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HCV infection poses a global health threat, with significant morbidity and mortality. This study examines HCV trends in a large Italian region from 2015 to 2022, considering demographic changes, evolving clinical profiles, treatment regimens and outcomes, including the impact of the COVID-19 pandemic. This multicentre retrospective study analysed demographics, clinical histories and risk factors in 6882 HCV patients. The study spanned before and after the direct-acting antiviral (DAA) era, and the COVID-19 period, focusing on treatment outcomes (SVR12, non-SVR12 and patients lost to follow-up). Statistical methods included ANOVA, multinomial logistic regression, Kruskal-Wallis test and chi-square analysis, and were conducted adhering to the intention-to-treat (ITT) principle. The cohort, mainly Italian males (average age 58.88), showed Genotype 1 dominance (56.6%) and a high SVR12 rate (97.5%). The pandemic increased follow-up losses, yet SVR12 rates remained stable, influenced by factors like age, gender, cirrhosis and comorbidities. Despite COVID-19 challenges, the region sustained high SVR12 rates in HCV care, emphasising the importance of sustained efforts in HCV care. Continuous screening and targeted interventions in high-risk populations are crucial for achieving WHO elimination targets. The study highlights the resilience of HCV care during the pandemic and provides insights for future public health strategies.
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Importance: Convalescent plasma (CP) has been generally unsuccessful in preventing worsening of respiratory failure or death in hospitalized patients with COVID-19 pneumonia. Objective: To evaluate the efficacy of CP plus standard therapy (ST) vs ST alone in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia. Design, Setting, and Participants: This prospective, open-label, randomized clinical trial enrolled (1:1 ratio) hospitalized patients with COVID-19 pneumonia to receive CP plus ST or ST alone between July 15 and December 8, 2020, at 27 clinical sites in Italy. Hospitalized adults with COVID-19 pneumonia and a partial pressure of oxygen-to-fraction of inspired oxygen (Pao2/Fio2) ratio between 350 and 200 mm Hg were eligible. Interventions: Patients in the experimental group received intravenous high-titer CP (≥1:160, by microneutralization test) plus ST. The volume of infused CP was 200 mL given from 1 to a maximum of 3 infusions. Patients in the control group received ST, represented by remdesivir, glucocorticoids, and low-molecular weight heparin, according to the Agenzia Italiana del Farmaco recommendations. Main Outcomes and Measures: The primary outcome was a composite of worsening respiratory failure (Pao2/Fio2 ratio <150 mm Hg) or death within 30 days from randomization. Results: Of the 487 randomized patients (241 to CP plus ST; 246 to ST alone), 312 (64.1%) were men; the median (IQR) age was 64 (54.0-74.0) years. The modified intention-to-treat population included 473 patients. The primary end point occurred in 59 of 231 patients (25.5%) treated with CP and ST and in 67 of 239 patients (28.0%) who received ST (odds ratio, 0.88; 95% CI, 0.59-1.33; P = .54). Adverse events occurred more frequently in the CP group (12 of 241 [5.0%]) compared with the control group (4 of 246 [1.6%]; P = .04). Conclusions and Relevance: In patients with moderate to severe COVID-19 pneumonia, high-titer anti-SARS-CoV-2 CP did not reduce the progression to severe respiratory failure or death within 30 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04716556.
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COVID-19/terapia , Mortalidade Hospitalar , Hospitalização , Imunização Passiva , Plasma , Insuficiência Respiratória , Idoso , COVID-19/complicações , COVID-19/mortalidade , Progressão da Doença , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Padrão de Cuidado , Soroterapia para COVID-19RESUMO
Persons living with HIV should remain on antiretroviral therapy (ART) indefinitely; however, a switch in the drug regimen is often necessary. In order to investigate if reasons for switching ART changed over time, we retrospectively analyzed reasons for switching and characteristics of switches among patients at Santa Maria Annunziata Hospital (OSMA), Florence area, Tuscany, Italy, over two periods (November 2012-October 2013 and November 2014-October 2015). The reasons for switching were classified as: simplification; virologic failure; occurrence of co-morbidities; and drug tolerability/toxicity issues. In period 1 (2012-2013), 18% patients changed their regimen vs. 13.5% in period 2 (2014-2015) (p = 0.019). Among reasons for switching, switches for simplification significantly increased from 41% in period 1 to 53% in period 2 (p = 0.004), with an increasing use of single tablet regimens (p = 0.002); no other statistically significant differences were found in other reasons for switching in periods 1 and 2. Characteristics of patients and of switches were analyzed and described. According to our data, the main reason for switching is now simplification, reflecting the recent changes in recommendations aimed to enhance adherence and quality of life, and to minimize, at the same time, drug toxicity and side effects.
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Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Infecções por HIV/tratamento farmacológico , Comprimidos/administração & dosagem , Carga Viral/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/psicologia , Humanos , Itália , Masculino , Qualidade de Vida , Estudos Retrospectivos , Comprimidos/efeitos adversos , Falha de Tratamento , Resultado do TratamentoAssuntos
Terapia Antirretroviral de Alta Atividade/métodos , Prescrições de Medicamentos/estatística & dados numéricos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Adulto , Distribuição por Idade , Idoso , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Estudos Retrospectivos , Distribuição por Sexo , Resposta Viral Sustentada , Adulto JovemRESUMO
BACKGROUND: We aimed to assess cancer incidence and mortality for all-causes and factors related to risk of death in an Italian cohort of HIV infected unselected patients as compared to the general population. METHODS: We conducted a retrospective (1986-2012) cohort study on 16 268 HIV infected patients enrolled in the MASTER cohort. The standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were computed using cancer incidence rates of Italian Cancer Registries and official national data for overall mortality. The risk factors for death from all causes were assessed using Poisson regression models. RESULTS: 1,195 cancer cases were diagnosed from 1986 to 2012: 700 AIDS-defining-cancers (ADCs) and 495 non-AIDS-defining-cancers (NADCs). ADC incidence was much higher than the Italian population (SIR = 30.8, 95% confidence interval 27.9-34.0) whereas NADC incidence was similar to the general population (SIR = 0.9, 95% CI 0.8-1.1). The SMR for all causes was 11.6 (11.1-12.0) in the period, and it decreased over time, mainly after 1996, up to 3.53 (2.5-4.8) in 2012. Male gender, year of enrolment before 1993, older age at enrolment, intravenous drug use, low CD4 cell count, AIDS event, cancer occurrence and the absence of antiretroviral therapy were all associated independently with risk of death. CONCLUSIONS: In HIV infected patients, ADC but not NADC incidence rates were higher than the general population. Although overall mortality in HIV infected subjects decreased over time, it is about three-fold higher than the general population at present.
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Infecções por HIV/epidemiologia , Neoplasias/mortalidade , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Incidência , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Abuso de Substâncias por Via Intravenosa/epidemiologia , Adulto JovemAssuntos
Complexo Mycobacterium avium/genética , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Tuberculose Pulmonar/diagnóstico , Idoso , Feminino , Genes Bacterianos , Humanos , Itália , Dados de Sequência Molecular , Complexo Mycobacterium avium/isolamento & purificação , Análise de Sequência de DNARESUMO
TLRs trigger innate immunity that recognizes conserved motifs of invading pathogens, resulting in cellular activation and release of inflammatory factors. The influence of TLR activation on resistance to HIV-1 infection has not been investigated in HIV-1 exposed seronegative (ESN) individuals. PBMCs isolated from heterosexually ESN individuals were stimulated with agonists specific for TLR3 (poly I:C), TLR4 (LPS), TLR7 (imiquimod), and TLR7/8 (ssRNA40). We evaluated expression of factors involved in TLR signaling cascades, production of downstream effector immune mediators, and TLR-expression in CD4+ and CD14+ cells. Results were compared with those obtained in healthy controls (HCs). ESN individuals showed: 1) comparable percentages of CD14+/TLR4+ and CD4+/TLR8+ CD14+/TLR8+ cells; 2) higher responsiveness to poly I:C, LPS, imiquimod, and ssRNA40 stimulation, associated with significantly increased production of IL-1beta, IL-6, TNF-alpha, and CCL3; 3) augmented expression of mRNA specific for other targets (CCL2, CSF3, CSF2, IL-1alpha, IL-8, IL-10, IL-12, cyclooxygenase 2) demonstrated by broader TLRs pathway expression analyses; and 4) increased MyD88/MyD88s(short) ratio, mainly following TLR7/8 stimulation. We also compared TLR-agonist-stimulated cytokine/chemokine production in CD14+ PBMCs and observed decreased IFN-beta production in ESN individuals compared with HCs upon TLR7/8-agonist stimulation. These data suggest that TLR stimulation in ESN individuals results in a more robust release of immunologic factors that can influence the induction of stronger adaptive antiviral immune responses and might represent a virus-exposure-induced innate immune protective phenotype against HIV-1.
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Infecções por HIV/imunologia , Soronegatividade para HIV/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Imunidade Adaptativa/imunologia , Aminoquinolinas/imunologia , Células Cultivadas , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Citocinas/genética , Citocinas/metabolismo , Citometria de Fluxo , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Imiquimode , Imunidade Inata/imunologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/imunologia , Poli I-C/imunologia , RNA Mensageiro/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/imunologia , Receptor 8 Toll-Like/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Tenofovir with full-dose didanosine has been associated with paradoxical CD4 + T cell decrease despite virological suppression. We investigated whether tenofovir plus didanosine at a weight-adjusted dosage could be responsible for such an effect, and factors associated with CD4 + T cell count evolution under this combination. METHODS: This was a prospective observational multicohort study (Italian MASTER and Spanish Hospital Carlos III HIV cohorts). Patients with HIV plasma viral load suppression for >/= 6 months who switched to an antiretroviral combination including tenofovir plus didanosine were studied, as long as virological success was maintained. CD4 + T cell count variations over time (slopes) were compared before and after switching to tenofovir plus didanosine using linear mixed models and segmented regression analysis. RESULTS: Annual time-weighted CD4 + T cell count slope did not change significantly after the prescription of tenofovir plus didanosine: it was 14 cells/mm(3) [95% confidence interval (CI) - 7 to 35] from month - 24 to month - 12, 12 cells/mm(3) (95% CI - 14 to 38) from month - 12 to the time of switching, 30 cells/mm(3) (95% CI 5-55) from switching to month + 12 and 15 cells/mm(3) (95% CI - 8 to 39) from month + 12 to month + 24 after switching to tenofovir plus didanosine. No significant change in the slope of the segment after the switch to tenofovir plus didanosine-containing regimens when compared with the segment preceding the intervention was found (CD4 + T cell count slope change: 24 cells/mm(3); 95% CI - 10 to 58). Similar results were obtained using CD4 + T cell percentage over total lymphocytes. The significant independent predictors of lower CD4 + T cell count slope were older age (P = 0.006), lower nadir CD4 + T cell count (P < 0.001) and positive hepatitis C virus antibody (P = 0.03). Moreover, reduced estimated creatinine clearance was an additional independent predictor of lower CD4 + T cell count slope (P = 0.02), but only after excluding nadir CD4 + T cell count. CONCLUSIONS: Tenofovir plus didanosine (weight-adjusted dosage) was not associated with paradoxical CD4 + T cell decrease in our patients maintaining undetectable HIV plasma viral load for a maximum of 24 months after switching. Several factors could explain variability in CD4 + T cell count evolution in these patients.
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Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/fisiologia , Didanosina/uso terapêutico , Infecções por HIV/sangue , HIV-1 , Organofosfonatos/uso terapêutico , Adenina/uso terapêutico , Adulto , Envelhecimento/fisiologia , Terapia Antirretroviral de Alta Atividade , Estudos de Coortes , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Caracteres Sexuais , Tenofovir , Resultado do Tratamento , Carga ViralRESUMO
Data from 197 patients for whom highly active antiretroviral therapy (HAART) failed, who started a new regimen chosen under the guide of resistance testing results interpreted by experts, were retrospectively studied, provided that at least 2 determinations of adherence and plasma drug concentrations were performed during the follow-up. Univariate and multivariable logistic regression analyses were conducted, using confirmed virologic response at week 24 as outcome measure (i.e., achievement of undetectable HIV plasma viral load at any time point before week 24 and its maintenance up to week 24). Suboptimal drug concentrations (odds ratio [OR]: 0.3; 95% confidence interval [CI] 0.2-0.7; p = 0.006) and suboptimal adherence (OR: 0.4; 95% CI 0.2-0.8; p = 0.014) were both negative independent predictors of sustained virologic response, while the use of boosted protease inhibitor-containing regimens resulted to be protective (OR: 2.4; 95% CI 1.1-5.3; p = 0.032).
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Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Cooperação do Paciente , Terapia de Salvação , Adulto , Fármacos Anti-HIV/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Carga ViralRESUMO
OBJECTIVE: To determine the impact of genotypic inhibitory quotient (GIQ) for lopinavir (LPV) in patients failing HAART with limited antiretroviral exposure. DESIGN: Retrospective analysis of a prospective trial. METHODS: Lopinavir GIQ was calculated as the ratio between the mean trough concentration (C(trough)) and the number of protease mutations using eight different HIV drug resistance mutation lists or algorithms. Early (by week 12) and confirmed (up to week 24) virological response (HIV-RNA< 400 copies/mL, ECVR) was used as dependent variable in logistic regression model. RESULTS: Seventy-one of 109 (65%) patients achieved ECVR. At multivariable logistic regression analysis, each mug/mL increase of GIQ was correlated with increasing probability of ECVR as far as the following mutations were computed: multi-protease inhibitor (PI) associated mutations listed by IAS (OR=1.17; 95% CI=0.99-1.39; P=0.058), mutations associated with LPV resistance by ANRS algorithm (OR=1.21; 95% CI=1.02-1.44; P=0.03), major mutations associated with LPV resistance by Stanford database (OR=1.16; 95% CI=1-1.35; P=0.05), and the whole set of mutations associated with LPV resistance in the same database (OR=1.22; 95% CI=1.02-1.46; P=0.03). Using ROC curve method, a specific threshold GIQ was assessed, above which this parameter could predict ECVR with the highest sensitivity (74.6% with GIQ obtained through Stanford LPV mutations) or specificity (89.5% with GIQ obtained through ANRS LPV mutations). CONCLUSIONS: Our results suggest that increasing GIQ can improve virological outcome even in patients with limited exposure to PIs. Further studies are necessary to understand what HIV protease mutations should be considered and whether such mutations should be weighted differently to improve LPV GIQ predictive value.
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Farmacorresistência Viral/genética , Inibidores da Protease de HIV/farmacocinética , Protease de HIV/genética , HIV-1/efeitos dos fármacos , Pirimidinonas/farmacocinética , Adulto , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Protease de HIV/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/genética , Humanos , Modelos Logísticos , Lopinavir , Masculino , Valor Preditivo dos Testes , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , RNA Viral/sangue , Terapia de SalvaçãoRESUMO
OBJECTIVE: This retrospective longitudinal cohort study compared the virological and immunological responses to highly active antiretroviral therapy containing either efavirenz or lopinavir/ritonavir in previously antiretroviral-naive HIV-infected patients. PATIENTS AND METHODS: A total of 472 patients were selected (348 efavirenz and 124 lopinavir/ritonavir). The primary endpoint of this study was virological success (HIV RNA <50 copies/mL). The immunological response was assessed on the basis of either CD4+ T cell count variations (absolute and percentage) with respect to baseline values or categorical endpoints (defined as either a CD4+ T cell increase of > or =1;50 cells/mm(3) at week 24 or of > or =1;75 cells/mm(3) at week 48). RESULTS: At intention-to-treat (ITT) analysis, the adjusted odds ratio of virological success for patients who started lopinavir/ritonavir, compared with those who started efavirenz, was 0.54 (95% CI: 0.33-0.89, P = 0.016) at week 24 and 0.40 (95% CI: 0.33-0.89, P = 0.002) at week 48. However, patients receiving lopinavir/ritonavir had a more pronounced CD4+ T cell recovery, demonstrating both a mean absolute and percentage increase up to week 48 (MANOVA P < 0.0001). CONCLUSIONS: Although comparisons of drug efficacy in non-randomized studies should be viewed with caution, from a virological point of view efavirenz-containing regimens performed as well (on-treatment analysis) or better (ITT analysis) than those containing lopinavir/ritonavir. In contrast, immunological outcome appeared to favour lopinavir/ritonavir.
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Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Soropositividade para HIV/tratamento farmacológico , Oxazinas/uso terapêutico , Pirimidinonas/administração & dosagem , Ritonavir/administração & dosagem , Adulto , Alcinos , Benzoxazinas , Contagem de Linfócito CD4 , Estudos de Coortes , Ciclopropanos , Quimioterapia Combinada , Feminino , Seguimentos , Soropositividade para HIV/imunologia , Humanos , Estudos Longitudinais , Lopinavir , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Repeated exposure to HIV is not always associated with infection and multiple cohorts of HIV-exposed but seronegative individuals (ESN) have been described. HIV-specific CD4 and CD8 T lymphocytes are detected both in HIV patients and in ESN; we verified whether different patterns of HIV-specific memory T lymphocytes would be detected in individuals in whom exposure to HIV results or does not result in infection. METHODS: Gag-specific T cells were analysed in 15 ESN, 14 HIV patients, and 15 healthy controls using extensive flow cytometry analysis. RESULTS: Data confirmed that gag-specific T lymphocytes are present in ESN. Gag-specific T cells mainly secrete interleukin-2 in ESN and interferon-gamma in HIV patients. In addition the CD4/CD8 and the memory/naive ratios are altered, central memory (45RA-/CCR7+) CD4 and CD8 T lymphocytes are more abundant, and terminally differentiated (45RA+/CCR7- and 27-/28-) CD8 T lymphocytes are augmented in ESN individuals. CONCLUSIONS: Exposure to HIV occurs in high risk seronegative individuals; the observation that naive cells and CM are skewed in ESN indicate that this exposure is robust enough to modulate the CM/EM ratio. The increase in late effectors and in natural killer cells seen in ESN suggests a role for these cells in preventing actual infection.
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Soronegatividade para HIV/imunologia , Soropositividade para HIV/imunologia , HIV , Linfócitos T/imunologia , Adulto , Relação CD4-CD8 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Proteína do Núcleo p24 do HIV/análise , Humanos , Memória Imunológica , Interferon gama/metabolismo , Interleucina-2/metabolismo , Contagem de Linfócitos , MasculinoRESUMO
A total of 347 pol gene sequences from 88 Tuscan and 259 Apulian subjects (including 52 non-Italians and 9 children) were analyzed phylogenetically. Forty-four (12.6%) non-B subtypes were found, including 3.4% C, 1.4% F1, 0.8% G, and 0.3% each for J and A pure subtypes, and 3.7% CRF02_AG, 1.4% CRF01_AE, 0.6% BF, and 0.3% CRF06-cpx recombinant forms. An additional sample close-matched the pol gene of an unique recombinant form (URF AGK 99GR303). The non-B subtypes were from 40 adults and 4 children; 12 of these 44 patients were epidemiologically linked. Thirty-three of the 44 non-B viruses pertained to non-Italian immigrants and 11 to Italians, signifying that 63.4% immigrants and 3.7% Italians harbored non-B subtypes. The overall frequency of non-B subtypes was higher in Tuscany than in Apulia (18.1% vs. 10.8%). Moreover, 6.1% and 3.0% non-B subtypes were found among Italians from Florence and Apulia, respectively, while 52.1% and 72.4% of immigrants living in Tuscany and Apulia harbored non-B subtypes. Women infected by means of sexual contact prevailed among non-Italian adults; the majority of Italians were males and admitted high-risk sexual behavior. Four Italians had a history of extensive travel in countries of high endemicity. Social and epidemiological changes are responsible for an increasing circulation of non-B subtypes in Italy. Although non-B subtypes principally infect non-Italian patients, in Italy they can no longer be considered exclusively restricted to subjects from endemic areas.
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Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/classificação , Filogenia , Recombinação Genética , Adolescente , Adulto , Criança , Pré-Escolar , Emigração e Imigração , Feminino , Produtos do Gene pol/genética , HIV-1/genética , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Análise de Sequência de DNAAssuntos
HIV-1/efeitos dos fármacos , HIV-1/genética , Inibidores da Transcriptase Reversa/farmacologia , Substituição de Aminoácidos , Estudos de Coortes , Farmacorresistência Viral/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/enzimologia , Humanos , Técnicas In Vitro , Fenótipo , Polimorfismo Genético , Estudos ProspectivosRESUMO
Human alpha defensins 1, 2, and 3 are produced by CD8 T cells of HIV-infected long-term nonprogressors and have an antiviral activity. alpha Defensins were examined in peripheral blood mononuclear cells (PBMCs), cervical-vaginal mononuclear cells (CVMCs), and cervical biopsies of 9 HIV-1-exposed but uninfected women (ESNs), 10 HIV-infected patients (HIV), and 13 low-risk healthy controls (HCs). Results showed that, whereas alpha defensin production and alpha defensin-expressing CD8 lymphocytes were comparable in ESNs and HIV patients, constitutive alpha defensin production by peripheral CD8 and CVMCs was augmented in ESNs compared with HCs (P = 0.001 and P = 0.058, respectively); alpha defensin mRNA was increased in PBMCs of ESNs; unstimulated, alpha defensin-expressing peripheral and mucosal CD8 lymphocytes were 10-fold higher in ESNs compared with HCs (P = 0.003 and P = 0.01, respectively); and alpha defensin mRNA and alpha defensin-expressing cells were augmented in cervical biopsies of ESN compared with HCs (mRNA:P = 0.03). The differences were reduced upon in vitro mitogen stimulation. A robust constitutive production of alpha defensin is seen in HIV-exposed uninfected individuals; these peptides could have a role in the potentially protective immune response that characterizes ESNs.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Soropositividade para HIV/imunologia , alfa-Defensinas/análise , Biópsia , Células Cultivadas , Colo do Útero/imunologia , Colo do Útero/patologia , Características da Família , Feminino , Citometria de Fluxo , Soropositividade para HIV/patologia , Heterossexualidade , Humanos , Imuno-Histoquímica , Leucócitos Mononucleares/imunologia , Masculino , Mucosa/imunologia , RNA Mensageiro/análise , RNA Mensageiro/genética , Vagina/imunologia , alfa-Defensinas/genéticaRESUMO
We compared 2 rules-based genotype interpretation systems and real or virtual phenotype through a retrospective analysis of a prospective trial. Genotypes were determined with VircoGEN II (VIRCO) and were interpreted with either RetroGram 1.4 or TRUGENE HIV-1 (guidelines 3.0) or original virtual phenotype (Virtual Phenotype; VIRCO), as available in the year 2000. Among 188 human immunodeficiency virus (HIV) type 1 isolates, overall concordance (kappa agreement) was observed for the 2 rules-based systems, whereas striking discordances were noted between them and real and virtual phenotype interpretations for stavudine, didanosine, zalcitabine, abacavir, and amprenavir (kappa<0.4). Clinical evaluation of a subset of 173 patients showed that both rules-based sensitivity scores were independently associated with HIV RNA loads <400 copies/mL at week 16 of during-treatment analysis (TRUGENE: odds ratio [OR], 2.90; 95% confidence interval [CI], 1.52-5.52; P=.001; RetroGram: OR, 2.34; 95% CI, 1.21-4.55; P=.012), whereas, in contrast to real or virtual phenotype, interpretations according to biological cut-offs were not (OR, 1.91; 95% CI, 0.77-4.76; P=.162).
Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Terapia de Salvação , Adulto , Farmacorresistência Viral , Feminino , Genes Virais/genética , Genótipo , Humanos , Masculino , Razão de Chances , Fenótipo , Fatores de Risco , Resultado do TratamentoRESUMO
We compared viroimmunologic response after real phenotype (r-PHT) versus virtual phenotype (v-PHT) in patients failing highly active antiretroviral therapy (HAART). A total of 201 patients with >2 years of exposure, more than six experienced drugs, >1000 HIV RNA copies/mL, and on stable HAART for >6 months were randomized to the r-PHT or v-PHT arm. The primary end point was the proportion of HIV plasma viral load (pVL) <400 copies/mL. Secondary end points were absolute pVL change, proportion of pVL reduction >0.5 log(10) copies/mL, and absolute CD4 cell change. In the intention-to-treat-last observation carried forward analysis, study outcomes were not significantly different between arms over 48 weeks of follow-up: 20% and 24% pVL <400 copies/mL; 58% and 61% pVL reduction >0.5 log(10) copies/mL; -0.92 and -0.94(10) log copies/mL mean pVL decrease; and +41.6 and +94.4 cells/mm(3) mean absolute CD4 increase in the r-PHT and v-PHT arms, respectively. On-treatment analyses gave similar results. In the multivariate analysis of pVL <400 copies/mL, the following covariates were independent predictors at week 48: adherence (OR p= 0.25; p=.002), baseline CD4 (OR = 4.39; p=.007), intravenous drug use as risk factor for HIV acquisition (OR = 0.33; p=.024), and sensitivity score of the new regimens by biologic cut-offs (OR = 1.84; p=.029). Prescribed drugs for which patients were naive resulted in marginal prediction (OR = 1.93; p=.054). In conclusion, virologic and immunologic outcomes did not differ when r-PHT or v-PHT was used in this cohort of heavily pretreated patients. Several factors should be considered to take better advantage of resistance testing, including treatment history, clinical status, and patients' ability to adhere to treatment.