摘要:

ObjectiveTo determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors.DesignProspective randomized controlled trial.SettingMulticenter community-based clinical trials network.PatientsOne-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy.InterventionsRandomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input.Main outcomes measuresPlasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels.ResultsThe average baseline CD4 cell count was 230 × 106cells/l and the median HIV-1 RNA was 28 085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10for the 78 GART patients and -0.61 log10for the 75 no-GART patients (treatment difference: −0.53 log, 95% confidence interval, −0.77 to −0.29;P = 0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible.ConclusionIn patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo evaluate the importance of the number of active drugs, as determined by phenotypic resistance testing, in achieving virological response in successive salvage regimens.DesignPhenotypic study of 57 plasma samples corresponding to 24 patients who had sequentially received three protease inhibitor-containing regimens. Phenotypic susceptibility to a drug (active drug) was defined as less than a four-fold-increase in the IC50in comparison with the wild type.Main outcome measureVirological response according to the number of active drugs (three versus two or fewer), HIV load, length of antiretroviral exposure, and line of protease inhibitor-based therapy (first, second and third regimen).ResultsBefore the first protease inhibitor-based therapy, the median time on antiretroviral treatment was 42 months, and before the second and third protease inhibitor-salvage regimens it was 10 and 8 months, respectively. The number of patients receiving three active drugs simultaneously was 24, 35 and 31% in each line of therapy. At week 12, a close correlation was found between the presence of three active drugs in the antiretroviral regimen and the rate of virological response, in comparison with those patients receiving two or fewer active drugs [76 versus 45%, relative risk (RR), 1.7; 95% confidence interval (CI) 1.1–2.6;P = 0.028]. In a multivariate analysis, the use of two or fewer active drugs was an independent predictor of lack of response, regardless of HIV load, length of previous antiretroviral exposure and line of salvage therapy (RR, 4.5; 95%CI, 1.1–18.3;P = 0.03). Of note, a higher rate of response was observed in patients receiving the first protease inhibitor-containing regimen in comparison with those in subsequent protease inhibitor-based salvage regimens (83 versus 50 versus 28%,P < 0.01), even when only those patients receiving three active drugs were included (100 versus 71 versus 60%).ConclusionsThis data confirm the usefulness of phenotypic testing in guiding antiretroviral therapy in heavily pretreated patients. The number of active drugs and the line of salvage therapy are independent predictors of virological response, regardless of HIV load and the length of antiretroviral exposure.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo investigate the steady-state pharmacokinetics of a once-daily dosing regimen of saquinavir soft gelatin capsules in combination with a low dose of ritonavir in HIV-1-infected individuals.DesignOpen-label, multi-dose, pharmacokinetic pilot study.PatientsSeven HIV-1-infected individuals who were treated with saquinavir hard gelatin capsules 400 mg twice daily + ritonavir liquid formulation 400 mg twice daily were switched to saquinavir soft gelatin formulation 1600 mg once daily in combination with ritonavir liquid formulation 200 mg once daily (day 0). Patients were instructed to ingest saquinavir and ritonavir simultaneously in the morning and with a meal.MethodsSteady-state pharmacokinetics of saquinavir and ritonavir were assessed during a 24 h dosing interval after 2 weeks of continued therapy (day 14). Plasma saquinavir and ritonavir concentrations were measured using a validated high performance liquid chromatography assay. In addition, plasma HIV-1 RNA, and fasting total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels were measured on days 0 and 14. A non-compartmental pharmacokinetic method was used to calculate the area under the plasma concentration versus time curve (AUC[0−−24h]), the maximum and trough plasma concentrations (CmaxandCmin), the time to reachCmax(Tmax), the elimination half-life (t1/2), the apparent clearance (Cl/F), and the apparent volume of distribution (V/F).ResultsMedian (range) values of the pharmacokinetic parameters for saquinavir after 2 weeks of treatment were:AUC[0−24h], 19 802h* ng/ml (3720–74 016);Cmax, 2936 ng/ml (573–6848);Cmin, 84 ng/ml (11–854);Tmax, 3.5 h (3.0–4.0),t1/2, 6.8 h (4.6–10.2);Cl/F, 81 l/h (22–430);V/F, 1189 l (215–3086). Ritonavir concentrations were always below the 90% effective concentration of 2100 ng/ml (medianCmax, 1323 ng/ml; range, 692–1528 ng/ml). No significant changes were observed for total serum cholesterol, high-density lipoprotein, and low-density lipoprotein levels between days 0 and 14 (P ⩾ 0.24). In six out of seven patients the fasting serum triglyceride levels were lower 2 weeks after the treatment switch (median decrease was 32%,P = 0.03). No significant changes in plasma HIV-1 RNA concentrations were observed between days 0 and 14. The regimen was generally well tolerated.ConclusionsThis pharmacokinetic study indicates that the combination of 1600 mg of saquinavir (soft gelatin capsules) and 200 mg of ritonavir (liquid formulation) in a once-daily dosing regimen generally results in therapeutic plasma concentrations of saquinavir. Due to the large interindividual variation in saquinavir exposure, the monitoring of saquinavir concentrations in plasma is warranted. These pharmacokinetic findings rationalize the further clinical evaluation of once-daily dosing of this combination of protease inhibitors.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo develop and optimize a fast and quantitative recombinant strategy for evaluating the HIV-1 phenotype to protease inhibitors (PI).Design and methodsA non-replicative HIV-1 molecular vector (designated pΔproΔenv) capable of expressing exogenous HIV-1 protease-encoding sequences was developed in this study. The HIV-1 protease sequences were amplified from either viral isolates or plasma samples (both from 21 HIV-1-infected individuals, 19 of whom were failing different anti-HIV-1 combination treatments) and cloned in the pΔproΔenvbackbone. The HIV-1 recombinant phenotype to PI was determined directly after transfection of viral chimeric clones by measuring protease activity and calculating a percentage sensitivity index (SI%; the ratio between the results from each clone and those from a PI-sensitive reference strain).ResultsThe SI% values obtained from the recombinant clones paralleled the IC50results of the viral isolates and documented different degrees of resistance and cross-resistance to PI, compatible, with few exceptions, with the respective genotype. Interestingly, an inverse correlation between SI% values and the presence of primary mutations for resistance to PI (P = 0.0038 andP = 0.0414, for indinavir and ritonavir, respectively) and a difference in SI% between samples harbouring an increasing number of mutations (indinavir,P = 0.022; ritonavir,P = 0.0466) were observed.ConclusionThe data substantiate the reliability of the novel strategy for a fast (5 day) quantitative evaluation of HIV-1 phenotype to PI, and indicate that this method may contribute to the understanding of mechanisms of virus resistance to PI.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectivesLamivudine has potent activity against HIV-1 and hepatitis B virus (HBV). Co-infection with these two viruses is common, and this may therefore influence the choice of antiretroviral therapies. A cohort of co-infected patients treated with lamivudine were studied in order to evaluate the differential effects of lamivudine on the two viral populations within the same individual after 44–52 weeks of therapy.Design and methodsRetrospective virological analysis of an HIV-1/HBV co-infected lamivudine cohort derived from a randomized, placebo-controlled study of lamivudine in HIV infection, the CAESAR study.ResultsFive of thirteen patients with HBV viral load > 10 000 copies/ml after 44–52 weeks of lamivudine therapy had genotypic drug resistance. Four of these five had a rebound of viral replication over the period of study and in one case this was associated with an alanine transaminase serum elevation. Ten of the thirteen patients had a 44–52 week HIV viral load > 1000 copies/ml, all of whom also had HIV reverse transcriptase M184V or M184I mutations.ConclusionsExtrapolating these results to the population yields an estimated 1-year incidence of drug-resistant HBV of at least 14% in lamivudine-treated HIV-1/HBV co-infected patients. The clinical and virological benefit of HBV lamivudine monotherapy in co-infected patients should be balanced against the potential for emergence of drug resistance. Further, these data suggest that the determinants of HIV and HBV drug resistance are different and that parallel evolution, rather than co-evolution of HBV and HIV-1 in co-infected individuals occurs.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectivesSpecific antibodies to HIV envelope that inactivate virus at the mucosal surfaces involved in sexual contact are of interest for the design of a vaccine against HIV-1. It has been suggested that, in frequently HIV-exposed but uninfected individuals, HIV-specific mucosal antibody responses may exist and play a role in resistance against HIV. This study investigated HIV-1 envelope specific mucosal antibody responses in HIV-resistant sex workers in west Africa.MethodsA group of 26 exposed uninfected female commercial sex workers from the Gambia, who have had repeated exposures to HIV-1 and HIV-2 were studied. We assessed the presence of vaginal IgA and IgG in vaginal swabs against a range of HIV-1 and HIV-2 envelope presentations and performed HIV-1 neutralization assays.ResultsNo significant vaginal IgA or IgG responses against HIV-1 or HIV-2 were detected, and none of the vaginal secretions tested displayed any HIV-1 neutralizing activity.ConclusionVaginal antibody responses against HIV were not found in Gambian sex workers who resist HIV infection. Resistance against HIV infection can therefore occur in the absence of specific antibodies against HIV at the genital mucosa. A protective role for HIV-envelope specific IgA in resistance against HIV-1 infection in exposed uninfected individuals as reported in the literature is uncertain.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

DesignA selection of primary and transformed cell types were evaluated for their susceptibility to infection with human herpesvirus 8 (HHV-8)/Kaposi's sarcoma- associated herpesvirus.MethodsSources of HHV-8 included Kaposi's sarcoma lesion punch biopsies that were either cocultured directly with target cells or that were first cocultured with human lymphocytes to derive HHV-8-containing fluids that were inoculated onto target cells. HHV-8 was also obtained from primary effusion lymphoma-derived cell lines. Techniques to detect infection included the PCR, immunofluorescence assays andin situhybridization.ResultsSusceptible cells included human umbilical cord blood mononuclear cells (UCMC), adult CD19 B cells, macrophages and certain endothelial cells of human and animal origin, including some that are transformed with human papilloma virus type 16 E6 and E7 genes. The infection of lymphocytes did not yield established lymphoblastoid cell lines (LCL) and virus infection persisted for only 4–7 days. However, long-term HHV-8 infection of UCMC could be achieved by coinfection with Epstein–Barr virus. HHV-8 could also infect UCMC LCL recently derived by Epstein–Barr virus transformation, but long-established LCL could not be infected with HHV-8.ConclusionsThese data provide further biological evidence in cell culture for the limited cellular host range of HHV-8 to CD19 B cells, macrophages, and certain endothelial cells.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveImmune stimulation of CD4 lymphocytes is thought to enhance HIV-1 replicationin vivo. Therefore, we sought to define the impact of clinical events identified as putative immune activators on the variability of plasma HIV-1 RNA levels in persons with CD4 cell counts greater than 500 × 106cells/l.DesignWe prospectively recorded clinical events and measured plasma HIV-1 RNA levels weekly for 24 weeks in 16 HIV-1-infected adults who were not receiving antiretroviral therapy and who had CD4 cell counts greater than 500 × 106cells/l.MethodsStandard weekly interviews were conducted to capture potential immune activators (e.g., infections, immunizations, and allergic reactions). All plasma HIV-1 RNA levels were measured using the Amplicor HIV-1 Monitor assay (Roche Diagnostics, Branchburg, New Jersey, USA) according to the manufacturer's instructions.ResultsParticipants had remarkably stable viral loads during the 6 month study period. Infections were significantly more frequent during the 7 days prior to individual HIV-1 RNA measurements that exceeded the assay variation thresholds determined for this study (± 0.324 log) than during the comparable time periods preceding stable measurements (P= 0.023). As a group, the eight participants who had one to four HIV-1 RNA measurements that exceeded the thresholds experienced more infections and declining CD4 cell counts over the study course compared to the eight participants whose measurements all fell within the thresholds (P= 0.058 and 0.053 respectively).ConclusionsOur study suggests that in untreated HIV-1-infected persons with CD4 cell count greater than 500 × 106cells/l, viral load is generally quite stable, although acute minor infections are associated with transient fluctuations generally lasting no more than 1 week.

ISSN:0269-9370    

出版商:OVID    

年代:2000

数据来源: OVID