摘要:

Objective:To determine the incidence of Kaposi's sarcoma (KS) in a prospective longitudinal cohort of HIV-1-infected individuals before during and after the introduction of highly active antiretroviral therapy (HAART) and to compare the incidence of KS between specific HAART regimens.Design:Univariate and multivariate analysis of 8640 HIV-1-infected individuals.Methods:The protective effect of HAART regimens based on either protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI) on the development of KS was examined in prospectively recorded data to determine whether treatments based on the two types of drug were comparable with regard to a reduction in the incidence of KS.Results:A total of 1204 patients with KS were identified. The incidence of KS decreased from 30/1000 patient-years prior to 1995 to 0.03/1000 patient-years in 2001. Multivariate analysis showed that age, nadir CD4 cell count and antiretroviral class exposure were significant independent predictors of KS. NNRTI-based HAART (adjusted rate ratio, 0.42; 95% confidence interval 0.24–0.37) had a similar protective effect to PI-based HAART (adjusted rate ratio, 0.47; 95% confidence interval 0.38–0.58). Most patients who develop KS on HAART [30/35 (86%)] had evidence of virological treatment failure.Conclusion:PI- and NNRTI-based HAART regimens are equally effective as protection against KS. This is the first study to demonstrate a decreased incidence of an AIDS-defining disease with NNRTI-based therapy.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:The acute phase of HIV and SIV infections leads to a host/virus equilibrium, and accumulating evidence suggests that this early phase dictates further progression towards AIDS. To gain insight into the early events that determine rapid disease progression, we performed a longitudinal study in the SIV rhesus macaque model, allowing an in-depth analysis of the primary stage of infection.Methods:We assessed viral replication (quantification of replicating and infected cells in lymph nodes, plasma viral load), immune response (cytotoxic T lymphocyte, antibody, proliferative responses), apoptosis and cycling cells (Ki-67 labelling) on lymph nodes and blood in nine rhesus macaques infected with the pathogenic SIVmac251 isolate.Results:Six primates remained asymptomatic during the one year follow-up period of the study, whereas three developed AIDS within 5–6 months. During the first 2 weeks of infection, peak numbers of apoptotic cells in the lymph node T-cell areas were significantly higher in the three future rapid progressors than in the six future slow progressors, and were correlated with subsequent viraemia levels measured 6 months after infection. The numbers of infected or cycling cells in the same lymph node T-cell areas, however, only became significantly different in future rapid and slow progressors 8 weeks after infection, at the end of the primary phase.Conclusion:Our findings identified extensive apoptosis induction in peripheral lymphoid organs as an early and predictive event that may play a crucial role in impairing the capacity of the immune system to control viral replication and progression towards disease.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:The development of drugs that can be used as topical microbicides is currently recognized as a priority area of research.Design:A preclinical evaluation of the potential effectiveness of TMC120, a non-nucleoside reverse transcriptase inhibitor (NNRTI), as a topical microbicide to prevent vaginal HIV-1 transmission in a humanized severe combined immunodeficient (hu-SCID) mouse model.Methods:Reconstituted mice received an intravaginal application of a TMC120-containing gel 20 min prior to a non-invasive vaginal challenge with cell-associated HIV. The possible cytotoxic effect of TMC120-containing-gel on lymphocytes was assessed and theirin vivomigration was followed using fluorescently labelled human lymphocytes. Systemic infection was monitored by p24 antigen detection in culture supernatant from cocultured intraperitoneal cells using antigen capture enzyme-linked immunosorbent assay test and by the presence of integrated proviral HIV-1 DNA in DNA extracted from spleen cells.In vivomigration of labelled lymphocytes was examined by analysis of cells isolated from regional lymph nodes.Results:In this model, systemic infection was successfully inhibited by the presence of TMC120-containing gel at vaginal level. Thein vivomigration of human lymphocytes from the vagina to regional lymph nodes, following the deposition of TMC120-containing gel, excluded the possibility that inhibition of systemic infection was a result of NNRTI toxicity.Conclusions:Vaginal transmission of HIV was successfully prevented by the application of a gel formulation containing TMC120. This is the first evidence of thein vivoeffectiveness of a microbicide preparation containing an NNRTI against cell-associated HIV.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:Infection with simian immunodeficiency virus (SIV), like HIV, can lead to central nervous system (CNS) abnormalities. One of the alterations observed in the brain is the accumulation of highly activated CD8 lymphocytes that, while fighting the infection, may cause tissue damage. In order to determine whether these CD8 cells in the brain comprise a distinct clonal population the expression of T-cell receptor (TCR) genes of two SIV-infected monkeys with CNS abnormalities were analyzed, comparing brain to periphery.Methods:RNA from magnetically sorted CD8+ cells obtained from the brain, blood, lymph nodes, and spleen was analyzed for the distribution of 24 Vβ family genes by reverse transcriptase-polymerase chain reaction followed by Southern blot. The CDR3 region of the most enriched family in each brain was sequenced in all the sites for comparison.Results:The pattern of Vβ distribution in the brain and the periphery was polyclonal, but an increase in certain Vβ families was found in the brain, suggesting that regional mechanisms participate in the determination of the local clonal specificities. The sequence of the CDR3 domain of predominant Vβ families in the brain revealed that approximately one-third of the CD8 cells were not identified in the periphery.Conclusion:CD8 cells in the brain exhibit a distinct clonal repertoire. This distinction may have implications for regional immunity, regulation, or selection of site-specific viral mutants.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:Leflunomide inhibitsde novopyrimidine synthesis by inhibiting the activity of dihydroorotic acid dehydrogenase and has other immunomodulatory properties that make it a promising candidate for an anti-HIV drug.Objectives:To compare the anti-HIV activity of leflunomide with that of the immunomodulatory drugs hydroxyurea and mycophenolic acid; to assess whether there is an additive or synergistic effect when leflunomide is used in conjunction with mycophenolic acid; and to characterize the molecular mechanism of the anti-HIV activity of leflunomide.Methods:Anti-HIV activity was examined in peripheral blood mononuclear cells. CD4 cell survival was examined in tonsillar lymphocytes by fluorescence-activating cell sorting.Results:Leflunomide decreased HIV replication by approximately 75% at concentrations that can be obtained with conventional dosing. This activity was similar to that of hydroxyurea but superior to mycophenolic acid. Leflunomide and mycophenolic acid together have modest additive anti-HIV effects. Restoration of HIV replication by uridine indicates that leflunomide's primary mechanism at lower concentrations is inhibition of dihydroorotic acid dehydrogenase while at higher concentrations additional mechanisms may be involved.Conclusions:Leflunomide's anti-HIV activity and clinical profile make it an attractive candidate for further study of its effects. Since HIV RNA levels are an effective predictor of AIDS-free survival, leflunomide's partial suppression of HIV RNA may be valuable in certain patients.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:In HIV-positive individuals administration of intermittent interleukin (IL)-2 in addition to highly active antiretroviral therapy (HAART) induces expansion of the peripheral T cell pool with dilution of signal joint T cell receptor excision circles (sjTREC) that cannot be used to measure thymic output. We analysed whetherin vitrothymopoiesis could be used to predictin vivothymic output in IL-2 treated subjects.Design and methods:We correlated the relative variation of peripheral CD4 T cells over 12 months in HIV-positive subjects on HAART or HAART + IL-2 with the mean levels of both sjTREC and T cells developed in chimeric murine foetal thymic organ cultures (FTOC) reconstituted with circulating progenitors.Results:In contrast with HAART treated individuals in which these values were directly correlated, in subjects receiving HAART + IL-2 the increase of CD4 T cellsin vivowas correlated to neither sjTREC number nor to reconstitution of FTOC, probably reflecting a main effect of IL-2 in the expansion of the peripheral T cell pool. Nevertheless, addition of IL-2 to HAART determined a significant increase ofin vitrothymopoietic potential in individuals with undetectable viraemia.Conclusions:The increased T cell developmentin vitroafter addition of IL-2 to HAART suggests that intermittent IL-2 administration may exert a positive influence on lymphopoiesis. In two subjects with positive viraemia treated with IL-2 we observed reducedin vitrodevelopment of T cell precursors suggesting that the positive influence of IL-2 on thymopoiesis could be secondary to the control of viral replication by HAART. These observations provide novel evidence in support of the potential beneficial use of IL-2 in HAART treated individuals.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:Among perinatally infected children, the effects of certain alleles of theCCR5andCCR2genes on the rate of disease progression remain unclear. We addressed the effects ofCCR5-Δ32andCCR2-64Iin an international meta-analysis.Methods:Genotype data were contributed from 10 studies with 1317 HIV-1-infected children (7263 person-years of follow-up). Time-to-event analyses were performed stratified by study and racial group. Endpoints included progression to clinical AIDS, death, and death after the diagnosis of clinical AIDS. The time-dependence of the genetic effects was specifically investigated.Results:There was large heterogeneity in the observed rates of disease progression between different cohorts. For progression to clinical AIDS, bothCCR5-Δ32andCCR2-64Ishowed overall non-significant trends for protection [hazard ratios 0.84, 95% confidence interval (CI) 0.58–1.23; and 0.87, 95% CI 0.67–1.14, respectively]. However, analyses of survival showed statistically significant time-dependence. No deaths occurred amongCCR5-Δ32carriers in the first 3 years of life, whereas there was no protective effect (hazard ratio 0.95; 95% CI 0.43–2.10) in later years (P= 0.01 for the time-dependent model). ForCCR2-64I, the hazard ratio for death was 0.69 (95% CI 0.39–1.21) in the first 6 years of life and 2.56 (95% CI 1.26–5.20) in subsequent years (P< 0.01 for the time-dependent model).CCR5-Δ32andCCR2-64Ioffered no clear protection after clinical AIDS had developed.Conclusion:TheCCR5-Δ32andCCR2-64Ialelles are associated with a decreased risk of death among perinatally infected children, but only for the first years of life.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:To evaluate the safety, efficacy, and clinical, virological, and immunological responses in HIV-1-infected children receiving nevirapine as part of combination antiretroviral therapy (ART).Methods:A review of case notes of all HIV-1-infected children 96 weeks after starting nevirapine, under a national compassionate access scheme between August 1997 and March 1999 in the UK. Nevirapine was dosed according to the manufacturer's guidelines.Results:Seventy-four children (36 boys, 28 naive to ART) were enrolled, with a median age of 5.2 years, viral load of 5.1 log copies/ml and CD4 lymphocyte count of 13.5%. The liquid formulation and tablets of nevirapine were well tolerated. The proportions of patients achieving undetectable viral load levels at weeks 12, 24, 48 and 96 were 30, 40, 36 and 33%, respectively (intention-to-treat analysis). Of children not on a protease inhibitor who received more than 300 mg/m2/day of nevirapine, 60% had undetectable viral loads at week 96, compared with 17% on recommended doses. Outcomes were similar for patients receiving nevirapine once or twice daily. CD4 cell count percentages increased significantly, with median values sustained above 25% by week 48 onwards.Z-scores for weight and height increased significantly during 96 weeks of treatment. Rash occurred in 20%, of which four (5%) were severe. There were no cases of Stevens–Johnson syndrome.Conclusion:Nevirapine was mostly well tolerated, and was associated with encouraging clinical and immunological responses. Virological responses in this cohort support the use of nevirapine doses greater than 300 mg/m2/day, which is higher than currently recommended by the manufacturers.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To determine the prevalence of hepatitis B virus (HBV) genotypic resistance to lamivudine, identify risk factors associated with lamivudine resistance, and characterize the pattern of HBV polymerase mutations in patients co-infected with HIV.Design:Retrospective cross-sectional study.Methods:Thirty-three chronic HBV-infected patients were identified from a cohort of 1719 HIV-infected individuals. Patient information was collected from case records, HBV DNA was measured on stored serum by polymerase chain reaction, and positive samples underwent sequencing of HBV polymerase, basal core promoter and precore regions.Results:Three groups of patients were identified: group 1 were viraemic in the absence of lamivudine-resistance mutations, group 2 were viraemic in association with lamivudine-resistance mutations, and group 3 were not viraemic. Group 2 patients with lamivudine-resistant mutations had significantly higher HBV-DNA viral loads but did not differ in duration of lamivudine therapy, HBV genotype, HIV viral load or CD4 cell count compared with patients with wild-type HBV. Group 2 individuals also demonstrated significantly higher serum alanine aminotransferase (ALT) levels than group 1, who were higher than group 3. Unique mutations were detected in HBV polymerase, including rtV173L plus rtL180M plus rtM204V, which occurred in three patients. This virus has the in-vitro characteristics of a ‘vaccine escape’ mutant of HBV.Conclusion:Genotypic HBV lamivudine resistance was found in 39% of HIV–HBV co-infected individuals treated with lamivudine as part of highly active antiretroviral therapy. These patients exhibited significantly elevated HBV viral loads and serum ALT, and three were infected with a lamivudine-resistant HBV strain that was potentially transmissible to HBV-vaccinated individuals.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Context:Single-dose intrapartum and neonatal nevirapine (NVP) reduces perinatal HIV transmission and is in increasingly common use throughout the developing world.Objective:We studied risk factors for perinatal transmission in the setting of NVP.Design and setting:A prospective cohort study at two public obstetrical clinics in Lusaka, Zambia.Patients and methods:In a volunteer sample of HIV-infected pregnant women and their newborns, the women received a 200 mg oral dose of NVP at the onset of labor; their infants received 2 mg/kg of NVP syrup within 24 h of birth. The main outcome measure was the infant HIV infection status at 6 weeks of life, determined by DNA polymerase chain reaction.Results:Only 31 of 278 (11.2%) infants were infected at 6 weeks. In logistic regression, viral load exceeding the median [adjusted odds ratio (AOR), 3.1; 95% confidence interval (CI), 1.1–8.7] and 1 h or less elapsing between NVP ingestion and delivery (AOR, 5.0; 95% CI, 1.8–14) were associated with transmission. Women delivering within 1 h of NVP ingestion had a lower mean drug concentration (351 versus 942 ng/ml;P< 0.001) and were more likely to have a ‘sub-therapeutic’ NVP level of less than 100 ng/ml (56 versus 20%;P< 0.001) than those who delivered more than 1 h post-ingestion. However, concentrations < 100 ng/ml were not more likely to be associated with transmission than concentrations ⩾ 100 ng/ml (12.9 versus 11.7%;P= 0.8). We did not identify a threshold concentration below which risk of transmission increased.Conclusions:We confirmed low perinatal transmission rates with single-dose NVP. At least 1 h of pre-delivery NVP prophylaxis was a critical threshold for efficacy.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID