摘要:

BackgroundAcquired HIV-specific cell-mediated immune responses have been observed in exposed–uninfected individuals, and it has been inferred, but not demonstrated, that these responses constitute a part of natural protective immunity to HIV. This inference was tested prospectively in the natural exposure setting of maternal–infant HIV transmission in a predominantly breast-fed population.MethodsCord blood from infants of HIV-seropositive women in Durban, South Africa, were tested forin vitroreactivity to a cocktail of HIV envelope peptides (Env) using a bioassay measuring interleukin-2 production in a murine cell line. Infants were followed with repeat HIV RNA tests up to 18 months of age to establish which ones acquired HIV-infection.ResultsT-helper cell responses to Env were detected in 33 out of 86 (38%) cord blood samples from infants of HIV-seropositive women and in none of nine samples from seronegative women (P= 0.02). Among infants of HIV-seropositive mothers, three out of 33 with T-helper responses to Env were already infected before delivery (HIV RNA positive on the day of birth), two were lost to follow-up, and none of the others (out of 28) were found to be HIV infected on subsequent tests. In comparison, six out of 53 infants unresponsive to Env were infected before delivery, and eight out of 47 (17%) of the others were found to have acquired HIV infection intrapartum or post-partum through breast-feeding (P= 0.02).ConclusionsT-helper cell responses to HIV envelope peptides were detected in more than one-third of newborns of HIV-infected women; no new infections were acquired by these infants at the time of delivery or post-natally through breast-feeding if these T-helper cell responses were detected in cord blood.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo analyse cell membrane proteins (CMP) acquired by HIV-1 present in the plasma of asymptomatic patients, and their modifications after a cycle of highly active antiretroviral therapy (HAART) and interleukin (IL)-2.Design and methodsPlasma samples from eight drug-naive asymptomatic subjects underwent immobilized antibody capture (IAC) to detect CMP on the surface of circulating HIV-1. The CMP considered were lymphocyte subset markers (CD45RA, CD45RO), activation markers (HLA-DR), adhesion molecules (LFA-3), costimulatory proteins (B7-2), lymph-node homing receptors (CD62L) and pro-apoptosis molecules (FasL). This analysis was repeated after one cycle of HAART + IL-2, after virus rebound.ResultsLFA-3, followed by CD45RO and HLA-DR, are the most represented CMP on the surface of circulating virions in naive asymptomatic patients; CD45RA, CD62L, B7-2 and FasL are detected only occasionally. After rebound, a significant reduction of CD45RO and HLA-DR, but not of LFA-3, is observed on virions, whereas CD45RA and CD62L, as well as other molecules, are not affected, remaining almost undetectable.ConclusionsAssuming that CMP on HIV-1 reflect the cellular origin of virions, activated T cells expressing CD45RO, HLA-DR, and LFA-3 may be the main source of HIV-1 in asymptomatic patients. After a cycle of HAART + IL-2, followed by therapy interruption, CD45RA and CD62L are detected on virions rarely, indicating that even during virus rebound, expanded naive T cells do not become a major target of virus replication. Furthermore, the presence of HLA-DR on rebound HIV-1 is decreased, consistent with decreased activation of the HIV-producing cells. More extensive investigation may clarify the significance of these findings with respect to pathogenesis.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo determine whether HIV-1 can be recovered from blood monocytes as well as resting, memory CD4 T lymphocytes of patients on highly active antiretroviral therapy (HAART) with undetectable plasma viraemia and whether infection is active or latent.DesignFive patients with plasma HIV-1-RNA levels of less than 500 copies/ml for at least 3 months and less than 50 copies/ml at the time of sampling were initially selected, followed by an additional five patients with viral loads of less than 50 copies/ml for 3 months or more.MethodsMonocytes were isolated from blood by plastic adherence, then further purified by a second adherence step or CD3 depletion before co-culture with CD8-depleted donor peripheral blood mononuclear cells. Virus isolates were examined for mutations conferring resistance to reverse transcriptase or protease inhibitors and for genotype. The highly purified monocytes were also analysed for the presence of proviral and unintegrated viral DNA and multiply spliced (MS) viral mRNA by polymerase chain reaction.ResultsVirus was recovered from monocytes of five patients. Sequencing of the recovered viruses did not reveal multiple drug resistance, and was consistent with a non-syncytium-inducing/CCR5 phenotype. Proviral DNA was detectable in monocytes from all subjects, and unintegrated HIV-1 DNA and MS RNA was found in four out of five populations examined.ConclusionRecovery of replication-competent virus from some HAART patients indicates that monocytes can also harbour HIV-1. Detection of circular, viral DNA and spliced RNA, albeit at very low levels, in these cells suggests that their infection is recent and transcriptionally active rather than latent.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo study the safety of discontinuing cytomegalovirus (CMV) maintenance therapy among patients with cured CMV retinitis receiving highly active antiretroviral therapy (HAART).MethodsPatients with a history of CMV retinitis who were receiving anti-CMV maintenance therapy and who had a CD4 cell count > 75 × 106cells/l and a plasma HIV RNA level < 30 000 copies/ml while on HAART were included in a multicentre prospective study. Maintenance therapy for CMV retinitis was discontinued at enrolment and all the patients were monitored for 48 weeks by ophthalmological examinations and by determination of CMV markers, CD4 cell counts and plasma HIV RNA levels. T helper-1 anti-CMV responses were assessed in a subgroup of patients. The primary study endpoint was recurrence of CMV disease.ResultsAt entry, the 48 assessable patients had been taking HAART for a median of 18 months. The median CD4 cell count was 239 × 106cells/l and the median HIV RNA load was 213 copies/ml. Over the 48 weeks, 2 of the 48 patients had a recurrence of CMV disease. The cumulative probability of CMV retinitis relapse was 2.2% at week 48 (95% confidence interval, 0.4–11.3) and that of all forms of CMV disease 4.2%. CMV blood markers remained negative throughout follow-up. The proportion of patients with CMV-specific CD4 T cell reactivity was 46% at baseline and 64% at week 48.ConclusionsCMV retinitis maintenance therapy may be safely discontinued in patients with CD4 cell counts above 75 × 106cells/l who have been taking HAART for at least 18 months.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundAzodicarbonamide (ADA), a HIV-1 zinc finger inhibitor, targets a new step in viral replication and cell infectivity.ObjectiveA first phase I/II clinical study of ADA.MethodsADA was administered at escalating doses concomitantly with current antiviral therapy during a 3-month open-label period in patients with advanced AIDS and documented virological failure. After 3 months, patients were randomized in a double-blind placebo-controlled withdrawal, ADA being given at the highest tolerated dosage.ResultsFifteen patients with advanced disease failing on combined antiretroviral therapy, 75% of them with proven phenotypic resistance, had a median baseline CD4 cell count of 85 × 106cells/l, CD4/CD8 cell ratio of 0.09 and median plasma RNA viral load of 4.2 log10copies/ml. Tolerance to ADA was dose dependent and some patients developed nephrolithiasis, glucose intolerance or showed an ADA-related cytotoxicity towards CD4 cells at higher dosages. No patient died during the study period. ADA increased CD4 cell percentage, increased the CD4/CD8 cell ratio and decreased plasma RNA viral load from baseline. At the end of the double-blind period, the ADA group, but not the placebo group, showed a significant response (P< 0.05). No phenotypic resistance to ADA was observed. Overall, 3/11 patients (27%) had consistent viral load reductions > 0.5 log10copies/ml compared with baseline and 5/11 (45%) showed a CD4 cell recovery from baseline > 33%. In responders, ADA induced a median peak increase in CD4 cell percentage change from baseline of 65% (range 47–243%), and viral load decrease of 1.04 log10copies/ml (range 0.52–1.23).ConclusionsThe maximal tolerated dosage of ADA appears to be 2 g (three times daily). This study provides safety results that will allow larger clinical trials to confirm the preliminary efficacy data.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo describe the viral response to HAART by weeks 4 and 8 in previously antiretroviral-naive patients. To assess whether the weeks 4 or 8 viral loads are useful predictors of viral suppression by week 24.DesignA large clinical database including 453 antiretroviral-naive patients whose plasma viral load was monitored every 4 weeks.MethodsObserved probabilities of achieving a viral load ⩽ 500 copies/ml by week 24 (days 84–168) from starting highly active antiretroviral therapy (HAART) were calculated according to viral loads at weeks 4 and 8.ResultsA total of 42.4% of patients (153/361) reached ⩽ 500 copies/ml viral load by week 4 and 70.4% (245/348) by week 8. Viral suppression below 500 copies/ml by 4–8 weeks was similar irrespective of the pre-HAART viral load. In patients with viral loads above 10 000 copies/ml at week 4, 60.6% (20/33) achieved ⩽ 500 copies/ml by week 24. In patients with viral loads still above 10 000 copies/ml at week 8, only 42.3% (11/26) achieved ⩽ 500 copies/ml by week 24, and only 33.3% (3/9) maintained viral suppression below 500 copies/ml to week 48.ConclusionViral loads at weeks 4 and 8 should be monitored to detect early signs of low subsequent viral suppression. For previously antiretroviral-naive patients whose viral loads after 8 weeks of HAART are still above 10 000, there is an urgent need to assess adherence to therapy, drug levels and resistance, so management can be modified accordingly to reduce the rate of week 24 virological failure.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundAmong adults with advanced HIV infection in developing countries, bacteremia due toMycobacterium tuberculosis(MTB) is common and bacteremia due toM. bovis(bacille Calmette–Guérin; BCG) is rare. Comparable data are not available for children with HIV.ObjectiveTo compare the prevalence of bacteremia due toM. tuberculosisorM. bovisBCG in hospitalized children and adults with HIV infection in a developing country with a high prevalence of tuberculosis and HIV and > 95% BCG immunization coverage.DesignDescriptive cross-sectional study.MethodsProspectively hospitalized patients in Lusaka, Zambia who were suspected to have HIV infection underwent phlebotomy for HIV ELISA, HIV viral load, and lysis-centrifugation blood culture for mycobacteria. Histories were obtained and patients were examined for BCG scars. Mycobacterial isolates were identified using DNA probes for MTB complex (MTBC), multiplex PCR and IS6110typing.ResultsThe median age of 387 HIV-positive children was 15 months; 98% were BCG immunized. The median age of 344 HIV-positive adults was 32 years; 44% were BCG immunized. Blood cultures were positive for mycobacteria in six children (2%) and 38 adults(11%) (P< 0.001). The six pediatric isolates included five MTBC (40% clustered) and one BCG. The 38 adult isolates included 36 MTBC (16% clustered) and twoM. aviumcomplex.ConclusionBacteremia due to MTB is less common among children than adults with advanced HIV infection in Zambia. Bacteremia due toM. bovisBCG is rare even among children with recent BCG immunization and symptomatic HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo characterize the antiviral response and tolerability of a multi-drug rescue therapy (MDRT) among heavily pretreated patients.MethodsObservational study conducted in a single, university-based tertiary referral clinic. Patients (n = 106) who failed several prior regimens started MDRT including at least five antiretroviral (ARV) drugs between August 1997 and June 1998. The most common starting regimen included three nucleoside reverse transcriptase inhibitors and two protease inhibitors, which was prescribed to 45 (42.5%) patients. Virologic response was defined as plasma viral load < 400 copies/ml on at least two consecutive visits.ResultsMedian prior ARV exposure was seven drugs over a median time of 43 months. Fifty-nine percent of the patients were phenotypically (VIRCO Antivirogram) resistant at baseline to seven or more ARV. Median plasma viral load change following initiation of MDRT was −1.04 log10 copies/ml over a median of 15 months. Using intention-to-treat analysis 40% of patients had plasma viral load values < 400 copies/ml between weeks 47 and 57 of follow-up. Twenty-six patients (25%) experienced severe laboratory abnormalities or subjective adverse drug effects and six of these participants discontinued therapy.ConclusionMDRT induced a substantial antiviral response in this heavily pretreated group of patients despite extensive phenotypic resistance at baseline. Adverse effects were frequent but generally manageable. Our data suggest that relying exclusively on historical, clinical and laboratory evidence may not be sufficient to rule out a possible antiviral response when multiple drug regimens are used in this heavily pretreated patient population.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveLimited information exists on the clinical usefulness of drug level monitoring for efavirenz, a once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI). The aim of this study was to determine whether efavirenz plasma concentration monitoring could predict treatment failure and central nervous system (CNS) tolerability.MethodsBlood samples were obtained from 130 HIV-infected patients receiving efavirenz in combination with other antiretroviral agents for more than 3 months. Efavirenz plasma concentrations were measured by high-performance liquid chromatography. An evaluation of CNS side-effects was performed and the viral load, CD4 cell count and other clinical and laboratory data were assessed. In 85 patients, these measures were repeated at 3 month intervals.ResultsEfavirenz plasma levels (n = 226) were measured at an average of 14 h after drug intake. Drug concentrations ranged from 125 to 15 230 μg/l (median 2188). Large inter-patient (CV 118%) and limited intra-patient (CV 30%) variabilities were observed in efavirenz levels. Virological failure was observed in 50% of patients with low efavirenz levels (< 1000 μg/l) versus 22 and 18% in patients with 1000–4000 μg/l or more than 4000 μg/l, respectively. CNS toxicity was approximately three times more frequent in patients with high efavirenz levels (> 4000 μg/l) compared with patients with 1000–4000 μg/l.ConclusionTreatment failure and CNS side-effects are associated with low and high efavirenz plasma levels, respectively. The important inter-individual variability in efavirenz levels strongly argues for dose adjustment on the basis of therapeutic drug monitoring to optimize treatment.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo examine delayed presentation for HIV testing and primary care in the second decade of the AIDS epidemic.DesignCohort study in two urban hospitals in the USA between February 1994 and April 1996.MethodsA total of 203 consecutive outpatients on initial HIV primary care presentation were interviewed about sociodemographic characteristics, alcohol and drug use, social support, sexual practices, HIV testing, awareness of possible HIV infection, and CD4 cell count.Main outcome measureDuration of delay to medical presentation in years based on CD4 cell count, factors independently associated with low CD4 cell counts, frequency of awareness of HIV risk before testing.ResultsThe estimated mean duration between acquiring HIV infection and initial presentation to primary care was 8.1 years (95% CI 7.5, 8.6) based on our cohort's median initial CD4 cell count of 280/μl. Male sex, older age, and no jail time were associated with lower CD4 cell counts; 34% reported not being aware that they were at risk of HIV before testing. Heterosexual intercourse as a risk behavior for HIV was the most statistically significant factor for personal unawareness of HIV risk. Of those who acknowledged awareness, the mean time between awareness of HIV risk and testing was 2.5 years (median 1.0 year).ConclusionIn the pre-highly active antiretroviral therapy era, HIV-infected patients frequently initiated primary medical care years after initial infection, at a time of advanced immunosuppression. Over one-third of HIV-infected patients were not cognisant of their HIV risk before testing, a condition significantly associated with heterosexual intercourse as the only HIV risk behavior.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID