Is long-term virological response related to CCR5 Delta32 deletion in HIV-1-infected patients started on highly active antiretroviral therapy?: CCR5 D32 in HIV treated patients

International audienceOBJECTIVE: The aim of the study was to determine whether the chemokine (C-C motif) receptor 5 (CCR5) Delta32 deletion is associated with long-term response to combination antiretroviral treatment (cART) in HIV-1-infected patients. METHODS: The genetic substudy of the Agence Nationale de Recherche sur le SIDA (ANRS) CO8 APROCO-COPILOTE cohort included 609 patients who started protease inhibitor-containing cART in 1997-1999. Patients were considered to have a sustained virological response if all plasma HIV RNA measurements in the period considered were <500 HIV-1 RNA copies/ml, allowing for a single blip. Virological response was compared between patients heterozygous for CCR5 Delta32 (Delta32/wt) and wild-type patients (wt/wt) from month 4 to year 3 and from month 4 to year 5. Logistic regression analysis was used to adjust for baseline demographical data, HIV RNA, CD4 cell count, antiretroviral exposure status, time spent on antiretroviral therapy at years 3 and 5 and adherence to treatment (month 4 to year 3 or 5). RESULTS: A sustained virological response was more frequent in Delta32/wt than in wt/wt patients from month 4 to year 3, with 66%vs. 52% of patients, respectively, showing a sustained response (P=0.02); after adjustment for potential confounders, the association of Delta32 with a sustained response was nearly significant (P=0.07). A sustained virological response was also more frequent in Delta32/wt patients up to year 5, with 48% showing a sustained response vs. 35% of wt/wt patients (P=0.01); after adjustment, Delta32 remained significantly associated with a sustained virological response up to year 5 (P=0.04). There was no association with CD4 response. CONCLUSION: The Delta32 deletion in Delta32/wt patients is associated with a beneficial virological response to cART in the long term. Whether this association is a direct effect of the Delta32 deletion remains unclear and requires confirmation in further observational studies

Delayed HIV diagnosis and initiation of antiretroviral therapy: inequalities by educational level, COHERE in EuroCoord.

OBJECTIVES In Europe and elsewhere, health inequalities among HIV-positive individuals are of concern. We investigated late HIV diagnosis and late initiation of combination antiretroviral therapy (cART) by educational level, a proxy of socioeconomic position. DESIGN AND METHODS We used data from nine HIV cohorts within COHERE in Austria, France, Greece, Italy, Spain and Switzerland, collecting data on level of education in categories of the UNESCO/International Standard Classification of Education standard classification: non-completed basic, basic, secondary and tertiary education. We included individuals diagnosed with HIV between 1996 and 2011, aged at least 16 years, with known educational level and at least one CD4 cell count within 6 months of HIV diagnosis. We examined trends by education level in presentation with advanced HIV disease (AHD) (CD4 <200 cells/μl or AIDS within 6 months) using logistic regression, and distribution of CD4 cell count at cART initiation overall and among presenters without AHD using median regression. RESULTS Among 15 414 individuals, 52, 45,37, and 31% with uncompleted basic, basic, secondary and tertiary education, respectively, presented with AHD (P trend <0.001). Compared to patients with tertiary education, adjusted odds ratios of AHD were 1.72 (95% confidence interval 1.48-2.00) for uncompleted basic, 1.39 (1.24-1.56) for basic and 1.20 (1.08-1.34) for secondary education (P < 0.001). In unadjusted and adjusted analyses, median CD4 cell count at cART initiation was lower with poorer educational level. CONCLUSIONS Socioeconomic inequalities in delayed HIV diagnosis and initiation of cART are present in European countries with universal healthcare systems and individuals with lower educational level do not equally benefit from timely cART initiation

Alzheimers Dement

Introduction: The free and cued selective reminding test is used to identify memory deficits in mild cognitive impairment and demented patients. It allows assessing three processes: encoding, storage, and recollection of verbal episodic memory. Methods: We investigated the neural correlates of these three memory processes in a large cohort study. The Memento cohort enrolled 2323 outpatients presenting either with subjective cognitive decline or mild cognitive impairment who underwent cognitive, structural MRI and, for a subset, fluorodeoxyglucose-positron emission tomography evaluations. Results: Encoding was associated with a network including parietal and temporal cortices; storage was mainly associated with entorhinal and parahippocampal regions, bilaterally; retrieval was associated with a widespread network encompassing frontal regions. Discussion: The neural correlates of episodic memory processes can be assessed in large and standardized cohorts of patients at risk for Alzheimer's disease. Their relation to pathophysiological markers of Alzheimer's disease remains to be studied

Correction to: Partnership for Research on Ebola VACcination (PREVAC): protocol of a randomized, double-blind, placebo-controlled phase 2 clinical trial evaluating three vaccine strategies against Ebola in healthy volunteers in four West African countries.

Following the publication of the original article [1], we were notified of an error in the affiliation of 3 authors of the article: Celine Roy, Laura Richert and Genevieve Chene. Their affiliation was initially mentioned as: “Partnership for Research on Ebola Virus in Liberia (PREVAIL), Monrovia, Liberia” However, their correct affiliation is: Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, CIC 1401, EUCLID/F-CRIN Clinical Trials Platform, F-33000, Bordeaux, France.tp

Delayed HIV diagnosis and initiation of antiretroviral therapy: inequalities by educational level, COHERE in EuroCoord

Objectives:In Europe and elsewhere, health inequalities among HIV-positive individuals are of concern. We investigated late HIV diagnosis and late initiation of combination antiretroviral therapy (cART) by educational level, a proxy of socioeconomic position.Design and methods:We used data from nine HIV cohorts within COHERE in Austria, France, Greece, Italy, Spain and Switzerland, collecting data on level of education in categories of the UNESCO/International Standard Classification of Education standard classification: non-completed basic, basic, secondary and tertiary education. We included individuals diagnosed with HIV between 1996 and 2011, aged at least 16 years, with known educational level and at least one CD4(+) cell count within 6 months of HIV diagnosis. We examined trends by education level in presentation with advanced HIV disease (AHD) (CD4(+) <200cells/l or AIDS within 6 months) using logistic regression, and distribution of CD4(+) cell count at cART initiation overall and among presenters without AHD using median regression.Results:Among 15414 individuals, 52, 45,37, and 31% with uncompleted basic, basic, secondary and tertiary education, respectively, presented with AHD (P trend <0.001). Compared to patients with tertiary education, adjusted odds ratios of AHD were 1.72 (95% confidence interval 1.48-2.00) for uncompleted basic, 1.39 (1.24-1.56) for basic and 1.20 (1.08-1.34) for secondary education (P <0.001). In unadjusted and adjusted analyses, median CD4(+) cell count at cART initiation was lower with poorer educational level.Conclusions:Socioeconomic inequalities in delayed HIV diagnosis and initiation of cART are present in European countries with universal healthcare systems and individuals with lower educational level do not equally benefit from timely cART initiatio

Impact of body weight on virological and immunological responses to efavirenz-containing regimens in HIV-infected, treatment-naive adults

OBJECTIVE: The prevalence of overweight and obesity is increasing among HIV-infected patients. Whether standard antiretroviral drug dosage is adequate in heavy individuals remains unresolved. We assessed the virological and immunological responses to initial efavirenz (EFV)-containing regimens in heavy compared to normal-weight HIV-infected patients. DESIGN: Observational European cohort collaboration study. METHODS: Eligible patients were antiretroviral-naïve with documented weight prior to EFV start and follow-up viral loads after treatment initiation. Cox regression analyses evaluated the association between weight and time to first undetectable viral load (50 copies/ml) after initial suppression over 5 years of follow-up. Recovery of CD4 cell count was evaluated 6 and 12 months after EFV initiation. Analyses were stratified by weight (kg) group (I - 55, 80, 85, 90, 95). RESULTS: The study included 19 968 patients, of whom 9.1, 68.3, 9.1, 5.8, 3.5, and 4.3% were in weight groups I-VI, respectively. Overall, 81.1% patients attained virological suppression, of whom 34.1% subsequently experienced viral load rebound. After multiple adjustments, no statistical difference was observed in time to undetectable viral load and virological rebound for heavier individuals compared to their normal-weight counterparts. Although heaviest individuals had significantly higher CD4 cell count at baseline, CD4 cell recovery at 6 and 12 months after EFV initiation was comparable to normal-weight individuals. CONCLUSION: Virological and immunological responses to initial EFV-containing regimens were not impaired in heavy individuals, suggesting that the standard 600 mg EFV dosage is appropriate across a wide weight range

Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response : a sub-study of the NEAT001/ANRS143 randomized trial

OBJECTIVES: NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure. METHODS: Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0-24 and C24 with time to virological failure was evaluated by Cox regression. RESULTS: Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P < 0.001). No significant relationship was demonstrated between darunavir AUC0-24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53-9.80), P = 0.269; and 1.82 (0.61-5.41), P = 0.279, respectively]. CONCLUSIONS: Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity

Partnership for Research on Ebola VACcination (PREVAC): protocol of a randomized, double-blind, placebo-controlled phase 2 clinical trial evaluating three vaccine strategies against Ebola in healthy volunteers in four West African countries

International audienceAbstract Introduction The Ebola virus disease (EVD) outbreak in 2014–2016 in West Africa was the largest on record and provided an opportunity for large clinical trials and accelerated efforts to develop an effective and safe preventative vaccine. Multiple questions regarding the safety, immunogenicity, and efficacy of EVD vaccines remain unanswered. To address these gaps in the evidence base, the Partnership for Research on Ebola Vaccines (PREVAC) trial was designed. This paper describes the design, methods, and baseline results of the PREVAC trial and discusses challenges that led to different protocol amendments. Methods This is a randomized, double-blind, placebo-controlled phase 2 clinical trial of three vaccine strategies against the Ebola virus in healthy volunteers 1 year of age and above. The three vaccine strategies being studied are the rVSVΔG-ZEBOV-GP vaccine, with and without a booster dose at 56 days, and the Ad26.ZEBOV,MVA-FN-Filo vaccine regimen with Ad26.ZEBOV given as the first dose and the MVA-FN-Filo vaccination given 56 days later. There have been 4 versions of the protocol with those enrolled in Version 4.0 comprising the primary analysis cohort. The primary endpoint is based on the antibody titer against the Ebola virus surface glycoprotein measured 12 months following the final injection. Results From April 2017 to December 2018, a total of 5002 volunteers were screened and 4789 enrolled. Participants were enrolled at 6 sites in four countries (Guinea, Liberia, Sierra Leone, and Mali). Of the 4789 participants, 2560 (53%) were adults and 2229 (47%) were children. Those < 18 years of age included 549 (12%) aged 1 to 4 years, 750 (16%) 5 to 11 years, and 930 (19%) aged 12–17 years. At baseline, the median (25th, 75th percentile) antibody titer to Ebola virus glycoprotein for 1090 participants was 72 (50, 116) EU/mL. Discussion The PREVAC trial is evaluating—placebo-controlled—two promising Ebola candidate vaccines in advanced stages of development. The results will address unanswered questions related to short- and long-term safety and immunogenicity for three vaccine strategies in adults and children. Trial registration ClinicalTrials.gov NCT02876328 . Registered on 23 August 2016