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:

BackgroundA syndrome characterized by hypertriglyceridaemia, hypercholesterolaemia, hyperinsulinaemia, and lipodystrophy has been found to be associated with highly active antiretroviral treatment (HAART) including protease inhibitors. A marker predicting this syndrome has been previously identified in the gene encoding the sterol-regulatory element-binding protein (SREBP)-1c, a regulator of triglycerides, cholesterol, insulin, and adipocytes.ObjectiveA possible inhibition of SREBP-1c-dependent genes by the protease inhibitor indinavir and its possible reversal by the lipid-lowering drug simvastatin were studied.MethodsThe effects of indinavir and simvastatin on the inhibition/activation of SREBP-1c-dependent genes were compared with the effects of indinavir and simvastatin on the inhibition/activation of SREBP-1c-independent genes.ResultsIndinavir inhibited the SREBP-1c-dependent genes encoding the lipoprotein lipase (103nmol/l resulted in an inhibition of 12.4%;P= 0.0051) and the fatty acid synthase (103nmol/l resulted in an inhibition of 30.3%;P= 0.036) in a dose-dependent fashion but not the SREBP-1c-independent gene encoding the low-density lipoprotein receptor. Simvastatin antagonized the indinavir-induced SREBP-1c-inhibition.ConclusionsIndinavir inhibits important effector genes of the SREBP-1c pathway, explaining major HAART-related adverse effects.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectivesTo determine whether HIV-exposed, uninfected subjects (EUs) having HIV-specific effector activity are at a reduced risk for seroconverting compared with EUs with no HIV-specific effector responses.DesignTwenty-eight intravenous drug users (IVDU) with documented risk for HIV infection over a 1-year period were screened for the presence of HIV-specific CD8+ effector cell activity. Group I included 18 IVDUs who remained seronegative despite exposure to HIV through needle sharing with partner(s) known to be HIV infected. Group II included 10 IVDUs who seroconverted after similar HIV exposure.MethodsThe enzyme-linked immunospot (ELIspot; Mabtech AB, Nacka, Sweden) assay was used to measure the frequency of HIV-specific interferon-γ secreting cells. Peripheral blood mononuclear cells (PBMC) were stimulated with a panel of synthetic HIV peptides in a major histocompatibility complex class I antigen-restricted fashion. PBMC from group II were obtained from timepoints 7 months or less before seroconversion.ResultsTwelve of 18 (66.7%) persistently seronegative subjects versus none of 10 seroconverters exhibited detectable HIV-specific effector responses at the sampling date (P< 0.001; Fisher's exact test). This represents an odds ratio of 40.38 (95% confidence intervals 2.95 to > 3000).ConclusionEUs who have developed HIV-specific effector responses are at a reduced risk for seroconversion compared with EUs who do not develop this type of immunity. This observation supports the hypothesis that HIV-specific effector responses are a correlate of immune protection from HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

BackgroundTwo of the fusion inhibitors T-20 and 5-helix polypeptide have been shown to be potent inhibitors of cell-to-cell fusion and are currently under investigation as therapy for HIV-1.ObjectivesTo examine variability of HIV-1 gp41 heptads repeat regions (HR1 and HR2), with special emphasis on the presence of T-20 resistance mutations and 5-helix variability at critical epitopes, in treatment-naive patients infected with diverse HIV-1 subtypes from different geographic regions.MethodsA total of 150 specimens representing HIV-1 group M subtypes (A–G) from persons naive to HIV-1 viral entry inhibitor therapy were used to amplify and sequence a 506 bp segment of transmembrane protein.ResultsIn general, both HR1 (a.a. 540–593) and HR2 (a.a. 628–673) domains were highly conserved. Sequence analysis of the T-20 resistant domain (a.a. 547–549, GIV) revealed that 99% of the specimens (149 of 150) carried a T-20 sensitive genotype. The critical epitopes involved in the 5-helix interaction include residues at positions 628W, 631W, 635I, 638Y, 642I, 645L, 649S, 652Q, 656N, and 659E. Analysis of the 150 specimens revealed that all had identical residues at six of these positions, whereas two positions had minor variations (635 and 649) and two (645 and 659) appeared to have subtype-specific substitutions.ConclusionsThis data indicates that there is limited resistance to T-20 in these worldwide populations and that the critical epitopes for effective 5-helix binding are highly conserved across all subtypes. Taken together, these data suggest that T-20 and 5-helix should provide useful additives to current antiretroviral therapy for clinical management of HIV disease.