摘要:

Objective:To compare antiretroviral efficacy, safety and tolerance of three dosing regimens of the novel nucleoside reverse transcriptase inhibitor, abacavir (1592U89) over 24 weeks and its efficacy in open-label combination with zidovudine and lamivudine.Design:Sixty HIV-1-infected antiretroviral therapy naive subjects (entry criteria; CD4+ cell count ≥ 100 cells/mm3, plasma HIV-1 RNA ≥ 30 000 copies/ml), randomized into 20 subjects per cohort received 100, 300 or 600 mg abacavir twice daily. Subjects successfully completing 24 weeks' randomized therapy could switch to open label therapy (abacavir, zidovudine, lamivudine at 300, 300 and 150 mg twice daily, respectively) for a further 24 weeks of study, as could subjects meeting one or more switch criteria.Methods:Subjects were assessed for antiretroviral activity by measuring changes in plasma HIV-1 RNA load and CD4+ cell counts. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses.Results:At week 4, subjects receiving 300 or 600 mg abacavir twice daily had greater reductions in plasma HIV-1 RNA (median changes −1.55 and −1.61 log10copies/ml, respectively); differences (P= 0.007 andP≤ 0.001, respectively) than subjects receiving 100 mg abacavir twice daily (median change, −0.63 log10copies/ml). Differences between the 300 and 600 mg twice daily groups were not clinically or statistically significant. At 24 weeks, analysis showed a median change in plasma HIV-1 RNA of −0.70 and −1.30 log10copies/ml in the 300 and 600 mg twice daily groups, respectively. During the open label phase in which zidovudine/lamivudine was added to 300 mg abacavir twice daily, a further median reduction in plasma HIV-1 RNA of 1.74 log10copies/ml was seen. At 48 weeks pooled data from all abacavir-treated subjects showed a sustained reduction in plasma HIV-1 RNA of 2.8 log10copies/ml; 65% and 43% of subjects had ≤ 400 and ≤ 50 HIV-1 RNA copies/ml, respectively, and a further median increase of 111 CD4+ cells/mm3were seen. Abacavir was generally well tolerated with few clinically significant adverse events. Two subjects (3.3%) developed hypersensitivity reactions to abacavir. There were no differences between the groups with regard to serious adverse events.Conclusions:In terms of antiretroviral therapy naive subjects, treatment with 300 or 600 mg abacavir twice daily was statistically superior to a 100 mg twice daily dose at 4 weeks. Combinations therapy containing abacavir-zidovudine-lamivudine was a highly effective antiretroviral regimen, resulting in substantial reductions in plasma HIV-1 RNA which may be comparable to combinations containing protease inhibitors. Abacavir was generally tolerated.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objectives:To evaluate, over 12 weeks, the antiretroviral activity and safety of abacavir, used alone and in combination with zidovudine (ZDV), as treatment for HIV-1-infected subjects who had limited or no antiretroviral treatment.Design:Seventy-nine HIV-1-infected subjects, with CD4 cell counts 200–500 × 106/l and <12 weeks of previous treatment with ZDV were enrolled in a multicenter study. Subjects were randomly assigned to one of four cohorts receiving abacavir monotherapy for the first 4 weeks (200, 400, or 600 mg every 8 h daily, or 300 mg every 12 h daily) and, thereafter, combination therapy of abacavir with 600 mg ZDV or ZDV placebo, administered in a double-blind manner for an additional 8 weeks.Methods:Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4+ cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities during the 12-week period and for 4 weeks post-treatment.Results:Treatment with abacavir, alone or in combination with ZDV, produced marked decreases in plasma HIV-1 RNA loads and increases in CD4+ cell counts in all groups. At week 4, median plasma HIV-1 RNA loads decreased by 1.11–1.77 log10copies/ml and median CD4+ cell counts increased by 63–111 × 106/l in all groups. At week 12, median HIV-1 RNA loads decreased by 1.02–2.24 log10copies/ml (abacavir monotherapy) and by 1.81–2.01 log10copies/ml (abacavir-ZDV); median CD4+ cell counts increased by 79–195 × 106/l (abacavir monotherapy) and by 93–142 × 106/l (abacavir-ZDV). At week 12, the percentage of subjects who had plasma HIV-1 RNA levels below 400 and 40 copies/ml were 28 and 11%, respectively (abacavir monotherapy) and 69 and 22%, respectively (abacavir-ZDV). Eight subjects (10%) discontinued the study prematurely because of adverse events; nausea (n = 4) and hypersensitivity (n = 3) were the most common reasons for withdrawal. There were no deaths among the study subjects.Conclusions:In HIV-infected subjects who have received little or no prior antiretroviral therapy, treatment with abacavir alone or in combination with ZDV is well tolerated and resulted in sustained improvements in key immunologic and virologic efficacy parameters through 12 weeks.

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

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background:Host genetic factors, such as HLA alleles, play an important role in mediating the course of HIV-1 disease progression through largely undefined mechanisms.Objectives:To examine the association of HLA markers with HIV-1 RNA plasma viral load and other factors associated with course of disease progression in HIV-1 infection.Design and methods:A group of 139 HIV-1 seroconverters from the Multicenter AIDS Cohort Study had been typed for a variety of HLA markers. HIV-1 RNA plasma viral load was measured from frozen plasma specimens obtained approximately 9 months following seroconversion. CD4+ cell counts were available from the same study visit. Statistical analysis was performed using survival techniques and linear regression models to quantify the relative associations of an HLA score profile, HIV-1 RNA plasma viral load, CD4+ cell count and age with each other and with rate of progression to AIDS and death.Results:Cox proportional hazards models showed statistically significant differences in time to AIDS by HLA score profile category per unit increase [relative hazard (RH), 0.64;P< 0.0001], HIV-1 RNA plasma viral load per 10-fold increase (RH, 2.04;P= 0.0003), and CD4+ cell count per 100 cell (× 106/l) increase (RH, 0.90;P= 0.02). Multivariate linear regression showed that viral load was 39% lower (P= 0.0001) for each unit increase in HLA score profile and 13% lower (P= 0.002) for each 100 cell (× 106/l) increase in CD4+ cell count.Conclusions:The means by which the HLA score profile influences the time to AIDS is probably through immunologic responses that affect the rate of HIV-1 replication, as manifested by the HIV-1 RNA plasma viral load during the first 6–12 months following acute infection.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objectives:To evaluate the impact of early initiation of highly active antiretroviral therapy (HAART) on disease-induced T-cell activation and maturation abnormalities during asymptomatic HIV infection.Design:A prospective open-label trial of zidovudine, lamivudine and ritonavir in treatment-naive asymptomatic HIV-infected individuals with CD4 cells ≥ 400 × 106/l.Methods:Peripheral blood CD4+ and CD8+ T cells derived from 15 asymptomatic HIV-infected individuals (median baseline CD4+ cells, 608 × 106/l; CD8+ cells, 894 × 106/l; plasma HIV RNA, 3.93 log10copies/ml) undergoing therapy with zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and ritonavir (600 mg twice daily) were assessed for changes in expression of phenotypic markers of T-cell activation (HLA-DR and CD38) and maturation (CD45RA and CD45RO). At weeks 0, 2, 4, 8, 12, 16, 20 and 24, T-cell subsets were quantified by flow cytometry and plasma HIV viral loads determined using reverse transcription PCR.Results:HAART-induced decrease in plasma HIV RNA levels coincided with a significant reduction in numbers of activated CD4+/HLA-DR+ (maximum change, −36%;P≤ 0.05), CD8+/HLA-DR+ (maximum change, −66%;P≤ 0.005) and CD8+/CD38+ (maximum change, −51%;P≤ 0.01) T cells. A concomitant significant increase in numbers of naive CD4+/CD45RA+ (maximum change, +12%;P≤ 0.005) and memory CD4+/CD45RO+ (maximum change, +6%;P≤ 0.05) T cells was also evident, which contrasted with a significant decrease in memory CD8+/CD45RO+ cells (maximum change, −42%;P≤ 0.005).Conclusion:The observed ability of HAART during early asymptomatic HIV infection to initiate rapid reversal of disease-induced T-cell activation and maturation abnormalities, while preserving pretherapy levels of immune function, supports the concept that therapeutic advantage is to be gained by commencing early aggressive antiretroviral therapy.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background:CD8+ T-cell counts usually increase soon after infection with HIV, whereas CD4+ cell counts decrease. The result of these changes in T-cell subpopulation subsets in most HIV-infected subjects is inversion of the CD4 : CD8 ratio from greater than 1.0 typical of uninfected persons to less than 1.0 after infection.Subjects:Six HIV-infected individuals were identified in whom the CD4 : CD8 ratio remained normal throughout follow-up (4.0–11.25 years). They all maintained levels of CD4+ cells above 500 × 106/l and had never received antiretroviral therapy. Because HIV-specific cytotoxic T lymphocytes (CTL) have been implicated in control of HIV during the asymptomatic phase of disease, we screened these individuals for the presence of HIV-specific CTL activity.Methods:CTL activity was assessed in freshly isolated peripheral blood mononuclear cells (PBMC) and in phytohaemagglutinin-stimulated interleukin-2 expanded cell lines established from PBMC. Cytotoxicity to HIV-1env,gag,polandnefgene products was surveyed in a 4 h51Cr-release assay using autologous Epstein-Barr virus (EBV) transformed B cells infected with vaccinia constructs expressing each of these HIV genes. The immunodominant CTL epitope and MHC class I antigen restriction specificity of HIV-specific CTL was mapped when present. Plasma viral load was assessed by branched DNA assay. Attempts were made to isolate virus from these individuals by the PBMC coculture assay.Results:None of the six immunologically normal HIV-infected (INHI) subjects exhibited direct HIV-specific CTL activity in their freshly isolated PBMC compared with 16 (47%) out of 34 HIV disease progressors (P= 0.03, χ2test) and one out of 10 seronegative subjects. Three of the six INHI subjects had detectable memory HIV-specific precursor CTL (pCTL) activity inin vitro-activated T-cell lines compared with 25 (73.5%) out of 34 HIV-1 disease progressors and in none out of 10 seronegative individuals. All three INHI subjects had Gag-specific pCTL, and none had reverse transcriptase-specific pCTL. Plasma HIV viraemia in all six INHI subjects was below the level of detection by branched DNA assay (< 500 copies/ml). Virus could not be isolated from four of these individuals despite multiple attempts to do so by PBMC coculture assays.Conclusions:Direct HIV-specific CTL activity mediated by activated circulating PBMC was undetectable in six INHI individuals under conditions where it is frequently observed in HIV disease progressors. Despite the absence of cells activated for killing HIV-infected targets in the circulation of these individuals, they appeared able to control their HIV infection by maintaining normal levels of CD4 and CD8 cells and low viral load.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background:In healthy people, oral and pharyngeal epithelium preferentially carries Epstein-Barr virus (EBV) belonging to a genotype that possesses three copies of a 29 base-pair repeat in the first intron of theBZLF-1gene, while peripheral blood mostly carries a genotype that bears two copies. Whether EBV shows differential tropism in HIV-1-coinfected hosts, who are prone to develop oral hairy leukoplakia, has not been studied.Methods:Tongue scrapings and CD45+-enriched peripheral blood cells of 20 HIV-1-infected patients and 40 healthy controls were examined. EBV-specific DNA was amplified from segments in the first intron of theBZLF-1gene, in exon C of theLMP-1gene, and the type A/B-specifying domain of theEBNA-3Cgene. Size polymorphisms of these amplicons were assessed by agarose gel electrophoresis, and DNA sequence differences amongBZLF-1gene amplicons by single-strand conformation polymorphism analysis.Results:The predominant EBV genotype in peripheral blood as well as tongue carried two copies of theBZLF-1repeat. In controls, although theBZLF-1genotype with two copies was exclusively detected in the blood, the genotype with three copies predominated in the tongue. The findings could not be correlated with EBV genotyped according size polymorphisms in theEBNA-3CorLMP-1genes. DNA sequences of a proportion or all of the clones derived from theBZLF-1amplicons in the tongues of HIV-1-infected patients were identical to those in the blood.Conclusions:These findings are consistent with EBV haematogenous superinfection of the tongue of HIV-positive individuals. Such superinfection may precede or lead to the development of oral hairy leukoplakia.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To discriminate cases of visceral leishmaniosis (VL) following a primary infection from cases originating in a reactivation of a latentLeishmaniainfection and to assess the impact of CD4+ T-cell counts on the occurrence of VL in patients with HIV disease.Methods:We searched by Western blotting for the presence ofLeishmania infantum-specific antibodies in the sera of 236 HIV-positive patients. We performed a follow-up of antileishmanial serology and analysed the evolution of the CD4+ T-cell counts for 14 HIV-positive VL patients and for 18 HIV-positiveLeishmania-seropositive patients without VL.Results:This study (1) showed that the VL disease/Leishmaniainfection ratio in HIV-positive individuals is high (1 : 10); (2) discriminated between a primaryLeishmaniainfection (five patients who converted fromLeishmania-seronegative toLeishmania-seropositive) and a reactivation of a latent infection (seven patients); (3) showed that HIV-positive individuals with dramatically low CD4+ T-cell counts maintained or generated a specific antileishmanial antibody production; (4) demonstrated that the primary-VL appeared at significantly higher (P= 0.028) CD4+ T-cell levels than the reactivation-VL; (5) documented the existence of HIV-positiveLeishmania-seropositive individuals who despite a severe and prolonged immunosuppression did not develop VL (eight of 18).Conclusion:Our data stress the utility of the follow-up by Western blotting for an early diagnosis of VL, and therefore an early treatment, for HIV-positive patients living in endemic areas. They suggest that in a latentLeishmaniainfection supplementary control mechanism(s) might operate in addition to the T-cell-mediated response, and provide a further example of non-appearance of an opportunistic infection despite a severe reduction in CD4+ T cells.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Introduction:Regeneration of CD4+ T lymphocytes has been shown to be thymus-dependent in bone marrow transplant recipients and after intensive chemotherapy. The rate of CD4+ T cell regeneration is correlated positively with enlargement of the thymus, as shown on radiographs, and higher rates of CD4+ T lymphocyte regeneration were observed in children as compared with adults, consistent with thymic function diminishing with age. We hypothesized that in HIV infected patients CD4+ T cell recovery during highly active antiretroviral therapy (HAART) may also be thymus dependent. Therefore, repopulation of naive (CD45RA+), memory (CD45RO+) and total CD4+ T lymphocytes and total CD8+ T lymphocytes in peripheral blood was assessed in 13 HIV infected children during the initial 3 months of HAART.Results:Significantly higher recovery rates of naive, memory and total CD4+ T cells were observed in children below the age of 3 years as compared with older children. Kinetics of total CD8+ T cells showed no relation to age. Moreover, recovery rates of naive CD4+ T cells in patients below 3 years of age were 10–40 fold higher as compared with previously reported naive CD4+ T cell recovery rates in adults on HAART.Conclusions:High recovery rates of naive, memory and total CD4+ T cells can be achieved in children below 3 years of age. Changes in CD8 counts did not correlate with age. These results indicate that regeneration of CD4+ T cells during HAART may be a thymus-dependent process.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID