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

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/mm3 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/mm3 . 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.

Benefit of Early versus Deferred Antiretroviral Therapy on Progression of Liver Fibrosis among People with HIV in the START Randomized Trial.

The role of antiretroviral therapy (ART) in reducing or contributing to liver fibrosis in persons with human immunodeficiency virus (HIV) is unclear. We evaluated participants in the Strategic Timing of AntiRetroviral Treatment (START) trial for liver fibrosis using the AST to Platelet Ratio Index (APRI) and Fibrosis-4 Index (FIB-4), and assessed for a benefit of early versus delayed ART on liver fibrosis progression. ART-naïve persons with high CD4 counts (>500 cells/µL) from 222 clinical sites in 35 countries were randomized to receive ART either at study enrollment (immediate treatment arm) or when their CD4 count fell below 350 cells/µL (deferred treatment arm). The following outcomes were evaluated: fibrosis (APRI > 0.5 or FIB-4 > 1.45), significant fibrosis (APRI > 1.5 or FIB-4 > 3.25), hepatic flare, and resolution of elevated APRI and FIB-4 scores. Of the 4,684 enrolled into the START study, 104 did not have APRI or FIB-4 results and were excluded. Among 4,580 participants (2,273 immediate treatment; 2,307 deferred treatment), the median age was 36 years, 26.9% were female, and 30.4% were black. Three percent had an alcoholism or substance abuse history, 6.4% had hepatitis B and/or C, and 1.1% had significant fibrosis at baseline. The median CD4 count was 651, and 5.3% had HIV RNA ≤ 200. Immediate arm participants were at lower risk of developing increased fibrosis scores than deferred arm participants (hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.57-0.78; P < 0.001) and more likely to have resolution of elevated baseline scores (HR 1.6; 95% CI 1.3-1.9; P < 0.001). Conclusions: Significant liver fibrosis was rare among ART-naïve HIV-positive persons with high CD4 counts. Our findings suggest a benefit of early ART in preventing the development of liver fibrosis.

The Effect of Interrupted/Deferred Antiretroviral Therapy on Disease Risk: A SMART and START Combined Analysis.

Background: Pooled data from the SMART and START trials were used to compare deferred/intermittent versus immediate/continuous antiretroviral therapy (ART) on disease risk. Methods: Endpoints assessed were AIDS, serious non-AIDS (SNA), cardiovascular disease (CVD), cancer, and death. Pooled (stratified by study) hazard ratios (HRs) from Cox models were obtained for deferred/intermittent ART versus immediate/continuous ART; analyses were conducted to assess consistency of HRs across baseline-defined subgroups. Results: Among 10156 participants, there were 124 AIDS, 247 SNA, 117 cancers, 103 CVD, and 120 deaths. Interventions in each trial led to similar differences in CD4 count and viral suppression. Pooled HRs (95% confidence interval) of deferred/intermittent ART versus immediate/continuous ART were for AIDS 3.63 (2.37-5.56); SNA 1.62 (1.25-2.09); CVD 1.59 (1.07-2.37); cancer 1.93 (1.32-2.83); and death 1.80 (1.24-2.61). Underlying risk was greater in SMART than START. Given the similar HRs for each trial, absolute risk differences between treatment groups were greater in SMART than START. Pooled HRs were similar across subgroups. Conclusions: Treatment group differences in CD4 count and viral suppression were similar in SMART and START. Likely as a consequence, relative differences in risk of AIDS and SNA between immediate/continuous ART and deferred/intermittent ART were similar. Clinical Trials Registration: NCT00027352 and NCT00867048.

In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus.

BACKGROUND: Effective HIV treatment with antiretroviral therapy has prolonged survival and shifted causes of death to non-AIDS illnesses such as cardiovascular disease. We have shown that inflammation and HIV viral load associate with pro- and anticoagulant factor imbalances resulting in increased thrombin generation when mathematically modeled. We explore the hypothesis that factor compositional imbalance, corresponding to increased in silico thrombin generation, predicts mortality among HIV+ persons. METHODS: In a nested case-control study of HIV+ individuals on continuous antiretroviral therapy in two large trials, we evaluated cases (any non-violent mortality, n = 114) and matched controls (n = 318). Thrombin generation in response to a tissue-factor initiator for each individual was calculated by a mathematical model incorporating levels of factors (F)II, V, VII, VIII, IX, X, antithrombin, tissue factor pathway inhibitor, and protein C (PC) measured at study entry to the trials. In silico thrombin generation metrics included clot time, maximum rate (MaxR), maximum level (MaxL), and area under the curve (AUC). RESULTS: Levels of antithrombin and PC decreased, while FV and FVIII were higher in cases vs controls. This resulted in a more procoagulant phenotype with increased MaxR, MaxL, and AUC in cases compared to controls (P < 0.05 for all). CONCLUSIONS: Antithrombin, FV, FVIII, and PC were the major contributors to the increased thrombin generation associated with mortality risk. Our results suggest that mortality in HIV is associated with an increase in in silico thrombin generation via altered balance of pro- and anticoagulant factors, likely due to an inflammatory response signal, and resulting coagulopathy.

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.

Inflammation-Related Morbidity and Mortality Among HIV-Positive Adults: How Extensive Is It?

OBJECTIVE: To determine the rate of grade 4, potentially life-threatening events not attributable to AIDS, cardiovascular disease (CVD), or non-AIDS cancer among participants on antiretroviral therapy and to describe associations of these events with interleukin-6 (IL-6) and D-dimer. DESIGN: Cohort study. METHODS: HIV-infected participants on antiretroviral therapy (N = 3568) with an HIV-RNA level ≤ 500 copies/mL were followed for grade 4, AIDS, CVD, non-AIDS cancer, and all-cause mortality events. Grade 4 events were further classified masked to biomarker levels as reflecting chronic inflammation-related disease (ChrIRD) or not (non-ChrIRD). Associations of baseline IL-6 and D-dimer with events were studied using Cox models. RESULTS: Over a median follow-up of 4.3 years, 339 participants developed a grade 4 event (22.9 per 1000 person-years); 165 participants developed a ChrIRD grade 4 event (10.7 per 1000 person-years). Grade 4 events were more common than AIDS (54 participants), CVD (132), and non-AIDS cancer (80) events, any of which developed in 252 participants (17.1 per 1000 person-years). Grade 4 and AIDS events were associated with similar risks of death. Higher IL-6 [hazard ratio (HR) = 1.19 per doubling of biomarker; P = 0.003] and D-dimer (HR = 1.23; P < 0.001) levels were associated with an increased risk of grade 4 events. IL-6 associations were stronger for ChrIRD (HR = 1.38; P < 0.001) than non-ChrIRD grade 4 events (HR = 1.11; P = 0.21). CONCLUSIONS: Morbidity and mortality associated with activation of inflammatory and coagulation pathways include conditions other than AIDS, CVD, and non-AIDS cancer events. Effective inflammation-dampening interventions could greatly affect the health of people with HIV.

Immediate Antiretroviral Therapy Reduces Risk of Infection-Related Cancer During Early HIV Infection.

BACKGROUND: In the Strategic Timing of Antiretroviral Treatment (START) study, immediate combination antiretroviral therapy (cART) initiation reduced cancer risk by 64%. We hypothesized that risk reduction was higher for infection-related cancer and determined by differences in CD4 cell counts and human immunodeficiency virus (HIV) RNA between the study arms. METHODS: Incident malignancies in START were categorized into infection-related and infection-unrelated cancer. We used Cox models to assess factors associated with both cancer categories. We used sequential adjustment for baseline covariates, cancer risk factors, and HIV-specific variables to investigate potential mediators of cancer risk reduction with immediate cART. RESULTS: There were 14 cancers among persons randomized to immediate cART (6 infection-related and 8 infection-unrelated) and 39 cancers in the deferred arm (23 infection-related and 16 infection-unrelated); hazard ratios of immediate vs deferred cART initiation were 0.26 (95% confidence interval [CI], .11-.64) for infection-related and 0.49 (95% CI, .21-1.15) for infection-unrelated cancer. Independent predictors of infection-related cancer were older age, higher body mass index, low- to middle-income region, HIV RNA, and baseline CD8 cell count. Older age and baseline CD8 cell count were independent predictors of infection-unrelated cancer. Adjustment for latest HIV RNA level had little impact on the protective effect of immediate cART on infection-related cancer. Adjustment for latest HIV RNA level, but not for CD4 cell count or cancer risk factors, attenuated the effect of immediate cART on infection-unrelated cancer. CONCLUSIONS: Immediate cART initiation significantly reduces risk of cancer. Although limited by small sample size, this benefit does not appear to be solely attributable to HIV RNA suppression and may be also mediated by other mechanisms.

Interleukin 6 Is a Stronger Predictor of Clinical Events Than High-Sensitivity C-Reactive Protein or D-Dimer During HIV Infection.

BACKGROUND: Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer levels are linked to adverse outcomes in human immunodeficiency virus (HIV) infection, but the strength of their associations with different clinical end points warrants investigation. METHODS: Participants receiving standard of care in 2 HIV trials with measured biomarker levels were followed to ascertain all-cause death, non-AIDS-related death, AIDS, cardiovascular disease (CVD), and non-AIDS-defining malignancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) of each end point for quartiles and log2-transformed IL-6, hsCRP, and D-dimer levels were calculated using Cox models. Marginal models modelling multiple events tested for equal effects of biomarker levels on different end points. RESULTS: Among 4304 participants, there were 157 all-cause deaths, 117 non-AIDS-related deaths, 101 AIDS cases, 121 CVD cases, and 99 non-AIDS-defining malignancies. IL-6 was more strongly associated with most end points, compared with hsCRP. IL-6 appeared to be a stronger predictor than D-dimer for CVD and non-AIDS-defining malignancies, but 95% CIs overlapped. Independent associations of IL-6 were stronger for non-AIDS-related death (HR, 1.71; 95% CI, 1.43-2.04) and all-cause death (HR, 1.56; 95% CI, 1.33-1.84) and similar for CVD (HR, 1.35; 95% CI, 1.12-1.62) and non-AIDS-defining malignancies (HR, 1.30; 95% CI, 1.06-1.61). There was heterogeneity of IL-6 (P < .001) but not hsCRP (P = .15) or D-dimer (P = .20) as a predictor for different end points. CONCLUSIONS: IL-6 is a stronger predictor of fatal events than of CVD and non-AIDS-defining malignancies. Adjuvant antiinflammatory and antithrombotic therapies should be tested in HIV-infected individuals.

Design of a Randomized Controlled Trial for Ebola Virus Disease Medical Countermeasures: PREVAIL II, the Ebola MCM Study.

BACKGROUND: Unique challenges posed by emerging infectious diseases often expose inadequacies in the conventional phased investigational therapeutic development paradigm. The recent Ebola outbreak in West Africa presents a critical case-study highlighting barriers to faster development. During the outbreak, clinical trials were implemented with unprecedented speed. Yet, in most cases, this fast-tracked approach proved too slow for the rapidly evolving epidemic. Controversy abounded as to the most appropriate study designs to yield safety and efficacy data, potentially causing delays in pivotal studies. Preparation for research during future outbreaks may require acceptance of a paradigm that circumvents, accelerates, or reorders traditional phases, without losing sight of the traditional benchmarks by which drug candidates must be assessed for activity, safety and efficacy. METHODS: We present the design of an adaptive, parent protocol, ongoing in West Africa until January 2016. The exigent circumstances of the outbreak and limited prior clinical experience with experimental treatments, led to more direct bridging from preclinical studies to human trials than the conventional paradigm would typically have sanctioned, and required considerable design flexibility. RESULTS: Preliminary evaluation of the "barely Bayesian" design was provided through computer simulation studies. The understanding and public discussion of the study design will help its future implementation.

Investigation of Efavirenz Discontinuation in Multi-ethnic Populations of HIV-positive Individuals by Genetic Analysis.

BACKGROUND: Efavirenz (EFV) based antiretroviral therapy is expanding worldwide. However discontinuation of EFV containing regimens is common in some patients, particularly black patients, due most often to neuropsychiatric side effects. These adverse drug effects often result in premature drug discontinuation, as well as considerable morbidity. METHODS: We genotyped CYP2A6, CYP2B6 and CYP3A4, which encode enzymes principally involved in EFV metabolism, from patients enrolled in the multinational SMART, FIRST and ESPRIT studies, for whom outcome data of treatment adherence was available. Patients with loss or decrease of function single nucleotide polymorphisms (SNPs) in the above genes were assigned a risk score based upon the number of SNPs present weighted relative to whether CYP2B6 (main metabolism pathway) and/or CYP2A6 and CYP3A4 (accessory pathways) were involved. Cox regression models were used to study the association between high genetic risk and time from initiation to EFV discontinuation. Failure was defined as discontinuation of an antiretroviral regimen other than for virologic failure or protocol determined discontinuation. FINDINGS: Patients with highest pharmacogenetic risk, as defined by cumulative SNPs in CYP2A6, CYP2B6 and CYP3A4, have an increased risk of discontinuation of EFV containing therapy compared to patients with lower genetic risk scores (adjusted HR 1.9, 95% CI 1.2, 3.1, P = 0.009). High genetic risk score was not associated with an increased risk of discontinuing atazanavir or nevirapine. High genetic risk was present more often in blacks compared to non-blacks (Adjusted OR 4.5, 95% CI: 1.9,10.5), and treatment discontinuation was also increased in blacks overall (Adjusted HR 1.4, 95% CI 1.0, 1.9). However, high genetic risk was more associated with treatment discontinuation than race alone for both blacks (Adjusted OR 1.9, 95% CI 0.8, 4.8) and non-blacks (Adjusted OR 5.3, 95% CI 1.5, 18.0). INTERPRETATION: Premature discontinuation of ART delays the time to effective long term viral suppression, and is associated with significant morbidity. Pharmacogenetic testing may predict those with a high risk of EFV discontinuation, and therefore should be considered in patients in whom initiation of EFV based ART is being considered. FUNDING: Funded by NIH.

Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study.

BACKGROUND: Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. METHODS AND FINDINGS: A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with ≥3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR ≤ 60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts. In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1:393 chance of developing CKD in the next 5 y in the low risk group (risk score < 0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0-4, 103 events) and high risk groups (risk score ≥ 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. CONCLUSIONS: Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.

Interleukin-6, high sensitivity C-reactive protein, and the development of type 2 diabetes among HIV-positive patients taking antiretroviral therapy.

BACKGROUND: HIV infection is associated with increased levels of inflammatory markers. Inflammation is hypothesized to play a role in the development of type 2 diabetes. Data addressing this issue among HIV-positive participants are limited. METHODS: A cohort of 3695 participants without diabetes, taking antiretroviral therapy and with an average CD4⁺ count of 523 cells/mm³, were followed for an average of 4.6 years. Diabetes risk associated with baseline levels of high sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) was assessed using Cox proportional hazards regression models. Analyses considered baseline levels of factors associated with diabetes risk and HIV-related measures. RESULTS: One hundred thirty-seven patients developed diabetes requiring drug treatment during follow-up (8.18 per 1000 person-years). Median levels of IL-6 and hsCRP were significantly higher among those who developed diabetes compared with those who did not: 3.45 versus 2.50 pg/mL for IL-6 and 4.91 versus 3.29 µg/mL for hsCRP (P < 0.001). Adjusted hazard ratios associated with a doubling of IL-6 and hsCRP were 1.29 (95% confidence interval: 1.08 to 1.55; P = 0.005) and 1.22 (95% confidence interval: 1.10 to 1.36; P < 0.001), respectively. Body mass index (P < 0.001), age (P = 0.013), coinfection with hepatitis B or C (P = 0.03), nonsmoking status (P = 0.034), and use of lipid-lowering treatment (P = 0.008) were also associated with an increased risk of diabetes. CONCLUSIONS: These findings indicate that low-grade systemic inflammation is an underlying factor in the pathogenesis of diabetes.

Severity of cardiovascular disease outcomes among patients with HIV is related to markers of inflammation and coagulation.

BACKGROUND: In the general population, raised levels of inflammatory markers are stronger predictors of fatal than nonfatal cardiovascular disease (CVD) events. People with HIV have elevated levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer; HIV-induced activation of inflammatory and coagulation pathways may be responsible for their greater risk of CVD. Whether the enhanced inflammation and coagulation associated with HIV is associated with more fatal CVD events has not been investigated. METHODS AND RESULTS: Biomarkers were measured at baseline for 9764 patients with HIV and no history of CVD. Of these patients, we focus on the 288 that experienced either a fatal (n=74) or nonfatal (n=214) CVD event over a median of 5 years. Odds ratios (ORs) (fatal versus nonfatal CVD) (95% confidence intervals [CIs]) associated with a doubling of IL-6, D-dimer, hsCRP, and a 1-unit increase in an IL-6 and D-dimer score, measured a median of 2.6 years before the event, were 1.39 (1.07 to 1.79), 1.40 (1.10 to 1.78), 1.09 (0.93 to 1.28), and 1.51 (1.15 to 1.97), respectively. Of the 214 patients with nonfatal CVD, 23 died during follow-up. Hazard ratios (95% CI) for all-cause mortality were 1.72 (1.28 to 2.31), 1.73 (1.27 to 2.36), 1.44 (1.15 to 1.80), and 1.88 (1.39 to 2.55), respectively, for IL-6, D-dimer, hsCRP, and the IL-6 and D-dimer score. CONCLUSIONS: Higher IL-6 and D-dimer levels reflecting enhanced inflammation and coagulation associated with HIV are associated with a greater risk of fatal CVD and a greater risk of death after a nonfatal CVD event. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrial.gov Unique identifier: SMART: NCT00027352, ESPRIT: NCT00004978, SILCAAT: NCT00013611.

Biomarkers of inflammation, coagulation and microbial translocation in HIV/HCV co-infected patients in the SMART study.

BACKGROUND: Previous results from the SMART study showed that HIV/viral hepatitis co-infected persons with impaired liver function are at increased risk of death following interruption of antiretroviral therapy (ART). OBJECTIVES: To investigate the influence of fibrosis and ART interruption on levels of biomarkers of inflammation, coagulation and microbial translocation in HIV/HCV co-infected persons in the SMART study. STUDY DESIGN: All HIV/HCV co-infected persons with stored plasma at study entry and at six months of follow-up were included (N=362). D-dimer, IL-6, sCD14 and hepatic synthesized coagulation markers were measured and compared according to the liver fibrosis marker hyaluronic acid (HA) at study entry. Percent difference in changes in biomarker levels from study entry to month 6 was compared between randomization groups and according to study entry HA levels. RESULTS: At study entry, persons with elevated HA (>75ng/mL vs. ≤75ng/mL) had higher median (IQR) levels of IL-6 [4.14pg/mL (2.60-6.32) vs. 2.74pg/mL (1.88-3.97)] and soluble CD14 [2163ng/mL (1952-2916) vs. 1979ng/mL (1742-2310)] (p<0.001). Elevated HA was also associated with alterations of both pro- and anti-coagulation markers but the overall coagulation profile was not affected. Interruption of ART lead to a particularly pronounced increase in IL-6 levels in persons with elevated HA levels (p=0.01 for interaction between randomization group and continuous HA level). CONCLUSIONS: HIV/HCV co-infected persons with impaired liver function are in an enhanced pro-inflammatory state which is further exacerbated upon interruption of ART.

Adjudicated morbidity and mortality outcomes by age among individuals with HIV infection on suppressive antiretroviral therapy.

BACKGROUND: Non-AIDS conditions such as cardiovascular disease and non-AIDS defining cancers dominate causes of morbidity and mortality among persons with HIV on suppressive combination antiretroviral therapy. Accurate estimates of disease incidence and of risk factors for these conditions are important in planning preventative efforts. METHODS: With use of medical records, serious non-AIDS events, AIDS events, and causes of death were adjudicated using pre-specified criteria by an Endpoint Review Committee in two large international trials. Rates of serious non-AIDS which include cardiovascular disease, end-stage renal disease, decompensated liver disease, and non-AIDS cancer, and other serious (grade 4) adverse events were determined, overall and by age, over a median follow-up of 4.3 years for 3,570 participants with CD4+ cell count ≥300 cells/mm³ who were taking antiretroviral therapy and had an HIV RNA level ≤500 copies/mL. Cox models were used to examine the effect of age and other baseline factors on risk of a composite outcome of all-cause mortality, AIDS, or serious non-AIDS. RESULTS: Five-year Kaplan-Meier estimates of the composite outcome, overall and by age were 8.3% (overall), 3.6% (<40), 8.7% (40-49) and 16.1% (≥50), respectively (p<0.001). In addition to age, smoking and higher levels of interleukin-6 and D-dimer were significant predictors of the composite outcome. The composite outcome was dominated by serious non-AIDS events (overall 65% of 277 participants with a composite event). Most serious non-AIDS events were due to cardiovascular disease and non-AIDS cancers. CONCLUSIONS: To date, few large studies have carefully collected data on serious non-AIDS outcomes. Thus, reliable estimates of event rates are scarce. Data cited here, from a geographically diverse cohort, will be useful for planning studies of interventions aimed at reducing rates of serious non-AIDS events among people with HIV.

Short communication: CD4 T cell declines occurring during suppressive antiretroviral therapy reflect continued production of Casp8p41.

Most patients on suppressive antiretroviral therapy (ART) experience improvements in CD4 T cell count. However, some patients with undetectable viral load continue to lose CD4 T cells for unknown reasons. Casp8p41 is a host-derived protein fragment that is present only in productively infected cells and that causes the death of HIV-infected cells. We questioned whether ongoing CD4(+) T cell losses while on suppressive ART were associated with subclinical HIV replication causing production of Casp8p41. We analyzed the association of Casp8p41 content with subsequent CD4 losses in patients on continuous suppressive ART and in patients who discontinued ART after Casp8p41 content was determined, adjusting for age, baseline CD4(+) T cell count, and baseline HIV RNA level. Casp8p41 expression in memory CD4(+) T cells was measured by intracellular flow cytometry and was correlated with viral load and CD4(+) T cell change over time. In patients who stopped therapy after Casp8p41 content was determined, baseline Casp8p41 content did not predict CD4(+) T cell change. However, in patients on continuous ART, higher baseline Casp8p41 content was associated with a greater odds of a CD4(+) T cell decline at 6 months (p=0.01). Therefore, patients on suppressive ART, who have ongoing production of Casp8p41, have an increased risk of CD4 T cell losses, suggesting that subclinical HIV replication is driving both Casp8p41, which in turn causes a CD4(+) T cell decline.

HIV replication alters the composition of extrinsic pathway coagulation factors and increases thrombin generation.

BACKGROUND: HIV 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 RESULTS: Extrinsic 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. CONCLUSIONS: HIV 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.

Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons.

BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. METHODS: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. RESULTS: A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. CONCLUSIONS: In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

Biomarkers and bacterial pneumonia risk in patients with treated HIV infection: a case-control study.

BACKGROUND: Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist. METHODS: We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1∶1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls. RESULTS: Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm(3). Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively). CONCLUSIONS: In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.