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2.  Low Completeness of Bacteraemia Registration in the Danish National Patient Registry 
PLoS ONE  2015;10(6):e0131682.
Bacteraemia is associated with significant morbidity and mortality and timely access to relia-ble information is essential for health care administrators. Therefore, we investigated the complete-ness of bacteraemia registration in the Danish National Patient Registry (DNPR) containing hospital discharge diagnoses and surgical procedures for all non-psychiatric patients. As gold standard we identified bacteraemia patients in three defined areas of Denmark (~2.3 million inhabitants) from 2000 through 2011 by use of blood culture data retrieved from electronic microbiology databases. Diagnoses coded according to the International Classification of Diseases, version 10, and surgical procedure codes were retrieved from the DNPR. The codes were categorized into seven groups, ranked a priori according to the likelihood of bacteraemia. Completeness was analysed by contin-gency tables, for all patients and subgroups. We identified 58,139 bacteraemic episodes in 48,450 patients; 37,740 episodes (64.9%) were covered by one or more discharge diagnoses within the sev-en diagnosis/surgery groups and 18,786 episodes (32.3%) had a code within the highest priority group. Completeness varied substantially according to speciality (from 17.9% for surgical to 36.4% for medical), place of acquisition (from 26.0% for nosocomial to 36.2% for community), and mi-croorganism (from 19.5% for anaerobic Gram-negative bacteria to 36.8% for haemolytic strepto-cocci). The completeness increased from 25.1% in 2000 to 35.1% in 2011. In conclusion, one third of the bacteraemic episodes did not have a relevant diagnosis in the Danish administrative registry recording all non-psychiatric contacts. This source of information should be used cautiously to iden-tify patients with bacteraemia.
doi:10.1371/journal.pone.0131682
PMCID: PMC4488274  PMID: 26121584
3.  Risk Factors for Hospitalization Due to Community-Acquired Sepsis – A Population-Based Case-Control Study 
PLoS ONE  2015;10(4):e0124838.
Background
The aim of the study was to estimate risk factors for hospitalization due to sepsis and to determine whether these risk factors vary by age and gender.
Methods
We performed a population-based case-control study of all adult patients admitted to a medical ED from September 2010 to August 2011. Controls were sampled within the hospital catchment-area. All potential cases were manually validated using a structured protocol. Vital signs and laboratory values measured at arrival were registered to define systemic inflammatory response syndrome and organ dysfunction. Multivariable logistic regression was used to elucidate which predefined risk factors were associated with an increased or decreased risk hospitalization due to sepsis.
Results
A total of 1713 patients were admitted with sepsis of any severity. The median age was 72 years (interquartile range: 57–81 years) and 793 (46.3%) were male. 621 (36.3%) patients were admitted with sepsis, 1071 (62.5%) with severe sepsis and 21 (1.2%) with septic shock. Episodes with sepsis of any severity were associated with older age (85+ years adjusted OR 6.02 [95%CI: 5.09–7.12]), immunosuppression (4.41 [3.83–5.09]), alcoholism-related conditions (2.90 [2.41–3.50]), and certain comorbidities: psychotic disorder (1.90 [1.58–2.27]), neurological (1.98 [1.73–2.26]), respiratory (3.58 [3.16–4.06]), cardiovascular (1.62 [1.41–1.85]), diabetes (1.82 [1.57–2.12]), cancer (1.44 [1.22–1.68]), gastrointestinal (1.71 [1.44–2.05]) and renal (1.46 [1.13–1.89]). The strength of the observed associations for comorbid factors was strongest among younger individuals.
Conclusions
Hospitalization due to sepsis of any severity was associated with several independent risk factors, including age and comorbid factors.
doi:10.1371/journal.pone.0124838
PMCID: PMC4405362  PMID: 25898024
4.  Nontraumatic Hypotension and Shock in the Emergency Department and the Prehospital setting, Prevalence, Etiology, and Mortality: A Systematic Review 
PLoS ONE  2015;10(3):e0119331.
Background
Acute patients presenting with hypotension in the prehospital or emergency department (ED) setting are in need of focused management and knowledge of the epidemiology characteristics might help the clinician. The aim of this review was to address prevalence, etiology and mortality of nontraumatic hypotension (SBP ≤ 90 mmHg) with or without the presence of shock in the prehospital and ED setting.
Methods
We performed a systematic literature search up to August 2013, using Medline, Embase, Cinahl, Dare and The Cochrane Library. The analysis and eligibility criteria were documented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-guidelines) and The Cochrane Collaboration. No restrictions on language, publication date, or status were imposed. We used the Newcastle-Ottawa quality assessment scale (NOS-scale) and the Strengthening the Reporting of Observational studies in Epidemiology (STROBE-statement) to assess the quality.
Results
Six observational studies were considered eligible for analysis based on the evaluation of 11,880 identified papers. Prehospital prevalence of hypotension was 19.5/1000 emergency medicine service (EMS) contacts, and the prevalence of hypotensive shock was 9.5-19/1000 EMS contacts with an inhospital mortality of shock between 33 to 52%. ED prevalence of hypotension was 4-13/1000 contacts with a mortality of 12%. Information on mortality, prevalence and etiology of shock in the ED was limited. A meta-analysis was not feasible due to substantial heterogeneity between studies.
Conclusion
There is inadequate evidence to establish concise estimates of the characteristics of nontraumatic hypotension and shock in the ED or in the prehospital setting. The available studies suggest that 2% of EMS contacts present with nontraumatic hypotension while 1-2% present with shock. The inhospital mortality of prehospital shock is 33-52%. Prevalence of hypotension in the ED is 1% with an inhospital mortality of 12%. Prevalence, etiology and mortality of shock in the ED are not well described.
doi:10.1371/journal.pone.0119331
PMCID: PMC4366173  PMID: 25789927
5.  Neutrophil-to-lymphocyte ratio, calprotectin and YKL-40 in patients with chronic obstructive pulmonary disease: correlations and 5-year mortality – a cohort study 
Background
Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and progressive decline in pulmonary function. Neutrophil-to-lymphocyte ratio (NLR), YKL-40 and calprotectin are biomarkers of inflammation and predict mortality in patients with different inflammatory diseases. We aimed to investigate the correlation between levels of these three biomarkers and neutrophil granulocyte and lymphocyte count in patients with moderate to very severe COPD stratified by use of systemic glucocorticoids. Furthermore, we studied the ability of these biomarkers to predict all-cause mortality.
Methods
386 patients with moderate to very severe COPD were followed prospectively for 10 years. Patients were divided into two groups according to systemic glucocorticoid use at baseline. Correlations between biomarkers were assessed by Spearman’s Rho, and mortality was evaluated in uni- and multivariate Cox regression analyses with hazard ratios (HR) and 95% confidence intervals (CI).
Results
Plasma calprotectin was positively correlated with neutrophil granulocyte count and NLR. No significant association was found between plasma YKL-40 and the cellular biomarkers, irrespective of glucocorticoid treatment. In the group not treated with systemic glucocorticoids, plasma calprotectin [HR 1.002 (95% CI 1.000 – 1.004)], NLR [HR 1.090 (1.036 – 1.148)] and lymphocyte count [HR 0.667 (0.522 – 0.851)] were significantly associated with higher mortality. In the group treated with systemic glucocorticoids, higher plasma YKL-40 was significantly associated with mortality in univariate Cox regression analysis [HR 1.006 (1.003 – 1.008)].
Conclusions
Calprotectin was related to neutrophil granulocyte count and NLR in patients with moderate to very severe COPD in stable phase and not in treatment with systemic glucocorticoids. Lymphopenia, higher plasma calprotectin and higher NLR were independent predictors of increased all-cause mortality in this group. Our data also suggests that treatment with systemic glucocorticoids has a significant impact on the ability of inflammatory biomarkers to predict all-cause mortality.
Trial registration
ClinicalTrials.gov NCT00132860.
doi:10.1186/s12950-015-0064-5
PMCID: PMC4407303  PMID: 25908927
COPD; Neutrophil-to-lymphocyte ratio; Calprotectin; YKL-40; Lymphopenia; Mortality; Glucocorticoids; Prognosis
6.  Liver Stiffness Measurement among Patients with Chronic Hepatitis B and C: Results from a 5-Year Prospective Study 
PLoS ONE  2014;9(11):e111912.
Liver stiffness measurement (LSM) is widely used to evaluate liver fibrosis, but longitudinal studies are rare. The current study was aimed to monitor LSM during follow-up, and to evaluate the association of LSM data with mortality and liver-related outcomes. We included all patients with chronic viral hepatitis and valid LSM using Fibroscan. Information about liver biopsy, antiviral treatment, and clinical outcome was obtained from medical records and national registers. The study included 845 patients: 597 (71%) with hepatitis C virus (HCV), 235 (28%) with hepatitis B virus (HBV) and 13 (2%) with dual infection. The initial LSM distribution (<7/7–9.9/10–16.9/≥17 kPa) was 58%/16%/14%/12%. Among patients with initial LSM values of 7–9.9 kPa, 60% of HCV patients and 83% of HBV patients showed LSM values of <7 kPa at the latest follow-up. Progression rates (defined as >20% and >2 kPa increase, with one measure >7 kPa) were 3.4/100 person years (PY) for HCV and 1.5/100 PY for HBV infected patients. Patients with LSM values of ≥17 kPa had the same liver-related complication incidence as patients with biopsy-proven cirrhosis (11.1 versus 12.1/100 PY). Thirteen liver-related deaths occurred among HCV patients (0.6/100 PY), but none among HBV patients. Among patients who died of liver-related causes, all but one had baseline LSM values of ≥17 kPa. Overall, patients with LSM values <17 kPa were not associated with adverse outcomes. In contrast, LSM values ≥17 kPa were associated with significant risk of liver-related problems. The results of the current study suggest that clinical decisions should not be taken based on a single LSM measurement.
doi:10.1371/journal.pone.0111912
PMCID: PMC4219798  PMID: 25369038
7.  Long term effectiveness of once-daily unboosted atazanavir plus abacavir/lamivudine as a switch strategy in subjects with virological suppression 
Journal of the International AIDS Society  2014;17(4Suppl 3):19810.
Background
Use of unboosted atazanavir (ATV400) is approved in the US but not in Europe [1]. Due to pharmacokinetic interactions it should not be used with tenofovir but can be used with abacavir/lamivudine (ABC/3TC) [1, 2,3]. Effectiveness data of ATV400+ABC/3TC as a switch strategy in clinical routine however are scant.
Methods
We evaluated treatment outcomes of ATV400+ABC/3TC in pre-treated subjects in the EuroSIDA cohort with undetectable HIV-1 RNA, and previous ABC experience or assumed previous HLA B57*01 testing. We performed a time to loss of virologic response (TLOVR below 50 c/mL) and a snapshot analysis at 48, 96 and 144 weeks. Virological failure (VF) was defined as a confirmed plasma HIV-1 RNA >50 c/mL.
Results
We included 258 subjects: 176 (68%) male, median age 46 (IQR 41, 53) y, 225 (87.2%) white, hepatitis virus co-infection 36%, median baseline CD4 at switch 540 cells (360, 700), time with VL≤ 50 c/mL 45 (24, 69) months. The median calendar year of switching was 2008 (2006, 2010). The 3rd drug in previous regimen was ATV/r in 70 (27.1%), other PI/r in 25 (9.7%), and other 163 (63.2%); 85 (32.9%) had previously failed with a PI. The virological response at 48/96/144 weeks was, respectively, 89.5 [95% CI 85.1, 92.9]/88 [83.4, 91.7]/86.3% [81.6, 90.4] (TLOVR, composite endpoint failure or stop for any reason) and the risk of VF was 8.3/7.6/7.6%. In the snapshot analysis HIV-RNA was below 50 c/mL in 72.5/65.9/51.6%, respectively, and >50 c/mL in 6.6/5.4/4.3%. Only 0.8/1.9/3.5% discontinued due to adverse events. There was a high rate of discontinuations due to other reasons or with VL missing in window. In a multivariate adjusted analysis, we observed an association between VF and nadir CD4 count (RH 0.60 [0.39, 0.93] per 100 cells higher), time with VL≤50 c/mL (RH 0.89 [0.81, 0.98] per 6 months longer) and previous failure with a PI (3.04 [1.36, 6.80]). There was no association with gender, age, hepatitis virus co-infection, CD4 count at time of switching or third drug used in the previous regimen.
Conclusions
A switch to ATV400+ABC/3TC in selected subjects with HIV-RNA below 50 c/mL is associated with relatively low rates of VF and discontinuation due to adverse events. Use might be considered in those with long-term suppression and without prior PI failure. Larger cohorts are required to further define the appropriate selection criteria.
doi:10.7448/IAS.17.4.19810
PMCID: PMC4225315  PMID: 25397554
8.  How do bacteraemic patients present to the emergency department and what is the diagnostic validity of the clinical parameters; temperature, C-reactive protein and systemic inflammatory response syndrome? 
Objective
Although blood cultures are often ordered based on the presence of fever, it is a clinical challenge to identify patients eligible for blood cultures. Our aim was to evaluate the diagnostic value of temperature, C-reactive-protein (CRP), and Systemic Inflammatory Response Syndrome (SIRS) to identify bacteraemic patients in the Medical Emergency Department (MED).
Methods
A population-based cohort study including all adult patients at the MED at Odense University Hospital between August 1st 2009 - August 31st 2011.
Results
11,988 patients were admitted to the MED within the study period. Blood cultures were performed on 5,499 (45.9%) patients within 2 days of arrival, of which 418 (7.6%) patients were diagnosed with bacteraemia. This corresponded to 3.5% of all patients. 34.1% of the bacteraemic patients had a normal rectal temperature (36.0°–38.0°C) recorded at arrival, 32.6% had a CRP < 100 mg/L and 28.0% did not fulfil the SIRS criteria.
For a temperature cut-point of >38.0°C sensitivity was 0.64 (95% CI 0.59–0.69) and specificity was 0.81 (0.80–0.82) to identify bacteraemic patients.
Conclusion
One third of the acute medical bacteraemic patients had a normal temperature at arrival to the MED. A normal temperature combined with a CRP < 100 mg/L and no SIRS criteria, ruled out bacteraemia.
doi:10.1186/1757-7241-22-39
PMCID: PMC4107625  PMID: 25027551
Bacteraemia; Emergency medicine; C-reactive protein; Temperature; Systemic inflammatory response syndrome
9.  Drug resistance in HIV patients with virological failure or slow virological response to antiretroviral therapy in Ethiopia 
BMC Infectious Diseases  2014;14:181.
Background
The ongoing scale-up of antiretroviral therapy (ART) in sub-Saharan Africa has prompted the interest in surveillance of transmitted and acquired HIV drug resistance. Resistance data on virological failure and mutations in HIV infected populations initiating treatment in sub-Saharan Africa is sparse.
Methods
HIV viral load (VL) and resistance mutations pre-ART and after 6 months were determined in a prospective cohort study of ART-naïve HIV patients initiating first-line therapy in Jimma, Ethiopia. VL measurements were done at baseline and after 3 and 6 months. Genotypic HIV drug resistance (HIVDR) was performed on patients exhibiting virological failure (>1000 copies/mL at 6 months) or slow virological response (>5000 copies/mL at 3 months and <1000 copies/mL at 6 months).
Results
Two hundred sixty five patients had VL data available at baseline and at 6 months. Virological failure was observed among 14 (5.3%) participants out of 265 patients. Twelve samples were genotyped and six had HIV drug resistance (HIVDR) mutations at baseline. Among virological failures, 9/11 (81.8%) harbored one or more HIVDR mutations at 6 months. The most frequent mutations were K103N and M184VI.
Conclusions
Our data confirm that the currently recommended first-line ART regimen is efficient in the vast majority of individuals initiating therapy in Jimma, Ethiopia eight years after the introduction of ART. However, the documented occurrence of transmitted resistance and accumulation of acquired HIVDR mutations among failing patients justify increased vigilance by improving the availability and systematic use of VL testing to monitor ART response, and underlines the need for rapid, inexpensive tests to identify the most common drug resistance mutations.
doi:10.1186/1471-2334-14-181
PMCID: PMC4234735  PMID: 24708645
10.  A Novel Fibrosis Index Comprising a Non-Cholesterol Sterol Accurately Predicts HCV-Related Liver Cirrhosis 
PLoS ONE  2014;9(4):e93601.
Diagnosis of liver cirrhosis is essential in the management of chronic hepatitis C virus (HCV) infection. Liver biopsy is invasive and thus entails a risk of complications as well as a potential risk of sampling error. Therefore, non-invasive diagnostic tools are preferential. The aim of the present study was to create a model for accurate prediction of liver cirrhosis based on patient characteristics and biomarkers of liver fibrosis, including a panel of non-cholesterol sterols reflecting cholesterol synthesis and absorption and secretion. We evaluated variables with potential predictive significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5–6, as the outcome variable. A new index, referred to as Nordic Liver Index (NoLI) in the paper, was based on the model: Log-odds (predicting cirrhosis) = −12.17+ (age×0.11) + (BMI (kg/m2)×0.23) + (D7-lathosterol (μg/100 mg cholesterol)×(−0.013)) + (Platelet count (x109/L)×(−0.018)) + (Prothrombin-INR×3.69). The area under the ROC curve (AUROC) for prediction of cirrhosis was 0.91 (95% CI 0.86–0.96). The index was validated in a separate cohort of 83 patients and the AUROC for this cohort was similar (0.90; 95% CI: 0.82–0.98). In conclusion, the new index may complement other methods in diagnosing cirrhosis in patients with chronic HCV infection.
doi:10.1371/journal.pone.0093601
PMCID: PMC3974766  PMID: 24699777
11.  How Well Do Discharge Diagnoses Identify Hospitalised Patients with Community-Acquired Infections? – A Validation Study 
PLoS ONE  2014;9(3):e92891.
Background
Credible measures of disease incidence, trends and mortality can be obtained through surveillance using manual chart review, but this is both time-consuming and expensive. ICD-10 discharge diagnoses are used as surrogate markers of infection, but knowledge on the validity of infections in general is sparse. The aim of the study was to determine how well ICD-10 discharge diagnoses identify patients with community-acquired infections in a medical emergency department (ED), overall and related to sites of infection and patient characteristics.
Methods
We manually reviewed 5977 patients admitted to a medical ED in a one-year period (September 2010-August 2011), to establish if they were hospitalised with community-acquired infection. Using the manual review as gold standard, we calculated the sensitivity, specificity, predictive values, and likelihood ratios of discharge diagnoses indicating infection.
Results
Two thousand five hundred eleven patients were identified with community-acquired infection according to chart review (42.0%, 95% confidence interval [95%CI]: 40.8–43.3%) compared to 2550 patients identified by ICD-10 diagnoses (42.8%, 95%CI: 41.6–44.1%). Sensitivity of the ICD-10 diagnoses was 79.9% (95%CI: 78.1–81.3%), specificity 83.9% (95%CI: 82.6–85.1%), positive likelihood ratio 4.95 (95%CI: 4.58–5.36) and negative likelihood ratio 0.24 (95%CI: 0.22–0.26). The two most common sites of infection, the lower respiratory tract and urinary tract, had positive likelihood ratios of 8.3 (95%CI: 7.5–9.2) and 11.3 (95%CI: 10.2–12.9) respectively. We identified significant variation in diagnostic validity related to age, comorbidity and disease severity.
Conclusion
ICD-10 discharge diagnoses identify specific sites of infection with a high degree of validity, but only a moderate degree when identifying infections in general.
doi:10.1371/journal.pone.0092891
PMCID: PMC3963967  PMID: 24663388
12.  Plasma YKL-40 and all-cause mortality in patients with chronic obstructive pulmonary disease 
Background
Chronic obstructive pulmonary disease (COPD) is hallmarked by inflammatory processes and a progressive decline of lung function. YKL-40 is a potential biomarker of inflammation and mortality in patients suffering from inflammatory lung disease, but its prognostic value in patients with COPD remains unknown. We investigated whether high plasma YKL-40 was associated with increased mortality in patients with moderate to very severe COPD.
Methods
Four hundred and ninety-three patients with moderate to very severe COPD were followed prospectively for up to 10 years. Patients were divided into two groups according to plasma YKL-40: concentration higher than the 75th percentile for age-matched healthy subjects (i.e. high levels) and normal levels. Outcome was overall survival (OS) and was evaluated in uni- and multivariate proportional hazards Cox regression analyses and adjusted for factors affecting mortality.
Results
Median plasma YKL-40 was increased in patients with COPD (81 ng/ml, p < 0.001) compared to healthy subjects (40 ng/ml). Patients with high plasma YKL-40 had a hazard ratio (HR) of 1.42 (95% CI: 1.15–1.75, p = 0.001) for all-cause mortality. Multivariate analysis showed that YKL-40 (HR 1.38; 95% CI: 1.11–1.72, p = 0.004), age (HR 1.05; 95% CI: 1.03–1.06, p < 0.0001), Severe COPD (HR 1.35; 95 CI: 1.03-1.76, p = 0.03) very severe COPD (HR 2.19; 95% CI: 1.60 - 2.99 < 0.0001), neutrophil granulocyte count (HR 1.05; 95% CI: 1.01-1.08, p = 0.01), and a smoking history of > 40 years (HR 1.38; 95% CI: 1.11-1.71, p = 0.003) were independent prognostic markers of OS.
Conclusion
High plasmaYKL-40 is associated with increased mortality in patients with moderate to very severe COPD, suggesting a role for YKL-40 as a potential biomarker of mortality in this patient group.
Trial registration
ClinicalTrials.gov: NCT00132860.
doi:10.1186/1471-2466-13-77
PMCID: PMC3890498  PMID: 24373580
COPD; Inflammation; Mortality; Prognosis; YKL-40
14.  Statin Therapy and Mortality in HIV-Infected Individuals; A Danish Nationwide Population-Based Cohort Study 
PLoS ONE  2013;8(3):e52828.
Background
Recent studies have suggested that statins possess diverse immune modulatory and anti-inflammatory properties. As statins might attenuate inflammation, statin therapy has been hypothesized to reduce mortality in HIV-infected individuals. We therefore used a Danish nationwide cohort of HIV-infected individuals to estimate the impact of statin use on mortality before and after a diagnosis of cardiovascular disease, chronic kidney disease or diabetes.
Methods
We identified all Danish HIV-infected individuals (1,738) who initiated HAART after 1 January 1998, and achieved virological suppression within 180 days. Date of first redemption of a prescription of statin was obtained from the Danish National Prescription Registry. We used Poisson regression analysis to assess adjusted mortality rate ratios (aMRR). First, time was censored at date of virological failure (VL >500 copies/ml). Second, time was not censored at virological failure. All analyses were adjusted for potential confounders.
Results
In the analyses confined to observation time without virological failure (+ censoring) statin therapy was associated with a non-statistically significant reduced rate of death (aMRR 0.75; 95% CI: 0.33–1.68). No difference was observed in the analysis with no censoring (aMRR 1.17; 95% CI: 0.66–2.07). Use of statin seemed to reduce mortality in individuals after a diagnosis of comorbidity {(+ censoring: aMRR: 0.34; 95% CI: 0.11–1.04), (−censoring: aMRR: 0.64; 95% CI: 0.32–1.29)}. No difference in rate of death could be detected before first date of diagnosis of comorbidity {(+ censoring: aMRR: 1.12; 95% CI: 0.34–3.62), (−censoring: aMRR: 0.90; 95% CI: 0.28–2.88)}.
Conclusion
Statin therapy might reduce all-cause mortality in HIV-infected individuals, but the impact on individuals with no comorbidity seems small or absent. An unambiguous proof of a causal relation can only be obtained in a randomized controlled trial, but the sample size predicted may be prohibitive for its conduct.
doi:10.1371/journal.pone.0052828
PMCID: PMC3587599  PMID: 23469159
15.  PNPLA 3 I148M genetic variant associates with insulin resistance and baseline viral load in HCV genotype 2 but not in genotype 3 infection 
BMC Medical Genetics  2012;13:82.
Background
Hepatic steatosis in HCV patients has been postulated as a risk factor associated with a higher frequency of fibrosis and cirrhosis. A single genetic variant, PNPLA3 I148M, has been widely associated with increased hepatic steatosis. Previous studies of the PNPLA3 I148M sequence variant in HCV infected individuals have reported an association between this variant and prevalence of steatosis, fibrosis, and cirrhosis. To evaluate the impact of PNPLA3 I148M variant on metabolic traits and treatment response in HCV genotype 2 and 3 infected patients.
Methods
Three hundred and eighty-two treatment naïve HCV genotype 2 or 3 infected patients were included in a phase III, open label, randomized, multicenter, investigator-initiated trial (the NORDynamIC study), in which pretreatment liver biopsies were mandatory. PNPLA3I148M genotyping was performed in a total of 359 Caucasian patients.
Results
In HCV genotype 2 infected patients carrying the PNPLA3 148M allele, there was significantly increased insulin resistance (P = 0.023) and lower viral load (P = 0.005) at baseline as well as the first seven days of antiviral treatment. These results were not observed in HCV genotype 3 infected patients.
Conclusions
Our results suggest a possible association between the PNPLA3 148M allele and insulin resistance as well as baseline viral load in HCV genotype 2, but not in genotype 3.
doi:10.1186/1471-2350-13-82
PMCID: PMC3495049  PMID: 22978414
Hepatitis C; PNPLA 3; Insulin resistance; Viral load
16.  Risk of Diabetes Mellitus in Persons with and without HIV: A Danish Nationwide Population-Based Cohort Study 
PLoS ONE  2012;7(9):e44575.
Objective
In a nationwide, population-based cohort study we assessed the risk of diabetes mellitus (DM) in HIV-infected individuals compared with the general population, and evaluated the impact of risk factors for DM in HIV-infected individuals.
Methods
We identified 4,984 Danish-born HIV-infected individuals from the Danish HIV Cohort Study and a Danish born population-based age- and gender-matched comparison cohort of 19,936 individuals (study period: 1996–2009). Data on DM was obtained from the Danish National Hospital Registry and the Danish National Prescription Registry. Incidence rate ratios (IRR) and impact of risk factors including exposure to Highly Active Antiretroviral Therapy (HAART) and antiretroviral drugs were estimated by Poisson regression analyses.
Results
In the period 1996–1999 risk of DM was higher in HIV-infected individuals compared to the comparison cohort (adjusted IRR: 2.83; 95%CI: 1.57–5.09), both before (adjusted IRR: 2.40; 95%CI: 1.03–5.62) and after HAART initiation (adjusted IRR: 3.24; 95% CI: 1.42–7.39). In the period 1999–2010 the risk of DM in HIV-infected individuals did not differ from that of the comparison cohort (adjusted IRR: 0.90; 95% CI: 0.72–1.13), although the risk was decreased before HAART-initiation (adjusted IRR: 0.45; 95%CI: 0.21–0.96). Increasing age, BMI and the presence of lipoatrophy increased the risk of DM, as did exposure to indinavir, saquinavir, stavudine and didanosine.
Conclusion
Native HIV–infected individuals do not have an increased risk of developing DM compared to a native background population after year 1998. Some antiretroviral drugs, not used in modern antiretroviral treatment, seem to increase the risk of DM.
doi:10.1371/journal.pone.0044575
PMCID: PMC3440341  PMID: 22984529
17.  Plasma HIV Viral Rebound following Protocol-Indicated Cessation of ART Commenced in Primary and Chronic HIV Infection 
PLoS ONE  2012;7(8):e43754.
Objectives
The magnitude of HIV viral rebound following ART cessation has consequences for clinical outcome and onward transmission. We compared plasma viral load (pVL) rebound after stopping ART initiated in primary (PHI) and chronic HIV infection (CHI).
Design
Two populations with protocol-indicated ART cessation from SPARTAC (PHI, n = 182) and SMART (CHI, n = 1450) trials.
Methods
Time for pVL to reach pre-ART levels after stopping ART was assessed in PHI using survival analysis. Differences in pVL between PHI and CHI populations 4 weeks after stopping ART were examined using linear and logistic regression. Differences in pVL slopes up to 48 weeks were examined using linear mixed models and viral burden was estimated through a time-averaged area-under-pVL curve. CHI participants were categorised by nadir CD4 at ART stop.
Results
Of 171 PHI participants, 71 (41.5%) rebounded to pre-ART pVL levels, at a median of 50 (95% CI 48–51) weeks after stopping ART. Four weeks after stopping treatment, although the proportion with pVL≥400 copies/ml was similar (78% PHI versus 79% CHI), levels were 0.45 (95% CI 0.26–0.64) log10 copies/ml lower for PHI versus CHI, and remained lower up to 48 weeks. Lower CD4 nadir in CHI was associated with higher pVL after ART stop. Rebound for CHI participants with CD4 nadir >500 cells/mm3 was comparable to that experienced by PHI participants.
Conclusions
Stopping ART initiated in PHI and CHI was associated with viral rebound to levels conferring increased transmission risk, although the level of rebound was significantly lower and sustained in PHI compared to CHI.
doi:10.1371/journal.pone.0043754
PMCID: PMC3432055  PMID: 22952756
18.  Adherence to national guidelines for initiation of antiretroviral regimens in HIV patients: a Danish nationwide study 
AIM
To determine the adherence to the national guidelines for start of highly active antiretroviral treatment (HAART) in HIV infected patients.
METHODS
We used a Danish nationwide cohort of HIV infected patients to calculate the fraction of patients who in the period 1997–2006 started HAART according to the guidelines from The Danish Society of Infectious Diseases. We used Kaplan-Meier tables to estimate time from fulfilling the criteria for start of HAART to initiation of the treatment. Cox regression and logistic regression was used to identify risk factors for delayed initiation of treatment and chance of being included in clinical trials.
RESULTS
The study included 3223 patients, 74% of whom initiated HAART in the study period. Ninety-four% fulfilled the criteria for start of HAART, with minor differences over calendar periods. Ninety-four% initiated a recommended regimen or were included in a clinical trial. Intravenous drug use predicted initiation of a non-recommended regimen and delay in start of HAART, while non-Caucasians were less likely to be included in clinical trials.
CONCLUSIONS
In a Western world setting, the adherence to national guidelines for start of HAART can be high. We suggest that simplicity of the guidelines, centralization of treatment and involvement of local clinicians in the development of guidelines are of major importance for high adherence to treatment guidelines.
doi:10.1111/j.1365-2125.2011.03935.x
PMCID: PMC3141193  PMID: 21306418
antiretroviral therapy; guideline adherence; HIV
19.  Impact of Obesity on the Bioavailability of Peginterferon-α2a and Ribavirin and Treatment Outcome for Chronic Hepatitis C Genotype 2 or 3 
PLoS ONE  2012;7(5):e37521.
Background and Aims
Having a body mass index above or equal to 30 kg/m2 in conjunction with chronic hepatitis C virus infection is associated with non-responsiveness to treatment with interferon and ribavirin, but details regarding the mechanisms whereby obesity reduces the efficacy of therapy remain unclear.
Methods
This study evaluated impact of obesity on outcome as well as interferon and ribavirin concentrations following standard-of-care fixed dosing with peginterferon-α2a 180 µg once weekly and ribavirin 800 mg daily among 303 HCV genotype 2/3-infected patients enrolled in the per-protocol analysis of a recently completed phase III trial (NORDynamIC).
Results
Patients with BMI ≥30 kg/m2 showed poorer outcome following 24 weeks of therapy (SVR 62% vs. 89% for BMI ≥30 vs. <30; P = 0.006) along with significantly higher steatosis grade (P = 0.002), HOMA-IR (P<0.0001), triglyceride levels (P = 0.0002), and baseline viral load (P = 0.028). Obesity was also significantly associated with lower plasma interferon concentrations on days 3, 7, and 29 (P = 0.02, P = 0.0017, and P<0.0001, respectively) and lower plasma ribavirin concentrations day 29 (P = 0.025), and lower concentration of interferon in turn was associated with a poorer first phase reduction in HCV RNA (P<0.0001). In multivariate analysis, ribavirin concentrations week 12, interferon concentrations day 29, and baseline HCV RNA levels were independent predictors of achieving SVR among patients treated for 24 weeks (n = 140).
Conclusions
Reduced bioavailability of interferon and ribavirin along with higher baseline viral load are dominant risk factors for treatment failure in obese patients with chronic hepatitis C.
doi:10.1371/journal.pone.0037521
PMCID: PMC3360051  PMID: 22655053
21.  Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection 
The Journal of Infectious Diseases  2011;203(6):780-790.
Background. Chronic human immunodeficiency virus (HIV) infection is associated with intestinal permeability and microbial translocation that contributes to systemic immune activation, which is an independent predictor of HIV disease progression. The association of microbial translocation with clinical outcome remains unknown.
Methods. This nested case-control study included 74 subjects who died, 120 of whom developed cardiovascular disease and 81 of whom developed AIDS during the Strategies for Management of Anti-Retroviral Therapy (SMART) study with matched control subjects. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), soluble CD14 (sCD14), endotoxin core antibody (EndoCAb), and 16S ribosomal DNA (rDNA) were measured in baseline plasma samples.
Results. Subjects with the highest quartile of sCD14 levels had a 6-fold higher risk of death than did those in the lowest quartile (95% confidence interval, 2.2–16.1; P<.001), with minimal change after adjustment for inflammatory markers, CD4+ T cell count, and HIV RNA level. No other marker was significantly associated with clinical outcomes. I-FABP, LPS, and sCD14 were increased and EndoCAb was decreased in study subjects, compared with healthy volunteers. sCD14 level correlated with levels of IL-6, C-reactive protein, serum amyloid A and D-dimer.
Conclusions. sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection. Therapeutic attenuation of innate immune activation may improve survival in patients with HIV infection.
doi:10.1093/infdis/jiq118
PMCID: PMC3071127  PMID: 21252259
22.  Impact of IL28B-Related Single Nucleotide Polymorphisms on Liver Histopathology in Chronic Hepatitis C Genotype 2 and 3 
PLoS ONE  2012;7(1):e29370.
Background and Aims
Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of HCV infection as well as outcome following peginterferon and ribavirin therapy among HCV genotype 1 infected patients. The present study aimed to evaluate the impact of IL28B SNP variability on liver histology in the context of a phase III treatment trial (NORDynamIC) for treatment-naïve patients with chronic HCV genotype 2 or 3 infection, where pretreatment liver biopsies were mandatory.
Methods
Three hundred and thirty-nine Caucasian patients had samples available for IL28B genotyping (rs12979860) of whom 314 had pretreatment liver biopsies that were evaluated using the Ishak protocol, allowing for detailed grading and staging of liver histopathology.
Results
IL28B CCrs12979860 genotype in HCV genotype 3 infected patients was associated with higher ALT levels (p<0.0001), higher AST to platelet ratio index (APRI; p = 0.001), and higher baseline viral load (p<0.0001) as compared to patients with the CT or TT genotypes. Additionally the CCrs12979860 genotype entailed more pronounced portal inflammation (p = 0.02) and steatosis (p = 0.03). None of these associations were noted among HCV genotype 2 infected patients.
Conclusion
This study shows that the CCrs12979860 SNP is associated with more pronounced liver histopathology in patients chronically infected with HCV genotype 3, which may be secondary to higher viral load. The finding that IL28B variability did not impact on liver pathology or viral load among genotype 2 infected patients implies that IL28B may differentially regulate the course of genotype 2 and 3 infection.
doi:10.1371/journal.pone.0029370
PMCID: PMC3258245  PMID: 22253715
23.  Impact of Non-HIV and HIV Risk Factors on Survival in HIV-Infected Patients on HAART: A Population-Based Nationwide Cohort Study 
PLoS ONE  2011;6(7):e22698.
Background
We determined the impact of three factors on mortality in HIV-infected patients who had been on highly active antiretroviral therapy (HAART) for at least one year: (1) insufficient response to (HAART) and presence of AIDS-defining diseases, (2) comorbidity, and (3) drug and alcohol abuse and compared the mortality to that of the general population.
Methodology/Principal Findings
In a Danish nationwide, population-based cohort study, we used population based registries to identify (1) all Danish HIV-infected patients who started HAART in the period 1 January 1998–1 July 2009, and (2) a comparison cohort of individuals matched on date of birth and gender (N = 2,267 and 9,068, respectively). Study inclusion began 1 year after start of HAART. Patients were categorised hierarchically in four groups according to the three risk factors, which were identified before study inclusion. The main outcome measure was probability of survival from age 25 to 65 years. The probability of survival from age 25 to age 65 was substantially lower in HIV patients [0.48 (95% confidence interval (CI) 0.42–0.55)] compared to the comparison cohort [0.88 (0.86 to 0.90)]. However, in HIV patients with no risk factors (N = 871) the probability of survival was equivalent to that of the general population [0.86 (95% CI 0.77–0.92)]. In contrast, the probability of survival was 0.58 in patients with HIV risk factors (N = 704), 0.30 in patients with comorbidities (N = 479), and 0.03 in patients with drug or alcohol abuse (N = 313).
Conclusions
The increased risk of death in HIV-infected individuals is mainly attributable to risk factors that can be identified prior to or in the initial period of antiretroviral treatment. Mortality in patients without risk factors on a successful HAART is almost identical to that of the non–HIV-infected population.
doi:10.1371/journal.pone.0022698
PMCID: PMC3143183  PMID: 21799935
24.  Head and neck cancer in HIV patients and their parents: a Danish cohort study 
Clinical Epidemiology  2011;3:217-227.
Background:
The mechanism for the increased risk of head and neck cancer (HNC) observed in HIV patients is controversial. We hypothesized that family-related risk factors increase the risk of HNC why we estimated the risk of this type of cancer in both HIV patients and their parents.
Methods:
We estimated the cumulative incidence and incidence rate ratios (IRRs) of HNC in 1) a population of all Danish HIV patients identified from the Danish HIV Cohort Study (n = 5053) and a cohort of population controls matched on age and gender (n = 50,530) (study period; 1995–2009) and 2) the parents of HIV patients and population controls (study period 1978–2009). To assess the possible impact of human papilloma virus (HPV)–associated cancers, the sites of squamous cell HNCs were categorized as HPV related, potentially HPV related, and potentially HPV unrelated.
Results:
Seventeen (0.3%) HIV patients vs 80 (0.2%) population controls were diagnosed with HNC cancer in the observation period. HIV patients had an increased risk of HNC (IRR 3.05 [95% CI 1.81–5.15]). The IRR was considerably increased in HIV patients older than 50 years (adjusted IRR; 4.58 [95% CI 2.24–9.35]), diagnosed after 1995 (adjusted IRR 6.31 [95% CI 2.82–14.08]), previous or current smoker (adjusted IRR 4.51 [95% CI 2.47–8.23]), with baseline CD4 count 350 cells/μL (adjusted IRR; 3.89 [95% CI 1.95–7.78]), and men heterosexually infected with HIV (adjusted IRR 5.54 [95% CI 1.96–15.66]). Fifteen (83%) of the HIV patients diagnosed with HNC were current or former smokers. The IRR of squamous cell HNC in HIV patients was high at HPV-relate sites, potentially HPV-related sites, and potentially HPV-unrelated sites. Both fathers and mothers of HIV patients had an increased risk of HNC (adjusted IRR for fathers 1.78 [95% CI 1.28–2.48], adjusted IRR for mothers 2.07 [95% CI 1.05–4.09]).
Conclusion:
HIV appears to be a marker of behavioral or family-related risk factors that affect the incidence of HNC in HIV patients.
doi:10.2147/CLEP.S19875
PMCID: PMC3157492  PMID: 21857789
HIV; head and neck cancer incidence; matched cohort; population controls; parents
25.  Lung cancer in HIV patients and their parents: A Danish cohort study 
BMC Cancer  2011;11:272.
Background
HIV patients are known to be at increased risk of lung cancer but the risk factors behind this are unclear.
Methods
We estimated the cumulative incidence and relative risk of lung cancer in 1) a population of all Danish HIV patients identified from the Danish HIV Cohort Study (n = 5,053) and a cohort of population controls matched on age and gender (n = 50,530) (study period; 1995 - 2009) and 2) their parents (study period; 1969 - 2009). Mortality and relative risk of death after a diagnosis of lung cancer was estimated in both populations.
Results
29 (0.6%) HIV patients vs. 183 (0.4%) population controls were diagnosed with lung cancer in the observation period. HIV patients had an increased risk of lung cancer (adjusted incidence rate ratio (IRR); 2.38 (95% CI; 1.61 - 3.53)). The IRR was considerably increased in HIV patients who were smokers or former smokers (adjusted IRR; 4.06 (95% CI; 2.66 - 6.21)), male HIV patients with heterosexual route of infection (adjusted IRR; 4.19 (2.20 - 7.96)) and HIV patients with immunosuppression (adjusted IRR; 3.25 (2.01 - 5.24)). Both fathers and mothers of HIV patients had an increased risk of lung cancer (adjusted IRR for fathers; 1.31 (95% CI: 1.09 - 1.58), adjusted IRR for mothers 1.35 (95% CI: 1.07 - 1.70)). Mortality after lung cancer diagnose was increased in HIV patients (adjusted mortality rate ratio 2.33 (95%CI; 1.51 - 3.61), but not in the parents. All HIV patients diagnosed with lung cancer were smokers or former smokers.
Conclusion
The risk was especially increased in HIV patients who were smokers or former smokers, heterosexually infected men or immunosuppressed. HIV appears to be a marker of behavioural or family related risk factors that affect the incidence of lung cancer in HIV patients.
doi:10.1186/1471-2407-11-272
PMCID: PMC3135571  PMID: 21702995
HIV; lung cancer incidence; matched cohort; population controls; parents; immunosuppression

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