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ABSTRACT: In a randomized trial, AIDS Clinical Trials Group (ACTG) protocol 5146 (A5146) investigated the use of therapeutic drug monitoring (TDM) to adjust doses of HIV-1 protease inhibitors (PIs) in patients with prior virologic failure on PI-based therapy who were starting a new PI-based regimen. The overall percentage of "PI trough repeats" such as rescheduled visits or redrawn PI trough specimens increased from 2% to 5% to 10% as the process progressed from the clinical sites, the pharmacology specialty laboratory, and the study team, respectively. Cumulatively, this represents a 17% rate of failure to obtain adequate PI trough sample. While targeting a turnaround of 7 days or less from sample receipt to a drug concentration report, 12% of the received specimens required a longer period to report concentrations. The implementation of dosing changes in the TDM arm were achieved within 7 days or less for 56% of the dose change events and within 14 days or less for 77% of dose change events. This quality assurance analysis provides a valuable summary of the specific points in the TDM process that could be improved during a multicenter clinical trial including: 1) shortening the timeline of sample shipment from clinical site to the laboratory; 2) performing the collection of PI trough specimen within the targeted sampling window by careful monitoring of the last dose times and collection times by the clinicians; 3) increasing patient adherence counseling to reduce the number of samples that are redrawn due to suspecting inconsistent adherence; and 4) decreasing the time to successful TDM-based dose adjustment. The application of some of these findings may also be relevant to single-center studies or clinical TDM programs within a hospital.
Therapeutic drug monitoring 08/2010; 32(4):458-66. · 2.43 Impact Factor
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Lisa M Demeter,
Hongyu Jiang,
A Lisa Mukherjee,
Gene D Morse,
Robin DiFrancesco,
Robert DiCenzo,
Carrie Dykes,
Prakash Sista,
Lee Bacheler,
Karin Klingman, Alex Rinehart,
Mary Albrecht
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ABSTRACT: Whether therapeutic drug monitoring of protease inhibitors improves outcomes in HIV-infected patients is controversial. We evaluated this strategy in a randomized, open-label clinical trial, using a normalized inhibitory quotient (NIQ), which incorporates drug exposure and viral drug resistance. NIQs < or = 1 may predict poor outcome and identify patients who could benefit from dose escalation.
Eligible patients had a viral load > or =1000 copies/ml on a failing regimen, and began a new protease inhibitor containing regimen at entry. All FDA-approved protease inhibitors available during the study recruitment (June 2002-May 2006) were allowed. One hundred and eighty-three participants with NIQ < or = 1, on the basis of their week 2 protease inhibitor trough concentration and pre-entry drug resistance test, were randomized at week 4 to standard of care (SOC) or protease inhibitor dose escalation (TDM). The primary endpoint was change in log10 plasma HIV-1 RNA concentration from randomization to 20 weeks later.
Ninety-one patients were randomized to SOC and 92 to TDM. NIQs increased more in the TDM arm compared to SOC (+69 versus +25%, P = 0.01). Despite this, TDM and SOC arms showed no difference in outcome (+0.09 versus +0.02 log10, P = 0.17). In retrospective subgroup analyses, patients with less HIV resistance to their protease inhibitors benefited from TDM (P = 0.002), as did black and Hispanic patients (P = 0.035 and 0.05, respectively). Differences between black and white patients persisted when accounting for protease inhibitor susceptibility.
There was no overall benefit of TDM. In post hoc subgroup analyses, TDM appeared beneficial in black and Hispanic patients, and in patients whose virus retained some susceptibility to the protease inhibitors in their regimen.
AIDS (London, England) 01/2009; 23(3):357-68. · 4.91 Impact Factor
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Bart Winters,
Julio Montaner,
P Richard Harrigan,
Brian Gazzard,
Anton Pozniak,
Michael D Miller,
Sean Emery,
Frank van Leth,
Patrick Robinson,
John D Baxter,
Marie Perez-Elias,
Delivette Castor,
Scott Hammer, Alex Rinehart,
Hans Vermeiren,
Elke Van Craenenbroeck,
Lee Bacheler
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ABSTRACT: Clinically relevant cutoffs are needed for the interpretation of HIV-1 phenotypic resistance estimates as predicted by "virtual" phenotype HIV resistance analysis.
Using a clinical data set containing 2596 treatment change episodes in 2217 patients in 8 clinical trials and 2 population-based cohorts, drug-specific linear regression models were developed to describe the relation between baseline characteristics (resistance, viral load, and treatment history), new treatment regimen selected, and 8-week virologic outcome.
These models were used to derive clinical cutoffs (CCOs) for 6 nucleoside/nucleotide reverse transcriptase inhibitors (zidovudine, lamivudine, stavudine, didanosine, abacavir, and tenofovir), 3 unboosted protease inhibitors (PIs; indinavir, amprenavir, and nelfinavir), and 4 ritonavir-boosted PIs (indinavir/ritonavir, amprenavir/ritonavir, saquinavir/ritonavir, lopinavir/ritonavir). The CCOs were defined as the phenotypic resistance levels (fold change [FC]) associated with a 20% and 80% loss of predicted wild-type drug effect and depended on the drug-specific dynamic range of the assay.
The proposed CCOs were better correlated with virologic response than were biological cutoffs and provide a relevant tool for estimating the resistance to antiretroviral drug combinations used in clinical practice. They can be applied to diverse patient populations and are based on a consistent methodologic approach to interpreting phenotypic drug resistance.
JAIDS Journal of Acquired Immune Deficiency Syndromes 06/2008; 48(1):26-34. · 4.43 Impact Factor
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Andrew R Zolopa,
Laura C Lazzeroni, Alex Rinehart,
Françoise Brun Vezinet,
François Clavel,
Ann Collier,
Brian Conway,
Roy M Gulick,
Mark Holodniy,
Carlo-Frederico Perno,
Robert W Shafer,
Douglas D Richman,
Mark A Wainberg,
Daniel R Kuritzkes
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ABSTRACT: Resistance testing is considered standard of care in HIV medicine, but there is no standard interpretation system for genotype tests. We sought to determine how much agreement exists within a group of experts in the interpretation of complex genotypes.
Genotypes from clinical specimens were sent to an international panel of 12 resistance experts. Phenotypic susceptibility testing of these clinical isolates was performed with antivirogram. Experts predicted phenotype fold change category (<2.5-fold change, 2.5-4.0-fold change, >4.0- to 7.0-fold change, >7.0- to 10-fold change, >10- to 20-fold change, or >20-fold change) and predicted expected drug activity for each of 16 antiretroviral drugs. Experts were also asked to make treatment recommendations on the basis of the genotype.
The experts predicted the exact phenotype fold change category correctly 44% of the time, but they varied widely by antiretroviral drug (range, 25%-74%). The highest accuracy was observed for lamivudine (74%) and the nonnucleoside reverse transcriptase inhibitors (66%-69%). Experts generally predicted higher levels of resistance to the remaining nucleoside reverse transcriptase inhibitors than what was found by phenotypic testing. Agreement among experts in predicting phenotype fold change category ranged widely depending on the drug (median agreement, 42% [range, 28%-74%]); the same pattern was observed in predicting expected drug activity (median agreement, 45% [range, 32%-87%]). Experts agreed on treatment recommendations in a median of 79% of instances, and recommendations were consistent over time, with blinded retesting.
Although their ability to predict phenotype from a genotype varied for individual antiretroviral drugs, this expert panel had a high degree of agreement in deriving treatment recommendations from the genotype.
Clinical Infectious Diseases 08/2005; 41(1):92-9. · 9.15 Impact Factor
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ABSTRACT: To evaluate antiviral activity, tolerability, and safety of the protease inhibitor (PI) TMC114 boosted with low-dose ritonavir (RTV).
A randomized, open-label, controlled, phase IIA clinical trial in 15 sites in Europe with 50 HIV-1-infected patients who had taken multiple PIs.
At entry, PIs in non-suppressive regimens were replaced with TMC114/RTV (300/100 or 600/100 mg twice daily, or 900/100 mg once daily) or left unchanged for 14 days. The time-averaged difference (DAVG) in HIV-1 RNA from baseline, change in HIV-1 RNA from baseline, proportions achieving plasma HIV-1 RNA < 400 copies/ml and > or = 0.5 and > or = 1.0 log10 copies/ml reductions in HIV-1 RNA, and safety were assessed.
DAVG responses in all TMC114/RTV groups (range, -0.56 to -0.81 log10 copies/ml) were significantly greater (P < 0.001) than in the controls (-0.03 log10 copies/ml). Median change at day 14 was -1.38 and +0.02 log10 copies/ml for all TMC114/RTV groups and the control group, respectively. A reduction of > or = 0.5 and > or = 1.0 log10 copies/ml was attained by 97% and 76% of patients, respectively, in all TMC114/RTV groups and by 25% and 17%, respectively, in the control group. HIV-1 RNA < 400 copies/ml at any time during treatment was achieved by 40% in the TMC114/RTV groups and 8% in the control group. Most common reported adverse events were gastrointestinal and central nervous system disorders (mild to moderate severity). No dose relationship was observed. Biochemical, haematological and electrocardiographic parameters showed no significant changes.
TMC114/RTV demonstrated a potent antiretroviral effect over 14 days in multiple-PI-experienced patients and was generally well tolerated.
AIDS 06/2005; 19(9):943-7. · 6.24 Impact Factor
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Scott A Wegner,
Mark R Wallace,
Naomi E Aronson,
Sybil A Tasker,
David L Blazes,
Cindy Tamminga,
Susan Fraser,
Matthew J Dolan,
Kevin T Stephan,
Nelson L Michael, [......],
Maryanne T Vahey,
Joyce L Gilcrest,
LaRee Tracy,
Mark J Milazzo,
Daniel J Murphy,
Paula McKenna,
Kurt Hertogs, Alex Rinehart,
Brendan Larder,
Deborah L Birx
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ABSTRACT: The long-term efficacy of making resistance testing routinely available to clinicians has not been established. We conducted a clinical trial at 6 US military hospitals in which volunteers infected with human immunodeficiency virus type-1 were randomized to have routine access to phenotype resistance testing (PT arm), access to genotype resistance testing (GT arm), or no access to either test (VB arm). The primary outcome measure was time to persistent treatment failure despite change(s) in antiretroviral therapy (ART) regimen. Overall, routine access to resistance testing did not significantly increase the time to end point. Time to end point was significantly prolonged in the PT arm for subjects with a history of treatment with > or =4 different ART regimens or a history of treatment with nonnucleoside reverse-transcriptase inhibitors before the study, compared with that in the VB arm. These results suggest that routine access to resistance testing can improve long-term virologic outcomes in HIV-infected patients who are treatment experienced but may not impact outcome in patients who are naive to or have had limited experience with ART.
Clinical Infectious Diseases 03/2004; 38(5):723-30. · 9.15 Impact Factor
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ABSTRACT: To evaluate antiviral activity, tolerability, safety and pharmacokinetics of treatment with TMC125 (a non-nucleoside reverse transcriptase inhibitor), 900 mg twice daily for 7 days.
Randomized, double-blind, placebo-controlled, phase IIA clinical trial.
Two hospital clinics in Moscow and St Petersburg, Russian Federation.
Nineteen antiretroviral-naive, HIV-1-infected subjects.
Randomization (2:1) was to twice daily treatment with either 900 mg TMC125 or matched placebo as monotherapy for 7 days.
Change in plasma HIV-1 RNA from baseline values (primary); change in CD4 cell counts from baseline, and evaluation of safety, tolerability and pharmacokinetics of TMC125 treatment (secondary).
A mean decrease from baseline in plasma HIV-1 RNA of 1.99 log10 copies/ml and 0.06 log10 copies/ml was achieved after 7 days in the TMC125 and placebo groups, respectively (P < 0.001). Plasma viral daily decay rates of 0.33 log10 copies/ml and 0.02 log10 copies/ml were observed in the TMC125 and placebo groups, respectively (P < 0.001). A steady-state plasma concentration of TMC125 was attained within 5 days of treatment with a mean minimum concentration of 246 ng/ml and a mean maximum concentration of 419 ng/ml. The majority of subjects did not report any adverse events. No abnormalities consistent with changes in blood chemistry, haematology, urinalysis, electrocardiograph or vital signs were observed.
TMC125 administered as monotherapy for 7 days yielded a 1.99 log10 copies/ml reduction in HIV-1 RNA in antiretroviral-naive, HIV-1-infected subjects. TMC125 was well tolerated and represents a promising and highly potent, next generation non-nucleoside reverse transcriptase inhibitor candidate.
AIDS 11/2003; 17(17):2487-94. · 6.24 Impact Factor
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Elena Ferrer,
Daniel Podzamczer,
Mireia Arnedo,
Emilio Fumero,
Paula McKenna, Alex Rinehart,
José L Pérez,
María J Barberá,
Tomás Pumarola,
José M Gatell,
Francisco Gudiol
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ABSTRACT: For the 127 Spanish patients enrolled in the Combine Study, a resistance substudy was performed with 100 (79%) plasma samples obtained at baseline and with 18 samples obtained from 19 patients at the time they experienced treatment failure. At baseline, primary mutations to nonnucleoside reverse-transcriptase inhibitors and protease inhibitors were not detected, whereas mutations to nucleoside reverse-transcriptase inhibitors were observed in 10% of patients. At failure, mutations were detected in 7 of 16 patients. An agreement in the results of virtual and real phenotypes was observed in the 93 samples in which both tests were performed.
The Journal of Infectious Diseases 03/2003; 187(4):687-90. · 6.41 Impact Factor
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Ann C Collier,
Camlin Tierney,
Gerald F Downey,
Susan H Eshleman,
Angela Kashuba,
Karin Klingman,
Emanuel N Vergis,
Gary E Pakes,
James F Rooney, Alex Rinehart,
John W Mellors
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ABSTRACT: To compare activity and safety of a regimen containing lopinavir/ritonavir (LPV/r) + fosamprenavir (FPV) to regimens with LPV/r or FPV + r and to test the hypothesis that a ritonavir-enhanced dual protease inhibitor (PI) regimen has better antiviral activity.
This study was a multicenter, open-label, randomized study. HIV-infected adults with prior PI failure were selectively randomized based on prior PI experience to either LPV/r, FPV + r, or LPV/r + FPV. All patients received tenofovir DF and 1 to 2 nucleoside reverse transcriptase inhibitors.
Baseline characteristics were similar across arms. Study enrollment and follow-up were stopped early (N = 56) because pharmacokinetic analyses showed significantly lower LPV and FPV exposures in the dual-PI arm. At Week 24, proportions achieving >1 log10 decline in HIV RNA or <50 copies/mL in the dual-PI versus single-PI arms combined were 75% vs. 61% in intent-to-treat (ITT, p = .17) and 100% vs. 64% in as-treated (AT) analyses (p = .02), respectively. Median CD4+ T cell/mm3 increases were 81 vs. 41 (ITT, p = .4) and 114 vs. 43 (AT, p = .08), respectively. Clinical events and toxicity rates were not different between arms.
The trial was unable to show a difference between dual versus single PIs in ITT analyses but favored dual PIs in AT analyses.
HIV Clinical Trials 9(2):91-102. · 1.64 Impact Factor
