Both baseline HIV-1 drug resistance and antiretroviral drug levels are associated with short-term virologic responses to salvage therapy

Baxter, John D.; Merigan, Thomas C.; Wentworth, Deborah; Neaton, James D.; Hoover, Marie L.; Hoetelmans, Richard M. W.; Piscitelli, Stephen C.; Verbiest, W; Mayers, Douglas L.

doi:10.1097/00002030-200205240-00006

Cited by 42 publications

(31 citation statements)

References 17 publications

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“…Another important determinant of antiretroviral therapeutic success is antiretroviral pharmacokinetics. 25,26 The large interpatient variability in blood concentrations of antiretroviral agents results primarily from differences in drug absorption and clearance. 27 We measured only tenofovir serum concentrations and not tenofovir intracellular concentrations or levels of the other antiretroviral agents in the regimens.…”

Section: E852mentioning

confidence: 99%

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

et al. 2005

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ABSTRACT. Objectives. Highly active antiretroviral therapy has altered the course of HIV infection among children, but new antiretroviral agents are needed for treatment-experienced children with drug-resistant virus. Tenofovir disoproxil fumarate (DF) is a promising agent for use in pediatric salvage therapy, because of its tolerability, efficacy, and resistance profile. We designed this study to provide preliminary pediatric safety and dosing information on tenofovir DF, while also providing potentially efficacious salvage therapy for heavily treatment-experienced, HIV-infected children.Methods. Tenofovir DF, alone and in combination with optimized background antiretroviral regimens, was studied among 18 HIV-infected children (age range: 8.3-16.2 years) who had progressive disease with >2 prior antiretroviral regimens, in a single-center, open-label trial. Tenofovir DF monotherapy for 6 days was followed by the addition of individualized antiretroviral regimens. Subjects were monitored with HIV RNA reverse transcription-polymerase chain reaction, flow cytometry, and routine laboratory studies; monitoring for bone toxicity included measurement of lumbar spine bone mineral density (BMD) with dual-energy x-ray absorptiometry. Subjects were monitored through 48 weeks.Results. Two subjects developed grade 3 elevated hepatic transaminase levels during monotherapy and were removed from the study. The remaining 16 subjects had a median of 4 antiretroviral agents (range: 3-5 agents) added to tenofovir DF. HIV plasma RNA levels decreased from a median pretreatment level of 5.4 log 10 copies per mL (range: 4.1-5.9 log 10 copies per mL) to 4.21 log 10 copies per mL at week 48 (n ‫؍‬ 15), with 6 subjects having <400 copies per mL, including 4 with <50 copies per mL. The overall median increases in CD4 ؉ T cell counts were 58 cells per mm 3 (range: ؊64 to 589 cells per mm 3 ) at week 24 and 0 cells per mm 3 (range: ؊274 to 768 cells per mm 3 ) at week 48. The CD4 ؉ cell responses among the virologic responders were high and sustained.The major toxicity attributed to tenofovir DF was a >6% decrease in BMD for 5 of 15 subjects evaluated at week 48, necessitating the discontinuation of tenofovir DF therapy for 2; all 5 subjects experienced >2 log 10 copies per mL decreases in HIV plasma RNA levels.Conclusions. Tenofovir DF-containing, individualized, highly active antiretroviral therapy regimens were well tolerated and effective among heavily treatmentexperienced, HIV-infected children.

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Section: E852mentioning

confidence: 99%

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

et al. 2005

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confidence: 91%

“…When no mutations are present or when there are too many, the extent of TPV exposure is less relevant. Altogether, these data suggest that the integration of information on the values of the pharmacokinetic parameters and drug resistance changes could improve the management of most antiretroviral-experienced HIV-infected patients treated with TPV (1,22,26).The inhibitory quotient (IQ) is a pharmacological parameter that combines a measure of exposure and susceptibility to a particular drug. The IQ (or phenotypic IQ) is calculated as the C trough divided by the serum-adjusted 50% inhibitory concentration (IC 50 ).…”

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confidence: 99%

Use of Different Inhibitory Quotients To Predict Early Virological Response to Tipranavir in Antiretroviral-Experienced Human Immunodeficiency Virus-Infected Patients

Morello

Mendoza²,

Soriano³

et al. 2009

Antimicrob Agents Chemother

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Information about the relationship between pharmacological parameters and an early virological response to tipranavir (TPV) is scarce. Human immunodeficiency virus (HIV)-infected patients who had received TPV as part of a salvage regimen were analyzed retrospectively. A virological response was defined as a decline in the HIV RNA level of >1 log unit or to <50 copies/ml between weeks 4 and 12 of therapy. The virtual inhibitory quotient (vIQ) was calculated as the ratio of the TPV plasma trough concentration (C trough )/virtual change in the 50% inhibitory concentration. Three genotypic inhibitory quotients (gIQs) were calculated by using different TPV resistance mutation scores ( Tipranavir (TPV) is a nonpeptidic human immunodeficiency virus (HIV) protease inhibitor (PI) that has been demonstrated to have activity against multidrug-resistant HIV type 1 (HIV-1) isolates (2,4,7,12). On the basis of its differential biochemical structure, the resistance profile of TPV seems to differ from the resistance profiles of the rest of the PIs. Twentyone mutations located at 17 codons have been reported to be associated with a loss of susceptibility to TPV (13). Moreover, two scores have recently weighted the virological impact of distinct TPV resistance-associated mutations (19, 24). These scores incorporate mutations associated with resistance to TPV as well as those associated with hypersusceptibility to TPV, allowing the more accurate interpretation of the genotypic changes that influence the antiviral activity of TPV.Resistance to ritonavir-boosted PIs generally develops gradually and requires the accumulation of several mutations within the HIV protease gene. Partial PI activity can still be recognized when enough drug exposure exists and when viruses harboring only a few protease-associated resistance mutations are present. In this regard, previous studies have shown a good correlation between the TPV plasma trough concentration (C trough ) and the viral response in the subset of patients infected with viruses carrying an intermediate number of TPV resistance-associated mutations (20,23). When no mutations are present or when there are too many, the extent of TPV exposure is less relevant. Altogether, these data suggest that the integration of information on the values of the pharmacokinetic parameters and drug resistance changes could improve the management of most antiretroviral-experienced HIV-infected patients treated with TPV (1,22,26).The inhibitory quotient (IQ) is a pharmacological parameter that combines a measure of exposure and susceptibility to a particular drug. The IQ (or phenotypic IQ) is calculated as the C trough divided by the serum-adjusted 50% inhibitory concentration (IC 50 ). Alternative quotients have been developed and include the virtual IQ (vIQ), the normalized IQ (nIQ), and the genotypic IQ (gIQ). The vIQ is the ratio between the C trough and the virtual phenotype (the expected change in viral susceptibility associated with a particular genotypic mutation profile) multiplied by the serum-ad...

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“…PIs show significant interindividual pharmacokinetic variability for identical dosing regimens (7,14,31,33). High PI concentrations have been associated with toxicity, while subtherapeutic concentrations have been associated with virologic failure (2,3,9,11,12,28,30,31,32). These findings have led to interest in the use of therapeutic drug monitoring (TDM), which individualizes therapy to maximize outcomes and minimize toxicity (1,7,10).…”

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confidence: 99%

Clinical Evaluation of a Dried Blood Spot Assay for Atazanavir

Schooneveld¹,

Swindells²,

Nelson

et al. 2010

Antimicrob Agents Chemother

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Current procedures for obtaining and measuring plasma concentrations of HIV protease inhibitors (PIs) are technically challenging. Dried blood spot (DBS) assays offer a way to overcome many of the obstacles. We sought to develop a DBS assay for quantitation of the PI atazanavir (ATV) and to compare this method with a previously validated plasma assay. We prospectively enrolled 48 patients with well-controlled HIV disease who had been on ATV for at least 7 days. ATV was quantified from plasma by use of high-performance liquid chromatography (HPLC). A reversed-phase ultrahigh-performance liquid chromatography (UPLC) assay was utilized for DBS samples. The concentrations of ATV quantified in a DBS matrix showed very strong agreement with those measured in plasma (r 2 ‫؍‬ 0.988). The mean difference in ATV concentration between the two methods was ؊10.8% (95% confidence interval [95% CI], ؊7.65% to ؊13.95%), indicating that the DBS method has a slight negative bias. A majority (97.8%) of the differences in concentration between the two assays fell within ؎2 standard deviations. ATV concentrations were lower in subjects who had detectable HIV RNA in plasma (mean, 543 ng/ml) than in those with HIV RNA of <50 copies/ml (mean, 1,582 ng/ml) (P ‫؍‬ 0.03, Wilcoxon rank-sum test). In conclusion, our study demonstrated that ATV quantitation in a DBS matrix is feasible and accurate. DBS use offers a convenient alternative for measuring plasma concentrations of ATV and may have utility in monitoring of drug concentrations in clinical practice and in future studies.Presently, approximately 33 million persons are living with human immunodeficiency virus (HIV) disease (35). Treatment options for HIV disease have expanded over the last 15 years, particularly with the introduction of protease inhibitors (PIs) as a component of combination antiretroviral therapy (ART). Use of these agents has been associated with significant decreases in morbidity and mortality (13,16,29). Despite the efficacy of PIs, a substantial number of patients still experience virological failure (23). PIs show significant interindividual pharmacokinetic variability for identical dosing regimens (7,14,31,33). High PI concentrations have been associated with toxicity, while subtherapeutic concentrations have been associated with virologic failure (2,3,9,11,12,28,30,31,32). These findings have led to interest in the use of therapeutic drug monitoring (TDM), which individualizes therapy to maximize outcomes and minimize toxicity (1, 7, 10). Currently, the literature does not support and guidelines do not recommend routine use of TDM in HIV-infected adults (8, 21).Atazanavir (ATV) is an azapeptide PI approved for use in both treatment-naïve and treatment-experienced patients (18). It has the advantage of being dosed once a day and can be used with or without ritonavir (RTV), although coadministration of RTV is preferred (8). The current techniques for quantitation of ATV (as well as all other PIs) are plasma-or serum-based analytical procedures. These procedures ...

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Both baseline HIV-1 drug resistance and antiretroviral drug levels are associated with short-term virologic responses to salvage therapy

Abstract: In salvage therapy, both the number of active drugs and the DL for each drug in the new regimen determine the antiviral response.

Cited by 42 publications

References 17 publications

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

Use of Different Inhibitory Quotients To Predict Early Virological Response to Tipranavir in Antiretroviral-Experienced Human Immunodeficiency Virus-Infected Patients

Clinical Evaluation of a Dried Blood Spot Assay for Atazanavir

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