Anti-gp41 antibody levels reflect HIV viral suppression and cellular reservoir in long-term antiretroviral-treated trial participants.

BACKGROUND: A major challenge to HIV cure strategies is the quantification of persistent reactivation-prone virus in people living with HIV. OBJECTIVES: To determine whether anti-gp41 antibody levels correlate with viral suppression and HIV-1 DNA levels in patients on ART. METHODS: Participants with plasma HIV-1 RNA below 50 copies/mL for >12 months were included from three ANRS cohorts (COPANA, MONOI and APROCO). Antibody levels to gp41 were measured by a low-sensitivity enzyme-linked immunoassay. Correlations with patient and virus characteristics, plasma HIV-1 RNA load (standard and ultrasensitive tests) and cell-associated HIV-1 DNA were assessed. RESULTS: Median age was 41 years and 77.5% of the 683 participants were men. Median CD4+ T cell count was 582 cells/mm3 and median viral suppression duration was 6.6 years (IQR 2.0-9.5). The overall median anti-gp41 antibody titre was 1.3 (IQR 0.6-1.9); median HIV-1 DNA level was 2.6 (IQR 2.1-3.0) log10 copies/106 leucocytes; and HIV-1 RNA was undetectable in 56% of samples. A lower titre of anti-gp41 antibodies correlated with male gender, longer viral suppression and lower HIV-1 DNA burden. Sustained undetectable HIV-1 RNA was associated with lower anti-gp41 levels [median 1.1 (IQR 0.5-1.6) versus 1.4 (IQR 0.7-1.9), P = 0.009]. CONCLUSIONS: Anti-gp41 levels decreased with the duration of antiviral suppression on ART. Lower titres were associated with lower HIV-1 DNA levels and longer duration of viral suppression, reflecting minimal antigen stimulation. Anti-gp41 antibody titration may be a useful biomarker reflecting long-term HIV-1 suppression on ART.

Low to medium-low risk perception for dengue, chikungunya and Zika outbreaks by infectious diseases physicians in France, Western Europe.

BACKGROUND: Many tropical countries are currently experiencing dengue (DEN), chikungunya (CHIK) and also more recently Zika (ZIKA) epidemics (particularly in Latin America). Although the risk of transmission and spread of these infections in temperate regions remains a controversial issue, vector-borne diseases have been widely reported in the media and have been the focus of preventive strategies by national and international policy-makers and public health authorities. In this context, we wanted to determine the extent of risk perception in infectious diseases (ID) physicians of the current and future risk of arboviral disease introduction, autochthonous case development and epidemic scenarios in France, Western Europe. METHODS: To this aim, we developed an original standardized questionnaire survey which was disseminated by the French Infectious Diseases Society to ID physician members. RESULTS: We found that ID physicians perceived the risk of introduction and outbreak development of DEN, CHIK and ZIKA in France to be low to medium-low. Generalized Linear Model(s) identified medical school training, the extent of professional experience, and awareness of the French national plan regarding arboviral infections as significant predictors for lower risk perception among respondents. CONCLUSION: Despite the fact that arboviral diseases are increasingly being imported into France, sometimes resulting in sporadic autochtonous transmission, French ID physicians do not perceive the risk as high. Better communication and education targeting health professionals and citizens will be needed to enhance the effectiveness of the French national plan to prepare against arboviral diseases.

High heterogeneity in community-acquired pneumonia inclusion criteria: does this impact on the validity of the results of randomized controlled trials?

BACKGROUND: There is no consensus on the most accurate combination of diagnostic criteria to define community acquired pneumonia (CAP). We describe inclusion criteria in randomized controlled trials (RCT) of CAP and assess their performance for the diagnosis of formally identified CAP. METHODS: RCTs related to CAP recorded on ClinicalTrials.gov were analysed. Due to high heterogeneity, we divided close CAP inclusion criteria into patterns (i.e. combinations of inclusion criteria). To assess their diagnostic performances, these CAP definition patterns were applied to a reference population of 319 suspected CAP patients, in whom the CAP diagnosis had been confirmed (n = 163) or excluded (n = 156) by an adjudication committee after a systematic thoracic CT-scan and a 28-day follow-up period. RESULTS: In the 47 RCTs included in the analysis, 42 different CAP inclusion criteria combinations were identified and 8 patterns created. This heterogeneity was not explained either by the trials' methodology or by their objectives. When applied to the reference population, the performance ranges of the 8 definition patterns were 9.8-56.4% for sensitivities, 56.4 97.4% for specificities, 63.6 83.6% for positive predictive values and 50.8-66.7% for negative predictive values. None of the CAP definitions had both sensitivity and specificity superior to 65%. Depending on the CAP definition, the rate of included patients without CAP ("false positives") ranged from 1 to 21%. CONCLUSIONS: CAP diagnostic criteria within RCTs are heterogeneous, which may have far-reaching consequences on validity of RCT results.

Failure to achieve immunological recovery in HIV-infected patients with clinical and virological success after 10 years of combined ART: role of treatment course.

OBJECTIVES: We assessed factors, including treatment course, associated with failure to obtain a 10 year immunological response after starting first-generation PI-containing combined ART (cART). PATIENTS AND METHODS: In the prospective COPILOTE cohort of HIV-infected patients started on a first-generation PI-containing regimen in 1997-99, the impact of cART history on the failure to achieve immunological response measured at 10 years was assessed by multivariate logistic regression models in the 399 patients with clinical and virological success of cART. RESULTS: Failure of CD4 response (CD4 >500/mm3) was associated with age ≥40 years at baseline (P < 0.001), CD4 cell counts ≤500/mm3 at month 4 (P = 0.016) or month 12 (P < 0.001) and ≥3 months of cART interruption (P = 0.016). Factors associated with failure to achieve complete immunological response (CD4 >500/mm3 and CD4:CD8 ratio >1) were CD4:CD8 ratio ≤0.8 at month 8 (P < 0.001) or month 12 (P < 0.001), ≥3 months of cumulative cART interruption (P = 0.011), ≥3 antiretroviral regimens (P = 0.009) and ≤4 treatment lines (P = 0.015). Baseline CD4 and CD4:CD8 ratio were not predictors of the 10 year immunological outcomes. CONCLUSIONS: In this therapeutic cohort of patients starting first-generation PI-containing cART in 1997-99, poor initial immunological response had a negative impact on 10 year CD4 and CD4 plus CD4:CD8 ratio response, despite prolonged virological success. Lack of treatment interruption may improve long-term immunological outcome in HIV infection.

CD4 cell count response to first-line combination ART in HIV-2+ patients compared with HIV-1+ patients: a multinational, multicohort European study.

Background: CD4 cell recovery following first-line combination ART (cART) is poorer in HIV-2+ than in HIV-1+ patients. Only large comparisons may allow adjustments for demographic and pretreatment plasma viral load (pVL). Methods: ART-naive HIV+ adults from two European multicohort collaborations, COHERE (HIV-1 alone) and ACHIeV2e (HIV-2 alone), were included, if they started first-line cART (without NNRTIs or fusion inhibitors) between 1997 and 2011. Patients without at least one CD4 cell count before start of cART, without a pretreatment pVL and with missing a priori-defined covariables were excluded. Evolution of CD4 cell count was studied using adjusted linear mixed models. Results: We included 185 HIV-2+ and 30321 HIV-1+ patients with median age of 46 years (IQR 36-52) and 37 years (IQR 31-44), respectively. Median observed pretreatment CD4 cell counts/mm3 were 203 (95% CI 100-290) in HIV-2+ patients and 223 (95% CI 100-353) in HIV-1+ patients. Mean observed CD4 cell count changes from start of cART to 12 months were +105 (95% CI 77-134) in HIV-2+ patients and +202 (95% CI 199-205) in HIV-1+ patients, an observed difference of 97 cells/mm3 in 1 year. In adjusted analysis, the mean CD4 cell increase was overall 25 CD4 cells/mm3/year lower (95% CI 5-44; P = 0.0127) in HIV-2+ patients compared with HIV-1+ patients. Conclusions: A poorer CD4 cell increase during first-line cART was observed in HIV-2+ patients, even after adjusting for pretreatment pVL and other potential confounders. Our results underline the need to identify more potent therapeutic regimens or strategies against HIV-2.

Discussing HIV Status: Is It Easier After 10 Years of Antiretroviral Treatment? The ANRS CO8 APROCO-COPILOTE Cohort.

This study's objective was to explore the factors associated with the belief (or not) by people living with HIV that it is easier to talk about their seropositivity 10 years after initiating a protease inhibitor-containing ART. All patients in the ANRS CO8 APROCO-COPILOTE cohort who completed a self-administered questionnaire at 10 years of follow-up were included in this study. Forty-four percent of patients declared that discussing their seropositivity with their family was easier 10 years later, while 28 % declared this was true for discussing their status with a new sexual partner. Having a low socioeconomic status, not receiving social support from a steady partner and declaring a low number of discomforting symptoms 12 months after PI initiation were all independently associated with less difficulty in discussing seropositivity. This study highlights the difficulties in disclosing HIV 10 years after PI initiation, and the important influence of psychosocial factors and patients' daily-life experience on disclosure.

Early Chest Computed Tomography Scan to Assist Diagnosis and Guide Treatment Decision for Suspected Community-acquired Pneumonia.

RATIONALE: Clinical decision making relative to community-acquired pneumonia (CAP) diagnosis is difficult. Chest radiograph is key in establishing parenchymal lung involvement. However, radiologic performance may lead to misdiagnosis, rendering questionable the use of chest computed tomography (CT) scan in patients with clinically suspected CAP. OBJECTIVES: To assess whether early multidetector chest CT scan affects diagnosis and management of patients visiting the emergency department with suspected CAP. METHODS: A total of 319 prospectively enrolled patients with clinically suspected CAP underwent multidetector chest CT scan within 4 hours. CAP diagnosis probability (definite, probable, possible, or excluded) and therapeutic plans (antibiotic initiation/discontinuation, hospitalization/discharge) were established by emergency physicians before and after CT scan results. The adjudication committee established the final CAP classification on Day 28. MEASUREMENTS AND MAIN RESULTS: Chest radiograph revealed a parenchymal infiltrate in 188 patients. CAP was initially classified as definite in 143 patients (44.8%), probable or possible in 172 (53.8%), and excluded in 4 (1.2%). CT scan revealed a parenchymal infiltrate in 40 (33%) of the patients without infiltrate on chest radiograph and excluded CAP in 56 (29.8%) of the 188 with parenchymal infiltrate on radiograph. CT scan modified classification in 187 (58.6%; 95% confidence interval, 53.2-64.0), leading to 50.8% definite CAP and 28.8% excluded CAP, and 80% of modifications were in accordance with adjudication committee classification. Because of CT scan, antibiotics were initiated in 51 (16%) and discontinued in 29 (9%), and hospitalization was decided in 22 and discharge in 23. CONCLUSIONS: In CAP-suspected patients visiting the emergency unit, early CT scan findings complementary to chest radiograph markedly affect both diagnosis and clinical management. Clinical trial registered with www.clinicaltrials.gov (NCT 01574066).

Increased systemic immune activation and inflammatory profile of long-term HIV-infected ART-controlled patients is related to personal factors, but not to markers of HIV infection severity.

OBJECTIVES: The objective of this study was to analyse the respective roles of personal factors and HIV infection markers on the systemic immune activation/inflammatory profile of long-term antiretroviral treatment-controlled patients. PATIENTS AND METHODS: A panel of soluble immune activation/inflammatory biomarkers was measured in 352 HIV-infected treatment-controlled patients from the APROCO-COPILOTE cohort, all of whom were started on a PI in 1997-99 and had a final evaluation 11 years later, and in 59 healthy controls. RESULTS: A total of 81.5% of the patients were male, with the following characteristics: median age 49 years; 620 CD4 cells/mm(3); 756 CD8 cells/mm(3); CD4/CD8 ratio 0.81; BMI 23.0 kg/m(2); waist-to-hip ratio 0.95. Markers of inflammation-high-sensitivity (hs) IL-6 (median and IQR) (1.3 pg/L, 0.7-2.6), hs C-reactive protein (CRP) (2.1 mg/L, 0.9-4.5) and D-dimer (252 ng/mL, 177-374)-were elevated compared with healthy controls (P < 0.001) and strongly related to each other, as were markers of immune activation [soluble (s) CD14 (1356 ng/mL, 1027-1818), ß2-microglobulin (2.4 mg/L, 2.0-3.1) and cystatin-C (0.93 mg/L, 0.82-1.1)]. Inflammatory and immune activation markers were also associated with each other. In HIV-infected patients: age was related to D-dimer, ß2-microglobulin and cystatin-C levels; being a smoker was related to increased IL-6 and cystatin-C; and BMI and waist-to-hip ratio were related to CRP. Conversely, markers of HIV infection, current CD4 or CD8 values, CD4 nadir, CD4/CD8 ratio, AIDS stage at initiation of PIs, current viral load and duration of ART were not associated with immune activation/inflammation markers. CONCLUSIONS: In these long-term treatment-controlled HIV-infected patients, all systemic markers of inflammation and immune activation were increased compared with healthy controls. This was related to demographic and behavioural factors, but not to markers of severity of the HIV infection. Intervention to decrease low-grade inflammation must thus prioritize modifiable personal factors.

Late presentation for HIV care across Europe: update from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study, 2010 to 2013.

Late presentation (LP) for HIV care across Europe remains a significant issue. We provide a cross-European update from 34 countries on the prevalence and risk factors of LP for 2010-2013. People aged ≥ 16 presenting for HIV care (earliest of HIV-diagnosis, first clinic visit or cohort enrollment) after 1 January 2010 with available CD4 count within six months of presentation were included. LP was defined as presentation with a CD4 count < 350/mm(3) or an AIDS defining event (at any CD4), in the six months following HIV diagnosis. Logistic regression investigated changes in LP over time. A total of 30,454 people were included. The median CD4 count at presentation was 368/mm(3) (interquartile range (IQR) 193-555/mm(3)), with no change over time (p = 0.70). In 2010, 4,775/10,766 (47.5%) were LP whereas in 2013, 1,642/3,375 (48.7%) were LP (p = 0.63). LP was most common in central Europe (4,791/9,625, 49.8%), followed by northern (5,704/11,692; 48.8%), southern (3,550/7,760; 45.8%) and eastern Europe (541/1,377; 38.3%; p < 0.0001). There was a significant increase in LP in male and female people who inject drugs (PWID) (adjusted odds ratio (aOR)/year later 1.16; 95% confidence interval (CI): 1.02-1.32), and a significant decline in LP in northern Europe (aOR/year later 0.89; 95% CI: 0.85-0.94). Further improvements in effective HIV testing strategies, with a focus on vulnerable groups, are required across the European continent.

Determinants of cerebral lesions in endocarditis on systematic cerebral magnetic resonance imaging: a prospective study.

BACKGROUND AND PURPOSE: Cerebral lesions are frequent complications of infective endocarditis (IE) and have a prognostic impact. Cerebral MRI identifies lesions in a high number of patients. However, their determinants have not been identified. The aim of the study was to define the determinants of cerebral lesions in patients with IE undergoing systematic cerebral MRI. METHODS: Determinants of ischemic lesions and of microbleeds were prospectively analyzed in 120 patients with left-sided IE, using systematic cerebral MRI. RESULTS: Median age was 60 years (interquartile range 51-72); IE occurred on a prosthetic valve in 37 patients (30.8%) and was due to Streptococci in 47 patients and Staphylococci in 36; 15 (12.5%) had neurological symptoms. MRI detected ischemic lesions in 64 patients (53.3%; territorial lesions in 32 and small lesions in 57) and microbleeds in 72 (60.0%). In multivariate analysis, ischemic lesions were associated with vegetation length (odds ratio 1.10/mm; 95% confidence interval 1.03-1.16; P=0.003) and Staphylococcus aureus IE (odds ratio 2.65; 95% confidence interval 1.01-6.96; P=0.05). A vegetation length >4 mm identified ischemic lesions with a sensitivity of 74.6% and a specificity of 51.5%. Microbleeds were associated with prosthetic IE (odds ratio 8.01; 95% confidence interval 2.58-24.90; P=0.0003) and not with prior anticoagulant therapy (P=0.67). CONCLUSIONS: Systematic cerebral MRI frequently detects ischemic lesions and microbleeds during acute IE. The high sensitivity of MRI shows that each millimeter increase in vegetation length is associated with a 10% increase in the rate of ischemic lesions. Conversely, microbleeds are associated only with prosthetic IE in this study. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00144885.

Risk factors and outcomes for late presentation for HIV-positive persons in Europe: results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE).

BACKGROUND: Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality. METHODS AND FINDINGS: LP was defined in Collaboration of Observational HIV Epidemiological Research Europe (COHERE) as HIV diagnosis with a CD4 count <350/mm(3) or an AIDS diagnosis within 6 months of HIV diagnosis among persons presenting for care between 1 January 2000 and 30 June 2011. Logistic regression was used to identify factors associated with LP and Poisson regression to explore the impact on AIDS/death. 84,524 individuals from 23 cohorts in 35 countries contributed data; 45,488 were LP (53.8%). LP was highest in heterosexual males (66.1%), Southern European countries (57.0%), and persons originating from Africa (65.1%). LP decreased from 57.3% in 2000 to 51.7% in 2010/2011 (adjusted odds ratio [aOR] 0.96; 95% CI 0.95-0.97). LP decreased over time in both Central and Northern Europe among homosexual men, and male and female heterosexuals, but increased over time for female heterosexuals and male intravenous drug users (IDUs) from Southern Europe and in male and female IDUs from Eastern Europe. 8,187 AIDS/deaths occurred during 327,003 person-years of follow-up. In the first year after HIV diagnosis, LP was associated with over a 13-fold increased incidence of AIDS/death in Southern Europe (adjusted incidence rate ratio [aIRR] 13.02; 95% CI 8.19-20.70) and over a 6-fold increased rate in Eastern Europe (aIRR 6.64; 95% CI 3.55-12.43). CONCLUSIONS: LP has decreased over time across Europe, but remains a significant issue in the region in all HIV exposure groups. LP increased in male IDUs and female heterosexuals from Southern Europe and IDUs in Eastern Europe. LP was associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis, with significant variation across Europe. Earlier and more widespread testing, timely referrals after testing positive, and improved retention in care strategies are required to further reduce the incidence of LP.

Adherence to and effectiveness of highly active antiretroviral treatment for HIV infection: assessing the bidirectional relationship.

BACKGROUND: It is well established that high adherence to HIV-infected patients on highly active antiretroviral treatment (HAART) is a major determinant of virological and immunologic success. Furthermore, psychosocial research has identified a wide range of adherence factors including patients' subjective beliefs about the effectiveness of HAART. Current statistical approaches, mainly based on the separate identification either of factors associated with treatment effectiveness or of those associated with adherence, fail to properly explore the true relationship between adherence and treatment effectiveness. Adherence behavior may be influenced not only by perceived benefits-which are usually the focus of related studies-but also by objective treatment benefits reflected in biological outcomes. METHODS: Our objective was to assess the bidirectional relationship between adherence and response to treatment among patients enrolled in the ANRS CO8 APROCO-COPILOTE study. We compared a conventional statistical approach based on the separate estimations of an adherence and an effectiveness equation to an econometric approach using a 2-equation simultaneous system based on the same 2 equations. RESULTS: Our results highlight a reciprocal relationship between adherence and treatment effectiveness. After controlling for endogeneity, adherence was positively associated with treatment effectiveness. Furthermore, CD4 count gain after baseline was found to have a positive significant effect on adherence at each observation period. This immunologic parameter was not significant when the adherence equation was estimated separately. In the 2-equation model, the covariances between disturbances of both equations were found to be significant, thus confirming the statistical appropriacy of studying adherence and treatment effectiveness jointly. CONCLUSIONS: Our results, which suggest that positive biological results arising as a result of high adherence levels, in turn reinforce continued adherence and strengthen the argument that patients who do not experience rapid improvement in their immunologic and clinical statuses after HAART initiation should be prioritized when developing adherence support interventions. Furthermore, they invalidate the hypothesis that HAART leads to "false reassurance" among HIV-infected patients.

[Is infective endocarditis prophylaxis always recommended?]. / La prophylaxie de l'endocardite infectieuse est-elle toujours recommandée?

Infective endocarditis prophylaxis is a preventive strategy that has been recommended in various countries for more than 50 years. It is based on the plausible assumption that infectious endocarditis is, at least partially, avoidable. Traditionally, prophylaxis has consisted in the administration of an antibiotic agent in subjects with high-risk heart disease, or before high-risk interventions. More than 20 years ago, the indications of antibiotic prophylaxis were reduced and limited to high-risk patients and interventions, essentially valve replacement, or dental procedures with mucosal involvement, while the recommendations for overall non-antibiotic preventive measures, as well as recommendations for earlier diagnosis, have been reinforced.

Cellular HIV-1 DNA quantification and short-term and long-term response to antiretroviral therapy.

BACKGROUND: The aim of our study was to determine whether HIV-1 DNA level before antiretroviral therapy (ART) was associated with short- and long-term virological and immunological responses. METHODS: Patients starting first-line protease inhibitor-containing regimens were enrolled in a prospective multicentre cohort in 1998-99. HIV-1 DNA was quantified using real-time PCR at baseline and after 1 year of ART. The association between HIV-1 DNA and virological and immunological responses after 1 and 7 years on ART was studied in multivariate regression models along with other biological and clinical variables. Virological failure (VF) at month 12 (M12) was defined as a plasma HIV-1 RNA >500 copies/mL. Time to death or two plasma HIV-1 RNA >500 copies/mL between M12 and M84 was studied for long-term VF. RESULTS: HIV-1 DNA levels were measured in 148 patients. The median baseline peripheral blood mononuclear cell (PBMC) HIV-1 DNA was 3.7 log(10) copies/10(6) PBMCs. At M12, the median PBMC HIV-1 DNA was 2.99 log(10) copies/10(6) PBMCs. The median decrease in PBMC HIV-1 DNA between M0 and M12 was -0.7 log(10) copies/10(6) PBMCs. Higher baseline PBMC HIV-1 DNA and plasma HIV-1 RNA were independently associated with a higher risk of VF at M12. Only the baseline plasma HIV-1 RNA was independently associated with long-term virological response. The baseline CD4 cell count was the only parameter associated with short- and long-term immunological responses. CONCLUSIONS: HIV-1 DNA impacted the virological response in our cohort. Further research is warranted to study the impact of HIV-1 DNA with currently recommended first-line cART.

Effect of early cerebral magnetic resonance imaging on clinical decisions in infective endocarditis: a prospective study.

BACKGROUND: Neurologic complications of endocarditis can influence diagnosis, therapeutic plans, and prognosis. OBJECTIVE: To describe how early cerebral magnetic resonance imaging (MRI) affects the diagnosis and management of endocarditis in hospitalized adults. DESIGN: Single-center prospective study between June 2005 and October 2008. (ClinicalTrials.gov registration number: NCT00144885) SETTING: Tertiary care university hospital in France. PATIENTS: 130 patients with endocarditis. INTERVENTION: Cerebral MRI with angiography performed up to 7 days after admission and before any surgical intervention. MEASUREMENTS: 2 experts jointly established the endocarditis diagnostic classification (according to Duke-modified criteria) and therapeutic plans just before and after MRI and then compared them. RESULTS: Endocarditis was initially classified as definite in 77 patients and possible in 50 and was excluded in 3. Sixteen patients (12%) had acute neurologic symptoms. Cerebral lesions were detected by MRI in 106 patients (82% [95% CI, 75% to 89%]), including ischemic lesions in 68, microhemorrhages in 74, and silent aneurysms in 10. Solely on the basis of MRI results and excluding microhemorrhages, diagnostic classification of 17 of 53 (32%) cases of nondefinite endocarditis was upgraded to either definite (14 patients) or possible (3 patients). Endocarditis therapeutic plans were modified for 24 (18%) of the 130 patients, including surgical plan modifications for 18 (14%). Overall, early MRI led to modifications of diagnosis or therapeutic plan in 36 patients (28% [CI, 20% to 36%]). LIMITATION: Investigators did not assess whether the MRI-related changes in diagnosis and therapeutic plans improved patient outcomes or led to unnecessary procedures and increased costs. CONCLUSION: Cerebral lesions were identified by MRI in many patients with endocarditis but no neurologic symptoms. The MRI findings affected both diagnostic classifications and clinical management plans. PRIMARY FUNDING SOURCE: French Ministry of Health.

Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial.

BACKGROUND: Neuraminidase inhibitors are thought to be efficacious in reducing the time to alleviation of symptoms in outpatients with seasonal influenza. The objective of this study was to compare the short-term virological efficacy of oseltamivir-zanamivir combination versus each monotherapy plus placebo. METHODS AND FINDINGS: We conducted a randomized placebo-controlled trial with 145 general practitioners throughout France during the 2008-2009 seasonal influenza epidemic. Patients, general practitioners, and outcome assessors were all blinded to treatment assignment. Adult outpatients presenting influenza-like illness for less than 36 hours and a positive influenza A rapid test diagnosis were randomized to oseltamivir 75 mg orally twice daily plus zanamivir 10 mg by inhalation twice daily (OZ), oseltamivir plus inhaled placebo (O), or zanamivir plus oral placebo (Z). Treatment efficacy was assessed virologically according to the proportion of patients with nasal influenza reverse transcription (RT)-PCR below 200 copies genome equivalent (cgeq)/µl at day 2 (primary outcome), and clinically to the time to alleviation of symptoms until day 14. Overall 541 patients (of the 900 planned) were included (OZ,  =192; O, n=176; Z, n=173), 49% male, mean age 39 years. In the intention-to-treat analysis conducted in the 447 patients with RT-PCR-confirmed influenza A, 46%, 59%, and 34% in OZ (n=157), O (n=141), and Z (n=149) arms had RT-PCR<200 cgeq/µl (-13.0%, 95% confidence interval [CI] -23.1 to -2.9, p=0.025; +12.3%, 95% CI 2.39-22.2, p=0.028 for OZ/O and OZ/Z comparisons). Mean day 0 to day 2 viral load decrease was 2.14, 2.49, and 1.68 log(10) cgeq/µl (p=0.060, p=0.016 for OZ/O and OZ/Z). Median time to alleviation of symptoms was 4.0, 3.0, and 4.0 days (+1.0, 95% CI 0.0-4.0, p=0.018; +0.0, 95% CI -3.0 to 3.0, p=0.960 for OZ/O and OZ/Z). Four severe adverse events were observed. Nausea and/or vomiting tended to be more frequent in the combination arm (OZ, n=13; O, n=4; and Z, n=5 patients, respectively). CONCLUSIONS: In adults with seasonal influenza A mainly H3N2 virus infection, the oseltamivir-zanamivir combination appeared less effective than oseltamivir monotherapy, and not significantly more effective than zanamivir monotherapy. Despite the theoretical potential for the reduction of the emergence of antiviral resistance, the lower effectiveness of this combination calls for caution in its use in clinical practice. TRIAL REGISTRATION: www.ClinicalTrials.govNCT00799760.

Nevirapine Use Is Associated with Higher Bone Mineral Density in HIV-1 Positive Subjects on Long-Term Antiretroviral Therapy.

We assessed bone mineral density (BMD) in a cohort of human immunodeficiency virus (HIV)-positive patients after a median of 11 years of combination antiretroviral therapy (cART) and evaluated the respective role of HIV infection and antiretroviral drugs (ARVs). A cross-sectional study of 162 participants (131 male) from the ANRS-C08 cohort was performed with bone dual-energy X-ray absorptiometry (DXA) scans and renal assessment. The window of exposure to ARVs was defined as an exposure of more than six cumulative months during the last 3 years before the DXA evaluation to account for a cumulative exposure that could affect bone remodeling. The association with low BMD (Z-score < -2) was assessed by a multiple logistic regression model. The study population was 50 years (median), hepatitis C virus (HCV) (18%), and hepatitis B virus (HBV) (8%) coinfection with HIV-RNA <50 c/mL in 89%, median CD4 of 619/mm3. Prevalence of low BMD was 18% in males and 6% in females. The factors associated with a Z-score < -2 in males were uric acid renal loss [adjusted odds ratio (aOR): 6.1; 95% confidence interval (CI): 1.2-31.5; p = .03], HCV coinfection (aOR: 4.0; 95% CI: 1.3-12.2; p = .02), and less frequent window of exposure to nevirapine (NVP) (aOR: 0.1; 95% CI: 0.02-0.6; p = .01). For the full study sample, there was a strong positive association between duration of exposure to NVP and lumbar spine Z-score (p = .004). HIV-positive patients exposed to long-term cART have a high incidence of low BMD. Tenofovir disoproxil fumarate and ritonavir-boosted protease inhibitors did not seem to be associated with increased risk of low BMD, whereas NVP exposure appeared to have an independent positive association.

Long-term evolution and determinants of renal function in HIV-infected patients who began receiving combination antiretroviral therapy in 1997-1999, ANRS CO8 APROCO-COPILOTE.

Among 1121 patients (90% Caucasian) infected by the human immunodeficiency virus (HIV), the glomerular filtration rate increased (+0.72 mL/min/1.73 m(2)/month) from treatment initiation to month 16 (the rate increase was lower among men and those with low body mass index, AIDS, or receipt of indinavir), then remained stable up to 7 years. Kidney function should be monitored in patients previously exposed to indinavir.

Cerebral microbleeds are frequent in infective endocarditis: a case-control study.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) have been described using MRI in patients with cardiovascular risk factors or prior stroke and could be an indicator of small vessel disease. CMBs have been reported in isolated cases of infective endocarditis (IE), but their frequency and the association of CMBs with IE have not yet been studied. METHODS: A case-control imaging study in a referral institutional tertiary care center was conducted. Systematic brain MRIs, including T2*-weighted sequences, were performed in 60 patients with IE within 7 days of hospital admission and in 120 age- and gender-matched control subjects without IE. Two neuroradiologists, who were blinded to patient characteristics, independently assessed the presence, location, and size of CMBs using a standardized form. RESULTS: The interobserver agreement level on the presence of CMBs was high with a kappa coefficient range (95% CI) of 0.70 (0.42 to 0.98) for subcortical regions to 0.91 (0.82 to 0.99) for cortical areas. CMBs were more prevalent in patients with IE (57% [n=34]) than in control subjects (15% [n=18]; matched OR, 10.06; 95% CI, 3.88 to 26.07). Moreover, the OR of IE increased gradually with CMBs number with an OR of 6.12 (95% CI, 2.09 to 17.94) for one to 3 CMBs and of 20.12 (95% CI, 5.20 to 77.80) for >3 CMBs. CONCLUSIONS: CMBs are highly frequent in patients with IE. The strong association found between IE and CMBs supports the need for further evaluation of CMBs as additional diagnostic criteria of IE.