摘要:

Objective:To determine the rate of plasma HIV-1 RNA rebound in patients stopping highly active antiretroviral therapy (HAART) after achieving undetectable viral load.Design:Sequential plasma HIV RNA levels were measured in six patients during the 21 days following withdrawal from HAART.Methods:Plasma samples were obtained from six patients who chose to withdraw from HAART because of lipodystrophy, narcotic overdose, insomnia and/or high blood pressure. Longitudinal plasma viral load was determined in triplicate upon stopping therapy.Results:All patients had plasma viral loads below 50 HIV RNA copies/ml at the time of stopping therapy and had had levels below 500copies/ml for a median of 390 days (range 39-542 days). Plasma HIV rebound upon stopping therapy was rapid (median increase 0.2 log/day; range 0.15-0.42 log/day) and initially appeared to follow first-order kinetics. Plasma HIV RNA levels returned to greater than 500copies/ml within 6 to 15 days (median 10 days) and approached or exceeded pre-therapy levels in all patients within 21 days of stopping therapy. Extrapolating backwards to the time at which individuals stopped therapy suggested that patients had tens of thousands of total body plasma HIV RNA copies despite having ‚undetectable‚ plasma HIV RNA.Conclusions:HIV RNA in plasma rebounds within days of stopping antiretroviral therapy. A considerable burden of total body plasma HIV RNA likely remains even during effective HAART therapy.

ISSN:0269-9370    

出版商:OVID    

年代:1999

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective:To investigate the effect of highly active antiretroviral treatment (HAART) on neutrophil and monocyte function in patients with moderately advanced HIV-1 infection.Design:Eighteen HIV-1-infected patients with CD4 T cell counts below 350/ml, no concomitant active infection, and no previous use of protease inhibitors were treated with indinavir or ritonavir and two reverse-transcriptase inhibitors and were followed up for 9 months. Ten age- and sex-matched healthy subjects were included as controls.Methods:The functional activity of neutrophils and monocytes was measured by assessing chemotaxis towards a bacterial peptide, killing activity againstCandida albicans, and oxidative burst as measured by chemiluminescence production.Results:Neutrophils and monocytes from the treatment group exhibited a significantly diminished baseline chemotactic and fungicidal activity compared with healthy controls (P<0.001). After starting HAART, there was a significant improvement in chemotaxis and fungicidal activity of phagocytic cells (P<0.001). Values of chemotaxis reached normal ranges in 13 out of 18 patients (72%) for neutrophils and eight out of 18 (44%) for monocytes, whereas phagocyte killing was rarely restored to normal values (3/18 cases for monocytes and 0/18 for neutrophils). The administration of HAART was also associated with significantly increased phagocyte chemiluminescence production in response to phorbol-12-myristate 13-acetate or opsonizedC. albicans(P<0.01).Conclusion:The functional improvement of two critical components of innate antimicrobial immunity, such as neutrophils and monocytes, may contribute to the improved cell-mediated immune responses against opportunistic infections in HAART-treated patients.

ISSN:0269-9370    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective:CD8 T cells, expressing cell surface molecules distinct from those on resting and naive T cells, are increased in HIV infection. The association of increased CD38 and human leukocyte antigen DR (HLA-DR) CD8 T cells with poor prognosis has suggested that activated CD8 T cells may aggravate HIV infection. We examined whether other immunological parameters might influence the viral setpoint.Design:Peripheral T cells from nine untreated patients, obtained after primary HIV infection when plasma HIV had stabilized, were examined for proteins expressed in activated versus resting, memory versus naive, and cytolytic versus non-cytolytic T cells.Methods:The proportion of CD8 T cells that stain for CD38 and HLA-DR, CD28 and CD57 was compared with plasma viraemia and CD4 cell count. These parameters were also compared with the proportion of CD4 and CD8 T cells that express CD62L and CD45RA, present on naive cells and down-modulated in memory cells. Internal staining for the cytotoxic protein granzyme A was also examined.Results:An increase in CD38 and CD38 HLA-DR CD8 T cells correlated with increased plasma viral RNA (P<0.00002,P<0.03, respectively). An increase in CD8 T cells expressing granzyme A was associated with lower CD4 cell counts (P<0.04). However, the expansion of CD57 and CD62L-CD45RA+CD8 T cells was associated with a lower viral setpoint (P<0.01,P<0.02, respectively).Conclusion:Phenotypically defined activated CD8 T cells may have different functions in HIV infection. Activated CD8 T cells that are CD57 or CD62L-CD45RA+may be beneficial, because their expansion in untreated patients correlates with a reduced viral setpoint after primary infection.

ISSN:0269-9370    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective:HIV-1 is characterized by a high degree of genetic variation and can be divided into at least 10 distinct genetic subtypes. The purpose of this study was to investigate whether the rate of disease progression shows subtype-specific differences.Design:The investigation was divided into two parts; one study in which 49 ethnic Africans were compared with 49 ethnic Swedes irrespective of the subtype of the infecting virus, and a second study in which 126 individuals infected with different genetic subtypes (28 with subtype A, 59 with subtype B, 21 with subtype C and 18 with subtype D) were compared.Methods:CD4 cell counts, the rate of CD4 cell decline, plasma HIV-1 RNA levels, clinical status and antiviral treatment were prospectively and retrospectively recorded. The HIV-1 subtype had previously been determined by direct sequencing of the V3 domain of theenvgene.Results:There were no significant differences in the rate of CD4 cell decline or clinical disease progression between Africans and Swedes over an observation period of 2 years. Similarly, there were no differences in the rate of CD4 cell decline, clinical progression or plasma HIV-1 RNA levels between individuals infected with subtypes A, B, C or D over a mean observation period of 44 months.Conclusion:Neither the genetic subtype of the virus nor the ethnicity of the host appear to be major determinants of disease progression.

ISSN:0269-9370    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective:The envelope glycoprotein complex (gp120/gp41)nof HIV-1 is one of the viral products responsible for increased apoptosis in HIV infection. Here the role of the chemokine receptor CXCR4 in HIV-1 envelope protein-induced apoptosis was investigated.Methods:Apoptosis occurring in cocultures of chronically HIV-1 IIIB-infected cells with CD4 target cells expressing the CXCR4 receptor was quantified by terminal deoxinucleotidyl transferase dUTP nick end labeling (TUNEL) or propidium iodide staining followed by fluorescent antibody cell sorting, which allows the evaluation of single-cell killing. Moreover global (single cell- and syncytium-associated) apoptosis was quantified by a new radioactive TUNEL-derived assay.Results:By using these different techniques it was shown that single and syncytium-forming CD4 T cells die by apoptosis upon contact with envelope protein expressing cells independently of viral replication. Moreover, both the CXCR4 agonist SDF-1a, and the antagonist AMD3100, showed inhibitory effects on HIV-1 envelope protein-induced apoptosis in the CD4 T-cell subset of peripheral blood mononuclear cells and CD4 cell lines. CXCR4 signalling-induced by HIV-1 envelope proteins in CD4 T cells was not detected. Furthermore, it was shown that envelope protein-induced apoptosis can occur after treating target cells with the Gi-protein inhibitor pertussis toxin.Conclusions:Evidence is provided for a role of CXCR4 in the mechanisms of HIV envelope protein-induced pathogenesis, contributing to selective CD4 cell killing. The results suggest that CXCR4 is involved in HIV-1-induced apoptosis; however, this role does not appear to involve G-protein-mediated CXCR4 signalling.

ISSN:0269-9370    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective:The nucleoside analog 3‚-azido-3‚-deoxythymidine (ZDV) has widespread clinical use but also is carcinogenic in newborn mice exposed to the drugin uteroand becomes incorporated into newborn mouse DNA. This pilot study was designed to determine ZDV incorporation into human blood cell DNA from adults and newborn infants.Design:In this prospective cohort study, peripheral blood mononuclear cells (PBMC) were obtained from 28 non-pregnant adults and 12 pregnant women given ZDV therapy, six non-pregnant adults with no exposure to ZDV, and six non-pregnant adults who last received ZDV ≥6 months previously. In addition, cord blood leukocytes were obtained from 22 infants of HIV-1-positive, ZDV-exposed women and from 12 infants unexposed to ZDV. There were 11 mother-infant pairs involving HIV-1-positive women.Methods:DNA was extracted from PBMC obtained from non-pregnant HIV-1-positive adults taking ZDV, pregnant HIV-1-positive women given ZDV during pregnancy, and from adults not taking ZDV. Cord blood leukocytes were examined from infants exposed to ZDVin uteroand from unexposed controls. DNA samples were assayed for ZDV incorporation by anti-ZDV radioimmunoassay (RIA).Results:The majority (76%) of samples from ZDV-exposed individuals, pregnant women (8 of 12), non-pregnant adults (24 of 28), or infants at delivery (15 of 22), had detectable ZDV-DNA levels. The range of positive values for ZDV-treated adults and infants was 25-544 and 22-452 molecules ZDV/106nucleotides, respectively. Analysis of 11 mother-infant pairs showed variable ZDV-DNA incorporation in both, with no correlation by pair or by duration of drug treatment during pregnancy. Two of the 24 samples from individuals designated as controls were positive by anti-ZDV RIA. The 20-fold range for ZDV-DNA values in both adults and infants suggested large interindividual differences in ZDV phosphorylation.Conclusions:Incorporation of ZDV into DNA was detected in most of the samples from ZDV-exposed adults and infants. Therefore, the biologic significance of ZDV-DNA damage and potential subsequent events, such as mutagenicity, should be further investigated in large cohorts of HIV-positive individuals. The interindividual variability of ZDV incorporation into DNA in humans is considerable and consistent with reported variability in the formation of the ZDV-trisphosphate.

ISSN:0269-9370    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective:To investigate the outcome in children perinatally infected with HIV-1 whose mothers received zidovudine (ZDV) monotherapy in pregnancy.Design:Observational retrospective study of a prospectively recruited cohort.Setting:Italian Register for HIV Infection in Children.Patients:A group of 216 children perinatally infected with HIV-1, born in 1992-1997 and derived prospectively from birth: 38 children had mothers receiving ZDV monotherapy and for 178 children the mothers received no antiretroviral treatment during pregnancy.Main outcome measures:The estimated probability of developing severe disease or severe immune suppression, survival probability [95% confidence interval (CI)] within 3 years, and the hazard ratio (95% CI), adjusted for year of birth, maternal clinical condition at delivery, birthweight and treatments (Pneumocystis cariniipneumonia chemoprophylaxis and/or antiretroviral therapy before the onset of severe disease, severe immune suppression or death) were compared.Results:Comparison of HIV-1-infected children whose mothers were treated with ZDV with children whose mothers were not treated showed that the former group had a higher probability of developing severe disease [57.3% (95% CI 40.9-74.3)versus 37.2% (95% CI 30.0-45.4); log-rank test 7.83,P=0.005; adjusted hazard ratio 1.8 (95% CI 1.1-3.1)] or severe immune suppression [53.9% (95% CI 36.3-73.5) versus 37.5% (95% CI 30.0-46.2); log-rank test 5.58,P=0.018; adjusted hazard ratio 2.4, (95% CI: 1.3-4.3)] and a lower survival [72.2% (95% CI 50.4-85.7) versus 81.0% (95% CI 73.7-86.5); log-rank test 4.23,P=0.039; adjusted hazard ratio of death 1.9 (95% CI 1.1-3.6)].Conclusions:This epidemiological observation could stimulate virologic studies to elucidate whether this rapid progression depends onin uteroinfection or transmission of resistant virus. Findings may suggest a need to hasten HIV-1 diagnosis in infants of ZDV-treated mothers and undertake an aggressive antiretroviral therapy in those found to be infected.

ISSN:0269-9370    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective:To examine whether the serial measurement of plasma cytokine levels can assist in the early recognition of AIDS/tuberculosis patients with poor response to anti-tuberculosis treatment.Design:Longitudinal, prospective cohort study.Setting:A university hospital, the largest centre for HIV/AIDS patients in Taiwan.Methods:Between January 1997 and September 1998, 25 consecutive patients with advanced HIV infection and suspected tuberculosis were enrolled in the study. Plasma samples were obtained on day 1 (baseline), 3, 7 and 14 of anti-tuberculosis treatment and the levels of tumour necrosis factor-a (TNF-a) were measured. Patients were classified as either responders or non-responders according to the results of assessment of symptoms and follow-up cultures during the sixth and eighth week of anti-tuberculosis treatment. Thirty consecutive HIV-negative tuberculosis patients were also enrolled in the study.Results:The data of a total of 16 AIDS patients (median CD4 cell count 16¥106/l; 12 responders and four non-responders) and 21 HIV-negative patients (16 responders and five non-responders), whose tuberculosis was culture-proven, were included for analysis. In responders, TNF-a levels declined remarkably within the first week of anti-tuberculosis treatment; however, the decline of TNF-a levels in non-responders was significantly less [the median ratio of TNF-a level on day 7 to that at baseline was 0.32 versus 0.85 (P<0.001) in AIDS patients; 0.34 versus 0.80 (P=0.001) in HIV-negative patients). The lack of a ≥50% reduction in pre-treatment TNF-a levels during the first week of treatment was strongly associated with a poor response to anti-tuberculosis treatment (P=0.001 in AIDS patients;P<0.001 in HIV-negative patients).Conclusion:Serial measurement of plasma TNF-a levels may help to assess the response to anti-tuberculosis treatment in AIDS patients, in spite of very low CD4 cell counts. Failure of TNF-a levels to decline by ≥50 % of pre-treatment levels in the first week of treatment may be an early surrogate marker of a poor response.

ISSN:0269-9370    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objectives:To describe changes in haemoglobin over time and to determine the joint prognostic value of the current haemoglobin, CD4 lymphocyte count and viral load among patients from across Europe.Patients:The analysis included 6725 patients from EuroSIDA, an observational, prospective cohort of patients with HIV from across Europe.Methods:Normal haemoglobin was defined as haemoglobin greater than 14g/dl for men and 12g/dl for women; mild anaemia was 8-14g/dl for men and 8-12g/dl for women; severe anaemia was defined as less than 8g/dl for both males and females. Linear regression techniques were used to estimate the annual change in haemoglobin; standard survival techniques were used to describe disease progression and risk of death.Results:At recruitment to the study, 40.4% had normal levels of haemoglobin, 58.2% had mild anaemia and 1.4% had severe anaemia. At 12 months after recruitment, the proportion of patients estimated to have died was 3.1% [95% confidence interval (CI) 2.3-3.9] for patients without anaemia, 15.9% for patients with mild anaemia (95% CI 14.5-17.2) and 40.8% for patients with severe anaemia (95% CI 27.9-53.6;P<0.0001). In a multivariate, time-updated Cox proportional hazards model, adjusted for demographic factors, AIDS status and each antiretroviral treatment as time-dependent covariates, a 1g/dl decrease in the latest haemoglobin level increased the hazard of death by 57% [relative hazard (RH) 1.57; 95% CI 1.41-1.75;P<0.0001], a 50% drop in the most recent CD4 lymphocyte count increased the hazard by 51% (RH 1.51; 95% CI 1.35-1.70;P<0.0001) and a log increase in the latest viral load increased the hazard by 37% (RH 1.37; 95% CI 1.15-1.63;P=0.0005).Conclusions:Severe anaemia occurred infrequently among these patients but was associated with a much faster rate of disease progression. Among patients with similar CD4 lymphocyte counts and viral load, the latest value of haemoglobin was a strong independent prognostic marker for death.

ISSN:0269-9370    

出版商:OVID    

年代:1999

数据来源: OVID