T Cell Immunogenicity, Gene Expression Profile, and Safety of Four Heterologous Prime-Boost Combinations of HIV Vaccine Candidates in Healthy Volunteers: Results of the Randomized Multi-Arm Phase I/II ANRS VRI01 Trial.

Heterologous prime-boost strategies are of interest for HIV vaccine development. The order of prime-boost components could be important for the induction of T cell responses. In this phase I/II multi-arm trial, three vaccine candidates were used as prime or boost: modified vaccinia Ankara (MVA) HIV-B (coding for Gag, Pol, Nef); HIV LIPO-5 (five lipopeptides from Gag, Pol, Nef); DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, Env gp160 clade B). Healthy human volunteers (n = 92) were randomized to four groups: 1) MVA at weeks 0/8 + LIPO-5 at weeks 20/28 (M/L); 2) LIPO-5 at weeks 0/8 + MVA at weeks 20/28 (L/M); 3) DNA at weeks 0/4/12 + LIPO-5 at weeks 20/28 (G/L); 4) DNA at weeks 0/4/12 + MVA at weeks 20/28 (G/M). The frequency of IFN-γ-ELISPOT responders at week 30 was 33, 43, 0, and 74%, respectively. Only MVA-receiving groups were further analyzed (n = 62). Frequency of HIV-specific cytokine-positive (IFN-γ, IL-2, or TNF-α) CD4+ T cells increased significantly from week 0 to week 30 (median change of 0.06, 0.11, and 0.10% for M/L, L/M, and G/M, respectively), mainly after MVA vaccinations, and was sustained until week 52. HIV-specific CD8+ T cell responses increased significantly at week 30 in M/L and G/M (median change of 0.02 and 0.05%). Significant whole-blood gene expression changes were observed 2 wk after the first MVA injection, regardless of its use as prime or boost. An MVA gene signature was identified, including 86 genes mainly related to cell cycle pathways. Three prime-boost strategies led to CD4+ and CD8+ T cell responses and to a whole-blood gene expression signature primarily due to their MVA HIV-B component.

Cystatin C and Urine Albumin to Creatinine Ratio Predict 5-Year Mortality and Cardiovascular Events in People Living With HIV.

BACKGROUND: Identifying people with HIV (PWH) at risk for chronic kidney disease, cardiovascular events, and death is crucial. We evaluated biomarkers to predict all-cause mortality and cardiovascular events, and measured glomerular filtration rate (mGFR) slope. METHODS: Biomarkers were measured at enrollment. Baseline and 5-year mGFR were measured by plasma iohexol clearance. Outcomes were a composite criterion of all-cause mortality and/or cardiovascular events, and mGFR slope. RESULTS: Of 168 subjects, 146 (87.4%) had undetectable HIV load. Median follow-up was 59.1 months (interquartile range, 56.2-62.1). At baseline, mean age was 49.5 years (± 9.8) and mean mGFR 98.9 mL/min/1.73m2 (± 20.6). Seventeen deaths and 10 cardiovascular events occurred during 5-year follow-up. Baseline mGFR was not associated with mortality/cardiovascular events. In multivariable analysis, cystatin C (hazard ratio [HR], 5.978; 95% confidence interval [CI], 2.774-12.88; P < .0001) and urine albumin to creatinine ratio (uACR) at inclusion (HR, 1.002; 95% CI, 1.001-1.004; P < .001) were associated with mortality/cardiovascular events. Area under receiver operating curve of cystatin C was 0.67 (95% CI, .55-.79) for mortality/cardiovascular event prediction. Biomarkers were not associated with GFR slope. CONCLUSIONS: uACR and cystatin C predict all-cause mortality and/or cardiovascular events in PWH independently of mGFR.

Hematogenous osteomyelitis in childhood can relapse many years later into adulthood: A retrospective multicentric cohort study in France.

To describe the epidemiological, clinical, laboratory, and radiological features and the management of adult patients who experienced a relapse between 2003 and 2015 of an acute hematogenous osteomyelitis acquired in childhood.A retrospective multicentric cohort study was conducted in 5 centers in France.Thirty-seven patients were included. The median age was 40 years (28-56), and 26 (70%) were male. The first site of infection was the distal femur (n = 23, 62%). The median time between the osteomyelitis in childhood and the relapse in adulthood was 26 years (13-45). Thirty-four (92%) patients reported inflammatory local clinical manifestations, 17 (46%) draining fistula, 10 (27%) fever. Most patients had intramedullary gadolinium deposition (with or without abscess) on magnetic resonance imaging. Most relapses were monomicrobial infections (82%). Staphylococcus aureus was the most commonly found microorganism (82%), expressing a small colony variant phenotype in 3 cases. Most patients (97%) had a surgical treatment, and the median duration of antibiotics for the relapse was 12 weeks. All patients had a favorable outcome, no patient died and no further relapse occurred. We count 2 femoral fractures on osteotomy site.Osteomyelitis in childhood can relapse later in adulthood, especially in patients with lack of care during the initial episode. Osteotomy and prolonged antimicrobial therapy are required for clinical remission.

Primary physicians' attitudes toward their patients receiving a proposal to participate in a vaccine trial.

A trustworthy relationship between primary physicians (PPs) and their patients is crucial for vaccine acceptance. Little is known about attitudes of PPs toward participation of their patients in a preventive vaccine trial (PVT) proposed by investigation sites.A cross-sectional study was conducted in Auvergne-Rhône-Alpes region (France) including an anonymous questionnaire for general practitioners (GPs) and other specialists as well as face-to-face interviews. A scenario of a patient, with chronic medical conditions, invited to participate in a PVT and reporting this situation to his/her PP was drawn up. PPs' attitudes were assessed in quantitative approach by a 5-point Likert scale and in qualitative approach by semi-directed individual interviews.Among the 521 respondents to the questionnaire, 429 (82.3%) were GPs and 92 (17.7%) were other specialists. Only 7.5% (39/521) of respondents regularly practice clinical research. Confronted with the scenario, 312 respondents (59.8%) declared they would give their opinion spontaneously. Before giving their opinion, PPs would like more information about the trial (91.4%, n = 476). Whatever their attitude, 488 (93.7%) would be influenced by available safety data. Face-to-face interviews confirmed that PPs lack of knowledge about clinical research, and would like to obtain information from investigators, particularly about safety.PPs seem to be concerned by the decision of their patients to participate or not in a PVT but would like more information about the trial and clinical research before giving their opinion. Getting PPs to be more involved in the enrollment of patients in PVT may improve recruitment.

A high mucosal blocking score is associated with HIV protection.

BACKGROUND: Early steps of HIV infection are mediated by the binding of the envelope to mucosal receptors as α4ß7 and the C-type lectins DC-SIGN and langerin. Previously Env-specific B-cell responses have been reported in highly exposed seronegative individuals (HESN). METHOD: Here, we studied gp120-specific antibodies ability to block HIV interaction with α4ß7, DC-SIGN and/or langerinin HESN. New cell-based assays were developed to analyze whether antibodies that can alter gp120 binding to α4ß7, DC-SIGN and/or langerin are induced in HESN. A mucosal blocking score (MBS) was defined based on the ability of antibodies to interfere with gp120/α4ß7, gp120/DC-SIGN, and gp120/langerin binding. A new MBS was evaluated in a cohort of 86 HESN individuals and compared with HIV+ patients or HIV- unexposed healthy individuals. RESULTS: Antibodies reducing gp120 binding to both α4ß7 and DC-SIGN were present in HESN serum but also in mucosal secretions, whereas antibodies from HIV+ patients facilitated gp120 binding to DC-SIGN. Any correlation was observed between MBS and the capacity of antibodies to neutralize infection of α4ß7 CD4+ T cells with primary isolates. CONCLUSIONS: MBS is significantly associated with protection in HESN and might reflect altered HIV spreading to mucosal-associated lymphoid tissues.

Viral rebound in semen after antiretroviral treatment interruption in an HIV therapeutic vaccine double-blind trial.

OBJECTIVES: This study aimed to determine the timing and level of HIV rebound in blood and seminal plasma and to characterize the HIV rebounding populations after antiretroviral treatment interruption (ATI) in HIV-1-infected participants enrolled in a therapeutic vaccine trial. DESIGN: A 12-week (W) ATI period was proposed at W36 to patients enrolled in the VRI02/ANRS149-LIGHT trial. Paired blood and semen samples were collected before (W32 or W36) and during ATI (W38, W40, W42, W44, and W48). METHODS: HIV-RNA and HIV-DNA were quantified sequentially from blood and semen samples. Ultradeep sequencing (UDS; Roche/454) of partial env HIV-DNA/RNA (C2V3) was performed in both compartments. RESULTS: HIV-RNA rebounded in blood plasma and seminal plasma of all ten participants after ATI [median peak of 5.12 log10 cp/ml (range: 4.61-6.35) and 4.26 log10 cp/ml (3.20-4.67), respectively]. HIV-RNA rebound was detected in blood plasma as soon as W38 in 8/10 patients, and in seminal plasma between W38 and W40 in 8/10 patients. Phylogenetic approaches showed intermingled HIV-RNA populations from plasma and semen during ATI, suggesting a lack of viral compartmentalization between blood and semen. CONCLUSION: Our data demonstrate rapid and high HIV rebound in semen after ATI, raising concerns about high risk of HIV sexual transmission during HIV cure trials.

Vaccines for healthcare-associated infections: present, future, and expectations.

INTRODUCTION: In spite of the widespread implementation of preventive strategies, the prevalence of healthcare-associated infections (HAIs) remains high. HAIs are associated with multidrug resistant organisms, and in the post-antibiotic era, alternative strategies such as vaccines are needed for their management. AREAS COVERED: Vaccines to prevent HAIs could be proposed to at-risk patients, or to healthcare workers (HCWs) to prevent cross-transmission. After searches in Pubmed and clinicaltrials.gov, existing vaccines and vaccines under clinical development are presented in this narrative review. Issues associated with the use of vaccines to prevent HAIs are discussed. EXPERT COMMENTARY: Future vaccines against HAIs will contribute to fight antibiotic resistance and thus reduce the burden of HAIs. At this stage, the goal of obtaining effective vaccines against S.aureus, C. difficile and gram-negative bacteria has not yet been achieved. Obtaining an efficient response to vaccines in at-risk patients for HAIs is also challenging, and future strategies of vaccination need to address this difficulty. The efficacy of vaccines for HCWs in reducing the spread of nosocomial outbreaks is counterbalanced by the lack of adherence to vaccine policies among HCWs. The acceptance of future vaccines to prevent carriage and infection with organisms involved in HAIs in HCWs will probably be a challenge.

Diagnostic challenges of kidney diseases in HIV-infected patients.

INTRODUCTION: Chronic kidney disease (CKD) is a prevalent comorbidity in persons living with HIV infection (PLWH) associated with an increase in cardiovascular morbidity and all-cause mortality. Furthermore, early diagnosis of CKD is difficult in PLWH. Areas covered: We reviewed the main diagnostic tools for CKD in PLWH, and discussed their strengths and limits. We performed a literature search on PubMed to identify reviews and clinical trials dealing with attractive kidney biomarkers of CKD in PLWH, with the following key words: 'HIV AND kidney', 'HIV AND Kidney biomarkers', 'CKD AND Kidney biomarkers'. Expert commentary: Currently, CKD diagnosis is based on the estimation of Glomerular Filtration Rate (GFR), and measurement of proteinuria by urine protein/creatinine ratio (uPCR). These parameters are independent and complementary predictors of outcomes. GFR estimates are lacking in accuracy in PLWH. The best GFR estimate is CKD-EPI study equation. Moreover, low-grade proteinuria is associated with an increased risk of kidney disease progression in PLWH, and guidelines derived from the general population may lack sensitivity. Different biomarkers of kidney diseases like N-acetyl beta glucosaminidase (NAG), Kidney Injury Molecule-1 (KIM-1), and Alpha-1-microglobulin may predict kidney disease progression and mortality in PLWH. Others may help clinicians detect antiretroviral-induced tubulopathy, or predict cardiovascular events. More studies are needed to validate the routine use of these types of biomarkers.

Epidemiology and clinical relevance of Staphylococcus aureus intestinal carriage: a systematic review and meta-analysis.

INTRODUCTION: Recent data highlight the importance of screening more than one site for improving the detection of S. aureus colonization. Intestinal carriage is frequently under-investigated and its clinical impact ought to be defined a better way. Areas covered: This review and meta-analysis provide an updated overview of prevalence, characteristics and clinical significance of S. aureus intestinal carriage in different populations, both for methicillin-susceptible and -resistant S. aureus strains. Expert commentary: Intestinal S. aureus carriage is documented with higher prevalence in children and in patients with S. aureus skin and soft tissue infections. This site of colonization was shown to be associated with a high risk of dissemination in the environment and with S. aureus infection. Intestinal carriage is frequently retrieved in nasal carriers, reflecting probably an association with a high bacterial load. Exclusive intestinal carriage present in one third of intestinal carriers can be associated with infection. Comparative genotyping analysis of different strains from nasal and extra-nasal sites of carriage, including the intestinal ones, in the same individuals, would allow a better comprehension of the pathophysiology of S. aureus endogenous infection. It could also permit to improve the prevention of these infections by decolonization of sites implicated in infection genesis.

Humoral responses against HIV in male genital tract: role in sexual transmission and perspectives for preventive strategies.

: Most new HIV infections occur via sexual routes. The induction of protective anti-HIV antibodies in genital mucosa is an important step toward reducing HIV transmission. Mucosal anti-HIV antibodies may play a dual role by either protecting against HIV transmission or facilitating it. Protective properties against HIV of mucosal IgGs and IgAs exhibiting neutralizing or antibody-dependent cell-mediated cytotoxicity activities have been described in highly exposed seronegative individuals. Conversely, some IgGs may facilitate the crossing of HIV free-particles through epithelial barriers by transcytosis. Hence knowledge of the mechanisms underlying anti-HIV antibody production in the genital tract and their exact role in sexual transmission may help to develop appropriate preventive strategies based on passive immunization or mucosal vaccination approaches. Our review focuses on the characteristics of the humoral immune responses against HIV in the male genital tract and related prevention strategies.

Anti-N-methyl-D-aspartate receptor encephalitis after Herpes simplex virus-associated encephalitis: an emerging disease with diagnosis and therapeutic challenges.

INTRODUCTION: Morbidity and mortality of Herpes simplex virus encephalitis (HSE) remain high. Relapses of neurological signs may occur after initial clinical improvement under acyclovir treatment. METHODS: We report here a case of post-HSE anti-N-methyl-d-aspartate receptor-mediated encephalitis in an adult and perform a systematic search on PubMed to identify other cases in adults. RESULTS: We identified 11 previously published cases, to discuss diagnostic and therapeutic management. Symptoms in adults are often inappropriate behaviors, confusion and agitation. Diagnosis of anti-NMDA-R encephalitis after HSE is often delayed. Treatment consists in steroids, plasma exchange, and rituximab. Prognosis is often favorable. CONCLUSION: Anti-NMDA-R antibodies should be searched in cerebrospinal fluid of patients with unexpected evolution of HSE. This emerging entity reopens the hot debate about steroids in HSE.

Immunization of HIV-infected adult patients - French recommendations.

Human immunodeficiency virus (HIV)-infected patients remain at increased risk of infection including vaccine-preventable diseases. Vaccines are therefore critical components in the protection of HIV-infected patients from an increasing number of preventable diseases. However, missed opportunities for vaccination among HIV-infected patients persist and vaccine coverage in this population could be improved. This article presents the French recommendations regarding immunization of HIV-infected adults in the light of the evidence-based literature on the benefits and the potential risks of vaccines among this vulnerable population.

Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy with tenofovir/emtricitabine/maraviroc/raltegravir in treatment-naive HIV patients.

OBJECTIVE: We assessed the virological efficacy of a 6 month maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with maraviroc/raltegravir. METHODS: HIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA <50 copies/mL stopped tenofovir/emtricitabine at week (W) 24 and pursued maraviroc/raltegravir until W48. The primary endpoint was the virological response defined by HIV-RNA <50 copies/mL at W48. RESULTS: Thirty-three patients were analysed. Patients were mostly male (94%), Caucasians (91%), MSM (82%); their median age was 42 years. At baseline, median CD4 cell count was 453 cells/mm3 and HIV-RNA was 4.3 log copies/mL. All patients had CCR5-tropic viruses by genotropism and phenotropism assays. All but one patient had an HIV-RNA < 50 copies/mL at W24 and entered the simplification phase. Virological success was maintained at W48 in 88% (90% CI 79%-97%) of patients. N155H mutation was detected at failure in one patient. No tropism switch was observed. Raltegravir and maraviroc plasma exposure were satisfactory in 92% and 79% of 41 samples from 21 patients. Five severe adverse events (SAEs) were observed up to W48; none was related to the study drugs. Four patients presented grade 3 AEs; none was related to the study. No grade 4 AE was observed. No patient died. CONCLUSIONS: Maraviroc/raltegravir maintenance therapy following a 6 month induction phase with maraviroc/raltegravir/tenofovir/emtricitabine was well tolerated and maintained virological efficacy in these carefully selected patients.

Major influence of CD4 count at the initiation of cART on viral and immunological reservoir constitution in HIV-1 infected patients.

BACKGROUND: A persistent immune activation is observed in gut during HIV-1 infection, which is not completely reversed by a combined antiretroviral therapy (cART). The impact of the time of cART initiation may highly influence the size of the viral reservoir and the ratio of CD4(+)/CD8(+) T cells in the gut. In this study, we analyzed the characteristics of HIV rectal reservoir of long-term treated patients, regarding their blood CD4(+) T cells count at the time of cART initiation. RESULTS: Twenty-four consenting men were enrolled: 9 exhibiting a CD4(+) T cells count >350/mm(3) ("high-level CD4 group") and 15 < 350/mm(3) ("low-level CD4 group") in blood, at the start of cART. An immunophenotypical analysis of T and B cells subpopulations was performed in blood and rectal biopsies. HIV cell-associated DNA loads and qualitative intra-cellular RNA were determined in both compartments. The ratio of CD4(+)/CD8(+) T cells was significantly decreased in the blood but not in the rectum of the "low-level CD4 group" of patients. The alteration in ß7(+) CD4(+) T cells homing was higher in this group and was correlated to a low ratio of CD4(+)/CD8(+) T cells in blood. An initiation of cART in men exhibiting a low-level CD4 count was also associated with an alteration of B cells maturation. HIV blood and gut DNA reservoirs were significantly lower in the "high-level CD4 group" of men. A high HIV DNA level was associated to a detectable intracellular HIV RNA in rectum. CONCLUSIONS: An early initiation of cART could significantly preserve gut immunity and limit the viral reservoir constitution.

Prospective evaluation of RT-PCR on sputum versus culture, urinary antigens and serology for Legionnaire's disease diagnosis.

OBJECTIVES: Legionnaires' disease (LD) is a severe disease associated with community and hospital-acquired pneumonia, frequently under diagnosed. The main aim of our study was to determine the value of PCR for the diagnosis of LD in routine clinical practice. METHODS: In a prospective study, from March 2007 to April 2010, the value of PCR on non-invasive respiratory specimens (NIRS) was compared to those of the other available tools for LD diagnosis in patients hospitalized for pneumonia. RESULTS: Among 254 consecutive cases of pneumonia included, 24 cases were LD (19 confirmed and 5 probable) representing the first documented microbiological etiology. Molecular diagnosis of LD was performed on NIRS by using 16S rRNA PCR, and secondarily mip PCR, with no discrepant results between the 2 methods: it was found positive in 14 cases and led to identify 2 supplementary probable cases of LD. Based on clinical and at least 2 positive LD tests, PCR yielded a better diagnostic value than antigen urinary test (12 vs 10 cases). CONCLUSION: These results revealed that molecular diagnosis of LD on NIRS is reliable and may contribute to better identify cases of LD.

Vaccination errors in general practice: creation of a preventive checklist based on a multimodal analysis of declared errors.

BACKGROUND: Vaccination is a common act in general practice in which, as in all procedures in medicine, errors may occur. To our best knowledge, in this area, few tools exist to prevent them. OBJECTIVE: To create a checklist that could be used in general practice in order to avoid the main errors. METHODS: From April to July 2013, we systematically searched for vaccination errors using three sources: a review of literature, individual interviews with 25 health care workers and supervised peer review groups meeting at the Medicine school of Saint-Etienne (France). The errors most frequently retrieved were used to create the checklist that was regularly submitted to interviewed caregivers to improve its construction and content; its stabilization has been conceived as an evidence of finalization. RESULTS: The checklist's draw-up included three parts allowing verification at each stage of the vaccination process: before, during and after the vaccine administration. Before the vaccination, items to be checked were mainly does my patient need and may he/she receive this vaccine in accordance with the national French vaccination guidelines? During the preparation and the administration of vaccination, items to be checked were are the patient and the practitioner comfortable? Is all the material needed correctly prepared? Is the appropriate route defined? Ultimately, after the vaccination, most items to be checked concerned traceability. This checklist seemed useful and usable by the panel of practitioners questioned. CONCLUSION: This vaccination checklist may be useful to prevent errors. Its efficacy and feasibility in clinical practice will require further testing.

Identifying Hemodialysis Patients With the Highest Risk of Staphylococcus aureus Endogenous Infection Through a Simple Nasal Sampling Algorithm.

In contrast to Staphylococcus aureus intermittent nasal carriers, persistent ones have the highest risk of infection. This study reports the usefulness of a simple nasal sampling algorithm to identify the S. aureus nasal carriage state of hemodialysis patients (HPs) and their subsequent risk of infection.From a cohort of 85 HPs, 76 were screened for S. aureus nasal carriage once a week during a 10-week period. The S. aureus nasal load was quantified by using either culture on chromogenic medium or fully automated real-time polymerase chain reaction assay. Molecular typing was used to compare strains from carriage and infection.The algorithm based on quantitative cultures was able to determine the status of S. aureus nasal carriage with a sensitivity of 95.8%, a specificity of 94.2%, a positive predictive value of 88.5%, and a negative predictive value of 98.0%. Of note, the determination of the S. aureus carriage state was obtained on the first nasal sample for all the 76 HPs, but 1 (98.7%). The algorithm based on quantitative polymerase chain reaction assay directly from the specimen yielded similar performances. During the 1-year follow-up after the last sampling episode, HPs classified as persistent nasal carriers with the algorithm were found to have a higher risk of S. aureus infection than those classified as nonpersistent carriers (P < 0.05), especially for infections of endogenous origin (P < 0.001).This simple algorithm is reliable for determining the S. aureus nasal carriage status in clinical practice and could contribute to characterize at an early stage of take-up patients with the highest risk of S. aureus infection.

Pre-travel advice seeking from GPs by travellers with chronic illness seen at a travel clinic.

PURPOSE: Travellers are ageing and frequently report chronic illness. Pre-travel health advice is crucial, particularly in this subgroup, and general practitioners (GPs) are first in line for treatment adjustment before departure. Our aim is to evaluate pre-travel health advice seeking from GPs by travellers with chronic illness seen at a travel clinic. METHODS: A cross-sectional observational survey using a questionnaire was conducted between August 2013 and July 2014 in travellers attending the travel medicine clinic of a tertiary university hospital in France. RESULTS: During the study, 2019 travellers were included. Mean age was 39.4 years (±18.8). Three hundred and ninety-one (19.4%) travellers reported a history of a chronic illness. Arterial hypertension and diabetes mellitus were the most frequently reported illnesses, affecting, respectively, 168 (8.3%) travellers and 102 (5.1%). Hajj pilgrims were more likely to report a history of chronic illness than other travellers. Only 810 (40.1%) travellers sought pre-travel advice from their GP. Six hundred and fifty-two (40.1%) healthy travellers and 158 (40.5%) travellers reporting chronic illness sought pre-travel advice from their GP (P = 0.96). CONCLUSION: Travellers with a history of chronic illness do not seek pre-travel health advice from their GP more frequently than healthy travellers. Travel health specialists are generally not the best practitioners to manage the care of underlying medical conditions presenting risks during travel. However, GPs offer continuity and disease management expertise to improve the specificity of pre-travel planning. Thus, ongoing collaboration between the traveller, GP and travel health specialist is likely to yield the best outcomes.