摘要:

Objective:To determine markers that are associated with the durability of virologic response to therapy with HIV protease inhibitors in HIV-infected individuals.Design:This study encompassed two retrospective analyses of the duration of virologic response to protease inhibitor therapy. The first analysis included 29 patients receiving either monotherapy or combination therapy with the protease inhibitor ritonavir whose plasma HIV RNA levels rebounded from the point of greatest decline with mutations associated with resistance to ritonavir. The second analysis included a cohort of 102 patients who initially responded to randomized treatment with either monotherapy with ritonavir or combination therapy with ritonavir and zidovudine.Methods:Durability of response was defined as the time from the initiation of therapy to the point at which plasma HIV RNA displayed a sustained increase of at least 0.6 log10copies/ml from the nadir value. In the first analysis, durability of response was analyzed with respect to baseline HIV RNA, HIV RNA at the nadir, and the drop in HIV RNA from baseline to the nadir. In the second analysis, time to rebound was examined using Kaplan–Meier analysis, stratifying by either baseline HIV RNA or HIV RNA at the nadir.Results:In both analyses, the durability of response was not highly associated with either baseline RNA or the magnitude of RNA decline from baseline. Instead, a strong relationship was observed between the durability of response and the nadir plasma HIV-1 RNA value (P< 0.01). The nadir in viral load was generally reached after 12 weeks of randomized therapy.Conclusions:Viral RNA determinations at intermediate timepoints may be prognostic of impending virologic failure of protease inhibitor therapy. Therapeutic strategies that allow intensification of initial antiretroviral regimens in the subset of patients with incomplete virological response before the emergence of high level resistance should be investigated.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objectives:To investigate whether immunization with recombinant HIV-1 envelope protein derived from a clinical isolate could protect macaques from infection with anin vivopassaged chimeric simian–human immunodeficiency virus (SHIV).Design and methods:A total of 16 animals were studied from which three groups of four animals were immunized with vaccine formulations of the CC-chemokine receptor-5-binding recombinant gp120 of HIV-1W6.1D. Four weeks after the last immunization, all 16 animals were intravenously challenged within vivopassaged SHIV derived from the same HIV-1 group B clinical isolate (W6.1D) as the vaccines.Results:Vaccine protection from infection was demonstrated in 10 out of 12 macaques immunized with recombinant gp120. Complete protection from infection was achieved with all of the animals that received the SBAS2–W6.1D formulation, a potent inducer of both T-cell and humoral immune responses. Partial protection was achieved with SBAS1–W6.1D, a formulation based on immunomodulators known to induce T-cell responses in humans. In vaccinated animals that were infected, virus load was reduced and infection was delayed.Conclusions:In a relatively large number of primates, vaccine efficacy was demonstrated with a clinically relevant HIV-1 vaccine. These results reveal that it is possible to induce sterilizing immunity sufficient to protect from infection with SHIV which was passaged multiple timesin vivo. Our findings have implications for current HIV-1 clinical vaccine trials and ongoing efforts to develop safe prophylactic AIDS vaccines.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To determine the value of plasma HIV-1 RNA and CD4 cell count as predictors of the clinical benefit of antiretroviral treatment.Design and setting:The CAESAR (Canada, Australia, Europe, South Africa) trial randomized 1840 patients (inclusion CD4 cell count, 25–250 × 106/l) to add either placebo, lamivudine (3TC) or 3TC plus loviride in a double-blinded fashion to baseline treatments (zidovudine, zidovudine–didanosine or zidovudine–zalcitabine) for 1 year.Patients:This analysis included 487 patients with data on CD4 cell count and HIV-1 RNA after 12–20 weeks of treatment and subsequent follow-up for clinical progression.Main outcome measures:The correlation between 12–20-week change in CD4 cell count, HIV-1 RNA and progression to AIDS or death in the placebo group was used to predict the clinical benefit of the 3TC-containing arms of the trial, given their effects on CD4 cell count and HIV-1 RNA.Results:After 12–20 weeks of treatment, HIV-1 RNA fell by 0.37 log10copies/ml in the 3TC arms versus a rise of 0.05 log10copies/ml in the placebo arm. The 12–20-week CD4 cell count rose by 35 × 106/l in the 3TC arm versus a fall of 8 × 106/l in the placebo arm. After 12–20 weeks of treatment, a reduction in HIV-1 RNA of 1 log10at 12–20 weeks predicted a 49% reduction in progression [hazard ratio (HR), 0.51; 95% confidence interval (CI), 0.30–0.87] and a rise in CD4 cell count of 50 × 106/l predicted a 51% reduction in progression (HR, 0.49; 95% CI, 0.33–0.73). Using the model from the placebo arm, the rises in CD4 cell count and reductions in HIV-1 RNA during 3TC treatment predicted a 59% reduction in progression to AIDS or death. The observed clinical benefit was a 57% reduction in progression for the 3TC arms versus placebo (HR, 0.43; 95% CI, 0.26–0.71).Conclusions:Rises in CD4 cell count and reductions in HIV-1 RNA were reliable in predicting the clinical benefit of 3TC in the CAESAR trial.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To determine whether HIV and sexually transmitted disease (STD) incidence rates among young men in northern Thailand have declined since the establishment of the ‘100% Condom Program’, and to prospectively document changes in the association between behavioral risk factors and incident HIV and STD infections.Setting:Thirteen military bases in northern Thailand.Methods:Serial prospective cohorts of 19–23-year-old male conscripts (n = 4086) inducted into military service from six northern Thai provinces between 1991 and 1993 were followed at 6-month intervals for incident HIV and STD through May 1995. HIV incidence was determined by serology, and incident STD were reported by conscripts as diagnosed by health-care providers.Results:HIV incidence declined from a rate of 2.48 per 100 person-years during 1991–1993 to 0.55 per 100 person-years during 1993–1995. STD incidence showed an even greater decline, with a 10-fold decrease from 1991–1993 to 1993–1995. Behavioral risk factors for incident STD infections included a history of prior STD and sex with girlfriends and sex workers. Inconsistent condom use remained a strong predictor of incident STD among brothel visitors. Other previously-reported risk factors in 1991–1993 such as illicit drug use, frequency and cost of brothel visits, and low socioeconomic status were not associated with incident STD or HIV in 1993–1995.Conclusions:Although several studies have recently reported decreased prevalence of HIV and STD infections in Thailand, these data demonstrate that a dramatic decrease in the incidence rates of STD, including HIV infection, has occurred among young men in military service in northern Thailand. The Thai AIDS prevention and control program might be implemented by other countries experiencing major epidemics of heterosexually transmitted HIV infections. Similar prevention programs targeted at other populations in Thailand and elsewhere in Asia are needed to decrease the spread of the HIV epidemic.

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:

Objective:To calculate the expected prevalence of resistant HIV mutants before antiviral therapy.Design:HIV replication generates virus mutants. The prevalence of these mutants is determined by mutation and selection/fitness. Some mutations will confer drug resistance and it is crucial for the success of antiviral drug therapy to determine whether these resistant viruses are present before the initiation of therapy.Methods:A quasispecies equation was used to calculate the expected frequency of drug-resistant virus prior to therapy.Results and conclusions:We show how the pretreatment frequency of resistant virus depends on the number of point mutations between wild-type and mutant virus, the selective disadvantage of the resistant mutant and the intermediate mutants, and the mutation rate.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To develop anin vitromodel for infection of primary human cells with Kaposi's sarcoma (KS) herpesvirus (KSHV).Design:The recent identification of a herpesvirus associated with KS, its successful isolationin vitro, and its complete DNA sequencing facilitates experiments on the pathogenesis of AIDS-related KS. Completed studies demonstrate that the endothelial cells lining the vascular slits in KS lesions are productively infected with KSHV and may be the principal site of virus replication. We have designed a model system to study the infection of primary human cells with KSHV.Methods:A coculture technique was used with KS cells (KS-1) and primary dermal microvascular endothelial cells.Results:We detected increasing viral DNA concentrations as well as viral mRNA suggesting that a productive virus infection occurs in the target cells. Infection of these cells is dose- and time-dependent and is inhibited by lobucavir, foscarnet and 9-(2-phosphomethoxyethyl) adenine. With a modification of the model, KSHV can be serially passaged in primary cells in excess of 16 passages.Conclusions:This novel model assay system makes new studies on the role of KSHV and KSHV-induced cellular products on the pathogenesis of KS possible. It also provides a high volume screening method to detect agents that inhibit KSHV infection of primary endothelial cells.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To alter the natural course of HIV-1 infection by inducing or potentiating immune responses to HIV-1 envelope glycoprotein.Design:Multicentre, double-blind, three-arm, placebo-controlled study.Setting:Outpatients attending clinics in two University Hospitals.Patients:Ninety-nine asymptomatic HIV-1-infected adults with CD4+ T-cell counts > 400 and < 600 × 106/l and no previous antiretroviral therapy were included.Interventions:Patients were randomly assigned to three groups treated with: (i) gp160 in alum over a 2-year period in combination with placebo for the full study duration (n = 32); (ii) gp160 in alum over a 2-year period in combination with zidovudine for the full study duration (n = 34); and (iii) alum over a 2-year period in combination with zidovudine for the full study duration (n = 33).Results:Immunotherapy was well tolerated and no significant differences in disease progression were seen in the treatment groups. The majority of patients (85%) receiving gp160 showed persistent lymphoproliferative responses to the immunogen and to a different Env antigen preparation. CD4+ cell count changes in patients receiving zidovudine alone were significantly higher than those seen in patients receiving immunotherapy alone after 1 year of treatment. Zidovudine administration was associated with initial transient reduction of plasma viraemia.Conclusions:Prolonged immunization with a soluble HIV-1 subunit provided no benefit to asymptomatic HIV-1-infected patients and was inferior to zidovudine monotherapy. Furthermore, immunization with gp160 shortened the duration of the transient viral load reduction induced by zidovudine.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background:The T-cell stimulatory function of accessory cells isolated from peripheral blood lymphocytes of AIDS patients has been reported to be suppressed. These patients also have elevated levels of the immunosuppressive factor transforming growth factor (TGF)-β1 in their serum and plasma.Objective:To explore the role of TGF-β1 in the loss of accessory cell function of peripheral blood lymphocytes from AIDS patients.Methods:Fluorescent labeled anti-TGF-β1 and confocal microscopy were used to detect the presence of TGF-β1 on the cell membrane of dendritic cells. To assess the role of TGF-β1 in the inhibition of accessory cell function in AIDS, antibodies against TGF-β1 or the TGF-β1 type III receptor, β-glycan, were added to a mixed lymphocyte reaction.Results:TGF-β1 was detected on the cell membrane of dendritic cells isolated from AIDS patients. The addition of blocking antibodies against either TGF-β1 or β-glycan restored the T-cell stimulatory function to accessory cells from these patients.Conclusions:T-cell stimulatory function was not irreversibly lost in AIDS patients. Our data suggested that β-glycan-TGF-β1 immunosuppressive complexes may contribute to the suppression of accessory cell function in these patients.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To examine tolerance and efficacy of a zidovudine plus lamivudine combination in HIV-infected children without previous exposure to antiretroviral drugs.Methods:Thirteen vertically infected children (aged 4 months to 10 years) were treated with zidovudine (approximately 100 mg/m2three times daily) and lamivudine (4 mg/kg twice daily). CD4 T-cell count, plasma HIV RNA concentration, complete blood count and blood chemistry profile were monitored before treatment and at months 1, 3 and 6.Results:In general, treatment was well tolerated. One child developed slight neutropenia in the presence of antineutrophil antibodies. CD4 cell count increased from 851 ± 621 × 106/l at baseline to 1073 ± 945 × 106/l at month 3 (P< 0.05) and to 1133 ± 728 × 106/l at month 6 (P= 0.01). CD4+ cell count increased in 10 patients after 3 months and in 11 patients treated for 6 months. One child showed a continuous decrease of CD4 cells despite treatment. Before treatment the plasma HIV RNA concentration was elevated in nine children (> 4.0 log10copies/ml) and decreased in all of them: by month 1, the mean reduction was −1.16 log10copies/ml; by month 3, −1.38 log10copies/ml; and by month 6, −1.53 log10copies/ml compared with baseline. However, one child showed steadily increasing viral load from 2.7 log10copies/ml to a maximum of 4.52 log10copies/ml, surprisingly in association with increasing numbers of CD4 cells. This child was switched to a new combination regimen after 6 months of treatment. Plasma HIV RNA levels below limit of detection were reached in six patients: after 1 month of treatment in one patient, after 3 months in five patients, and after 6 months in six patients. There was a mean reduction of viral load from 4.56 log10± 4.63 log10copies/ml (n = 13) to 3.8 log10± 3.9 log10copies/ml (P< 0.05; n = 9) after 1 month, to 3.67 log10± 3.88 log10copies/ml (P< 0.01; n = 13) after 3 months, and to 3.64 log10± 3.95 log10copies/ml after 6 months of treatment (P< 0.001; n = 13).Conclusions:This pilot study demonstrates the feasibility of zidovudine-lamivudine combination in children not previously exposed to antiretroviral drugs. This promising combination should therefore be evaluated in larger trials.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID