Comparison of HIV-1 genotypic resistance test interpretation systems in predicting virological outcomes over time

Abstract

Background: Several decision support systems have been developed to interpret HIV-1 drug resistance genotyping results. This study compares the ability of the most commonly used systems (ANRS, Rega, and Stanford's HIVdb) to predict virological outcome at 12, 24, and 48 weeks.

Methodology/principal findings: Included were 3763 treatment-change episodes (TCEs) for which a HIV-1 genotype was available at the time of changing treatment with at least one follow-up viral load measurement. Genotypic susceptibility scores for the active regimens were calculated using scores defined by each interpretation system. Using logistic regression, we determined the association between the genotypic susceptibility score and proportion of TCEs having an undetectable viral load (<50 copies/ml) at 12 (8-16) weeks (2152 TCEs), 24 (16-32) weeks (2570 TCEs), and 48 (44-52) weeks (1083 TCEs). The Area under the ROC curve was calculated using a 10-fold cross-validation to compare the different interpretation systems regarding the sensitivity and specificity for predicting undetectable viral load. The mean genotypic susceptibility score of the systems was slightly smaller for HIVdb, with 1.92+/-1.17, compared to Rega and ANRS, with 2.22+/-1.09 and 2.23+/-1.05, respectively. However, similar odds ratio's were found for the association between each-unit increase in genotypic susceptibility score and undetectable viral load at week 12; 1.6 [95% confidence interval 1.5-1.7] for HIVdb, 1.7 [1.5-1.8] for ANRS, and 1.7 [1.9-1.6] for Rega. Odds ratio's increased over time, but remained comparable (odds ratio's ranging between 1.9-2.1 at 24 weeks and 1.9-2.2 at 48 weeks). The Area under the curve of the ROC did not differ between the systems at all time points; p = 0.60 at week 12, p = 0.71 at week 24, and p = 0.97 at week 48.

Conclusions/significance: Three commonly used HIV drug resistance interpretation systems ANRS, Rega and HIVdb predict virological response at 12, 24, and 48 weeks, after change of treatment to the same extent.

Figure 1. Schematic definition of a treatment change episode.

The treatment change episode requirements are as follows: (1) a baseline genotypic drug-resistance and viral load test between 90 days before and 8 days after change of therapy (2) at least one follow-up viral load measurement at 12 (8–16), 24 (16–32), or 48 (44–52) weeks.

Figure 2. Drug resistance prevalences.

Percentage of sequences having resistance mutations to NRTI (red), NNRTI (yellow), PI (green), and Multi drug resistance (MDR) (blue).

Figure 3. Total Genotypic Susceptibility Scores for ANRS, HIVdb, and Rega.

Total Genotypic Susceptibility Scores were calculated using the arithmetic sum of the individual scores given by the systems for each specific drug given in a regimen. We classified the GSS score for ANRS, HIVdb, and Rega in the following categories: 0 to <1, 1 to <2, 2 to <3, 3 to <4, and ≥4. GSS scores were calculated for 3759 TCEs.

Figure 4. Association between Genotypic Susceptibility Score and undetectable viral load.

The adjusted odds ratios (ORs) with 95% confidence intervals for RNA levels <50 copies/ml at (A) 12 weeks, (B) 24 weeks, and (C) 48 weeks per unit increase of GSS according to ANRS, HIVdb, and Rega. These odds ratios were adjusted for log viral load at start of therapy and real time to viral load measurement, and similar to the unadjusted odds ratios.

Figure 5. ROC curves for the logistic models for ANRS, HIVdb, and Rega at 12 weeks.

The sensitivity, 1-specificity, and specificity are given in the table for the cut-off points 0.5 (A), 1.5 (B), 2.5 (C), and 3.5 (D) for ANRS, HIVdb, and Rega.

Figure 6. Association of undetectable viral load and Genotypic Susceptibility Score over time.

Kaplan Meier curves showing the association between time to undetectable viral load and the proportion of TCEs having an undetectable viral load for the 5 Genotypic Susceptibility Score groups for (A) ANRS (B) HIVdb and (C) Rega. Due to lost to follow-up at later viral load measurement time points, we limited the follow-up time to 30 weeks.