Understanding the relationship between type-2 diabetes, MRI markers of neurodegeneration and small vessel disease, and dementia risk: a mediation analysis.

To explore to which extent neurodegeneration and cerebral small vessel disease (SVD) could mediate the association between type-2 diabetes and higher dementia risk. The analytical sample consisted in 2228 participants, out of the Three-City study, aged 65 and older, free of dementia at baseline who underwent brain MRI. Diabetes was defined by medication intake or fasting or non-fasting elevated glucose levels. Dementia status was assessed every 2 to 3 years, during up to 12 years of follow-up. Brain parenchymal fraction (BPF) and white matter hyperintensities volume (WMHV) were selected as markers of neurodegeneration and cerebral SVD respectively. We performed a mediation analysis of the effect of baseline BPF and WMHV (mediators) on the association between diabetes and dementia risk using linear and Cox models adjusted for age, sex, education level, hypertension, hypercholesterolemia, BMI, smoking and alcohol drinking status, APOE-ε4 status, and study site. At baseline, 8.8% of the participants had diabetes. Diabetes (yes vs. no) was associated with higher WMHV (ßdiab = 0.193, 95% CI 0.040; 0.346) and lower BPF (ßdiab = -0.342, 95% CI -0.474; -0.210), as well as with an increased risk of dementia over 12 years of follow-up (HRdiab = 1.65, 95% CI 1.04; 2.60). The association between diabetes status and dementia risk was statistically mediated by higher WMHV (HRdiab=1.05, 95% CI 1.01; 1.11, mediated part = 10.8%) and lower BPF (HRdiab = 1.12, 95% CI 1.05; 1.20, mediated part = 22.9%). This study showed that both neurodegeneration and cerebral SVD statistically explained almost 30% of the association between diabetes and dementia.

Understanding factors associated with the trajectory of subjective cognitive complaints in groups with similar objective cognitive trajectories.

BACKGROUND: Cognitive complaints are often regarded as an early sign of Alzheimer's disease (AD) but may also occur in several other conditions and contexts. This study examines the correlates of cognitive complaint trajectories over a 5-year period in individuals who shared similar objective cognitive trajectories. METHODS: We analyzed a subsample (n = 1748) of the MEMENTO cohort, consisting of individuals with subjective cognitive decline or mild cognitive impairment at baseline. Participants were stratified based on their latent MMSE trajectory over a 5-year period: "high and increasing," "subtle decline," and "steep decline." Within each of the three strata, we used a latent-class longitudinal approach to identify distinct trajectories of cognitive complaints. We then used multiple logistic regressions to examine the association between these complaint trajectories and several factors, including AD biomarkers (blood pTau/Aß42 ratio, cortical thickness, APOE genotype), anxiety, depression, social relationships, a comorbidity-polypharmacy score, and demographic characteristics. RESULTS: Among participants with high and increasing MMSE scores, greater baseline comorbidity-polypharmacy scores (odds ratio (OR) = 1.30, adjusted p = 0.03) were associated with higher odds of moderate and increasing cognitive complaints (as opposed to mild and decreasing complaints). Baseline depression and social relationships also showed significant associations with the complaint pattern but did not survive correction for multiple comparisons. Among participants with subtle decline in MMSE scores, greater baseline depression (OR = 1.76, adjusted p = 0.02) was associated with higher odds of moderate and increasing cognitive complaints (versus mild and decreasing). Similarly, baseline comorbidity-polypharmacy scores and pTau/Aß42 ratio exhibited significant associations, but they did not survive correction. Among participants with a steep decline in MMSE scores, greater baseline comorbidity-polypharmacy scores increased the odds of moderate complaints (versus mild, OR = 1.38, unadjusted p = 0.03, adjusted p = 0.32), but this effect did not survive correction for multiple comparisons. CONCLUSIONS: Despite similar objective cognitive trajectory, there is heterogeneity in the subjective perception of these cognitive changes. This perception was explained by both AD-related and, more robustly, non-AD-related factors. These findings deepen our understanding of the multifaceted nature of subjective cognitive complaints in individuals at risk for dementia and underscore the importance of considering a range of factors when interpreting cognitive complaints.

Investigating the association between cancer and the risk of dementia: Results from the Memento cohort.

INTRODUCTION: Studies on the association of cancer and risk of dementia are inconclusive due to result heterogeneity and concerns of survivor bias and unmeasured confounding. METHODS: This study uses data from the Memento cohort, a French multicenter cohort following persons with either mild or isolated cognitive complaints for a median of 5 years. Illness-death models (IDMs) were used to estimate transition-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for incident cancer in relation to dementia from time since study entry. RESULTS: The analytical sample (N = 2258) excluded 65 individuals without follow-up information. At the end of follow-up, 286 individuals were diagnosed with dementia, 166 with incident cancer, and 95 died. Incident cancer was associated with a reduced risk of dementia (HR = 0.58, 95% CI = 0.35-0.97), with a corresponding E-value of 2.84 (lower CI = 1.21). DISCUSSION: This study supports a protective relationship between incident cancer and dementia, encouraging further investigations to understand potential underlying mechanisms.

ASSESSMENT OF EARLY CHANGES IN SPECTRAL DOMAIN-OPTICAL COHERENCE TOMOGRAPHY AFTER INITIATION OF TREATMENT WITH INTRAVITREAL AFLIBERCEPT (EYLEA) OVER A 12-WEEK PERIOD FOR PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Multicenter French Study (START).

PURPOSE: To assess early changes in spectral-domain optical coherence tomography during the loading phase with intravitreal aflibercept therapy in patients with neovascular age-related macular degeneration. METHODS: In this prospective, open-label, single-arm, multicenter study, patients with neovascular age-related macular degeneration, who were antivascular endothelial growth factor treatment-naïve, received three monthly initial doses of intravitreal aflibercept 2 mg. The primary outcome was the proportion of patients with dry spectral-domain optical coherence tomography at 12 weeks, defined as an absence of intraretinal edema, intraretinal cysts, subretinal fluid, and subretinal pigment epithelium fluid. RESULTS: Fifty eyes of 50 patients were investigated. At 12 weeks, 34.0% (17/50) had dry spectral-domain optical coherence tomography. Marked reductions were observed for all other spectral-domain optical coherence tomography parameters. The mean macular central thickness fell significantly from 463.2 ± 184.3 µm at baseline to 288.9 ± 76.8 µm at Week 12 (P < 0.0001). The mean best-corrected visual acuity also improved significantly from 61.0 ± 16.0 letters at baseline to 66.6 ± 19.0 letters at Week 12 (P = 0.0006). CONCLUSION: The anatomic and functional outcomes improved over the 12-week study period. All outcome variables peaked after the third aflibercept injection, confirming the benefit of three initial doses.

Efficacy and safety of varenicline for smoking cessation in people living with HIV in France (ANRS 144 Inter-ACTIV): a randomised controlled phase 3 clinical trial.

BACKGROUND: Tobacco smoking is common in people living with HIV, but high-quality evidence on interventions for smoking cessation is not available in this population. We aimed to assess the efficacy and safety of varenicline with counselling to aid smoking cessation in people living with HIV. METHODS: The ANRS 144 Inter-ACTIV randomised, parallel, double-blind, multicentre, placebo-controlled phase 3 trial was done at 30 clinical hospital sites in France. People living with HIV who had smoked at least ten cigarettes per day for 1 year or longer, were motivated to stop smoking, were not dependent on another psychoactive substance, and had no history of depression or suicide attempt were eligible. Using a computer-generated randomisation sequence, we allocated (1:1) the patients to receive either varenicline titrated to two 0·5 mg doses twice daily or placebo twice daily for 12 weeks, plus face-to-face counselling. Patients and investigators were masked to treatment group allocation. Patients who were not abstinent at week 24 were offered open-label varenicline for 12 additional weeks. The primary outcome was the proportion of smokers continuously abstinent from week 9 to week 48. Smoking status was confirmed by carbon monoxide in exhaled air. Primary analyses were done in both the intention-to-treat (ITT) population and modified ITT (mITT) population, which comprised all patients who took at least one tablet of their assigned study treatment. The safety analyses were done in the mITT population. The trial is registered at ClinicalTrials.gov, number NCT00918307. The trial status is complete. FINDINGS: From Oct 26, 2009, to Dec 20, 2012, of 303 patients assessed for eligibility, 248 patients were randomly assigned to the varenicline group (n=123) or the placebo group (n=125). After randomisation, one participant initially assigned to the placebo group was excluded from the ITT analysis for a regulatory reason (no French health-care coverage). 102 patients in the varenicline group and 111 patients in the placebo group received at least one dose of their assigned treatment and were included in the mITT analysis. In the ITT analysis, varenicline was associated with a higher proportion of patients achieving continuous abstinence over the study period (week 9-48): 18 (15%, 95% CI 8-21) of 123 in the varenicline group versus eight (6%, 2-11) of 124 in the placebo group, adjusted odds ratio (OR) 2·5 (95% CI 1·0-6·1; p=0·041). In the mITT analysis, varenicline was also associated with higher continuous abstinence: 18 (18%, 95% CI 10-25) of 102 versus eight (7%, 2-12) of 111 in the placebo group (adjusted OR 2·7, 95% CI 1·1-6·5; p=0·029). The incidence of depression was 2·4 per 100 person-years (95% CI 0·6-9·5; two [2%] of 102) in the varenicline group and 12·4 per 100 person-years (95% CI 6·9-22·5; 11 [10%] of 111) in the placebo group. 14 (7%) of 213 participants had 18 cardiovascular events: six (6%) of 102 people in the varenicline group and eight (7%) of 111 people in the placebo group. INTERPRETATION: Varenicline is safe and efficacious for smoking cessation in people living with HIV and should be recommended as the standard of care. FUNDING: The French National Institute for Health and Medical Research (INSERM)-French National Agency for Research on AIDS and Viral Hepatitis (ANRS) and Pfizer.

Effect of Dietary Supplementation With Lutein, Zeaxanthin, and ω-3 on Macular Pigment: A Randomized Clinical Trial.

Importance: Nutritional uptake of lutein, zeaxanthin, and ω-3 polyunsaturated fatty acids may increase macular pigment optical density (MPOD) and thereby protect against the development of age-related macular degeneration (AMD). Objectives: To estimate the efficiency of dietary supplementation containing lutein, zeaxanthin, ω-3 polyunsaturated fatty acids, and vitamins to increase the density of macular pigment in first-generation offspring of parents with neovascular AMD. Design, Setting, and Participants: This study was a randomized clinical trial (Lutein Influence on Macula of Persons Issued From AMD Parents [LIMPIA]) with a 6-month treatment period, followed by a 6-month follow-up period. Analyses were based on the intent-to-treat principle. The setting was 2 university hospitals in France (at Bordeaux and Dijon) from January 2011 (first participant first visit) to February 2013 (last participant last visit). The analysis was conducted from January to November 2016. Participants were 120 individuals free of any retinal ocular disease. They were first-generation offspring of parents with neovascular AMD. Interventions: Participants were randomized in a 1:1 ratio to receive either 2 daily dietary supplementation capsules or placebo for 6 months. Main Outcomes and Measures: The primary assessment criterion was the evolution of MPOD after 6 months of supplementation (value of both eligible eyes) measured using the modified MPD-Visucam 200 (Carl Zeiss Meditec) and the modified Heidelberg Retina Angiograph (Heidelberg Engineering) (HRA) at 0.98° eccentricity. The statistical analysis was adjusted for hospital and for risk factors. Results: Overall, 120 participants (60 in each group) were included, and 239 eyes were analyzed (119 in the lutein plus zeaxanthin [L + Z] group and 120 in the placebo group). Their mean (SD) age was 56.7 (6.6) years, and 71.7% (n = 86) were female. A statistically significant increase in plasma lutein and zeaxanthin was shown in the L + Z group after 3 months and 6 months of treatment compared with the placebo group. However, the difference between groups in the evolution of MPOD measured by HRA 0.98° eccentricity between 6 months and baseline was 0.036 (95% CI, -0.037 to 0.110) (P = .33). Conclusions and Relevance: Among first-generation offspring of parents with neovascular AMD in the LIMPIA trial, MPOD as measured with the modified HRA and the MPD-Visucam was not modified after 6 months of lutein and zeaxanthin dietary supplementation despite plasma levels showing continuous exposure to lutein and zeaxanthin. Further research is necessary to understand the mechanism of absorption and metabolism of these nutrients in the macula, the best way to measure MPOD, and the clinical benefit for the patients. Trial Registration: clinicaltrials.gov Identifier: NCT01269697.

Causes of Death in HIV-Infected Individuals with Immunovirologic Success in a National Prospective Survey.

