A randomized controlled trial to evaluate antiretroviral salvage therapy guided by rules-based or phenotype-driven HIV-1 genotypic drug-resistance interpretation with or without concentration-controlled intervention: the Resistance and Dosage Adapted Regimens (RADAR) study.

BACKGROUND: It is not well defined whether concentration-controlled intervention
(CCI) and rules-based human immunodeficiency virus (HIV) type 1 genotype
drug-resistance interpretation (GI) or virtual phenotype drug-resistance
interpretation (VPI) may improve the outcome of HIV salvage therapy.
METHODS: In a prospective, randomized, controlled trial, patients were randomized
(on a factorial basis) to change treatment after either GI or VPI, and they then
were further randomized to the control arm (no CCI) or the CCI arm. Protease
inhibitor (PI) and nonnucleoside reverse-transcriptase inhibitor (NNRTI) trough
concentration (Ctrough) values were determined at weeks 1, 4, 12, and 24 of the
study.
RESULTS: Among 230 patients, virological benefit (defined by an HIV RNA load of
<400 copies/mL at week 24) was not statistically different, either between
patients in the GI and VPI arms or between patients in the CCI and control arms.
A virological benefit was found for patients in the CCI arm, compared with
patients in the control arm, but this benefit was not statistically significant
(56.8% vs. 64.3% at week 4 and 63.6% vs. 74% at week 12). Dosage adaptation was
possible for only a fraction of patients, because of low rates of treatment
adherence or patient refusal to increase dosages. In the logistic regression
analysis, independent predictors of virological response at week 24 were a PI
Ctrough value and/or an NNRTI Ctrough value in the higher quartiles (or above
cutoff levels) and a low number of PIs previously received. Moreover, receipt of
a regimen that contained PIs boosted with ritonavir was an independent predictor
of virological response.
CONCLUSIONS: The present study did not support the routine use of CCI for
patients undergoing salvage treatment, probably as a result of existing
difficulties associated with its clinical application. However, a higher Ctrough
value appeared to be correlated with treatment response. No major differences
were found between VPI or GI when they are used together with expert advice for
the selection of salvage treatment combinations.