ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To investigate the ability of granulocyte-macrophage colony-stimulating factor (GM–CSF) and IFN-α to induce the differentiation of peripheral monocytes into dendritic cells (DC) and their ability to trigger an HIV-specific CD8 T-cell response.Methods:Monocytes isolated from both seronegative controls and HIV-infected individuals were differentiated into DC using GM–CSF with either IL-4 or IFN-α for 7 days. We assessed the phenotypic characteristics and IL-12 production by flow cytometry. The ability of DC to trigger CD8 T-cell responses was assessed by means of ELISpot and cytotoxicity assays. In addition, HIV-1-RNA levels were measured in culture supernatants.Results:Compared with control DC generated in the presence of GM–CSF and IL-4, DC generated in the presence of GM–CSF and IFN-α expressed higher levels of MHC class I molecules and produced similar or higher levels of IL-12 after CD40 ligation orStaphyloccus aureus Cowanstimulation. GM–CSF/IFN-α DC expressed low levels of CD4, CXCR4 and DC-SIGN and did not produce detectable virus during the differentiation period. Pulsed GM–CSF/IFN-α DC were found to prime CD8 T cells from HIV-negative controls to exert cytotoxic activity against target cells expressing HIV antigens. HIV peptide-pulsed GM–CSF/IFN-α DC promote specific IFN-γ production by autologous CD8 T cells from HIV-seronegative donors. Furthermore, GM–CSF/IFN-α DC from HIV-seropositive patients efficiently present HIV peptides to autologous CD8 T lymphocytes.Conclusion:GM–CSF and IFN-α allow the generation of DC with high CD8 T-cell stimulating abilities. Therefore, this strategy may represent a novel approach to therapeutic vaccination in HIV disease.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To determine the rate of virological rebound and factors associated with rebound among patients on highly active antiretroviral therapy (HAART) with previously undetectable levels of viraemia.Design:An observational cohort study of 2444 patients from the EuroSIDA study.Methods:Patients were followed from their first viral load under 400 copies/ml to the first of two consecutive viral loads above 400 copies/ml. Incidence rates were calculated using person-years of follow-up (PYFU), Cox proportional hazards models were used to determine factors related to rebound.Results:Of 2444 patients, 1031 experienced virological rebound (42.2%). The incidence of rebound decreased over time; from 33.5 in the first 6 months after initial suppression to 8.6 per 100 PYFU at 2 years after initial suppression (P< 0.0001). The rate of rebound was lower for treatment-naive compared with treatment-experienced patients. In multivariate models, patients who changed treatment were more likely to rebound, as were patients with higher viral loads on starting HAART. Treatment-naive patients were less likely to rebound. Among pretreated patients, those who were started on new nucleosides were less likely to rebound.Conclusion:The rate of virological rebound decreased over time, suggesting that the greatest risk of treatment failure is in the months after initial suppression. Treatment-naive patients were at a lower risk of rebound, but among drug-experienced patients, those who added new nucleosides had a lower risk of rebound, as were patients with a good immunological response.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To determine the expressions of multiple genes in the subcutaneous adipose tissue of HIV-positive, highly active antiretroviral therapy (HAART)-treated patients with and without lipodystrophy.Design and methods:Real-time polymerase chain reaction was used to measure gene expressions in this cross-sectional study.Results:The messenger RNA concentrations of adipose transcription factors (peroxisome proliferator-activated receptor (PPAR) gamma and delta and sterol regulatory element binding protein 1c) were all significantly lower in the lipodystrophic than the non-lipodystrophic group. The mRNA concentration of PPAR-γ co-activator 1 (PGC-1), which regulates mitochondrial biogenesis, was lower in the lipodystrophic than the non-lipodystrophic group. The mRNA expression of lipoprotein lipase, acyl coenzyme A synthase and glucose transport protein 4 were significantly lower in the lipodystrophic than the non-lipodystrophic group, but the mRNA concentrations of fatty acid transport and binding proteins were similar in both groups. The mRNA concentrations of IL-6 and CD45 (a common leukocyte marker) were significantly higher in the lipodystrophic than the non-lipodystrophic group.Conclusion:Multiple alterations characterize gene expression in the subcutaneous adipose tissue of patients with HAART-associated lipodystrophy compared with HIV-positive, HAART-treated patients without lipodystrophy. The low expression of transcription factors inhibits adipocyte differentiation. The low expression of PGC-1 may contribute to mitochondrial defects. In addition, IL-6 and CD45 expressions are increased, the latter implying an excessive number of cells of leukocyte origin in lipodystrophic adipose tissue. Mitochondrial injury and an excess of proinflammatory cytokines may lead to increased apoptosis. All these changes may contribute to the loss of subcutaneous fat in HAART-associated lipodystrophy.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To investigate the patterns of intra-subject (between medication) adherence to antiretroviral therapy.Design:A prospective, observational, 3-month study of adherence to antiretroviral therapy at an inner-city clinic in 40 HIV-infected subjects.Methods:Adherence was monitored monthly by the use of medication event monitoring system (Aprex) caps placed on each antiretroviral drug in a subject's regimen. Agreement between different drug classes and dosing schedules, for each subject, was quantified by estimating the mean difference in adherence, with 95% limits of agreement. An analysis of variance model was used to estimate the variance of the differences. Individual dosing calendars were examined for each subject.Results:The dosing schedule was a strong predictor of intra-subject adherence. Regardless of the subject's overall adherence rate, high or low, when subjects missed a dose of one medication, they missed a dose of both medications taken at that dosing time. Conversely, when medications were scheduled to be taken together, regardless of the drug class, the medications were taken at the same times. The majority of the subjects took medications at obviously incorrect times. Problematical adherence was related to thrice-daily dosing and food restrictions.Conclusion:This is the first report objectively to quantify intra-subject adherence to antiretroviral therapy and report the findings in detail. We observed clear patterns of drug-taking behavior among the subjects in our study. To the extent that medication scheduling is a controllable factor, our report provides an insight into specific patterns of behavior that may be targets for adherence counseling.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:Antiretroviral prevention of mother to child HIV-1 is established but tolerance remains to be assessed.Aim:To determine the risk for persistent mitochondrial dysfunction in HIV-uninfected children born to seropositive mothers.Method:An exhaustive study in a large prospective cohort with predetermined algorithm of the unexplained symptoms compatible with mitochondrial dysfunction. A total of 2644 of 4392 children were exposed to antiretrovirals. Complementary investigations were carried out on a case-by-case basis using classification with a diagnostic probability scale, based on experience with constitutional diseases. A spontaneous notification register for children not included in the cohort was created.Results:Good circumstantial evidence of mitochondrial dysfunction was found for twelve children. Seven were from the cohort. All presented neurological symptoms, often associated with abnormal magnetic resonance image (10 of 12) and/or a significant episode of hyperlactatemia (seven of 12). All had either a profound deficit in one of the respiratory chain complexes (11 of 12) and/or a typical histological pattern (two of 12). All were perinatally exposed to antiretrovirals. None of them had perinatal morbidity that could explain this symptomatology. The 18-month incidence was 0.26% (95% confidence interval, 0.10–0.54) in exposed children, in comparison with the general figure of 0.01% for paediatric neuro-mitochondrial diseases in the general population. Fourteen other children in the cohort, all exposed to antiretrovirals, had unexplained symptoms, mostly neurological, for which one of the possible differential diagnoses was mitochondrial dysfunction. Close similarities in clinical, neuroradiological and histological findings strongly suggest a common pathological process in all these 26 children.Conclusion:Children exposed to nucleoside analogues during the perinatal period are at risk of a neurological syndrome associated with persistent mitochondrial dysfunction.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To determine the effects of highly active antiretroviral therapy (HAART) on survival in AIDS-related primary central nervous system lymphoma (PCNSL).Methods:Survival in consecutive patients with PCNSL at a large county teaching hospital from 1995 to 2001 were analyzed by the log rank test and Cox proportional hazards ratios (HR) were calculated for factors potentially affecting survival.Results:During the study period, 25 patients were diagnosed with PCNSL: 19 definite and 6 probable. At diagnosis, median CD4 cell count was 12 × 106cells/l (range 1–151) and median HIV viral load was 5.3 log10copies/ml (range 3.9–5.9). Sixteen patients died (median survival 87 days; range, 0 to > 2112). Longer survival was noted for patients who received HAART after diagnosis [HR for death, 0.06; 95% confidence interval (CI), 0.01–0.48]. Six of seven HAART-treated patients were alive versus 0/18 untreated patients at a median follow-up time of 667 days (P= 0.0007 by log rank test). A survival benefit was seen for patients who had ⩾ 0.5 log10copies/ml decrease in HIV viral load after diagnosis (n = 6; HR, 0.07; 95% CI, 0.01–0.55) and for patients with a significant CD4 cell rebound (increase ⩾ 50 × 106cells/l) in response to HAART (n = 6): all survived versus 0/19 survived (P= 0.0003). Cranial radiation therapy (n = 13) prolonged survival (HR, 0.20; 95% CI, 0.07–0.58). Median survival was only 29 days for 11 patients who received neither radiation nor HAART.Conclusions:Receipt of HAART after diagnosis is associated with a significantly longer survival in patients with AIDS-related CNS lymphoma.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To develop a stepwise methodology for the development and validation of clinically relevant genotypic score for resistance to antiretroviral drugs and to apply this approach to the genotypic resistance to abacavir.Methods:All patients having received abacavir during the Narval trial were included in this study. The impact of each nucleoside analogue resistance mutation on the virologic response to abacavir was studied in a univariate analysis. Mutations with aPvalue < 0.20 and those selected by abacavir were retained. According to the number of mutations three levels of resistance were defined. A multivariate analysis accounting for confonding variables assessed whether the genotypic score was an independent predictor of the response. The robustness of the score was analysed using the bootstrap resampling method.Results:In the 175 patients exposed to abacavir, the strongest association between the decrease in viral load and the number of mutations was observed with a set of six mutations at codons 41, 67, 210, 215, 74 and 184 of the reverse transcriptase gene. In patients with fewer than four mutations (no evidence of resistance) the median decrease in viral load was –1.64 log10copies/ml while it was –0.69 log10and –0.19 log10in those with four (possible resistance) and five or six (resistance) mutations respectively. In the multivariate analysis this score was an independent predictor of the response. The bootstrap analysis showed the robustness of the score.Conclusions:We developed a new strategy for the analysis of correlation between genotype profile at baseline and virologic response.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To determine mortality due to end-stage liver disease (ESLD) in a nationwide cohort of HIV-infected patients 5 years after the introduction of highly active antretroviral therapy (HAART) and to compare this with that observed before and during the early years of HAART.Designand methods: All departments of internal medicine and infectious diseases from the GERMIVIC Study Group prospectively recorded all deaths in HIV-infected patients during 2001. Sixty-five departments, following a total of 25 178 HIV-infected patients, participated in the study. Results were compared with those of previous surveys conducted using similar methodology in 1995 and 1997.Results:Among 265 deaths observed during 2001, 129 (48.7%) were related to AIDS, 38 (14.3%) to ESLD, and 98 (36.7%) to other causes. Mortality due to ESLD represented 28% of non AIDS-related deaths; 36 of the 38 patients (95%) dying from ESLD had chronic hepatitis C virus (HCV) infection. In 2001, deaths due to ESLD (14.3%) were significantly more frequent than in 1995 (1.5%;P< 0.01) and 1997 (6.6%;P< 0.01). During this interval, the prevalence of hepatocellular carcinoma as a cause of death increased (1995, 4.7%; 1997, 11%; 2001, 25%;P< 0.05), as did alcohol consumption (P< 0.01).Conclusions:In the post-HAART era, ESLD due to HCV is a growing cause of mortality in HIV-infected patients. Increased longevity attributable to HAART, and a higher prevalence of alcohol consumption, are probably involved in this trend.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:To estimate the prevalence rates of HIV and other sexually transmitted infections (STI) among unregistered sex workers, and to describe their sociodemographic characteristics and sexual behaviours, and the reasons why they were not officially registered as sex workers, in order to design specific public health interventions.Methods:A one-stage cluster-sample survey was conducted in Dakar in 2000. Unregistered sex workers were interviewed in randomly selected establishments (official and clandestine bars, brothels and nightclubs), and blood, endocervical and vaginal samples were collected for laboratory diagnosis.Results:A total of 390 women with a median age of 29 years were recruited. One-seventh of them were under the legal age for prostitution in Senegal (21 years). The median length of prostitution was 24 months and 73.5% of the women stated regular prostitution. Three-quarters of the women were found to have markers for at least one infection. The prevalence rates were as follows: HIV-1, 6.0%; HIV-2, 3.6%; HIV-1+2, 0.4%; syphilis, 23.8%; gonorrhea, 22.0%; chlamydial infection, 20.0%; trichomoniasis, 22.4%; candidiasis, 19.0%; and bacterial vaginosis, 28.8%. The main reported reason for non-registration was ignorance of the legal system and its procedures (19.4%); 18.9% of the women refused to register. One-third of the women reported that their clients used condoms inconsistently or never.Conclusion:This survey suggests that a multidimensional public health response is needed in Senegal, comprising legal information, downwards revision of the legal age for prostitution, and specific medical follow-up based on education, condom promotion and management of STI for non-registered sex workers.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID