1. TCE (Treatment Change Episode)
A Treatment Change Episodes (TCE) is a set of relevant data surrounding a treatment change for studying predictors of responses to new antiretroviral (ARV) therapy.
To determine how a patient is responding to a new regimen, the longitudinal data from a patient who received multiple courses of treatment is divided into time blocks. Each time block contains what happened before switching to a new regimen and what happened after the new regimen.
A TCE aggregates data from a relevant time block for evaluating the response to a new regimen. The start date of the new regimen is defined as "baseline". The TCE contains the following data:
- plasma HIV-1 RNA levels at the time of the treatment change ('baseline viral load')
- Sequence (mutation information) at the time of treatment change ('baseline genotype')
- ARVs prior to baseline
- ARVs in the new salvage regimen
- plasma HIV-1 RNA levels at subsequent time points (12 weeks, 24 weeks etc) after the new treatment begins ('clinical outcome')
2. TCE XML Schema
The TCE XML Schema elements and constraints were developed to represent the temporal relationship among ARVs, plasma HIV-1 RNA levels, CD4 lymphocyte concentrations /µL (CD4 counts), and genotypic drug resistance data surrounding a treatment change.
Each TCE XML Schema must have a treatment change (or baseline) time point that may be assigned a date or calendar year. The preceding and subsequent data are demarcated according to the number of weeks from baseline. The treatment regimen received before the baseline is represented as a list of regimens or as a list of one or more ARVs or ARV classes. Genotypic drug resistance test results are represented as nucleotide sequences or lists of amino acid mutations obtained at specific times prior to the treatment change. Optional elements include the nadir CD4 count, gender, age, ethnicity, and a metadata element for annotating the treatment-change episode.
The TCE XML Schema can be found at http://hivdb.stanford.edu/TCEs/schema/TCE.xsd
3. TCE Repository
TCE Repository archives ≥1,500 TCEs obtained different clinic populations. Each TCE in the Repository is represented using TCE XML Schema. All share following characteristics:
- presence of an evidence for virological failure prior to a change in therapy defined as one or more plasma HIV-1 RNA levels >1,000 copies/ml within eight weeks preceding the change
- a complete list of ARVs received prior to baseline available
- a change in ARVs occurring within 24 weeks of a baseline genotypic resistance test
- a new salvage regimen administered for at least four weeks
- one or more CD4 counts within 24 weeks prior to the ARV change
- two or more plasma HIV-1 RNA levels within the first 36 weeks following the ARV change.
The TCE Repository can be found here.
4. TCE Finder
TCE Finder accepts as input parameters: (1) the ARVs used prior to the baseline, and/or (2) the ARVs used for the new salvage therapy.
A summary of matching TCEs are presented to the user in a table. The table contains the following fields: ARVs received prior to baseline, genotypic resistance test results at baseline, the salvage ARV regimen, 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 TCE Finder can be found here.
4.1 Input Form
4.1.1 ARVs received prior to starting a new salvage regimen (baseline)
This section allows a user to find TCEs of patients who had received specific ARVs prior to the baseline (starting a new salvage therapy). For each corresponding ARV class, the user can set the number of ARVs in that class:
- ">=0" means 0 or more drugs belonging to the ARV class had been given, which means any treatment history for that ARV class is acceptable;
- "= 0" indicates no ARVs belonging to the ARV class had been given;
- "=1" indicates only one ARV belonging to the ARV class had been given;
- ">=1" indicates one or more ARVs belonging to the ARV class had been given.
Users can also set a list of specific ARVs given prior to the baseline by checking a box provided for each ARV.
4.1.2 New salvage regimen
This section of the form allows users to find TCEs of patients who received a specific salvage therapy. Users can indicate the ARV class combination comprising the new salvage regimen.
- "Yes" field means the new regimen should include the ARV class.
- "No" means the new regimen should not include the ARV class.
- "Optional" means the retrieved TCEs could optionally include ARVs belonging to the corresponding ARV class in its salvage regimen.
Users can also set a list of specific ARVs included in the new salvage regimen by checking a box provided for each ARV.
4.1.3 Default paramters
If users press "submit" without changing the default parameters, TCE Finder will retrieve TCEs from patients who
- received one or more NRTIs, one or more NNRTIs, and one or more PIs as their new salvage regimens and optionally received RAL, MVC, or T20
- had received NRTIs or no NRTIs, NNRTIs or no NNRTIs, PIs or no PIs and optionally RAL, MVC or T20 prior to starting the new salvage therapy, which means any past treatment history is acceptable.
4.2 ARV Drug Abbreviation
- NRTI (nucleoside RT inhibitor)s : 3TC - lamivudine; TDF - tenofovir; d4T - stavudine; ddI - didanosine; ABC - abacavir; AZT - zidovudine; FTC - emtricitabine.
- NNRTI (non-nucleoside RT inhibitor)s: EFV - efavirenz; NVP - nevirapine; ETR - etravirine; DLV - delavirdine.
- PI (protease inhibitor)s: LPV - lopinavir; FPV - fosamprenavir; SQV - saquinavir; IDV - indinavir; ATV - atazanavir; NFV - nelfinavir; DRV - darunavir; TPV - tipranavir; "r" - ritonavir-boosting;
*Notes: In the TCE Finder Form, FPVr also includes unboosted FPV and boosted/unboosted amprenavir (APV); SQVr includes unboosted SQV; IDVr includes unboosted IDV; ATVr includes unboosted ATV. However, in the TCE Finder output, PIs will be indicated according to whether they were boosted or not.
- RAL - raltegravir; MVC - maraviroc; T20 - enfuvirtide.
5. TCE Viewer
TCE Viewer takes data formatted using the TCE xml schema and generates a TCE graph.
The figure below is an example of TCE graph. It shows the temporal relationship
between an ARV treatment change, plasma HIV-1 RNA levels and CD4 counts.
The TCE Viewer can be found here.
- The plot at the top right part of the figure encompasses a user-defined time window (indicated in weeks)
surrounding a treatment change (indicated by BL, baseline).
- ARVs are shown beneath the TCE timeline.
- Plasma HIV-1 RNA levels in log copies/ml are shown in red (right axis).
- CD4 counts are shown in blue(left axis).
- The times genotypes were obtained are indicated by vertical dotted lines and are
numbered in a box at the bottom of the vertical line.
- The upper left table contains the CD4 nadir and lists the ARV treatments received
prior to the pre-BL treatment. For each treatment, duration in months, plasma HIV-1 RNA log copies/ml
(rounded to a single digit), and the final CD4 count on the regimen are shown.
- The genotype table lists all amino acid differences from consensus B and shows drug-resistance associated mutations in red.