摘要:

ObjectiveTo investigate the molecular mechanisms of nucleoside analogue reverse transcriptase inhibitor (NRTI)-associated mitochondrial dysfunction.MethodsPeripheral blood samples were collected from 10 healthy individuals, 10 HIV-infected, NRTI-treated patients with lipoatrophy, and four HIV-infected patients naive to all antiretrovirals. DNA was isolated from the leukocytes and the mitochondrial genome analyzed for DNA depletion, deletions and point mutations.ResultsWe were not able to detect mitochodrial DNA (mtDNA) depletion, deletions, or DNA rearrangements in any of the specimens, including one from a patient with fulminant lactic acidosis. A complete analysis of the entire mitochondrial genome by temporal temperature gradient gel electrophoresis revealed several nucleotide substitutions in blood mtDNA of several HIV infected patients.ConclusionWe found no evidence for NRTI-associated mtDNA depletion or gross mtDNA mutations in leukocytes of HIV-infected patients, regardless of their treatment history. Thus, either NRTI-induced mutations in mtDNA are tissue-specific or alternatively, pre-existent mtDNA variations in HIV disease predispose to the development of clinically apparent mitochondrial dysfunction during NRTI therapy. The significance of mtDNA variations in the development of mitochondrial-related clinical conditions in HIV patients with or without NRTI therapy is to be further investigated.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo study the role of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) during HIV infection.MethodsIntracellular CTLA-4 expression, determined by flow-cytometry, and proliferative responses to HIV antigens, were studied in peripheral blood mononuclear cells (PBMC) from 93 HIV-1-infected [HIV(+)] patients and 40 HIV-1 seronegative controls.ResultsThe proportions of CTLA-4 expressing CD4+ T cells were: (1) significantly higher in HIV(+) patients, 10.95 ± 0.66%, than in controls, 6 ± 0.45% (P< 0.0001); (2) inversely correlated to CD4+ counts (r= −0.67,P< 0.005, n = 16, drug-naive patients;r= −0.57,P< 0.0001, n = 77, HAART-treated patients); and (3) positively correlated to proportion of activated (HLA-DR+CD3+) (r= 0.53,P< 0.0001) and memory (CD45RO+CD4+) T cells (r= 0.46,P< 0.001). CD28 median fluorescence intensity in CTLA-4- cells was twice that in CTLA-4+ cells (140 ± 5.3 versus 70 ± 2.28,P< 0.00001), whereas cells low in CD28 and CD4, expressed more CTLA-4 (P< 0.0001). Higher proportion of CTLA-4+CD4+ cells expressed CCR5 and Ki-67, in comparison with CTLA-4-CD4+ cells, (65 ± 11.9 and 25 ± 7.5% versus 27 ± 8.9 and 3.7 ± 2%,P< 0.0001 andP< 0.01, respectively). Among HAART-treated patients, with viral load below detectable levels, CD4+ cells increase was inversely correlated to %CTLA-4+CD4+ cells (r= −0.5,P= 0.003, n = 39). Proliferation of PBMC to anti-CD3, gp-120 depleted HIV-1 antigen or HIV-1 p24 stimulation was inversely correlated with CTLA-4 levels (r= −0.68,P= 0.0035;r= −0.38,P= 0.04; andr= −0.43,P= 0.028, respectively).Conclusions(1) CTLA-4 is upregulated during HIV infection and may therefore account for CD4 T-cell decline and anergy in HIV-1 infection. (2) Increased levels of CTLA-4 may undermine immune responses and in the HAART-treated patient-immune reconstitution. (3) Blocking of CTLA-4 may offer a novel approach for immune-based therapy in HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo measure the effects of combined chemotherapy and highly active antiretroviral therapy (HAART) on immune cell counts and plasma HIV-1 RNA loads in patients with AIDS-related lymphoma (ARL) to determine the implications for opportunistic infection prophylaxis and medium-term immune function.Design and methodsPeripheral blood total lymphocyte count, CD4 T-cell count, CD8 T-cell count, CD19 B-cell count, CD16/CD56 natural killer cell count and plasma HIV-1 RNA load were prospectively measured at ARL diagnosis, at 1 and 3 months during and 1, 3 and 6 months after chemotherapy in twenty patients receiving HAART.ResultsSignificant declines in T-helper cell (CD4) count, natural killer cell (CD16/CD56) and B lymphocyte count (CD19 cells) occurred during the first 3 months of chemotherapy. There was no significant alteration in the T-cytotoxic cell (CD8) count, CD4 percentage or HIV-1 RNA load during the study period. The T-helper cell and natural killer cell counts recovered to pre-treatment levels within 1 month of finishing chemotherapy. The recovery of B-cells was slower with pre-treatment levels only being achieved after 3 months. The recovery of CD4 T-cell count following completion of chemotherapy was more rapid than described for ARL patients who were not receiving concomitant HAART.ConclusionsBy combining chemotherapy with HAART, immune function is better maintained in the medium term. The CD4 T-cell count falls by 50% during chemotherapy and this will help to identify patients who require opportunistic infection prophylaxis during chemotherapy.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveIn this study we evaluated the possibility that plasma viral load elevations secondary to influenza vaccination in HIV-1-seropositive individuals with previously undetectable viral loads (< 200 copies/ml) could develop resistance-bearing mutations in the viral reverse transcriptase (RT) and protease regions.MethodsThirty-four patients with undetectable viral burdens on highly active antiretroviral therapy (HAART) were evaluated for elevations in plasma viral load 2 and 4 weeks post-influenza vaccination. Plasma from patients whose viral load increased after vaccination was subject to genotypic resistance analysis by the line probe assay (LiPA) to determine whether primary resistance-bearing mutations developed during this period and at follow-up. Stored plasma was used to evaluate whether RT or protease mutations existed pre-vaccination.ResultsSeven out of 34 patients were found to experience elevations in their viral load after influenza vaccination. Two of the patients revealed evidence of primary RT or protease mutations not demonstrated in earlier pre-vaccination samples. One patient failed therapy after vaccination, and one patient revealed post-vaccination viral load elevations that eventually led to the progressive development of primary zidovudine mutations.ConclusionEvidence is presented that supports the contention that a small subset of patients who experience viral load elevations after influenza vaccination can develop mutational changes in the RT region of the viral genome either acutely or after a failure of the viral load to return to undetectable levels.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background and objectivesThe use of cannabinoids for appetite stimulation and the management of wasting and antiretroviral side-effects has become a common practice in the care of HIV-infected individuals. We present pharmacokinetic data from a randomized placebo-controlled study designed to evaluate the metabolic effects of smoked marijuana and dronabinol in HIV-infected patients receiving indinavir (IDV) or nelfinavir (NFV).MethodsSubjects on stable regimens containing IDV 800 mg every 8 h (n = 28) or NFV 750 mg three time a day (n = 34) were randomized to one of three treatment arms: 3.95% THC marijuana cigarettes, dronabinol 2.5 mg capsules or placebo capsules administered three times daily. Serial blood sampling was performed at baseline and on day 14 of treatment. The changes in NFV and IDV pharmacokinetics were measured as the median percentage change from baseline.ResultsAt day 14, the 8-h area under the curve (AUC8) changed by −10.2% (P= 0.15), maximum concentration (Cmax) by −17.4% (P= 0.46), and minimum concentration (Cmin) by −12.2% (P= 0.28) for patients in the NFV marijuana arm (n = 11). Similar decreases had occurred by day 14 among patients in the IDV marijuana arm (n = 9): AUC8had changed by −14.5% (P= 0.074), Cmaxby −14.1% (P= 0.039), and Cminby −33.7% (P= 0.65).ConclusionDespite a statistically significant decrease in Cmaxof IDV in the marijuana arm, the magnitude of changes in IDV and NFV pharmacokinetic parameters in the marijuana arm are likely to have no short-term clinical consequence. The use of marijuana or dronabinol is unlikely to impact antiretroviral efficacy.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectivesTo demonstrate the feasibility of a concentration-controlled approach to combination antiretroviral therapy, and to compare the virological responses and safety of this strategy versus conventional fixed-dose therapy.DesignA prospective, randomized, 52 week, open-label trial of concentration-controlled compared with conventional dose zidovudine, lamivudine, and indinavir therapy conduced in a university-based general clinical research center in the United States.PatientsForty antiretroviral-naive individuals with plasma HIV-RNA levels > 5000 copies/ml.InterventionsZidovudine, lamivudine, and indinavir plasma concentrations were measured in all participants. Doses were adjusted in those assigned to concentration-controlled therapy to achieve levels equal to or greater than target values.Main outcome measuresThe proportion of patients who achieved the desired drug concentrations, the proportion of patients with HIV-RNA levels < 50 copies/ml at week 52, and safety and tolerance in the concentration-controlled versus conventional therapy arms.ResultsSignificantly more concentration-controlled recipients achieved the desired concentration targets for all three drugs: 15 of 16 concentration-controlled recipients compared with nine of 17 conventional recipients (P= 0.017) had HIV-RNA levels < 50 copies/ml at week 52. No difference was observed in the occurrence of drug-related clinical events or laboratory abnormalities between the two treatment arms.ConclusionConcentration-controlled therapy implemented simultaneously for three antiretroviral agents was feasible, as well tolerated as conventional therapy, and resulted in a greater proportion of recipients with HIV-RNA levels < 50 copies/ml after 52 weeks. These findings provide a scientific basis to challenge the accepted practice of administering the same dose of antiretroviral agents to all adults, ignoring the concentrations actually achieved.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

BackgroundFirst results of Trilège demonstrated that the strategy of less intensive antiviral therapy is less effective than continuation of triple-drug therapy.ObjectiveTo compare the final number of failures at month 18 and to study viral dynamics in patients experiencing a virological failure.DesignLongitudinal follow-up from a randomized controlled trial.SettingForty-three AIDS clinical-trial units.PatientsA total of 279 HIV-1 infected adults randomized in Trilège.MeasurementsAnalysis of recurrent values of HIV RNA > 500 copies/ml beyond time to virologic failure.ResultsA total of 83 patients experienced virological failure by month 18; 10 in the zidovudine (ZDV) + lamivudine (3TC) + indinavir (IDV) arm, 46 in the ZDV + 3TC arm, and 27 in the ZDV + IDV arm, confirming previous results. Whatever the treatment ultimately received, 87% of patients had an HIV RNA < 500 copies/ml at month 18 with no statistical difference between randomized arms. Patients experiencing a failure in the triple-drug regimen had a greater tendency to maintain HIV RNA > 500 copies/ml beyond the time of virological failure than patients in both less intensive treatment groups who experienced failure. Lower levels of HIV RNA at failure and reinitiating of either the original triple-drug regimen or a new combination of nucleoside analogue reverse transcriptase inhibitors and protease inhibitors were associated with lower hazard ratios for developing recurrent HIV RNA > 500 copies/ml.ConclusionResults confirmed the failure of a less intensive regimen to maintain patients with a viral suppression (HIV RNA < 500 copies/ml). Although there is a lower incidence of failure in the triple-drug regimen, randomization to a less intensive regimen of ZDV + 3TC or ZDV + IDV was not detrimental, as treatment modification, either to the original triple regimen, or a different regimen was successful.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveLipid lowering therapy is used increasingly in persons with HIV infection in the absence of safety data or information on drug interactions with antiretroviral agents. The primary objectives of this study were to examine the effects of ritonavir (RTV) plus saquinavir soft-gel (SQVsgc) capsules on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin, and the effect of pravastatin on the pharmacokinetics of nelfinavir (NFV) in order to determine clinically important drug–drug interactions.DesignRandomized, open-label study in healthy, HIV seronegative adults at AIDS Clinical Trials Units across the USA.MethodsThree groups of subjects (arms 1, 2, and 3) received pravastatin, simvastatin or atorvastatin (40 mg daily each) from days 1–4 and 15–18. In these groups, RTV 400 mg and SQVsgc 400 mg twice daily were given from days 4–18. A fourth group (arm 4) received NFV 1250 mg twice daily from days 1–14 with pravastatin 40 mg daily added from days 15–18. Statin and NFV levels were measured by liquid chromatography/tandem mass spectrometry.ResultsFifty-six subjects completed both pharmacokinetic study days. In arms 1–3, the median estimated area under the curves (AUC)0−−24for the statins were: pravastatin (arm 1, n = 13), 151 and 75 nguu.h/ml on days 4 and 18 (decline of 50% in presence of RTV/SQVsgc), respectively (P= 0.005); simvastatin (arm 2, n = 14), 17 and 548 nguu.h/ml on days 4 and 18 (increase of 3059% in the presence of RTV/SQVsgc), respectively (P< 0.001); and total active atorvastatin (arm 3, n = 14), 167 and 289 nguu.h/ml on days 4 and 18 (increase of 79% in the presence of RTV/SQVsgc), respectively (P< 0.001). In arm 4, the median estimated AUC0−−8for NFV (24 319 versus 26 760 nguu.h/ml;P= 0.58) and its active M8 metabolite (15 565 versus 14 571 nguu.h/m;P= 0.63) were not statistically different from day 14 to day 18 (without or with pravastatin).ConclusionsSimvastatin should be avoided and atorvastatin may be used with caution in persons taking RTV and SQVsgc. Dose adjustment of pravastatin may be necessary with concomitant use of RTV and SQVsgc. Pravastatin does not alter the NFV pharmacokinetics, and thus appears to be safe for concomitant use.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo compare the effect of treatment decisions guided by phenotypic resistance testing (PRT) or standard of care (SOC) on short-term virological response.DesignA prospective, randomized, controlled clinical trial conducted in 25 university and private practice centers in the United States.ParticipantsA total of 272 subjects who failed to achieve or maintain virological suppression (HIV-1-RNA plasma level > 2000 copies/ml) with previous exposure to two or more nucleoside reverse transcriptase inhibitors and one protease inhibitor.InterventionsRandomization was to antiretroviral therapy guided by PRT or SOC.Main outcome measuresThe percentage of subjects with HIV-1-RNA plasma levels less than 400 copies/ml at week 16 (primary); change from baseline in HIV-1-RNA plasma levels and number of ‘active’ (less than fourfold resistance) antiretroviral agents used (secondary).ResultsAt week 16, using intent-to-treat (ITT) analysis, a greater proportion of subjects had HIV-1-RNA levels less than 400 copies/ml in the PRT than in the SOC arm (P= 0.036, ITT observed;P= 0.079, ITT missing equals failure). An ITT observed analysis showed that subjects in the PRT arm had a significantly greater median reduction in HIV-1-RNA levels from baseline than the SOC arm (P= 0.005 for 400 copies/ml;P= 0.049 for 50 copies/ml assay detection limit). Significantly more subjects in the PRT arm were treated with two or more ‘active’ antiretroviral agents than in the SOC arm (P= 0.003).ConclusionAntiretroviral treatment guided prospectively by PRT led to the increased use of ‘active’ antiretroviral agents and was associated with a significantly better virological response.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectivesTo monitor changes in the numbers of CD8 lymphocytes expressing the activated CD38++ phenotype in peripheral blood samples from patients with primary HIV infection (PHI) treated with highly active antiretroviral therapy (HAART).MethodsZidovudine, lamivudine, abacavir and amprenavir were initiated during PHI as part of the Quest study. Absolute numbers of CD8+/CD38++ T cells were determined using three-colour flow cytometry, and plasma viral load (VL) was measured using the Roche Amplicor method.ResultsThe median, pre-therapy CD8+/CD38++ T cell count was 461/mm3(interquartile range 216, 974) in 131 patients compared with normal control values of less than 20 cells/mm3. Levels fell markedly in parallel with VL within the first 2 weeks of HAART initiation, to a median of 47 cells/mm3at 28 weeks (median 436 cell decline;P< 0.001). At that time, 80% of patients had a VL less than 50 copies/ml, and 16.3% of all patients had less than 20 CD8+/CD38++ T cells/mm3. A continued decrease in CD8+/CD38++ T cell count occurred in 67.2% of patients whose VL was maintained below 50 copies/ml (median change from first to last value −18 cells/mm3;P< 0.001).ConclusionAfter the initiation of HAART in PHI, CD8+/CD38++ lymphocytes declined rapidly in parallel with VL, and allowed for a normalization of CD8+/CD38++ T cell numbers in a subset of patients at week 28. Cell numbers continued to decline in patients who maintained VL below 50 copies/ml, indicating that the CD8+/CD38++ T cell count may represent a marker of residual viral replication when VL falls below detectable levels after HAART intervention.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID