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OBJECTIVES: NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure.METHODS: Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0-24 and C24 with time to virological failure was evaluated by Cox regression.RESULTS: Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P<0.001). No significant relationship was demonstrated between darunavir AUC0-24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53-9.80), P=0.269; and 1.82 (0.61-5.41), P=0.279, respectively].CONCLUSIONS: Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.

The prognostic impact of mild/moderate liver impairment among critically ill patients is not known. We aimed to determine whether acute liver impairment, as measured by several biomarkers, (i) is frequent, (ii) influences prognosis and (iii) to determine whether such an effect is specific for infected critically ill patients. A biomarker and clinical cohort study based on a randomized controlled trial. All-cause mortality was the primary endpoint. Biomarkers hyaluronic acid (HA), bilirubin, albumin, alkaline phosphatase and the international normalized ratio (INR) were determined. Multivariable statistics were applied to estimate risk increase according to liver biomarker increase at baseline and the model was adjusted for age, APACHE II, severe sepsis/septic shock vs. milder infection, chronic alcohol abuse Charlson's co-morbidity index, cancer disease, surgical or medical patient, body mass index, sex, estimated glomerular filtration rate, mechanical ventilation and the other biomarkers. Time-to-event graphs were used. The patients were critically ill patients (n = 1096) from nine mixed medical/surgical intensive care units without known hepatobiliary disease. HA levels differed between infected patients (median 210.8 ng/mL [IQR: 93.2-556.6]) vs. the non-infected (median 56.8 ng/mL [IQR: 31.9-116.8], p < 0.001). Serum HA quartiles 2, 3 and 4 were independent predictors of 90-day all-cause mortality for the entire population (infected and non-infected). However, the signal was driven by the infected patients (positive interaction test, no signal in non-infected patients). Among infected patients, HA quartiles corresponded directly to the 90-day risk of dying: 1st quartile: 57/192 = 29.7%, 2nd quartile: 84/194 = 43.3%, 3rd quartile: 90/193 = 46.6%, 4th quartile: 101/192 = 52.3 %, p for trend: <0.0001. This finding was confirmed in adjusted analyses: hazard ratio vs. 1st quartile: 2nd quartile: 1.3 [0.9-1.8], p = 0.14, 3rd quartile: 1.5 [1.1-2.2], p = 0.02

INTRODUCTION: Lolland-Falster consists of two islands in the southern part of Denmark where income is lower and life expectancy is shorter than in the general Danish population. It is a mixed rural-provincial area with approximately 100,000 inhabitants. The Lolland-Falster Health Study was initiated to gain knowledge on the determinants of health in this disadvantaged area.METHODS: The study is a household-based prospective cohort study including people of all ages. The entire household of randomly selected inhabitants is allocated either to an invited group or to an uninvited, non-contacted control group. The data collection encompasses questionnaires, physical examination and biological samples, i.e. blood and urine for same-day analysis and biobank storage, and saliva and faeces also for biobank storage. The civil registration number links collected data for each individual, family and household, with information in Danish registers. The data collection started in February 2016 and is estimated to end by 2019 after the enrolment of 20,000 people.ANALYSIS: A number of in-depth sub-studies are planned. Emphasis will be given to analysis of intra- and inter-family variations in health determinants, genetics, lifestyle and health status. Ethics: Region Zealand's Ethical Committee on Health Research (SJ-421) and the Danish Data Protection Agency (REG-24-2015) approved the study.TRIAL REGISTRATION: Clinicaltrials.gov (NCT02482896). Strength and limitations of this study: The strength of this study is that Lolland-Falster Health Study is a useful scientific resource for investigating cross-sectional difference and time trends within and between individuals, families and households. LOFUS adds diversity to the previously collected Danish population studies in urbanized areas. The limitation is that data collection is expensive.CONCLUSIONS: LOFUS will contribute to the knowledge on health in disadvantaged, rural-provincial areas.

Background Using data from a large European collaborative study, we aimed to identify the circumstances in which treated HIV-infected individuals will experience similar mortality rates to those of the general population. Methods Adults were eligible if they initiated combination anti-retroviral treatment (cART) between 1998 and 2008 and had one prior CD4 measurement within 6 months. Standardized mortality ratios (SMRs) and excess mortality rates compared with the general population were estimated using Poisson regression. Periods of follow-up were classified according to the current CD4 count. Results Of the 80 642 individuals, 70% were men, 16% were injecting drug users (IDUs), the median age was 37 years, median CD4 count 225/mm3 at cART initiation and median follow-up was 3.5 years. The overall mortality rate was 1.2/100 person-years (PY) (men: 1.3, women: 0.9), 4.2 times as high as that in the general population (SMR for men: 3.8, for women: 7.4). Among 35 316 individuals with a CD4 count ≥500/mm3, the mortality rate was 0.37/100 PY (SMR 1.5); mortality rates were similar to those of the general population in non-IDU men [SMR 0.9, 95% confidence interval (95% CI) 0.7-1.3] and, after 3 years, in women (SMR 1.1, 95% CI 0.7-1.7). Mortality rates in IDUs remained elevated, though a trend to decrease with longer durations with high CD4 count was seen. A prior AIDS diagnosis was associated with higher mortality. Conclusions Mortality patterns in most non-IDU HIV-infected individuals with high CD4 counts on cART are similar to those in the general population. The persistent role of a prior AIDS diagnosis underlines the importance of early diagnosis of HIV infection

Accurate ascertainment of the number of children living with human immunodeficiency virus (HIV) is important to plan paediatric and adolescent health services. In Europe, the first generation of perinatally HIV-infected survivors are transferring to adult care and their health needs are unknown. We undertook an online survey of HIV cohort studies participating in the EuroCoord Network of Excellence to ascertain the number of perinatally HIV-infected (pHIV) patients included, to compare it with those published by the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) and to assess the ability of countries to follow up pHIV patients after transfer to adult care. At the end of 2013, 16 countries in EuroCoord reported 8,229 pHIV patients in follow-up in cohorts, compared with 5,160 cumulative diagnoses reported by the ECDC in the same area. Follow-up of pHIV patients after transfer to adult care varied. It is likely that the number of diagnoses of perinatal HIV reported to ECDC is an underestimate, although this varies by country. Further work is needed to refine estimates and encourage follow-up in adult HIV cohorts to investigate long-term outcomes and improve the care of the next generation of children with HIV.

BACKGROUND: It is unclear whether biomarkers of alveolar damage (surfactant protein D, SPD) or conductive airway damage (club cell secretory protein 16, CC16) measured early after intensive care admittance are associated with one-month clinical respiratory prognosis. If patients who do not recover respiratory function within one month can be identified early, future experimental lung interventions can be aimed toward this high-risk group. We aimed to determine, in a heterogenous critically ill population, whether baseline profound alveolar damage or conductive airway damage has clinical respiratory impact one month after intensive care admittance.METHODS: Biobank study of biomarkers of alveolar and conductive airway damage in intensive care patients was conducted. This was a sub-study of 758 intubated patients from a 1200-patient randomized trial. We split the cohort into a "learning cohort" and "validating cohort" based on geographical criteria: northern sites (learning) and southern sites (validating).RESULTS: Baseline SPD above the 85th percentile in the "learning cohort" predicted low chance of successful weaning from ventilator within 28 days (adjusted hazard ratio 0.6 [95% CI 0.4-0.9], p = 0.005); this was confirmed in the validating cohort. CC16 did not predict the endpoint. The absolute risk of not being successfully weaned within the first month was 48/106 (45.3%) vs. 175/652 (26.8%), p < 0.0001 (high SPD vs. low SPD). The chance of being "alive and without ventilator ≥20 days within the first month" was lower among patients with high SPD (adjusted OR 0.2 [95% CI 0.2-0.4], p < 0.0001), confirmed in the validating cohort, and the risk of ARDS was higher among patients with high SPD (adjusted OR 3.4 [95% CI 1.0-11.4], p = 0.04)-also confirmed in the validating cohort.CONCLUSION: Early profound alveolar damage in intubated patients can be identified by SPD blood measurement at intensive care admission, and high SPD level is a stro

BACKGROUND: Cytomegalovirus (CMV) infection in transplant recipients is reported to replicate with a doubling time of 1.2-2 days, and weekly screening is recommended for early diagnosis. We re-evaluated these features in our cohort of transplant recipients.METHODS: The CMV doubling time of the first CMV infection in the first year post-transplant could be calculated for 193 recipients of haematopoietic stem cell or solid organ transplantation. Factors determining the proportion of recipients with a high diagnostic CMV viral load (≥ 18,200 IU/mL) were explored using mathematical simulation.FINDINGS: The overall median doubling time was 4.3 days (IQR 2.5-7.8) and was not influenced by prior CMV immunity, or type of transplantation (p > 0.4). Assuming a fixed doubling time of 1.3 days and screening intervals of 7 or 10 days, 11.1% and 33.3% were projected to have a high CMV viral load at diagnosis, compared to 1.4% and 4.3% if the doubling time varies as observed in our cohort. Consistently, 1.9% of recipients screened weekly had a high diagnostic virus load.INTERPRETATION: Screening intervals can be extended to 10 days in cohorts with comparable CMV doubling time, whereas shorter than 7 days is required in cohorts with shorter doubling times to maintain pre-emptive screening quality.

OBJECTIVE: Use of antibiotics in critically ill patients may increase the risk of invasive Candida infection. The objective of this study was to determine whether increased exposure to antibiotics is associated with increased prevalence of invasive Candida infection.DESIGN: Substudy using data from a randomized controlled trial, the Procalcitonin And Survival Study 2006-2010.SETTING: Nine multidisciplinary ICUs across Denmark.PATIENTS: A total of 1,200 critically ill patients.INTERVENTION: Patients were randomly allocated to either a "high exposure" antibiotic therapy (intervention arm, n = 604) or a "standard exposure" guided by current guidelines (n = 596).MEASUREMENTS AND MAIN RESULTS: Seventy-four patients met the endpoint, "invasive Candida infection," 40 in the high exposure arm and 34 in standard exposure arm (relative risk = 1.2; 95% CI, 0.7-1.8; p = 0.52). Among medical patients in the high exposure arm, the use of ciprofloxacin and piperacillin/tazobactam was 51% and 75% higher than in the standard exposure arm; no difference in antibiotic exposure was observed between the randomized arms in surgical patients. Among medical intensive care patients, invasive Candida infection was more frequent in the high exposure arm (6.2%; 27/437) than in standard exposure arm (3.3%; 14/424) (hazard ratio = 1.9; 95% CI, 1.0-3.6; p = 0.05). Ciprofloxacin used at study entry independently predicted invasive Candida infection (adjusted hazard ratio = 2.1 [1.1-4.1]); the risk gradually increased with duration of ciprofloxacin therapy: six of 384 in patients not exposed (1.6%), eight of 212 (3.8%) when used for 1-2 days (hazard ratio = 2.5; 95% CI, 0.9-7.3), and 31 of 493 (6.3%) when used for 3 days (hazard ratio = 3.8; 95% CI, 1.6-9.3; p = 0.002). Patients with any ciprofloxacin-containing antibiotic regimen the first 3 days in the trial had a higher risk of invasive Candida infection than did patients on any antibiotic regimen not contai

BACKGROUND: Standard first-line antiretroviral therapy for HIV-1 infection includes two nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs), but these drugs have limitations. We assessed the 96 week efficacy and safety of an NtRTI-sparing regimen.METHODS: Between August, 2010, and September, 2011, we enrolled treatment-naive adults into this randomised, open-label, non-inferiority trial in treatment-naive adults in 15 European countries. The composite primary outcome was change to randomised treatment before week 32 because of insufficient virological response, no virological response by week 32, HIV-1 RNA concentration 50 copies per mL or higher at any time after week 32; death from any cause; any new or recurrent AIDS event; or any serious non-AIDS event. Patients were randomised in a 1:1 ratio to receive oral treatment with 400 mg raltegravir twice daily plus 800 mg darunavir and 100 mg ritonavir once daily (NtRTI-sparing regimen) or tenofovir-emtricitabine in a 245 mg and 200 mg fixed-dose combination once daily, plus 800 mg darunavir and 100 mg ritonavir once daily (standard regimen). This trial was registered with ClinicalTrials.gov, number NCT01066962.FINDINGS: Of 805 patients enrolled, 401 received the NtRTI-sparing regimen and 404 the standard regimen, with median follow-up of 123 weeks (IQR 112-133). Treatment failure was seen in 77 (19%) in the NtRTI-sparing group and 61 (15%) in the standard group. Kaplan-Meier estimated proportions of treatment failure by week 96 were 17·8% and 13·8%, respectively (difference 4·0%, 95% CI -0·8 to 8·8). The frequency of serious or treatment-modifying adverse events were similar (10·2 vs 8·3 per 100 person-years and 3·9 vs 4·2 per 100 person-years, respectively).INTERPRETATION: Our NtRTI-sparing regimen was non-inferior to standard treatment and represents a treatment option for patients with CD4 cell counts higher than 200 cells per μL.FUNDING: European Union Sixth Framework

Background. Some human immunodeficiency virus (HIV)-infected individuals initiating combination antiretroviral therapy (cART) with low CD4 counts achieve viral suppression but not CD4 cell recovery. We aimed to identify (1) risk factors for failure to achieve CD4 count >200 cells/mu L after 3 years of sustained viral suppression and (2) the association of the achieved CD4 count with subsequent mortality. Methods. We included treated HIV-infected adults from 2 large international HIV cohorts, who had viral suppression (<= 500 HIV type 1 RNA copies/mL) for >3 years with CD4 count <= 200 cells/mu L at start of the suppressed period. Logistic regression was used to identify risk factors for incomplete CD4 recovery (<= 200 cells/mu L) and Cox regression to identify associations with mortality. Results. Of 5550 eligible individuals, 835 (15%) did not reach a CD4 count >200 cells/mu L after 3 years of suppression. Increasing age, lower initial CD4 count, male heterosexual and injection drug use transmission, cART initiation after 1998, and longer time from initiation of cART to start of the virally suppressed period were risk factors for not achieving a CD4 count >200 cells/mu L. Individuals with CD4 <= 200 cells/mu L after 3 years of viral suppression had substantially increased mortality (adjusted hazard ratio, 2.60; 95% confidence interval, 1.86-3.61) compared with those who achieved CD4 count >200 cells/mu L. The increased mortality was seen across different patient groups and for all causes of death. Conclusions. Virally suppressed HIV-positive individuals on cART who do not achieve a CD4 count >200 cells/mu L have substantially increased long-term mortality.

ATRIPLA is licensed for use only in HIV-positive persons whose viral loads <50 for ≥3 months. We investigated the use of ATRIPLA as first-line antiretroviral therapy (ART) in EuroSIDA using a web-based survey performed in Autumn 2012. 96/112 clinics (85.7 %) completed the survey. Recommendations when initiating first-line ART was TRUVADA plus efavirenz in 36 (37.5 %), ATRIPLA in 35 (36.5 %), a different first-line regimen in 12 clinics (12.5 %), and no recommendation in 7 clinics (7.3 %). ATRIPLA was commonest in Northern (15/21 clinics; 71.4 %), and least common in Eastern Europe (2/31 clinics; 6.5 %; p < 0.0001). Over one-third of the participating clinics in this survey were using ATRIPLA as first-line antiretroviral therapy, despite EMA recommendations. © 2014 The Author(s)., SCOPUS: ar.j, info:eu-repo/semantics/published

Background. Some human immunodeficiency virus (HIV)-infected individuals initiating combination antiretroviral therapy (cART) with low CD4 counts achieve viral suppression but not CD4 cell recovery. We aimed to identify (1) risk factors for failure to achieve CD4 count >200 cells/?L after 3 years of sustained viral suppression and (2) the association of the achieved CD4 count with subsequent mortality.Methods. We included treated HIV-infected adults from 2 large international HIV cohorts, who had viral suppression (?500 HIV type 1 RNA copies/mL) for >3 years with CD4 count ?200 cells/?L at start of the suppressed period. Logistic regression was used to identify risk factors for incomplete CD4 recovery (?200 cells/?L) and Cox regression to identify associations with mortality.Results. Of 5550 eligible individuals, 835 (15%) did not reach a CD4 count >200 cells/?L after 3 years of suppression. Increasing age, lower initial CD4 count, male heterosexual and injection drug use transmission, cART initiation after 1998, and longer time from initiation of cART to start of the virally suppressed period were risk factors for not achieving a CD4 count >200 cells/?L. Individuals with CD4 ?200 cells/?L after 3 years of viral suppression had substantially increased mortality (adjusted hazard ratio, 2.60; 95% confidence interval, 1.86-3.61) compared with those who achieved CD4 count >200 cells/?L. The increased mortality was seen across different patient groups and for all causes of death.Conclusions. Virally suppressed HIV-positive individuals on cART who do not achieve a CD4 count >200 cells/?L have substantially increased long-term mortality. The Author 2014., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: Some human immunodeficiency virus (HIV)-infected individuals initiating combination antiretroviral therapy (cART) with low CD4 counts achieve viral suppression but not CD4 cell recovery. We aimed to identify (1) risk factors for failure to achieve CD4 count >200 cells/µL after 3 years of sustained viral suppression and (2) the association of the achieved CD4 count with subsequent mortality.METHODS: We included treated HIV-infected adults from 2 large international HIV cohorts, who had viral suppression (≤500 HIV type 1 RNA copies/mL) for >3 years with CD4 count ≤200 cells/µL at start of the suppressed period. Logistic regression was used to identify risk factors for incomplete CD4 recovery (≤200 cells/µL) and Cox regression to identify associations with mortality.RESULTS: Of 5550 eligible individuals, 835 (15%) did not reach a CD4 count >200 cells/µL after 3 years of suppression. Increasing age, lower initial CD4 count, male heterosexual and injection drug use transmission, cART initiation after 1998, and longer time from initiation of cART to start of the virally suppressed period were risk factors for not achieving a CD4 count >200 cells/µL. Individuals with CD4 ≤200 cells/µL after 3 years of viral suppression had substantially increased mortality (adjusted hazard ratio, 2.60; 95% confidence interval, 1.86-3.61) compared with those who achieved CD4 count >200 cells/µL. The increased mortality was seen across different patient groups and for all causes of death.CONCLUSIONS: Virally suppressed HIV-positive individuals on cART who do not achieve a CD4 count >200 cells/µL have substantially increased long-term mortality.

Background. Few studies consider the incidence of individual AIDS-defining illnesses (ADIs) at higher CD4 counts, relevant on a population level for monitoring and resource allocation. Methods. Individuals from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) aged ≥14 years with ≥1 CD4 count of ≥200 μL between 1998 and 2010 were included. Incidence rates (per 1000 personyears of follow-up [PYFU]) were calculated for each ADI within different CD4 strata; Poisson regression, using generalized estimating equations and robust standard errors, was used to model rates of ADIs with current CD4 ≥500/μL. Results. A total of 12 135 ADIs occurred at a CD4 count of ≥200 cells/μL among 207 539 persons with 1 154 803 PYFU. Incidence rates declined from 20.5 per 1000 PYFU (95% confidence interval [CI], 20.0-21.1 per 1000 PYFU) with current CD4 200-349 cells/μL to 4.1 per 1000 PYFU (95% CI, 3.6-4.6 per 1000 PYFU) with current CD4 ≥ 1000 cells/μL. Persons with a current CD4 of 500-749 cells/μL had a significantly higher rate of ADIs (adjusted incidence rate ratio [aIRR], 1.20; 95% CI, 1.10-1.32), whereas those with a current CD4 of ≥1000 cells/μL had a similar rate (aIRR, 0.92; 95% CI, 79-1.07), compared to a current CD4 of 750-999 cells/μL. Results were consistent in persons with high or low viral load. Findings were stronger for malignant ADIs (aIRR, 1.52; 95% CI, 1.25-1.86) than for nonmalignant ADIs (aIRR, 1.12; 95% CI, 1.01-1.25), comparing persons with a current CD4 of 500-749 cells/μL to 750-999 cells/μL. Discussion. The incidence of ADIs was higher in individuals with a current CD4 count of 500-749 cells/μL compared to those with a CD4 count of 750-999 cells/μL, but did not decrease further at higher CD4 counts. Results were similar in patients virologically suppressed on combination antiretroviral therapy, suggesting that immune reconstitution is not complete until the CD4 increases to >750 cells/μL. © The Author 2013. Published by Oxford Univ, SCOPUS: ar.j, info:eu-repo/semantics/published

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.

EuroSIDA in EuroCoord, info:eu-repo/semantics/nonPublished

Despite the increasing success of antiretroviral therapy (ART), virologic failure of the 3 original classes [triple-class virologic failure, (TCVF)] still develops in a small minority of patients who started therapy in the triple combination ART era. Trends in the incidence and prevalence of TCVF over calendar time have not been fully characterised in recent years.

To explore whether a strategy of more intensive antibiotic therapy leads to emergence or prolongation of renal failure in intensive care patients.