Correlation of drug-exposure scores with logarithmized resistance factors.

<p>Genotypes in T_Pheno 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^™ or PhenoSense^™) 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

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

Number of phenotypes by drug in the pheno datasets.

<p>Number of phenotypes by drug in the pheno datasets.</p

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

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_PRRT and T_IN were obtained from the EuResist database and contain protease and reverse-transcriptase and integrase sequences, respectively. TP is a subset of T_PRRT ∪ T_IN 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_[resistance]. Bars depicting mean performances were calculated only using drugs that are common to Exposure and ExposurePheno models, as well as to geno2pheno_[resistance]. 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

Demographics of subjects with successfully obtained HIV-1 <i>pol</i> sequences.

<p>Demographics of subjects with successfully obtained HIV-1 <i>pol</i> sequences.</p

Dataset cheat sheet.

<p>Dataset cheat sheet.</p

Performance of prediction of therapy-success for therapies in EuResistTCE, EuResistTCE_TP, and HIVdbTCE.

<p>Performance of prediction of therapy-success for therapies in EuResistTCE, EuResistTCE_TP, and HIVdbTCE.</p

Antiretroviral drug resistance mutations in Tanzanian subjects at first line clinico-immunological ART failure.

<p>A) stratified by treatment duration (n = 38); B) stratified by CD4 cells at failure (n = 36).</p