ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo characterize immune phenotype and thymic function in HIV-1-infected adults with excellent virologic and poor immunologic responses to highly active antiretroviral therapy (HAART).MethodsCross-sectional study of patients with CD4 T cell rises of ⩾ 200 × 106cells/l (CD4 responders; n = 10) or < 100 × 106cells/l (poor responders; n = 12) in the first year of therapy.ResultsPoor responders were older than CD4 responders (46 versus 38 years;P< 0.01) and, before HAART, had higher CD4 cell counts (170 versus 35 × 106cells/l;P= 0.11) and CD8 cell counts (780 versus 536 × 106cells/l; P= 0.02). After a median of 160 weeks of therapy, CD4 responders had more circulating naive phenotype (CD45+CD62L+) CD4 cells (227 versus 44 × 106cells/l; P= 0.001) and naive phenotype CD8 cells (487 versus 174 × 106cells/l; P =0.004) than did poor responders (after 130 weeks). Computed tomographic scans showed minimal thymic tissue in 11/12 poor responders and abundant tissue in 7/10 responders (P =0.006). Poor responders had fewer CD4 cells containing T cell receptor excision circles (TREC) compared with CD4 responders (2.12 versus 27.5 × 106cells/l; P =0.004) and had shorter telomeres in CD4 cells (3.8 versus 5.3 kb; P= 0.05). Metabolic labeling studies with deuterated glucose indicated that the lower frequency of TREC-containing lymphocytes in poor responders was not caused by accelerated proliferation kinetics.ConclusionPoor CD4 T cell increases observed in some patients with good virologic response to HAART may be caused by failure of thymic T cell production.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundThe adult human thymus contributes tode novoT cell synthesis; such synthesis can be assessed by analyzing T cell receptor excision circles (TREC).MethodsTREC levels were measured in total peripheral blood mononuclear cells (PBMC) and CD4- and CD8-enriched cells of 29 HIV-positive patients with maximal viral suppression. The expression of CD45RA+CD45RO−, CD45RA+CD62L+, CD45RO−CD27+CD95low and HLA-DR+CD38+ was assessed using three-color flow cytometric analysis of whole blood. Thymic index score was based on computed tomographic scans of the thymus. The relationship of TREC with thymic index and the expression of the naive phenotypes was evaluated.ResultsTREC expression was not statistically different in these HIV-positive patients from that in age-matched HIV-negative controls. Among HIV-positive patients with CD4 cell count of > 500 × 106cells/l after antiretroviral therapy (n = 15), PBMC TREC levels correlated with the expression of CD45RA+CD45RO− and CD45RA+CD62L+ naive phenotypes, and inversely correlated with the expression of HLA-DR+CD38+. The change between pre- and post-therapy CD4 cell counts for these 15 patients significantly correlated with both thymic index and expression of the CD45RA+CD45RO− phenotype.ConclusionsThe finding that TREC expression was equivalent between HIV-positive patients after therapy and HIV-negative donors suggests that there is no reduction in thymic output among HIV-positive individuals after therapy. Given that TREC is inversely correlated with HLA-DR/CD38 expression, its analysis in studies of thymopoiesis should be evaluated in the context of maximum viral suppression to reduce HIV-mediated immune activation and/or by normalizing for cell turnover.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Objective and designIn an attempt to determine the mechanisms underlying the CD4 T cell expansions in patients receiving intermittent interleukin (IL)-2, a cohort of 10 HIV infected patients were studied during a 5-day cycle of IL-2 to measure rates of apoptosis, the expression of activation markers in CD4 and CD8 T cell subsets and the serum levels of proinflammatory cytokines. All patients were receiving highly active antiretroviral therapy.MethodsPeripheral blood mononuclear cells were tested pre- and at the completion of IL-2 treatment with annexin V/7-AAD for the measurement of apoptosis. Phenotypic analyses of T lymphocytes were performed in parallel. Serum levels of interferon (IFN)γ, granulocyte–macrophage colony stimulating factor, IL-6 and tumor necrosis factor (TNF)α were tested by enzyme-linked immunosorbent assay.ResultsIL-2 increased the spontaneous apoptosis rates of CD4 and CD8 T lymphocytes (P= 0.003). Expression of HLA-DR, CD38 and CD95 increased on both CD4 and CD8 T lymphocytes whereas CD25 induction was observed exclusively on CD4 T cells. Significant increases of serum IL-6 and TNFα levels were noted in all patients whereas viral loads remained unchanged.ConclusionAdministration of IL-2 for 5 days in HIV infected patients leads to enhanced apoptosis of both CD4 and CD8 T cells despite an eventual increase of the CD4 T cell count. A profound activation state with induction of activation markers on T cells and high levels of TNFα and IL-6 accompanies the increased apoptosis during the IL-2 cycle. These data suggest that the CD4 expansions seen in the context of intermittent IL-2 therapy are the net result of increases in both cell proliferation and cell death.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo estimate the prevalence of resistance-conferring mutations to antiretroviral drugs in previously untreated patients with chronic HIV-1 infection as a basis for French recommendations on viral genotyping before antiretroviral treatment initiation.DesignResistance mutations were sought in samples from 404 patients seen in 23 specialized centres throughout metropolitan France in 1998.MethodsThe protease and reverse transcriptase (RT) genes of plasma virions were sequenced. Primary and secondary protease and RT gene mutations were identified from the International AIDS Society resistance testing – USA panel.ResultsThe prevalence of patients with primary and secondary mutations were 3.7% (95% CI 1.7–5.7) and 50.3% (95% CI 45.0–55.6), respectively. The prevalence of patients with mutations associated with resistance to nucleoside RT inhibitors (NRTI) and non-nucleoside RT inhibitors was 3.3% (95% CI 1.5–5.1) and 0.8% (95% CI 0.0–1.7), respectively. The prevalence of patients with NRTI primary mutations differed according to whether seropositivity had been diagnosed more or less than one year previously (0.2 versus 2.2%P= 0.023). Primary mutations associated with protease inhibitor resistance occurred at a prevalence of 1.9% (95% CI 0.5–3.4) with no difference according to the duration of known seropositivity.ConclusionIn France, in 1998, the prevalence of patients with primary mutations associated with resistance to antiretroviral drugs was low. Genotyping before the initiation of therapy was not recommended in chronically HIV-1-infected naive patients. A national sentinel survey of resistance in this clinical setting is performed regularly to update the recommendations for resistance testing.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundThe role combination therapy with interferon alfa-2b and tribavirin (US: ribavirin) plays in producing sustained virological responses in patients with HIV and chronic hepatitis C (HCV) infection is still unknown.ObjectivesTo determine the feasibility and sustained response of interferon alfa-2b and tribavirin combination therapy.DesignPhase II study.MethodsSeventeen patients were enrolled at the National Cancer Institute, Aviano, Italy and received combination therapy with interferon alfa-2b 3 MIU subcutaneously three times a week plus tribavirin 1000–1200 mg/day for 24 weeks. Antiretroviral therapy was concomitantly given in all but one patient.ResultsAt the end of treatment, five (31%) patients achieved clearance of HCV RNA and 11 (69%) showed normalized liver function enzyme levels. In three patients, serum HCV RNA concentration was still undetectable 24 weeks after treatment, with an overall sustained virological response rate of 19% The serum liver enzymes were still normal in 10 patients 24 weeks after treatment, the overall sustained biochemical response rate being 62% All patients with HCV RNA clearance at the end of treatment and 24 weeks after treatment had a concomitant biochemical response. Overall the combination treatment was well tolerated.ConclusionsOur data confirm that the combination of interferon alfa-2b and tribavirin is well tolerated and feasible in patients with HIV–HCV co-infection and it can be associated safely with highly active antiretroviral therapy. The sustained response achieved with the drug combination does not seem to be any better than that achieved with 12 months of monotherapy with interferon alfa-2b.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo investigate the effect of cerebrospinal fluid (CSF) of HIV-1-seropositive patients with and without HIV-1-associated dementia complex (HADC) on the intracellular Ca2+regulation of cultured cortical astrocytes.DesignIn a blinded study the effects of CSF samples from HADC patients and from HIV-1-seropositive but not demented patients on intracellular Ca2+regulation of cultured cortical astrocytes were investigated. Astrocytes were chosen because they contribute to both electrophysiological and immunological processes within the brain.MethodsAstrocytes were incubated in CSF samples for 1 h, loaded with the Ca2+indicator dye Fura-2 and intracellular Ca2+responses upon glutamate application were measured.ResultsCSF samples from 10 out of 11 HADC patients induced a significant reduction of the intracellular Ca2+increase upon glutamate application. On the contrary, seven out of 10 CSF samples from HIV-1-seropositive patients without HADC as well as 10 out of 10 CSF samples from HIV-1-seronegative controls did not affect the intracellular Ca2+response.ConclusionsOur data strongly confirm the hypothesis that CSF samples of HADC patients contain soluble factors which interfere with the function of astrocytes. These factors may include HIV-1 proteins, locally released cytokines or neurotoxins.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo compare the response to protease inhibitor (PI) and efavirenz-containing combination therapy among treatment-naive HIV-infected persons.DesignProspective observational cohort study.MethodsResponse to treatment was analysed according to the intent-to-treat principle among antiretroviral-naive patients who started either efavirenz (n = 89) or PI (n = 183) plus two nucleoside reverse transcriptase inhibitors between February 1999 and March 2000 using Kaplan–Meier and multivariable Cox proportional hazard regression methods. Primary endpoint was time to undetectable plasma viral load. Secondary endpoints included the number of CD4 cells gained, virological rebound, treatment change, and clinical progression.ResultsPatients on PI regimens had lower median CD4 counts (165 versus 216 ×5 106/l;P= 0.15) and were more likely to have AIDS at initiation of treatment (25% versus 15%P= 0.048) than patients starting efavirenz regimens. The probability of reaching plasma HIV-1 RNA < 400 copies/ml was higher with efavirenz- than with PI-containing regimens [adjusted hazard ratio, 1.75; 95% confidence interval (CI), 1.34–2.29]. Median times to undetectable viral load were 58 days (95% CI, 44–70 days) for efavirenz-treated and 88 days (95% CI, 79–98 days) for PI-treated patients. The median number of CD4 cells gained in the first 6 months (90 × 106cells/l with efavirenz, 107 × 106cells/l with PI;P= 0.63), time to and reasons for treatment change, time to viral rebound, drug intolerance and clinical progression rates were similar in the two treatment groups.ConclusionsTreatment with efavirenz-, compared with PI-based regimens, appeared to result in a superior virological response but no difference in immunological or clinical efficacy. The relevance of these observations remains to be determined in studies with longer follow-up.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo determine whether the peripheral fat wasting (lipodystrophy), which is seen in association with highly active antiretroviral therapy (HAART) that includes a nucleoside reverse transcriptase inhibitor (NRTI), is associated with a decrease in subcutaneous adipose tissue mitochondrial DNA (mtDNA) content or with large mtDNA deletions or insertions.DesignA four cohort cross-sectional study.MethodsThe mtDNA content of subcutaneous fat tissue from the neck, abdomen and thigh was determined by polymerase chain reaction utilizing the amplification of three different mtDNA fragments. The results from HIV-infected patients with peripheral fat wasting following more than 6 months of NRTI-containing HAART were compared with the results from three different control cohorts: HIV-infected patients with a similar treatment history without lipodystrophy; HIV-infected patients naive to antiretroviral therapy and HIV sero-negative participants.ResultsA decrease in mtDNA content was found in HAART-treated HIV-infected patients with peripheral fat wasting in comparison with subjects in the control cohorts. No large mitochondrial deletions or insertions were found.ConclusionsLipodystrophy with peripheral fat wasting following treatment with NRTI-containing HAART is associated with a decrease in subcutaneous adipose tissue mtDNA content.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundLipodystrophy, dyslipidaemia and insulin resistance often complicate protease inhibitor-containing antiretroviral therapy. The aims of this study were to determine if these are reversible with continued HIV suppression following protease inhibitor substitution.MethodsEighty-one HIV protease inhibitor recipients (78 male; mean antiretroviral therapy, 55 months) with predominant peripheral lipoatrophy, HIV RNA < 400 copies/ml plasma for at least the preceding 6 months, and no prior abacavir, non-nucleoside analogue or adefovir therapy were randomized 3 : 2 to continue nucleoside analogues and substitute protease inhibitor(s) with abacavir, nevirapine, adefovir and hydroxyurea (n = 49) or to continue all therapy (n = 32) with an option to switch at week 24. The primary endpoints were total body fat and HIV RNA at week 24. Other assessments were regimen safety, regional body composition, metabolic parameters, quality of life, and CD4 T-lymphocyte counts to week 48.ResultsThere was a greater decline in total body fat in the switch group than in the continue group (−1.6 and −0.4 kg, respectively at week 24;P= 0.006). This comprised greater declines in limb and subcutaneous abdominal fat, and in intra-abdominal fat of patients with moderate or severe abdominal fat accumulation. Viral suppression was similar, despite 18 (37%) switch group patients ceasing at least one study drug by week 24 because of adverse events. Total cholesterol and triglycerides declined more in the switch group (bothP< 0.002). High density lipoprotein cholesterol increased significantly in both groups at week 48 (P< 0.02). There was no change for any glycaemic parameter.ConclusionsIn predominantly lipoatrophic patients, switching from HIV protease inhibitor therapy lead to improved lipids and less intra-abdominal fat, but also to less peripheral fat, and had minimal effect on insulin resistance. Virological control in these heavily pretreated patients was unaffected, despite frequent switch drug cessations.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID