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Expanded Multivariable Models to Assist Patient Selection for Long-Acting Cabotegravir + Rilpivirine Treatment: Clinical Utility of a Combination of Patient, Drug Concentration, and Viral Factors Associated With Virologic Failure
  june 21 2023
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Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants.
Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population-baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination).
Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P < .05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses.
The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≥first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA.
Risk of CVF According to Combinations of Baseline and Postbaseline Factors Virologic outcomes were summarized according to combinations of those factors found to be important predictors in the MVA to see how these findings could be applied clinically to assess CVF risk. Given the correlation between HIV-1 subtype A6/A1 and the integrase L74I polymorphism [18, 19], only HIV-1 subtype A6/A1 was included. Model-predicted first troughs were included versus troughs after 44 weeks of injections, given their proximity to baseline.
A total of 1292 participants with complete records were available for this analysis (Figure 1). Of participants with ≥3 baseline and postbaseline factors present (3% [n = 39/1292]), 20.5% (n = 8/39) had CVF with a 36.4% sensitivity and 97.6% specificity, and a PPV and NPV of 20.5% and 98.9%, respectively (Table 3 and Supplementary Table 4). As the number of factors decreased, so did the proportion of participants with CVF (≥2 factors, 7.3% [n = 17/232]; 1 factor, 1.3% [n = 5/396]; 0 factors, 0% [n = 0/664]). This same pattern was observed when including BMI ≥30 kg/m2 as a fifth factor (≥2 factors, 5.7% [n = 18/318]; 1 factor, 1.0% [n = 4/391]; 0 factors, 0% [n = 0/583]). Among participants with initial CAB or RPV troughs ≥first quartile as their only factor, 0.6% (n = 1/160) and 0.7% (n = 1/137) had CVF, respectively; when both CAB and RPV troughs were ≥first quartile, this rate was 2.7% (n = 3/113).
Pharmacokinetics in Relation to Virologic Outcome
Of the 22 MVA participants who received CAB + RPV LA and had CVF, 18/22 (82%) had model-predicted CAB and/or RPV trough concentrations within the first quartile 4 weeks after initial injection, including 10/22 (45%) with concentrations for both drugs in the lower quartiles (Supplementary Figures 4A–D).

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