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1.
PLoS Pathog ; 15(8): e1007991, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31425551

RESUMO

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.

2.
Nat Commun ; 10(1): 3705, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420544

RESUMO

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.

3.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31126691

RESUMO

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.

4.
Pharmacotherapy ; 39(4): 501-507, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30723941

RESUMO

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/mm3 (IQR 37-241 cells/mm3 ). 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/mm3 ). 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.

5.
Expert Opin Pharmacother ; 20(4): 423-434, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30614744

RESUMO

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.


Assuntos
Antibacterianos/uso terapêutico , Pneumonia Associada a Assistência à Saúde/tratamento farmacológico , Idoso , Animais , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Fatores de Risco , Staphylococcus aureus/efeitos dos fármacos
6.
Expert Opin Pharmacother ; 19(13): 1503-1509, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30198789

RESUMO

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.


Assuntos
Cefalosporinas/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Pneumonia Bacteriana/tratamento farmacológico , Antibacterianos/uso terapêutico , Cefalosporinas/isolamento & purificação , Humanos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação
7.
J Acquir Immune Defic Syndr ; 79(5): 612-616, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30179983

RESUMO

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.

8.
Infection ; 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30003490

RESUMO

PURPOSE: To describe the demographic, clinical, and microbiological profile of native vertebral osteomyelitis (NVO) in aged patients as compared to that of younger patients, to identify differences that could motivate changes in clinical management. METHODS: Retrospective, observational cohort study (1990-2015) including all adult patients with microbiologically confirmed NVO divided into 2 groups: aged (≥ 65 years) vs younger (18-64 years). RESULTS: 247 patients included, 138 aged and 109 younger. Relative to younger patients, the aged had higher rates of healthcare-related infection (40.6 vs 25.7%, p = 0.014), previous known heart valve disease (29.7 vs 9.2%, p < 0.001), and concomitant infective endocarditis (38.4 vs 20.2%, p = 0.002). The groups showed similar rates of symptomatic spinal cord compression (14.5 vs 11.9%, p = 0.556) and paraspinal abscesses (62.3 vs 68.8%, p = 0.288) at presentation. There was a trend to lower spine surgery rates in the aged (11.6 vs 17.4%, p = 0.192). On univariate analysis, Staphylococcus aureus infection was associated with higher in-hospital mortality in aged (29%, OR 4.3, 95% CI 1.61-11.45). In-hospital mortality was higher among the aged (14.5 vs 6.4%, p = 0.044) as well as relapse rate due to treatment failure (3.4 vs 1%, p = 0.377). CONCLUSIONS: The findings underscore the importance of preventing healthcare-related infection and maintaining high clinical suspicion of infective endocarditis in aged NVO patients to implement proper management. S. aureus infection had a poorer prognosis in this population. As compared to younger patients, spinal surgery rates were slightly lower and overall prognosis poorer in the aged, despite similar rates of symptomatic spinal cord compression and abscesses at presentation.

9.
Clin Infect Dis ; 67(6): 958-961, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-29659759

RESUMO

We investigate whether the clinical presentations and outcomes of Legionella pneumonia in human immunodeficiency virus (HIV)-infected patients were comparable to those seen in non-HIV-infected patients (case-control design). HIV-infected individuals presented neither a more severe disease nor a worse clinical outcome than matched HIV-negative control patients.

10.
Eur J Clin Microbiol Infect Dis ; 37(7): 1289-1295, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29651615

RESUMO

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.


Assuntos
Antígenos de Bactérias/urina , Cromatografia de Afinidade/métodos , Imunofluorescência/métodos , Pneumonia Pneumocócica/diagnóstico , Polissacarídeos Bacterianos/urina , Idoso , Antígenos de Bactérias/imunologia , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/microbiologia , Feminino , Humanos , Masculino , Pneumonia Pneumocócica/microbiologia , Polissacarídeos Bacterianos/imunologia , Estudos Prospectivos , Sensibilidade e Especificidade , Streptococcus pneumoniae/imunologia
11.
AIDS Rev ; 20(1): 3-13, 2018 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29369304

RESUMO

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.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/efeitos adversos , Feminino , Infecções por HIV/complicações , Infecções por HIV/imunologia , Humanos , Síndrome Inflamatória da Reconstituição Imune/etiologia , Síndrome Inflamatória da Reconstituição Imune/prevenção & controle , Masculino
12.
Artigo em Inglês | MEDLINE | ID: mdl-28971876

RESUMO

The aim of the current study was to compare community-acquired acute pyelonephritis (CA-APN) with health care-associated acute pyelonephritis (HCA-APN), describe the outcomes, and identify variables that could predict antimicrobial susceptibility. We conducted an observational study that included all consecutive episodes of acute pyelonephritis (APN) in adults during 2014 at a Spanish university hospital. From each episode, demographic data, comorbidities, clinical presentation, microbiological data, antimicrobial therapy, and outcome were recorded. A multivariable logistic regression model was performed to define the variables associated with antimicrobial resistance. A total of 607 patients, 503 (82.9%) with CA-APN and 104 (17.1%) with HCA-APN, were included in the study. Patients with HCA-APN were older than patients with CA-APN (70.4 versus 50.6 years; P < 0.001) and had higher rates of previous urinary tract infections (UTIs) (56.5% versus 24.5%; P < 0.001) and previous antibiotic use (56.8% versus 22.8%; P < 0.001). Escherichia coli was more frequently isolated from patients with CA-APN than from patients with HCA-APN (79.9% versus 50.5%; P < 0.001). The rates of resistance of Escherichia coli strains from CA-APN patients versus HCA-APN patients were as follows: amoxicillin-clavulanic acid, 22.4% versus 53.2% (P = 0.001); cefuroxime, 7.7% versus 43.5% (P = 0.001); cefotaxime, 4.3% versus 32.6% (P < 0.001); ciprofloxacin, 22.8% versus 74.5% (P < 0.001); and co-trimoxazole, 34.5% versus 58.7% (P = 0.003). The site of acquisition, recurrent UTIs, and previous antibiotic use were independent risk factors for antimicrobial resistance. Relapse rates were significantly higher when definitive antimicrobial treatment was not adequate (37.1% versus 9.3% when definitive antimicrobial treatment was adequate; P < 0.001). Our study reflects the rise of resistance to commonly used antibiotics in acute pyelonephritis. In order to choose the adequate empirical antibiotic therapy, risk factors for resistance should be considered.


Assuntos
Antibacterianos/uso terapêutico , Infecção Hospitalar/tratamento farmacológico , Farmacorresistência Bacteriana , Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/efeitos dos fármacos , Pielonefrite/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Cefotaxima/uso terapêutico , Cefuroxima/uso terapêutico , Ciprofloxacino/uso terapêutico , Estudos de Coortes , Infecções Comunitárias Adquiridas , Infecção Hospitalar/microbiologia , Infecção Hospitalar/patologia , Pesquisa Empírica , Escherichia coli/crescimento & desenvolvimento , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Feminino , Hospitais Universitários , Humanos , Modelos Logísticos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Pielonefrite/microbiologia , Pielonefrite/patologia , Fatores de Risco , Espanha , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Infecções Urinárias/microbiologia , Infecções Urinárias/patologia
13.
Lancet HIV ; 4(12): e536-e546, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28729158

RESUMO

BACKGROUND: Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1. METHODS: The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to-treat exposed population). We used a non-inferiority margin of -12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402. FINDINGS: Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL (mean difference 10·5%, 95% CI 3·1-17·8, p=0·005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor-associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the dolutegravir group than the atazanavir group reported drug-related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications. INTERPRETATION: The non-inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV-1 infection in treatment-naive women. FUNDING: ViiV Healthcare.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Didesoxinucleosídeos/administração & dosagem , Emtricitabina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Lamivudina/administração & dosagem , Tenofovir/administração & dosagem , Adulto , Fármacos Anti-HIV/farmacologia , Didesoxinucleosídeos/farmacologia , Combinação de Medicamentos , Quimioterapia Combinada , Emtricitabina/farmacologia , Feminino , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Lamivudina/farmacologia , Pessoa de Meia-Idade , Tenofovir/farmacologia , Resultado do Tratamento
14.
MBio ; 8(4)2017 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-28698276

RESUMO

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 in situ 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 ex vivo 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 ex vivo 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.IMPORTANCE 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.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Citometria de Fluxo/métodos , Infecções por HIV/virologia , HIV-1/genética , Hibridização in Situ Fluorescente/métodos , Transcrição Genética , Adulto , Linfócitos T CD4-Positivos/ultraestrutura , Infecções por HIV/imunologia , HIV-1/imunologia , HIV-1/fisiologia , Humanos , Memória Imunológica , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Pessoa de Meia-Idade , RNA Viral/genética , Receptores de IgG/genética , Análise de Célula Única , Carga Viral , Latência Viral
15.
AIDS ; 31(16): 2227-2233, 2017 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-28723712

RESUMO

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.


Assuntos
Neoplasias do Ânus/diagnóstico , Testes Diagnósticos de Rotina/métodos , Infecções por HIV/complicações , Homossexualidade Masculina , Papillomaviridae/isolamento & purificação , Lesões Intraepiteliais Escamosas Cervicais/diagnóstico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade
17.
AIDS ; 31(9): 1245-1252, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28252530

RESUMO

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.


Assuntos
Neoplasias do Ânus/epidemiologia , Infecções por HIV/complicações , Homossexualidade Masculina , Lesões Intraepiteliais Escamosas Cervicais/epidemiologia , Adulto , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco
18.
Antivir Ther ; 22(1): 89-90, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27546463

RESUMO

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.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Cobicistat/efeitos adversos , Ergotamina/efeitos adversos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Isquemia/etiologia , Doença Aguda , Adulto , Fármacos Anti-HIV/administração & dosagem , Cobicistat/administração & dosagem , Interações de Medicamentos , Quimioterapia Combinada , Ergotamina/administração & dosagem , Humanos , Perna (Membro) , Masculino , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/tratamento farmacológico
19.
Expert Opin Investig Drugs ; 25(6): 653-65, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26998623

RESUMO

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.


Assuntos
Infecção Hospitalar/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Animais , Anticorpos Monoclonais/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Desenho de Drogas , Farmacorresistência Bacteriana Múltipla , Humanos , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Pneumonia Associada à Ventilação Mecânica/microbiologia , Guias de Prática Clínica como Assunto
20.
Antivir Ther ; 21(4): 345-52, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26756461

RESUMO

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.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1 , Viremia , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/sangue , Falha de Tratamento
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