Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359

This study compared antiretroviral activity among 6 "salvage" therapy regimens. The study was a prospective, randomized, 2x3 factorial, multicenter study of the AIDS Clinical Trials Group. The study enrolled 277 human immunodeficiency virus (HIV)-infected patients naive to nonnucleoside analogues who had taken indinavir >6 months. The patients had 2000-200,000 HIV RNA copies/mL. Patients received saquinavir with ritonavir or nelfinavir together with delavirdine and/or adefovir and were followed for safety and antiretroviral response between baseline and week 16. At week 16, 30% (77/254) of patients had 相似文献   

A randomized, comparative study of lamivudine plus stavudine, with indinavir or nelfinavir, in treatment-experienced HIV-infected patients

OBJECTIVE: To compare adherence and clinical outcome with two modalities of highly active antiretroviral therapy (HAART), in HIV-infected patients. DESIGN: Randomized, open-label, prospective study. SETTING: Tertiary care centre in Spain. PATIENTS: A total of 112 non-naive HIV-infected patients, recruited from March 1998 through August 1998, were studied. INTERVENTIONS: Triple drug therapy with stavudine and lamivudine, plus indinavir or nelfinavir. MAIN OUTCOME MEASURES: Adherence, side-effects, and immunological, virological, and clinical efficacy of treatment were assessed at 3-month intervals. RESULTS: After a median follow-up of 9 months, 32% of patients in the indinavir group versus 50% of those in the nelfinavir group showed adequate adherence in all clinical appointments (P= 0.0559). Adherence was superior in the nelfinavir group in every visit. After 6 months of treatment 48% of subjects in the indinavir group and 70% of those in the nelfinavir group exhibited adequate adherence (P= 0.0311). After 9 months 35% of patients in the indinavir group and 59% of those in the nelfinavir group showed adequate adherence (P= 0.0291). Side-effects provoked discontinuation of treatment in 34% of patients in the indinavir group and 12% of patients in the nelfinavir group (P= 0.0073). Immunological and virological efficacy were similar in both groups. CONCLUSIONS: Adherence to a HAART regimen with stavudine plus lamivudine plus nelfinavir was superior to a regimen with stavudine plus lamivudine plus indinavir. Side-effects provoked more discontinuation of treatment in the indinavir group than in the nelfinavir group.     

Variable prediction of antiretroviral treatment outcome by different systems for interpreting genotypic human immunodeficiency virus type 1 drug resistance

To determine the variability of genotypic human immunodeficiency virus (HIV) type 1 drug-resistance interpretation by available expert systems and its clinical implications, 261 subjects for whom a potent antiretroviral regimen was failing who were starting salvage therapy were evaluated. The association of the genotypic susceptibility score (GSS) of the salvage regimen, according to 11 interpretation systems, with HIV RNA outcomes for 6 months was examined. GSS was highly variable, as determined by the different interpretation systems, and showed independent correlation with changes from baseline HIV RNA levels at 6 months with 5 systems--Stanford hivdb, GuideLines 3.0, Retrogram 1.4, HIVresistanceWeb, and S?o Paulo University. Most GSSs predicted virologic response in regimens containing stavudine, lamivudine, efavirenz, or indinavir. Selected systems predicted response in regimens containing didanosine, abacavir, or nelfinavir, and no system predicted outcome of boosted protease inhibitors. GSSs predicted changes in HIV RNA levels better in adherent patients than in nonadherent individuals. Interpretation may be improved, and knowledge should be used uniformly throughout different expert systems.     

Impact of human immunodeficiency virus type 1 subtypes on virologic response and emergence of drug resistance among children in the Paediatric European Network for Treatment of AIDS (PENTA) 5 trial

The association between virologic response and human immunodeficiency virus type 1 (HIV-1) subtype was investigated in 113 HIV-1-infected children randomly assigned to receive zidovudine plus lamivudine, zidovudine plus abacavir, or lamivudine plus abacavir in the Paediatric European Network for Treatment of AIDS (PENTA) 5 trial. Symptomatic children (n=68) also received nelfinavir; asymptomatic children (n=45) were randomly assigned to receive nelfinavir or placebo. HIV-1 subtypes A, B, C, D, F, G, H, A/E, and A/G were found in 15%, 41%, 16%, 9%, 5%, 2%, 1%, 5%, and 7% of the children, respectively. Resistance assay failure rates were higher for non-B subtypes than for B subtypes (genotype, P=.01; phenotype, P=.02). HIV-1 subtype was not associated with virologic response at 24 and 48 weeks after initiation of treatment. No differences were observed in the frequency of development of resistance mutations L90M (P=1.00) and D30N (P=.61) in B and non-B viruses. In conclusion, no evidence that subtype determined virologic response to therapy was found.     

Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study

BACKGROUND: Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment. METHODS: Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized. RESULTS: The 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G-->T and CYP2C19 681G-->A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G-->A. CONCLUSIONS: Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.     

Value of patient self-report and plasma human immunodeficiency virus protease inhibitor level as markers of adherence to antiretroviral therapy: relationship to virologic response.

Three methods of adherence to antiretroviral therapy were evaluated for 149 patients infected with human immunodeficiency virus (HIV): plasma level of protease inhibitors (PIs), patient self-report, and routine biological parameters associated with the use of some antiretroviral drugs. Adherence to therapy was estimated from a score calculated from answers to a self-administered questionnaire and on the basis of measurement of relevant plasma and blood levels. Of the 149 patients, 112 had a virologic response, and 122 had adequate trough PI levels. Plasma PI levels and virologic outcome were significantly correlated (P<.0001). The adherence score was significantly correlated with virologic response (P<.001). Macrocytosis was significantly associated with virologic response in the patients treated with zidovudine or stavudine (P=.006). PI level was the higher significant predictor of virologic response (P=.0003). Self-reported adherence (P=.01) and macrocytosis (P=.05) were also independently associated with antiretroviral efficacy.     

Prospective comparison of first-line nelfinavir therapy versus nelfinavir introduction in rescue antiretroviral regimens

In order to establish the role of the protease inhibitor nelfinavir in current clinical practice, a prospective 18-month open-label comparison of efficacy and tolerability of nelfinavir was performed among HIV-infected patients who either incorporated nelfinavir in their first-line highly active antiretroviral therapy (HAART) regimen (group A, 57 patients), or who added nelfinavir to a rescue antiretroviral regimen (following at least two attempts with protease inhibitor-based HAART) (group B, 67 patients). All evaluable data were analyzed according to the prior and concurrent antiretroviral therapy, including genotypic resistance assays for patients undergoing salvage therapy. A significantly better virologic outcome (as expressed by a > 2 log(10) drop of plasma viremia versus baseline or attainment of undetectable levels), was shown among patients belonging to group A versus group B, where a number of genotypic mutations possibly elicited by previous anti-HIV treatment strongly impaired a potent and sustained nelfinavir activity. On the whole, the immunologic response (as expressed by the mean CD4(+) lymphocyte count versus baseline), substantially paralleled the virologic one in all analyzed subgroups, but a tendency toward a maintained immunologic competence was also observed in the majority of patients experiencing virologic failure. Nelfinavir introduction was sufficiently safe, because a limited percentage of patients suffered from mild-to-moderate, novel, or continuing adverse events, which proved significantly more frequent in the salvage group but did not affect adherence to HAART.     

Mechanisms of early virologic failure in antiretroviral-naive patients starting protease inhibitor-containing regimens: the APROVIR Study

The virologic and pharmacologic mechanisms of virologic failure (VF) were studied in 243 antiretroviral-naive patients starting first-line protease inhibitor (PI)-containing therapy (nelfinavir in 66% and indinavir in 19%). Among the 220 patients with follow-up data, VF occurred in 35 (16%) during the first year of follow-up. A higher baseline virus load and poorer adherence to therapy were associated with VF. At the time of VF, key PI-resistance mutations were detected in 11 (48%) of 23 patients who started on nelfinavir but were absent in 6 patients with indinavir treatment failure. PI plasma levels were more often below the range of active concentrations in VF with wild-type viruses (74%) than in VF with PI-resistant viruses (25%; P=.02). The mechanisms of early VF and of selection of PI-resistant viruses differed by type of PI and were dependent on PI plasma levels.     

Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides

OBJECTIVE: To determine if particular components of antiretroviral drug regimens are associated with greater insulin resistance, dyslipidemia, and peripheral lipoatrophy. METHODS: Metabolic and body composition variables were measured prospectively over 64 weeks in 334 antiretroviral-naive, HIV-infected subjects who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine/lamivudine or didanosine/stavudine in a factorial design, multicenter trial. Subjects assigned to efavirenz (n = 110) were compared with those assigned to nelfinavir (n = 99); subjects assigned to zidovudine/lamivudine (n = 154) were compared with those assigned to didanosine/stavudine (n = 180). A subset of 157 subjects had serial dual-energy X-ray absorptiometry (DEXA) scans. RESULTS: Lipid measures increased in all groups. Greater increases in high density lipoprotein (HDL) cholesterol occurred with efavirenz than with nelfinavir. Greater increases in total cholesterol, non-HDL cholesterol and HDL cholesterol occurred with stavudine and didanosine than with zidovudine/lamivudine. There were no differences in insulin resistance in the comparisons. After initial increases in the first 16 weeks, median limb fat decreased. Greater changes in percentage changes in limb fat occurred with didanosine/stavudine (-16.8%) than with zidovudine/lamivudine (+4.0%; P < 0.001 for overall change from baseline) and with nelfinavir (-13.1%) compared with efavirenz (+1.8%; P = 0.003). CONCLUSIONS: Over 64 weeks, all regimens were associated with increases in lipids but insulin resistance did not differ between groups. Regimens containing didanosine/stavudine and regimens containing nelfinavir were associated with greater loss of limb fat.     

Virologic and immunologic response to regimens containing nevirapine or efavirenz in combination with 2 nucleoside analogues in the Italian Cohort Naive Antiretrovirals (I.Co.N.A.) study

This nonrandomized study compared the virologic and immunologic responses to potent regimens containing either efavirenz or nevirapine after considering potential systematic differences between patients receiving these drugs. Virologic failure was defined as the first of 2 consecutive measurements of virus load >500 human immunodeficiency virus RNA copies/mL. Of the 694 patients included in the analysis, 460 (66.3%) started nevirapine and 234 (33.7%) started efavirenz. The adjusted relative hazard of virologic failure for patients who started nevirapine, compared with those who started efavirenz, was 2.08 (95% confidence interval, 1.37-3.15; P=.0006). In addition, patients receiving efavirenz tended to recover 5 CD4 cells/microL more per quarter (P=.05). Although comparisons of drug efficacy in nonrandomized studies should be viewed with caution, no results from randomized controlled comparisons of these drugs are thought to be available. The findings of this study are in agreement with those of other observational studies.     

Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected individuals

BACKGROUND: Both virological failure and the toxicity of HIV protease inhibitors have been related to interindividual variability of plasma drug concentrations. Therapeutic drug monitoring (TDM) offers the possibility to detect patients with drug concentrations outside therapeutic ranges, who can subsequently benefit from dose modifications. METHODS: ATHENA was a randomized controlled clinical trial. Subjects were randomly assigned to either a TDM group, in which the results of drug concentration measurements plus advice were reported to their treating physician, or to a control group for whom TDM results were not reported. This analysis refers to treatment-naive patients who started a regimen containing indinavir or nelfinavir before November 1999. FINDINGS: A total of 147 patients were randomly assigned: 92 to nelfinavir, 55 to indinavir. After one year of follow-up significantly fewer patients in the TDM group had discontinued nelfinavir or indinavir than in the control group: 17.4 versus 39.7%. This was mainly driven by a significantly lower rate of discontinuation because of virological failure in nelfinavir patients: 2.4% in the TDM group versus 17.6% in the control group, and by a non-significant difference in the rate of discontinuation because of toxicity in indinavir patients: 14.3% in the TDM group versus 29.6% in the control group. In a non-completer equals failure analysis of all randomized patients, the TDM group showed a significantly higher proportion of patients with a viral load below 500 copies after 12 months of treatment (78.2 versus 55.1%). INTERPRETATION: TDM of nelfinavir and indinavir in treatment-naive patients improves treatment response.