A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy

Cohen, Calvin; Hunt, Susan; Sension, Michael; Farthing, Charles; Conant, Marcus A.; Jacobson, Susan; Nadler, Jeffrey P.; Verbiest, W; Hertogs, Kurt; Ames, Michael; Rinehart, Alex; Graham, Neil M.H.

doi:10.1097/00002030-200203080-00009

Cited by 180 publications

(96 citation statements)

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“…In some studies among adults, resistance testing was shown to provide short-term benefits, especially after initial HAART failure. [38][39][40] However, a large randomized study showed no benefit of resistance testing. 41 Although resistance testing has been adopted widely, other factors (such as toxicity, tolerability, pill burden, and drug-drug pharmacokinetic and resistance interactions), many of which affect adherence greatly, may be more important than viral resistance results alone in designing salvage regimens involving Ն5 drugs to treat highly resistant virus.…”

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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“…R esistance testing significantly improves response to antiretroviral therapy in patients infected with HIV type 1 (HIV-1), as was recently demonstrated in retrospective and prospective studies (1)(2)(3). Drug resistance can either be directly assessed by phenotypic assays or can be deduced from genotypic assays, which are based on sequencing of the relevant parts of the viral genome (4).…”

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confidence: 99%

Diversity and complexity of HIV-1 drug resistance: A bioinformatics approach to predicting phenotype from genotype

Beerenwinkel

Schmidt

Walter

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

209

159

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Drug resistance testing has been shown to be beneficial for clinical management of HIV type 1 infected patients. Whereas phenotypic assays directly measure drug resistance, the commonly used genotypic assays provide only indirect evidence of drug resistance, the major challenge being the interpretation of the sequence information. We analyzed the significance of sequence variations in the protease and reverse transcriptase genes for drug resistance and derived models that predict phenotypic resistance from genotypes. For 14 antiretroviral drugs, both genotypic and phenotypic resistance data from 471 clinical isolates were analyzed with a machine learning approach. Information profiles were obtained that quantify the statistical significance of each sequence position for drug resistance. For the different drugs, patterns of varying complexity were observed, including between one and nine sequence positions with substantial information content. Based on these information profiles, decision tree classifiers were generated to identify genotypic patterns characteristic of resistance or susceptibility to the different drugs. We obtained concise and easily interpretable models to predict drug resistance from sequence information. The prediction quality of the models was assessed in leave-one-out experiments in terms of the prediction error. We found prediction errors of 9.6 -15.5% for all drugs except for zalcitabine, didanosine, and stavudine, with prediction errors between 25.4% and 32.0%. A prediction service is freely available at http:͞͞cartan.gmd.de͞geno2pheno.html.

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“…Only randomized prospective trials can provide a conclusive insight into the relative clinical benefit value of interventions based on different systems for predicting HIV-1 drug resistance, as has been demonstrated for sequence-based and phenotypic systems (Baxter et al, 2000;Clevenbergh et al, 2000;Cohen et al, 2002;Durant et al, 1999;Tural et al, 2002). The current results however support further efforts to investigate such clinical benefit of the version 1 LiPA Assay, or any other assay, which measures only a selected number of resistance mutations.…”

Section: Discussionmentioning

confidence: 62%

Virologic therapy response significantly correlates with the number of active drugs as evaluated using a LiPA HIV-1 resistance scoring system

Ziermann

Celis

Derdelinckx

et al. 2004

Journal of Clinical Virology

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Background: Resistance testing is increasingly accepted as a tool in guiding the selection of human immunodeficiency virus type 1 (HIV-1) antiretroviral therapy in HIV-1 infected individuals who fail their current regimen. Objectives: To descriptively compare the correlation between virologic treatment response and results using three genotypic HIV-1 drug resistance interpretation systems: the VERSANT ® HIV-1 Resistance Assay (LiPA) system and two sequence-based interpretation systems. Study design: Specimens from 213 HIV-1-infected subjects, either starting (n = 104) or switching to (n = 109) a regimen of three or four anti retroviral drugs, were collected retrospectively at baseline and after 3 months of uninterrupted therapy. The correlation between viral load change and the number of predicted active drugs in the treatment regimen was assessed. An interpretation algorithm was recently developed to process VERSANT ® HIV-1 Resistance Assay (LiPA) data. The number of active drugs predicted using this algorithm was rank correlated with the viral load change over a 3-month treatment period. For comparison, a similar calculation was made using two sequence-based algorithms (REGA version 5.5 and VGI GuideLines™ Rules 4.0), both applied on the same sequences. Results: Statistically significant (p<0.05) correlation coefficients for each of the three HIV-1 drug resistance interpretation systems were observed in the treatment-experienced subjects on a 3-drug regimen (-0.39, -0.38, and -0.42, respectively) as well as on a 4-drug regimen (-0.33, -0.31, and -0.37, respectively). However, no significant correlation was observed in treatment-naïve subjects, probably due to the very low frequency of drug resistance in these subjects. Conclusion: All three genotypic drug resistance interpretation systems (LiPA version 1, REGA version 5.5, and VGI GuideLines™ Rules 4.0) were statistically significantly correlated with virologic therapy response as measured by viral load testing.

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A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy

Abstract: Antiretroviral treatment guided prospectively by PRT led to the increased use of "active" antiretroviral agents and was associated with a significantly better virological response.

Cited by 180 publications

References 16 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

Diversity and complexity of HIV-1 drug resistance: A bioinformatics approach to predicting phenotype from genotype

Virologic therapy response significantly correlates with the number of active drugs as evaluated using a LiPA HIV-1 resistance scoring system

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