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo identify crucial immunological characteristics of a group of patients, defined ‘CD4-exploders', who were able to fully reconstitute their immune system after receiving highly active antiretroviral therapy (HAART).PatientsAmong a population of 540 HIV-positive patients treated with HAART, six individuals were identified who experienced a nadir of less than 85 × 106CD4+ cells/l, had major opportunistic infections (four out of six), started HAART in 1996 or 1997, and showed a rapid and relevant CD4+ lymphocyte increase (mainly due to virgin cells), in some cases regardless of virological control.MethodsEnzyme-linked immunosorbent assay for the determination of interleukin (IL)-7 plasma levels; flow cytometry to analyse surface antigens and CD127 (IL-7 receptor α-chain) expression; quantitative-competitive (QC) PCR for detecting cells containing T-cell receptor rearrangement excision circles (TREC); chest-computed tomography (CT) to analyse thymus volume and content.ResultsIn ‘CD4-exploders', high levels of TREC+ lymphocytes were found among CD4+ T cells, which also contained a high percentage of naive cells. However, CT revealed a dramatic depletion of intrathymic lymphoid tissue. Plasma levels of IL-7 were significantly high. Most CD4+ and CD8+ T lymphocytes expressed CD127, whose level was similar to that of healthy donors. CD127 expression on CD8+ lymphocytes was markedly higher than in HIV-positive individuals treated with the same therapy or in patients with AIDS.ConclusionIn ‘CD4-exploders', HAART-induced reconstitution of the T-cell compartment is independent from thymus volume, and is favoured by the upregulation of the IL-7/IL-7 receptor system.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo evaluate the durability and correlates of the effectiveness of highly active antiretroviral therapy (HAART) in terms of AIDS-related mortality and morbidity, HIV viremia, and CD4 cell count.Design and settingThe HIV Outpatient Study (HOPS), a prospective observational cohort from eight clinics in the USA that has been running since 1994.ParticipantsMortality and opportunistic infection (OI) rates were calculated for 1769 HOPS patients with CD4 cell count ever < 100 × 106/l. Data from 1022 HAART recipients with CD4 cell count ever < 500 × 106/l were analyzed.Main outcome measuresMortality and AIDS-related OI rates. Treatment success was defined as a reduction in plasma HIV RNA copies/ml of 1.0 log10or more, or to an undetectable level, with a stable or rising CD4 cell count. Durable success was a successful response lasting at least 12 consecutive months.ResultsHAART use remained high; mortality and OIs low. Patients received a mean of 1.8 HAART regimens. Median time on first HAART (n = 1022) was 11.8 months; second HAART (n = 424) 7.4 months; and third HAART (n = 213) 7.2 months. Treatment success was most likely for pre-HAART treatment naive patients; durably successful first HAART most often contained one protease inhibitor, particularly indinavir or nelfinavir (P= 0.006, adjusted for prior antiretroviral therapy). Durable success was most likely with first (49.0%) than with second (29.6%,P= 0.013) or third or more HAART regimens (14.9%,P< 0.0001). Time to success with first HAART was shorter for durable than non-durable responders (3.6 versus 5.3 months, respectively; unadjustedP= 0.002).ConclusionsDurable response to HAART was associated with being pre-HAART therapy naive, prompt response to HAART, and single protease inhibitor-based initial HAART (indinavir or nelfinavir). Sequential HAART regimens were of progressively shorter duration, demonstrated less viral suppression and CD4 cell count benefit, yet low morbidity and mortality rates were sustained.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectivesTo describe the characteristics and predictors of transient plasma viral load (pVL) rebounds among patients on stable antiretroviral therapy and to determine the effect of one or more pVL rebounds on virological response at week 52.MethodsIndividual data were combined from 358 patients from the INCAS, AVANTI-2 and AVANTI-3 studies. Logistic regression models were used to determine the relationship between the magnitude of an increase in pVL and the probability of returning to the lower limit of quantification (LLOQ: 20–50 copies/ml) and to determine the odds of virological success at 52 weeks associated with single and consecutive pVL rebounds.ResultsA group of 165 patients achieved a pVL nadir < LLOQ; of these, 85 patients experienced pVL rebounds within 52 weeks. The probability of a pVL rebound was greater among patients who did not adhere to treatment (68% vs 49%;P< 0.05). The probability of reachieving virological suppression after a pVL rebound was not associated with the magnitude of the rebound [odds ratio (OR), 0.86;P= 0.56] but was associated with triple therapy (OR, 2.22;P= 0.06) or non-adherence (OR, 0.40;P= 0.04). The probability of virological success at week 52 was not associated with an isolated pVL rebound but was less likely after detectable pVL at two consecutive visits.ConclusionsAn isolated pVL rebound was not associated with virological success at 52 weeks but rebounds at two consecutive visits decreased the probability of later virological success. Given their high risk of short-term virological failure, patients who present with consecutive detectable pVL measurements following complete suppression should be considered ideal candidates for intervention studies.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveNon-typhoidal salmonella (NTS) bacteraemia is a common, recurrent illness in HIV-infected African adults. We aimed to describe the presentation and outcome of NTS bacteraemia, the pattern of recurrence, and to determine whether recurrence results from re-infection or recrudescence.DesignOne hundred consecutive adult inpatients with NTS bacteraemia in Blantyre, Malawi, were treated with chloramphenicol. Survivors were prospectively followed to detect bacteraemic recurrence.MethodsIndex and recurrent isolates were typed by antibiogram, pulsed-field gel electrophoresis and plasmid analysis to distinguish recrudescence from re-infection.ResultsInpatient mortality was 47%, and 1-year mortality was 77%. A total of 77 out of 78 cases were HIV positive. Anaemia was associated with inpatient death, and several features of AIDS were associated with poor outpatient survival. Among survivors, 43% (19/44) had a first recurrence of NTS bacteraemia at 23–186 days. Among these, 26% (5/19) developed multiple recurrences up to 245 days. No recurrence was seen after 245 days, despite follow-up for up to 609 days (median 214). Suppurative infections were not found at presentation, and were only seen twice at recurrence. Index and recurrent paired isolates were identical by phenotyping and genotyping, consistent with recrudescence, rather than re-infection.ConclusionNTS bacteraemia has a high mortality (47%) and recurrence (43%) rate in HIV-infected African adults. Recurrence is caused by recrudescence rather than re-infection. As focal infections were rarely found, recrudescence may often be a consequence of intracellular tissue sequestration. There is an urgent need for improved primary treatment and secondary prophylaxis in Africa.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

BackgroundHIV-1 subtype B is largely predominant in the Caribbean, although other subtypes have been recently identified in Cuba.ObjectivesTo examine HIV-1 genetic diversity in Cuba.MethodsThe study enrolled 105 HIV-1-infected individuals, 93 of whom had acquired the infection in Cuba. DNA from peripheral blood mononuclear cells was used for polymerase chain reaction amplification and sequencing ofpol(protease–reverse transcriptase) andenv(V3 region) segments. Phylogenetic trees were constructed using the neighbour-joining method. Intersubtype recombination was analysed by bootscanning.ResultsOf the samples, 50 (48%) were of subtype B and 55 (52%) of diverse non-B subtypes and recombinant forms. Among non-B viruses, 12 were non-recombinant, belonging to six subtypes (C, D, F1, G, H and J), the most frequent of which was subtype G (n = 5). The remaining 43 (78%) non-B viruses were recombinant, with 14 different forms, the two most common of which were Dpol/Aenv(n = 21) and U(unknown)pol/Henv(n = 7), which grouped in respective monophyletic clusters. Twelve recombinant viruses were mosaics of different genetic forms circulating in Cuba. Overall, 21 genetic forms were identified, with all known HIV-1 group M subtypes present in Cuba, either as non-recombinant viruses or as segments of recombinant forms. Non-B subtype viruses were predominant among heterosexuals (72%) and B subtype viruses among homo- or bisexuals (63%).ConclusionAn extraordinarily high diversity of HIV-1 genetic forms, unparalleled in the Americas and comparable to that found in Central Africa, is present in Cuba.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID