摘要:

Background:The immunological response to HIV-1 infection has been postulated to impede superinfection with a second virus; however, a few recent reports have documented cases of HIV-1 superinfection in humans either from different viral clades or from the same clade.Objective:To differentiate between co-infection and superinfection in a patient harboring a distinct wild-type HIV 4 months after primary infection with drug-resistant HIV.Methods:Detailed dye primer and clonal sequencing along with length polymorphism analysis was used to investigate the evolutionary linkage between viral populations sampled at different timepoints.Results:After a set point viral load of −6000 copies HIV RNA/ml, the viral load jumped to 34 000 copies/ml at month 4 and, shortly after, to almost 200 000 copies/ml. At that time a second viral strain was first detected by dye primer sequencing of apolfragment. These findings were confirmed by analysis of a 1300 bpgag–polfragment and clonal sequencing and phylogenetic analysis of the V3 region. Length polymorphism analysis of the gp120 V4–V5 region showed that the second viral population was absent even as a minority population until month 4, when it was found to be the majority population, and the initial variant was present only as a minority. Both strains were subtype B.Conclusion:These data support intraclade HIV-1 superinfection by wild-type virus in the absence of antiretroviral therapy in a patient initially infected with drug-resistant HIV. The substantially different in-vivo viral growth characteristics observed illustrate the potential for superinfection to impact disease progression.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:Immune reconstitution after highly active antiretroviral therapy (HAART) in HIV-infected patients has led to an increase in the number of new CD4 T lymphocytes. Neolymphopoiesis in the thymus has been proposed as a mechanism in T-cell regeneration. Nevertheless, factors involved in the regeneration of T cells by thymic-dependent pathways in HIV-infected patients under HAART are still unknown and might be of relevance in HIV infection. The aim of this work was to study the role of IL-7 in the thymic rebound of HIV-infected adults under HAART.Design:To study the association between IL-7 and thymic function-related markers, these variables were measured in 49 antiretroviral-naive HIV-infected patients at baseline and at weeks 12, 24, 36 and 48 of treatment.Methods:Thymic function-related markers: thymic volume, naive phenotype, and T-cell receptor excision circles (TREC) bearing-cells, were evaluated by computed tomography, flow cytometry, and quantitative polymerase chain reaction, respectively. IL-7 levels were evaluated using a high sensitivity colorimetric enzyme-linked immunosorbent assay.Results:At baseline, we found an inverse correlation between IL-7 levels and thymic function-associated parameters: thymic volume, naive T cells and TREC-bearing cells. After 48 weeks of therapy increased levels of thymic function-related markers along with a significant decrease in IL-7 levels were found. IL-7 levels at baseline were the only independently associated variable with respect to changes in thymic volume at weeks 12, 24 and 48 of follow-up.Conclusion:These data suggest that IL-7 plays an important role in thymic rebound in adult HIV-infected patients under HAART.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:Current genotypic algorithms suggest that the HIV-1 protease inhibitors (PI) lopinavir (LPV) and amprenavir (APV) have distinct resistance profiles. However, phenotypic data indicate that cross-resistance is more common than expected.Methods:Protease genotype (GT) and phenotype (PT) from 1418 patient viruses with reduced PI susceptibility and/or resistance-associated mutations (training data) were analyzed. Samples were classified as LPV resistant by GT (GT-R) if six or more LPV mutations were present, and by PT (PT-R) if the 50% inhibitory concentration (IC50) fold-change (FC) was over 10.Results:There were 182 samples (13%) that were GT-S but PT-R for LPV. A comparison of the mutation prevalence in PT-R/GT-S samples with that in PT-S/GT-S samples identified mutations associated with LPV PT-R. Several previously defined LPV mutations were found to have a stronger than average effect (e.g., M46I/L, I54V/T, V82A/F), and new variants at known positions (e.g., I54A/M/S, V82S) were identified. Other mutations, including known APV resistance mutations, were found to contribute to reduced LPV susceptibility. A new LPV genotypic interpretation algorithm was constructed that improved overall genotypic/phenotypic concordance from 80% to 91%. The algorithm demonstrated a concordance rate of 90% when tested on 523 new samples. Cross-resistance between APV and LPV was greater in samples with primary APV resistance mutations than in those lacking them.Conclusions:The current LPV mutation score does not fully account for many resistant viruses. Consequently, cross-resistance between LPV and APV is underappreciated. Phenotypic results from large and diverse patient virus populations should be used to guide the development of more accurate GT interpretation algorithms.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:To study the long-term CD4 cell responses to highly active antiretroviral therapy (HAART) in treatment-naive patients whose viral loads remained below 500 copies/ml for prolonged periods.Design:A total of 237 patients whose viral loads remained below 500 copies/ml for one year or more. Median follow-up was 1.9 years.Methods:CD4 cell counts were analysed to investigate long-term immunological response using mixed-effects models with the slope allowed to change after 1, 12 and 24 months of HAART.Results:The median baseline CD4 cell count was 175 cells/mm3. After an initial rapid increase in the first month after HAART (97.2 cells/mm3a month), increases in CD4 cell counts continued less rapidly (11.6 cells/mm3a month). This increase slowed by 2.4 cells/mm3a month after one year. CD4 cell counts continued increasing after 2 years, but the rate of increase again slowed (estimated slope at 2 years 5.4 cells/mm3a month; decrease in slope from year 2 compared with years 1–2 3.7 cell/mm3a month). A total of 198 out of 211 patients (94%) with measurements at baseline and one year experienced an increase in CD4 cell counts in this interval; 81 and 67% had an increasing slope between 1 and 2 and 2 and 3 years, respectively. By the end of follow-up, CD4 cell counts had increased by 319 cells/mm3, and were more than 500 cells/mm3in 40% of patients.Conclusion:Although the rate of immune recovery slowed after 2 years, CD4 cell counts rose in most and began to return to levels seen in HIV-negative individuals.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:Little prospective data are published on the natural history of HIV-associated lipodystrophy (HIVLD) in individuals beginning their first antiretroviral regimen. To investigate this a study was designed to explore changes in body composition occurring with antiretroviral therapy.Study design:A non-randomized, prospective, exploratory study of 40, HIV-infected men, naive to treatment, beginning antiretroviral therapy. Regular assessments of body composition, and metabolic and immunological parameters were performed.Results:Mean follow-up was 96 (SD 45) weeks of therapy. There were increases in limb fat, central abdominal fat and lean mass over the initial 24 weeks of therapy followed by a selective, progressive loss of limb fat from week 24. There was a median 13.6% [interquartile range (IQR), 0.9–26.3] loss of limb fat per year from week 24 onwards. Treatment with stavudine, higher baseline HIV RNA, higher baseline ‘T’ score and lower week 24 lean mass were associated with higher rate of limb fat loss from week 24. In multivariate analysis, treatment with stavudine was the strongest independent factor associated with rate of limb fat loss (P= 0.05). Hypercholesterolaemia developed early in treatment, whereas hypertriglyceridaemia, hyperinsulinaemia and decreased bone mineral density developed later. The largest changes in CD4 cell counts and HIV viral load, seen early into treatment, were associated with gain rather than loss of fat.Conclusions:This is the first prospective study demonstrating that treatment with antiretrovirals results in progressive, selective loss of limb fat. Loss of limb fat occurred after the period of most intense immune restoration, making an immune aetiology unlikely.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:A polymorphism at position −589 in the interleukin 4 (IL-4) promoter region was recently described as being associated with the presence of syncytium-inducing CXCR4 using (X4) HIV-1 variants.Objective:To study the IL-4 promoter polymorphism −589T in relation to HIV-1 disease progression and acquisition of X4 HIV-1 variants.Design and methods:Retrospective longitudinal study among 342 HIV-1-infected homosexual men who participated in the Amsterdam Cohort study. Polymerase chain reaction was used in combination with restriction analysis to identify IL-4 promoter genotypes.Results:Carriers of the −589T allele (either −589 C/T heterozygotes or −589 T/T homozygotes), showed comparable progression to AIDS [relative hazard (RH), 0.94;P= 0.71], and survival (RH IL-4 −589 C/T or T/T, 0.94;P= 0.69) as carriers of the −589 C/C genotype (the reference group). In contrast to a previous study, we found that the −589T polymorphism was associated with a delayed acquisition of X4 HIV-1 variants (RH, 0.56;P= 0.02 for IL-4 −589 C/T or T/T) and a reduced number of CCR5 expressing memory CD4 T cells.Conclusion:In the Amsterdam Cohort of homosexual men with HIV infection, the IL-4 −589T promoter polymorphism was associated with a delayed acquisition of X4 variants but did not affect overall disease progression.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To compare one protease inhibitor (PI)-based and two PI-sparing antiretroviral therapy regimens.Methods:International, open label, randomized study of antiretroviral drug-naive patients, with CD4 lymphocyte counts ⩾ 200 × 106cells/l and plasma HIV-1 RNA levels > 500 copies/ml. Treatment assignment to stavudine and didanosine plus indinavir or nevirapine or lamivudine. Primary study endpoint was the percentage of patients with plasma HIV-1 RNA levels < 500 copies/ml after 48 weeks in the intention-to-treat analysis (ITT).Results:In total, 298 patients were enrolled. After 48 weeks, the percentage of patients in the indinavir, nevirapine and lamivudine arms with HIV-1 RNA < 500 copies/ml was 57.0%, 58.4% and 58.7%, respectively, in an ITT analysis. After 96 weeks of follow-up, these percentages were 50.0%, 59.6% and 45.0%, respectively. The percentage of patients with HIV-1 RNA < 50 copies/ml was significantly less for those allocated to lamivudine in an on-treatment analysis after 48 and 96 weeks of follow-up. Patients in the nevirapine arm experienced a smaller increase in the absolute number of CD4 T lymphocytes. There were no significant differences in the incidence of serious adverse events.Conclusions:A comparable virological response can be achieved with first-line PI-base and PI-sparing regimens. The triple nucleoside regimen utilized may be less likely to result in viral suppression to < 50 copies/ml, while the nevirapine-based regimen is associated with a lower increase in CD4 T lymphocytes.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To evaluate the antiviral triple combination didanosine (ddI), interferon-alfa (IFN-α), and ribavirin for potential synergy in inhibition of HIV-1 replicationin vitro.Methods:Phytohaemagglutinin-stimulated cord blood mononuclear cells were infected with HIV-1IIIBor the HXB2D molecular clone of HIV-1 then cultured with interleukin-2 with ddI, ribavirin or IFN-α, alone and in combination. Reverse transcriptase activity was measured after 7 days to determine the inhibitory concentration of 50% (IC50) for the various drugs in replicate assays. Analysis of combined effects was performed using both the median effect principle (CalcuSyn, Biosoft®) and three-dimensional modelling (MacSynergy II).Results:The triple combination was highly synergistic against HIV-1in vitrowith combination indices < 1. The mean IC50was reduced from 6.85 to 0.90 μmol/l (P< 0.001) for ddI and from 6.58 to 1.00 μmol/l (P< 0.001) for IFN-α. No increased cytotoxicity was observed. Results were similar with both viral strains and using both analyses. In the triple combination, increasing concentrations of IFN-α resulted only a slight enhancement of synergy: synergy volumes were 134 [95% confidence limit (CL), 77–191] with 5 U IFN-α and 214.92 (95% CL, 116–314) with 10 U. This supporting the observation that the majority of the synergistic activity was derived from the combination of ddI and ribavirin, with IFN-α providing additional additive suppression.Conclusions:This novel triple combination has the potential to provide simultaneous activity against both HIV and hepatitis C and deserves further study to determine if can be safely administered in the clinical setting.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:Subpopulations of HIV with mutations associated with resistance to antiretroviral drugs often have reduced replicative capacity, so virus with resistance mutations for all existing and new antiretroviral drugs is likely to be appreciably impaired. Issues of toxicity, quality of life and economics mean that the simultaneous use of all these drugs in combination is unrealistic. We aimed to explore the use of sequential monotherapy regimens using a mathematical model of quasi-species dynamics, to see if these could take advantage of the poor replicative capacity of highly resistant virus.Methods:We assume for each of seven drugs that a single mutation is associated with the ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. Parameters included were drug efficacy, the cost of resistance mutations and the number of new target cells arising daily.Results:The use of seven drugs in a daily/weekly sequential monotherapy cycle led to substantial viral suppression (in the presence of all resistant viral subpopulations) for a wider range of parameter values than a continuous five-drug regimen. Although on any one day/week there is a viral subpopulation with R > 1 (e.g. that with resistance only to the current drug), this subpopulation does not have time to grow sufficiently during the short period when that drug is being taken.Conclusion:These results provide a rationale for trials of sequential regimens, using as wide a number of drugs with different resistance-associated mutations as possible, as a potential ‘resistance-proof’ strategy for achieving significant viral load suppression.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:To study the effectiveness, adherence and tolerance of a once-a-day highly active antiretroviral therapy regimen in adults in Senegal.Design and methods:In a prospective, open-label one-arm study, 40 treatment-naive HIV-1-infected patients took the following three drugs once a day at bedtime: didanosine, lamivudine and efavirenz. The primary endpoint was the percentage of patients with plasma HIV-1 RNA below 500 copies/ml at 6 months. The analysis was done on an intent-to treat basis.Results:Eighty-five per cent of patients were at Centers for Disease Control and Prevention stage B or C and the plasma HIV RNA level was 5.4 ± 0.4 log10copies/ml at baseline. The percentage of patients with plasma HIV-1 RNA below 500 copies/ml at 6 months was 95% [95% confidence interval (CI), 83–99]. The proportions of patients with plasma HIV-1 RNA below 50 copies/ml at months 3, 6, 9, 12 and 15 were 26% (n = 39; 95% CI, 12–39), 78% (n = 40; 95% CI, 65–90), 70% (n = 40; 95% CI, 56–84), 77% (n = 39; 95% CI, 64–90) and 69% (n = 39; 95% CI, 55–84), respectively. The CD4 cell count was 164 ± 75 × 106/l at baseline and increased by a mean of 199 ± 101 × 106/l at month 15. Permanent treatment discontinuation was never necessary for serious adverse effects. Adherence was excellent, as shown by plasma drug concentrations and according to the results of the questionnaire.Conclusions:The once-daily regimen of didanosine, lamivudine and efavirenz was safe, easy-to-take and demonstrated strong antiretroviral and immunologic effects in African patients with advanced HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID