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.

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.

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.

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.

The Genotyping Resistance Profile of the Pol Gene Detected in Blood of Newly Diagnosed HIV-Positive Men Is Durably Archived in the Gut Whatever the Time of Initiation of cART.

OBJECTIVE: To evaluate the mutational patterns on the pol gene of the main HIV-1 strain archived in cell genome of 10 chronically infected men according to their clinical and therapeutic history. The genotyping resistance profiles were compared between the first blood plasma available at the time of HIV diagnosis and rectal biopsies and PBMC sampled 1-5 years after the initiation of combined antiretroviral therapy (cART). METHODS: HIV-1 RNA and cell-associated HIV-1 DNA were quantified by Abbott Real-Time HIV-1 and Generic HIV® DNA cell (Biocentric) assays. The mutations in protease and reverse transcriptase genes were assessed by the Trugene® assay (Siemens). The C2V3 region was amplified to determine the viral tropism. RESULTS: In 9 patients, slight or no differences were observed between the 3 resistance profiles. Those mostly detected were related to the resistance to nucleos(t)ide (D67N, L210W, T215A, T69D) and nonnucleoside (K103N, V106I, V179I) inhibitors. In 1 rilpivirine-treated patient, the M230I mutation was detected in PBMC. No change of viral tropism was observed between samples. CONCLUSION: These data suggest that resistance mutations harbored by the main HIV strain in plasma at the time of diagnosis are durably archived in DNA cells whatever the delay between infection and initiation of therapy in patients well controlled by cART.

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.

Mycoplasma hominis, a Rare but True Cause of Infective Endocarditis.

Mycoplasma spp. are rarely recognized agents of infective endocarditis. We report a case of Mycoplasma hominis prosthetic valve endocarditis diagnosed by 16S ribosomal DNA (rDNA) PCR and culture of valves in a 74-year-old man. We reviewed the literature and found only 8 other cases reported.

Tenosynovitis: a rare presentation of tuberculosis better known by hand surgeons than infectious diseases specialists.

PURPOSE: Clinical presentation of tuberculosis is pleomorphic. Some forms are rare and better known by surgeons than infectious disease specialists. METHODS: We describe a rare case of isolated chronic tenosynovitis of the wrist due to Mycobacterium tuberculosis in a 66-year-old man and review similar cases in the literature. RESULTS: On literature search, only 23 other cases of tuberculous tenosynovitis were retrieved. Our case is similar, with an insidious classical presentation. The diagnosis was suggested at the surgical presentation by the presence of rice body masses. CONCLUSION: The diagnosis of tuberculous tenosynovitis should be considered in chronic tenosynovitis. Functional prognosis may be committed without adequate treatment.

Guillain-Barré syndrome associated with Mycobacterium bovis lymphadenitis.

Guillain-Barré syndrome (GBS) is an autoimmune disease that can be triggered by different infectious agents. Here we report the case of a 26-year-old Algerian woman who developed GBS associated with a Mycobacterium bovis cervical lymphadenitis. Following intravenous immunoglobulin therapy, the patient's neurologic state returned to normal after 3 months. The lymphadenitis responded more slowly to the antituberculous treatment and an excision of necrotic cervical lymph nodes had to be performed four times. Antibiotics were administered for 16 months: ethambutol was stopped after 2 months, and rifampicin and isoniazid pursued for 14 months. An extensive etiological investigation showed that, in this case, the only likely infectious trigger GBS was the concomitant M. bovis infection. To our knowledge, this is the first report of GBS triggered by M. bovis. We performed a literature review revealing that the association between tuberculosis and Guillain-Barré syndrome is very rare (only seven cases previously reported) but is not coincidental. Physicians should be aware that tuberculosis can be a cause of GBS.

Infection due to Mycobacterium thermoresistibile: a case associated with an orthopedic device.

Mycobacterium thermoresistibile is a rapidly growing environmental nontuberculous mycobacterium, seldom reported in human infections. Here, we describe a rare case of tibial-nail-related osteomyelitis due to Mycobacterium thermoresistibile. We also review the literature about the infections caused by this pathogen.

Smoking is a risk factor of organ/space surgical site infection in orthopaedic surgery with implant materials.

PURPOSE: In recent guidelines, smoking is reported as a factor increasing the risk of surgical site infection (SSI). The accurate analysis of the literature shows that this recommendation relies on low level of evidence in orthopaedic surgery with material implantation (arthroplasty components or implants for internal fixation). This study aimed to assess the attributable risk of smoking on organ/space SSI in orthopaedic surgery with implants. METHODS: Risk factors of organ/space SSI were studied in a prospective cohort including 3,908 patients from June 2003 to December 2006. RESULTS: Smoking was found as a significant risk factor for organ/space SSI. We also observed a significant difference between smokers and non-smokers for surgical wound complications (hematoma, discharge or wound dehiscence) during the period between surgical procedure and discharge from hospital. CONCLUSION: This is the first large prospective report of a significant association between smoking and organ/space SSI in orthopaedic surgery with implants.

Quantification by real-time PCR assay of Staphylococcus aureus load: a useful tool for rapidly identifying persistent nasal carriers.

The Cepheid Xpert MRSA/SA nasal PCR assay was compared to culture for quantifying Staphylococcus aureus load from 104 nasal samples (r = 0.91, P < 0.0001). Using a bacterial load-based algorithm, the test was found able to predict the carrier state in 32 of 35 healthy volunteers (22 persistent and 13 nonpersistent carriers).

Transmission by super-spreading event of pandemic A/H1N1 2009 influenza during road and train travel.

The investigation of clustered cases of pandemic A/H1N1 2009 influenza virus infection (21 children, 3 adults) during a summer camp, led to the identification of transportation as the circumstance of transmission. Results suggest that super-spreading of flu can occur in a confined space without sufficient air renewal.

Average adherence to boosted protease inhibitor therapy, rather than the pattern of missed doses, as a predictor of HIV RNA replication.

Consecutive missed doses may differentially impact the efficacy of antiretroviral therapy associated with the use of a nonnucleoside reverse-transcriptase inhibitor (NNRTI) and a ritonavir-boosted protease inhibitor (PI). In a cohort of 72 subjects receiving a boosted PI, average adherence to dosage was a better predictor of human immunodeficiency virus (HIV) replication than was the duration or frequency of treatment interruption. In contrast with an NNRTI, consecutive missed doses of a boosted PI did not emerge as a major risk factor for HIV replication.

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.