Publications by authors named "Joaquín Burgos"

46 Publications

An overview of cilastatin + imipenem + relebactam as a therapeutic option for hospital-acquired and ventilator-associated bacterial pneumonia: evidence to date.

Expert Opin Pharmacother 2021 Jul 12:1-11. Epub 2021 Jul 12.

Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

: Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are prevalent nosocomial infections with a worrisomely increasing prevalence of multidrug-resistant causative organisms, including those with resistance to carbapenems. The addition of relebactam, a β-lactamase inhibitor, to imipenem treatment restores the antimicrobial activity against the most of multidrug-resistant Gram-negative bacteria, including some carrying β-lactamase enzyme-type carbapenemases.: The aim of this article is to summarize the current evidence regarding imipenem/relebactam for the treatment of HAP/VAP. The authors discuss its chemistry, pharmacokinetics/pharmacodynamics, microbiology, tolerance and clinical efficacy. The results of clinical trials have demonstrated an efficacy of imipenem/relebactam similar to that of its comparator for the treatment of patients with HAP/VAP. Different studies have also shown its good safety profile, which is better than that of the combination of other β-lactams with other antibiotics.: This drug should be incorporated as a new therapeutic option for the treatment of patients with HAP/VAP, especially as an alternative treatment in patients with confirmed infections caused by multidrug-resistant Gram-negatives.
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http://dx.doi.org/10.1080/14656566.2021.1939680DOI Listing
July 2021

Peripheral and lung resident memory T cell responses against SARS-CoV-2.

Nat Commun 2021 05 21;12(1):3010. Epub 2021 May 21.

Infectious Diseases Department, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

Resident memory T cells (T) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, T are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7 T cells secreting IL-10. In convalescent patients, lung-T are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting T cells as important for future protection against SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41467-021-23333-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140108PMC
May 2021

Investigational and Experimental Drugs for Community-Acquired Pneumonia: the Current Evidence.

J Exp Pharmacol 2020 19;12:529-538. Epub 2020 Nov 19.

Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain.

Community-acquired pneumonia (CAP) is a common infection with a constantly evolving etiological spectrum. This changing etiology conditions the adequate selection of optimal therapeutic regimens, both in empirical and definitive treatments. In recent years, new antimicrobials have been approved by regulatory authorities for use in CAP, although it is necessary to continue incorporating new antimicrobial agents that improve the activity profile in relation to the appearance of bacterial resistance in certain pathogens, such as pneumococcus, or . Delafloxacin, omadacycline and lefamulin are the most recently approved antibiotics for CAP. These three antibiotics have shown non-inferiority to their comparators for the treatment of CAP with an excellent safety profile. However, in the 2019 ATS/IDSA guidelines, it has been considered that more information is needed to incorporate these new drugs into community-based treatment. New antimicrobials, such as solithromycin and nemonoxacin, are currently being studied in Phase III clinical trials. Both drugs have shown non-inferiority against the comparators and an acceptable safety profile; however, they have not yet been approved by the regulatory authorities. Several drugs are being tested in Phase I and II clinical trials. These include zabofloxacin, aravofloxacin, nafithromycin, TP-271, gepotidacin, radezolid, delpazolid, and CAL02. The preliminary results of these clinical trials allow us to assure that most of these drugs may play a role in the future treatment of CAP.
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http://dx.doi.org/10.2147/JEP.S259286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682597PMC
November 2020

Voriconazole and tamsulosin: A clinically relevant drug- drug interaction.

Enferm Infecc Microbiol Clin (Engl Ed) 2020 Nov 4. Epub 2020 Nov 4.

Servicio de Farmacia, Hospital Universitari Vall d'Hebron, Barcelona, España.

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http://dx.doi.org/10.1016/j.eimc.2020.10.003DOI Listing
November 2020

Screening for asymptomatic STIs in HIV-infected men who have sex with men.

Sex Transm Infect 2021 03 4;97(2):170-171. Epub 2020 Aug 4.

Department of Infectious Diseases, Vall d'Hebron Hospital, Barcelona, Spain.

We aimed to study the prevalence, characteristics and risk factors of asymptomatic sexually transmitted infections (STIs) in HIV-infected men who have sex with men (MSM). We conducted a prospective cross-sectional study, including asymptomatic HIV-infected MSM attending regular visits between December 2014 and December 2017. Of the 301 patients included, 60 patients (19.9%) presented at least one STI. The most common STI was syphilis (33 of 69 STIs), followed by chlamydia (19 of 69), gonorrhoea (10 of 69), hepatitis C virus (4 of 69) and lymphogranuloma venereum (3 of 69). Illicit drug use during sex was the only variable significantly associated with the presence of an STI on multivariate analysis (OR 2.13; 95% CI 1.17-3.89). We were unable to identify a subgroup of patients where we could potentially avoid STI screening. Our findings support current guidelines that recommend routine screening for all HIV-infected MSM regardless of their self-reported sexual history.
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http://dx.doi.org/10.1136/sextrans-2020-054560DOI Listing
March 2021

Response to direct-acting antivirals for hepatitis C treatment in vertically HIV/HCV co-infected patients.

J Viral Hepat 2020 09 22;27(9):955-958. Epub 2020 May 22.

Hospital General Universitario Gregorio Marañón and Gregorio Marañón Research Institute (IiSGM), Madrid, Spain.

Direct-acting antivirals (DAAs) for HCV treatment have improved tolerance and efficacy among adults, but experience in vertical transmission is scarce. In our vertically HIV/HCV co-infected youth cohort of 58 patients, DAA achieved excellent rates of cure among naïve and pretreated individuals. Treating vertically infected seems important as 29.6% displayed advanced fibrosis at treatment initiation.
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http://dx.doi.org/10.1111/jvh.13308DOI Listing
September 2020

Lipidomics Reveals Reduced Inflammatory Lipid Species and Storage Lipids after Switching from EFV/FTC/TDF to RPV/FTC/TDF: A Randomized Open-Label Trial.

J Clin Med 2020 Apr 25;9(5). Epub 2020 Apr 25.

Internal Medicine Department. Complexo Hospitalario Universitario de Vigo; IIS Galicia Sur, 36312 Vigo, Spain.

HIV and antiretroviral therapy affect lipid metabolism. Lipidomics quantifies several individual species that are overlooked using conventional biochemical analyses, outperforming traditional risk equations. We aimed to compare the plasma lipidomic profile of HIV patients taking efavirenz (EFV) or rilpivirine (RPV). Patients ≥ 18 years old on EFV co-formulated with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) with HIV-RNA < 50 copies/mL for ≥6 months were randomized to continue EFV/FTC/TDF (n = 14) or switch to RPV/FTC/TDF (n =15). Lipidomic analyses conducted by mass spectrometry (MS) were performed at baseline and after 12 and 24 weeks. OWLiver Care and OWLiver tests were performed to estimate the presence of fatty liver disease (NAFLD). No significant differences (83% male, median age 44 years, 6 years receiving EFV/FTC/TDF, CD4 count 740 cells/mm, TC 207 [57 HDL-C/133 LDL-C] mg/dL, TG 117 mg/dL) were observed between the groups at baseline. Significant reductions in plasma lipids and lipoproteins but increased circulating bilirubin concentrations were observed in patients who switched to RPV/FTC/TDF. Patients on RPV/FTC/TDF showed a decrease in the global amount of storage lipids (-0.137 log [fold-change] EFV vs. 0.059 log [fold-change] RPV) but an increase in lysophosphatidylcholines (LPCs) and total steroids. Compared with EFV, RPV increased metabolites with anti-inflammatory properties and reduced the repository of specific lipotoxic lipids.
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http://dx.doi.org/10.3390/jcm9051246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288166PMC
April 2020

An overview of ceftolozane sulfate + tazobactam for treating hospital acquired pneumonia.

Expert Opin Pharmacother 2020 Jun 26;21(9):1005-1013. Epub 2020 Mar 26.

Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona , Barcelona, Spain.

Introduction: Ceftolozane-tazobactam is a combination of a new cephalosporin, with activity similar to that of ceftazidime, and a known inhibitor of beta-lactamases. This compound shows excellent activity against most gram-negative organisms causative of hospital-acquired pneumonia (HAP) or ventilator-acquired pneumonia (VAP), including extended spectrum beta-lactamase (ESBL)-producing Enterobacterales and multidrug-resistant (MDR) .

Areas Covered: This article reviews the spectrum of activity, the main pharmacokinetic and pharmacodynamic characteristics and the clinical efficacy and safety of ceftolozane-tazobactam in the treatment of HAP/VAP in adult patients.

Expert Opinion: The results of a randomized clinical trial have demonstrated an efficacy and safety profile of ceftolozane-tazobactam similar to that of its comparator for the treatment of patients with HAP/VAP. Several retrospective studies have shown good efficacy of the drug for the treatment of respiratory infections caused by MDR . The use of this drug may be incorporated as a new therapeutic option for the treatment of patients with HAP/VAP in a carbapenem-saving setting or as a therapeutic alternative with a better safety profile than other therapeutic options in patients with infections caused by MDR .
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http://dx.doi.org/10.1080/14656566.2020.1739269DOI Listing
June 2020

Incidence of malignancy in a Spanish cohort of patients infected by the human immunodeficiency virus.

Med Clin (Barc) 2020 10 28;155(7):288-294. Epub 2020 Jan 28.

Vall d'Hebron Institut de Recerca, Barcelona, España; Servicio de Enfermedades Infecciosas, Hospital Universitario Vall d'Hebron, Barcelona, España.

Introduction: A higher incidence of malignancies has been described in patients with HIV infection compared to the general population.

Patients And Methods: Observational retrospective study in patients with HIV infection followed up at the Vall d'Hebron University Hospital (Barcelona, Spain) between 2009 and 2017. The objective of this research was to estimate the incidence of malignancies in HIV patients and their surveillance. Age and sex-adjusted incidence was compared to the incidence calculated by the Spanish Cancer Registry network (REDECAN) in 2015.

Results: We included 2,773 patients (41,238 patients-year). Two hundred and eleven malignancies were diagnosed in 182 patients. Non-AIDS defining cancers accounted for 78.2% of the malignancies. The global incidence of cancer was 485 cases per 100,000 person-years. Twenty-year mortality rate was 31.2% in patients with cancer and 7.8% in patients without cancer. In men, adjusted for age, the incidence of malignancies was higher than the incidence in the general population (978.4 vs. 641 cases per 100,000 person-years, P<.001). The most common malignancies in men were lung cancer, Kaposi sarcoma and Hodgkin lymphoma. In women, the incidence of malignancies was not higher than in the general population (340.6 vs. 404.7 cases per 100,000 person-years, P=.27). The most common malignancies among women were lung cancer, head and neck cancer, cervical cancer and Hodgkin's lymphoma.

Conclusions: Men with HIV infection showed a statistically significant higher incidence of malignancies compared to the general Spanish population. Lung cancer was the most common non-AIDS defining cancer.
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http://dx.doi.org/10.1016/j.medcli.2019.12.001DOI Listing
October 2020

An overview of lefamulin for the treatment of community acquired bacterial pneumonia.

Expert Opin Pharmacother 2020 Apr 20;21(6):629-636. Epub 2020 Jan 20.

Infectious Diseases Department, University Hospital Vall d'Hebron, Autonomous University of Barcelona , Barcelona, Spain.

Introduction: Lefamulin is a novel antibiotic that belongs to the pleuromutilin class with excellent activity against all microorganisms, including atypical pathogens, that cause community-acquired pneumonia (CAP).

Areas Covered: This article reviews the spectrum of activity, the main pharmacokinetic and pharmacodynamic characteristics of lefamulin as well as its clinical efficacy and safety in the treatment of CAP in adult patients.

Expert Opinion: The clinical efficacy of lefamulin in patients with non severe CAP has been demonstrated in 2 randomized clinical trials. Precisely one of the limitations of the phase 3 trials is that the proportion of severe CAP cases is very low. Its particular mechanism of action, affecting ribosomal protein synthesis, provides a low probability of cross-resistance to other commonly used antibiotics in CAP. These findings, together with the antimicrobial activity of lefamulin, its pharmacokinetic parameters and safety profile make it a good alternative for outpatient treatment of CAP. In patients hospitalized with CAP, lefamulin can be used as a potential oral step-down agent after an intravenous regimen with beta-lactams, or as a therapeutic alternative in patients with β-lactam allergies.
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http://dx.doi.org/10.1080/14656566.2020.1714592DOI Listing
April 2020

A case report of long treatment with Itraconazole in a patient with chronic Chagas disease.

BMC Infect Dis 2019 Nov 9;19(1):956. Epub 2019 Nov 9.

Department of Infectious Diseases, Vall d'Hebrón, University Hospital, Pº Vall d'Hebrón 119-129, 08035, Barcelona, Spain.

Background: Current available treatments (benznidazole and nifurtimox) for Chagas disease (CD) show limited efficacy in chronic phase and frequent undesirable effects. Ergosterol synthesis inhibitors (ESI) had been considered as promising drugs for CD treatment and despite its recent poor results in several clinical trials, different strategies have been proposed to optimize its role in this infection.

Case Presentation: We present a case of chronic Chagas disease in patient diagnosed with HIV who received treatment for histoplasmosis with itraconazol during twelve months. Even though T. cruzi rt-PCR was persistently negative during treatment, when itraconazol was stopped she presented with a positive blood rt-PCR.

Conclusion: Several studies using different ESI had been published for CD treatment. Either in vitro or in vivo assays demonstrated activity against T. cruzi of the different triazole derivatives so different clinical trials had been carried out to evaluate its efficacy and safety. Despite contradictory evidence in the animal model, longer treatments along with other treatment strategies previously proposed suggests that ESI failure rates in positive peripheral blood rt-PCR are higher than that obtained with the current treatments of choice.
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http://dx.doi.org/10.1186/s12879-019-4608-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842451PMC
November 2019

Latency reversal agents affect differently the latent reservoir present in distinct CD4+ T subpopulations.

PLoS Pathog 2019 08 19;15(8):e1007991. Epub 2019 Aug 19.

Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

Latency reversal agents (LRAs) have proven to induce HIV-1 transcription in vivo but are ineffective at decreasing the size of the latent reservoir in antiretroviral treated patients. The capacity of the LRAs to perturb the viral reservoir present in distinct subpopulations of cells is currently unknown. Here, using a new RNA FISH/flow ex vivo viral reactivation assay, we performed a comprehensive assessment of the viral reactivation capacity of different families of LRAs, and their combinations, in different CD4+ T cell subsets. We observed that a median of 16.28% of the whole HIV-reservoir induced HIV-1 transcripts after viral reactivation, but only 10.10% of these HIV-1 RNA+ cells produced the viral protein p24. Moreover, none of the LRAs were powerful enough to reactivate HIV-1 transcription in all CD4+ T cell subpopulations. For instance, the combination of Romidepsin and Ingenol was identified as the best combination of drugs at increasing the proportion of HIV-1 RNA+ cells, in most, but not all, CD4+ T cell subsets. Importantly, memory stem cells were identified as highly resistant to HIV-1 reactivation, and only the combination of Panobinostat and Bryostatin-1 significantly increased the number of cells transcribing HIV within this subset. Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4+ T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.
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http://dx.doi.org/10.1371/journal.ppat.1007991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715238PMC
August 2019

Expression of CD20 after viral reactivation renders HIV-reservoir cells susceptible to Rituximab.

Nat Commun 2019 08 16;10(1):3705. Epub 2019 Aug 16.

Infectious Disease Department, Hospital Universitari Vall d'Hebrón, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

The identification of exclusive markers to target HIV-reservoir cells will represent a significant advance in the search for therapies to cure HIV. Here, we identify the B lymphocyte antigen CD20 as a marker for HIV-infected cells in vitro and in vivo. The CD20 molecule is dimly expressed in a subpopulation of CD4-positive (CD4) T lymphocytes from blood, with high levels of cell activation and heterogeneous memory phenotypes. In lymph node samples from infected patients, CD20 is present in productively HIV-infected cells, and ex vivo viral infection selectively upregulates the expression of CD20 during early infection. In samples from patients on antiretroviral therapy (ART) this subpopulation is significantly enriched in HIV transcripts, and the anti-CD20 monoclonal antibody Rituximab induces cell killing, which reduces the pool of HIV-expressing cells when combined with latency reversal agents. We provide a tool for targeting this active HIV-reservoir after viral reactivation in patients while on ART.
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http://dx.doi.org/10.1038/s41467-019-11556-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697690PMC
August 2019

Organizing pneumonia secondary to influenza infection: Two case reports and a literature review.

Enferm Infecc Microbiol Clin (Engl Ed) 2020 Mar 22;38(3):123-126. Epub 2019 May 22.

Infectious Diseases Department, University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

Background: Organizing pneumonia (OP) is a rare complication of influenza virus infection but scarce data are available. The recognition of this entity is important because require appropriate treatment.

Methods: We report two cases and perform a systematic review on PubMed database. Only cases with histological confirmation of OP and influenza virus positive laboratory test were included.

Results: We collected 16 patients. Median age was 52 year, 20% of patients were smokers and 43.8% had not any comorbidity. Influenza A virus infection was diagnosed in 75%. Clinical manifestation consisted on a respiratory deterioration with a median time of appearance of 14 days. Radiological pattern observed was ground-glass opacities with consolidations. Survival was observed in 12 patients (75%). All three patients who did not receive steroid treatment died.

Conclusion: Physicians must be aware that patients with influenza infection with a torpid course could be developing OP and prompt corticoid therapy should be instaured.
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http://dx.doi.org/10.1016/j.eimc.2019.04.006DOI Listing
March 2020

Effectiveness of Once/Day Dolutegravir Plus Boosted Darunavir as a Switch Strategy in Heavily Treated Patients with Human Immunodeficiency Virus.

Pharmacotherapy 2019 04 22;39(4):501-507. Epub 2019 Mar 22.

Infectious Diseases Department, Vall d'Hebron University Hospital, Barcelona, Spain.

Study Objective: Dual therapy with once/day dolutegravir (DTG) plus boosted darunavir (DRV/b) may be a suitable and effective strategy with a high genetic barrier to resistance in patients infected with human immunodeficiency virus (HIV). Our aim was to evaluate the effectiveness of DTG plus DRV/b (DTG+DRV/b) as a switch strategy in HIV-infected patients, irrespective of their history of virologic failure (VF).

Design: Multicenter retrospective cohort study.

Setting: Human immunodeficiency outpatient treatment clinics at three university hospitals in Spain.

Patients: Fifty HIV-infected adults who had a stable antiretroviral treatment (ART) regimen and an undetectable viral load for at least 6 months, and whose ART was switched to once/day DTG+DRV/b between January 2015 and January 2018 were included in the analysis. Historical genotype at the time of VF was available in 44 patients.

Measurements And Main Results: Patients were followed until VF or treatment discontinuation for any reason. The primary outcome was the percentage of patients with a viral load of 50 copies/mL or lower at the last follow-up visit. Secondary outcomes included changes in CD4 cell count, lipid profile, and renal function. Of the 50 patients included, median time of viral suppression was 52 months (interquartile range [IQR] 18-103 mo) and nadir CD4 89 cells/mm (IQR 37-241 cells/mm ). Patients had a history of a median of 8 ART combinations (IQR 4-11 combinations) and 3 VFs (IQR 2-8 VFs). The historical genotypes from 44 patients showed 41 patients (93.2%) with nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance-associated mutations (RAMs), 32 (72.7%) with nonnucleoside reverse transcriptase inhibitor (NNRTI) RAMs, and 12 (27.3%) with primary protease inhibitor (PI) RAMs; 7 (15.9%) had darunavir RAMs, and no patients had baseline integrase strand transfer inhibitor RAMs. Thirty-seven patients (84.1%) had resistance to at least two antiretroviral classes. After a median of 25 months (IQR 17-28 mo) of follow-up, 49 patients (98%) maintained a viral load of 50 copies/mL or lower, and 1 patient (2%) had VF. No new RAMs emerged at VF. At week 4, serum creatinine concentration increased a median of 0.12 mg/dl (0.03-0.23 mg/dl). At last visit, total cholesterol and low-density lipoprotein cholesterol levels increased by a median of 9 mg/dl (IQR -18 to 40 mg/dl) and 16 mg/dl (IQR -9 to 40 mg/dl), respectively, whereas CD4 cell count remained stable (median +13 cell/mm ).

Conclusion: In this cohort of heavily treated HIV-infected patients with virologic suppression, switching to the combination of DTG+DRV/b was a convenient regimen that was highly effective and had good tolerability.
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http://dx.doi.org/10.1002/phar.2227DOI Listing
April 2019

Chemical pharmacotherapy for hospital-acquired pneumonia in the elderly.

Expert Opin Pharmacother 2019 03 7;20(4):423-434. Epub 2019 Jan 7.

a Infectious Diseases Department , University Hospital Vall d'Hebron, Autonomous University of Barcelona , Barcelona , Spain.

Introduction: Hospital-acquired pneumonia (HAP) is a potentially serious infection that primarily affects older patients. The number of patients affected by multidrug-resistant (MDR) bacteria is increasing, including infection from strains of Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas aeruginosa.

Areas Covered: This article focuses specifically on HAP, excluding patients afflicted by ventilator-associated pneumonia (VAP). The pathogenesis and clinical features of HAP in the elderly are discussed as well as specific drug pharmacokinetic and pharmacodynamic considerations in elderly patients. The current recommended guidelines for the management of HAP are also discussed. Finally, the authors provide evidence on the empirical therapy used for the treatment of HAP and widely consider specific-pathogen treatment of HAP in elderly patients.

Expert Opinion: In patients not at risk of MDR organism infection, antibiotics including piperacillin-tazobactam, cefepime, carbapenems or fluorquinolones are recommended. However, the emergence of MDR organisms as causal agents of HAP makes it necessary to accurately assess risk factors to these pathogens and revise our knowledge on specific antimicrobial susceptibility patterns from each institution. The authors believe that broader-spectrum empiric antibiotic therapies that target P. aeruginosa and methicillin-resistant S. aureus are best recommended in elderly patients at risk of HAP infection by MDR strains.
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http://dx.doi.org/10.1080/14656566.2018.1559820DOI Listing
March 2019

Ceftobiprole medocaril for the treatment of community-acquired pneumonia.

Expert Opin Pharmacother 2018 Sep 10;19(13):1503-1509. Epub 2018 Sep 10.

a Infectious Diseases Department , University Hospital Vall d'Hebron. Autonomous University of Barcelona , Barcelona , Spain.

Introduction: Ceftobiprole is a novel broad-spectrum cephalosporin with excellent activity against a broad range of pathogens that are important in community-acquired pneumonia (CAP), including drug-resistant pneumococci, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa. Areas covered: This article reviews the spectrum of activity, the main pharmacological and pharmacodynamic characteristics of ceftobiprole as well its clinical efficacy and safety in the treatment of CAP in adult patients. Expert opinion: Taking into account that the current treatment guidelines for CAP recommend the use of an adequate empirical therapy to improve its prognosis, ceftobiprole shows a profile of antimicrobial activity that would cover most etiological agents in patients with risk factors for infection caused by multidrug resistant organisms. The results of the pivotal clinical trial of patients hospitalized with CAP treated with ceftobiprole showed a high rate of clinical cure. The clinical tolerance of ceftobiprole in clinical trials was generally very good. These findings make ceftobiprole a good parenteral therapeutic alternative for the empirical treatment of CAP that requires hospitalization, especially in patients with risk factors for CAP caused by resistant microorganisms.
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http://dx.doi.org/10.1080/14656566.2018.1516749DOI Listing
September 2018

Brief Report: Effectiveness of Trichloroacetic Acid vs. Electrocautery Ablation for the Treatment of Anal High-Grade Squamous Intraepithelial Lesion in HIV-Infected Patients.

J Acquir Immune Defic Syndr 2018 12;79(5):612-616

Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: Trichloroacetic acid (TCA) and electrocautery ablation (ECA) are 2 of the main treatment options for anal high-grade squamous intraepithelial lesion (HSIL). Our aim was to compare the efficacy and tolerance of TCA vs. ECA for HSIL.

Methods: Retrospective uncontrolled study of HIV-infected men who have sex with men who had an anal HSIL treated with TCA or ECA. On-treatment effectiveness was evaluated at 6-8 weeks after treatment. A complete response was defined as resolution of HSIL, a partial response as regression to low-grade lesion, and recurrence as biopsy-proven HSIL during follow-up. A propensity-score analysis was used to adjust efficacy to potential confounding.

Results: From May 2009 to March 2018, 182 and 56 cases of anal HSIL were treated with ECA and TCA, respectively. Comparing ECA with TCA, a complete response was observed in 33.5% (95% confidence interval: 25.8 to 41.6) vs. 60.7% (50.0 to 74.8) and a partial response in 28.0% (20.3 to 36.0) vs. 23.2% (12.5 to 37.3), respectively (P < 0.001). These differences were maintained in the propensity-score analyses. Side effects were common in both treatment, but tolerance was reported as good in 80.6% (74.2 to 89.2) and 82.6% (73.9 to 93.9) of cases treated with ECA and TCA, respectively, and no serious events were described. Recurrence cumulative incidence for the first 12 months was 14.6% (9.1 to 23.1) for ECA episodes and 27.6% (11.5 to 57.7) for TCA (P = 0.183).

Conclusions: Our study showed a higher efficacy of TCA than ECA with similar rates of side effects. In our opinion, considering the benefits of TCA, it should be considered as a first-line therapy for most anal HSIL management.
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http://dx.doi.org/10.1097/QAI.0000000000001847DOI Listing
December 2018

Usefulness of Sofia Pneumococcal FIA® test in comparison with BinaxNOW® Pneumococcal test in urine samples for the diagnosis of pneumococcal pneumonia.

Eur J Clin Microbiol Infect Dis 2018 Jul 13;37(7):1289-1295. Epub 2018 Apr 13.

Microbiology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

The Sofia Pneumococcal FIA® test is a recently introduced immunofluorescent assay automatically read aimed to detect Streptococcus pneumoniae antigen in urine. The aim of this study was to evaluate the usefulness of SofiaFIA® urinary antigen test (UAT) in comparison with classical immunochromatographic BinaxNOW® test for the diagnosis of pneumococcal pneumonia (PP). Observational study was conducted in the Hospital Universitari Vall d'Hebron from December 2015 to August 2016. Consecutive adult patients diagnosed of pneumonia and admitted to the emergency department in whom UAT was requested were prospectively enrolled. Paired pneumococcal UAT was performed (BinaxNOW® and SofiaFIA®) in urine samples. To assess the performance of both tests, patients were categorized into proven PP (isolation of S. pneumoniae in sterile fluid) or probable PP (isolation of S. pneumoniae in respiratory secretion). Sensitivity, specificity, and concordance were calculated. A total of 219 patients with pneumonia were enrolled, of whom 14% had a proven or probable PP, 22% a non-pneumococcal etiology, and 64% an unidentified pathogen. Concordance between tests was good (κ = 0.81). Sensitivity of SofiaFIA® and BinaxNOW® UAT was 78.6 and 50% for proven PP (p = 0.124), and 74.2 and 58% for proven/probable PP (p = 0.063). Specificity for both tests was 83.3 and 85.5% for proven and proven/probable PP. In patients without an identified pathogen, SofiaFIA® test was positive in 33 (23.6%) cases and BinaxNOW® in 25 (17.8%), so Sofia Pneumococcal FIA® detected 32.6% more cases than BinaxNOW® (p = 0.001). Sofia Pneumococcal FIA® test showed an improved sensitivity over visual reading of BinaxNOW® test without a noticeable loss of specificity.
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http://dx.doi.org/10.1007/s10096-018-3248-0DOI Listing
July 2018

Antiretroviral Therapy in Advanced HIV Disease: Which is the Best Regimen?

AIDS Rev 2018 Jan-Mar;20(1):3-13

Department of Infectious Diseases, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Advanced HIV disease, defined as a CD4 cell count below 200 cells/μl or the presence of an AIDS-defining illness, remains common among HIV-infected individuals who first present for medical care. In developed countries, nearly 30% of new HIV diagnoses occurred at advanced stages of the disease, and it is important because advanced HIV disease has been associated with worse clinical outcomes, including lower rates of virological response, higher morbidity, and higher mortality. However, there are scarce data regarding which is the best antiretroviral regimen in these patients. Nowadays, integrase inhibitor-based regimens are widely recommended as the best initial therapy for treatment-naïve HIV-infected patients by all international guidelines. However, these guidelines hardly mention the recommended regimens in individuals with advanced HIV disease. Otherwise, recent data indicating a higher risk of immune reconstitution inflammatory syndrome associated to the use of integrase inhibitors have raised concerns on the use of these drugs in patients with advanced HIV disease. The aim of this article is to review the available evidence from randomized clinical trials for the best treatment in patients with advanced HIV disease.
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October 2018

The role of oncogenic human papillomavirus determination for diagnosis of high-grade anal intraepithelial neoplasia in HIV-infected MSM.

AIDS 2017 10;31(16):2227-2233

aInfectious Diseases Department bAnatomical Pathology Department, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron cInternal Medicine Department, Hospital Universitari del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.

Objective: To assess the oncogenic human papillomavirus (HPV) determination and the cotesting HPV and anal cytology value to detect high-grade anal intraepithelial neoplasia (HGAIN) in a cohort of HIV-MSM.

Design And Methods: Prospective study of HIV-infected MSM who underwent screening for anal dysplasia. Screening program includes anal cytology, HPV testing, and high-resolution anoscopy (HRA) at each visit. Histological samples were obtained if suspicious lesions were revealed by HRA. Sensitivity and specificity of the different tests were calculated by using histological results of HRA-guided biopsy as the reference test for HGAIN diagnosis.

Results: From May 2009 to August 2016, 692 HIV-infected MSM underwent 1827 anal cytologies, 1841 HRA examinations, and 1607 HPV testing. At first screening visit, anal cytology results were abnormal in 418 (60.4%) of 692 patients, and oncogenic HPV genotypes were found in 482 (79.5%) of 606 patients. Anal cytology showed a sensitivity of 89.2% [95% confidence interval (CI); 80.7-94.2] and a specificity of 44.2% (95% CI; 40.2-48.2) to detect HGAIN. Oncogenic HPV testing had 90.4% sensitivity (95% CI; 82-86.8) and 24.4% specificity (95% CI; 20.8-28.3). Cotesting showed a 97.4% sensitivity (95% CI; 91-99.3) and 14% specificity (95% CI; 11.2-17.3). In patients with atypical squamous cells of uncertain significance on cytology, oncogenic HPV testing had 91.3% sensitivity and 28.3% specificity to detect HGAIN.

Conclusion: Abnormal cytology and oncogenic HPV determination showed similar sensitivity for detecting HGAIN. The two tests used together improved the sensitivity but with lowered specificity. In our opinion, HPV testing does not improve HGAIN detection and should not replace anal cytology as a standard screening test for HIV-infected MSM.
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http://dx.doi.org/10.1097/QAD.0000000000001605DOI Listing
October 2017

A Novel Single-Cell FISH-Flow Assay Identifies Effector Memory CD4 T cells as a Major Niche for HIV-1 Transcription in HIV-Infected Patients.

mBio 2017 07 11;8(4). Epub 2017 Jul 11.

Department of Infectious Diseases, Hospital Universitari Vall d'Hebrón, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain

Cells that actively transcribe HIV-1 have been defined as the "active viral reservoir" in HIV-infected individuals. However, important technical limitations have precluded the characterization of this specific viral reservoir during both treated and untreated HIV-1 infections. Here, we used a novel single-cell RNA fluorescence hybridization-flow cytometry (FISH-flow) assay that requires only 15 million unfractionated peripheral blood mononuclear cells (PBMCs) to characterize the specific cell subpopulations that transcribe HIV RNA in different subsets of CD4 T cells. In samples from treated and untreated HIV-infected patients, effector memory CD4 T cells were the main cell population supporting HIV RNA transcription. The number of cells expressing HIV correlated with the plasma viral load, intracellular HIV RNA, and proviral DNA quantified by conventional methods and inversely correlated with the CD4 T cell count and the CD4/CD8 ratio. We also found that after infection of unstimulated PBMCs, HIV-infected T cells upregulated the expression of CD32. In addition, this new methodology detected increased numbers of primary cells expressing viral transcripts and proteins after viral reactivation with latency reversal agents. This RNA FISH-flow technique allows the identification of the specific cell subpopulations that support viral transcription in HIV-1-infected individuals and has the potential to provide important information on the mechanisms of viral pathogenesis, HIV persistence, and viral reactivation. Persons infected with HIV-1 contain several cellular viral reservoirs that preclude the complete eradication of the viral infection. Using a novel methodology, we identified effector memory CD4 T cells, immune cells preferentially located in inflamed tissues with potent activity against pathogens, as the main cells encompassing the transcriptionally active HIV-1 reservoir in patients on antiretroviral therapy. Importantly, the identification of such cells provides us with an important target for new therapies designed to target the hidden virus and thus to eliminate the virus from the human body. In addition, because of its ability to identify cells forming part of the viral reservoir, the assay used in this study represents an important new tool in the field of HIV pathogenesis and viral persistence.
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http://dx.doi.org/10.1128/mBio.00876-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513707PMC
July 2017

Risk factors of high-grade anal intraepithelial neoplasia recurrence in HIV-infected MSM.

AIDS 2017 06;31(9):1245-1252

aInfectious Diseases Department bAnatomical Pathology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR) cInternal Medicine Department, Hospital Universitari del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.

Objective: To assess risk factors of high-grade anal intraepithelial neoplasia (HGAIN) recurrence in a cohort of HIV-infected MSM.

Design And Methods: Consecutive HIV-infected 100 MSM with a history of successfully treated intra-anal HGAIN with electrocautery were followed with anal cytology, human papillomavirus (HPV) determination, and high-resolution anoscopy (HRA) at 3-6-month intervals. HGAIN recurrence was analyzed using Kaplan-Meier analysis. Risk factors of recurrence were assessed using Cox proportional hazards regression. The value of different tests for detecting recurrence was also assessed.

Results: After a mean follow-up of 17.6 months, 39 of the 100 patients [39%, 95% confidence interval (CI): 29-49] developed recurrent HGAIN, 24 at the previously treated site, and 15 at a different site. The probability of recurrence was 23.5% at 12 months (95% CI: 13.9-33.1) and 53.3% at 24 months (95% CI: 34.3-72.7). Risk factors of recurrence were presence of hepatitis C antibodies (hazard ratio 2.79; 95% CI: 1.04-7.53), nadir CD4 cell count less than 200 cells/μl (hazard ratio 2.61; 95% CI: 1.06-6.44), and HGAIN lesions affecting at least two octants of anal circumference (hazard ratio 8.27; 95% CI: 1.1-62). Infection by at least two HPV oncogenic strains increased the risk of recurrence (hazard ratio 2.3; 95% CI: 0.98-5.42). HRA, anal cytology, and oncogenic HPV determination test showed a sensitivity of 100, 79.4, and 86.7%, and a specificity of 57.7, 36.6, and 34.7%, respectively, for detecting HGAIN recurrence.

Conclusion: The risk of HGAIN recurrence in HIV-infected MSM is high. Regular posttreatment follow-up of these patients is mandatory, and performing direct HRA appears to be the best strategy.
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http://dx.doi.org/10.1097/QAD.0000000000001433DOI Listing
June 2017

Acute leg ischaemia in an HIV-infected patient receiving antiretroviral treatment.

Antivir Ther 2017 22;22(1):89-90. Epub 2016 Aug 22.

Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

An HIV-infected patient treated with tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat developed severe acute ischaemia of both legs during a migraine episode. After being interrogated he admitted taking an ergotamine-containing preparation. Ergotism due to interaction between ergotics and cobicistat was diagnosed. We describe the first reported case of this interaction.
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http://dx.doi.org/10.3851/IMP3075DOI Listing
January 2018

[Early diagnosis of anal intraepithelial neoplasia associated with human papillomavirus. What is the best strategy?].

Enferm Infecc Microbiol Clin 2016 Aug-Sep;34(7):397-9

Servicio de Enfermedades Infecciosas, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, España; Vall d'Hebron Institut de Recerca, Barcelona, España. Electronic address:

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http://dx.doi.org/10.1016/j.eimc.2016.07.005DOI Listing
March 2018

Investigational drugs in phase I and phase II clincial trials for the treatment of hospital-acquired pneumonia.

Expert Opin Investig Drugs 2016 Jun 1;25(6):653-65. Epub 2016 Apr 1.

a Infectious Diseases Department, University Hospital Vall d'Hebron , Universitat Autònoma de Barcelona , Barcelona , Spain.

Introduction: Hospital acquired pneumonia (HAP) is one of the main infections acquired by patients during a stay in hospital. The main issue when dealing with patients with HAP and ventilator associated pneumonia (VAP) is the increasing role of multi-drug resistant organisms (MDROs).

Areas Covered: In this review the authors summarize the actual situation of MDROs as a cause of HAP and VAP. They also review the current treatment options stated in the most important international guidelines. Finally, they focus on the investigational drugs that have reached the phase III stage of development and the novel compounds that are being studied in phase I and II clinical trials.

Expert Opinion: Thanks to their excellent activity against MDROs, drugs in development for the treatment of HAP and VAP can significantly improve the therapeutic options available. In selected patients, the possibility to administer directed therapy with monoclonal antibodies to specific pathogens is an exciting strategy in the fight against widespread resistance.
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http://dx.doi.org/10.1517/13543784.2016.1168803DOI Listing
June 2016

Withdrawing inactive NRTIs in HIV-1 subjects with suppressed viraemia: a randomized trial.

J Antimicrob Chemother 2016 May 23;71(5):1346-51. Epub 2016 Jan 23.

HIV Unit and 'Lluita contra la SIDA' Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain Universitat de Vic (UVIC) - Universitat Central de Catalunya, Vic, Spain.

Background: Extensively pretreated subjects with virological failure (VF) may receive salvage regimens containing NRTIs with only residual or no activity. Once virological suppression is achieved, their contribution remains elusive.

Methods: This was a multicentre, randomized, prospective study. Subjects with at least one prior VF, HIV-1 RNA <50 copies/mL for ≥6 months and receiving a regimen with at least two active drugs (one of them a boosted PI) were randomized 1:1 to stop (experimental arm) or maintain (control arm) NRTIs. EudraCT: 2012-000198-21.

Results: Ninety subjects were randomized (experimental, n = 45; and control, n = 45). The mean age was 50 years, 80% were male, the mean CD4+ cell count was 542 cells/mm(3) and the median number of prior VFs was 3. Seventy-four subjects (82%) harboured the mutation M184V/I and the median number of thymidine-associated mutations was 3 (IQR: 0-4). In the experimental arm, thirty-two (71%) subjects removed one NRTI and 13 (29%) subjects removed two. Twenty-two of 45 (49%) discontinued tenofovir disoproxil fumarate. Forty-one of 45 (91.1%, experimental arm) and 44 of 45 (97.8%, control arm) had HIV-1 RNA <50 copies/mL at 48 weeks (difference: -6.7%; 95% CI: -17.4, 4.1). In a post-hoc analysis allowing NRTI reintroduction, efficacy rates were 95.6% and 97.8%, respectively (difference: -2.2%; 95% CI: -7.2, 2.7). Rates of discontinuation at 48 weeks were 2% in both arms. One subject developed a late VF with resistance selection.

Conclusions: In patients receiving a successful multidrug salvage regimen with at least two active drugs (one a boosted PI), the withdrawal of inactive NRTIs was safe, rates of VF were low and drug resistance was uncommon at 48 weeks in this small study. This strategy could potentially prevent long-term toxicities, reduce the number of drugs and reduce costs if non-inferiority was met in a fully powered trial.
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http://dx.doi.org/10.1093/jac/dkv461DOI Listing
May 2016

Impact of low-level viraemia on virological failure in HIV-1-infected patients with stable antiretroviral treatment.

Antivir Ther 2016 12;21(4):345-52. Epub 2016 Jan 12.

Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: Low-level viraemia (LLV) occurs in 20-40% of patients achieving viral suppression with antiretroviral therapy (ART). The risk of virological failure (VF: confirmed HIV RNA >200 copies/ml) in these patients is still a matter of debate.

Methods: This is a prospective cohort study in HIV-infected adults attending the HIV clinic of a tertiary care hospital in Spain. Patients with HIV RNA <25 copies/ml and stable ART for at least 6 months presenting LLV (defined as HIV RNA between 25-1,000 copies/ml) from January 2011 to January 2013 were included and followed until VF or end of follow-up in June 2014.

Results: A total of 300 out of 1,733 (17.3%) patients with undetectable viraemia for 4.2 years showed LLV: 25-50 copies/ml in 167 (55.7%) patients, 51-200 copies/ml in 111 (37%) and 201-1,000 copies/ml in 22 (7.3%) cases. After a median follow-up of 2.6 years, 23 (7.7%) patients presented VF. No patient with a single or multiple unconfirmed LLV went on to develop VF. HIV RNA >200 copies/ml (HR 59.6; 95% CI 15.7, 227), ritonavir-boosted protease inhibtor (PI/r)-based dual therapy (HR 10.2; 95% CI 2.1, 49.8) and PI/r monotherapy (HR 7.9; 95% CI 1.4, 43.3) were associated with VF. Persistent LLV, defined as HIV RNA <200 copies/ml in at least three consecutive samples, for at least 12 weeks, was detected in 27 (1.6%) patients and 14 (51.9%) of those evolved to VF.

Conclusions: Nearly one-fifth of patients on suppressive ART showed LLV and 8% of them developed VF. HIV RNA >200 copies/ml was the strongest predictor of VF. Over half of patients with persistent viraemia <200 copies/ml showed VF.
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http://dx.doi.org/10.3851/IMP3023DOI Listing
January 2018

Darunavir and ritonavir total and unbound plasmatic concentrations in HIV-HCV-coinfected patients with hepatic cirrhosis compared to those in HIV-monoinfected patients.

Antimicrob Agents Chemother 2015 Nov 17;59(11):6782-90. Epub 2015 Aug 17.

Hospital Vall d'Hebron, Infectious Diseases Department, Universitat Autònoma de Barcelona, Barcelona, Spain Institut de Recerca Vall d'Hebron, Barcelona, Spain.

Our objective was to describe the pharmacokinetic (PK) parameters of total and unbound darunavir and ritonavir concentrations in HIV-hepatitis C virus (HCV)-coinfected patients with cirrhosis, as ritonavir-boosted darunavir is mainly metabolized in the liver, and hepatic cirrhosis might modify darunavir-ritonavir concentrations. This was a prospective, case-control, and unicenter study. HIV-HCV-coinfected patients with compensated cirrhosis (cases) and HIV-monoinfected patients with normal liver function (controls) were included. Darunavir-ritonavir was given at 800/100 mg once daily. Patients were followed for 24 weeks to assess safety and efficacy. A steady-state 12-h PK study was performed. Total and unbound concentrations were determined by liquid chromatography-tandem mass spectrometry. The unbound fraction was obtained by ultrafiltration. The plasma area under the concentration-time curve (AUC) and oral clearance (CL/F) were assessed by noncompartmental models. Thirty patients (20 cases and 10 controls) were included. Among cirrhotic patients, the Child-Pugh score was C in 4 cases, B in 1 case, and A in 15 cases; the median (interquartile range) transient elastography values were 20 kPa (14 to 26 kPa), and 5 patients had prior clinical decompensations. There were no significant differences in the darunavir PK parameters between cases and controls except for longer time to maximum plasma concentrations (Tmax) and half-lives in the cirrhotic patients. There were no significant differences in ritonavir total concentrations, but the unbound concentrations were higher in cirrhotic patients. There were significant correlations between the darunavir total and unbound concentrations in both cirrhotic patients and controls. There were no differences in PK parameters based on Child-Pugh score, liver elasticity, gender, or use of concomitant medications. In conclusion, in HIV-HCV-coinfected patients with clinically compensated cirrhosis receiving darunavir-ritonavir at 800/100 mg once daily, the darunavir total and unbound concentrations are similar to those observed in noncirrhotic patients, and dose adjustments are not necessary.
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http://dx.doi.org/10.1128/AAC.01099-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604348PMC
November 2015

The problem of early mortality in pneumococcal pneumonia: a study of risk factors.

Eur Respir J 2015 Aug 28;46(2):561-4. Epub 2015 May 28.

Infectious Diseases Dept, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.1183/09031936.00034415DOI Listing
August 2015
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