摘要:

Objective:To determine the rate of virological treatment failure with protease inhibitor therapy in unselected patients and to assess underlying risk factors.Design and setting:Retrospective study in two German tertiary care treatment centres.Patients:A total of 198 HIV-infected patients treated with protease inhibitors in 1996.Main outcome measures:Levels of HIV RNA 1–6 months after start of treatment; definition of treatment failure of < 1 log10reduction in plasma HIV RNA within 6 months after starting protease inhibitor therapy; multivariate analysis of risk factors for treatment failures.Results:A total of 226 treatment episodes with protease inhibitors were evaluable (saquinavir, 83; ritonavir, 47; indinavir, 96). The rate of virological treatment failure was 44% (saquinavir, 64%; ritonavir, 38%; indinavir, 30%). In a multivariate analysis, the following independent risk factors for virological failure were found: CD4 cell count, pretreatment with antiretroviral drugs (number), and protease inhibitor (compound). The relative risk reduction for each CD4 cell count increase was 0.997 (P= 0.012), 2.64 for pretreatment with one or two drugs versus no drug (P= 0.05), 2.97 for pretreatment with more than two drugs versus no drug (P= 0.05), and 4.62 for treatment with saquinavir versus indinavir (P= 0.001).Conclusion:An unexpectedly high rate of virological treatment failure of protease inhibitor therapy was found in an unselected cohort of HIV-infected patients. Response to antiretroviral combination therapy in normal clinical practice may considerably differ from results of randomized clinical trials. Further studies are warranted to find optimal treatment strategies for both initial and salvage therapy.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective:To investigate the role of the Fas–Fas ligand (FasL) interaction in HIV-1-induced apoptosis of primary CD4+ T lymphocytes.Design:Activated CD4+ T lymphocytes are the main target of HIV, and T-cell activation leads to the expression of Fas–FasL and enhances HIV-mediated apoptosis. Phytohemagglutinin-activated primary CD4+ T cells were infected with HIV; the process of cell death was examined, and whether the dying and dead cells were the productively infected cells. The modulation of Fas and FasL expression and its role in HIV-induced cell death was also investigated.Methods:The number of viable and dead cells was determined by trypan blue exclusion. Apoptosis was quantified using an enzyme-linked immunosorbent assay measuring the release of cytoplasmic histone-associated DNA fragments. The percentage of HIV-infected cells was determined by FACS analysis, and viral production was assessed by a p24 core antigen assay. The following three markers, HIV-gp-120, annexin-V and 7-AAD, were used to monitor the apoptotic process in HIV-negative and positive cells. Fas and FasL expression was analyzed at the RNA level by reverse transcription polymerase chain reaction and at the protein level by flow cytometry. The contribution of Fas–FasL interactions to apoptosis was examined by blocking experiments using the antagonist ZB4 anti-Fas antibody.Results:HIV-induced apoptosis in activated purified CD4+ T lymphocytes required infectious virus and was dose-dependent. Apoptosis in HIV-infected cultures was mostly confined to productively infected cells. The expression of Fas and FasL was not significantly modulated by infection and blocking Fas-FasL interactions did not reduce the extent of apoptosis.Conclusions:HIV-induced apoptosis of activated CD4+ T cellsin vitrois confined to productively infected cells and is not mediated by a Fas–FasL interaction.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Design:Infection of the human promyelocytic cell line HL-60 with NL4-3, a molecularly cloned HIV-1 strain that productively infects T cells, results in adaptation of the virus and production of a variant, NL4-3(M). Unlike NL4-3, NL4-3(M) has a rapid cytopathic effect in HL-60 and other myeloid cell lines.Objective:To demonstrate that the tropism of NL4-3(M) is extended to primary monocyte-derived macrophages (MDM), and to determine whether the envelope gene,env, of NL4-3(M) is responsible for cytopathicity in HL-60 cells and replication in MDM.Methods:A chimeric virus (NL4-3envA) containing the majority ofenvof NL4-3(M) was generated, and tested for virus replication and cytopathic effect in H9 and HL-60 cells, as well as for virus replication in primary MDM. To assess virus replication, the cultures were analyzed for expression of viral envelope glycoproteins on the infected cells and production of extracellular HIV-1 p24 antigen. Cytopathic effect on HL-60 cells was evaluated by monitoring the viabilities of the cultures. In addition, the majority ofenvof NL4-3envA was sequenced.Results:The biological phenotypes of NL4-3, NL4-3(M), and NL4-3envA are distinctly different. Although both NL4-3(M) and NL4-3envA replicate in MDM, only NL4-3(M) is rapidly cytopathic in HL-60 cells. Nine amino-acid changes were identified within the envelope glycoproteins of NL4-3envA compared with NL4-3.Conclusions:The viral determinants of NL4-3(M) sufficient to extend the tropism of this virus to MDM reside, in part, in env. These genetic determinants are distinct from the viral determinants that control the cytopathic phenotype of this virus in HL-60 cells.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objectives:To determine, first, whether the plasma and lymphocytes of HIV-positive individuals and AIDS patients have alterations in the major thiols glutathione and cysteine, and/or their oxidative disulphide and mixed disulphide products; and, secondly, whether thiol/disulphide status differs in patients with sulphonamide drug hypersensitivity reactions.Design:Thiols provide critical cellular defence against toxic drug reactive intermediates and endogenous oxidative stress, and may modulate HIV replication. Glutathione is reported to be low in HIV-positive individuals and AIDS patients, but this is controversial and the mechanism responsible is unknown. Also unknown is whether altered thiol/disulphide status determines the predisposition of HIV-positive and AIDS patients to drug reactions.Methods:Thiols and disulphides were measured by high-performance liquid chromatography.Results:Both plasma thiols were decreased by approximately 58% in HIV-positive individuals and AIDS patients compared with uninfected controls (P< 0.05), with increases of up to threefold in oxidized products (P< 0.05). Similarly, in lymphocytes, thiols were decreased by 30–35% (P< 0.05), with apparent increases in oxidized products. For both glutathione and cysteine, the thiol/disulphide ratios also were decreased (P< 0.05). The plasma and lymphocyte glutathione thiol/disulphide ratios were highly correlated (r = 0.7661;P= 0.0001) among all subjects. No parameters differed in patients with drug reactions, or with antiretroviral therapy.Conclusions:The enhanced thiol oxidation in HIV-positive individuals and AIDS patients indicates oxidative stress, which also contributes to thiol depletion, and may enhance damage to macromolecular targets. These mechanisms may contribute to enhanced viral replication and other pathological outcomes. HIV-positive individuals' and AIDS patients' predisposition to drug hypersensitivity reactions appears to be unrelated to thiol/disulphide status.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective:To define a clearex vivoflow cytometric phenotype for adult human microglia that would distinguish it from all other macrophage lineage cells in the central nervous system (CNS) or blood, and to utilize this phenotype to examine the activation state and CD4 expression of microglia freshly derived from CNS tissue of HIV-positive patients and those with other neurological diseases.Design:Fresh human CNS tissue from both HIV-uninfected and HIV-infected individuals was obtained by biopsy or resection, and cells isolated immediately, labelled for flow cytometry and analysed.Methods:A Percoll density gradient isolation technique and phenotypic characteristics used for rodent microglia were applied and modified.Results:Resident microglia could clearly be defined by the flow cytometric phenotype CD45lowCD4−CD11b+ CD11chighmajor histocompatibility complex (MHC) class II+ CD26− CD14−. Assuming normally low-level MHC class II expression in the healthy CNS, it was likely that MHC class II positivity reflected underlying pathology necessitating biopsy or resection and appeared to be a ‘leaky’ activation marker. Microglia activation was observed in specimens from only six (35%) out of 17 HIV-uninfected but all four (100%) HIV-infected patients, defined strictly as any level of upregulation of CD4 expression, to produce the phenotype CD45low/mediumCD4lowCD11b+ CD11chighMHC class II+/++ CD26− CD14−. Where examined by immunohistology, CD68 was also upregulated in these cases.Conclusions:When activated in situ, microglia express low levels of CD4 and this is always seen in tissue from HIV-infected patients. Using the flow cytometric phenotype established here, microglia from HIV-infected tissue can now be isolated in pure form and studied directlyex vivo.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective:To evaluate sequence evolution in relation to different rates of disease progression in infants infected with HIV-1.Design:Variability in the gp120 V3 region was analysed in HIV-1-infected children with different clinical courses, slow progression (n = 2) versus progressive disease (n = 3).Methods:Cloning and sequencing of virus-derived DNA from uncultured peripheral blood mononuclear cells was performed at two to three timepoints from birth and up to the fifth year of life. Sequence variability was estimated by calculating the genetic distance and the proportion and ratio of synonymous and non-synonymous nucleotide substitutions over time.Results:Genetic distances were significantly shorter in children with fast progression to disease, a predominance of synonymous nucleotide substitutions also being detected at later timepoints. Conversely, a preferential accumulation of non-synonymous nucleotide substitutions was apparent in children with slow disease progression. Furthermore, a positive correlation between a decreased ratio of synonymous/non-synonymous nucleotide substitutions and the ability of children's sera to react with synthetic peptides representing the autologous virus sequence was determined.Conclusion:Data suggest that an antigenically more diverse virus population emerges in infected children with slower progression to disease as a result of a stronger immune pressure.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective:To elucidate the relationship between the activity of CMV disease and adrenocortical function in patients with AIDS.Design and patients:CMV retinitis and CMV antigenemia assay (CMV-Ag: numbers of polymorphonuclear leukocytes positive for CMV pp65 antigen per 1.5 × 105cells) are the least invasive and easily accessible examinations to assess the CMV disease activity. All HIV-infected patients with CD4+ lymphocyte counts < 50 × 106/l who were admitted to the Research Hospital of the Institute of the Medical Science (University of Tokyo) between May 1995 to April 1996 were included in this study.Methods:Fundoscopic examination on CMV retinitis and CMV-Ag were chosen as methods to assess CMV activity because of their simplicity. Adrenocortical function was evaluated by basal plasma adrenocorticotropin, plasma cortisol, plasma aldosterone, plasma renin activity, and responses of plasma cortisol and plasma aldosterone to 250 µg intravenous cosyntropin [rapid adrenocorticotropin test (RAT)].Results:Thirty patients were enrolled in this study with a maximum CD4+ lymphocyte count of 32 × 106/l. Eleven out of 30 patients showed impaired RAT response (37%). Fourteen out of 30 patients had CMV retinitis. A significant correlation was found between the presence of CMV retinitis and subnormal cortisol response (P< 0.005). Sixteen out of the 30 patients were CMV-Ag-positive. A significant correlation was found between CMV-Ag positivity and subnormal cortisol response to RAT (P< 0.005). CMV-Ag levels in the patients with subnormal cortisol response to RAT were significantly higher than those with normal response (P< 0.001). Importantly, five patients with subnormal cortisol response but not overt adrenal insufficiency at the time of RAT developed overt disease shortly afterwards. Autopsy was performed in six patients with subnormal cortisol response and showed multiple inclusion bodies indicative of CMV adrenitis.Conclusion:The adrenal gland is most frequently affected by CMV in AIDS patients. Our result suggests that CMV retinitis or CMV-Ag positivity independently serve as an indication of possible adrenal dysfunction.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective:To evaluate high-dose intravenous methotrexate in primary central nervous system (CNS) lymphoma in HIV-infected patients.Design:An uncontrolled pilot trial.Setting:An infectious diseases department in Paris, France.Patients:All consecutive AIDS patients with primary CNS lymphoma attending the same unit from August 1994 to March 1996.Interventions:Methotrexate was intravenously administered at a dose of 3 g/m2every 14 days with leucovorin rescue. A maximum of six cycles was planned. Steroids were given to all patients and haematological growth factors were administered as required.Main outcome measures:Rate of response, time to response and survival.Results:Fifteen patients (10 with histological documentation) were recruited. The median time since clinical onset was 27 days (range, 7–69 days), median Karnofsky score was 51 (range, 30–70), and mean CD4+ cell count was 30 ± 19 × 106/l (range, 7–69 × 106/l). Complete responses, defined as clinical improvement and disappearance of contrast-enhancing brain abnormalities on computed tomography or magnetic resonance imaging, were obtained in seven out of 15 patients (three out of 10 patients with histological diagnosis and four out of five patients without histological confirmation). The Karnofsky score of these seven patients improved to 80 ± 10 (range, 70–100). The mean time taken to respond was 62 ± 20 days (range, 45–90 days). One patient relapsed at 6 months. Six patients failed to respond, and two died of severe sepsis on days 15 and 45. The median survival time was 290 days (range, 11–570 days): 73 days (range, 11–570 days) in the 10 patients with histological diagnosis, and 347 days (range, 286–409 days) in the five patients without histological confirmation. Side-effects occurred in 10 patients, with gastrointestinal disorders in five, mucositis and skin rash in two, and fever in three patients; however, these events were mild and did not require cycle postponement or dose changes. No cognitive dysfunction occurred.Conclusion:Methotrexate appears to be an attractive alternative to radiation therapy for primary CNS lymphoma and is associated with a far greater improvement in quality of life relative to historical series of radiation therapy.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Objective:To determine the incidence of AIDS-defining opportunistic infections and malignancies over a 5-year period from 1992 to 1996.Study population:Subcohort of 1003 homosexual men with HIV infection and CD4 count less than 200 × 106cells/l from the Frankfurt AIDS Cohort Study.Methods:Data including the earliest date that a CD4 T-lymphocyte count < 200 × 106/l was reached and the dates of AIDS-defining events were compiled from medical records. Incidence analyses for AIDS-defining events and death during the subsequent 5 years (1992–1996) were performed using rates per 100 person-years of exposure.Results:During the observation period, the number of patients per year with CD4 T-lymphocyte counts < 200 × 106/l varied between 402 and 511. In 1992, 56.7% of patients experienced at least one AIDS-defining illness, and 20.7% in 1996. The annual number of AIDS-defining events per 100 patient-years of observation declined from 143.5 in 1992 to 38.3 in 1996, and the number of AIDS-related deaths fell from 25.7 to 12.9. Analysis of the number of events confirmed this trend for malignancies and single opportunistic infections, with the exception of mycobacterial diseases.Conclusions:The incidence of AIDS-defining events in patients with advanced HIV infection at Frankfurt University Hospital has declined by more than 70% from 1992 to 1996.

ISSN:0269-9370    

出版商:OVID    

年代:1997

数据来源: OVID