Abdominal Tuberculosis: Experience from Two Tertiary-Care Hospitals in the Paris Region.

Abdominal tuberculosis (ATB) is uncommon and not very well known by clinicians. We describe the characteristics, evolution, and treatment of patients with ATB in two large hospitals in the Paris region. We reviewed all records of patients treated for ATB, from January 01, 2010 to December 01, 2016, diagnosed by bacteriological and/or histological methods or highly suspected because of clinical/radiological features. We included 80 patients, with a median (IQR) age of 39 (29-50) years, with 56.2% being males. Among them, 63.7% had African origins, 15% Asian, and 11.2% European. Twenty-nine had a cause of immunosuppression (n = 21 HIV infection). The main abdominal localizations were lymph nodes (72.5%), peritoneum (62.5%), and solid organs (25%). Extra-abdominal localizations were recorded in 65 (81.2%) patients. Tuberculosis was proven bacteriologically in 71%, histologically in 50%, and solely clinical/radiological in 10% of cases. Patients received standard therapy for a median duration of 9 months, with a favorable outcome. Corticosteroid therapy was used in 15 cases, either for paradoxical reaction or to prevent complications. Abdominal TB was mainly represented by lymphatic and peritoneal localizations, proven bacteriologically, and associated with extra-abdominal localizations in most cases. The use of steroids remains controversial, but it does not seem systematically needed in case of abdominal involvement.

Prevalence and Risk Factors for Anal Human Papillomavirus Infection in Human Immunodeficiency Virus-Positive Men Who Have Sex with Men.

Background: We assessed prevalence and risk factors for anal human papillomavirus (HPV) in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM), who are at high-risk of HPV-related anal cancer. Methods: APACHES is a multicentric, prospective study of anal HPV infection and lesions in HIV-positive MSM aged ≥35 years. At baseline, participants underwent anal swabs for HPV and cytology, plus high-resolution anoscopy. High-risk HPV (HR-HPV) was tested by Cobas4800, with genotyping of HR-HPV positives by PapilloCheck. Results: Among 490 participants, prevalence of HPV16 and HR-HPV was 29% and 70%, respectively, and did not differ significantly by age, sexual behavior, or markers of HIV or immune deficiency. Smoking was the only, albeit weak (odds ratio, 1.8; 95% confidence interval, 1.2-2.7), predictor of HR-HPV. High-risk HPV and HPV16 prevalence increased strongly with anal diagnosis severity, both by worse cytological/histological (composite) diagnosis at APACHES baseline and worse historical diagnosis. HPV16 rose from 19% among participants who were negative for lesions to 63% among participants with high-grade lesions. In contrast, non-HPV16 HR-HPVs were less prevalent in high-grade (37%) than negative (64%) composite diagnosis, and their causal attribution was further challenged by multiple HPV infections. Conclusions: Human papillomavirus 16 is ubiquitously frequent among human immunodeficiency virus -positive men having sex with men, and more strongly associated with high-grade anal lesions than other high-risk types, confirming it as a target for anal cancer prevention.

Clinical Indications and Compassionate Use of Phage Therapy: Personal Experience and Literature Review with a Focus on Osteoarticular Infections.

The history of phage therapy started with its first clinical application in 1919 and continues its development to this day. Phages continue to lack any market approval in Western medicine as a recognized drug, but are increasingly used as an experimental therapy for the compassionate treatment of patients experiencing antibiotic failure. The few formal experimental phage clinical trials that have been completed to date have produced inconclusive results on the efficacy of phage therapy, which contradicts the many successful treatment outcomes observed in historical accounts and recent individual case reports. It would therefore be wise to identify why such a discordance exists between trials and compassionate use in order to better develop future phage treatment and clinical applications. The multitude of observations reported over the years in the literature constitutes an invaluable experience, and we add to this by presenting a number of cases of patients treated compassionately with phages throughout the past decade with a focus on osteoarticular infections. Additionally, an abundance of scientific literature into phage-related areas is transforming our knowledge base, creating a greater understanding that should be applied for future clinical applications. Due to the increasing number of treatment failures anticipatedfrom the perspective of a possible post-antibiotic era, we believe that the introduction of bacteriophages into the therapeutic arsenal seems a scientifically sound and eminently practicable consideration today as a substitute or adjuvant to antibiotic therapy.

Diphtheria in Mayotte, 2007-2015.

Epidemiology of diphtheria in the southwestern Indian Ocean is poorly documented. We analyzed 14 cases of infection with toxigenic Corynebacterium diphtheriae reported during 2007-2015 in Mayotte, a French department located in this region. Local control of diphtheria is needed to minimize the risk for importation of the bacterium into disease-free areas.

Molecular epidemiology and mechanisms of resistance of azithromycin-resistant Neisseria gonorrhoeae isolated in France during 2013-14.

OBJECTIVES: The objective of this study was to determine the prevalence and mechanisms of azithromycin resistance of Neisseria gonorrhoeae French isolates from 2013 to 2014. METHODS: N. gonorrhoeae samples isolated in a network of laboratories were tested for susceptibility to azithromycin between April 2013 and March 2014. Fifty-four isolates that were non-susceptible to azithromycin and 18 susceptible isolates were characterized for molecular mechanisms of resistance by PCR/sequencing and genotyped using N. gonorrhoeae multiantigen sequence typing (NG-MAST). RESULTS: Among the 970 N. gonorrhoeae isolates, 54 (5.56%) were non-susceptible to azithromycin, 9 (1%) were resistant and 45 (4.6%) showed intermediate resistance. Azithromycin-non-susceptible isolates harboured a C2599T mutation in the rrl gene encoding the 23S rRNA alleles (5.5%), a C substitution in the mtrR promoter (5.5%), an A deletion in the mtrR promoter (53.7%) and mutations in the L4 ribosomal protein (14.8%) and in the MtrR repressor (25.9%). No isolates showed an L22 mutation or carried an erm, ere, mef(A)/(E) or mphA gene. Thirty different STs were highlighted using the NG-MAST technique. The predominant genogroups non-susceptible to azithromycin were G21 (31%), G1407 (20%) and G2400 (15%). Genogroup G2400 (15%) was revealed to be a novel cluster prevalent in the south of France and resistant to azithromycin, ciprofloxacin and tetracycline. CONCLUSIONS: Our study highlights that the prevalence of resistance of N. gonorrhoeae to azithromycin in France is low and essentially due to multiple genetic mutations. Its dissemination occurs through three major genogroups including a novel one in France (G2400).

Tenofovir DF/emtricitabine and efavirenz combination therapy for HIV infection in patients treated for tuberculosis: the ANRS 129 BKVIR trial.

BACKGROUND: HIV-infected patients with TB need simplified, effective and well-tolerated antiretroviral regimens. METHODS: The French ANRS 129 BKVIR open trial evaluated the once-daily tenofovir DF/emtricitabine and efavirenz combination, started within 12 weeks after TB treatment initiation, in antiretroviral-naive HIV-1-infected patients. Success was defined as an HIV-1 RNA <50 copies/mL and TB cure at 48 weeks. RESULTS: TB was confirmed microbiologically (90%) or histologically (10%) in 69 patients (71% male; median age 43 years; 54% born in Africa). The median time between TB treatment initiation and antiretroviral therapy was 8 weeks (range 1-22 weeks). At baseline, median HIV-1 RNA was 5.4 log10 copies/mL and median CD4 cell count 74 cells/mm(3). In the ITT analysis, combined success at week 48 was achieved in 57/69 patients (83%, 95% CI 74-92). Twelve patients did not achieve virological success, and TB was not cured in one of them. Among the 47 patients who fully adhered to the strategy, the success rate was 96% (95% CI 90-100) and was not affected by low rifampicin and isoniazid serum concentrations. Forty-nine serious adverse events were reported in 31 patients (45%), and 11 led to antiretroviral drug interruption. All adverse events resolved. The immune reconstitution inflammatory syndrome occurred in 23 patients (33%, 95% CI 22-44), and was associated with a low baseline BMI (P = 0.03) and a low haemoglobin level (P = 0.02). CONCLUSION: These results support the use of tenofovir DF/emtricitabine and efavirenz combination therapy for HIV infection in patients with TB.

Quality and safety requirements for sustainable phage therapy products.

The worldwide antibiotic crisis has led to a renewed interest in phage therapy. Since time immemorial phages control bacterial populations on Earth. Potent lytic phages against bacterial pathogens can be isolated from the environment or selected from a collection in a matter of days. In addition, phages have the capacity to rapidly overcome bacterial resistances, which will inevitably emerge. To maximally exploit these advantage phages have over conventional drugs such as antibiotics, it is important that sustainable phage products are not submitted to the conventional long medicinal product development and licensing pathway. There is a need for an adapted framework, including realistic production and quality and safety requirements, that allows a timely supplying of phage therapy products for 'personalized therapy' or for public health or medical emergencies. This paper enumerates all phage therapy product related quality and safety risks known to the authors, as well as the tests that can be performed to minimize these risks, only to the extent needed to protect the patients and to allow and advance responsible phage therapy and research.

Biomarkers of CD4+ T-cell activation as risk factors for tuberculosis-associated immune reconstitution inflammatory syndrome.

OBJECTIVE: Patients coinfected with HIV and Mycobacterium tuberculosis frequently experience a paradoxical worsening of tuberculosis (TB) symptoms early after the initiation of combination antiretroviral therapy (cART). This immune reconstitution inflammatory syndrome (TB-IRIS) can lead to significant morbidity and needs to be distinguished from TB recurrence due to ineffective treatment. We investigated whether plasma biomarkers could predict the occurrence of TB-IRIS. DESIGN: ANRS 129 BKVIR is a single-arm multicentre trial that enrolled 69 cART-naïve HIV-1-infected patients treated for TB. The patients received once-daily tenofovir/emtricitabine/efavirenz first-line regimen. TB-IRIS cases (IRIS+) were validated by an Event Review Committee. METHODS: A panel of 26 plasma biomarkers was monitored longitudinally for 24 weeks from cART initiation onward, using multiplexed assays and high-sensitivity ELISA. Statistical analyses of biomarkers were adjusted for test multiplicity. RESULTS: One-third of patients (n=23) experienced TB-IRIS. The inflammatory cytokines and chemokines interleukin (IL)-6, IL-8, interferon-gamma-induced protein 10 (IP-10), and tumour necrosis factor-alpha (TNF-α) showed increased plasma levels at week 4 in IRIS-positive (IRIS+) patients (P<0.05 for each biomarker). The soluble IL-2 receptor sCD25, which is released upon CD4 T-cell activation, was significantly increased at week 0 in IRIS+ patients (P<0.05), and remained elevated throughout follow-up. IL-7, a key homeostatic cytokine for CD4 T-cells, showed a trend for higher values in the TB-IRIS group. Both sCD25 and IL-7 baseline levels were independently associated with a shorter time to TB-IRIS occurrence (P=0.005 and P=0.02, respectively). CONCLUSION: These findings support a role for CD4 T-cell activation prior to massive inflammation in the development of TB-IRIS.

Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial.

BACKGROUND: Concurrent treatment of HIV and tuberculosis is complicated by drug interactions. We explored the safety and efficacy of raltegravir as an alternative to efavirenz for patients co-infected with HIV and tuberculosis. METHODS: We did a multicentre, phase 2, non-comparative, open-label, randomised trial at eight sites in Brazil and France. Using a computer-generated randomisation sequence, we randomly allocated antiretroviral-naive adult patients with HIV-1 and tuberculosis (aged ≥18 years with a plasma HIV RNA concentration of >1000 copies per mL) to receive raltegravir 400 mg twice a day, raltegravir 800 mg twice daily, or efavirenz 600 mg once daily plus tenofovir and lamivudine (1:1:1; stratified by country). Patients began study treatment after the start of tuberculosis treatment. The primary endpoint was virological suppression at 24 weeks (HIV RNA <50 copies per mL) in all patients who received at least one dose of study drug (modified intention-to-treat analysis). We recorded death, study drug discontinuation, and loss to follow-up as failures to achieve the primary endpoint. We assessed safety in all patients who received study drugs. This study is registered in ClinicalTrials.gov, number NCT00822315. FINDINGS: Between July 3, 2009, and June 6, 2011, we enrolled and randomly assigned treatment to 155 individuals; 153 (51 in each group) received at least one dose of the study drug and were included in the primary analysis. 133 patients (87%) completed follow-up at week 48. At week 24, virological suppression was achieved in 39 patients (76%, 95% CI 65-88) in the raltegravir 400 mg group, 40 patients (78%, 67-90) in the raltegravir 800 mg group, and 32 patients (63%, 49-76) in the efavirenz group. The adverse-event profile was much the same across the three groups. Three (6%) patients allocated to efavirenz and three (6%) patients allocated to raltegravir 800 mg twice daily discontinued the study drugs due to adverse events. Seven patients died during the study (one in the raltegravir 400 mg group, four in the raltegravir 800 mg group, and two in the efavirenz group): none of the deaths was deemed related to study treatment. INTERPRETATION: Raltegravir 400 mg twice daily might be an alternative to efavirenz for the treatment of patients co-infected with HIV and tuberculosis. FUNDING: French National Agency for Research on AIDS and Viral Hepatitis (ANRS), Brazilian National STD/AIDS Program-Ministry of Health.

Changing patterns of disseminated gonococcal infection in France: cross-sectional data 2009-2011.

OBJECTIVES: Disseminated gonococcal infections (DGIs) are rare. We describe the characteristics of DGIs in France. METHODS: This is a 3-year retrospective analysis of DGI cases collected through two networks of microbiologists and infectious disease specialists in France between 2009 and 2011. DGI was defined either by the isolation of Neisseria gonorrhoeae from blood and synovial fluid or by the existence of a clinical syndrome consistent with DGI and the isolation of N gonorrhoeae from any site. We describe the epidemiological, clinical and microbiological characteristics and outcomes of DGIs. RESULTS: 21 patients (9 women, 12 men; 18-62 years old) were diagnosed with DGI. The number of DGI cases increased between 2009 and 2011. Two men who had sex with men were coinfected with HIV. We found 28 extragenital locations, including arthritis (14 cases), tenosynovitis (7), skin lesions (4), endocarditis (1), prostatitis (1) and pelvic inflammatory disease (1). Genital signs were present in five patients. The diagnosis was confirmed by cultures in 20 patients-blood (4), synovial fluid (11), genital (3), throat (1), urine (1)-and by molecular biology on a pharyngeal swab in 1 patient. Seven cases were resistant to fluoroquinolones. The patients were treated with ceftriaxone, associated with corticosteroids (two cases) and surgery (six cases). Four patients had joint sequelae. CONCLUSIONS: DGIs are increasing. Men seem to be at higher risk than women. Joint involvement was common. Microbiological diagnosis was based on culture, however molecular biology using pharyngeal swabs was helpful when cultures were negative.

Missed opportunities for HIV testing in newly-HIV-diagnosed patients, a cross sectional study.

BACKGROUND: In France, 1/3 HIV-infected patients is diagnosed at an advanced stage of the disease. We describe missed opportunities for earlier HIV testing in newly-HIV-diagnosed patients. METHODS: Cross sectional study. Adults living in France for ≥1 year, diagnosed with HIV-infection ≤6 months earlier, were included from 06/2009 to 10/2010. We collected information on patient characteristics at diagnosis, history of HIV testing, contacts with healthcare settings, and occurrence of HIV-related events 3 years prior to HIV diagnosis. During these 3 years, we assessed whether or not HIV testing had been proposed by the healthcare provider upon first contact in patients notifying that they were MSM or had HIV-related conditions. RESULTS: 1,008 newly HIV-diagnosed patients (mean age: 39 years; male: 79%; MSM: 53%; diagnosed with an AIDS-defining event: 16%). During the 3-year period prior to HIV diagnosis, 99% of participants had frequented a healthcare setting and 89% had seen a general practitioner at least once a year. During a contact with a healthcare setting, 91/191 MSM (48%) with no HIV-related conditions, said being MSM; 50 of these (55%) did not have any HIV test proposal. Only 21% (41/191) of overall MSM who visited a healthcare provider received a test proposal. Likewise, 299/364 patients (82%) who sought care for s had a missed opportunity for HIV testing. CONCLUSIONS: Under current screening policies, missed opportunities for HIV testing remain unacceptably high. This argues in favor of improving risk assessment, and HIV-related conditions recognition in all healthcare facilities.

Visiting one's native country: the risks of nonadherence in HIV-infected sub-Saharan migrants--ANRS VIHVO study.

The aim of this study was to evaluate to what extent travel-related factors may cause adherence failure to antiretroviral therapy (ART) in otherwise adherent migrants when traveling back to Africa. HIV-infected sub-Saharian migrants living in France with a plasma HIV viral load < 200 copies/mL, with no change in ART for ≥3 months and who were about to visit their native country for between 2 weeks and 6 months were enrolled for the study. Patients completed a self-administered adherence questionnaire both at enrollment and during the week following their return to France. Adherence failure occurred in 23 (11.5%) of 200 patients. Negative perception about ART effectiveness (adjusted odds ratio = 4.3; 95% confidence interval = 1.3-13.7), unexpected traumatic events during their stay in their native country (7.8; 2.3-26.1), and a prolongation of their stay (5.2; 1.4-20.4) were independently associated with a higher likelihood of adherence failure. Owning/renting one's house in France (0.30; 0.10-0.96), singlehood (0.23; 0.05-1.00), and HIV status disclosure (0.19; 0.05-0.76) were correlates of sustained adherence during traveling.

[The French Committee for the prevention and control of influenza and the 2009 influenza pandemic: Lessons learnt]. / Comité de lutte contre la grippe et la pandémie 2009 : retour d'expérience.

The Committee for the Prevention and Control of Influenza (Comité de lutte contre la Grippe - CLCG) is an advisory committee to the French Health Minister for a medical and scientific collective expertise on the measures to be implemented to control or to reduce the impact of an epidemic or a pandemic of influenza. Appointed by decree, the CLCG consists of ex-officio members; representatives of French Agencies strongly involved by influenza and qualified personalities, representing various fields of expertise. Collective expertise is based on consensus after thorough collective discussion. A notice is drafted in reply to every official question and passed on either to the Chief Medical Officer, or, when the question concerns vaccines, to the Technical Committee of the vaccinations for which the CLCG acted as a working group. The CLCG was extremely active throughout the pandemic. The objective of this article is to describe in a factual way its output throughout this period of sanitary crisis. This article presents and compare chronologically and in a factual way the state of the scientific knowledge about influenza due to the A(H1N1)pdm09 virus and the CLCG notices. Between the alert launched by the WHO the 24th of April and the 31st of December 2009, CLCG met on 40 occasions. Its work dealt in particular with patient care, recommendations on medical treatment (antivirals, seasonal and pandemic vaccines), and on virological diagnosis. Whatever the defects of its expertise delivered in a context of urgency, which was a difficult exercise, the CLCG fulfilled its advisory to the health authorities. However, the pandemic experience showed that this expertise must be improved by insuring the recognition and the visibility of the advisory committee and by defining their exact position in the chain of decision.

Diphtheria: a zoonotic disease in France?

Thanks to vaccination, diphtheria has almost disappeared in France. The case definition, used for mandatory notification, was expanded in 2003 to include toxin-producing strains of Corynebacterium ulcerans. We describe the epidemiology of diphtheria in France from 1990 to 2008. No cases occurred between 1990 and 2001. Since 2002, 19 cases have been reported: 4 cases due to Corynebacterium diphtheriae related to exposure in endemic countries, and 15 cases due to other corynebacteria, including 4 cases of pseudomembranous pharyngitis, mainly related to contact with domestic animals. High vaccination coverage in the population and sensitive surveillance need to be maintained. Moreover, control measures need to be adapted to the non-C. diphtheriae toxigenic species.

[Influenza in elderly patients]. / Grippe du sujet âgé.

Elderly population increases in France. Myxovirus influenza affect each year 2 to 7 millions of persons. Younger are most frequently infected but rates of serious illness and death are highest among persons aged >65 years. Some clinical forms are misleading, because of associated underlying illness. Thus, rapid diagnostic test are important to take appropriate preventive measures. Annual vaccination is deeply recommended for older people, on the one hand for health care worker on the other hand.

Eagle effect in Corynebacterium diphtheriae.

The in vivo relevance of the paradoxical bactericidal effect (the Eagle effect) is not evident. We found in vitro a paradoxical bactericidal effect of amoxicillin on 2 strains of nontoxigenic Corynebacterium diphtheriae. Then, using an experimental rabbit model of endocarditis, we evaluated the in vivo relevance of this phenomenon. Rabbits were assigned to the following groups: no treatment (control group), continuous amoxicillin infusion simulating a dosage of 200 mg/kg/day in humans, and continuous amoxicillin infusion simulating a dosage of 20 mg/kg/day in humans. The low dosage (20 mg/kg/day) was significantly more effective than the high dosage (200 mg/kg/day) against both strains (P<.025), confirming the paradoxical bactericidal effect observed in vitro.

Lack of control of T cell apoptosis under HAART. Influence of therapy regimen in vivo and in vitro.

BACKGROUND: Increased and premature T cell apoptosis is recognized as a feature of HIV infection, and its normalization during highly active antiretroviral therapy (HAART) is thought to contribute to quantitative CD4 T cell restoration. DESIGN: Cross-sectional study of spontaneous, CD3- and CD95-mediated apoptosis in lymphocytes from 53 HIV-infected individuals taking HAART. METHODS: Overnight stimulation of peripheral blood mononuclear cells (PBMC) with coated anti-CD3 or anti-CD95 monoclonal antibodies or incubation overnight in medium. Apoptosis in CD4 and CD8 T cells was measured by flow cytometry. For in vitro assay of antiretroviral drugs, normal PBMC were prestimulated with anti-CD3 monoclonal antibodies and apoptosis was induced by ligation of CD95. The expression of active caspase-8 and caspase-3 was examined by flow cytometry. RESULTS: We report for the first time that important levels of T cell apoptosis may persist under HAART, in spite of a rise in CD4 T cells from baseline and a sustained suppression of plasmatic viral load. Spontaneous CD3- or CD95-induced apoptosis levels were inversely correlated with the in vivo number of CD4 T cells and the CD4/CD8 ratio, but not with the viral load or duration of antiretroviral therapy. Regimens including lamivudine are associated with persistent T cell apoptosis, particularly following CD95 ligation. Lamivudine was also found to stimulate in vitro CD95-induced apoptosis and caspase activation in pre-activated T lymphocytes from healthy donors. CONCLUSION: The immunomodulatory effect of lamivudine may be one of the contributing factor to increased levels of T cell apoptosis under HAART. The data suggest that there is a requirement for physiological apoptosis during HAART.