This prospective multi-center observational survey describes causes of death and their trends from 2000 to 2010 among treated HIV-infected patients with immunovirologic success (PIVS) in France. In 90 clinical sites providing HIV care and treatment, representing a cohort of 82,000 patients in 2010, the underlying causes of death and characteristics of deceased patients were prospectively recorded in 2000, 2005, and 2010 by using a standardized form. We provide data on PIVS, define as patients with a CD4+ T cell value above 500/mm3 and a plasma HIV-1 RNA below 50 copies/ml at their last periodic checkup before death, compare them with immunovirologic uncontrolled patients, and describe trends in these data from 2000 onward. The main underlying causes of death of the 120 PIVS recorded in 2010 were: a non-AIDS/nonviral hepatitis-related malignancy (19%), suicide (12.5%), cardiovascular disease (11.5%), and liver disease (11%). Only three PIVS died of an AIDS-related event. Socioeconomic difficulty was identified in 41% of PIVS in 2010. This percentage had constantly grown since 2000 (p < .001). Median age at death also increased (40, 46, and 52 years in 2000, 2005, and 2010, respectively; p < .001). The distribution of the main causes of death of PIVS was statistically different from that of uncontrolled patients (p < .001). Although immunovirologic control is fundamental, a parallel multidisciplinary approach to care is essential to accurately detect and treat comorbidities, particularly cancer, psychiatric disorders, and cardiovascular disease. Psychosocial aspects must be considered.

Kaposi Sarcoma Risk in HIV-Infected Children and Adolescents on Combination Antiretroviral Therapy From Sub-Saharan Africa, Europe, and Asia.

BACKGROUND: The burden of Kaposi sarcoma (KS) in human immunodeficiency virus (HIV)-infected children and adolescents on combination antiretroviral therapy (cART) has not been compared globally. METHODS: We analyzed cohort data from the International Epidemiologic Databases to Evaluate AIDS and the Collaboration of Observational HIV Epidemiological Research in Europe. We included HIV-infected children aged <16 years at cART initiation from 1996 onward. We used Cox models to calculate hazard ratios (HRs), adjusted for region and origin, sex, cART start year, age, and HIV/AIDS stage at cART initiation. RESULTS: We included 24 991 children from eastern Africa, southern Africa, Europe and Asia; 26 developed KS after starting cART. Incidence rates per 100 000 person-years (PYs) were 86 in eastern Africa (95% confidence interval [CI], 55-133), 11 in southern Africa (95% CI, 4-35), and 81 (95% CI, 26-252) in children of sub-Saharan African (SSA) origin in Europe. The KS incidence rates were 0/100 000 PYs in children of non-SSA origin in Europe (95% CI, 0-50) and in Asia (95% CI, 0-27). KS risk was lower in girls than in boys (adjusted HR [aHR], 0.3; 95% CI, .1-.9) and increased with age (10-15 vs 0-4 years; aHR, 3.4; 95% CI, 1.2-10.1) and advanced HIV/AIDS stage (CDC stage C vs A/B; aHR, 2.4; 95% CI, .8-7.3) at cART initiation. CONCLUSIONS: HIV-infected children from SSA but not those from other regions, have a high risk of developing KS after cART initiation. Early cART initiation in these children might reduce KS risk.

Immunity, inflammation and reservoir in patients at an early stage of HIV infection on intermittent ART (ANRS 141 TIPI Trial).

OBJECTIVES: The objective of this study was to assess clinical and biological changes during intermittent ART (I-ART) started early, with significant time spent on versus off ART, which has never before been studied in ART-naive patients with high nadir and current CD4 cell count. PATIENTS AND METHODS: ART-naive HIV-1-infected patients with baseline CD4 ≥ 500/mm(3) and nadir CD4 ≥ 400/mm(3) received 2 years of I-ART (6 month periods on once-daily boosted-PI-based ART, alternating with 6 month periods without ART) in a 2 year, Phase II, non-comparative multicentre trial. The trial is registered with ClinicalTrials.gov, number NCT 00820118. RESULTS: The CD4 cell count remained ≥ 500/mm(3) at 2 years in all 44 patients included in the study. The mean 2 year count was higher than the mean count at baseline in 24 patients overall (55%; 95% CI 40%-69%) and in 20 (65%; 95% CI 48%-81%) of the 31 patients who fully adhered to the trial strategy. All but three of these latter patients had HIV-1 RNA concentrations below 50 copies/mL after each 6 month 'on' period. Only one strategy-related genotypic mutation (M184I) was detected. The HIV-1 DNA median load fluctuated, but it did not differ between month 0 and month 24 (2.8 versus 2.6 log10 copies/10(6) leucocytes, P = 0.29). Biomarkers of inflammation and endothelial activation remained stable between month 0 and month 24. Naive CD4, CD8+CCR5+ and CD8+CD38+ T cell numbers tended to decline. One patient developed Burkitt's lymphoma and 12 patients reported sexually transmitted infections. CONCLUSIONS: In patients with high nadir and current CD4 cell counts, 2 year I-ART maintained the CD4 cell count above 500/mm(3), with no increase in the viral reservoir. Immune activation seems related to HIV replication, while inflammation seems to evolve independently and require specific attention.

Randomized Study of Noninferiority Comparing Prosthetic and Autologous Vein Above-Knee Femoropopliteal Bypasses.

BACKGROUND: The main aim of this study was to compare the 5 years rates of secondary patency of above-knee femoropopliteal revascularizations with autologous veins or prosthetic grafts. The secondary objectives were to compare the rates of primary patency, limb salvage, morbidity, and mortality between the 2 groups. METHODS: This was a single-blind randomized study of noninferiority (ratio 1:1), carried out in 11 centers of vascular surgery with 2 parallel groups between July 2002 and November 2005. Follow-up finished in May 2011. The monitoring protocol included a clinical examination and an ultrasound control at 1 month, 3 and 6 months, then annually. RESULTS: One hundred patients were included and randomized in the study, 52 in the prosthetic group and 48 in the autologous vein group. Four patients randomized in the vein group received a prosthetic graft. No patient was excluded from the analysis. In the in intent-to-treat analysis, the 5 years secondary patency was 84.6% in the prosthetic group (IC 95%, 71.9-93.1) and 70.8% in the autologous vein group (IC 95%: 55.9-83.1), and the difference in secondary patency between the prosthetic and the autologous vein groups was 13.8% (IC 95%, -4.4 to 32.0). In the under treatment analysis, the 5 years secondary patency was 96.2% among patients receiving a prosthesis (IC 95%, 80.4-99.9) and 90.5% among patients receiving an autologous vein (IC 95%, 66.9-98.9), and the difference in the rate of patency between prostheses and veins was 5.7% (IC 95%, -13.2 to 24.6). Although there was no significant difference at 5 years, the death rate and the rate of amputation were higher in the prosthetic group. CONCLUSIONS: Although it is impossible to conclude definitely to the noninferiority of prosthetic bypass compared with venous bypass because of the insufficient number of inclusions, this randomized study nevertheless showed at 5 years the satisfactory results obtained with prostheses compared with autologous vein for above-knee femoropopliteal bypasses.

Bone mineral density and inflammatory and bone biomarkers after darunavir-ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial.

BACKGROUND: Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen. METHODS: Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per µL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants. FINDINGS: Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine was greater in the standard group than in the NtRTI-sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI-sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p<0.0001). Seven new fractures occurred during the trial (two in the NtRTI-sparing group and five in the standard group). INTERPRETATION: A raltegravir-based regimen was associated with significantly less loss of bone mineral density than a standard regimen containing tenofovir disoproxil fumarate, and might be a treatment option for patients at high risk of osteopenia or osteoporosis who are not suitable for NtRTIs such as abacavir or tenofovir alafenamide. FUNDING: The European Union Sixth Framework Programme, Inserm-ANRS, Ministerio de Sanidad y Asuntos Sociales de España, Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories.

Diabetes and cognitive decline in a French cohort of patients infected with HIV-1.

OBJECTIVE: We investigated the relationship of diabetes and prediabetes with cognitive performances, assessed through raw test and z scores and according to neurocognitive impairment (NCI) classification in a cohort of individuals infected with HIV. METHODS: The ANRS CO3 Aquitaine cohort is a prospective hospital-based cohort of HIV-1-infected patients under routine clinical management in 6 public hospitals in southwestern France. Between 2007 and 2009, an ancillary study consisted of a neuropsychological battery of 10 tests at baseline and 2-year follow-up. The severity of NCI (normal, asymptomatic, mild, HIV dementia) was assessed according to international guidelines. RESULTS: At baseline (400 patients, 33 with prediabetes, 39 with diabetes), in cross-sectional multivariable analyses, patients with diabetes performed significantly worse on 9 neuropsychological tests that assessed memory, executive functions, attention, psychomotor speed, language, and manual dexterity. Participants with prediabetes had worse performances compared with those who had normal glycemia in 5 tests. The longitudinal analysis of the association between glycemia status at baseline and change in cognitive performances over 2-year follow-up (n = 283) suggested that patients with diabetes also showed a slightly higher decline on 5 of the 10 tests, those involving executive functions and memory functioning. Glycemia status at baseline was not significantly associated with NCI severity in cross-sectional (p = 0.44) and longitudinal (p = 0.64) analyses. CONCLUSIONS: In this hospital-based cohort of people living with HIV, diabetes, but not the other cardiovascular risk factors, is associated with worse cognitive performances in several cognitive domains and with larger decline in fewer domains over the short term.

Cancer-Related Causes of Death among HIV-Infected Patients in France in 2010: Evolution since 2000.

OBJECTIVES: The current study aimed at describing the distribution and characteristics of malignancy related deaths in human immunodeficiency virus (HIV) infected patients in 2010 and at comparing them to those obtained in 2000 and 2005. METHODS: Data were obtained from three national surveys conducted in France in 2010, 2005 and 2000. The underlying cause of death was documented using a standardized questionnaire fulfilled in French hospital wards involved in the management of HIV infection. RESULTS: Among the 728 deaths reported in 2010, 262 were cancer-related (36%). After a significant increase from 28% in 2000 to 33% in 2005 and 36% in 2010, cancers represent the leading cause of mortality in HIV infected patients. The proportion of deaths attributed to non-AIDS/non-hepatitis-related cancers significantly increased from 2000 to 2010 (11% of the deaths in 2000, 17% in 2005 and 22% in 2010, p<0.001), while those attributed to AIDS-defining cancers decreased during the same period (16% in 2000, 13% in 2005 and 9% in 2010, p = 0.024). Particularly, the proportion of respiratory cancers significantly increased from 5% in 2000 to 6% in 2005 and 11% in 2010 (p = 0.004). Lung cancer was the most common cancer-related cause of death in 2010 (instead of non-Hodgkin lymphoma so far) and represented the leading cause of death in people living with HIV overall. CONCLUSIONS: Cancer prevention (especially smoking cessation), screening strategies and therapeutic management need to be optimized in HIV-infected patients in order to reduce mortality, particularly in the field of respiratory cancers.

Recent developments in clinical trial designs for HIV vaccine research.

HIV vaccine strategies are expected to be a crucial component for controlling the HIV epidemic. Despite the large spectrum of potential candidate vaccines for both prophylactic and therapeutic use, the overall development process of an efficacious HIV vaccine strategy is lengthy. The design of clinical trials and the progression of a candidate strategy through the different clinical development stages remain methodologically challenging, mainly due to the lack of validated correlates of protection. In this review, we describe recent advances in clinical trial designs to increase the efficiency of the clinical development of candidate HIV vaccine strategies. The methodological aspects of the designs for early- (phase I and II) and later -stage (phase IIB and III) development are discussed, taking into account the specificities of both prophylactic and therapeutic HIV vaccine development.

Cardiovascular risk profile in women and dementia.

There is growing evidence for the importance of cardiovascular risk factors in dementia development, including Alzheimer's disease. As cardiovascular risk profiles vary greatly by gender, with men suffering a greater burden of cardiovascular risk in midlife, this could lead to differences in dementia risk. To explore current evidence on the association between components of the cardiovascular risk profile and dementia risk in women and men, we reviewed all studies reporting the risk of dementia associated with cardiovascular risk factors stratified by gender and found 53 eligible articles out of over 4,000 published since the year 2000. Consistent results were found: 1) for exposures acting specifically in women: Overweight/obesity (harmful) and physical activity (protective), and 2) for exposures acting similarly in women and men: Moderate alcohol (protective) and hypertension, diabetes, and depression (harmful). A modified effect of tobacco or high cholesterol/statin use remained controversial. Available data do not allow us to assess whether selection of men with healthier cardiovascular profile (due to cardiovascular death in midlife) could lead in late life either to a difference in the distribution of risk factors or to a differential effect of these risk factors by gender. We recommend that results on dementia risk factors, especially cardiovascular ones, be reported systematically by gender in all future studies. More generally, as cardiovascular risk profiles evolve over time, more attention needs to be paid to the detection and correction of cardiovascular risk factors, as early as possible in the life course, and as actively in women as in men.

Nutritional advice in older patients at risk of malnutrition during treatment for chemotherapy: a two-year randomized controlled trial.

OBJECTIVE: We tested the effect of dietary advice dedicated to increase intake in older patients at risk for malnutrition during chemotherapy, versus usual care, on one-year mortality. METHOD: We conducted a multicentre, open-label interventional, stratified (centre), parallel randomised controlled trial, with a 1∶1 ratio, with two-year follow-up. Patients were aged 70 years or older treated with chemotherapy for solid tumour and at risk of malnutrition (MNA, Mini Nutritional Assessment 17-23.5). Intervention consisted of diet counselling with the aim of achieving an energy intake of 30 kCal/kg body weight/d and 1.2 g protein/kg/d, by face-to-face discussion targeting the main nutritional symptoms, compared to usual care. Interviews were performed 6 times during the chemotherapy sessions for 3 to 6 months. The primary endpoint was 1-year mortality and secondary endpoints were 2-year mortality, toxicities and chemotherapy outcomes. RESULTS: Between April 2007 and March 2010 we randomised 341 patients and 336 were analysed: mean (standard deviation) age of 78.0 y (4·9), 51.2% male, mean MNA 20.2 (2.1). Distribution of cancer types was similar in the two groups; the most frequent were colon (22.4%), lymphoma (14.9%), lung (10.4%), and pancreas (17.0%). Both groups increased their dietary intake, but to a larger extent with intervention (p<0.01). At the second visit, the energy target was achieved in 57 (40.4%) patients and the protein target in 66 (46.8%) with the intervention compared respectively to 13 (13.5%) and 20 (20.8%) in the controls. Death occurred during the first year in 143 patients (42.56%), without difference according to the intervention (p = 0.79). No difference in nutritional status changes was found. Response to chemotherapy was also similar between the groups. CONCLUSION: Early dietary counselling was efficient in increasing intake but had no beneficial effect on mortality or secondary outcomes. Cancer cachexia antianabolism may explain this lack of effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT00459589.

Severe morbidity according to sex in the era of combined antiretroviral therapy: the ANRS CO3 Aquitaine Cohort.

OBJECTIVE: To describe trends and determinants of severe morbidity in HIV-infected women and men. DESIGN: A French prospective cohort of HIV-infected patients of both sexes and all transmission categories. METHODS: We used hospital admission data from January 2000 to December 2008. A severe morbid event (SME) was defined as a clinical event requiring hospitalization for ≥48 h, several events could be reported during hospitalization. Yearly incidence rates of SME were estimated and compared using Generalized Estimating Equations. RESULTS: Among 4,987 patients (27% women), followed for a median of 8.7 years, 1,473 (30%) were hospitalized (3,049 hospitalizations for 5,963 SME). The yearly incidence rate of hospitalization decreased in men, from 155 in 2000 to 80/1,000 person-years (PY) in 2008 and in women, from 125 to 71/1,000 PY, (p<0.001). This trend was observed for all SME except for hepatic events, stable in men (15 to 13/1,000 PY) and increasing in women (2.5 to 11.5), cardiovascular events increasing in men (6 to 10/1,000 PY) and in women (6 to 14) and non-AIDS non-hepatic malignancies increasing in men (4 to 7/1,000 PY) and stable in women (2.5). Intraveneous drug users, age >50 years, HIV RNA >10,000 copies, CD4 <500/mm3, AIDS stage, hepatitis C co-infection and cardiovascular risk factors (diabetes, high blood pressure, and tobacco use) were associated with SME. CONCLUSIONS: HIV-infected individuals in care in France require less and less frequently hospitalization. Women are now presenting with severe hepatic and cardio-vascular events. Disparities in SME between men and women are primarily explained by different exposure patterns to risk factors. Women should be targeted to benefit cardiovascular prevention policies as well as men.

Causes of death among HIV-infected patients in France in 2010 (national survey): trends since 2000.

OBJECTIVE: The Mortalité 2010 survey aimed at describing the causes of death among HIV-infected patients in France in 2010 and their evolution since 2000. DESIGN AND METHODS: A national sample of clinical sites, providing HIV care and treatment, notified and documented deaths using a standardized questionnaire. RESULTS: The 90 participating wards notified 728 deaths. Median age at death was 50 years (interquartile range 45-58) and 75% were men. The main underlying causes of death were AIDS-related (25% in 2010 vs. 36% in 2005 and 47% in 2000), non-AIDS non-viral hepatitis-related malignancy (22 vs. 17 and 11%), liver-related (11 vs. 15 and 13%), cardiovascular diseases (10 vs. 8 and 7%) and non-AIDS-related infections (9 vs. 4 and 7%). Malignancies (AIDS and non-AIDS-related) accounted for a third of all causes of death. AIDS accounted for 33% of all causes of death among patients mono-infected with HIV vs. only 13% among those co-infected with hepatitis B virus or hepatitis C virus. CONCLUSION: In 2010, 25% of the causes of death among HIV-infected patients remained AIDS-related. Improved screening and earlier HIV treatment should lead to a smaller proportion of deaths due to AIDS. The majority of patients died of various causes, whereas their HIV infection was well controlled under treatment. Improving case management of HIV-infected patients should include a multidisciplinary approach (prevention, screening, treatment), especially in oncology. Smoking cessation should be a priority goal.

Biomarkers of CD4+ T-cell activation as risk factors for tuberculosis-associated immune reconstitution inflammatory syndrome.

OBJECTIVE: Patients coinfected with HIV and Mycobacterium tuberculosis frequently experience a paradoxical worsening of tuberculosis (TB) symptoms early after the initiation of combination antiretroviral therapy (cART). This immune reconstitution inflammatory syndrome (TB-IRIS) can lead to significant morbidity and needs to be distinguished from TB recurrence due to ineffective treatment. We investigated whether plasma biomarkers could predict the occurrence of TB-IRIS. DESIGN: ANRS 129 BKVIR is a single-arm multicentre trial that enrolled 69 cART-naïve HIV-1-infected patients treated for TB. The patients received once-daily tenofovir/emtricitabine/efavirenz first-line regimen. TB-IRIS cases (IRIS+) were validated by an Event Review Committee. METHODS: A panel of 26 plasma biomarkers was monitored longitudinally for 24 weeks from cART initiation onward, using multiplexed assays and high-sensitivity ELISA. Statistical analyses of biomarkers were adjusted for test multiplicity. RESULTS: One-third of patients (n=23) experienced TB-IRIS. The inflammatory cytokines and chemokines interleukin (IL)-6, IL-8, interferon-gamma-induced protein 10 (IP-10), and tumour necrosis factor-alpha (TNF-α) showed increased plasma levels at week 4 in IRIS-positive (IRIS+) patients (P<0.05 for each biomarker). The soluble IL-2 receptor sCD25, which is released upon CD4 T-cell activation, was significantly increased at week 0 in IRIS+ patients (P<0.05), and remained elevated throughout follow-up. IL-7, a key homeostatic cytokine for CD4 T-cells, showed a trend for higher values in the TB-IRIS group. Both sCD25 and IL-7 baseline levels were independently associated with a shorter time to TB-IRIS occurrence (P=0.005 and P=0.02, respectively). CONCLUSION: These findings support a role for CD4 T-cell activation prior to massive inflammation in the development of TB-IRIS.

Fresh-frozen plasma transfusion did not reduce 30-day mortality in patients undergoing cardiopulmonary bypass cardiac surgery with excessive bleeding: the PLASMACARD multicenter cohort study.

BACKGROUND: During on-pump cardiac surgery, hemorrhagic complications occur frequently. Fresh-frozen plasma (FFP) is widely transfused to provide coagulation factors. Yet, no randomized clinical trial has demonstrated its benefits on mortality. We assessed the relationship between therapeutic transfusion of FFP and 30-day mortality in cardiac surgery patients suffering from excessive bleeding in a prospective cohort study. STUDY DESIGN AND METHODS: Adult patients who underwent on-pump cardiac surgery and experienced excessive bleeding during the 48-hour perioperative period were recruited from 15 French centers between February 2004 and January 2006. Patients who received a preventive FFP transfusion were excluded. The association between FFP transfusion and all cause 30-day mortality was estimated using a Cox proportional hazards model, adjusted for confounding. A propensity score (PS) sensitivity analysis was also performed. RESULTS: Among 967 patients included in this study, 58.1% received FFP. The median dose was 11.3 mL/kg (interquartile range, 7.6-19.5). The cumulative 30-day mortality rate was 11.3% (95% confidence interval [CI], 9.5-13.5). FFP transfusion was associated with a higher 30-day mortality (hazard ratio [HR], 3.2; 95% CI, 1.7-6.1) in univariate analysis; however, after adjusting for prognostic factors, there was no longer any association (HR, 1.5; 95% CI, 0.8-3.0, p = 0.20). The results of the PS analysis were consistent with the adjusted analysis. CONCLUSION: Among on-pump cardiac surgery patients experiencing excessive perioperative bleeding, there is no evidence of a beneficial impact of FFP transfusion on mortality.