摘要:

Both increased lymphocyte renewal with subsequent exhaustion of the immune system and impaired T-cell renewal have been put forth to account for CD4+T-cell depletion and development of AIDS in HIV-1–infected humans and SIV-infected nonhuman primates. In the present study, telomeric terminal restriction fragment length and telomerase activity were used as measures of proliferative activity of T lymphocytes from three nonhuman primate species before and after being infected with SIV. In peripheral blood T cells, our data show both species and T-cell–subset-specific differences in proliferative activity accompanied by different patterns of disease progression. A significant postinfection increase in telomerase/proliferative activity in CD4+T cells from seropositive sooty mangabeys and from normal progressor rhesus macaques was associated with asymptomatic infection or delayed disease progression, respectively, whereas a decrease in telomerase/proliferative activity detected in CD4+T cells postinfection from SIVsmmPBj14-infected pigtailed macaques was associated with rapid CD4+T-cell depletion and disease progression. The levels of telomerase activity observed in CD4+T cells from peripheral blood closely parallelled those seen in CD4+T cells in lymph node samples from selected animals. Our data suggest that an increase in proliferative activity of T lymphocytes in vivo may be associated with a favorable course of SIV infection in nonhuman primates.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Mitochondrial toxicity was assessed in the brains of developingErythrocebus patasmonkey fetuses exposed in utero to the nucleoside analogue drug zidovudine (3´-azido-3´deoxythymidine or AZT). PregnantE. patasmonkeys were given 0 (n= 5), 10 (n= 3), and 40 (n= 3) mg of AZT/day, equivalent to 21 and 86% of the human daily dose, for the last half (about 10 weeks) of gestation. Mitochondria were isolated from fetal cerebrum and cerebellum at birth and mitochondrial morphology was examined in these tissues by transmission electron microscopy (TEM). Oxidative phosphorylation (OXPHOS) enzyme specific activities were measured spectrophotometrically. Mitochondrial DNA (mtDNA) integrity and quantity were determined by Southern blot and slot blot analysis. In the cerebral mitochondria, reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase (complex I) specific activity decreased by 25% in monkeys treated with 40 mg of AZT/day compared with unexposed monkeys (p≥ .05). At the same AZT dose in the cerebral mitochondria, succinate dehydrogenase (complex II) and cytochromecreductase (complex IV)–specific activities showed dose-dependent increases (p≥ .05), compared with those in controls. In the cerebellum, no difference was seen in mitochondrial OXPHOS enzyme activities between unexposed and exposed fetuses. Furthermore, TEM demonstrated no difference in mitochondrial morphology in frontal cerebrum or cerebellum from unexposed and exposed fetuses, and all fetuses had similar amounts of mtDNA in both tissues. Cerebral mtDNA degradation was noted in the highest AZT dosage group, whereas mtDNA from cerebellum was uneffected. Thus, in fetal patas monkeys given a human equivalent daily dose of AZT during the last half of pregnancy, mitochondria in the fetal cerebrum appear to sustain moderate damage, while the fetal cerebellum mitochondria were not effected.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveRecent advances in antiretroviral therapy have led to effective but increasingly complex strategies for the treatment of HIV infection. In a previous study, we demonstrated that physicians' experience in the care of patients with AIDS improves survival. We conducted this study to determine whether greater physician experience is associated with earlier adoption and appropriate use of new antiretroviral treatment regimens.DesignRetrospective medical record review of a population-based sample of HIV-infected individuals who received antiretroviral treatment between December 1995 and May 1997 by primary care physicians practicing throughout the state of Washington. We classified antiretroviral regimens observed into one of four categories based on national treatment guidelines.ResultsThe use of new antiretroviral treatment regimens significantly increased during the study period; 22% of patients were treated with a protease inhibitor (PI)-based regimen or an alternative PI-or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen between December 1995 and November 1996, compared with 57% between April and May 1997 (p< .001). After controlling for CD4 count and the calendar period of treatment, patients cared for by physicians with greater HIV experience were significantly more likely to receive PI-based regimens or alternative PI-or NNRTI-based antiretroviral regimens (p= .02). Use of PI-based regimens was also associated with lower CD4 count (p< .001) and treatment after January 1997 (p= .02), but independent of patient demographic characteristics and the geographic location of physicians' practices.ConclusionsGreater physician experience in the care of persons with HIV infection is associated with earlier adoption of new antiretroviral treatment regardless of whether physicians practice in a rural or urban area.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The outcome of second-line protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART) was investigated in 263 patients who were failed by (n= 148) or intolerant of (n= 115) a first HAART regimen. The endpoints were virologic failure (decline in HIV RNA <1 log10copies/ml after ≥2 months) and discontinuation due to intolerance/toxicity. During a median follow-up of 483 days (33–1087 days), 154 patients (59%) discontinued the second regimen, 86 (33%) because of intolerance/toxicity; another 135 patients (51.3%) showed virologic failure. Independent factors associated with virologic failure (Cox's model) were 7 to 12 months of first HAART (hazard ratio [HR] 1.70 versus ≤6 months: 95% confidence interval [CI], 1.08–2.70) and gender (HR 1.58 males versus females: 95% CI, 1.04–2.30); the negatively associated factors were advanced age (HR 0.61 >34 years versus ≤34 years: 95% CI, 0.42–0.88), a saquinavir-containing first HAART (HR 0.57 versus indinavir: 95% CI, 0.34–0.93) and change due to intolerance/toxicity (HR 0.58 versus failure: 95% CI, 0.35–0.98). The independent variables predictive of discontinuation due to intolerance/toxicity were the reason for switching (HR 1.79 intolerance versus failure: 95% CI, 1.02–3.16) and the first protease inhibitor (PI) regimen (HR 0.42 ritonavir versus indinavir: 95% CI, 0.22–0.80). Given that patients who are failed by a first regimen are at high risk of having rescue therapy fail as well, second-line regimens including therapies directed by testing of drug resistance patterns of clinical viral isolates are warranted. Patients experiencing toxicity due to a first PI-containing regimen are at risk of toxicity to other PIs and should be addressed to PI-sparing HAART.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo compare self-reported nonadherence with antiretroviral therapy (ART) with predose plasma levels of protease inhibitor (PI).DesignA cross-sectional study of consecutive patients from a university-based HIV clinic in Rome, Italy, was conducted. One hundred and forty HIV-infected patients were prescribed regimens containing ritonavir or indinavir. A patient questionnaire assessing knowledge of treatment regimen, adherence behavior, reasons for taking and missing therapy, factors influencing adherence, and health behaviors was administered. A predose PI plasma level was measured concurrently.ResultsBy patient report, 12% missed at least one dose “yesterday,” and 24% missed doses in the last 3 days; 14% had a predose plasma concentration below the assay limit of quantitation (2 ritonavir and 18 indinavir samples). Confusion, poor psychological well-being, long office wait, running out of drugs between visits, having relatives to remind the patient to take medication, children, and alteration of sense of taste were related to unquantifiable predose levels of PI. In multivariable analysis, reported nonadherence (odds ratio [OR], 15.8; 95% confidence interval [CI], 4.0–63.3) and confusion (OR, 9.9; 95% CI, 1.4–69.6) were related to unquantifiable predose levels of PI.ConclusionSelf-report of missing a dose of antiretroviral medication “yesterday” was related to an unmeasurable plasma PI level.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundThe viral protease inhibitor ritonavir has the capacity to inhibit and induce the activity of cytochrome P450-3A (CYP3A) isoforms, leading to drug interactions that may influence the efficacy and toxicity of other antiretroviral therapies, as well as pharmacologic treatments of coincident or complicating diseases.MethodsThe inhibitory effect of ritonavir on the biotransformation of the hypnotic agents triazolam and zolpidem was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer study subjects received 0.125 mg triazolam or 5.0 mg zolpidem concurrent with low-dose ritonavir (four doses of 200 mg), or with placebo.ResultsRitonavir was a potent in vitro inhibitor of triazolam hydroxylation but was less potent as an inhibitor of zolpidem hydroxylation. In the clinical study, ritonavir reduced triazolam clearance to <4% of control values (p< .005), prolonged elimination half-life (41 versus 3 hours;p< .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. In contrast, ritonavir reduced zolpidem clearance to 78% of control values (p< .08), and slightly prolonged elimination half-life (2.4 versus 2.0 hours; NS). Benzodiazepine agonist effects of zolpidem were not altered by ritonavir.ConclusionShort-term low-dose administration of ritonavir produces a large and significant impairment of triazolam clearance and enhancement of clinical effects. In contrast, ritonavir produced small and clinically unimportant reductions in zolpidem clearance. The findings are consistent with the complete dependence of triazolam clearance on CYP3A activity, compared with the partial dependence of zolpidem clearance on CYP3A.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo determine the nature and strength of the relation between lean body mass and measures of health-related quality-of-living (HRQL) including physical functioning in men and women with HIV.DesignCross-sectional analysis using 619 patients with HIV infection from two cities in the northeastern United States.Main Outcome MeasuresLean body mass (LBM) was assessed by bioimpedance analysis (BIA). Physical functioning, general health perceptions, energy/fatigue, and number of days spent in bed in the last month were determined by patient self-report.ResultsData from 450 men and 169 women were analyzed. Mean age was 39 years, 37.6% were nonwhite, and mean CD4 counts were 352 cells/ml. In multivariable models, higher LBM was significantly associated with better physical functioning in men but not in women. In men, a 10-kg increment in LBM was associated with a 3.7 point (95% confidence interval [CI], 0.19–7.2) increment in physical functioning (0–100 scale). In similar analyses, higher LBM was significantly associated with better general health perceptions (10-kg increment in LBM associated with a 4.8 point [95% CI, 1.4–8.1] increment in general health perceptions), and fewer days in bed in the last month (10-kg increment in LBM associated with 0.9 [95% CI, −1.8–0] fewer days in bed). Lean body mass was not independently associated with energy/fatigue.ConclusionsIn this diverse population of persons with HIV, LBM was significantly related to physical functioning and other measures of HQRL in men, but not in women. In men, the relation was linear but relatively weak. These data have potential implications for assessing the clinical impact of interventions aimed at increasing LBM. Even in men, increases in LBM in the ranges that are currently achievable may produce relatively small improvements in physical functioning and other measures of HRQL.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

We evaluated the potential effectiveness of a spermicide cationic surfactant, benzalkonium chloride (BZK), to prevent the transmission of simian immunodeficiency virus (SIV) after intravaginal inoculation in 12 cynomolgus macaques. The inoculation procedure involved deposition of 6.7 ivag-AID50of cell-free SIVmac251 into the receiving vagina, four times over a 2-week period, at the end of the luteal phase of the menstrual cycle. Six randomly selected females received vaginally foam containing BZK (7.37%, wt/wt) before each inoculation (BZK group), whereas the remaining were not pretreated (control group). In controls, 5 animals presented persistent SIV infection and 1 had a transient viremia. The number of uninfected animals was higher in the BZK group (6 of 6) than in controls (0 of 6). These findings demonstrate that BZK placed in the vaginal receptacle prior to SIV inoculation provides a significant protection in vivo. The wide spectrum of antimicrobial activities of BZK (including HIV) in addition to its efficiency to block the transmucosal passage of SIV in the macaque model qualifies this drug as an attractive topical microbicide to prevent sexually transmitted infections in humans.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo determine the influence of prenatal zidovudine (ZDV) prophylaxis on the course of HIV-1 infection in children by comparing the clinical outcome of infants born to HIV-1–seropositive mothers who did versus those who did not receive ZDV during pregnancy.MethodsMedical records of HIV-1–seropositive mothers and their infants were reviewed retrospectively. Participants were divided according to maternal ZDV use: no ZDV (n= 152); ZDV (n= 139). The main outcome measure was rapid disease progression (RPD) in the infant, defined as occurrence of a category C disease or AIDS-related death before 18 months of age.ResultsHIV vertical transmission rates were significantly different (no ZDV versus ZDV: 22.3% versus 12.2%;p= .034). Among infected infants, the RPD rate was 29.4% in the no ZDV group compared with 70.6% in the ZDV group (p= .012), and prematurity was significantly associated with a higher risk of RPD (p= .027).ConclusionsThe rate of RPD was significantly higher among perinatally infected infants born to HIV-infected mothers treated with ZDV than among infected infants born to untreated mothers. The decreased proportion of infected infants with nonrapid disease progression in the former group might be related to the ability of ZDV to block intrapartum transmission preferentially and also to nonrapid disease progression resulting from intrapartum transmission.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID