ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo investigate the genotypic and phenotypic effects ofin vitroresistance selection with lamivudine and/or the second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) quinoxaline HBY097 using HIV-1 isolates carrying the multi-nucleoside resistance pattern linked to the Q151M mutation.MethodsVirus strains were selected in C8166 cells in the presence of increasing concentrations of lamivudine or HBY097. In parallel control experiments, the virus was cultured in C8166 cells in the absence of drugs. The entire reverse transcriptase encoding region was amplified using polymerase chain reaction and was subsequently sequenced. Antiviral activities of drugs were evaluated in C8166 cells.ResultsHigh-level resistant viruses were selected rapidly in the presence of lamivudine and quinoxaline (less than 10 passages). The multi-nucleoside resistance mutations were stable duringin vitroresistance selection. Lamivudine elicited the acquisition of the M184I mutation. Phenotypic resistance to all nucleoside-analog reverse transcriptase inhibitors (NRTIs) was increased when M184I was added to the multi-nucleoside resistance background in the absence of NNRTI-resistance mutations. In most cases of HBY097 resistance selection, at least two mutations associated with NNRTI resistance resulted in high-level NNRTI resistance. The NNRTI resistance-related mutations partially reversed the phenotypic resistance to most NRTIs, except to abacavir. The addition of the M184I mutation to the NNRTI-multi-nucleoside resistance set abolished this antagonizing effect for didanosine, zalcitabine and lamivudine, but further potentiated the phenotypic reversal for zidovudine and stavudine.ConclusionChanges in the non-nucleoside binding pocket must affect the conformation of residues at the dNTP binding site, and can result in a partial phenotypic reversal of the multi-nucleoside resistance phenotype.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo investigate the prevalence and relative titre of TT virus (TTV) DNA, and to examine the relationship between the extent of TTV viraemia and the immune status among 144 patients with HIV infection; 178 age- and sex-matched healthy individuals were also studied.MethodsTTV DNA was detected quantitatively by two distinct polymerase chain reaction (PCR) methods [untranslated region (UTR) and N22]. UTR PCR detects all TTV genotypes, and N22 PCR can primarily detect four major TTV genotypes (1–4).ResultsUsing UTR PCR and N22 PCR, respectively, TTV DNA was detected significantly more frequently in HIV-infected patients than in controls (99 versus 91%,P< 0.001; 56 versus 27%,P< 0.0001), and the relative titre (10N/ml) was significantly higher in HIV-infected patients [4.5 ± 1.2 (mean ± SD) versus 3.1 ± 0.9,P< 0.0001; 2.6 ± 1.5 versus 1.5 ± 0.9,P< 0.0001]. Age, sex, co-infection with hepatitis B or C virus, and risk factors for HIV transmission did not appear to be significant factors associated with the titre of TTV viraemia. However, the titre of TTV DNA was significantly higher in HIV-infected patients with AIDS (P< 0.0001), those with low CD4 T cell count (P< 0.0001), or those with high HIV viral loads (P= 0.0047).ConclusionTTV is highly prevalent and high-titred in HIV-infected patients. The TTV viral load may reflect the degree of immune status of these immunocompromised hosts.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo evaluate the correlation between immunohistochemical positive patterns (globular and filamentous structures) of β-amyloid precursor protein (β-APP), used as a marker of axonal damage, and the different distribution of HIV p24 antigens, in three different brain areas of AIDS patients.MethodsEighteen AIDS patients with HIV-related brain lesions were included in the study. Forty-nine sections from basal ganglia, frontal cortex and hippocampus were selected. After microwave oven pre-treatment, the sections were incubated with anti-HIV p24 and anti-β-APP monoclonal antibodies; the reactions were developed with peroxidase/3,3′diaminobenzidine. The positivity was graded by semi-quantitative scores. Double immunohistochemical staining was used to evaluate the co-localization of the antigens.ResultsHIV p24 immunohistochemistry was positive in 44 of 49 sections (89%), with a prevalence of interstitial positive cells and positive microglial nodules in 27 and 13 sections respectively. β-APP-positive structures were demonstrated in 23 of 44 sections (52%) with HIV-related lesions, and were absent from the five sections without viral expression. Globular and filamentous lesions were observed in 21 of 23 sections and 10 of 23 lesions respectively. Moreover, a high grade of globular type lesion was related to an elevated presence of diffuse interstitial HIV p24-positive cells in basal ganglia; double immunohistochemical reactions demonstrated the co-localization of β-APP globules and HIV p24 antigens.ConclusionsThe data obtained confirm the coexpression of β-APP and viral antigens in particular areas of the brain with HIV-related lesions; there is a strict correlation between β-APP globules (indicating chronic cerebral damage) and the interstitial pattern of HIV p24 immunohistochemistry.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo analyze V3 loop sequences of HIV-1 in three seropositive individuals who exhibited declines in viremia while receiving a V3-targeted vaccine.DesignRetrospective analysis of case series at an HIV Clinic, University of Tel Aviv.PatientsThree HIV-1-seropositive, PPD-DTHR-positive (PPD, Siebert purified protein derivative of tuberculin; DTHR, delayed type hypersensitivity reaction) individuals who had been inoculated with a mixture of PPD-cross-linked V3 peptides from five HIV strains and then exhibited declines in HIV-1 viremia during the course of vaccination in the absence of combination antiretroviral therapy and whose virus levels resurged once vaccine boosting was discontinued.ResultsDeclines in viremia were observed even when the viral V3 sequences of the patients’ HIV differed by at least one or two amino acid residues from those of the five peptides in the vaccine. Although viral mutants with amino acid substitutions within V3 appeared during vaccination, plasma virus loads remained at low levels for several months after these variants appeared. About a year after boosting was discontinued, anti-V3 peptide antibodies in the patients had declined and plasma virus returned to the prevaccination levels or higher. Compared with the isolates that predominated during the course of vaccination, the resurgent viruses contained zero to six amino acid residue differences in the V3 loop but few synonymous substitutions.ConclusionsViruses with altered V3 sequences did emerge but did not result in increased viremia during the course of vaccination. In two individuals where V3 mutations were absent in the virus that re-emerged after vaccine boosting ceased, resurgence could not have been a consequence of V3 changes.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo assess the safety, tolerance and activity of increasing doses of azithromycin in combination with pyrimethamine for the treatment of toxoplasmic encephalitis (TE) in patients with AIDS.DesignA phase I/II dose-escalation study of oral azithromycin in combination with pyrimethamine.SettingEight clinical sites in the United States.PatientsForty-two adult HIV-infected patients with confirmed or presumed acute TE.MethodsPatients were enrolled into three successive cohorts receiving azithromycin 900, 1200 and 1500 mg a day with pyrimethamine as induction therapy. The induction period was 6 weeks followed by 24 weeks of maintenance therapy.Main outcome measuresPatient response was evaluated clinically and radiologically.ResultsOf the 30 evaluable patients, 20 (67%) responded to therapy during the induction period. Ten experienced disease progression. Of the 15 patients who received maintenance therapy, seven (47%) relapsed. Six patients discontinued treatment during the induction period as a result of reversible toxicities. Treatment-terminating adverse events occurred most frequently among the patients receiving the 1500 mg dose.ConclusionThe combination of azithromycin (900–1200 mg a day) and pyrimethamine may be useful as an alternative therapy for TE among patients intolerant of sulfonamides and clindamycin, but maintenance therapy with this combination was associated with a high relapse rate. The combination was safe, but low-grade adverse events were common.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundThe timing of initiation of antiretroviral therapy is controversial. Current guidelines are heavily based on the principle of ‘hit early, hit hard', although the long-term implications of this approach are unknown.MethodsUsing Markov modeling and decision analysis we modeled the virologic outcomes over 10 years in a hypothetical population of 10 000 HIV-infected patients in which therapy (with the possibility of three sequential regimens before the development of multidrug-resistant virus) is started immediately versus starting progressively at rates of 5, 10, 15, 20 or 30% of the original population each year. The model used inputs from available clinical trial data: virologic success rate and durability of the response of the first and subsequent regimens. We performed one-way and two-way sensitivity analysis to evaluate changes in the input variables.ResultsIf therapy is started immediately in all patients, by 10 years 57% would be undetectable, but 38% would have detectable multidrug-resistant virus. In contrast, the population as a whole would have had better virologic outcomes if one waited before starting treatment at any progression rate; for example, initiating therapy in 10% of the subjects per year results in 64% of patients being undetectable and 24% with multidrug-resistant virus. Two-way sensitivity analysis demonstrates that immediate initiation should be at least 15 to 20% better than delayed antiretroviral therapy to justify immediate initiation of therapy over a wide range of success rates of the delayed start.ConclusionOur analysis, utilizing optimistic outcomes based on short-term clinical trials, provides a theoretical basis for questioning the current aggressive early use of therapy and should help prompt studies that look at when and how to start antiretroviral therapy.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo assess the effect of baseline HIV reverse transcriptase (RT) and protease sequence variation on virologic outcomes in a large cohort of antiretroviral-naive patients in British Columbia, Canada.MethodsPopulation sequencing of RT and protease was performed on baseline viral RNA of all antiretroviral-naive patients first seeking treatment in British Columbia between June 1997 and August 1998 (n = 479). Relative risks of virological failure associated with genotypic differences from a ‘standard’ HIV strain (HXB2) were assessed for up to 18 months.ResultsThe prevalence of key baseline mutations known to confer resistance to RT and protease inhibitors (PI) was 3.4 and 3.8%, respectively. No statistically significant impact on virologic outcomes could be established for these patients. However, the data suggest that some individuals (harboring a M184V mutation in RT or a V82I in protease) may have benefited from pre-therapy resistance tests. ‘Secondary’ mutations in the protease associated with resistance (e.g. codons 10, 36 or 63) were common, but the presence of these secondary mutations, either alone or in combination, did not appear to result in early loss of therapeutic virological suppression. Preliminary analyses suggest that an amino acid change at codon 35 in the protease may be associated with early treatment failure.ConclusionsThe results suggest that routine genotyping of naive patients about to start antiretroviral therapy would be of benefit to a relatively small proportion of the population. Secondary mutations associated with resistance to PI alone were not found to affect virologic outcomes significantly.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo characterize the pattern of HIV-1 susceptibility to protease inhibitors in patients failing an initial protease inhibitor-containing regimen.DesignA cross-sectional analysis of antiretroviral susceptibility.SettingHIV clinics in six metropolitan areas.PatientsEighty-eight HIV-infected adults with HIV RNA > 400 copies/ml after ⩾ 6 months of antiretroviral therapy, including the use of one protease inhibitor for ⩾ 3 months.MeasurementsThe frequency and magnitude of decreased susceptibility, measured with a phenotypic assay using recombinant constructs, to five protease inhibitors. Decreased susceptibility was defined as > 2.5-fold increase in the 50% inhibitory concentration (IC50) compared with drug sensitive control virus.ResultsAt study entry, patients were being treated with nelfinavir (63%), indinavir (25%), or another protease inhibitor (11%). HIV isolates from these patients were susceptible (fold change < 2.5) to all five protease inhibitors in 18% of patients and to none in 8%. Isolates from patients receiving nelfinavir were less likely to have reduced susceptibility to other protease inhibitors than isolates from patients treated with indinavir (P< 0.001) or one of the other three agents (P< 0.001), even after adjustment for the duration of prior protease inhibitor use. Reduced susceptibility to saquinavir and amprenavir was observed significantly less frequently than for the other protease inhibitors.ConclusionThe frequency of protease inhibitor cross-resistance and the magnitude of changes in susceptibility varied according to the initial protease inhibitor used in the failing treatment regimen. Significantly less protease inhibitor cross-resistance was demonstrated for isolates from patients failing a nelfinavir-containing regimen compared with those from patients receiving other protease inhibitors.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID