Publications by authors named "Luigia Elzi"

88 Publications

Risk assessment and seroprevalence of SARS-CoV-2 infection in healthcare workers of COVID-19 and non-COVID-19 hospitals in Southern Switzerland.

Lancet Reg Health Eur 2021 Feb 17;1:100013. Epub 2020 Dec 17.

Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland.

Background: Hospital healthcare workers (HCW), in particular those involved in the clinical care of COVID-19 cases, are presumably exposed to a higher risk of acquiring the disease than the general population.

Methods: Between April 16 and 30, 2020 we conducted a prospective, SARS-CoV-2 seroprevalence study in HCWs in Southern Switzerland. Participants were hospital personnel with varying COVID-19 exposure risk depending on job function and working site. They provided personal information (including age, sex, occupation, and medical history) and self-reported COVID-19 symptoms. Odds ratio (OR) of seropositivity to IgG antibodies was estimated by univariate and multivariate logistic regressions.

Findings: Among 4726 participants, IgG antibodies to SARS-CoV-2 were detected in 9.6% of the HCWs. Seropositivity was higher among HCWs working on COVID-19 wards (14.1% (11.9-16.5)) compared to other hospital areas at medium (10.7% (7.6-14.6)) or low risk exposure (7.3% (6.4-8.3)). OR for high vs. medium wards risk exposure was 1.42 (0.91-2.22),  = 0.119, and 1.98 (1.55-2.53), <0.001 for high vs. low wards risk exposure. The same was for true for doctors and nurses (10.1% (9.0-11.3)) compared to other employees at medium (7.1% (4.8-10.0)) or low risk exposure (6.6% (5.0-8.4)). OR for high vs. medium profession risk exposure was 1.37 (0.89-2.11),  = 0.149, and 1.75 (1.28-2.40),  = 0.001 for high vs. low profession risk exposure. Moreover, seropositivity was higher among HCWs who had household exposure to COVID-19 cases compared to those without (18.7% (15.3-22.5) vs. 7.7% (6.9-8.6), OR 2.80 (2.14-3.67), <0.001).

Interpretation: SARS-CoV-2 antibodies are detectable in up to 10% of HCWs from acute care hospitals in a region with high incidence of COVID-19 in the weeks preceding the study. HCWs with exposure to COVID-19 patients have only a slightly higher absolute risk of seropositivity compared to those without, suggesting that the use of PPE and other measures aiming at reducing nosocomial viral transmission are effective. Household contact with known COVID-19 cases represents the highest risk of seropositivity.

Funding: Henry Krenter Foundation, Ente Ospedaliero Cantonale and Vir Biotechnology.
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http://dx.doi.org/10.1016/j.lanepe.2020.100013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833818PMC
February 2021

PET findings after COVID-19 vaccination: "Keep Calm and Carry On".

Clin Transl Imaging 2021 May 13:1-6. Epub 2021 May 13.

Department of Medicine, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.

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http://dx.doi.org/10.1007/s40336-021-00430-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117802PMC
May 2021

'High prevalence of heterotopic ossification in critically ill patients with severe COVID-19' - Author's reply.

Clin Microbiol Infect 2021 07 16;27(7):1053. Epub 2021 Feb 16.

Department of Infectious Disease, Ospedale Regionale di Bellinzona e Valli Bellinzona, Bellinzona, Switzerland.

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http://dx.doi.org/10.1016/j.cmi.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884915PMC
July 2021

High prevalence of heterotopic ossification in critically ill patients with severe COVID-19.

Clin Microbiol Infect 2021 07 15;27(7):1049-1050. Epub 2021 Jan 15.

Department of Intensive Care Medicine, Regional Hospital of Bellinzona, Switzerland.

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http://dx.doi.org/10.1016/j.cmi.2020.12.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833636PMC
July 2021

Analysis of inappropriate prescribing in elderly patients of the Swiss HIV Cohort Study reveals gender inequity.

J Antimicrob Chemother 2021 02;76(3):758-764

University of Basel, Basel, Switzerland.

Background: The extent of inappropriate prescribing observed in geriatric medicine has not been thoroughly evaluated in people ageing with HIV. We determined the prevalence of and risk factors for inappropriate prescribing in individuals aged ≥75 years enrolled in the Swiss HIV Cohort Study.

Methods: Retrospective review of medical records was performed to gain more insights into non-HIV comorbidities. Inappropriate prescribing was screened using the Beers criteria, the STOPP/START criteria and the Liverpool drug-drug interactions (DDIs) database.

Results: For 175 included individuals, the median age was 78 years (IQR 76-81) and 71% were male. The median number of non-HIV comorbidities was 7 (IQR 5-10). The prevalence of polypharmacy and inappropriate prescribing was 66% and 67%, respectively. Overall, 40% of prescribing issues could have deleterious consequences. Prescribing issues occurred mainly with non-HIV drugs and included: incorrect dosage (26%); lack of indication (21%); prescription omission (drug not prescribed although indicated) (17%); drug not appropriate in elderly individuals (18%) and deleterious DDIs (17%). In the multivariable logistic regression, risk factors for prescribing issues were polypharmacy (OR: 2.5; 95% CI: 1.3-4.7), renal impairment (OR: 2.7; 95% CI: 1.4-5.1), treatment with CNS-active drugs (OR: 2.1; 95% CI: 1.1-3.8) and female sex (OR: 8.3; 95% CI: 2.4-28.1).

Conclusions: Polypharmacy and inappropriate prescribing are highly prevalent in elderly people living with HIV. Women are at higher risk than men, partly explained by sex differences in the occurrence of non-HIV comorbidities and medical care. Medication reconciliation and periodic review of prescriptions by experienced physicians could help reduce polypharmacy and inappropriate prescribing in this vulnerable, growing population.
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http://dx.doi.org/10.1093/jac/dkaa505DOI Listing
February 2021

Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology.

Cell 2020 11 16;183(4):1024-1042.e21. Epub 2020 Sep 16.

III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy.

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.
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http://dx.doi.org/10.1016/j.cell.2020.09.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494283PMC
November 2020

Diabetes mellitus is a risk factor for prolonged SARS-CoV-2 viral shedding in lower respiratory tract samples of critically ill patients.

Endocrine 2020 12 1;70(3):454-460. Epub 2020 Sep 1.

Ente Ospedaliero Cantonale, Division of Infectious Diseases, Regional Hospital Lugano, Lugano, Switzerland.

Purpose: The length of time a critically ill coronavirus disease 2019 (COVID-19) patient remains infectious and should therefore be isolated remains unknown. This prospective study was undertaken in critically ill patients to evaluate the reliability of single negative real-time polymerase chain reaction (RT-PCR) in lower tracheal aspirates (LTA) in predicting a second negative test and to analyze clinical factors potentially influencing the viral shedding.

Methods: From April 9, 2020 onwards, intubated COVID-19 patients treated in the intensive care unit were systematically evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by RT-PCR of nasopharyngeal swabs and LTA. The time to negativity was defined as the time between the onset of symptoms and the viral clearance in LTA. In order to identify risk factors for prolonged viral shedding, we used univariate and multivariate Cox proportional hazards models.

Results: Forty-eight intubated SARS-CoV-2 patients were enrolled. Overall, we observed that the association of the first negative RT-PCR with a second negative result was 96.7%. Median viral shedding was 25 (IQR: 21.5-28) days since symptoms' onset. In the univariate Cox model analysis, type 2 diabetes mellitus was associated with a prolonged viral RNA shedding (hazard ratio [HR]: 0.41, 95% CI: 0.06-3.11, p = 0.04). In the multivariate Cox model analysis, type 2 diabetes was associated with a prolonged viral RNA shedding (HR: 0.31, 95% CI: 0.11-0.89, p = 0.029).

Conclusion: Intubated patients with type 2 diabetes mellitus may have prolonged SARS-CoV-2 shedding. In critically ill COVID-19 patients, one negative LTA should be sufficient to assess and exclude infectivity.
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http://dx.doi.org/10.1007/s12020-020-02465-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459254PMC
December 2020

Prevalence of potential drug-drug interactions in patients of the Swiss HIV Cohort Study in the era of HIV integrase inhibitors.

Clin Infect Dis 2020 Jul 8. Epub 2020 Jul 8.

Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland.

Background: Prevalence of potential drug-drug interactions (PDDIs) between antiretroviral drugs (ARVs) and comedications was high in 2008 in a Swiss HIV Cohort Study (SHCS) survey. We reassessed the prevalence of PDDIs in the era of HIV integrase inhibitors (INIs), characterized by more favorable interaction profiles.

Methods: The prevalence of PDDIs in treated HIV positive individuals was assessed for the period: 01-12/2018 by linkage of the Liverpool HIV drug interactions and SHCS databases. PDDIs were categorized as harmful (red flagged), of potential clinical relevance (amber flagged) or of weak clinical significance (yellow flagged).

Results: In 9'298 included individuals, median age was 51 years (IQR 43; 58), and 72% were males. Individuals received unboosted INIs (40%), boosted ARVs (30%), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) (32%) based regimens. In the entire cohort, 68% received > 1 comedication, 14% had polypharmacy (> 5 comedications) and 29% had > 1 PDDI. Among individuals with comedication, the prevalence of combined amber and yellow PDDIs was 43% (33% amber - mostly with cardiovascular drugs - and 20% yellow flagged PDDIs) compared to 59% in 2008. Two percent had red flagged PDDIs (mostly with corticosteroids), the same as in the 2008 survey. Compared to 2008, fewer individuals received boosted ARVs (-24%) and NNRTIs (-13%) but the use of comedications was higher.

Conclusions: Prevalence of PDDIs was lower with more widespread use of INIs in 2018 than in 2008. Continued use of boosted regimens and increasing needs for comedications in this aging population impeded lower rates of PDDIs.
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http://dx.doi.org/10.1093/cid/ciaa918DOI Listing
July 2020

Chromobacterium violaceum bacteraemia: a new entity in Switzerland.

Swiss Med Wkly 2020 04 30;150:w20220. Epub 2020 Apr 30.

Ente Ospedaliero Cantonale, Ospedale Regionale di Bellinzona e Valli, Faido, Switzerland.

We report the uncommon clinical case of our patient, an 83-year-old woman with Alzheimer disease, who acquired a potentially fatal tropical infection in an open-air swimming pool in the Alps. Chromobacterium violaceum is a rare gram-negative anaerobe bacillus, generally associated with serious waterborne infections in tropical and subtropical regions. The patient presented to our emergency department with a 2-day history of fever and a small non-necrotic wound on the right leg after a minor injury 9 days before. It turned out to be the first infection in Switzerland due to C. violaceum, a deadly bacterium typical of tropical regions. C. violaceum appeared for the first time in Europe in the 2011. This is now the third documented case in less than a year and the second autochthonous infection ever in our continent. A delay in adequate treatment of this emerging pathogen may be associated with high fatality rates.
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http://dx.doi.org/10.4414/smw.2020.20220DOI Listing
April 2020

Sonography to Rule Out Tuberculosis in Sub-Saharan Africa: A Prospective Observational Study.

Open Forum Infect Dis 2019 Apr 25;6(4):ofz154. Epub 2019 Apr 25.

Ifakara Health Institute, United Republic of Tanzania.

Background: Patients with suspected tuberculosis are often overtreated with antituberculosis drugs. We evaluated the diagnostic value of the focused assessment with sonography for HIV-associated tuberculosis (FASH) in rural Tanzania.

Methods: In a prospective cohort study, the frequency of FASH signs was compared between patients with confirmed tuberculosis and those without tuberculosis. Clinical and laboratory examination, chest x-ray, Xpert MTB/RIF assay, and culture from sputum, sterile body fluids, lymph node aspirates, and Xpert MTB/RIF urine assay was done.

Results: Of 191 analyzed patients with a 6-month follow-up, 52.4% tested positive for human immunodeficiency virus, 21.5% had clinically suspected pulmonary tuberculosis, 3.7% had extrapulmonary tuberculosis, and 74.9% had extrapulmonary and pulmonary tuberculosis. Tuberculosis was microbiologically confirmed in 57.6%, probable in 13.1%, and excluded in 29.3%. Ten of eleven patients with splenic or hepatic hypoechogenic lesions had confirmed tuberculosis. In a univariate model, abdominal lymphadenopathy was significantly associated with confirmed tuberculosis. Pleural- and pericardial effusion, ascites, and thickened ileum wall lacked significant association. In a multiple regression model, abnormal chest x-ray (odds ratio [OR] = 6.19; 95% confidence interval [CI], 1.96-19.6; < .002), ≥1 FASH-sign (OR = 3.33; 95% CI, 1.21-9.12; = .019), and body temperature (OR = 2.48; 95% CI, 1.52-5.03; = .001 per °C increase) remained associated with tuberculosis. A combination of ≥1 FASH sign, abnormal chest x-ray, and temperature ≥37.5°C had 99.1% sensitivity (95% CI, 94.9-99.9), 35.2% specificity (95% CI, 22.7-49.4), and a positive and negative predictive value of 75.2% (95% CI, 71.3-78.7) and 95.0% (95% CI, 72.3-99.3).

Conclusions: The absence of FASH signs combined with a normal chest x-ray and body temperature <37.5°C might exclude tuberculosis.
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http://dx.doi.org/10.1093/ofid/ofz154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483805PMC
April 2019

A case of ulceroglandular tularemia presenting with lymphadenopathy and an ulcer on a linear morphoea lesion surrounded by erysipelas.

Int Med Case Rep J 2018 12;11:313-318. Epub 2018 Nov 12.

Department of Infectious Diseases, Regional Hospital of Bellinzona e Valli, 6500 Bellinzona, Ticino, Switzerland.

Tularemia is a zoonosis caused by the infection of (a gram-negative aerobic bacterium). Transmission to other animals or humans usually occurs through insect or tick bites, direct contact with a contaminated environment (mud or water), infected animals - mainly lagomorphs - or by ingesting undercooked meat or inhaling contaminated dust (hay or soil). This paper discusses the case of a 32-year-old man, who came to our Emergency Room presenting with persistent fever, inguinal lymphadenopathy, and an ulcer on his left lower limb on a linear morphoea lesion that had been there for some time. The lesion was surrounded by erysipelas. After hospitalization and tests, the patient was diagnosed with ulceroglandular tularemia. Antibiotic treatment with doxycycline resolved the clinical picture, but not the morphoea lesion.
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http://dx.doi.org/10.2147/IMCRJ.S178561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237246PMC
November 2018

Study protocol for a multicentre, cluster randomised, superiority trial evaluating the impact of computerised decision support, audit and feedback on antibiotic use: the COMPuterized Antibiotic Stewardship Study (COMPASS).

BMJ Open 2018 06 27;8(6):e022666. Epub 2018 Jun 27.

Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.

Introduction: Inappropriate use of antimicrobials in hospitals contributes to antimicrobial resistance. Antimicrobial stewardship (AMS) interventions aim to improve antimicrobial prescribing, but they are often resource and personnel intensive. Computerised decision supportsystems (CDSSs) seem a promising tool to improve antimicrobial prescribing but have been insufficiently studied in clinical trials.

Methods And Analysis: The COMPuterized Antibiotic Stewardship Study trial, is a publicly funded, open-label, cluster randomised, controlled superiority trial which aims to determine whether a multimodal CDSS intervention integrated in the electronic health record (EHR) reduces overall antibiotic exposure in adult patients hospitalised in wards of two secondary and one tertiary care centre in Switzerland compared with 'standard-of-care' AMS. Twenty-four hospital wards will be randomised 1:1 to either intervention or control, using a 'pair-matching' approach based on baseline antibiotic use, specialty and centre. The intervention will consist of (1) decision support for the choice of antimicrobial treatment and duration of treatment for selected indications (based on indication entry), (2) accountable justification for deviation from the local guidelines (with regard to the choice of molecules and duration), (3) alerts for self-guided re-evaluation of treatment on calendar day 4 of antimicrobial therapy and (4) monthly ward-level feedback of antimicrobial prescribing indicators. The primary outcome will be the difference in overall systemic antibiotic use measured in days of therapy per admission based on administration data recorded in the EHR over the whole intervention period (12 months), taking into account clustering. Secondary outcomes include qualitative and quantitative antimicrobial use indicators, economic outcomes and clinical, microbiological and patient safety indicators.

Ethics And Dissemination: Ethics approval was obtained for all participating sites (Comission Cantonale d'Éthique de la Recherche (CCER)2017-00454). The results of the trial will be submitted for publication in a peer-reviewed journal. Further dissemination activities will be presentations/posters at national and international conferences.

Trial Registration Number: NCT03120975; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-022666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042555PMC
June 2018

Light in the dark: F-FDG PET/CT in Staphylococcus aureus bacteremia of unknown origin.

Intensive Care Med 2018 04 13;44(4):488-489. Epub 2017 Nov 13.

Department of Intensive Care Medicine, Ente Ospedaliero Cantonale, Ospedale Regionale Bellinzona e Valli, 6500, Bellinzona, Switzerland.

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http://dx.doi.org/10.1007/s00134-017-4994-7DOI Listing
April 2018

Adverse events of raltegravir and dolutegravir.

AIDS 2017 08;31(13):1853-1858

aOspedale Regionale di Bellinzone e Valli, Bellinzona bDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, University of Basel, Basel cDepartment of Infectious Diseases, University Hospital Bern, University of Bern dDivision of Infectious Diseases, University Hospital Lausanne, Lausanne eDivision of Infectious Diseases, University Hospital Geneva, Geneva fDivision of Infectious Diseases, Cantonal Hospital St Gallen, St Gallen gDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, Zürich hInstitute of Medical Virology, University of Zürich, Zürich iDivision of Infectious Diseases, Regional Hospital Lugano, Lugano, Switzerland. *Luigia Elzi and Stefan Erb equally contributed to this article.

Objective: To compare the frequency and risk factors of toxicity-related treatment discontinuations between raltegravir and dolutegravir.

Design: Prospective cohort study.

Methods: All antiretroviral therapy (ART)-naïve and ART-experienced HIV-infected individuals from the Swiss HIV Cohort Study who initiated raltegravir or dolutegravir between 2006 and 2015 were investigated concerning treatment modification within the first year.

Results: Of 4041 patients initiating ART containing raltegravir (n = 2091) or dolutegravir (n = 1950), 568 patients discontinued ART during the first year, corresponding to a rate of 15.5 [95% confidence interval (CI) 14.5-16.9] discontinuations per 100 patient-years. Only 10 patients on raltegravir (0.5%) and two patients on dolutegravir (0.1%) demonstrated virologic failure. The main reason for ART discontinuation was convenience expressed as patient's wish, physician's decision, or treatment simplification (n = 302). Toxicity occurred in 4.3% of patients treated with raltegravir and 3.6% with dolutegravir, respectively. In multivariable analysis, the only independent risk factor for discontinuing ART because of toxicity was female sex (hazard ratio 1.98, 95% CI 1.45-2.71, P < 0.001).Neuropsychiatric complaints were the most commonly reported toxic adverse events and more frequent in the dolutegravir (n = 33, 1.7%) compared with the raltegravir group (n = 13, 0.6%). Risk of discontinuation for neurotoxicity was lower for raltegravir than for dolutegravir in multivariable analysis (hazard ratio 0.46, 95% CI 0.22-0.96, P = 0.037).

Conclusion: In this, large cohort raltegravir and dolutegravir-containing regimen demonstrated a high virologic efficacy. Drug toxicity was infrequent and discontinuation because of neuropsychiatric events within the first year of treatment was only marginal higher with dolutegravir compared with raltegravir. However, monitoring of neurotoxic side-effects of dolutegravir is important.
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http://dx.doi.org/10.1097/QAD.0000000000001590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566167PMC
August 2017

Intervention to Improve Appropriate Prescribing and Reduce Polypharmacy in Elderly Patients Admitted to an Internal Medicine Unit.

PLoS One 2016 30;11(11):e0166359. Epub 2016 Nov 30.

Division of Internal Medicine, University Hospital Basel, Basel, Switzerland.

Background: Polypharmacy and inappropriate medication prescriptions are associated with increased morbidity and mortality. Most interventions proposed to improve appropriate prescribing are time and resource intensive and therefore hardly applicable in daily clinical practice.

Objective: To test the efficacy of an easy-to-use checklist aimed at supporting the therapeutic reasoning of physicians in order to reduce inappropriate prescribing and polypharmacy.

Methods: We assessed the efficacy and safety of a 5-point checklist to be used by all physicians on the internal medicine wards of a Swiss hospital by comparing outcomes in 450 consecutive patients aged ≥65 years hospitalized after the introduction of the checklist, and in 450 consecutive patients ≥65 years hospitalized before the introduction of the checklist. The main measures were the proportion of patients with prescription of potentially inappropriate medications (PIMs) at discharge, according to STOPP criteria, and the number of prescribed medications at discharge, before and after the introduction of the checklist. Secondary outcomes were the prevalence of polypharmacy (≥ 5 drugs) and hyperpolypharmacy (≥ 10 drugs), and the prevalence of potentially inappropriate prescribing omissions (PPOs) according to START criteria.

Results: At admission 59% of the 900 patients were taking > 5 drugs, 13% ≥ 10 drugs, 37% had ≥ 1 PIM and 25% ≥ 1 PPO. The introduction of the checklist was associated with a significant reduction by 22% of the risk of being prescribed ≥ 1 PIM at discharge (adjusted risk ratios [RR] 0.78; 95% CI: 0.68-0.94), but not with a reduction of at least 20% of the number of drugs prescribed at discharge, nor with a reduction of the risk of PPOs at discharge.

Conclusions: The introduction of an easy-to-use 5-point checklist aimed at supporting therapeutic reasoning of physicians on internal medicine wards significantly reduced the risk of prescriptions of inappropriate medications at discharge.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166359PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130196PMC
July 2017

Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions with Efavirenz Involving Simultaneous Inducing and Inhibitory Effects on Cytochromes.

Clin Pharmacokinet 2017 04;56(4):409-420

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Background: Antiretroviral drugs are among the therapeutic agents with the highest potential for drug-drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously.

Methods: This study predicted the magnitude of the DDI between efavirenz, an inducer of CYP3A4 and inhibitor of CYP2C8, and dual CYP3A4/CYP2C8 substrates (repaglinide, montelukast, pioglitazone, paclitaxel) using a physiologically based pharmacokinetic (PBPK) modeling approach integrating concurrent effects on CYPs. In vitro data describing the physicochemical properties, absorption, distribution, metabolism, and elimination of efavirenz and CYP3A4/CYP2C8 substrates as well as the CYP-inducing and -inhibitory potential of efavirenz were obtained from published literature. The data were integrated in a PBPK model developed using mathematical descriptions of molecular, physiological, and anatomical processes defining pharmacokinetics. Plasma drug-concentration profiles were simulated at steady state in virtual individuals for each drug given alone or in combination with efavirenz. The simulated pharmacokinetic parameters of drugs given alone were compared against existing clinical data. The effect of efavirenz on CYP was compared with published DDI data.

Results: The predictions indicate that the overall effect of efavirenz on dual CYP3A4/CYP2C8 substrates is induction of metabolism. The magnitude of induction tends to be less pronounced for dual CYP3A4/CYP2C8 substrates with predominant CYP2C8 metabolism.

Conclusion: PBPK modeling constitutes a useful mechanistic approach for the quantitative prediction of DDI involving simultaneous inducing or inhibitory effects on multiple CYPs as often encountered with antiretroviral drugs.
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http://dx.doi.org/10.1007/s40262-016-0447-7DOI Listing
April 2017

Immune recovery in HIV-infected patients after Candida esophagitis is impaired despite long-term antiretroviral therapy.

AIDS 2016 07;30(12):1923-33

aInfection Biology Laboratory, Department of Biomedicine, University and University Hospital of Basel bDivision of Infectious Diseases and Hospital Epidemiology, Departments of Biomedicine and Clinical Research University Hospital of Basel, Basel cDepartment of Infectious Diseases, Bern University Hospital, University of Bern, Bern dDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich eInstitute of Medical Virology fSection of Immunology, Institute of Virology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland. *Claudia Stuehler and Claudia Bernardini contributed equally to this article.

Objective: Candida esophagitis belongs to the most common AIDS-defining diseases; however, a comprehensive immune pathogenic concept is lacking.

Design: We investigated the immune status of 37 HIV-1-infected patients from the Swiss HIV cohort study at diagnosis of Candida esophagitis, 1 year before, 1 year later and after 2 years of suppressed HIV RNA. We compared these patients with three groups: 37 HIV-1-infected patients without Candida esophagitis but similar CD4 cell counts as the patients at diagnosis (advanced HIV group), 15 HIV-1-infected patients with CD4 cell counts higher than 500 cells/μl, CD4 cell nadirs higher than 350 cells/μl and suppressed HIV RNA under combination antiretroviral therapy (cART) (early cART group) and 20 healthy individuals.

Methods: We investigated phenotype, cytokine production and proliferative capacity of different immune cells by flow cytometry and enzyme-linked immunosorbent spot.

Results: We found that patients with Candida esophagitis had nearly abolished CD4 cell proliferation in response to Candida albicans, significantly increased percentages of dysfunctional CD4 cells, significantly decreased cytotoxic natural killer cell counts and peripheral innate lymphoid cell counts and significantly reduced IFN-γ and IL-17 production compared with the early cART group and healthy individuals. Most of these defects remained for more than 2 years despite viral suppression. The advanced HIV group without opportunistic infection showed partly improved immune recovery.

Conclusion: Our data indicate that Candida esophagitis in HIV-1-infected patients is caused by an accumulation of multiple, partly Candida-specific immunological defects. Long-term immune recovery is impaired, illustrating that specific immunological gaps persist despite cART. These data also support the rationale for early cART initiation to prevent irreversible immune defects.
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http://dx.doi.org/10.1097/QAD.0000000000001126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949004PMC
July 2016

Ability to Work and Employment Rates in Human Immunodeficiency Virus (HIV)-1-Infected Individuals Receiving Combination Antiretroviral Therapy: The Swiss HIV Cohort Study.

Open Forum Infect Dis 2016 Jan 1;3(1):ofw022. Epub 2016 Feb 1.

Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research , University Hospital Basel.

Background.  Limited data exist on human immunodeficiency virus (HIV)-infected individuals' ability to work after receiving combination antiretroviral therapy (cART). We aimed to investigate predictors of regaining full ability to work at 1 year after starting cART. Methods.  Antiretroviral-naive HIV-infected individuals <60 years who started cART from January 1998 through December 2012 within the framework of the Swiss HIV Cohort Study were analyzed. Inability to work was defined as a medical judgment of the patient's ability to work as 0%. Results.  Of 5800 subjects, 4382 (75.6%) were fully able to work, 471 (8.1%) able to work part time, and 947 (16.3%) were unable to work at baseline. Of the 947 patients unable to work, 439 (46.3%) were able to work either full time or part time at 1 year of treatment. Predictors of recovering full ability to work were non-white ethnicity (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), higher education (OR, 4.03; 95% CI, 2.47-7.48), and achieving HIV-ribonucleic acid <50 copies/mL (OR, 1.83; 95% CI, 1.20-2.80). Older age (OR, 0.55; 95% CI, .42-.72, per 10 years older) and psychiatric disorders (OR, 0.24; 95% CI, .13-.47) were associated with lower odds of ability to work. Recovering full ability to work at 1 year increased from 24.0% in 1998-2001 to 41.2% in 2009-2012, but the employment rates did not increase. Conclusions.  Regaining full ability to work depends primarily on achieving viral suppression, absence of psychiatric comorbidity, and favorable psychosocial factors. The discrepancy between patients' ability to work and employment rates indicates barriers to reintegration of persons infected with HIV.
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http://dx.doi.org/10.1093/ofid/ofw022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777901PMC
January 2016

Travelling activity and travel-related risks after allogeneic haematopoietic stem cell transplantation - a single centre survey.

Swiss Med Wkly 2015 29;145:w14136. Epub 2015 May 29.

Clinical Microbiology, University Hospital Basel, Switzerland; Infection Biology, Department Biomedicine, University Basel, Switzerland.

Background: Travel activity and travel-related risks of patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT) remain largely unknown. The aim of our study was to examine travel activity after allo-HSCT including travel behaviour and travel patterns.

Methods: We analysed travel characteristics of allo-HSCT recipients by using a retrospective cross-sectional survey. Allo-HSCT patients were asked to complete a questionnaire during their annual health visits from 2010 to 2012.

Results: Overall, 118/153 (77%) participating patients reported travel activity for a total of 201 travelling episodes. Travellers versus non-travellers were receiving immunosuppressive treatment in 35.6% versus 65.7% (p=0.002), and had graft-versus-host-disease (GvHD) in 52.5% versus 62.9% (p=0.17). In a multivariate analysis, the time between the transplantation and the survey was the only factor associated with travel activity (p<0.0001) and taking pretravel advice (p<0.0001). In 34.8% of travel episodes pretravel advice was sought. Patients with pretravel advice reported travel-related symptoms more frequently. Minor respiratory (27/201) and gastrointestinal (23/201) symptoms were most frequently indicated. Four percent (8/201) of the patients were hospitalised while travelling.

Conclusion: We conclude that travelling after allo-HSCT is frequent and linked to the time since transplantation. We could not define specific risks for any destination. Nevertheless, pretravel advice and preparation are highly recommended for immunosuppressed patients.
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http://dx.doi.org/10.4414/smw.2015.14136DOI Listing
January 2016

Acute kidney injury KDIGO stage 2 to 3 in HIV-positive patients treated with cART--a case series over 11 years in a cohort of 1,153 patients.

Swiss Med Wkly 2015 29;145:w14135. Epub 2015 May 29.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Switzerland.

Objectives: We aimed to explore acute kidney injury (AKI) Kidney Disease Improving Global Guidelines (KDIGO) stage 2 to 3 in a cohort of antiretroviral treated HIV-infected individuals.

Methods: HIV-infected individuals of the Swiss HIV Cohort Study (Basel site), treated with combination antiretroviral therapy (cART) 2002-2013, were included. AKI was defined and classified according to the KDIGO Clinical Practice Guidelines for AKI. Data were prospectively collected and reports of kidney biopsies obtained from records.

Results: Among 1,153 cART-treated patients, 13 experienced AKI KDIGO stage 2 to 3 (1 patient stage 2, 12 patients stage 3; median age 46 years; 9 male; median CD4 count 366 cells/μl), corresponding to an incidence rate of AKI of 0.77 (95% confidence interval 0.45-1.33) per 1000 patient-years. Baseline estimated glomerular filtration rate (eGFR) was 87 ml/min (interquartile range 66-100). Ten patients were treated with tenofovir (TDF). Nine patients (69%) had ≥1 cardiovascular risk factor, only two patients had known pre-existing kidney disease. Three patients needed chronic and two temporary dialysis. AKI was associated with TDF therapy in 6 of 13 (46%) patients (mean TDF exposure time before AKI 41 months). Impaired renal function was partially reversible in all patients. In three patients with biopsy-proven pre-existing kidney disease (AA amyloidosis, calcineurin inhibitor-induced nephropathy and minimal change glomerulopathy), TDF potentially added to AKI.

Conclusions: AKI KDIGO stage 2 to 3 demonstrates complex associations at the individual level and can occur without early signs. Although treatment with TDF and presence of cardiovascular risk factors were found frequently, predicting AKI seems very difficult.
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http://dx.doi.org/10.4414/smw.2015.14135DOI Listing
January 2016

Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation and Association With Occurrence and Outcome of Invasive Aspergillosis.

J Infect Dis 2015 Sep 6;212(6):959-67. Epub 2015 Mar 6.

Infection Biology Laboratory, Department of Biomedicine Division of Infectious Diseases and Hospital Epidemiology, Department of Clinical Research.

Background: Invasive aspergillosis (IA) remains a leading cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To date, no reliable immunological biomarkers for management and outcome of IA exist. Here, we investigated reconstitution of antifungal immunity in patients during the first 12 months after HSCT and correlated it with IA.

Methods: Fifty-one patients were included, 9 with probable/proven IA. We determined quantitative and qualitative reconstitution of polymorphonuclear (PMN), CD4, CD8, and natural killer (NK) cells against Aspergillus fumigatus over 5 time points and compared the values to healthy donors.

Results: Absolute CD4 and CD8 cell counts, antigen-specific T-cell responses, and killing capacity of PMN against A. fumigatus were significantly decreased in all patients over 12 months. In patients with probable/proven IA, reactive oxygen species (ROS) production tended to be lower compared to patients without IA, and absolute NK-cell counts remained below 200 cells/µL. Patients with well-controlled IA showed significantly higher ROS production and NK-cell counts compared to patients with poor outcome.

Conclusions: This study highlights the importance of functional PMN, T-cell, and NK-cell immunity for the outcome of IA. Larger multicenter studies should address the potential use of NK-cell counts for the management of antifungal therapy.
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http://dx.doi.org/10.1093/infdis/jiv143DOI Listing
September 2015

AIDS defining opportunistic infections in patients with high CD4 counts in the combination antiretroviral therapy (cART) era: things ain't what they used to be.

J Int AIDS Soc 2014 2;17(4 Suppl 3):19621. Epub 2014 Nov 2.

Department of Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland.

Introduction: According to reports from observational databases, classic AIDS-defining opportunistic infections (ADOIs) occur in patients with CD4 counts above 500/µL on and off cART. Adjudication of these events is usually not performed. However, ADOIs are often used as endpoints, for example, in analyses on when to start cART.

Materials And Methods: In the database, Swiss HIV Cohort Study (SHCS) database, we identified 91 cases of ADOIs that occurred from 1996 onwards in patients with the nearest CD4 count >500/µL. Cases of tuberculosis and recurrent bacterial pneumonia were excluded as they also occur in non-immunocompromised patients. Chart review was performed in 82 cases, and in 50 cases we identified CD4 counts within six months before until one month after ADOI and had chart review material to allow an in-depth review. In these 50 cases, we assessed whether (1) the ADOI fulfilled the SHCS diagnostic criteria (www.shcs.ch), and (2) HIV infection with CD4 >500/µL was the main immune-compromising condition to cause the ADOI. Adjudication of cases was done by two experienced clinicians who had to agree on the interpretation.

Results: More than 13,000 participants were followed in SHCS in the period of interest. Twenty-four (48%) of the chart-reviewed 50 patients with ADOI and CD4 >500/µL had an HIV RNA <400 copies/mL at the time of ADOI. In the 50 cases, candida oesophagitis was the most frequent ADOI in 30 patients (60%) followed by pneumocystis pneumonia and chronic ulcerative HSV disease (Table 1). Overall chronic HIV infection with a CD4 count >500/µL was the likely explanation for the ADOI in only seven cases (14%). Other reasons (Table 1) were ADOIs occurring during primary HIV infection in 5 (10%) cases, unmasking IRIS in 1 (2%) case, chronic HIV infection with CD4 counts <500/µL near the ADOI in 13 (26%) cases, diagnosis not according to SHCS diagnostic criteria in 7 (14%) cases and most importantly other additional immune-compromising conditions such as immunosuppressive drugs in 14 (34%).

Conclusions: In patients with CD4 counts >500/ µL, chronic HIV infection is the cause of ADOIs in only a minority of cases. Other immuno-compromising conditions are more likely explanations in one-third of the patients, especially in cases of candida oesophagitis. ADOIs in HIV patients with high CD4 counts should be used as endpoints only with much caution in studies based on observational databases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224787PMC
http://dx.doi.org/10.7448/IAS.17.4.19621DOI Listing
January 2016

Surgical and antimicrobial treatment of prosthetic vascular graft infections at different surgical sites: a retrospective study of treatment outcomes.

PLoS One 2014 13;9(11):e112947. Epub 2014 Nov 13.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland; Department of Clinical Research, University Hospital Basel, Basel, Switzerland.

Objective: Little is known about optimal management of prosthetic vascular graft infections, which are a rare but serious complication associated with graft implants. The goal of this study was to compare and characterize these infections with respect to the location of the graft and to identify factors associated with outcome.

Methods: This was a retrospective study over more than a decade at a tertiary care university hospital that has an established multidisciplinary approach to treating graft infections. Cases of possible prosthetic vascular graft infection were identified from the hospital's infectious diseases database and evaluated against strict diagnostic criteria. Patients were divided into groups according to the locations of their grafts: thoracic-aortic, abdominal-aortic, or peripheral-arterial. Statistical analyses included evaluation of patient and infection characteristics, time to treatment failure, and factors associated specifically with cure rates in aortic graft infections. The primary endpoint was cure at one year after diagnosis of the infection.

Results: Characterization of graft infections according to the graft location did show that these infections differ in terms of their characteristics and that the prognosis for treatment seems to be influenced by the location of the infection. Cure rate and all-cause mortality at one year were 87.5% and 12.5% in 24 patients with thoracic-aortic graft infections, 37.0% and 55.6% in 27 patients with abdominal-aortic graft infections, and 70.0% and 30.0% in 10 patients with peripheral-arterial graft infections. In uni- and multivariate analysis, the type of surgical intervention used in managing infections (graft retention versus graft replacement) did not affect primary outcome, whereas a rifampicin-based antimicrobial regimen was associated with a higher cure rate.

Conclusions: We recommend that future prospective studies differentiate prosthetic vascular graft infections according to the location of the grafts and that rifampicin-based antimicrobial regimens be evaluated in clinical trials involving vascular graft infections caused by staphylococci.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112947PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231097PMC
December 2015

Does HIV antiretroviral therapy still need its backbone?

Lancet 2014 Nov 4;384(9958):1908-10. Epub 2014 Aug 4.

Departments of Medicine and Clinical Research, Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel 4031, Switzerland.

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http://dx.doi.org/10.1016/S0140-6736(14)61226-5DOI Listing
November 2014

[Psychosocial aspects on the treatment of HIV-infection].

Ther Umsch 2014 Aug;71(8):509-13

Klinik für Infektiologie und Spitalhygiene, Universitätsspital Basel.

Psychological and social factors have a deep impact on the treatment of HIV-infection, from the readiness to start antiretroviral therapy to treatment adherence over time. Among psychological factors, anxiety may affect HIV-infected persons in all stages of disease, from the disclosure of HIV diagnosis to the decision to start and maintain treatment. This is a lifelong challenge for both patients and doctors. Psychiatric comorbidities (depression, addiction) may enhance negative psychological effects of HIV. Among social factors, stigma and discrimination may occur in families and at work, leading to a loss of social support resulting in isolation and poverty. This may prevent HIV-positive individuals from seeking medical care. These aspects are particularly important in some groups of patients as injecting drug users and migrants. Acknowledgment and consideration of psychosocial factors are therefore essential for the long term success of antiretroviral therapy.
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http://dx.doi.org/10.1024/0040-5930/a000545DOI Listing
August 2014

[Treatment and prevention of opportunistic infections].

Ther Umsch 2014 Aug;71(8):475-82

Universitätsklinik für Infektiologie, Inselspital Bern.

Incidence as well as morbidity and mortality of opportunistic infections (OI) have declined remarkably since the availability of antiretroviral treatment (ART). Nearly half of all persons infected with HIV however do not know their HIV-status, and the diagnosis of an OI may be the first manifestation of their HIV infection. Therefore, knowledge of the presentation of OIs as well as their management should remain an essential part of clinicians' expertise. After starting ART the immune system will improve; in this context OI may be unmasked or the clinical presentation of known OI may worsen. Before starting ART therefore, it is essential to rule out any asymptomatic or latent OI. For the same reason, in the case of a known OI, the start of ART must often be deferred for some weeks after the start of OI treatment. Treatment of OIs is complex and often results in a large pill-burden for the patient with the potential for multiple drug-drug-interactions, particularly once ART has to be started. Many of the OI treatments are also associated with frequent drug side-effects and allergies. OIs can be prevented with specific antimicrobial agents once the CD4 have decreased below a defined threshold. However, the main prevention of OI is the timely recognition of HIV infection and an early start of ART before complications of OI appear.
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http://dx.doi.org/10.1024/0040-5930/a000540DOI Listing
August 2014

Is switching to an oral antibiotic regimen safe after 2 weeks of intravenous treatment for primary bacterial vertebral osteomyelitis?

BMC Infect Dis 2014 Apr 27;14:226. Epub 2014 Apr 27.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital, Petersgraben 4, Basel 4031, Switzerland.

Background: Vertebral osteomyelitis (VO) may lead to disabling neurologic complications. Little evidence exists on optimal antibiotic management.

Methods: All patients with primary, non-implant VO, admitted from 2000-2010 were retrospectively analyzed. Patients with endocarditis, immunodeficiency, vertebral implants and surgical site infection following spine surgery were excluded. Persistence of clinical or laboratory signs of inflammation at 1 year were defined as treatment failure. Logistic regression was used to estimate the odds ratios (OR) of switch to an oral regimen after 2 weeks.

Results: Median antibiotic treatment was 8.1 weeks in 61 identified patients. Switch to oral antibiotics was performed in 72% of patients after a median intravenous therapy of 2.7 weeks. Switch to oral therapy was already performed after two weeks in 34% of the patients. A lower CRP at 2 weeks was the only independent predictor for switch to oral therapy (OR 0.7, 95% confidence interval 0.5-0.9, p = 0.041, per 10 mg/l increase). Staphylococcus aureus was the most frequently isolated microorganism (21%). Indications for surgery, other than biopsy, included debridement with drainage of epidural or paravertebral abscess (26 patients; 42%), and CT-guided drainage (3 patients).During the follow-up, no recurrences were observed but 2 patients died of other reasons than VO, i.e. the 1 year intention to treat success rate was 97%.

Conclusions: Cure rates for non-implant VO were very high with partly short intravenous and overall antibiotic therapy. Switching to an oral antibiotic regimen after two weeks intravenous treatment may be safe, provided that CRP has decreased and epidural or paravertebral abscesses of significant size have been drained.
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http://dx.doi.org/10.1186/1471-2334-14-226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012835PMC
April 2014

Gastrointestinal bleeding associated with rivaroxaban administration in a treated patient infected with human immunodeficiency virus.

Swiss Med Wkly 2014 Jan 22;144:w13906. Epub 2014 Jan 22.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Switzerland.

The use of rivaroxaban in fixed dosing regimens without need for routine coagulation monitoring may lead to the misconception that there is a minimal risk of drug-drug interactions. We describe the case of a patient infected with human immunodeficiency virus (HIV) on salvage therapy who developed gastrointestinal bleeding while receiving the standard dose of rivaroxaban for the prevention of venous thromboembolism after surgery. This case clearly sends a warning that protease inhibitors should not be co-administered with rivaroxaban. Furthermore, it highlights the importance of clinicians' caution about potential drug-drug interactions.
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http://dx.doi.org/10.4414/smw.2014.13906DOI Listing
January 2014
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