12 research outputs found
Relationship between drug exposure, drug resistance, and therapeutic success.
<p>a) Prior to drug exposure, the virus typically does not carry drug-resistance mutations. In the absence of drug pressure, drug-susceptible virus can replicate at high titers (dark-green viral particles). b) If drug susceptibility is given, antiretroviral therapy frequently leads to the suppression of viral replication, which is a prerequisite for therapeutic success. While antiretroviral therapy is administered, however, drug concentrations fluctuate over the dosing interval and may vary within the different body compartments (orange-yellow gradient). This can give rise to sub-inhibitory concentrations in some compartments (light-yellow area in gradient), resulting in the selection of mutations that confer to the virus a selective advantage in the presence of the drug (light-green viral particles). These mutations need not result in virological therapy failure, since they may not enable the virus to replicate at high drug concentrations. c) Recurrence of sub-inhibitory drug concentrations can ultimately select for mutations that enable the virus to replicate even at the highest drug concentrations (red viral particles). d) The selection of drug-resistant virus leads to virological therapy failure: the virus replicates at high titers in spite of antiretroviral therapy.</p
Drug-combination counts for therapies in EuResistTCE and HIVdbTCE.
<p>The frequencies of the 20 most-frequent drug combinations in EuResistTCE (a) and HIVdbTCE (b) datasets are displayed above. 3TC: lamivudine, ABC: abacavir, AZT: zidovudine, d4T: stavudine, ddI: didanosine, FTC: emtricitabine, TDF: tenofovir, EFV: efavirenz, NVP: nevirapine, APV: amprenavir, ATV: atazanavir, DRV: darunavir, IDV: indinavir, LPV: lopinavir, NFV: nelfinavir, SQV: saquinavir.</p
Correlation of drug-exposure scores with logarithmized resistance factors.
<p>Genotypes in T<sub>Pheno</sub> were interpreted with drug-exposure models. The correlation of the resulting drug-exposure scores with the corresponding logarithmized resistance factors is displayed above. Note that drug-resistance assays (either Antivirogram<sup>™</sup> or PhenoSense<sup>™</sup>) are denoted by the colors of the bars, while the drug-exposure model types (Exposure or ExposurePheno) are denoted by the shading of the bars. Bars depicting the mean performances were calculated with the drugs for which Exposure and ExposurePheno models are available. Error bars indicate the standard deviation. 3TC: lamivudine, ABC: abacavir, AZT: zidovudine, d4T: stavudine, ddC: zalcitabine, ddI: didanosine, FTC: emtricitabine, TDF: tenofovir, DLV: delavirdine, EFV: efavirenz, ETR: etravirine, NVP: nevirapine, RPV: rilpivirine, APV: amprenavir, ATV: atazanavir, DRV: darunavir, FPV: fosamprenavir, IDV: indinavir, LPV: lopinavir, NFV: nelfinavir, SQV: saquinavir, TPV: tipranavir, EVG: elvitegravir, RAL: raltegravir.</p
Number of sequences by dataset and drug exposure.
<p>Number of sequences by dataset and drug exposure.</p
Performance of drug-exposure prediction.
<p>Performance of drug-exposure prediction was assessed with 10-fold cross validation on the development set and four test sets. Test sets T<sub>PRRT</sub> and T<sub>IN</sub> were obtained from the EuResist database and contain protease and reverse-transcriptase and integrase sequences, respectively. TP is a subset of T<sub>PRRT</sub> ∪ T<sub>IN</sub> and contains nucleotide sequences that were measured during therapy pauses. HIVdbExposure was obtained from the HIVdb TCE repository and contains protease and reverse-transcriptase sequences. Performance on the test sets was compared to that of geno2pheno<sub>[resistance]</sub>. Bars depicting mean performances were calculated only using drugs that are common to Exposure and ExposurePheno models, as well as to geno2pheno<sub>[resistance]</sub>. Error bars indicate the standard deviation. 3TC: lamivudine, ABC: abacavir, AZT: zidovudine, d4T: stavudine, ddC: zalcitabine, ddI: didanosine, FTC: emtricitabine, TDF: tenofovir, DLV: delavirdine, EFV: efavirenz, ETR: etravirine, NVP: nevirapine, RPV: rilpivirine, APV: amprenavir, ATV: atazanavir, DRV: darunavir, FPV: fosamprenavir, IDV: indinavir, LPV: lopinavir, NFV: nelfinavir, SQV: saquinavir, TPV: tipranavir, EVG: elvitegravir, RAL: raltegravir.</p
Number of phenotypes by drug in the pheno datasets.
<p>Number of phenotypes by drug in the pheno datasets.</p
Performance of prediction of therapy-success for therapies in EuResistTCE, EuResistTCE<sub>TP</sub>, and HIVdbTCE.
<p>Performance of prediction of therapy-success for therapies in EuResistTCE, EuResistTCE<sub>TP</sub>, and HIVdbTCE.</p
Concordance between the genotypic, ESTA and NGS results.
<p>Values were calculated using 37 samples for ESTA comparison and 45 samples for NGS analysis. g2p: geno2pheno<sub>[coreceptor]</sub>.</p
Influence of FPR cut-offs on PPV and number of patients elegible for MVC treatment.
<p>Values were calculated using all available RNA (n = 87) and DNA (n = 60) samples; ESTA (n = 37); NGS (n = 45). * No NGS values for the NGS FPR cut-off of 7.5% were available.</p