摘要:

ObjectiveTo evaluate whether controlled re-exposures to autologous HIV-1 could boost HIV-specific immunity and limit virus replication in patients with chronic HIV-1 infection.Patients and designSubjects with at least 2 years virus suppression during antiretroviral therapy and a CD4 : CD8 ratio > 1 were randomly assigned to interrupt highly active antiretroviral treatment (HAART) three times (n = 12) or to continue their previous HAART (n = 14).ResultsIn 10/12 interrupter patients a rebound of HIV-1 RNA was detected in all three structured treatment interruptions (STI). Plasma virus doubling time was shorter during the first STI than in the second and third STI, corresponding to an average 13% reduction in viral basic reproductive rate. However, the mean time before plasma viral load rose to > 50 copies/ml was significantly shorter in the second and third STI. The average frequency of HIV-specific CD8 T cells in the interrupter patients at the end of the third STI cycle was significantly higher compared with the baseline and the end of the first STI. A substantial increase in HIV-specific CD8 T cell frequencies was found in four interrupter patients, whereas there were no changes in all 14 non-interrupter individuals. A weak p24-specific T helper response developed in 5/12 interrupter patients compared with no response in non-interruptors, but these responses were transient and disappeared rapidly.ConclusionThe increase in the control of viral replication, and positive effects of STI on immune responses in this population should encourage the further development of HIV-specific immune-based therapeutic strategies.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundSome individuals with chronic HIV-1 infection have discontinued their drug therapy with consequent plasma virus rebound. In a small number of patients, a delayed or absent rebound in plasma virus load has been noted after drug cessation, apparently associated with prior drug interruptions and autologous boosting of HIV-1 specific immune responses. We hypothesized that cyclic structured treatment interruptions structured treatment interruptions (STI) could augment HIV-1 specific immune responses in chronic HIV-1 infection, which might help to control HIV-1 replication off therapy.MethodsWe initiated an STI pilot study in 10 antiretroviral treatment-naive HIV-1 chronically infected subjects with baseline CD4 T-cell counts > 500 × 106cells/l and plasma viral load > 5000 copies/ml who received highly active antiretroviral therapy (HAART) for 1 year with good response (plasma viral load < 20 copies/ml for at least 32 weeks). Three cycles of HAART interruption were performed.ResultsIn all of the patients viral load rebounded, but doubling times increased significantly between the first and third stops (P =0.008), and by the third stop, six out of nine subjects had a virological set-point after a median 12 months off therapy that was lower than baseline before starting HAART (ranging from 0.6 log10to 1.3 log10lower than baseline) and in four it remained stable below 5000 copies/ml. Those subjects who controlled viral replication developed significantly stronger HIV-1 specific cellular immune responses than subjects lacking spontaneous decline (P< 0.05). During viral rebounds no genotypic or phenotypic changes conferring resistance to reverse trancriptase inhibitors or protease inhibitors was detected, but mean absolute CD4 T-cell counts declined significantly, although never below 450 × 106/l and the mean value at 12 months off therapy was significantly higher than the pre-treatment level (P= 0.004).ConclusionsOur findings suggest that STI in chronic HIV-1 infection might augment HIV-1-specific cellular immune responses associated with a spontaneous and sustained drop in plasma viral load in some subjects but at the potential cost of lower CD4 T-cell counts.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo explore relationships between exposure to nevirapine and the virological response in HIV-1-infected individuals participating in the INCAS trial.MethodsThe elimination rate constant of plasma HIV-1 RNA (k) was calculated during the first 2 weeks of treatment with nevirapine, zidovudine and didanosine in 51 antiretroviral-naive HIV-1-infected patients. The relationships between the value ofk, the time to reach an undetectable HIV-1 RNA concentration in plasma (< 20 copies/ml) and the success of therapy after 52 weeks of treatment as dependent variables and the exposure to nevirapine, baseline HIV-1 RNA and baseline CD4 cell count as independent variables, were explored using linear regression analyses, proportional hazard models and logistic analyses, respectively.ResultsThe value ofkfor HIV-1 RNA in plasma was positively and significantly associated with the mean plasma nevirapine concentration during the first 2 weeks of therapy (P= 0.011) and the baseline HIV-1 RNA (P= 0.008). Patients with a higher exposure to nevirapine reached undetectable levels of HIV-1 RNA in plasma more rapidly (P= 0.03). From 12 weeks on, the median nevirapine plasma concentration was significantly correlated with success of therapy after 52 weeks (P< 0.02).ConclusionsA high exposure to nevirapine (in a twice daily regimen) is significantly associated with improved virological response in the short as well as in the long term. These findings suggest that optimization of nevirapine concentration might be used as a tool to improve virological outcome in (antiretroviral-naive) patients treated with nevirapine.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo evaluate dynamics in CD8 T cell expansions during highly active antiretroviral therapy (HAART).DesignVarious T cell subsets were isolated from blood and lymph nodes and analysed for T cell receptor (TCR) diversity.MethodsTCR complementarity determining region 3 (CDR3) spectratyping and single-strand conformation polymorphism (SSCP) analyses were performed in combination with sequencing to assess clonality of the subsets.ResultsStrongly skewed CDR3 patterns in total CD8 cells and the CD8 subsets CD45RO+CD27+ and CD45RO−CD27+ showed substantial dynamics in dominant CDR3 sizes, resulting in relative improvement of CDR3 size diversity in the first months of therapy. During sustained treatment, TCR diversity changed only moderately. SSCP profiles confirmed oligoclonality of TCR CDR3 perturbations. Various dominant CDR3 sizes for CD4 and CD8 T cells present in lymph nodes, but not in peripheral blood mononuclear cells, before the start of therapy emerged in peripheral blood early during therapy.ConclusionsHAART induces substantial changes in CD8 TCR diversity, eventually resulting in improvement of the repertoire. Clonal expansions observed in lymph nodes before therapy were observed in peripheral blood after therapy, suggesting that recirculation of CD4 and CD8 T cells from lymph nodes contributes to the early T cell repopulation. Decreased immune activation and possibly naive T cell regeneration subsequently decreased clonal expansions and perturbations in the CD8 TCR repertoire.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundAIDS-related non-Hodgkin's lymphoma (NHL) includes systemic lymphomas, often with brain involvement, and primary central nervous system (CNS) lymphomas.ObjectiveTo examine if measurement of soluble CD23 (sCD23) in cerebrospinal fluid (CSF) is useful in the diagnosis and follow-up of AIDS-related NHL.MethodsCD23 was measured by enzyme-linked immunosorbent assay and EBV DNA by nested polymerase chain reaction for a group of 134 patients. The NHL group included 14 patients with primary HIV-1 CNS lymphoma, 12 patients with brain involvement of systemic HIV-1 NHL and 10 patients with systemic HIV-1 NHL without brain involvement. These were compared with HIV-1-infected patients with cerebral toxoplasmosis (19), progressive multifocal leukoencephalitis (PML; 8) and AIDS-related dementia (17) and with asymptomatic HIV-1 carriers (54) and uninfected individuals (50). The levels of sCD23 were compared with the presence of Epstein–Barr virus (EBV) DNA in CSF.ResultsSignificantly higher levels of sCD23 were found in the CSF of the patients with brain lymphoma than in those with systemic NHL (P< 0.002) or with cerebral toxoplasmosis, PML and AIDS-related dementia (P< 0.0001). The sensitivity and specificity of sCD23 in CSF as a marker for detection of brain NHL were 77% and 94%, respectively. High levels of sCD23 were found in CSF from patients with brain NHL independently of the presence (18 out of 26) or absence (8 out of 26) of EBV DNA.ConclusionsThe sCD23 in CSF of HIV-1-infected patients may represent an additional, non-invasive marker for diagnosis of brain involvement in AIDS-related NHL.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundThe advent of highly active antiretroviral therapy (HAART) has reduced the incidence of most AIDS-related opportunistic illnesses (OI) and death in HIV-infected individuals. We investigated whether there are demographic disparities in HIV disease progression in the HAART era compared with before.MethodsHIV-infected patients in an urban HIV clinical practice in the USA were compared using survival methods for time to a new AIDS-defining OI or death in therapeutic era 1 (monotherapy and combination therapy; 1990–1995; n = 2016) versus era 2 (HAART; 1996–1999; n = 2165).ResultsA total of 1037 (51.4%) events occurred in era 1; 666 (30.8%) events occurred in era 2. In women, the median disease-free survival time increased by 14% (CD4 cell counts > 200 cells/mm3at baseline) and 34% (CD4 cell counts ⩽ 200) in era 2 compared with era 1, whereas for men it increased by 43 and 100%. The relative hazard (RH) of progression for women compared with men in era 2 compared with era 1 was 1.34. For injecting drug use (IDU), disease-free survival time increased by 16% and 34% in era 2 compared with era 1, whereas non-IDU improved by 65 and 135%. The RH of progression for IDU compared with non-IDU in era 2 compared with era 1 was 1.39. No significant differences were detected by race or other HIV transmission risk group.ConclusionDisease-free survival time was extended with the use of HAART, but these gains were not equally distributed by sex and IDU in our cohort.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundEnhanced susceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI) was recently described in association with increased resistance to nucleoside analogs (nucleoside reverse transcriptase inhibitors; NRTI).ObjectivesTo determine the prevalence of NNRTI hypersusceptibility, the genotypic correlates, and its impact on virologic response to efavirenz-based salvage therapy.MethodsGenotype and phenotype testing was performed retrospectively on baseline isolates from 30 patients who received salvage therapy containing efavirenz. NNRTI hypersusceptibility was defined as a 50% inhibitory concentration (IC50) of < 0.5 that of the wild-type control.ResultsEight isolates had major NNRTI mutations. Among the 22 isolates with no major NNRTI mutations, 11 (50%) were hypersusceptible to efavirenz, 10 (45%) to delavirdine, and eight (36%) to nevirapine. Among eight isolates with NNRTI mutations, NNRTI resistance was present, but at lower than expected levels. The number of NRTI mutations was correlated inversely with the fold decrease in susceptibility to efavirenz (Spearman's ρ, −0.57;P =0.005), delavirdine (ρ, −0.43;P =0.04), and nevirapine (ρ, −0.69;P< 0.001). Excluding subjects with NNRTI mutations, subjects with efavirenz hypersusceptibility at baseline had significantly better virologic suppression over 24 weeks than those without efavirenz hypersusceptibility (P< 0.001).ConclusionNNRTI hypersusceptibility is common in heavily treated but NNRTI naive patients and is related directly to NRTI resistance mutations. Among patients receiving efavirenz-containing regimens, NNRTI hypersusceptibility was associated with an improved virologic outcome after 24 weeks of therapy. A reversal of phenotypic resistance was seen in patients with NNRTI mutations in the presence of multiple NRTI mutations, but no obvious virologic benefit of this phenomenon was seen in this study.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo compare the effectiveness of first protease inhibitor (PI)-containing and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens.MethodsData were analysed from three large HIV patient databases: Apache HIV InsightTM(APACHE), Target Management Services (TMS) and Clinical Partners (CP). The effectiveness of therapy was the time taken for HIV-1 RNA to fall below detectable levels on first highly active antiretroviral therapy regimen (PI- or NNRTI-containing) and the subsequent time to failure (two consecutive detectable measurements). Comparisons were made using proportional hazards models, adjusting for differences in age, sex, previous reverse transcriptase inhibitor use, calendar year and baseline viral load and CD4 T-cell count.ResultsThe type of regimen was not associated with time to undetectable viral load in any of the three databases, all of which had high power to detect a difference. PI-containing regimens were significantly less likely to fail after reaching undetectable viral loads for APACHE and CP patients (relative hazard, 1.7; 95% confidence interval, 1.3–2.1 and relative hazard, 1.6; 95% confidence interval, 1.0–2.5 respectively). These results remained significant after allowing for an unmeasured confounder with moderate effect on risk. No significant association between time to failure and regimen was found for TMS patients, possibly due to low power (67% to detect a relative hazard of 1.5). No difference was found between regimens in the time taken for an increase of > 100 × 109cells/l in CD4 T-cell count. In the APACHE database, those on NNRTI-containing regimens were more likely to have a failing CD4 T-cell response.ConclusionsPI-containing regimens have a lower risk of treatment failure than NNRTI-containing regimens.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo evaluate the proposed WHO/UNAIDS criteria for initiating co-trimoxazole prophylaxis in adult HIV-infected patients in Africa [WHO clinical stages 2–4 or CD4 count < 500 × 106/l or total lymphocyte count (TLC) equivalent].DesignObservational cohort study of 5-year follow-up.SettingAdult HIV clinics, University of Cape Town, South Africa.MethodsEffect of prophylactic low dose co-trimoxazole (480 mg per day or 960 mg three times per week) on survival and morbidity was assessed in patients stratified by WHO clinical stage, CD4 T-lymphocyte count or TLC. Patients receiving antiretroviral therapy were excluded.ResultsCo-trimoxazole reduced mortality [adjusted hazard ratio (AHR), 0.56; 95% confidence interval (CI), 0.33–0.85;P> 0.001] and the incidence of severe HIV-related illnesses (AHR, 0.52; 95% CI, 0.38–0.68;P< 0.001) in patients with evidence of advanced immune suppression on clinical (WHO stages 3 and 4) or laboratory assessment (TLC < 1250 × 106/l or CD4 count < 200 × 106/l). No significant evidence of efficacy was found in patients with WHO stage 2 or CD4 count 200–500 × 106/l/TLC 1250–2000 × 106/l. If we had applied the WHO/UNAIDS recommendations 88.3% of our patients would have received co-trimoxazole prophylaxis at their initial clinic visit.ConclusionCo-trimoxazole in HIV-infected adults from an area in whichPneumocystis cariniipneumonia is uncommon demonstrated a survival benefit consistent with previous randomized trials. Further studies are needed to assess the optimal time of commencement of prophylaxis, as widespread co-trimoxazole use will lead to increasing antimicrobial resistance to other major pathogens in Africa.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo determine the risk factors for and trends in gonorrhea infections among HIV-infected persons.DesignLongitudinal review of medical records of HIV-infected patients.MethodsWe analyzed data about HIV-infected patients obtained from 1991 to 1998 in over 100 facilities participating in the Adult/Adolescent Spectrum of HIV Disease Project.ResultsThe overall incidence of gonorrhea was 9.5 cases per 1000 person–years. Factors associated with higher gonorrhea incidence (P< 0.01) included younger age, male–male sex, black race, HIV infection without AIDS (namely AIDS-defining opportunistic illness or CD4 cell count < 200 × 106cells/l), and recent recreational use of injection or non-injection drugs. There was an increase in the trend among men who have sex with men (P< 0.01) and a decrease in the trend among patients with heterosexual contact as their HIV exposure risk (P< 0.01). Among injection drug users there was no significant trend from 1991 to 1996, but there was an increase in gonorrhea incidence from 6.6 cases/1000 person–years in 1997 to 16.3 cases/1000 person–years in 1998.ConclusionsFollowing HIV diagnosis, some individuals continue to practice risky sexual behaviors which result in gonorrhea and may transmit HIV. The increase in the trend in gonorrhea incidence among HIV-infected men who have sex with men is of particular concern because it suggests an increase in risky sexual behaviors. These findings indicate a need for effective HIV prevention strategies that involve reducing risky sexual behaviors in HIV-infected persons.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID