HIV-Induced T-Cell Activation/Exhaustion in Rectal Mucosa Is Controlled Only Partially by Antiretroviral Treatment

Peripheral blood T-cells from untreated HIV-1-infected patients exhibit reduced immune responses, usually associated with a hyperactivated/exhausted phenotype compared to HAART treated patients. However, it is not clear whether HAART ameliorates this altered phenotype of T-cells in the gastrointestinal-associated lymphoid tissue (GALT), the main site for viral replication. Here, we compared T-cells from peripheral blood and GALT of two groups of chronically HIV-1-infected patients: untreated patients with active viral replication, and patients on suppressive HAART. We characterized the T-cell phenotype by measuring PD-1, CTLA-4, HLA-DR, CD25, Foxp3 and granzyme A expression by flow cytometry; mRNA expression of T-bet, GATA-3, ROR-γt and Foxp3, and was also evaluated in peripheral blood mononuclear cells and rectal lymphoid cells. In HIV-1+ patients, the frequency of PD-1+ and CTLA-4+ T-cells (both CD4+ and CD8+ T cells) was higher in the GALT than in the blood. The expression of PD-1 by T-cells from GALT was higher in HIV-1-infected subjects with active viral replication compared to controls. Moreover, the expression per cell of PD-1 and CTLA-4 in CD4+ T-cells from blood and GALT was positively correlated with viral load. HAART treatment decreased the expression of CTLA-4 in CD8+ T cells from blood and GALT to levels similar as those observed in controls. Frequency of Granzyme A+ CD8+ T-cells in both tissues was low in the untreated group, compared to controls and HAART-treated patients. Finally, a switch towards Treg polarization was found in untreated patients, in both tissues. Together, these findings suggest that chronic HIV-1 infection results in an activated/exhausted T-cell phenotype, despite T-cell polarization towards a regulatory profile; these alterations are more pronounced in the GALT compared to peripheral blood, and are only partiality modulated by HAART

Incident Tuberculosis during Antiretroviral Therapy Contributes to Suboptimal Immune Reconstitution in a Large Urban HIV Clinic in Sub-Saharan Africa

Antiretroviral therapy (ART) effectively decreases tuberculosis (TB) incidence long-term, but is associated with high TB incidence rates in the first 6 months. We sought to determine the incidence and the long-term effects of TB during ART on HIV treatment outcome, and the risk factors for incident TB during ART in a large urban HIV clinic in Uganda.Routinely collected longitudinal clinical data from all patients initiated on first-line ART was retrospectively analysed. 5,982 patients were included with a median baseline CD4+ T cell count (CD4 count) of 117 cells/mm(3) (interquartile range [IQR]; 42, 182). In the first 2 years, there were 336 (5.6%) incident TB events in 10,710 person-years (py) of follow-up (3.14 cases/100 pyar [95% CI 2.82-3.49]); incidence rates at 0-3, 3-6, 6-12 and 12-24 months were 11.25 (9.58-13.21), 6.27 (4.99-7.87), 2.47 (1.87-3.36) and 1.02 (0.80-1.31), respectively. Incident TB during ART was independently associated with baseline CD4 count of <50 cells/mm(3) (hazard ratio [HR] 1.84 [1.25-2.70], P = 0.002) and male gender (HR 1.68 [1.34-2.11], P<0.001). After two years on ART, the patients who had developed TB in the first 12 months had a significantly lower median CD4 count increase (184 cells/mm(3) [IQR; 107, 258, n = 118] vs 209 cells/mm(3) [124, 309, n = 2166], P = 0.01), a larger proportion of suboptimal immune reconstitution according to two definitions (increase in CD4 count <200 cells/mm(3): 57.4% vs 46.9%, P = 0.03, and absolute CD4 count <200 cells/mm(3): 30.4 vs 19.9%, P = 0.006), and a higher percentage of immunological failure according to the WHO criteria (13.6% vs 6.5%, P = 0.003). Incident TB during ART was independently associated with poor CD4 count recovery and fulfilling WHO immunological failure definitions.Incident TB during ART occurs most often within 3 months and in patients with CD4 counts less than 50 cells/mm(3). Incident TB during ART is associated with long-term impairment in immune recovery

Evaluation of antiretroviral therapy results in a resource-poor setting in Blantyre, Malawi.

Contains fulltext : 47457.pdf (publisher's version ) (Closed access)OBJECTIVE: To evaluate treatment results of the paying antiretroviral therapy (ART) clinic of Queen Elizabeth Central Hospital, a large public and teaching hospital in Blantyre, Malawi. The only ART was a fixed drug combination of stavudine, lamivudine and nevirapine. METHODS: Cross sectional study with interviews, laboratory tests (CD4 count, viral load, nevirapine plasma levels, transaminases) and data extraction from files. RESULTS: A total of 422 (59%) of the patients who started ART since 2000 were lost to follow-up. The 176 patients enrolled in the study had good virological and excellent clinical treatment results. The most common side effect was peripheral neuropathy. Nevirapine plasma levels were remarkably high and associated with successful virological treatment results. Two simple adherence questions pertaining to the use of medication in the previous 8 days corresponded well with nevirapine levels. The most important reasons for non-adherence were shortage of drugs in the hospital pharmacy and personal financial constraints. CONCLUSIONS: (1) Many patients were lost to follow-up. (2) High nevirapine levels contributed to good therapy results in those studied. (3) Simple adherence questions predicted subtherapeutic nevirapine levels. (4) Antiretroviral drug supply needs to be uninterrupted and free of charge, to prevent avoidable non-adherence

Broncoespasmo induzido pelo exercício em adolescentes asmáticos obesos e não-obesos Exercise-induced bronchospasm in obese and non-obese asthmatic adolescents

OBJETIVO: Avaliar e comparar a frequência e intensidade do broncoespasmo induzido pelo exercício (BIE) em adolescentes asmáticos obesos e não-obesos. MÉTODOS: Estudo transversal e descritivo realizado com 39 adolescentes de ambos os sexos, com idade entre dez e 16 anos, divididos em dois grupos conforme o histórico clínico de asma e/ou rinite alérgica e o índice de massa corporal: asmáticos obesos (n=18); asmáticos não-obesos (n=21). Utilizou-se o teste de broncoprovocação com exercício para a avaliação do BIE, considerando-se positiva uma diminuição do volume expiratório forçado no primeiro segundo (VEF1) >15% do valor pré-exercício. Para avaliar a intensidade e a recuperação do BIE, foram calculadas a queda percentual máxima do VEF1 (QM%VEF1) e a área acima da curva (AAC0-30). A análise estatística utilizou o teste exato de Fischer para comparar a frequência de BIE e o teste de Mann-Whitney para a intensidade e recuperação. Rejeitou-se a hipótese de nulidade se p<0,05. RESULTADOS: Não houve diferença significativa na frequência de BIE entre os grupos de asmáticos obesos (50%) e não-obesos (38%). Entretanto, a queda máxima do VEF1 e a AAC0-30 foram maiores nos asmáticos obesos em comparação aos não-obesos (respectivamente 37,7% e 455 versus 24,5% e 214, p<0,03). CONCLUSÕES: A obesidade não contribuiu para o aumento da frequência do BIE em asmáticos e não-asmáticos, entretanto, a obesidade contribuiu para o aumento da intensidade e do tempo de recuperação da crise de BIE em asmáticos<br>OBJECTIVE: To assess and compare the frequency and severity of exercise-induced bronchospasm (EIB) in obese and non-obese asthmatic adolescents. METHODS: Cross-sectional and descriptive study with 39 subjects aged ten to 16 years of both genders divided into two groups according to clinical history of asthma and/or allergic rhinitis and body mass index, as follows: asthmatic obese (n=18) and asthmatic non-obese (n=21). An exercise bronchoprovocation test was applied to diagnose EIB and was considered positive if the forced expiratory volume in one second (FEV1) decreased >15% in relation to pre-exercise FEV1. Maximum percent of fall in FEV1 (MF%FEV1) and the area above the curve (AAC0-30) were calculated to evaluate the intensity and recovery of EIB. Fisher exact test was used to compare the frequency of EIB and Mann-Whitney test to compare the severity and recovery of EIB. Null hypothesis was rejected when p<0.05. RESULTS: No significant difference was found in the frequency of EIB between the asthmatic obese (50%) and non-obese (38%) adolescents. However, the MF%FEV1 and AAC0-30 were significantly higher in the asthmatic obese as compared to the asthmatic non-obese patients (respectively, 37.7% and 455 versus 24.5% e 214, p<0.03). CONCLUSIONS: Obesity did not contribute to the increase of the frequency of EIB in asthmatic and non-asthmatic patients. However, obesity contributed to the increase of severity and recovery time of EIB in asthmatic