Standardized representation, visualization and searchable repository of antiretroviral treatment-change episodes

Abstract

Background: To identify the determinants of successful antiretroviral (ARV) therapy, researchers study the virological responses to treatment-change episodes (TCEs) accompanied by baseline plasma HIV-1 RNA levels, CD4+ T lymphocyte counts, and genotypic resistance data. Such studies, however, often differ in their inclusion and virological response criteria making direct comparisons of study results problematic. Moreover, the absence of a standard method for representing the data comprising a TCE makes it difficult to apply uniform criteria in the analysis of published studies of TCEs.

Results: To facilitate data sharing for TCE analyses, we developed an XML (Extensible Markup Language) Schema that represents the temporal relationship between plasma HIV-1 RNA levels, CD4 counts and genotypic drug resistance data surrounding an ARV treatment change. To demonstrate the adaptability of the TCE XML Schema to different clinical environments, we collaborate with four clinics to create a public repository of about 1,500 TCEs. Despite the nascent state of this TCE XML Repository, we were able to perform an analysis that generated a novel hypothesis pertaining to the optimal use of second-line therapies in resource-limited settings. We also developed an online program (TCE Finder) for searching the TCE XML Repository and another program (TCE Viewer) for generating a graphical depiction of a TCE from a TCE XML Schema document.

Conclusions: The TCE Suite of applications - the XML Schema, Viewer, Finder, and Repository - addresses several major needs in the analysis of the predictors of virological response to ARV therapy. The TCE XML Schema and Viewer facilitate sharing data comprising a TCE. The TCE Repository, the only publicly available collection of TCEs, and the TCE Finder can be used for testing the predictive value of genotypic resistance interpretation systems and potentially for generating and testing novel hypotheses pertaining to the optimal use of salvage ARV therapy.

Figure 1

Treatment-Change Episode (TCE) Finder. TCE Finder user interface including the input form (A) and output showing the summary of the TCEs matching the input criteria (B). The example shown here is searching TCEs containing DRV/r and RAL in the salvage regimen. Fifty-seven TCEs that met the input criteria were retrieved and the first five are shown in (A). For each TCE retrieved, the output table contains the following fields: ARVs received prior to baseline, genotypic resistance test results at baseline, plasma HIV-1 RNA levels obtained following the change in therapy, and a thumbnail image of each TCE that links to the graphical depiction of the TCE created by the TCE viewer. The graphical depiction of the last TCE in the output is shown in Figure 2.

Figure 2

Treatment-Change Episode (TCE) Viewer. TCE Viewer plots (i) antiretroviral (ARV) regimens, plasma HIV-1 RNA levels, and CD4 counts surrounding a treatment change (upper right); (ii) genotypic resistance test results (bottom); and (iii) a summary of the past ARV history (upper left). ARVs are shown beneath the TCE timeline; plasma HIV-1 RNA levels in log copies/ml are shown in red; and CD4 counts are shown in blue. Plasma HIV-1 RNA levels below the limits of quantification are indicated by inverted triangles. Genotype times are indicated by numbered vertical dotted lines. Genotypic resistance test results list amino acid differences from the consensus B protease and RT sequences. Nucleoside-, nonnucleoside, and protease inhibitor resistance mutations are colored. The past history summary shows the CD4 nadir and a list of past ARV regimens. For each past regimen, the plasma HIV-1 RNA levels rounded to the nearest log₁₀ value and the last CD4 count are shown.

Figure 3

Treatment change episodes (TCEs) of (A) PI-naïve and NRTI/NNRTI-experienced patients receiving a new regimen containing a ritonavir-boosted PI and (B) NNRTI-naïve and NRTI/PI-experienced patients receiving a new regimen containing an NNRTI. The flow diagrams illustrate the process by which the patients meeting the selection criteria where extracted from the TCE Repository. To reflect the clinical reality in resource limited settings, patients receiving an integrase inhibitor, fusion inhibitor, or maraviroc were excluded. The tables beneath the flow diagrams contain the numbers of patients (n) according to the specific PI/r (A) or NNRTI (B) and the proportions with virological suppression to <50 copies/ml within 48 weeks (virological response; VR). The NRTI GSS was derived using the Stanford HIVdb algorithm (http://hivdb.stanford.edu; accessed January 25, 2012). Abbreviations: PI - protease inhibitor; PI/r - ritonavir-boosted PI; NRTI - nucleoside RT inhibitor; NNRTI - non-nucleoside RT inhibitor; LPV - lopinavir; FPV - fosamprenavir; SQV - saquinavir; IDV - indinavir; ATV - atazanavir; DRV - darunavir; EFV - efavirenz; NVP – nevirapine.