BMJ Open

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)

J Antimicrob Chemother

Background: Sparing of antiretroviral drug classes could reduce the toxicity and cost of maintenance treatment for HIV infection. Objectives: To evaluate the non-inferiority of efficacy and the safety of lopinavir/ritonavir (r) monotherapy versus a single-tablet regimen of efavirenz, emtricitabine and tenofovir (EFV/FTC/TDF) over 2 years. Methods: Adults on stable ART with plasma HIV-1 RNA viral load <50 copies/mL for the past 12 months and no documented treatment failure were randomized to receive either lopinavir/r or EFV/FTC/TDF for 2 years. The primary endpoint was the proportion of patients without treatment failure at week 96 (viral load <50 copies/mL at week 96, confirmed at week 98), without study treatment discontinuation, a new AIDS-defining illness, or death. Results: In the ITT analysis, the primary endpoint was reached by, respectively, 64% and 71% of patients in the lopinavir/r (n = 98) and EFV/FTC/TDF arms (n = 97), yielding a difference of -6.8% (lower limit of the 95% two-sided CI: -19.9%). Sanger and UltraDeep sequencing showed the occurrence of PI mutations in the lopinavir/r arm (n = 4) and of NNRTI and/or NRTI mutations in the EFV/FTC/TDF arm (n = 2). No unexpected serious clinical events occurred. Conclusions: Lopinavir/r monotherapy cannot be considered non-inferior to EFV/FTC/TDF. PI resistance rarely emerged in the lopinavir/r arm and did not undermine future PI options. Two years of lopinavir/r monotherapy had no deleterious clinical impact when compared with EFV/FTC/TDF

Pharmacoecon Open

BACKGROUND: Protease inhibitor monotherapy is a simplified treatment strategy for virally suppressed HIV-positive patients that has the potential for cost savings, as fewer drugs are used than with combination therapy. However, evidence for its economic value is limited. OBJECTIVES: We assessed the cost-effectiveness of lopinavir/ritonavir monotherapy followed by treatment intensification in case of viral load rebound versus combination antiretroviral therapy (cART) with efavirenz/emtricitabine/tenofovir in HIV-1 infected patients with viral suppression in the ANRS 140 DREAM trial. METHODS: DREAM was conducted in 36 French Hospitals between 2009 and 2013. For each treatment strategy, we estimated the unadjusted and multivariate-adjusted mean costs (in euro, year 2010 values) and quality-adjusted life-years (QALYs) per patient, as well as incremental costs and QALYs per patient. We then assessed uncertainty using the cost-effectiveness acceptability curve, scenario analyses and cost-effectiveness price-threshold (CEPT) analysis. RESULTS: In the base-case analysis considering 2009-2013 antiretroviral drug (ARV) prices, adjusted incremental costs and QALYs were - euro3296 (95% confidence interval [CI] - 5202 to - 1391) and 0.006 (95% CI - 0.021 to 0.033), respectively, over 2 years, suggesting that monotherapy was cost-effective with a probability of 100% at various cost-effectiveness thresholds. In scenario analyses considering 2018 ARV prices, monotherapy remained cost-effective but with a lower probability (94% vs. 100% in the base-case analysis). The current price of cART would have to decrease by 34% to be cost-effective with a probability of 95%. CONCLUSION: Monotherapy appears to be cost-effective compared with cART for virologically suppressed HIV-positive patients in France. CEPT analysis is a useful tool to identify the preferred strategy to adopt given that ARV prices change rapidly. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00946595

Clin Infect Dis

Background: We pooled the results of three randomized trials that compared the efficacy of PI/r monotherapy and standard triple therapy as maintenance therapy and evaluated: 1) the distribution of ultrasensitive viral load (USVL) at week 96 (W96), 2) factors associated with virological success (VL50 copies/mL and was analyzed in intention-to-treat. USVL was measured with commercial standard Roche assay. A logistic model was used to investigate which variables were predictive of VF. The Fisher exact test was used to investigate differences in USVL at W96. Results: Among 609 patients, 73% were male with a median age of 44.4 years (IQR 39.8-52.1), the treatment duration was four years, (2.4-7.6), baseline CD4/CD8 ratio 0.8 (0.6-1.10), baseline CD4 cell count 564/mm3 (422-707), and 59% presented a baseline USVL<1 copy/mL. At W96, the proportion of USVL<1 copy/mL was significantly lower for PI/r monotherapy than triple therapy (65% versus 74%; p=0.04). Overall, baseline USVL<1 copy/mL, triple therapy, and being female were associated with an USVL<1 copy/mL at W96 (p<0.0001, p=0.049 and p=0.006). For PI/r monotherapy, receiving DRV/r rather than LPV/r was associated with an USVL<1 copy/mL at W96 (p=0.03). Factors associated with virological success at W96 were higher baseline CD4 cell count (p=0.034) and baseline USVL<1 copy/mL (p=0.0005). Conclusion: Although PI/r monotherapy is not widely recommended, this strategy is still sometimes used and USVL determination for virologically-controlled patients may help to select the best candidates for PI/r monotherapy

Lancet Infect Dis

Background To address the unmet medical need for an effective prophylactic vaccine against Ebola virus we assessed the safety and immunogenicity of three different two-dose heterologous vaccination regimens with a replication-deficient adenovirus type 26 vector-based vaccine (Ad26.ZEBOV), expressing Zaire Ebola virus glycoprotein, and a non-replicating, recombinant, modified vaccinia Ankara (MVA) vector-based vaccine, encoding glycoproteins from Zaire Ebola virus, Sudan virus, and Marburg virus, and nucleoprotein from the Tai Forest virus. Methods This randomised, observer-blind, placebo-controlled, phase 2 trial was done at seven hospitals in France and two research centres in the UK. Healthy adults (aged 18–65 years) with no history of Ebola vaccination were enrolled into four cohorts. Participants in cohorts I–III were randomly assigned (1:1:1) using computer-generated randomisation codes into three parallel groups (randomisation for cohorts II and III was stratified by country and age), in which participants were to receive an intramuscular injection of Ad26.ZEBOV on day 1, followed by intramuscular injection of MVA-BN-Filo at either 28 days (28-day interval group), 56 days (56-day interval group), or 84 days (84-day interval group) after the first vaccine. Within these three groups, participants in cohort II (14:1) and cohort III (10:3) were further randomly assigned to receive either Ad26.ZEBOV or placebo on day 1, followed by either MVA-BN-Filo or placebo on days 28, 56, or 84. Participants in cohort IV were randomly assigned (5:1) to receive one dose of either Ad26.ZEBOV or placebo on day 1 for vector shedding assessments. For cohorts II and III, study site personnel, sponsor personnel, and participants were masked to vaccine allocation until all participants in these cohorts had completed the post-MVA-BN-Filo vaccination visit at 6 months or had discontinued the trial, whereas cohort I was open-label. For cohort IV, study site personnel and participants were masked to vaccine allocation until all participants in this cohort had completed the post-vaccination visit at 28 days or had discontinued the trial. The primary outcome, analysed in all participants who had received at least one dose of vaccine or placebo (full analysis set), was the safety and tolerability of the three vaccination regimens, as assessed by participant-reported solicited local and systemic adverse events within 7 days of receiving both vaccines, unsolicited adverse events within 42 days of receiving the MVA-BN-Filo vaccine, and serious adverse events over 365 days of follow-up. The secondary outcome was humoral immunogenicity, as measured by the concentration of Ebola virus glycoprotein-binding antibodies at 21 days after receiving the MVA-BN-Filo vaccine. The secondary outcome was assessed in the per-protocol analysis set. This study is registered at ClinicalTrials.gov, NCT02416453, and EudraCT, 2015-000596-27. Findings Between June 23, 2015, and April 27, 2016, 423 participants were enrolled: 408 in cohorts I–III were randomly assigned to the 28-day interval group (123 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), the 56-day interval group (124 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), and the 84-day interval group (117 to receive Ad26.ZEBOV and MVA-BN-Filo, and 18 to receive placebo), and 15 participants in cohort IV were assigned to receive Ad26.ZEBOV and MVA-BN-Filo (n=13) or to receive placebo (n=2). 421 (99·5%) participants received at least one dose of vaccine or placebo. The trial was temporarily suspended after two serious neurological adverse events were reported, one of which was considered as possibly related to vaccination, and per-protocol vaccination was disrupted for some participants. Vaccinations were generally well tolerated. Mild or moderate local adverse events (mostly pain) were reported after 206 (62%) of 332 Ad26.ZEBOV vaccinations, 136 (58%) of 236 MVA-BN-Filo vaccinations, and 11 (15%) of 72 placebo injections. Systemic adverse events were reported after 255 (77%) Ad26.ZEBOV vaccinations, 116 (49%) MVA-BN-Filo vaccinations, and 33 (46%) placebo injections, and included mostly mild or moderate fatigue, headache, or myalgia. Unsolicited adverse events occurred after 115 (35%) of 332 Ad26.ZEBOV vaccinations, 81 (34%) of 236 MVA-BN-Filo vaccinations, and 24 (33%) of 72 placebo injections. At 21 days after receiving the MVA-BN-Filo vaccine, geometric mean concentrations of Ebola virus glycoprotein-binding antibodies were 4627 ELISA units (EU)/mL (95% CI 3649–5867) in the 28-day interval group, 10 131 EU/mL (8554–11 999) in the 56-day interval group, and 11 312 mL (9072–14106) in the 84-day interval group, with antibody concentrations persisting at 1149–1205 EU/mL up to day 365. Interpretation The two-dose heterologous regimen with Ad26.ZEBOV and MVA-BN-Filo was safe, well tolerated, and immunogenic, with humoral and cellular immune responses persisting for 1 year after vaccination. Taken together, these data support the intended prophylactic indication for the vaccine regimen. Funding Innovative Medicines Initiative and Janssen Vaccines & Prevention BV