摘要:

The consultation was jointly organized by the WHO-UNAIDS HIV Vaccine Initiative and the Quality Assurance and Safety of Biologicals Team of the World Health Organization (WHO). Thirty-four experts from 16 developed and developing countries attended the meeting, bringing together expertise from academic institutions, clinical trial centres, national and international regulatory authorities. Representatives of major pharmaceutical companies were also invited. The primary objective of the meeting was to identify gaps that need to be addressed from regulatory perspective to ensure appropriate progress of HIV vaccine development from basic research to human trials, licensing and future application, with a special focus on needs of developing countries. As a result of discussions, the following priority needs were identified and recommendations were made in order to establish an appropriate regulatory framework for the development and evaluation of preventive HIV/AIDS vaccines, which were divided in two main areas: (a) standardization and control of candidate HIV/AIDS vaccines, and (b) approaches to the conduct of clinical trials of candidate HIV/AIDS vaccines.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveDramatic increases have occurred in sexually transmitted diseases (STD) and in sexual risk behaviour among homosexual men in Amsterdam and internationally. We investigated whether these trends indicate a resurgence of the HIV epidemic.MethodsHIV incidence was determined among homosexual attendees of an STD clinic in Amsterdam, who had participated in semi-annual anonymous unlinked cross-sectional HIV prevalence studies from 1991 to 2001. Stored HIV-seropositive samples were tested with a less-sensitive HIV assay and, if non-reactive, were further tested for the presence of antiretroviral drugs, indicative of the use of highly active antiretroviral therapy. Seropositive men who tested non-reactive on the less-sensitive assay and had not used antiretroviral drugs were classified as recently infected (< 170 days). Annual HIV incidence and its changes were examined.ResultsAmong 3090 homosexual participants (median age 34 years), 454 were HIV infected, of whom 37 were recently infectioned. From 1991 to 2001 the overall incidence was 3.0 infections/100 person-years. Incidence increased over time (P= 0.02) and, strikingly, the increase was evident in older (⩾ 34 years) men (P< 0.01), but not in the young. Of men recently infected, 84% (n = 31) were unaware of their infection and 70.3% (n = 26) had a concurrent STD. These 26 men reportedly had sex with a total of 315 men in the preceding 6 months.ConclusionHIV incidence is increasing among homosexual attendees of an STD clinic. It is imperative to trace recently infected individuals, because they are highly infectious, and can thus play a key role in the spread of HIV.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

BackgroundThe CD4 T cells in mucosal subepithelia are the first cells to become infected during sexual transmission of HIV-1. Dendritic cells (DC) are located in the same area and are known to play a central role in antiviral immune responses. However, extensive viral replication, syncytia formation and cell death follows the interaction between T cells and DC previously exposed to HIV-1. Despite this, anti-HIV responses are generated that control viremia following acute infection.ObjectiveThe anti-HIV-1 cellular immune responses observed may be activated by sources other than productively infected DC. HIV-1 induces apoptosis both in cells it infects and in bystander cells. Furthermore, retroviral replication typically generates a predominance of defective particles. We tested whether DC exposed to antigen from either of these sources could elicit anti-HIV specific immune responses.Design and methodsApoptotic or necrotic monocytes infected with vaccinia virus vectors encoding HIV antigens, a cell line with integrated HIV-1 and apoptotic CD4 T cells pulsed with non-infectious or infectious HIV-1 virus were used as sources of antigens to assess cross presentation by DC. Furthermore, direct DC presentation of antigen from non-infectious and infectious HIV-1 was examined.ResultsWe find that dead cells expressing HIV-1 antigens as well as non-infectious HIV-1 particles can be acquired and processed by DC, leading to the activation, differentiation and expansion of viral antigen-specific CD4 and CD8 T cells from seropositive individuals.ConclusionsThese sources of antigens may be critical for the generation and maintenance of anti-HIV-1 immunity by DC.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo assess the impact of HIV-1 protease and reverse transcriptase (RT) mutations, and pharmacokinetic parameters on virological responses to nelfinavir (NFV)-containing highly active antiretroviral therapy.DesignNaive or antiretroviral-experienced HIV-1-infected subjects were included in a non-randomized, observational cohort study and received two nucleoside RT inhibitors + NFV (750 mg three times per day or 1250 mg twice per day). Virologic success was defined as a virus load < 50 copies/ml for > 6 months.MethodsRT and protease genes were sequenced at baseline and at the time of virological failure. Plasma NFV trough concentration (Cmin), maximum concentration (Cmax), and AUC0–τat steady-state were subjected to population pharmacokinetic analysis.ResultsPatients (n = 154) enrolled between November 1998 and February 2000 started a twice per day (n = 84) or three times per day (n = 70) NFV-based regimen as first- (n = 48) or second-line therapy when protease inhibitor-naive (n = 64) or -experienced (n = 42). Median follow-up duration was 16 months. Virologic failure occurred in 88 patients. No significant differences were observed between twice per day and three times per day regimens. According to multivariate analysis, NFV Cminand Cmax, CD4 cell count, number of baseline RT + protease gene mutations, D67N, M184V, T215F/Y in RT, and M36I in protease, were independent factors that were significantly predictive of failure. At failure, L10I, D30N, M36I, V77I, N88S/D or L90M protease mutations had emerged since baseline. Pharmacokinetic parameters were similar in patients with or without emergence of these neo-mutations. The more discriminating NFV Cminefficacy-threshold was estimated to be 1 mg/l.ConclusionsOur data confirm the association among individual pharmacokinetic parameters, genotype pattern and virological response to NFV-containing regimens.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo evaluate the prevalence, outcome and possible risk factors for hyperlactataemia and lactic acidosis in HIV-positive persons receiving antiretroviral therapy.MethodsCross-sectional and longitudinal data from a prospectively collected clinical database. Associations with antiretroviral regimen, clinical and laboratory parameters were assessed using univariate and multivariate Cox's proportional hazards model.ResultsPatients naive to therapy and patients on current therapy for a minimum of 4 months were assessed. Median lactate was 1.1 mol/l in 253 untreated individuals and 1.4 mmol/l in 1239 patients stable on therapy for at least 4 months. At least two on-therapy samples were available for 750 of the 1239 individuals, taken a median 92 days apart. Lactate measurement showed a low positive predictive value of 38.9% but a high negative predictive value (98%) for normal values. Lactate was elevated ⩾ 2.4 mmol/l in 102 individuals on at least one occasion. In the multivariate Cox's proportional hazards model, no demographic characteristics were associated with hyperlactataemia. Didanosine-containing regimens doubled the relative hazard of hyperlacatæmia compared with those sparing didanosine. Abacavir-containing regimens reduced the hazard of hyperlactatæmia. Choice of thymidine analogue did not influence risk. Hyperlactatæmia was associated with acid–base disturbance. Use of didanosine and female sex were over-represented amongst nine patients with severe hyperlactataemia (> 5 mmol/l) or lactic acidosis.ConclusionsScreening of lactate is of limited use in asymptomatic individuals on antiretroviral therapy. Raised lactate represents part of a spectrum of lactate and acid–base disturbance that infrequently includes lactic acidosis. Didanosine appears associated with an increased risk of hyperlactataemia.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo explore the feasibility of expressing the potent HIV-inactivating protein, cyanovirin-N (CV-N), in the human commensal bacteriumStreptococcus gordonii, as a possible approach for local delivery of CV-N to prevent sexual transmission of HIV-1.Design and methodsTo express CV-N inS. gordonii, we used the host-vector system we had previously developed. CV-N was expressed as a fusion protein both attached to the bacterial surface and secreted in soluble form in the supernatant of liquid cultures. The soluble form of recombinant CV-N was tested for gp120-binding activity in an enzyme-linked immunosorbent assay, whereasS. gordoniistrain expressing CV-N on the surface was analyzed in anin vitroHIV capturing assay.ResultsTwo recombinantS. gordoniistrains secreting or displaying CV-N on the bacterial surface were constructed and the expression of CV-N was confirmed by immunoblot and flow-cytometric analysis. The secreted form of recombinant CV-N exhibited a concentration-dependent binding to the envelope glycoprotein gp120 of HIV-1, whereas CV-N displayed on the bacterial surface was able to capture HIV virions efficiently.ConclusionThe anti-HIV protein CV-N inS. gordoniiwas expressed in a biologically active form. This represents a first step in the development of a system to deliver and maintain an effective concentration of a microbicide in the vaginal mucosa.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo study whether hepatitis C virus (HCV) co-infection or the severe elevation of transaminases is associated with survival after the initiation of antiretroviral combination therapy.DesignProspective hospital-based cohort (Aquitaine Cohort).MethodsHIV-infected adults started on an antiretroviral combination before 30 June 1999. HCV infection was defined as antibody detection or positive HCV RNA. Severe elevation of transaminases was defined as a value of aspartate or alanine aminotransferase (AST, ALT) above five times the upper limit of normal values. Survival was studied using a Cox model, including at least baseline HCV status and transaminases as a time-dependent covariate.ResultsOverall, 995 patients were analysed, including 576 HCV-positive individuals (58%). At baseline, HCV-positive patients were younger, more often injecting drug users and women, and had more frequently elevated transaminases. A shorter survival was associated with AIDS stage [hazard ratio (HR) versus non-AIDS 1.67; 95% confidence interval (CI) 1.03; 2.68], lower CD4 cell count (HR for 50 cells/mm3lower 1.33; CI 1.17; 1.51), lower haemoglobin (HR for 1 g/dl lower 1.20; CI 1.07; 1.35), lower platelet count (HR for 10 000 cells/mm3lower 1.04; CI 1.01; 1.07), and AST during follow-up (HR for⩾200 IU/l 2.30; CI 1.32; 4.03). HCV co-infection (HR 1.20; CI 0.75; 1.92) was not statistically associated with survival.ConclusionThe occurrence of a severe elevation of transaminases was associated with poorer survival, although HCV was not. If liver toxicity may be treatment induced, plasma drug concentrations could guide dosage adjustments of antiretroviral treatments currently prescribed to optimize their use.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo study the feasibility, effectiveness, adherence, toxicity and viral resistance in an African government HAART initiative.MethodsA prospective observational cohort study started in Dakar in August 1998. Initial treatment consisted of two nucleoside reverse transcriptase inhibitors and one protease inhibitor. The patients attended monthly medical examinations. Plasma HIV-1 RNA and CD4 cell counts were determined at baseline and every 6 months. Intention-to-treat analyses were performed.ResultsFifty-eight treatment-naive patients, mostly infected by HIV-1 strain CRF02-AG, were enrolled. Most were at an advanced stage of HIV disease (86.2% had AIDS). Adherence was good in 87.9% of patients and treatment was effective in most of them. Thus, HIV-1 RNA was undetectable in 79.6, 71.2, 51.4 and 59.3% of patients at months 1, 6, 12 and 18, respectively and the median viral load reduction was ∼2.5 log10copies/ml. The CD4 cell count rose by a median of 82, 147 and 180 × 106cells/l at months 6, 12 and 18, respectively. At the same time points, the cumulative probability of remaining alive or free of new AIDS-defining events was 94.8, 85.0 and 82.3%. Most adverse effects (80.8%) were mild or moderate and only two cases of drug resistance occurred.ConclusionThis study shows that HAART is feasible and well tolerated in African patients. Clinical and biological results were comparable to those seen in western cohorts, despite differences in the HIV-1 subtype distribution and an advanced disease stage when the treatment was initiated. Contrary to other recent studies in Africa, viral resistance rarely emerged.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo evaluate the efficacy of early initiation of highly active antiretroviral therapy (HAART), we compared the clinical course of two nested, matched cohorts within the Swiss HIV Cohort Study.MethodsWe selected all asymptomatic patients who started HAART between 1 January 1996 and 31 December 1999 with a CD4 cell count > 350 × 106/l. We then matched them with asymptomatic participants who were seen at around the same time and who remained untreated during the following 12 months. This control group was further matched for age, sex, CD4 cell count, viral load, and HIV risk category, generating 283 pairs of treated versus untreated patients.ResultsDuring observation of median 3.19 versus 2.66 years, CDC stage B/C occurred in 6.4% versus 21.2%, AIDS in 1.8% versus 5.3%, death in 2.1% versus 6.4%, and AIDS or death of ‘natural’ causes in 2.8% versus 6.7% of the treated versus untreated patients. In multivariable Cox regression analysis, treatment reduced the risk of clinical progression by a factor of four- to five fold. During follow-up, the treated group had significantly higher CD4 counts and lower HIV-1 RNA levels. Intolerance/adverse events led to change or stop of at least one drug in 35% of treated patients. The entire regimen was interrupted at least once by 41% of patients, and 24% had no treatment anymore at the end of follow-up.ConclusionsThe initiation of HAART in asymptomatic patients with CD4 cell count > 350 × 106/l significantly delayed clinical progression. However, the risk of severe clinical events with deferred therapy was low and must be counter balanced against the burden and toxicity of HAART.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID