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1.
Antimicrob Agents Chemother ; 47(1): 130-7, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12499180

ABSTRACT

The present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo. The PK databases consisted of 531 EFV concentrations (139 patients), 219 NFV concentrations (75 patients), and 66 IDV concentrations (11 patients). Time to virological failure was ascertained for all patients in the PK databases. PK data were fit with a population PK model that assumed exclusive hepatic elimination (the well-stirred model). Notable findings with respect to EFV PK and PD are as follows. (i) The hepatic clearance of EFV is unaltered by NFV, IDV, or SQV coadministration. (ii) The hepatic clearance of EFV appears to be 28% higher in white non-Hispanics than in African Americans and Hispanics (P = 0.03). (iii) Higher adherence scores (as measured with the Medication Event Monitoring System) are associated with marginally increased levels of exposure to EFV. (iv) In patients with no prior experience with nonnucleoside reverse transcriptase inhibitors (NNRTIs), a given percent increase in the oral clearance (CL/F) of EFV is associated with a greater percent increase in the hazard of virological failure (P < 0.0003). Among NNRTI-experienced patients, however, hazard is relatively uncorrelated with EFV CL/F.


Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , HIV Protease Inhibitors/pharmacokinetics , Indinavir/therapeutic use , Nelfinavir/therapeutic use , Oxazines/pharmacokinetics , Acquired Immunodeficiency Syndrome/metabolism , Adult , Alkynes , Bayes Theorem , Benzoxazines , Cyclopropanes , Drug Interactions , Female , HIV Protease Inhibitors/blood , HIV Protease Inhibitors/therapeutic use , Humans , Indinavir/blood , Male , Models, Biological , Nelfinavir/blood , Oxazines/blood , Oxazines/therapeutic use , Population Surveillance , Treatment Failure
2.
J Acquir Immune Defic Syndr ; 31(1): 20-6, 2002 Sep 01.
Article in English | MEDLINE | ID: mdl-12352146

ABSTRACT

CD4 T-cell recovery with potent antiretroviral therapy varies considerably among HIV-1-infected patients. Data from two studies that enrolled subjects at different stages of disease progression were retrospectively combined. This analysis assessed the association between patient-specific factors and three measures of CD4 T-cell recovery after the initiation of triple-drug therapy: overall changes in CD4 cell counts; changes in CD4 cell counts during the first 8 weeks (phase I); and changes in CD4 cell counts during weeks 8-24 (phase II). Higher initial HIV-1 RNA values corresponded to greater increases in overall and phase I changes in mean CD4 cell counts, particularly among subjects with less advanced disease. In the overall and phase II cases, those subjects with suppressed HIV RNA levels had consistently higher increases in mean CD4 cell counts across both baseline HIV-1 RNA levels and CD4 cell counts than did the respective unsuppressed group. Based on a multivariate model, increases in mean phase I CD4 cell counts corresponded to higher log baseline HIV-1 RNA levels (p =.0001) and log changes in HIV-1 RNA levels at week 4 (p =.03). Patients with earlier stages of disease (p =.0001) and females (p =.01) had higher increases in phase I changes. Phase II CD4 cell counts did not depend solely on baseline HIV-1 RNA levels and CD4 cell counts but on their interaction (p =.0001) as well as on achieving virologic suppression (p =.0009).


Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Anti-HIV Agents/administration & dosage , CD4 Lymphocyte Count , HIV-1 , Acquired Immunodeficiency Syndrome/immunology , Acquired Immunodeficiency Syndrome/virology , Double-Blind Method , Drug Therapy, Combination , Female , HIV-1/genetics , Humans , Male , RNA, Viral/blood , Regression Analysis , Retrospective Studies
3.
Clin Pharmacol Ther ; 72(2): 133-41, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12189360

ABSTRACT

OBJECTIVE: Pharmacokinetic interactions are expected when human immunodeficiency virus (HIV) protease inhibitors are coadministered because many are both substrates for and inhibitors of CYP3A4. The goal of this model-based pharmacokinetic analysis was to describe the differences observed in amprenavir pharmacokinetics among treatment arms in the Adult AIDS Clinical Trial Group (AACTG) study protocol 398 and to propose mechanisms to account for them. METHODS: One hundred seventy-six HIV-positive subjects receiving 1200 mg amprenavir twice daily as part of AACTG protocol 398 were included in the pharmacokinetic study. All patients also received background medications efavirenz, adefovir dipivoxil, and abacavir and, depending on the study arm, placebo or one of the following protease inhibitors: nelfinavir, indinavir, or saquinavir. A population pharmacokinetic model was fitted to a total of 565 amprenavir concentration measurements. The blood samples for concentration measurements were drawn at week 2 (12-hour pharmacokinetic study, approximately 7 samples per study; 46 patients) and at week 24 (6-hour pharmacokinetic study, approximately 5 samples per study; 10 patients). In addition, samples were collected at 1 or more follow-up visits (population pharmacokinetic study, 1 to 3 occasions per patient; 150 patients). RESULTS AND CONCLUSION: Amprenavir intrinsic clearance was significantly reduced relative to placebo by nelfinavir (-41%) and indinavir (-54%) but not by saquinavir. The absolute magnitude of amprenavir intrinsic clearance suggests that CYP3A4 inhibition by nelfinavir and indinavir is balanced by enzymatic induction in the presence of the background drug(s), most likely efavirenz. Amprenavir intrinsic clearance apparently increases by more than 30% between weeks 2 and 24, possibly because of the time course of CYP3A4 induction.


Subject(s)
HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/pharmacokinetics , Indinavir/pharmacology , Nelfinavir/pharmacology , Saquinavir/pharmacology , Sulfonamides/pharmacokinetics , Adult , Biological Availability , Carbamates , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Drug Administration Schedule , Drug Therapy, Combination , Female , Furans , Humans , Indinavir/administration & dosage , Male , Middle Aged , Mixed Function Oxygenases/antagonists & inhibitors , Nelfinavir/administration & dosage , Saquinavir/administration & dosage , Sulfonamides/administration & dosage , Sulfonamides/blood
4.
JAMA ; 288(2): 169-80, 2002 Jul 10.
Article in English | MEDLINE | ID: mdl-12095381

ABSTRACT

CONTEXT: Management of antiretroviral treatment failure in patients receiving protease inhibitor (PI)-containing regimens is a therapeutic challenge. OBJECTIVE: To assess whether adding a second PI improves antiviral efficacy of a 4-drug combination in patients with virologic failure while taking a PI-containing regimen. DESIGN: Multicenter, randomized, 4-arm trial, double-blind and placebo-controlled for second PI, conducted between October 1998 and April 2000, for which there was a 24-week primary analysis with extension to 48 weeks. SETTING: Thirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical Trials Units in the United States. PARTICIPANTS: A total of 481 human immunodeficiency virus (HIV)-infected persons with prior exposure to a maximum of 3 PIs and viral load above 1000 copies/mL. INTERVENTION: Selectively randomized assignment (per prior PI exposure) to saquinavir (n = 116); indinavir (n = 69); nelfinavir (n = 139); or placebo twice per day (n = 157); in combination with amprenavir, abacavir, efavirenz, and adefovir dipivoxil. MAIN OUTCOME MEASURES: Primary efficacy analysis involved the proportion with viral load below 200 copies/mL at 24 weeks. Other measures were changes in viral load and CD4 cell count from baseline, adverse events, and HIV drug susceptibility. RESULTS: Of 481 patients, 148 (31%) had a viral load below 200 copies/mL at week 24. The proportions of patients with a viral load below 200 copies/mL in the saquinavir, indinavir, nelfinavir, and placebo arms were 34% (40/116), 36% (25/69), 34% (47/139), and 23% (36/157), respectively. The proportion in the combined dual-PI arms was higher than in the amprenavir-plus-placebo arm (35% [112/324] vs 23% [36/157], respectively; P =.002). Overall, a higher proportion of nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients had a viral load below 200 copies/mL compared with NNRTI-experienced patients (43% [115/270] vs 16% [33/211], respectively; P<.001). Baseline HIV-1 hypersusceptibility to efavirenz (< or = 0.4-fold difference in susceptibility compared with reference virus) was associated with suppression of viral load at 24 weeks to below 200 copies/mL (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.62-7.33; P =.001), and more than 10-fold reduction in efavirenz susceptibility, with less likelihood of suppression at 24 weeks (OR, 0.28; 95% CI, 0.09-0.87; P =.03). CONCLUSIONS: In this study of antiretroviral-experienced patients with advanced immunodeficiency, viral load suppression to below 200 copies/mL was achieved in 31% of patients with regimens containing 4 or 5 new drugs. Use of 2 PIs, being naive to NNRTIs, and baseline hypersusceptibility to efavirenz were associated with a favorable outcome.


Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Organophosphonates , Reverse Transcriptase Inhibitors/therapeutic use , Adenine/pharmacokinetics , Adenine/therapeutic use , Adult , Alkynes , Anti-HIV Agents/adverse effects , Anti-HIV Agents/pharmacokinetics , Antiretroviral Therapy, Highly Active , Benzoxazines , CD4 Lymphocyte Count , Carbamates , Cyclopropanes , Dideoxynucleosides/pharmacokinetics , Dideoxynucleosides/therapeutic use , Disease Progression , Double-Blind Method , Drug Resistance, Viral , Female , Furans , HIV Infections/immunology , HIV Protease Inhibitors/adverse effects , HIV Protease Inhibitors/pharmacokinetics , Humans , Indinavir/pharmacokinetics , Indinavir/therapeutic use , Male , Nelfinavir/pharmacokinetics , Nelfinavir/therapeutic use , Oxazines/pharmacokinetics , Oxazines/therapeutic use , Proportional Hazards Models , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/pharmacokinetics , Saquinavir/pharmacokinetics , Saquinavir/therapeutic use , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use , Treatment Failure , Viral Load
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