ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To characterize reverse transcriptase (RT) mutations by their association with extent of nucleoside RT inhibitor (NRTI) therapy. To identify mutational clusters in RT sequences from persons receiving multiple NRTI.Design:A total of 1210 RT sequences from persons with known antiretroviral therapy were analyzed: 641 new sequences were performed at Stanford University Hospital; 569 were previously published.Methods:Chi-square tests and logistic regression were done to identify associations between mutations and NRTI therapy. Correlation studies were done to identify mutational clusters. The Benjamini–Hochberg procedure was used to correct for multiple comparisons.Results:Mutations at 26 positions were significantly associated with NRTI including 17 known resistance mutations (positions 41, 44, 62, 65, 67, 69, 70, 74, 75, 77, 116, 118, 151, 184, 210, 215, 219) and nine previously unreported mutations (positions 20, 39, 43, 203, 208, 218, 221, 223, 228). The nine new mutations correlated linearly with number of NRTI; 777 out of 817 (95%) instances occurred with known drug resistance mutations. Positions 203, 208, 218, 221, 223, and 228 were conserved in untreated persons; positions 20, 39, and 43 were polymorphic. Most NRTI-associated mutations clustered into three groups: (i) 62, 65, 75, 77, 115, 116, 151; (ii) 41, 43, 44, 118, 208, 210, 215, 223; (iii) 67, 69, 70, 218, 219, 228.Conclusions:Mutations at nine previously unreported positions are associated with NRTI therapy. These mutations are probably accessory because they occur almost exclusively with known drug resistance mutations. Most NRTI mutations group into one of three clusters, although several (e.g., M184V) occur in multiple mutational contexts.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To assess the frequency of shedding of polyomavirus JC virus (JCV) genotypes in urine of HIV-infected patients receiving highly active antiretroviral therapy (HAART).Methods:Single samples of urine and blood were collected prospectively from 70 adult HIV-infected patients and 68 uninfected volunteers. Inclusion criteria for HIV-infected patients included an HIV RNA viral load < 1000 copies, CD4 cell count of 200–700 × 106cells/l, and stable HAART regimen. PCR assays and sequence analysis were carried out using JCV-specific primers against different regions of the virus genome.Results:JCV excretion in urine was more common in HIV-positive patients but not significantly different from that of the HIV-negative group [22/70 (31%) versus 13/68 (19%);P= 0.09]. HIV-positive patients lost the age-related pattern of JCV shedding (P= 0.13) displayed by uninfected subjects (P= 0.01). Among HIV-infected patients significant differences in JCV shedding were related to CD4 cell counts (P= 0.03). Sequence analysis of the JCV regulatory region from both HIV-infected patients and uninfected volunteers revealed all to be JCV archetypal strains. JCV genotypes 1 (36%) and 4 (36%) were the most common among HIV-infected patients, whereas type 2 (77%) was the most frequently detected among HIV-uninfected volunteers.Conclusion:These results suggest that JCV shedding is enhanced by modest depressions in immune function during HIV infection. JCV shedding occurred in younger HIV-positive persons than in the healthy controls. As the common types of JCV excreted varied among ethnic groups, JCV genotypes associated with progressive multifocal leukoencephalopathy may reflect demographics of those infected patient populations.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To study the impact of antiretroviral therapy on the tropism of plasma HIV-1 virus populations during treatment response and virological escape.Design:To investigate whether the selective pressure exerted by antiretroviral treatment influences the tropism of the plasma virus populations, we retrospectively determined the co-receptor usage of viruses present in plasma samples obtained before and at varying intervals after starting antiviral therapy.Methods:The co-receptor usage of plasma virus was determined using our recently published tropism recombinant test (V. Trouplinet al., J Virol, 2001; 75:251–259). This assay relies on virus production by homologous recombination between a plasmid encoding the entire HIV genome except for a deletion of the major tropism determinant, and a polymerase chain reaction (PCR) product spanning this region and the adjoining flanking sequences, obtained by reverse transcriptase (RT)-PCR amplification of viral RNA from the patient's plasma.Results:Twenty-four of the 32 patients analysed harboured exclusively R5 virus in plasma before the initiation of treatment, whereas eight had mixed R5/X4 virus populations. In four of these eight patients, all of whom initially responded to treatment, the persistence of R5 virus in plasma was observed, whereas the X4 component of the virus population became undetectable. The suppression of the X4 virus component was a transient phenomenon and variants able to use CXCR4 re-emerged after a variable delay.Conclusions:The impact of therapy on virus populations differs according to virus tropism. Differences in target cell populations, tissue distribution and replication characteristics between R5 and X4 viruses could explain the preferential suppression of X4 virus.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:We explored the relevance of simple markers (clinical or laboratory markers not requiring sophisticated laboratories) in the decision of initiation of therapy in resource-poor settings.Methods:Among HIV-infected Ethiopian cohort participants, simple markers predicting short-term death were examined using time-dependent Cox proportional hazards models. Timing of hypothetical treatment was compared between guidelines using the simple markers (based on presence of at least one marker), guidelines recommended by the United States Department of Health and Human Services (based on CD4 cell count and viral load), and guidelines for resource-limited settings recommended by the World Health Organization (WHO).Results:From February 1997 to August 2001, 35 deaths were recorded among 155 HIV-positive participants. Simple independent predictors of death were low body mass index, HIV-related conditions, anaemia, and lymphocyte count < 1500 × 106/l. In such time as was covered by our study, 135 (87%) of 155 cohort participants would have had the same management under both the simple markers and the DHHS guidelines, i.e., would have been treated (n = 114, 74%) or not treated (n = 21, 14%). Of the 114 participants hypothetically treated under either set of guidelines, 91 (80%) would have started treatment at the same time. Application of the WHO guidelines for resource-limited settings (without CD4 cell counts) would have resulted in 11 participants dying without ever meeting a treatment indication during regular follow-up visits.Conclusion:Simple markers for the initiation of highly active antiretroviral therapy were identified among HIV-infected Ethiopian patients. The validity of these markers for monitoring patients’ improvement following therapy remains to be evaluated.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To evaluate phenotypic drug susceptibility and non-nucleoside reverse transcriptase inhibitor hypersusceptibility as predictors of the time to virological failure.Design:In a randomized clinical trial, phenotypic susceptibility was retrospectively determined among 131 exclusively nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients with baseline HIV-RNA levels greater than 2000 copies/ml. Subjects were assigned two NRTI drugs and were randomly assigned to nelfinavir, efavirenz, or both. Virological failure was defined as two HIV-RNA measurements of 2000 copies/ml or greater at or after week 16 and before treatment discontinuation.Methods:Using biological cut-offs to define resistance, assigned NRTI and randomized drug regimens, continuous and dichotomous phenotypic susceptibility scores (PSS) were calculated for each virus. Efavirenz hypersusceptibility as a dichotomous value was defined as less than 0.4-fold resistance. Associations between virological failure and continuous and dichotomous PSS were evaluated using Kaplan–Meier curves and Cox proportional hazards regression models.Results:A higher baseline viral load (P< 0.02) and lower dichotomous or continuous baseline PSS (P= 0.004 andP< 0.001, respectively) were independently associated with virological failure. In the 85 subjects who received efavirenz, efavirenz hypersusceptibility (P= 0.042, hazard ratio 0.43, 95% confidence interval 0.19–0.97) was independently associated with a reduced risk of virological failure.Conclusion:Reduced phenotypic susceptibility was a significant independent risk factor for virological failure. The presence of efavirenz hypersusceptibility appeared to enhance virological responses during treatment with efavirenz in combination with NRTIs. The retrospective calculation of continuous PSS accurately identified treatment regimens containing sufficient drug activity to prevent virological failure.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To compare continued indinavir (IDV) 8-hourly (q8h) with switching to indinavir/ritonavir (IDV/RTV) 12-hourly (q12h) in HIV-positive patients having suppressed viral load with IDV q8h plus two nucleoside reverse transcriptase inhibitors (NRTI).Design:Multicentre, international, randomized, open-label study enrolling HIV-1 infected patients on IDV 800 mg q8h plus two NRTI with CD4 cell counts ⩾ 100 × 106/l and plasma HIV RNA < 500 copies/ml for ⩾ 3 months.Methods:Patients were randomized to continue on the same regimen or to switch to IDV plus liquid RTV (IDV/RTV 800 mg/100 mg q12h). Primary endpoint was the proportion of patients remaining < 500 copies/ml at 48 weeks.Results:A total of 323 patients (IDV/RTV, 162; IDV, 161) were evaluable. At 48 weeks, the proportions of patients with plasma HIV RNA < 500 copies/ml were 93%, 88% and 58% in the IDV/RTV arm versus 92% (P= 1), 86% (P= 0.87) and 74% (P= 0.003) in the IDV arm using on-treatment (OT) and intent-to-treat (ITT) [switches included (ITT, S = I) and switches = failure (ITT, S = F)] analyses respectively. Mean increase in CD4 cell count was 88 × 106/cells/l (IDV/RTV arm) and 60 × 106cells/l (IDV arm) (P= 0.08). More patients discontinued study medication due to adverse events in the IDV/RTV arm than in the IDV arm (P< 0.001).Conclusions:Equivalence of continuing IDV q8h versus switching to IDV/RTV (liquid) q12h in suppressed stable patients was demonstrated by OT and ITT S = I analyses. However, the IDV q8h arm performed better when discontinuations were classified as failures. IDV/RTV q12h can be convenient and equally effective for patients able to tolerate it.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:IL-2 therapy increases memory and naive CD4 T cells in HIV-infected patients, but its effect on thymopoiesis is unknown. To investigate this effect, we quantified T-cell receptor rearrangement excision circles (TREC) in CD4 T cells from lymphopenic AIDS patients treated with highly active antiretroviral therapy and IL-2.Methods:CD4 cell subsets were evaluated by flow cytometry using anti-CD45RO/RA, CD62L, Ki67 and CD95 monoclonal antibodies. The proportion of recent thymic emigrant had been quantified by a real-time polymerase chain reaction assay for signal joint TREC in peripheral blood mononuclear and purified CD4 T cells.Results:At initiation of IL-2, TREC copies/μl of blood were correlated with naive T cell numbers and age. Both naive and TREC numbers/μl significantly increased over time in all patients, with a wide range of TREC increases. Higher percentages of CD4+CD45RO-negative cells positive for the Ki67 cell-cycle marker were found in patients with a low TREC increase, but remained stable under IL-2. TREC and naive cell recovery were correlated; they also correlated with the numbers of TREC and naive cells at the start of IL-2, and with age, suggesting a thymic origin for naive T-cell recovery. A mathematical model showing the linear recovery of naive cells and TREC under IL-2 also strongly suggested that a naive T-cell increase reflects thymic export and involves little net death and proliferation.Conclusion:Although we cannot rule out a mechanism of altered proliferation or death rate, the thymus plays an important role in the long-term recovery of naive T cells under IL-2 therapy.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:the aim of our work is to evaluate the role of statins and fibrates in the management of hyperlipidaemia in HIV-infected patients receiving highly active antiretroviral therapy.Design:Open-label, randomized, prospective study of the efficacy and safety of bezafibrate, gemfibrozil, fenofibrate, pravastatin and fluvastatin as pharmacologic treatment for protease inhibitor-related dyslipidaemia.Methods:Plasma lipid levels of 656 HIV-infected patients who referred to our tertiary care centre and were on protease inhibitor-based antiretroviral therapy for at least 12 months have been evaluated. All patients had HIV viral load < 50 copies/ml and presented with hypertriglyceridaemia of at least 6 months duration that was unresponsive to a hypolipidaemic diet; all have been treated with bezafibrate, gemfibrozil, fenofibrate, pravastatin, or fluvastatin for 12 months.Results:Of the 656 patients observed 113 (17.2%) received pharmacological therapy, while seven patients were excluded from evaluation due to early drop-out. Of the 106 evaluable subjects, bezafibrate was used in 25 cases, gemfibrozil in 22, fenofibrate in 22, pravastatin in 19, and fluvastatin in 18. At the close of 1-year follow-up, fibrates led to a reduction of 40.7% and 21.9% versus baseline triglyceridaemia and cholesterolaemia, respectively (P< 0.001), and statins led to a reduction of 34.8% and 25.2% versus baseline triglyceride and total cholesterol levels, respectively (P< 0.001), without significant differences according to each different administered hypolipidaemic drug.Conclusions:All administered statins and fibrates revealed a similar, significant efficacy in the treatment of diet-resistant hyperlipidaemia, and showed a favourable tolerability profile.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID