Comparison of oxidative stress markers in HIV-infected patients on efavirenz or atazanavir/ritonavir-based therapy

INTRODUCTION: Chronic low-grade inflammation and immune activation may persist in HIV patients despite effective antiretroviral therapy (ART). These abnormalities are associated with increased oxidative stress (OS). Bilirubin (BR) may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UGT1A1, thus increasing unconjugated BR levels, a distinctive feature of this drug. We compared changes in OS markers in HIV patients on ATV/r versus efavirenz (EFV)-based first-line therapies. MATERIALS AND METHODS: Cohort of the Spanish Research Network (CoRIS) is a multicentre, open, prospective cohort of HIV-infected patients naïve to ART at entry and linked to a biobank. We identified hepatitis C virus/hepatitis B virus (HCV/HBV) negative patients who started first-line ART with either ATV/r or EFV, had a baseline biobank sample and a follow-up sample after at least nine months of ART while maintaining initial regimen and being virologically suppressed. Lipoprotein-associated Phospholipase A2 (Lp-PLA2), Myeloperoxidase (MPO) and Oxidized LDL (OxLDL) were measured in paired samples. Marker values at one year were interpolated from available data. Multiple imputations using chained equations were used to deal with missing values. Change in the OS markers was modelled using multiple linear regressions adjusting for baseline marker values and baseline confounders. Correlations between continuous variables were explored using Pearson's correlation tests. RESULTS: 145 patients (97 EFV; 48 ATV/r) were studied. Mean (SD) baseline values for OS markers in EFV and ATV/r groups were: Lp-PLA2 [142.2 (72.8) and 150.1 (92.8) ng/mL], MPO [74.3 (48.2) and 93.9 (64.3) µg/L] and OxLDL [76.3 (52.3) and 82.2 (54.4) µg/L]. After adjustment for baseline variables patients on ATV/r had a significant decrease in Lp-PLA2 (estimated difference -16.3 [CI 95%: -31.4, -1.25; p=0.03]) and a significantly lower increase in OxLDL (estimated difference -21.8 [-38.0, -5.6; p<0.01] relative to those on EFV, whereas no differences in MPO were found. Adjusted changes in BR were significantly higher for the ATV/r group (estimated difference 1.33 [1.03, 1.52; p<0.01]). Changes in BR and changes in OS markers were significantly correlated. CONCLUSIONS: In virologically suppressed patients on stable ART, OS was lower in ATV/r-based regimens compared to EFV. We hypothesize these changes could be in part attributable to increased BR plasma levels.S

Changes in Cardiovascular Disease Risk Factors With Immediate Versus Deferred Antiretroviral Therapy Initiation Among HIV-Positive Participants in the START (Strategic Timing of Antiretroviral Treatment) Trial

Introduction-HIV infection and certain antiretroviral therapy (ART) medications increase atherosclerotic cardiovascular disease risk, mediated, in part, through traditional cardiovascular disease risk factors. Methods and Results-We studied cardiovascular disease risk factor changes in the START (Strategic Timing of Antiretroviral Treatment) trial, a randomized study of immediate versus deferred ART initiation among HIV-positive persons with CD4+ cell counts >500 cells/mm(3). Mean change from baseline in risk factors and the incidence of comorbid conditions were compared between groups. The characteristics among 4685 HIV-positive START trial participants include a median age of 36 years, a CD4 cell count of 651 cells/mm(3), an HIV viral load of 12 759 copies/mL, a current smoking status of 32%, a median systolic/diastolic blood pressure of 120/76 mm Hg, and median levels of total cholesterol of 168 mg/dL, low-density lipoprotein cholesterol of 102 mg/dL, and high-density lipoprotein cholesterol of 41 mg/dL. Mean follow-up was 3.0 years. The immediate and deferred ART groups spent 94% and 28% of follow-up time taking ART, respectively. Compared with patients in the deferral group, patients in the immediate ART group had increased total cholesterol and low-density lipoprotein cholesterol and higher use of lipid-lowering therapy (1.2%;95% CI, 0.1-2.2). Concurrent increases in high-density lipoprotein cholesterol with immediate ART resulted in a 0.1 lower total cholesterol to high-density lipoprotein cholesterol ratio (95% CI, 0.1-0.2). Immediate ART resulted in 2.3% less BP-lowering therapy use (95% CI, 0.9-3.6), but there were no differences in new-onset hypertension or diabetes mellitus. Conclusions-Among HIV-positive persons with preserved immunity, immediate ART led to increases in total cholesterol and lowdensity lipoprotein cholesterol but also concurrent increases in high-density lipoprotein cholesterol and decreased use of blood pressure medications. These opposing effects suggest that, in the short term, the net effect of early ART on traditional cardiovascular disease risk factors may be clinically insignificant.

Pasado y futuro de la infección por VIH. Un documento basado en la opinión de expertos

[EN] HIV infection is now almost 40 years old. In this time, along with the catastrophe and tragedy that it has entailed, it has also represented the capacity of modern society to take on a challenge of this magnitude and to transform an almost uniformly lethal disease into a chronic illness, compatible with a practically normal personal and relationship life. This anniversary seemed an ideal moment to pause and reflect on the future of HIV infection, the challenges that remain to be addressed and the prospects for the immediate future. This reflection has to go beyond merely technical approaches, by specialized professionals, to also address social and ethical aspects. For this reason, the Health Sciences Foundation convened a group of experts in different aspects of this disease to discuss a series of questions that seemed pertinent to all those present. Each question was presented by one of the participants and discussed by the group. The document we offer is the result of this reflection. [ES] La infección por VIH cumple ahora casi 40 años de existencia. En este tiempo, junto a la catástrofe y la tragedia que ha supuesto, ha representado también la capacidad de la sociedad moderna de asumir un reto de esta magnitud y de transformar, gracias al tratamiento antirretroviral, una enfermedad mayoritariamente letal en una enfermedad crónica, compatible con una vida personal y de relación prácticamente normales. Este aniversario parecía un momento idóneo para pararse a reflexionar sobre el futuro de la infección VIH, los retos que todavía quedan por abordar y las perspectivas para el inmediato futuro. Esa reflexión tiene que ir más allá de planteamientos meramente técnicos, de profesionales especializados, para abordar aspectos sociales y éticos. Por este motivo, la Fundación de Ciencias de la Salud convocó a un grupo de expertos en distintos aspectos de esta infección para discutir una serie de preguntas que parecieron pertinentes a todos los convocados. Cada pregunta era expuesta por uno de los participantes y discutida por el grupo. El documento que ofrecemos es el resultado de esa reflexión.For transparency purposes, we would like to inform you that GSK has contributed to the funding of this publication. Its content reflects the authors’ own opinions, criteria, conclusions and/or findings, which may not necessarily coincide with those of GSK. GSK always recommends that its products are used in accordance with the technical data sheet approved by the health authorities.S

Impact of late presentation of HIV infection on short-, mid- and long-term mortality and causes of death in a multicenter national cohort: 2004–2013

SummaryObjectivesTo analyze the impact of late presentation (LP) on overall mortality and causes of death and describe LP trends and risk factors (2004–2013).MethodsCox models and logistic regression were used to analyze data from a nation-wide cohort in Spain. LP is defined as being diagnosed when CD4 < 350 cells/ml or AIDS.ResultsOf 7165 new HIV diagnoses, 46.9% (CI95%:45.7–48.0) were LP, 240 patients died.First-year mortality was the highest (aHRLP.vs.nLP = 10.3[CI95%:5.5–19.3]); between 1 and 4 years post-diagnosis, aHRLP.vs.nLP = 1.9(1.2–3.0); and >4 years, aHRLP.vs.nLP = 1.5(0.7–3.1).First-year's main cause of death was HIV/AIDS (73%); and malignancies among those surviving >4 years (32%). HIV/AIDS-related deaths were more likely in LP (59.2% vs. 25.0%; p < 0.001). LP declined from 55.9% (2004–05) to 39.4% (2012–13), and reduced in 46.1% in men who have sex with men (MSM) and 37.6% in heterosexual men, but increased in 22.6% in heterosexual women.Factors associated with LP: sex (ORMEN.vs.WOMEN = 1.4[1.2–1.7]); age (OR31–40.vs.<30 = 1.6[1.4–1.8], OR41–50.vs.<30 = 2.2[1.8–2.6], OR>50.vs.<30 = 3.6[2.9–4.4]); behavior (ORInjectedDrugUse.vs.MSM = 2.8[2.0–3.8]; ORHeterosexual.vs.MSM = 2.2[1.7–3.0]); education (ORPrimaryEducation.vs.University = 1.5[1.1–2.0], ORLowerSecondary.vs.University = 1.3[1.1–1.5]); and geographical origin (ORSub-Saharan.vs.Spain = 1.6[1.3–2.0], ORLatin-American.vs.Spain = 1.4[1.2–1.8]).ConclusionsLP is associated with higher mortality, especially short-term- and HIV/AIDS-related mortality. Mid-term-, but not long-term mortality, remained also higher in LP than nLP. LP decreased in MSM and heterosexual men, not in heterosexual women. The groups most affected by LP are low educated, non-Spanish and heterosexual women

Differential body composition effects of protease inhibitors recommended for initial treatment of HIV infection: A randomized clinical trial

This article has been accepted for publication in Clinical Infectious Diseases ©2014 The Authors .Published by Oxford University Press on Clinical Infectious Disease 60.5. DOI: 10.1093/cid/ciu898Background. It is unclear whether metabolic or body composition effects may differ between protease inhibitor-based regimens recommended for initial treatment of HIV infection. Methods. ATADAR is a phase IV, open-label, multicenter randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Pre-defined end-points were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. Results. At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95%CI -0.6 to 21.6); and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95%CI -0.5 to 17.6). Seven vs. five patients discontinued atazanavir/ritonavir or darunavir/ritonavir due to adverse effects. Total and HDL cholesterol similarly increased in both arms, but triglycerides increased more in atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95%CI 726.7 to 4997.7; P=0.0090), limb fat (estimated difference 1403.3 gr; 95%CI 388.4 to 2418.2; P=0.0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm2; 95%CI 1.9 to 55.0; P=0.0362) increased more in atazanavir/ritonavir than in darunavir/ritonavir arm. Body fat changes in atazanavir/ritonavir arm were associated with higher insulin resistance. Conclusions. We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically-relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and total and subcutaneous fat than darunavir/ritonavir and fat gains with atazanavir/ritonavir were associated with insulin resistanceThis is an Investigator Sponsored Research study. It was supported in part by research grants from Bristol‐Myers Squibb and Janssen‐Cilag; Instituto de Salud Carlos III (PI12/01217) and Red Temática Cooperativa de Investigación en SIDA G03/173 (RIS‐EST11), Ministerio de Ciencia e Innovación, Spain. (Registration number: NCT01274780; registry name: ATADAR; EUDRACT; 2010‐021002‐38)

Long-term effects of evolocumab in participants with HIV and dyslipidemia: results from the open-label extension period

Objectives: People with HIV (PWH) are at an increased risk of atherosclerotic cardiovascular disease. Suboptimal responses to statin therapy in PWH may result from antiretroviral therapies (ARTs). This open-label extension study aimed to evaluate the long-term safety and efficacy of evolocumab up to 52\u200aweeks in PWH. Design: This final analysis of a multinational, placebo-controlled, double-blind, randomized phase 3 trial evaluated the effect of monthly subcutaneous evolocumab 420\u200amg on low-density lipoprotein cholesterol (LDL-C) during the open-label period (OLP) following 24\u200aweeks of double-blind period in PWH with hypercholesterolemia/mixed dyslipidemia. All participants enrolled had elevated LDL-C or nonhigh-density lipoprotein cholesterol (non-HDL-C) and were on stable maximally tolerated statin and stable ART. Methods: Efficacy was assessed by percentage change from baseline in LDL-C, triglycerides, and atherogenic lipoproteins. Treatment-emergent adverse events (TEAEs) were examined. Results: Of the 467 participants randomized in the double-blind period, 451 (96.6%) received at least one dose of evolocumab during the OLP (mean age of 56.4\u200ayears, 82.5% male, mean duration with HIV of 17.4\u200ayears). By the end of the 52-week OLP, the overall mean (SD) percentage change in LDL-C from baseline was -57.8% (22.8%). Evolocumab also reduced triglycerides, atherogenic lipid parameters (non-HDL-C, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, and lipoprotein[a]), and increased HDL-C. TEAEs were similar between placebo and evolocumab during the OLP. Conclusion: Long-term administration of evolocumab lowered LDL-C and non-HDL-C, allowing more PWH to achieve recommended lipid goals with no serious adverse events. Trail registration: NCT02833844. Video abstract: http://links.lww.com/QAD/C441

Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons

We show in human immunodeficiency virus-positive persons that the coronary artery disease effect of an unfavorable genetic background is comparable to previous studies in the general population, and comparable in size to traditional risk factors and antiretroviral regimens known to increase cardiovascular ris

All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997Ł2010

Abstract Background: Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIVinfected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population. Methods: We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 personyears (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender. Results: Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997. Conclusion: Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection