摘要:

Objective:To evaluate the clinical significance of hypersusceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI).Design:Analysis of a prospective clinical trial cohort.Patients:NNRTI-naive patients failing a stable antiretroviral regimen.Measurements:HIV phenotype, HIV RNA, and CD4 cell counts were prospectively collected after patients changed to a new regimen. Hypersusceptibility to NNRTI was defined as a fold-change (FC) in IC50(inhibitory concentration of 50%) of < 0.4.Results:The 177 patients had a mean HIV RNA of 4.1 log10copies/ml, CD4 cell count of 322 × 106cells/l and 41 months of prior antiretroviral treatment. Hypersusceptibility to one or more NNRTI was present in 29%. Both longer duration and reduced susceptibility to nucleoside reverse transcriptase inhibitors were associated with efavirenz hypersusceptibility (P< 0.05). NNRTI-containing regimens were initiated in 106 patients at baseline. The mean change in log10HIV RNA after 6 months was greater for patients with hypersusceptibility (−1.2 log10copies/ml; n = 21) than in patients without (−0.8 log10copies/ml; n = 77) (P =0.016). Differences persisted to month 12 (P =0.023). Multiple linear regression models confirmed that hypersusceptibility to NNRTI was a significant independent predictor of the magnitude of early (months 1–4) HIV RNA reduction, after accounting for the baseline HIV RNA and the number of drugs to which the patient's virus was susceptible (P< 0.02). CD4 cell increases (months 4–10) were 28– 60 × 106cells/l greater in patients with hypersusceptible virus (P⩽ 0.1).Conclusion:NNRTI hypersusceptibility occurred in more than 20% of nucleoside-experienced patients and was associated with greater reduction of HIV RNA and increase in CD4 cells.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Objective:The routine use of phenotypic drug resistance testing in patient management has revealed that many HIV-1 strains possess significantly increased drug sensitivity, or ‘hypersusceptibility’ compared with wild-type viruses. This study describes hypersusceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI) and was designed to determine the prevalence of and viral characteristics associated with NNRTI hypersusceptibility in patient-derived viruses.Methods:Retrospective analyses were performed on a large clinical laboratory dataset containing phenotypic drug susceptibility and genotypic sequence results from HIV-1 patient isolates. Genetically engineered viruses were used to confirm the role of certain nucleoside reverse transcriptase inhibitor (NRTI)-resistance mutations in NNRTI hypersusceptibility.Results:Hypersusceptibility to delavirdine, efavirenz and nevirapine was detected in 10.7, 10.8 and 8.0% of more than 17 000 consecutive plasma samples submitted for phenotypic susceptibility testing. In analyses limited to a subset of viruses derived from patients with known treatment histories, NNRTI hypersusceptibility was observed significantly more frequently among viruses from NRTI experienced/NNRTI-naive patients compared with viruses from NRTI/NNRTI-naive patients. Significant inverse correlations between NRTI and NNRTI susceptibility exist among the viruses from NRTI-experienced patients. Analyses of viruses classified according to their NNRTI susceptibility identified 18 positions in reverse transcriptase where substitutions were significantly associated with NNRTI hypersusceptibility.Conclusions:NNRTI hypersusceptibility is common among patient HIV-1 isolates, especially in NRTI-resistant viruses. Genotypic correlates of hypersusceptibility are complex and not easily defined by a simple analysis of NRTI-associated resistance mutations. NNRTI hypersusceptibility may provide an explanation for the superior virologic response to NNRTI-containing salvage regimens observed in NRTI-experienced patients in several clinical trials.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Objective:Despite readily detectable virus-specific CD8+ T cells in most HIV-infected patients, immune surveillance is eventually lost, leading to progression to AIDS. To investigate the underlying mechanism of this loss of immune control phenotypic analysis of HIV- and Epstein–Barr virus (EBV)-specific CD8+ T cells was performed.Design:In three clinically distinct groups, long-term asymptomatics, progressors to opportunistic infections and progressors to EBV-associated non-Hodgkin lymphoma's (NHL), both number and phenotype of virus-specific CD8+ T cells was studied longitudinally.Methods:The number of HIV- and EBV-specific T cells were determined using HLA-peptide tetrameric complexes. The phenotype of these virus-specific T cells was investigated by costaining with CD27 and CD45RO and thereby identifying specific subsets of CD8+ T cells.Results:Individuals co-infected with HIV and EBV persistently had low numbers of HIV-specific CD27− T cells, in contrast to rising numbers of EBV-specific CD27− CD8+ T cells. However, HIV-infected individuals developing EBV-associated AIDS-related NHL had very low numbers of EBV-specific CD27− CD8+ T cells. Higher numbers of HIV-specific CD27− CD8+ T cells were associated with delayed disease progression. Virus-specific CD27− T cells, compared with CD27+ T cells showed elevated interferon-gamma production in response to viral peptidesin vitro, indicative for strong effector function.Conclusions:Taken together, our data indicate that virus-specific CD27− T cells may be important effector T cells in controlling chronic viral infections in humans and that lack of differentiation into CD27− effector T cells may lead to progression of viral disease.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Objective:The pathogenic mechanisms underlying lipodystrophy in HIV-positive patients are largely unknown. TNF-α has many actions that are consistent with the features of lipodystrophy; therefore, an analysis was carried out to determine whether functionally active polymorphisms in the promoter region of the TNF-α gene are associated with the development of lipodystrophy.Design:Genetic case–control association study.Methods:Individuals were genotyped for the −238 and −308 polymorphisms in the TNF-α gene using polymerase chain reaction–restriction fragment length polymorphism analysis. The genotype and allele frequencies for 61 HIV-positive patients with lipodystrophy were compared with (a) 35 HIV-positive patients with no evidence of lipodystrophy and (b) 239 healthy HIV-negative individuals.Results:The frequency of the variant rare −238 allele was significantly different (P= 0.01) in HIV-positive patients with lipodystrophy than in those without lipodystrophy. At the genotype level, a trend towards a difference between patients with and without lipodystrophy was observed (χ2for linear trend 5.2,P= 0.02). For the −308 polymorphism, no difference was found in genotype and allele frequencies between HIV patients with and without lipodystrophy.Conclusions:The data suggest that the −238 (but not the −308) promoter region TNF-α gene polymorphism is a determinant in the development of HIV-related lipodystrophy. However, the results need to be confirmed in larger numbers of patients as well as in an ethnically diverse population.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background:The human monoclonal antibodies (MAbs) 2F5 and 2G12 were identified to be two of the most potent neutralizing antibodies against HIV-1. In a first human study they have been shown to be safe after repeated intravenous infusions to asymptomatic HIV-1-infected individuals. However, the antiviral effects of antibody treatment have not been fully analyzed in this first clinical trial.Methods:The aim of the present study was to gain a preliminary insight into the antiviral effects of 2F5 and 2G12 in humans. For this purpose, plasma samples obtained from the previous phase I study were studied for RNA copy numbers by reverse transcriptase-polymerase chain reaction. As a measure for activation of complement levels of the major complement factor C3 were measured by enzyme-linked immunosorbent assay. Flow cytometry was used to study T-lymphocyte counts and the amount of infected peripheral blood mononuclear cells (PBMC) was determined by co-culture with uninfected donor PBMC. Virus escape from antibody neutralization was determinedin vitroin a PBMC neutralization assay.Results:Transient reduction in viral loads was observed in five of seven patients. Vigorous complement activation was observed directly after HIV-specific antibody infusions. The number of infective peripheral blood mononuclear cells was reduced in some patients whereas CD4+ T-lymphocyte counts and CD4+/CD8+ ratios were transiently increased in all patients. Virus escape occurred only against 2G12.Conclusions:Analysis of disease progression markers indicate that antibody therapy may have antiviral effects. These findings suggest that neutralizing antibodies should be further evaluated as an alternative therapeutic approach in HIV-1 disease.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background:Despite effective highly active antiretroviral therapy (HAART), some patients infected with HIV have persistently low CD4 cell counts with risk of HIV disease progression. The addition of interleukin-2, a cytokine that stimulates CD4 T lymphocyte helper cells, may benefit patients with discordant responses.Methods:A total of 72 HIV-infected patients with CD4 cell counts of 25–200 × 106cells/l (median 145) and plasma HIV RNA < 1000 copies/ml were randomized in a multicentre study to receive open-label 4.5 × 106IU interleukin-2 subcutaneously twice daily for 5 days every 6 weeks plus their ongoing HAART or were maintained on HAART alone (control group). After 24 weeks, all patients received interleukin-2 therapy plus HAART up to week 80. Primary end-point was the CD4 T cell area under the curve minus baseline up to week 24.Results:After four cycles of interleukin-2, in an intent-to-treat analysis, the respective median CD4 cell area under the curve minus baseline values were +51 and +11 cells in the interleukin-2 (n = 34) and the control group (n = 36) (P< 0.0001). The percentage of patients in the two groups with CD4 cell counts > 200 × 106cells/l was 81% and 33%, respectively (P< 0.0001). At week 80, the median CD4 cell counts in the two groups were 380 and 270 × 106cells/l, respectively. Interleukin-2 treatment was reasonably well tolerated and did not result in sustained increases in plasma HIV RNA levels.Conclusions:Administration of interleukin-2 produces significant and sustained increase in CD4 cell counts in HAART-treated patients with persistent CD4 cell counts < 200 × 106cells/l.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Objective:To examine the prevalence and clinical correlates of subsequently measurable viremia in HIV-infected patients who have achieved viral suppression below the limits of quantification (< 50 copies/ml).Design:Non-randomized dynamic cohort study of ambulatory HIV patients in nine HIV clinics in eight cities.Patients:Patients had two consecutive HIV-1 RNA levels < 50 copies/ml (minimum, 2 months apart) that were followed by at least two more viral level determinations while remaining on the same antiretroviral therapy (ART) between January 1997 and June 2000 (median 485 days). Transiently viremic patients were defined having a subsequently measurable viremia but again achieved suppression < 50 copies/ml.Results:Of the 448 patients, 122 (27.2%) had transient viremia, 19 (4.2%) had lasting low-level viremia and 33 (7.4%) had lasting high-level viremia (defined as 50–400 and > 400 copies/ml, respectively). Only 16 (13.1%) of those who had transient viremia later had persistent viremia > 50 copies/ml. The occurrence of transient viremia did not vary with whether the patient was ART-naive or experienced (P= 0.31), or currently taking protease inhibitors or not (P= 0.08). On consistent ART, the median percentage increase in CD4 cell count was statistically different between subgroups of our cohort (Kruskal–Wallis,P= 0.002).Conclusions:Transiently detectable viremia, usually 50–400 copies/ml, was frequent among patients who had two consecutive HIV-1 RNA levels below the limits of quantification. In this analysis, such viremia did not appear to affect the risk of developing lasting viremia. Caution is warranted before considering a regimen as ‘failing’ and changing medications.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Objective:To further elucidate the immunopathogenesis of immune restoration diseases (IRD) in HIV patients responding to antiretroviral therapy and determine whether IRD associated with different opportunistic pathogens involve distinct immunopathological mechanisms.Design:DNA samples from patients with a range of IRD were typed for polymorphic loci in genes encoding immune-mediators.Methods:PCR–restriction fragment length polymorphism assays were used to type loci in theIL1A, IL1B, IL6, TNFAandIL12Bgenes. Alleles of a microsatellite in the CD30 promoter were determined by capillary electrophoresis.Results:Only 8% of patients with IRD associated with a herpesvirus infection carried IL12B-3′UTR*2, compared with 42–54% of patients with other or no IRD. Patients with IRD arising from mycobacterial infection rarely carried IL6-174*C (36% versus 61–71%) and never carried TNFA-308*2 (0% versus 23–52%). TNFA-308*2 was carried by 52% of patients who experienced IRD associated with a herpesvirus infection, as several patients with exacerbations of cytomegalovirus retinitis carried this as part of a HLA-A2,B44 haplotype. Polymorphisms inIL1A, IL1BandCD30showed no distinct patterns.Conclusions:Distinct cytokine-mediated mechanisms contribute to IRD initiated by herpesvirus and mycobacterial infections.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background:National and international guidelines call for the treatment of primary HIV infection (PHI) with combination antiretroviral therapy, although the ideal timing and duration of this intervention is unknown. Recent immunological studies of antiretroviral therapy on small numbers of patients with PHI have reported preservation of HIV-specific CD4 T-helper responses, ordinarily lost in the absence of intervention. We sought to investigate whether a short course of antiretroviral therapy (SCART) at PHI was sufficient to preserve HIV-specific cellular immunity.Methods:Forty-five subjects with confirmed PHI were offered SCART at diagnosis. HIV specific cellular immune responses and virological parameters were assessed at monthly intervals.Results:Thirty-seven of the subjects chose SCART at PHI, and achieved a plasma viral load < 50 RNA copies/ml by a median of 10 weeks (range, 4–32 weeks). Two of the 45 individuals had evidence of genotypic HIV drug resistance at baseline, and none developed new mutations following therapy. All patients who received SCART at PHI showed preservation of HIV-specific CD4 T-helper responses up to 64 weeks off SCART.Conclusion:SCART at PHI was safe, did not induce the development of drug resistance, and appeared sufficient to preserve HIV-specific CD4 T-helper responses. However, PHI is highly heterogeneous, and a large-scale randomized trial of SCART at PHI is now needed.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID