摘要:

Background:The use of protease inhibitors in the treatment of HIV-1 infection is associated with the new onset of diabetes mellitus, hyperlipidaemia and lipodystrophy. It is unclear whether these findings are coincidental or whether they reflect a causative effect of protease inhibitors.Objective:To evaluate the effect of treatment with protease inhibitors on insulin sensitivity, oral glucose tolerance and serum lipids in HIV-infected patients in order to determine whether treatment with protease inhibitors can cause peripheral insulin resistance.Design:Cross-sectional controlled study in HIV-infected patients treated with protease inhibitors to assess insulin sensitivity, oral glucose tolerance and changes in serum lipids.Methods:Sixty-seven patients treated with protease inhibitors, 13 therapy-naive patients and 18 HIV-negative control subjects were tested for insulin sensitivity (intravenous insulin tolerance test). In a subgroup of 24 treated patients, oral glucose tolerance was determined. Serum lipids prior to and under treatment with protease inhibitors were compared.Results:Patients on protease inhibitors had a significantly decreased insulin sensitivity when compared with therapy-naive patients (median, 75 and 156 μmol/l/min, respectively;p<0.001). All treated patients with impaired (n = 4) or diabetic (n = 9) oral glucose tolerance, and four out of 11 patients with normal glucose tolerance showed peripheral insulin resistance; all therapy-naive patients had normal insulin sensitivity. Treatment with protease inhibitors led to a significant increase in total triglycerides and cholesterol in the 67 treated patients (median increase, 113 and 37 mg/ml, respectively).Conclusion:Treatment with protease inhibitors is associated with peripheral insulin resistance, leading to impaired or diabetic oral glucose tolerance in some of the patients, and with hyperlipidaemia. Overall, there is a large variation in the severity and clinical presentation of protease inhibitor-associated metabolic side-effects.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background:Tritherapies including protease inhibitors improve clinical status and usually increase CD4 T cell count. However, the dissociation between the marked decreases in viral load and the incomplete restoration of CD4 cell counts with a three-drug combination has been reported. We assessed this potential difference among our patients.Methods:Patients were enrolled when a protease inhibitor was prescribed to them for the first time. Using a computerized medical record (ADDIS®), we retrospectively assessed a potential relationship between the increase in CD4 T cells (δCD4) at M3, M6 and variables including sex, age, CDC staging, protease inhibitor, prior antiviral therapy, CD8 and viral load at baseline. We used Epi-Info 6.4 and BMDP software.Results:Data were analyzed on 154 patients. The median CD4 T cell count was 157 at baseline, 215 at month 3 and 202 at month 6. The median viral load was 52 000 copies at baseline, 530 at month 3 and 500 at month 6. In a univariate analysis, a significant relationship was found between δCD4 and CD8 at baseline. A statistically significant negative correlation appeared between the CD8 cell count at baseline and δCD4 at M6 (r = −0.28, Pearson). Moreover, we found that there also was a relationship between δCD4 and viral load at baseline. There was a correlation between δCD4 at M6 and the viral load at MO (r = 0.37, Pearson). In a multiple regression model, after CD8 count at baseline had been accounted for, we found a significant correlation between δCD4 and viral load at baseline (multiple r = 0.33 at M3, and 0.40 at M6).Conclusions:Patients with a low viral load do not benefit from as great an increase in CD4 T cell count as others when they receive a tritherapy including protease inhibitors. These results suggest that another mechanism rather than direct viral pathogenicity leads to CD4 T cell destruction. This mechanism may not be efficiently stopped by antiviral therapy, especially protease inhibitors.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objectives:To evaluate blood and genital secretions from HIV-infected men for HIV-1 resistant to antiretroviral agents.Design:A longitudinal study of 11 men with HIV infection and persistent detectable HIV RNA levels in blood and semen on antiretroviral therapy.Methods:HIV-1 from the blood and seminal plasma, obtained before the initiation of a new therapeutic regimen and on therapy, were evaluated by population-based sequencing of reverse transcriptase (RT) and protease RNA for the development of resistance to antiretroviral therapy. The genetic relatedness of sequences over time was compared.Results:RT genotypic resistance markers were present in seminal plasma at baseline in three out of six individuals with previous RT inhibitor experience. Eight out of 10 men, from whom the viral sequence was available on new therapy, demonstrated the evolution of new resistance mutations in the blood or seminal plasma, or both. The evolution of resistance mutations in blood and semen were frequently discordant, although over time similar patterns were seen. In two individuals, protease inhibitor resistance mutations evolved in the blood but not in the major variant in seminal plasma. Comparisons of the viral sequences between blood and seminal plasma from six men revealed two patterns. Three men showed a clustering of sequences from blood and semen. Three had sequences that appeared to evolve separately in the two compartments.Conclusions:HIV-1 variants with genotypic resistance markers are present in the male genital tract and evolve over time on incompletely suppressive antiretroviral therapy. The absence of genotypic changes consistent with protease inhibitor resistance in the semen, despite their presence in blood plasma, suggests the possibility of limited penetration of these agents into the male genital tract. Sexual transmission of resistant variants may have a negative impact on treatment outcome in newly infected individuals and on the spread of the diseases within a population. Therapeutic strategies that fully suppress HIV-1 in the genital tract should be a public health priority.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To predict long-term (12 weeks or longer) virological responses to antiretroviral treatment from measurements made during the first few days on therapy.Methods:Forty-one HIV-1 -infected children were treated with ritonavir for 12 weeks followed by triple drug combination treatment, and the kinetics of virus decay in plasma, ritonavir concentration and CD4 cell counts were measured. A robust multivariate pattern recognition method was used for prediction of the long-term virological responses.Results:The virus decay rate constants calculated from measurements of plasma viral RNA concentrations on the first, second, third, fourth and seventh day on therapy, the drug concentrations in the plasma on day seven, and the pretreatment levels of viral RNA and CD4 cell counts, correlated with long-term levels of plasma HIV-1 RNA. The combination of these parameters contained sufficient information for correct and robust prediction of the long-term response in 88% of the treated children. The predictions of individual responses were stable as demonstrated by a cross-validation analysis, which was highly statistically significant (r = 0.87) and specific.Conclusion:These results demonstrate that multiple parameters determine the response to antiretroviral therapy and offer a very early measure of individual long-term responses, suggesting that treatment could be optimized after few days of therapy.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objectives:To examine the functional interaction between HIV-1 Tat protein and the TATA-binding protein (TBP).Design:HIV long terminal repeat reporter plasmids were cotransfected into mammalian andDrosophilainsect cells with expression vectors encoding Tat and vectors encoding TBP either alone or linked to an heterologous DNA-binding domain.Methods:The activity of the different reporters was compared in the presence or absence of Tat or TBP, or both, upon cotransfections into human andDrosophilainsect cell lines.Results:Tat protein is unable to transactivate enhancerless HIV-1 minimal promoter bearing only the TATA box and TAR. Artificial recruitment of human TBP (hTBP) to the enhancerless HIV minimal promoter was found to trigger gene expression and coexpression of Tat resulted in a marked synergy. Tat protein cooperated with DNA bound hTBP by inducing high levels of processive viral transcripts. Synergy between Tat and hTBP was also observed when both factors were targeted to a promoter DNA template. The functional cooperation between TBP and Tat was further demonstrated using theDrosophilaSchneider SL.2 cells. In these cells Tat protein alone was ineffective; however, coexpression ofDrosophilaTBP and Tat resulted in atrans-activating response region-dependent synergistic transactivation of basal transcription.Conclusion:The strong synergy between TBP and Tat in the absence of any DNA bound activator suggests that Tat stimulates transcription in an activator-independent manner most likely by a functional interaction with general transcription factors that occurs after TBP recruitment. Thus, efficient recruitment of TBP represents a limiting step for Tat transactivation.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To assess the influence of malabsorption on nutritional status and energy expenditure in patients at different stages of HIV infection.Design and Methods:Fifty HIV patients were classified into three groups: Group 1, HIV asymptomatic patients (n = 17); Group 2, AIDS without opportunistic infection (n = 16); Group 3, AIDS patients with active infection (n = 17). Clinically-healthy subjects (n = 19) were used as controls. Parameters measured were: anthropometry, body composition by tetrapolar bioelectrical impedance; resting energy expenditure (REE) by open-circuit indirect calorimetry; malabsoption by D-xylose absorption and triolein breath tests.Results:Malabsorption (defined as abnormality of xylose and/or fat absorption test) was found in 34 (68%) of patients: 9 (53%) Group 1; 11 (69%) Group 2; 14 (82%) Group 3. Twenty-seven (54%) had sugar malabsorption and 21 (42%) fat malabsorption. A significant relationship was observed between malabsorption and weight loss. REE measured was significantly lower in malabsorptive patients than in non-malabsorptive patients and controls (6006.3 ± 846.5 versus 6443.4 ± 985.5 versus 6802.1 ± 862.7 kJ/day, respectively;P<0.05). The REE adjusted for fat-free mass was lower in malabsorptive than in non-malabsorptive patients and slightly higher than in controls, although the differences were not statistically significant.Conclusions:The results suggest that malabsorption is a frequent feature in HIV infection and is related to the HIV-related weight loss. Hypermetabolism is not a constant phenomenon in HIV infection since, in the presence of malabsorption, our patients show an appropriate metabolic response with a compensatory decrease in REE.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background:Despite the comparatively conserved nature of the HIV-1 gag gene, countless quasispecies of the p17 gene coexist in HIV-1-infected patients. It is not known if the minor genetic differences in quasispecies will affect immune recognition.Objective:To characterize the antigenicity and immunogenicity of three different members of HIV-1 p17 quasispecies.Methods:Three members of HIV-1 p17 gene quasispecies, one from patient A (clone 9; qsA9) and two from patient E (clones 5 and 8; qsE5 and qsE8), were expressed and purified fromEscherichia coli. The antigenicity of the p17 proteins was analysed using sera from HIV-1-infected individuals, and the immunogenicity was evaluated using sera and lymphocytes from primed mice of three different haplotypes.Results:The antigenicity of the qsE5 and qsE8 p17 recombinant proteins were distinct when tested for reactivity with human p17 antibodies. The qsE5 and qsE8 p17 were equally immunogenic in H-2dmice, but not in H-2band H-2kmice. In H-2bmice the qsE8 protein induced higher levels of anti-p17 IgG2a, IgG2b and IgG3 than the qsE5 protein. Corroborating the IgG subclass pattern, H-2b-restricted qsE5-specific T cells produced higherin vitrolevels of interferon-y, but not of interleukin (IL)-4, IL-5 and IL-6, than qsE8-specific T cells, suggesting a more pronounced T-helper (TH)1-like response.Conclusions:The p17 gene quasispecies coexisting in the same patient at the same time may represent antigenically and immunogenically distinct proteins despite sequence homologies of above 90%. Subsequently, subtle differences between two p17 protein quasispecies are enough to prime different TH1/TH2 subsets. These findings will have implications for therapeutic HIV-1 immunizations.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objectives:To describe the methods and results of a standardized system for clinical endpoint determination for defining and reviewing endpoints in clinical trials for HIV-infected individuals.Design:A system was developed utilizing standard definitions for the 24 diagnoses or clinical events that serve as trial endpoints and together define the combined endpoint ‘progression of HIV disease’. A common set of case report forms were used for all trials. Thus, an event ofPneumocystis cariniipneumonia (PCP), for example, for a subject co-enrolled in an antiretroviral trial and a PCP prophylaxis trial was only reported once.Methods:A central committee was established to define clinical events and review endpoints across all studies. Events were classified according to established criteria for confirmed, probable and possible levels of certainty.Results:This report describes the methods used to ascertain and review endpoints, and summarized 2299 clinical events for 8097 subjects enrolled in one or more of nine clinical trials. Data on the diagnostic certainty of events and agreement between site clinicians and the endpoint committee are presented.Conclusions:Uniform classification of endpoints across AIDS clinical trials can be accomplished by multicenter, multitrial organizations with standardized definitions and review of endpoint documentation. Our experience suggests that nurse coordinators reviewing all submitted endpoints for every trial are warranted and the need for external review by a clinical events committee may depend on the type of trial conducted.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Context:There is little information available on the correlation between HIV-1 RNA level, CD4 cell count and the risk of progression to AIDS or death during treatment with reverse transcriptase inhibitors.ObjectivesTo define the correlation between HIV-1 RNA level, CD4 cell count and the 1 year risk of progression to AIDS or death.DesignPooled analysis of six randomized clinical trials of zidovudine/lamivudine versus control treatments.SettingInvestigational sites in Europe, North America, Australia and South Africa.PatientsThe trials recruited 1488 adult HIV-1-infected male and female patients aged ≥ 18 years, with inclusion CD4 cell count between 25 and 500 × 106cells/l. Patients were either nucleoside analogue-naive or pre-treated, and at all stages of HIV-1 disease.Main outcome measuresProgression (defined as all new and recurrent AIDS-defining events or death) was correlated with the HIV-1 RNA level and CD4 cell count during the first 8 to 52 weeks of treatment.ResultsDuring a median 1 year follow up, progression was largely restricted to patients with both low CD4 cell count (≤ 200 × 106cells/l) and high HIV-1 RNA level (> 5000 copies/ml). There was an increase in the incidence of progression events with rises in HIV-1 RNA level >5000 copies/ml and reductions in CD4 cell count under 200 × 106cells/l. The events occurring with HIV-1 RNA ≤ 5000 copies/ml were generally atypical.ConclusionsProgression to AIDS or death is rare for patients with HIV-1 RNA ≤ 5000 copies/ml, particularly when CD4 cell count is more than 200 × 106cells/l.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID