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.

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.

Realist evaluation of a theory-based life skills programme aiming to prevent addictive behaviours in adolescents: the ERIEAS study protocol.

INTRODUCTION: Adolescence is a sensitive life stage during which tobacco, alcohol and cannabis are used as ways to learn and adopt roles. There is a great deal of interest in substance use (SU) prevention programmes for young people that work to change representations of these products and help with mobilisation of life skills. Unfortunately, few existing programmes are evidence-based.In France, a programme called Expériences Animées (EA, Animated Experiences) has been developed, inspired by life skills development programmes that have been proven to be successful. The EA programme uses animated short movies and talks with high school and secondary school pupils about the use of psychoactive substances and addictions. By allowing life skills mobilisation and modifying representations and beliefs about SU, it is aimed at delaying initiation of use of psychoactive substances, preventing adolescents from becoming regular consumers, reducing the risks and harms related to the use of these substances and opening the way for adapted support measures.We are interested in understanding how, under what circumstances, through which mechanisms and among which adolescents the EA programme works. Therefore, we have developed the ERIEAS study ('Evaluation Réaliste de l'Intervention Expériences Animées en milieu Scolaire'; Realist Evaluation of the EA Intervention in Schools). METHODS AND ANALYSIS: EA will be conducted in 10 schools. A multi-case approach will be adopted with the aim of developing and adjusting an intervention theory. The study comes under the theory-driven evaluation framework. The investigation methodology will include four stages: (i) elaboration of a middle-range theory; (ii) data collection for validating/adjusting the theory; (iii) data analysis; and (iv) refinement and adjustment of the middle-range theory and definition of the programme's key functions. ETHICS AND DISSEMINATION: The study will provide evidence-based results to health authorities to help in the rollout of health promotion strategies in schools. It will provide knowledge about the strategic configurations most suitable for leading to life skills mobilisation and change young people's representations about SU. The project will be carried out with full respect of current relevant legislation (eg, the Charter of Fundamental Rights of the European Union) and international conventions (eg, Helsinki Declaration). It follows the relevant French legislation of the research category on interventional research protocol involving the human person. The protocol was approved by the Comité et Protection des Personnes (CPP), that is, Committee for the Protection of Persons CPP SUD-EST VI n°: AU 1525 and was reported to the Agence Française de Sécurité Sanitaire des Produits de Santé (ANSM) that is, the French National Agency for the Safety of Health Products. It is in conformity with reference methodology MR003 of Bordeaux University Hospital (CNIL n° 2 026 779 v0).Trial registration detailsThis research has been registered on ClinicalTrials.gov (No. NCT04110626).The research project is registered in the European database ID-RCB (No. 2019-A01003-54).

Patient-Reported Outcomes in First-Line Antiretroviral Therapy: Results From NEAT001/ANRS143 Trial Comparing Darunavir/Ritonavir in Combination With Tenofovir/Emtricitabine or Raltegravir.

BACKGROUND: There are few data comparing patient-reported outcomes (PROs) in randomized trials of initial antiretroviral therapy. We present results from a substudy of the NEAT001/ANRS143 trial. METHODS: The randomized trial compared first-line DRV/r 800/100 mg once daily plus RAL 400 mg twice daily and DRV/r plus TDF/FTC 245/200 mg once daily. Changes in PROs were assessed with 3 questionnaires: EuroQoL 5 domains (EQ-5D), Center for Epidemiologic Studies Depression (CES-D) scale, and HIV Treatment Satisfaction Questionnaire. Major depressive disorder (MDD) was defined as CES-D ≥ 16. General estimating equations were used to model change over 96 weeks in PROs from baseline. RESULTS: Of the 805 participants, 797 (99%) contributed to the substudy. Baseline PRO data were similar for the 2 randomized groups. Health status improved over time with a mean increase in EQ-5D visual analogue scale (VAS) of 8.0 by W96 [95% confidence interval (CI): 6.5 to 9.4; P < 0.001], and no statistically significant differences between groups (difference of 0.3 on VAS score (95% CI: -1.7 to 2.3); P = 0.7, global P value ≥0.05 for all domains over follow-up). There was no significant difference between groups on CES-D [difference of -0.1 (95% CI: -1.3 to 1.1); P = 0.9], or MDD during follow-up, adjusted for baseline MDD (odds ratio = 0.98, 95% CI: 0.82 to 1.18; P = 0.9). RAL + DRV/r group had lower level of convenience (P = 0.03) and fitted less well into patients' lifestyle (P = 0.007) than the TDF/FTC + DRV/r regimen, and was associated with lower treatment satisfaction [median score: 53 RAL + DRV/r vs 55 TDF/FTC + DRV/r (P = 0.001)]. CONCLUSION: PROs improved after starting antiretroviral therapy, with no statistically significant difference between groups. The lower satisfaction with RAL + DRV/r may be explained by twice-daily administration.

Chronic Hepatitis B and C Virus Infection and Risk for Non-Hodgkin Lymphoma in HIV-Infected Patients: A Cohort Study.

Background: Non-Hodgkin lymphoma (NHL) is the most common AIDS-defining condition in the era of antiretroviral therapy (ART). Whether chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection promote NHL in HIV-infected patients is unclear. Objective: To investigate whether chronic HBV and HCV infection are associated with increased incidence of NHL in HIV-infected patients. Design: Cohort study. Setting: 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). Patients: HIV-infected patients with information on HBV surface antigen measurements and detectable HCV RNA, or a positive HCV antibody test result if HCV RNA measurements were not available. Measurements: Time-dependent Cox models to assess risk for NHL in treatment-naive patients and those initiating ART, with inverse probability weighting to control for informative censoring. Results: A total of 52 479 treatment-naive patients (1339 [2.6%] with chronic HBV infection and 7506 [14.3%] with HCV infection) were included, of whom 40 219 (77%) later started ART. The median follow-up was 13 months for treatment-naive patients and 50 months for those receiving ART. A total of 252 treatment-naive patients and 310 treated patients developed NHL, with incidence rates of 219 and 168 cases per 100 000 person-years, respectively. The hazard ratios for NHL with HBV and HCV infection were 1.33 (95% CI, 0.69 to 2.56) and 0.67 (CI, 0.40 to 1.12), respectively, in treatment-naive patients and 1.74 (CI, 1.08 to 2.82) and 1.73 (CI, 1.21 to 2.46), respectively, in treated patients. Limitation: Many treatment-naive patients later initiated ART, which limited the study of the associations of chronic HBV and HCV infection with NHL in this patient group. Conclusion: In HIV-infected patients receiving ART, chronic co-infection with HBV and HCV is associated with an increased risk for NHL. Primary Funding Source: European Union Seventh Framework Programme.

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.