HIV & HAART Interruption Increase Inflammation and Disease
Reported by Jules Levin
CROI 2009 Feb 8-12 Montreal, Canada
Here are several studies at CROI related to inflammation. The first study from SMART finds increased inflammation markers in patients developing opportunistic diseases, which is in line with their findings presented last year at CROI that patients who interrupt therapy develop increased inflammation markers and are at greater risk for morbidities and all cause death. The 2nd study below ooked to confirm HAART interruption with increased inflammation markers and they did. Findings from the HEAT study below report no differences in flammation markers between abacavir and tenofovir in HEAT. The SMART group looked in an HIV-negative groupfor comparison and found HIV+ indiduals on or off HAART had higher inflammation markers compared to HIV-negative individuals and patients not on HAART had higher inflammation markers. An interesting study below found that genital tract inflammation by looking at pro-inflammatory vaginal cytokines led to increased HIV shedding in the genital tract in HIV+ women even after controlling for HIV viral load. Other studies below support that HIV itself causes various types of inflammation including in the gut. I suggest that HIV causes systemic inflammation and in and affecting key organs including the heart, kidney, bone, and the brain and CNS, and the consequences may affect future development of premature aging and the premature development of so-called non-AIDS events and related deaths from kidney disease, bone loss, heart disease, and cognitive impairment. Studies at CROI reported high levels of brain dysfunction and cognitive impairment persists despite HAART. We know cohort studies report high rates of osteopenia and osteoporisis at very early ages in HIV+, 50% osteopenia and 5-20% osteoporosis at average ages of 45 yrs. Until researchers decide to address these issues in earnest, that is by understanding the causes and looking for interventions, patients must make sure they take prevention measures: close monitoring of these conditions with primary HIV clinician and seeing specialists, good diet/nutrition and exercise. Jules Levin
Does Activation of Inflammatory and Coagulation Pathways Independently Predict the Development of Opportunistic Disease in Patients with HIV Infection?- yes, inflammatory markers associated with opportunistic diseases
Alison Rodger*1, Z Fox1, J Lundgren2, L Kuller3, C Boesecke4, D Gey2, A Skoutelis5, M Goetz6, A Phillips1, and for the INSIGHT SMART Study Group
1Univ Coll London, UK; 2Ctr for Viral Diseases, KMA, Copenhagen, Denmark; 3Univ of Pittsburgh, PA, US; 4Natl Ctr in HIV Epi and Clinical Res, Sydney, Australia; 5Patras Univ Med Sch, Greece; and 6VA Greater Los Angeles Hlthcare System, CA, US
Background: The SMART trial demonstrated a higher risk of opportunistic disease in patients on intermittent ART compared to those on continuous ART. Markers of activation of inflammatory and coagulation pathways were measured in a nested case control design within SMART to examine associations between biomarker levels and the risk of opportunistic disease..
Methods: Patients (n = 5472) with CD4 count >350 cells/ƒÊL were randomized to continuous ART or to CD4-guided intermittent ART. For patients who developed opportunistic disease (n = 91) and matched controls (n = 182), inflammatory (high-sensitivity C-reactive protein [hs-CRP], interleukin-6 [IL-6], amyloid A, and amyloid P) and coagulation (D-dimer and prothrobmin fragment 1+2) markers were determined at baseline and during follow-up (at time of latest plasma sample prior to the opportunistic disease event for the case and at a matched time-point for the control). Conditional logistic regression analyses were carried out to assess the associations between both baseline and latest levels of each biomarker with opportunistic disease.
Results: There were 91 cases of opportunistic disease during SMART: infective (n = 72, 79%), malignant (n = 12, 13%), and other (n = 7, 8%). After adjustment for baseline CD4 count, baseline HIV RNA levels, age and prior AIDS, both IL-6 and CRP demonstrated a significant trend towards an increased risk of opportunistic disease with increasing biomarker levels at baseline. Patients with hs-CRP levels ³5 mg/mL had 3.5 (95%CI 1.5 to 8.1) higher odds of an opportunistic disease compared to those with CRP levels <1 mg/mL, ptrend = 0.003, and patients with IL-6 ³3 pg/mL had 2.4 (95%CI 1.0 to 5.4) higher odds of an opportunistic disease compared to those with an IL-6 <1.5 pg/mL, ptrend = 0..02. No other baseline biomarkers were predictive of development of an opportunistic disease. After adjustment for baseline factors and the latest CD4 counts and HIV RNA levels, the latest hsCRP (OR 7.6, 95%CI 2.0 to 28.5) for those with hs-CRP ³5 mg/mL versus those with hsCRP <1 mg/mL, Ptrend = 0.002) and the latest IL-6 (OR 2.4, 95%CI 0.7 to 8.8) for patients with IL-6 ³3 pg/mL versus those with IL-6 <1.5 pg/mL, ptrend = 0.04) were independently associated with development of an opportunistic disease.
Conclusions: Higher levels of IL-6 and hs-CRP were independently associated with development of an opportunistic disease. Although reverse causality may have influenced this association, the fact that baseline levels also predicted opportunistic disease events makes it less likely. Use of these biomarkers could provide additional prognostic information for predicting risk of development of opportunistic disease.
Effect of HAART Interruption on Plasma Inflammatory Markers Associated with Cardiovascular Disease. 24-Month Results from a Randomized Study: interruption increased inflammation markers
"PATIENTS WITH VIRAL REPLICATION DUE TO HAART INTERRUPTION (DURING AT LEAST 70% OF STUDY PERIOD) PRESENTED AN INCREASE OF INFLAMMATORY MARKERS (MCP-1, sVCAM-1, IL-6) AFTER 24 MONTHS, COMPARED WITH PATIENTS UNDER CONTINUOUS THERAPY. RESULTS WERE CONFIRMED WHEN ONLY PATIENTS WHO WERE OFF TREATMENT TROUGHOUT ALL THE STUDY PERIOD WERE CONSIDERED FOR ANALYSIS. INTERESTINGLY, THESE PROTEINS ARE RELATED WITH ENDOTHELIUM AND SUB-ENDOTHELIUM DAMAGE AT THE EARLY STEPS OF ATHEROMA PLAQUE DEVELOPMENT. THEREFORE, OUR DATA MIGHT EXPLAIN IN PART THE HARMFUL CARDIOVASCULAR EFFECT OF HAART INTERRUPTION."
Montserrat Olmo*1, C Alonso-Villaverde2, M Pearanda3, F Gutierrez4, J Romeu5, M Larrousse6, P Domingo7, J Oteo8, J Curto1, D Podzamczer1, and STOPAR Study Team
1Hospital de Bellvitge, Barcelona, Spain; 2Hospital de Reus, Tarragona, Spain; 3Hospital Son Dureta, Mallorca, Spain; 4Hospital de Elche, Alicante, Spain; 5Hospital Trias i Pujol, Barcelona, Spain; 6Hosp Clin i Provincial, Barcelona, Spain; 7Hospital de Sant Pau i la Santa Creu, Barcelona, Spain; and 8Hosp de La Rioja, Logrono, Spain
Background: HAART interruption has been associated with an increase in cardiovascular risk. We analyzed the influence of CD4-guided HAART interruption on inflammatory markers associated with cardiovascular disease (CVD).
Methods: This was a sub-study of a randomized, multicenter, 36-month completed trial. HIV+ adults with undetectable viral load >6 months, CD4 >500, and CD4 nadir >100, receiving mainly NNRTI regimens, were allocated to therapy continuation or to therapy interruption. Interleukin (IL) -6, IL-8, macrophage chemotactic protein-1 (MCP-1), sVCAM-1, sCD40L, sP-selectin, and t-PA were measured by a multiplex cytometric bead-based assay (FlowCytomix Multiplex; BenderMedsystems; Austria) at baseline, and months 12, 24, and 36. Therapy-interruption patients with at least 70% time off HAART during the study period were analyzed. Data are presented as percentage of change from baseline and median values at each time point; 24-month results are presented.
Results: We included 77 eligible patients (44 therapy continuation, 33 therapy interruption). Groups were comparable for baseline characteristics: 77.9% men, median age 41 years, 36.4% homosexual, 32.5% former drug users, 6.5% AIDS, CD4 846 cells/mm3, total cholesterol/HDL-c/ LDL-c 5.1/1.3/3 mmol/L, triglycerides 1.7 mmol/L, glucose 5.1 mmol/L, and 83.1% NNRTI-based HAART. MCP-1 and sV-CAM-1 increased from baseline to month 12 and 24 only in therapy-interruption group. MCP-1 ranged from 255..5 pg/mL to 397 (p <0.001) at month 12 and 358.1 (p <0.002) at month 24. sV-CAM-1 ranged from 4052.5 ng/mL to 4833.8 (p <0.001) and 4706.5 (p =0.011), respectively. The percentage of change by treatment arm is shown in Figures 1 and 2; significant differences between therapy interruption and therapy continuation are evident at month 12. IL-6 increased from baseline to months 12 and 24 in therapy interruption group (p = 0.008 and p <0.001, respectively) and decreased in the therapy-continuation group (p <0.001 and p <0.001, respectively), with a trend to a significant difference between groups at month 12 (p = 0.063). No significant changes were observed in IL-8, sP-selectin, t-PA, or sCD40L. When only patients off HAART throughout the study period were considered for analysis, all the preceding results were confirmed.
Conclusions: Patients with viral replication due to HAART interruption presented elevated inflammatory markers (MCP-1, sVCAM-1, and IL-6) after 24 months when compared to those under viral control. As these cytokines correlate with endothelial damage and development of atherosclerotic plaque, our data may partially explain the harmful cardiovascular effect of HAART interruption. _
Expression of the Procoagulant Tissue Factor Is Increased on Monocytes in HIV Infection and Is Related to Immune Activation, Microbial Translocation, and Heightened Fibrinolysis
Elizabeth Mayne*1, N Funderburg2, M Kowlinowska2, W Jiang2, S Sieg2, and M Lederman2
1Univ of the Witwatersrand and Natl Hlth Lab Svc, Johannesburg, South Africa and 2Case Western Reserve Univ, Cleveland, OH, US
Background: Patients with HIV disease and AIDS are at heightened risk for vascular thrombosis. We hypothesized that this may be related, in part, to the microbial translocation and increased immune activation seen in HIV+ patients, as the procoagulant nature of inflammation and the up-regulated expression of tissue factor (TF) by lipopolysaccharide (LPS) are both well-described.
Methods: Peripheral blood was taken from HIV infected individuals and uninfected controls. Surface expression of tissue factor on monocytes and indices of cellular activation on T cells were measured by flow cytometry in fresh whole blood samples and also in peripheral blood mononuclear cells after cultivation with bacterial Toll-like receptor (TLR) ligands. Levels of D-dimers (a measure of fibrinolysis), and soluble CD14 (a measure of TLR 4 ligation by LPS) were measured by ELISA. Statistical analysis was performed using Wilcoxon signed rank tests.
Results: LPS and flagellin stimulation increased surface expression of TF on monocytes in vitro (mean percentage of TF + monocytes: unstimulated = 9.32%, LPS = 42.67%, flagellin = 44.1%, n = 7, p <0.001). The proportion of freshly obtained monocytes expressing TF differed significantly among HIV- donors, HIV+ patients with controlled (viral load <400) and uncontrolled viremia (viral load >400) (medians = 11%, 29%, and 47%, respectively, p <0.05). Up-regulation of TF expression correlated with indices of immune activation (percentage of CD38+ HLA-DR+ CD8+ T cells, R2 = 0.52). Among HIV+ individuals (n = 30) compared with controls (n = 10), plasma levels of soluble CD14 (median = 1592 and 1159 pg/mL, respectively, p <0.017) and levels of D-dimers (means = 434 and 213 fibrinogen equivalent units, respectively, p <0.05) were significantly increased, suggesting increased microbial translocation and fibrinolysis in patients. Tissue factor expression directly correlated with D-dimer and soluble CD14 levels in HIV+ patients with uncontrolled viremia (R2 = 0.68 and 0.33, respectively)
Conclusions: Microbial TLR ligands induce monocyte surface expression of the procoagulant TF. Monocyte TF expression is increased in HIV infected persons and correlates well with indices of immune activation. Among untreated patients, TF levels also correlate with markers of TLR ligation and fibrinolysis. We propose that sustained microbial translocation contributes to immune activation and the tendencies to thrombosis seen in HIV infection.
Increased Carotid Intima Media Thickness Is Associated with Depletion of Circulating Myeloid Dendritic Cells in Patients on Suppressive ART
M Lichtner1, R Rossi1, R Cuomo1, S Strano1, A Massetti1, Claudio M Mastroianni*2, and V Vullo1
1Sapienza Univ, Rome, Italy and 2Sapienza Univ, Polo Pontino, Latina, Italy
Background: The pathogenesis of accelerated atherosclerosis in HIV-infected patients has not well elucidated. Recent lines of evidence indicate that the accumulation of dendritic cells (DC) in the atheroma, especially myeloid DC (mDC), could stimulate both T cell recruitment and activation and may facilitate the release of chemokines, cytokines, and other inflammatory mediators, which are involved in the development and progression of HIV-associated atherosclerosis. We measured in patients on suppressive ART circulating mDC and plasmacytoid DC (pDC) and carotid intima media thickness (IMT), as marker for underlying atherosclerosis.
Methods: The study population included 36 HIV-infected patients (23 male, 13 female; age range 35 to 61 years) on suppressive ART regimen (median CD4 = 355 cells/ƒÊL). Controls were uninfected adults matched 1:1 to the HIV-infected group by age, gender, race, body mass index, and traditional cardiovascular risk factors. pDC and mDC were assessed by using a new whole blood single-platform based on TruCOUNT assay. The carotid IMT was measured separately in both right and left sides (6 predefined segments per side) using a color-doppler ultrasonography. The statistical analysis was done by the Mann-Whitney U test and the Spearman rank correlation test.
Results: The average value of carotid IMT (mean±SE) was significantly higher in the HIV-infected patients versus healthy controls (0.79 vs 0.6) (p <0.01). Despite effective ART, patients exhibited a significant reduction of circulating pDC and mDC when compared with healthy donors. The median pDC counts were 2078 cells/mL in patients vs 10,179 cells/mL of controls (p <0.001); the median mDC counts were 9453 cells/mL in patients vs 13,265 cells/mL of controls (p <0.04). The lowest levels of DC, especially mDC, were found in patients who had a greater increase in carotid IMT. The analysis of the correlation showed a statistically inverse association between the carotid IMT and the absolute number of mDC (-0.34; p = 0.03) No significant correlation was found between circulating pDC and carotid IMT.
Conclusions: The present findings suggest that the depletion of DC, especially, mDC in peripheral blood correlates with accelerated atherosclerosis in HIV-infected patients in spite of a suppressive ART regimen. It is possible a recruitment of mDC in the atheroma where these cells contribute to the tissue inflammation and atherosclerotic plaque destabilization.
Similar Reductions in Markers of Inflammation and Endothelial Activation after Initiation of Abacavir/Lamivudine or Tenofovir/Emtricitabine: The HEAT Study
Grace McComsey*1, K Smith2, P Patel3, N Bellos4, L Sloan5, P Lackey6, P Kumar7, D Sutherland-Phillips3, L Yau3, and M Shaefer3
1Case Western Reserve Univ Sch of Med, Cleveland, OH, US; 2Rush Univ Med Ctr, Chicago, IL, US; 3GlaxoSmithKline, Research Triangle Park, NC, US; 4Southwest Infectious Disease Assoc, Dallas, TX, US; 5North Texas Infectious Disease Consultants, Dallas, US; 6ID Consultants, Charlotte, NC, US; and 7Georgetown Univ Sch of Med, Washington, DC, US
Background: Endothelial dysfunction and chronic inflammation have been reported in HIV-1-infected subjects. In STACCATO, elevations in the endothelial marker vascular cell adhesion molecule-1 (sVCAM-1) were observed during treatment interruption. In SMART, baseline elevations in interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) were proposed as a mechanism for possible increased cardiovascular events in subjects taking abacavir (ABC). This analysis compared the effects of ABC/lamivudine (3TC) and tenofovir/embricitabine (TDF/FTC) on these biomarkers in a prospective, randomized study of ART-naive subjects to investigate causality.
Methods: Available samples from subjects randomized to ABC/3TC or TDF/FTC each with lopinavir/ritonavir were analyzed at baseline and weeks 48 and 96 for sVCAM-1, IL-6, and hsCRP. Biomarker concentrations were measured by Quest Diagnostics using ELISA (sVCAM-1, IL-6) and fixed rate nephelometry (hsCRP).
Results: This analysis included 476 subjects: mean age 39 years, 15% female, 45% non-white, with baseline median HIV-1 RNA and CD4+ of 4.88 log10 copies/mL and 211 cells/mm3, respectively. Mean percentage changes from baseline in sVCAM-1 and IL-6 were statistically significant at weeks 48 and 96 in both treatment arms. Reduction in hs-CRP from baseline was statistically significant in the TDF/FTC arm only. However, the reductions were not significantly different between arms for any of the 3 biomarkers (p >0.05). The low number of cardiovascular-related events (none related to study drug), ABC/3TC:1; TDF/FTC: 2, prevented correlation with any of the biomarkers.
Conclusions: Similar decreases in markers of inflammation and endothelial activation were observed over 96 weeks of treatment with ABC/3TC or TDF/FTC.. These data do not suggest that ABC/3TC or TDF/FTC contribute to an increase in cardiovascular risk mediated by inflammation or worsening endothelial activation. The findings from this randomized, prospective data do not support the hypothesis of increased inflammation attributed to ABC from recent observational, cohort studies.
Markers of Inflammation, Coagulation, and Renal Function in HIV-infected Adults in the Strategies for Management of ART Study and in 2 Large Population-based Studies, Coronary Artery Risk Development in Young Adults and Multi-Ethnic Study of Atherosclerosis
Jacqueline Neuhaus*, D Jacobs, and the INSIGHT SMART, MESA and CARDIA Study Groups
Univ of Minnesota, Minneapolis, US
Background: In the Strategies for Management of ART (SMART) trial, elevated study entry levels of interleukin-6 (IL-6) and D-dimer were strongly related to all-cause mortality and to cardiovascular disease (CVD). These markers, as well as high-sensitivity C-reactive protein (hsCRP) and cystatin-C, are associated with CVD and mortality in the general population. Understanding the magnitude by which these and other biomarkers are elevated as a consequence of HIV infection or ART could guide the development of interventions.
Methods: IL-6, hsCRP, D-dimer, and cystatin-C were measured by the same laboratory for SMART, the Coronary Artery Development in Young Adults (CARDIA) Study, and the Multi-Ethnic Study of Atherosclerosis (MESA). The latter 2 studies were population based and HIV infection was not ascertained, but was assumed to be rare and AIDS death was <1%. Comparisons between 33- to 44-year-old black and white participants enrolled by US sites in SMART and CARDIA and between 45 and 76 year old black, Hispanic, and white participants in SMART and MESA were made. Using log (natural) transformed values, analysis of covariance was carried out with the following co-variates: age, race, gender, body mass index, smoking, total/HDL cholesterol, diabetes, and blood pressure or lipid lowering treatment.
Results: At study entry median CD4+ counts were 557 and 584 in the 33- to 44-year-old and the 45- to 76-year old SMART age groups, respectively. More than 70% of SMART participants were on ART. Unadjusted medians of the biomarkers at study entry in SMART (assessed in 2002 to 2006) and MESA (2000 to 2002) and at year 15 in CARDIA (2000 to 2001) and percentage differences between the studies adjusted for the co-variates above (derived from natural log transformed values) are below. For SMART participants, median D-dimer was higher for those not taking ART at entry compared to those taking ART (0.49 vs 0.29 μg/mL). D-dimer levels for those on and off ART in SMART were higher than in MESA (p <0.001 for both). Other markers did not vary in a consistent manner by use of ART
Conclusions: Since levels of hsCRP, IL-6, D-dimer ,and cystatin-C are associated with risk of CVD or mortality in the general population, the higher levels of these markers in HIV-infected participants would predict adverse clinical outcomes.
Cervicovaginal Shedding of HIV-1 Is Related to Genital Tract Inflammation Independent of Changes in Vaginal Microbiota
Caroline Mitchell*1, J Hitti1, K Paul1, K Agnew1, R Gausman1, S Cohn2, A Luque2, and R Coombs1
1Univ of Washington, Seattle, US and 2Univ of Rochester, NY, US
Background: Genital tract inflammation from infection or other causes may increase genital shedding of HIV-1. We examined the relationship of pro-inflammatory vaginal cytokines and secretory leukocyte protease inhibitor (SLPI) with genital HIV-1 shedding after controlling for genital co-infections.
Methods: We enrolled 57 HIV-1-infected women in a prospective, observational study in Seattle, Washington (n = 38) and Rochester, New York (n = 19) and followed them every 3 to 4 months for a total of 391 visits (median visits per person, 6). At each visit, plasma and cervicovaginal lavage (CVL) were tested for HIV-1 RNA using an independently validated quantitative polymerase chain reaction (qPCR) assay. Vaginal swabs were tested for bacterial vaginosis/intermediate flora (Gram stain), yeast (culture), hydrogen peroxide-producing (H2O2+) Lactobacillus colonization (culture), Trichomonas vaginalis (In-Pouch), Neisseria gonorrhoeae, and Chlamydia trachomatis (Amplicor PCR). CVL was tested for interleukins (IL) -1b, -6, and -8 and SLPI using ELISA. We used linear regression with generalized estimating equations to examine effects of log10 cytokine concentrations on log10 CVL HIV-1 RNA, adjusted for log10 plasma HIV RNA, abnormal vaginal flora, H2O2+ Lactobacillus colonization, yeast and T.. vaginalis.
Results: Of 391 visits, we obtained complete data for analysis for 348 (89%). Mean entry CD4 count was 456±285 cells/ƒÊL, and use of ART was reported at 54% of baseline visits. Log10 CVL IL-1b and IL-8 were significantly associated with log10 CVL HIV-1 RNA and this persisted after adjusting for log10 plasma HIV RNA. For each doubling of log10 IL-1b, the geometric mean log10 CVL HIV-1 concentration was increased 1.20-fold (p = 0.001); for a doubling of IL-8, it increased 1.24-fold (p <0.001). After adjusting for the presence of H2O2+ Lactobacillus (61% visits), bacterial vaginosis or intermediate vaginal flora (45%), yeast (20%), and T. vaginalis (5%), this relationship was attenuated but still significant (IL-1b, p = 0.031; IL-8, p <0.001.)
Conclusions: The pro-inflammatory cytokines IL-1b and IL-8 are associated with higher cervicovaginal HIV-1 RNA concentrations, an association which persists after controlling for plasma viral load and vaginal microbial co-factors. This association suggests that there may be additional, non-infectious causes of inflammation that increase cervicovaginal HIV-1 shedding.
A Case Control Assessment of Platelet Function in HIV-1+ and HIV-1- Individuals
Claudette Satchell*1, A Cotter2, E O'Connor2, A Peace3, T Tedesco3, A Clare2, J Lambert1,2, G Sheehan1,2, D Kenny3, and P Mallon1,2
1Univ Coll Dublin, Ireland; 2Mater Misericordiae Univ Hosp, Dublin, Ireland; and 3Royal Coll of Surgeons in Ireland, Dublin
Background: Although dyslipidemia, inflammation, and endothelial dysfunction have been linked to increased cardiovascular disease (CVD) observed with HIV-1 infection and ART, the role of platelets is yet to be determined. We hypothesised that HIV infection would disrupt platelet reactivity.
Methods: We compared platelet reactivity in 20 fasted HIV+ subjects and 20 matched HIV- controls by measuring time-dependent platelet aggregation (by light absorbance) upon exposure to increasing concentrations of platelet agonists adenosine diphosphate (ADP), collagen, epinephrine, and thrombin receptor-activating peptide (TRAP). We analyzed relationships between platelet aggregation and demographic, treatment-related and inflammatory parameters using regression with data presented as median [IQR] unless otherwise stated.
Results: Groups were matched for age (HIV+ mean [SD] 34  years vs 34  years for control) and gender (both groups 65% male). In the HIV+ group, mean [SD] CD4+ T cell count was 329  cells/ƒÊL, HIV RNA was 50  copies/mL with 80% on ART. In the HIV+ group, both ADP and TRAP induced less platelet aggregation at sub-maximal concentrations in a pattern suggesting non-competitive inhibition (ADP 70 % vs 77 % aggregation at 10 mM, p = 0.035; TRAP 75 % vs 82 % at 10 mM, p = 0.011 and 79 % vs 86 % at 20 ƒÊM, p = 0.012). In contrast collagen and epinephrine affected platelet aggregation in a pattern suggesting competitive inhibition. Collagen induced less aggregation at mid-range concentrations (5 % vs 23 %, at 0.07 mg/mL, p = 0.007 and 65 % vs 73 % at 0.14 mg/mL, p = 0.014) with the concentration of collagen required to induce 50% aggregation (EC50) higher in the HIV+ group (0.11 [0.06] mg/mL vs 0.08 [0.03], p = 0.012). In contrast, the EC50 for epinephrine was lower in the HIV+ group (4.19 [7.47] mM vs 19.7 [109.58] mM, p = 0.014). In multivariate regression, CD8 percentage and being HIV+ were independently associated with ADP-induced and TRAP-induced platelet aggregation respectively while higher neutrophil count and lower diastolic blood pressure were independently associated with collagen-induced platelet aggregation.
Conclusions: This is the first study to show platelet dysfunction at multiple levels in HIV+ subjects with both clinical and HIV parameters associated. Further research into underlying mechanisms and examining the effect of ART is needed to determine how platelet dysfunction links to CVD in HIV+
96-Week Effects of Suppressive Efavirenz-containing ART, Abacavir, and Sex on High-sensitivity C-reactive Protein: ACTG A5095: I don't think this study compared effects on hsCRP by viral response, in other words patients achieving viral suppression may have improved hsCRP
Cecilia Shikuma*1, E Zheng2, H Ribaudo2, J Andersen2, M Glesby3, W Meyer III4, K Tashima5, B Bastow6, D Kuritzkes7, R Gulick3, and AIDS Clinical Trials Group A5095
1Univ of Hawaii, Honolulu, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Weill Med Coll of Cornell Univ, New York, NY, US; 4Quest Diagnostics, Baltimore, MD, US; 5Brown Univ, Providence, RI, US; 6Social & Sci Systems Inc, Silver Spring, MD, US; and 7Brigham and Women`s Hosp, Boston, MA, US
Background: High-sensitivity C-reactive protein (hs-CRP) levels predict cardiovascular risk and are associated with mortality in HIV-infected women. Indinavir-based therapy has been reported to result in stable or decreased hs-CRP levels. No information is available on hs-CRP changes with NNRTI-based therapy. We assessed the 96-week effects of efavirenz (EFV) -based therapy with or without abacavir (ABC) on hs-CRP levels among ARV-naive patients within the AIDS Clinical Trials Group A5095 trial.
Methods: hs-CRP was assayed in banked baseline and week-96 sera from 100 participants with HIV RNA <50 copies/mL at study weeks 24 and 96 who were randomized to and remained (through week 96 of study) on 1 of the 2 EFV-containing regimens of A5095: zidovudine (ZDV)/lamivudine (3TC)+EFV or ZDV/3TC/ABC+EFV. Analyses utilized all women enrolled in A5095 who satisfied these criteria with sufficient sample volume available (n = 39) and 61 randomly selected men from n = 346. hs-CRP levels at baseline and changes from week 0 to 96 were compared by sex and randomization arm by Wilcoxon rank sum test. Shifts in hs-CRP distribution were estimated by the Hodges-Lehmann method. Associations between week 0 to 96 changes in hs-CRP and week 0 to 96 changes in CD4 counts and fasting metabolic parameters were examined by Spearman correlation coefficients.
Results: The median hs-CRP level in the entire cohort was 2.3 mg/L (Q1 0.9, Q3 4.9) at baseline and not different for men and women (median 1..6 mg/L vs 2.6 mg/L, p = 0.36). Overall, there was an increase in hs-CRP from week 0 to 96 (median 1.3, p <0.001, [95%CI 0.7 to 2.7]). A larger increase in hs-CRP was seen for women compared to men (median 3.7 [95%CI 1.7 to 7.2] mg/L vs 0.5 [-0.3 to 1.3] mg/L, p = 0.001, shift in center of distribution 3.3 mg/L [95%CI 1.3 to 5.8]). This change was significant in women (p <0.001) but not in men (p = 0.15). No significant difference in hs-CRP levels was noted between the arms with (n = 39) and without ABC (n = 61), at baseline (median 3.2 mg/L vs 2..0 mg/L, p = 0.25) or change to week 96 (median 1.7 mg/L vs 1.1 mg/L, p = 0.50). Significant correlations were not detected between changes in hs-CRP and changes in CD4 count or fasting metabolic measures (p >0.30).
Conclusions: Durably suppressive therapy with EFV-based regimens did not improve hs-CRP levels over a 96-week period. Overall, an increase was seen which was greater for women than men. Inclusion of ABC had no significant effect on changes in hs-CRP levels.