drug conservation vs. the viral suppression arm (unadjusted drug conservation/viral suppression [HR (95%CI) = 1.8 (1.2-2.7)]. The decline in platelet count among drug conservation participants on fully suppressive ART correlated with the rise in D-dimer from study entry to either month 1 or 2 (r = -0.41; P = 0.02). Among drug conservation participants who resumed ART 74% recovered to their study entry platelet levels. Interrupting ART increases the risk of thrombocytopenia, but reinitiation of ART typically reverses it. Factors contributing to declines in platelets after interrupting ART may include activation of coagulation pathways or HIV-1 replication itself. The contribution of platelets in HIV-related procoagulant activity requires further study.

Protease inhibitors and cardiac autonomic function in HIV-infected patients: a cross-sectional analysis from the Strategies for Management of Antiretroviral Therapy (SMART) Trial

ObjectiveTo compare cardiac autonomic function as measured by heart rate variability for HIV-infected participants taking protease inhibitors (PIs) with those taking a non-nucleoside reverse transcriptase inhibitor without a PI (NNRTI-no...

Electrocardiographic Spatial QRS-T Angle and Incident Cardiovascular Disease in HIV-Infected Patients (from the Strategies for the Management of Antiretroviral Therapy [SMART] Study)

Widening of the electrocardiographic (ECG) spatial QRS-T angle has been predictive of cardiovascular disease (CVD) events in the general population. However, its prognostic significance in human immunodeficiency virus (HIV)-infected patients remains unknown. The spatial QRS-T angle was derived from the baseline resting 12-lead electrocardiogram of 4,453 HIV-infected patients aged 43.5 ± 9.3 years from the Strategies for Management of Antiretroviral Therapy (SMART) trial. CVD events were identified during a median follow-up of 28.7 months. Quartiles of the spatial QRS-T angle was calculated for men and women separately, and values in the upper quartile were considered as a widened angle (values >74° for women and >93° for men). A multivariate Cox proportional hazards analysis was used to examine the association between a widened baseline spatial QRS-T angle and incident CVD events. During 11,965 person-years of follow-up, 152 CVD events occurred at a rate of 1.27 events/100 person-years. The rate of CVD events in those with a widened spatial QRS-T angle was almost double the rate in those with a normal spatial QRS-T angle (rate ratio 1.94, 95% confidence interval 1.40 to 2.69; p <0.001). In a model adjusted for study treatment arm, demographics, CVD risk factors, HIV characteristics, inflammatory markers, and other ECG abnormalities, a widened spatial QRS-T angle was associated with a >50% increased risk of CVD events compared to a normal spatial QRS-T angle (hazard ratio 1.53, 95% confidence interval 1.07 to 2.17; p = 0.02). No interaction was seen by SMART trial arm (p value for interaction = 0.37) or gender (p value for interaction = 0.84). In conclusion, a widened spatial QRS-T angle was independently predictive of CVD events in HIV-infected patients receiving antiretroviral therapy. This highlights the potential role of routine electrocardiography as a simple noninvasive CVD risk-screening tool in HIV-infected patients.

Inflammation, Immune Activation, and CVD Risk in Individuals With HIV Infection

ANTIRETROVIRAL THERAPY (ART) PROLONGS LIFE, BUT individuals infected with human immunodeficiency virus (HIV) have a shorter life span than their uninfected counterparts and a greater than expected risk of cardiovascular disease (CVD). Part of the increased CVD risk associated with HIV infection can be attributed to an increased burden of traditional risk factors such as cigarette smoking, as well as the effects of ART on lipids, insulin resistance, and body composition. However, increasing evidence suggests that chronic inflammation and immune activation may play key roles in HIV-associated CVD. In individuals without HIV infection, markers of inflammation such as high-sensitivity C-reactive protein (CRP) and interleukin-6 predict CVD events and mortality. Similar although less robust findings have been described in individuals infected with HIV. In an observational study of 70 357 patients from Partners HealthCare, increased CRP levels and presence of HIV were independently associated with risk of acute myocardial infarction. Compared with patients who had normal CRP levels and without HIV infection, the odds ratio for acute myocardial infarction was greater than 4-fold higher among patients with HIV and increased CRP levels. In the Strategies for Management of Antiretroviral Therapy (SMART) study, interruption of ART was associated with greater mortality and CVD events compared with continuous ART, and higher levels of interleukin-6 and D-dimers were associated with all-cause mortality, suggesting that improvements in mortality in the setting of continuous ART may be mediated by a reduction in inflammation. Furthermore, among treatment-naive individuals infected with HIV, initiation of ART improved endothelial function within 4 weeks of treatment despite worsening lipids and the degree of improvement was associated with lower HIV RNA-1 levels. Taken together, these findings suggest that immediately after initiation, ART reduces CVD risk by decreasing inflammation and viral replication, despite having adverse effects on traditional CVD risk factors. However, individuals receiving treatment who have suppression of HIV replication have higher levels of inflammatory markers than uninfected individuals and persistent inflammation while taking ART appears to increase long-term CVD risk. The factors that contribute to ongoing inflammation and immune activation in the setting of chronic, treated HIV infection are incompletely understood and likely are different than in individuals without HIV in whom inflammation is driven, in large part, by visceral adiposity and its associated metabolic abnormalities. Depletion of CD4 cells in gut mucosal lymphoid tissue occurs early in HIV infection and may contribute to ongoing microbial translocation. This process is not completely reversed with ART, even when HIV replication appears to be suppressed. Increased levels of lipopolysaccharide and soluble CD14 (sCD14) persist in some individuals with treated HIV infection, suggesting that intestinal microbial translocation may contribute to persistent immune activation. Furthermore, increased levels of sCD14 are associated with increased all-cause mortality and HIV disease progression, as well as more rapid progression of carotid atherosclerosis. Other putative drivers of cellular activation and associated cytokine secretion include indirect effects of HIV gene products, direct infection of macrophages by HIV, and antigenic stimulation by latent viruses that are common in patients with HIV. Immunological abnormalities that are affected directly by HIV infection such as current and nadir CD4 cell count have been independently associated with CVD risk, as have markers of immune activation and senescence. In this issue of JAMA, Subramanian et al describe for the first time imaging of arterial wall inflammation using fluorine-2-deoxy-D-glucose positron emission tomography (FFDG-PET) in individuals with HIV. In a small crosssectional study, the authors demonstrated that individuals with HIV but without known coronary artery disease have higher aortic uptake of FDG (expressed as the target-tobackground ratio [TBR]) than risk factor–matched individuals without HIV, and have a level of aortic TBR similar to that of individuals without HIV with coronary artery disease. Patients with HIV infection had higher aortic TBR than controls even after adjusting for traditional CVD risk fac-

Assessing risk of a short‐term antiretroviral therapy discontinuation as a read‐out of viral control in immune‐based therapy

Although analytical treatment interruption is used as a strategy to test immunotherapeutic agents in HIV-infection, it may pose a risk for study participants. The potential risks of short-term interruption of antiretroviral therapy (ART) during treatment with an autologous dendritic cell immune-based therapy (AGS-004-001) were assessed using data from a subgroup of subjects in the strategies for management of antiretroviral therapy (SMART) study with matched eligibility criteria. A retrospective subgroup analysis of the SMART study population using the eligibility criteria and treatment stopping rules of AGS-004-001 study was analyzed. Key inclusion criteria for AGS-004-001 study were applied to the data collected from participants of the SMART study. There were 440 of 2,720 on the drug conservation arm and 436 of 2,752 on the viral suppression arm that matched the AGS-004-001 inclusion criteria and were used in the SMART subgroup analysis. In the first 16 weeks following randomization into the SMART study there were no deaths in either subgroup. There were two AIDS-related events in the drug conservation subgroup and one in the viral suppression subgroup, making the overall risk of AIDS-related events 2 per 100 person years (0.005%) and 1 per 100 person years (0.002%) in the two subgroups, respectively. There were 6/440 subjects (1.4%) in the drug conservation subgroup and 4/436 subjects (0.92%) in the viral suppression subgroup who experienced Grade 2 adverse events. These results demonstrated that analytical treatment interruption within the context of highly selective, closely monitored studies assessing the antiviral activity of immune-based agents should be an acceptable strategy for at least 16 weeks.

Inflammation predicts changes in high-density lipoprotein particles and apolipoprotein A1 following initiation of antiretroviral therapy

The effects of HIV infection and antiretroviral therapy (ART) on usual lipid levels have been reported. The effects of initiating versus deferring ART on high-density and low-density lipoprotein particle (HDL-P and LDL-P, respectively) concentrations and apolipoprotein (Apo) levels are not well described. In a subgroup of participants not taking ART at study entry who were randomized in the Strategies for Management of Antiretroviral Therapy (SMART) trial to immediately initiate ART ('viral suppression group') or to defer it ('drug conservation group'), lipoprotein particle concentrations and ApoA1 and ApoB levels were measured at baseline and at 2 and 6 months following randomization. Compared with drug conservation group (n = 126), HDL-P and ApoA1 levels increased among viral suppression participants (n = 128) after starting ART. At 6 months, viral suppression participants had 13% higher total HDL-P (P < 0.001) and 9% higher ApoA1 (P < 0.001). LDL-P, very low density lipoprotein particle, and ApoB did not differ significantly between the viral suppression and drug conservation groups. Among viral suppression participants, predictors of HDL-P and ApoA1 increases included baseline levels of high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6), but not HIV RNA level, CD4 cell count, or traditional cardiovascular disease risk factors. The effect of starting ART on changes in HDL-P and ApoA1 was greater for those with higher versus lower baseline levels of IL-6 (P = 0.001 and 0.08, respectively, for interaction) or hsCRP (P = 0.01 and 0.04, respectively, for interaction). HDL-P and ApoA1 increase following ART initiation, to a degree that depends on the degree of inflammation present at entry. These findings suggest that activation of inflammatory pathways contribute to HIV-associated changes in HDL.