Treatment With a Three-Drug Regimen for Pulmonary Tuberculosis Based on Rapid Molecular Detection of Isoniazid Resistance: A Noninferiority Randomized Trial (FAST-TB).

Background: The rationale behind the use of ethambutol in the standard tuberculosis treatment is to prevent the emergence of resistance to rifampicin in case of primary resistance to isoniazid. We evaluated whether early detection of isoniazid resistance using molecular testing allows the use an ethambutol-free regimen. Methods: FAST-TB, a phase 4, French, multicenter, open-label, non-inferiority trial, compared 2 strategies: (1) polymerase chain reaction (PCR)-based detection of isoniazid and rifampicin resistance at baseline using Genotype MTBDRplus version 2.0 followed by ethambutol discontinuation if no resistance was detected (PCR arm) and (2) a standard 4-drug combination, pending phenotypic drug-susceptibility results (C arm). Adult patients with smear-positive pulmonary tuberculosis were enrolled. The primary endpoint was the proportion of patients with treatment success defined as bacteriological or clinical cure at the end of treatment. A non-inferiority margin of 10% was used. Results: Two hundred three patients were randomized, 104 in the PCR arm and 99 in the C arm: 26.6% were female, median age was 37 (interquartile range, 28-51) years, 72.4% were born in Africa, and 5.4% were infected with human immunodeficiency virus. Chest x-ray showed cavities in 64.5% of the cases. Overall, 169 patients met criteria of treatment success: 87 of 104 (83.7%) in the PCR arm and 82 of 99 (82.8%) in the C arm with a difference of +0.8% (90% confidence interval, -7.9 to 9.6), meeting the noninferiority criteria in the intention-to-treat population (P = .02). Conclusions: In a setting with low prevalence of primary isoniazid resistance, a 3-drug combination with isoniazid, rifampicin, and pyrazinamide, based on rapid detection of isoniazid resistance using molecular testing, was noninferior to starting the recommended 4-drug regimen.

[Aggressive tumor progression during immunosuppressive therapy with abatacept]. / Une progression tumorale fulgurante sous abatacept.

INTRODUCTION: Co-stimulatory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibits T-cell activation. Clinically, CTLA-4 has been targeted in opposite ways: its blockade enhances antitumor immunity in the field of oncology, whereas CTLA-4 agonists such as abatacept are used for the treatment of immuno-inflammatory diseases as rheumatoid arthritis (RA). OBSERVATION: We herein report the case of a 69-year-old man with a history of severe RA successfully treated with abatacept, who showed unusually rapid progression of undifferentiated multi-metastatic carcinoma. DISCUSSION: Although no significant increase in malignancy has been reported in abatacept-treated patients, several case reports have documented the possible association with the acceleration of the progression of malignancy. Here, abatacept may have altered immune surveillance and hence allowed tumor growth.

Evolution of comorbidities in people living with HIV between 2004 and 2014: cross-sectional analyses from ANRS CO3 Aquitaine cohort.

BACKGROUND: The objective of the study was to describe the evolution of chronic non-AIDS related diseases and their risk factors, in patients living with HIV (PLHIV) in the French ANRS CO3 Aquitaine prospective cohort, observed both in 2004 and in 2014 in order to improve long-term healthcare management. METHODS: The ANRS CO3 Aquitaine cohort prospectively collects epidemiological, clinical, biological and therapeutic data on PLHIV in the French Aquitaine region. Two cross sectional analyses were performed in 2004 and 2014, to investigate the patient characteristics, HIV RNA, CD4 counts and prevalence of some common comorbidities and treatment. RESULTS: 2138 PLHIV (71% male, median age 52.2 years in 2014) were identified for inclusion in the study, including participants who were registered in the cohort with at least one hospital visit recorded in both 2004 and 2014. Significant increases in the prevalence of diagnosed chronic kidney disease (CKD), bone fractures, cardiovascular events (CVE), hypertension, diabetes and dyslipidaemia, as well as an increase in treatment or prevention for these conditions (statins, clopidogrel, aspirin) were observed. It was also reflected in the increase in the proportion of patients in the "high" or "very high" risk groups of the disease risk scores for CKD, CVE and bone fracture score. CONCLUSIONS: Between 2004 and 2014, the aging PLHIV population identified in the French ANRS CO3 Aquitaine prospective cohort experienced an overall higher prevalence of non-HIV related comorbidities, including CKD and CVD. Long-term healthcare management and long-term health outcomes could be improved for PLHIV by: careful HIV management according to current recommendations with optimal selection of antiretrovirals, and early management of comorbidities through recommended lifestyle improvements and preventative measures.

[Severity of illness index in autoimmune diseases: Have there any usefulness in medical practice?] / Les scores d'activité des maladies auto-immunes ont-ils une place en pratique quotidienne de médecine interne ?

INTRODUCTION: Assessing disease activity in patients suffering from autoimmune diseases is complex. Symptoms are multiple, often subjective and there are no reliable biomarkers. Many activity scores have been implemented to compare treatment efficacy in clinical trials. Their use in clinical practice is largely unknown. We performed a practical survey to analyze the use of activity scores in clinical practice to consider treatment response and to assess the determinants of their use. METHODS: A sample of French internists answered a questionnaire about activity scores of systemic lupus erythematosus, Sjögren's syndrome, autoimmune myositis and necrotizing vasculitis of small vessels. The frequency of use of these tools, the causes of their non-use, and the general opinion of practitioners about the place of theses scores in current practice were described. RESULTS: The form was completed by 92 internists. Seventy percent of them supported the use of activity scores in consultations, but actually used them in less than 25% of patient visits. The reasons for the low use of these scores are mainly the ignorance of their existence (42%) and their length or complexity (28%). CONCLUSION: The discrepancy between the ratio of practitioners who believe that scores have a place in daily practice and their actual use shows that the current scores do not meet the needs. The implementation of easily usable activity scores in inflammatory diseases remains a challenge for the internists.

[Cutaneous lesions during hot-tub hypersensitivity pneumonitis: Pseudomonas folliculitis ?] / Lésions cutanées au cours d'une pneumopathie d'hypersensibilité aux bains bouillonnants : folliculites à Pseudomonas ?

BACKGROUND: Interstitial lung disease, cutaneous rash and elevated serum angiotensin converting enzyme (ACE) may suggest diagnoses other than sarcoidosis. PATIENTS AND METHODS: A 58-year-old man had presented dyspnoea for 2 years with increased angiotensin-converting enzyme, as well as an interstitial syndrome and micronodules. The possibility of sarcoidosis was raised. Systemic corticosteroids resulted in improvement of the dyspnoea although it recurred on dose reduction. We noted fluctuating eczematous macules of the limbs with a histology of aspecific folliculitis. The identification of Mycobacterium avium complex (MAC) in the bronchoalveolar wash prompted us to initiate antimycobacterial therapy, but this was to no avail. Review of the CT-scan and questioning of the patient (daily use of a Jacuzzi for 7 years) resulted in diagnosis of hypersensitivity pneumonitis due to MAC. The cutaneous lesions were taken to indicate "hot tub folliculitis". Discontinuation of hot-tub use and a short course of oral corticosteroids resulted in healing within 4 months, with no recurrence at 2 years. DISCUSSION: HTL is a form of hypersensitivity pneumonitis due to the presence of MAC in the water of Jacuzzis. This condition regresses spontaneously without treatment on discontinuation of Jacuzzi use. Hot-tub folliculitis due to Pseudomonas aeruginosa (PA) presents as macules and papules on covered skin areas (swimsuit) within 48hours of bathing and often declines within 2 weeks. CONCLUSION: Our case is original as regards the concomitant lung and cutaneous involvement associated with Jacuzzi use, with an immunoallergic mechanism for the MAC and probably an infectious mechanism for the PA.

Proper use of carbapenems: Role of the infectious disease specialist.

OBJECTIVE: One of the objectives of the French national plan on antibiotics is to preserve antibiotic effectiveness. A group of infectious disease specialists of the University hospital of Bordeaux aimed to monitor the prescriptions of broad-spectrum antibiotics. Particular attention was paid to carbapenem (CBP) prescriptions given the increase in betalactamase- and carbapenemase-producing bacteria. PATIENTS AND METHODS: We carried out a three-step Professional Practice Evaluation (PPE): evaluation of CBP prescriptions made at the hospital between January and June 2013; CBP prescription training for prescribers; and another evaluation of CBP prescriptions between January and June 2014. RESULTS: Although the number of admissions remained stable between the two evaluation periods, CBP prescriptions decreased by 16%. The mean treatment duration was stable (9.6 days). Physicians asked for the infectious disease specialist's advice for 82% of CBP prescriptions in 2013 and for 83% in 2014. The number of case patients discussed at the multidisciplinary staff meetings for approval of CBP prescriptions increased from 16% in 2013 to 39% in 2014. Antibiotic de-escalation increased by 61% between the two periods. CONCLUSION: Professional Practice Evaluation, supervised by an infectious disease specialist, is a useful addition to weekly multidisciplinary staff meetings to improve CBP prescription.

[Survey of the prescriptions of proton pump inhibitors in patients admitted in an internal medicine ward: how is the compliance to the French guidelines?]. / Rapport sur l'utilisation des inhibiteurs de la pompe à protons : les recommandations françaises sont-elles respectées ?

PURPOSE: In June 2009, the national French authority for Health reported many off-label uses of proton pump inhibitors (PPI). Our objective was to analyse the justification and modalities of PPI prescriptions in patients before their admission in a department of internal medicine. METHODS: Data were prospectively collected during 5months. At admission, all prescriptions of PPI by general practitioners (GP) were recorded. The accordance of the prescriptions with the marketing authorization indications and the French guidelines in terms of duration of treatment or dosage was analyzed. These informations were obtained from computerized medical records and, if necessary, by contacting GPs. RESULTS: We collected 173 prescriptions. Fifty-six (32%) were in accordance with marketing authorization indications and, among them, 15 prescriptions (9% of all) respected the French guidelines about dosage and duration of treatment. One hundred and six prescriptions (61%) were not adequate and among them an off-label use was notified in 91 (53% of all); among them 33% for simple dyspeptic disorders, 23% for the prevention of NSAID-induced lesions in patients without risk factors, and finally 17% for the prevention of stress ulcer. Fifty-two prescriptions (30%) were unclassified due to incomplete data. CONCLUSION: Our study showed that a vast majority of the prescriptions for PPIs are not in accordance with French guidelines. Preventive actions against abusive prescriptions, withdrawal strategies or replacement of already prescribed PPIs should be implemented to reduce the risk of side effects and the economic impact of long term use of PPIs.

[Thrombotic thrombocytopenic purpura associated with interferon therapy in a HIV and HCV co-infected woman]. / Purpura thrombotique thrombocytopénique induit par l'interféron chez une femme co-infectée par le VIH et le VHC.

INTRODUCTION: Causes of acquired thrombotic thrombocytopenic purpura (TTP) are multiple and rarely iatrogenic. CASE REPORT: A 40-year-old, HIV and hepatitis C virus co-infected woman was treated with interferon and ribavirine and developed a TTP confirmed by the presence of anti-ADAMTS 13 antibodies. The outcome was favourable when treatment was discontinued and rituximab infusion administered. CONCLUSION: The occurrence of anemia and thrombocytopenia in patients treated with interferon and ribavirine is not always related to direct toxicities of these treatments. The ADAMS 13 testing may help the clinician to diagnose iatrogenic acquired TTP.

[Paradoxical reactions induced by antituberculous drugs in non-HIV infected patients: a cases series of four patients and literature review]. / Réactions paradoxales sous traitement antituberculeux chez des personnes non infectées par le VIH : quatre nouvelles observations et revue de la littérature.

INTRODUCTION: The features of paradoxical reactions (PR) that occurred in non-HIV infected patients treated with antituberculous drugs are diverse. We report four new cases of such PR and review the literature. PATIENTS AND METHODS: Were included all consecutive patients with PR that occurred in non-HIV infected patients who were treated for tuberculosis and followed-up in the department of internal medicine and infectious diseases between January 1st, 2009 and July 31st, 2010. RESULTS: Three of the patients were male. Their median age was 28.5 years. Tuberculous locations were pulmonary (two instances) and extrapulmonary (three instances). Paradoxical reactions occurred after a median of 5.5 weeks after initiation of antituberculous treatment. The PR presented as hypercalcemia (n=1), spondylitis of the 9th thoracic vertebra (n=1), intracerebral tuberculoma (n=1), pericardial effusion (n=1) and adenitis (n=3). Lymphopenia was present in three patients. Three out of the four patients received corticosteroid. Outcome was favorable in three patients. CONCLUSION: Pardoxical reactions are more common in patients who present with extrapulmonary tuberculosis. Intracerebral tuberculomas and spondylitis may be asymptomatic. Prescription of corticosteroids remains controversial except for intracerebral tuberculoma.

[Adherence between antibiotic prescriptions and guidelines in an internal medicine ward: an evaluation of professional practices]. / Adéquation entre les prescriptions antibiotiques et les recommandations dans un service de médecine interne : une démarche d'évaluation des pratiques professionnelles.

INTRODUCTION: This is an evaluation of professional practices (EPP) on antibiotic therapy in an internal medicine ward. MATERIAL AND METHODS: A 6-month prospective review of antibiotic prescriptions and their comparisons with local and national guidelines (drug, daily dose, administration, and duration) were performed. RESULTS: Antibiotic therapy on 227 infectious episodes was collected. According to local guidelines, we found 56% of totally respected (lower respiratory tract infections: 38%, urinary tract infections: 88% and skin infections: 73%), 33% of partially respected and 11% of non-appropriate prescriptions. Considering national guidelines for lower respiratory tract infections as references, the results were: totally respected prescriptions 81%, partially respected prescriptions 16%, and non-appropriate prescriptions 3%. CONCLUSION: This evaluation of the prescriptions allowed setting up long-lasting actions to improve clinical practice. This approach anticipates the procedures of EPP that will be needed for hospital accreditation and highlights the importance of considering several guidelines for the interpretation of the results.

[Lupus nephritis associated with common variable immunodeficiency: favourable outcome with intravenous immunoglobulin treatment]. / Néphropathie lupique liée à un déficit immunitaire commun variable d'évolution favorable sous immunoglobulines intraveineuses.

We report a 24-year-old woman who presented with a nephrotic syndrome as the revealing manifestation of systemic lupus erythematosus (SLE) and an associated hypogammaglobulinemia related to a common variable immunodeficiency (CVID). Outcome of SLE was favourable with intravenous immunoglobulin treatment solely. Relationships between SLE and CVID are discussed.

Structure-analysis of the HIV-1 integrase Y143C/R raltegravir resistance mutation in association with the secondary mutation T97A.

The HIV-1 integrase (IN) mutations Y143C/R are known as raltegravir (RAL) primary resistance mutations. In a previous study (S. Reigadas et al., PLoS One 5:e10311, 2010), we investigated the genetic pathway and the dynamics of emergence of the Y143C/R mutations in three patients failing RAL-containing regimens. In these patients, the Y143C/R mutation was associated with the T97A mutation. The aim of the present biochemical and molecular studies in vitro was to evaluate whether the secondary mutation, T97A, associated with the Y143C/R mutation could increase the level of resistance to RAL and impact IN activities. Site-directed mutagenesis experiments were performed with expression vectors harboring the region of the pol gene coding for IN. With a 3'-end processing assay, the 50% inhibitory concentrations (IC(50)) were 1.2 µM, 1.2 µM, 2.4 µM (fold change [FC], 2), and 20 µM (FC, 16.7) for IN wild type (WT), the IN T97A mutation, the IN Y143C/T97A mutation, and the IN Y143R/T97A mutation, respectively. FCs of 18 and 100 were observed with the strand transfer assay for IN Y143C/T97A and Y143R/T97A mutations, with IC(50) of 0.625 µM and 2.5 µM, respectively. In the strand transfer assay, the IN Y143C or R mutation combined with the secondary mutation T97A severely impaired susceptibility to RAL compared to results with the IN Y143C or R mutation alone. Assays without RAL suggested that the T97A mutation could rescue the catalytic activity which was impaired by the presence of the Y143C/R mutation. The combination of the T97A mutation with the primary RAL resistance mutations Y143C/R strongly reduces the susceptibility to RAL and rescues the catalytic defect due to the Y143C/R mutation. This result indicates that the emergence of the Y143C/R/T97A double-mutation pattern in patients is a signature of a high resistance level.

Menopause and HIV infection: age at onset and associated factors, ANRS CO3 Aquitaine cohort.

The aim of the paper is to describe the characteristics of postmenopausal HIV-infected women and to investigate the factors associated with an earlier onset of menopause in a hospital-based cohort. Information was collected using a self-administered questionnaire. A Cox model was used to determine factors associated with menopause. Among the 404 women who completed the questionnaire, 69 were naturally postmenopausal at the time of the study (median age at onset: 49 years, premature menopause <40 years: 12%). The onset of menopause was studied among the 41 women still menstruating at the enrollment in the cohort, and who experienced menopause during follow-up. African origin (hazard ratio [HR] = 8.16; 95% confidence interval [CI] = 2.23-29.89) and history of injecting drug use (IDU) (HR = 2.46; 95% CI = 1.03-5.85) were associated with an increased risk of earlier menopause. Women with a CD4 cell count <200 cells/mm(3) tended to reach menopause earlier (HR = 2.25; 95% CI = 0.94-5.39). Earlier occurrence of menopause seems to be associated with factors already reported in HIV-negative women (IDU, ethnicity) and with HIV-related immunodeficiency.

Parental catastrophizing about child's pain and its relationship with activity restriction: the mediating role of parental distress.

Recent research has demonstrated that parental behaviors have an important impact upon child and adolescent pain outcomes. At present, however, we do not know which parents engage in particular behaviors and why. In 2 studies, the impact of parental catastrophizing about their child's pain upon parental tendency to stop their child's pain-inducing activity was investigated. Further, the mediating role of parental distress was explored. In study 1, a sample of schoolchildren (n=62; M=12.48 years; SD=1.72) took part in a cold-pressor task. In study 2, a clinical sample of adolescents with chronic pain (n=36; M=15.68 years; SD=1.85) performed a 2-min walking task designed as a pain-inducing activity. In both studies, the accompanying parent was asked to watch their child performing the pain task. Findings revealed, for both studies, that parents with a high level of catastrophic thinking about their child's pain experienced more distress and a greater behavioral tendency of wanting to stop their child's pain-inducing activity. Further, parental feelings of distress mediated the relationship between parental catastrophic thinking and parents' tendency to restrict their child's activity. The findings are discussed in light of an affective-motivational conceptualization of pain and pain behavior. Parental catastrophizing was associated with parental tendency to restrict their child's engagement in a painful test, and this relationship was mediated by parental distress.

Expressive dimensions of pain catastrophizing: An observational study in adolescents with chronic pain.

Investigated was the relationship between pain catastrophizing and pain intensity in adolescents suffering from chronic pain (n = 38) and the extent to which they expressed communicative pain and pain-related protective behaviours. Adolescents were observed on video performing a 2-Min Walk Test (2MWT). Behaviours were coded on videotape. The adolescents' verbalizations about the 2MWT were also rated by their parents. Analyses revealed that higher levels of catastrophic thinking about pain were associated with higher levels of facial pain expressions and verbalizations about their pain experience, beyond the effects of age, gender, pain duration and pain intensity. Pain-related protective behaviours did not vary with the adolescents' level of pain catastrophizing, but varied with pain intensity. The findings corroborate the functional distinctiveness of different types of pain behaviours. The results are discussed in terms of the processes linking (1) catastrophizing to communicative pain behaviours and (2) pain to pain-related protective behaviours.

[Dilated cardiomyopathy and lipid-lowering drug muscle toxicity revealing late-onset Becker's disease]. / Cardiomyopathie dilatée et toxicité musculaire des hypolipémiants: une maladie de Becker de révélation tardive.

INTRODUCTION: The Becker's muscular dystrophy is a genetic myopathy due to mutations of the dystrophin gene, located in the Xp21 region, with a clinical expression usually occurring in young adults. EXEGESIS: We report an atypical case of late onset Becker's muscular dystrophy diagnosed at the age of 57. The patient suffered from mild skeletal muscle involvement revealed by the use of statins and fibrates, associated with severe dilating cardiomyopathy. The DNA analysis showed a deletion of the exons 11-13 in the Xp21 gene. CONCLUSION: The diagnostic of Becker's muscular dystrophy must be considered in all patients with persistently elevated CPK and/or primitive dilated cardiomyopathy, whatever the age of the patient.