Background:  A concern in developing co-receptor antagonists as a novel class of HIV therapeutics is the possible emergence of X4 variants during treatment. Our objective was to perform a detailed analysis of a patient harboring virus with a dual-tropic phenotype, who was inadvertently enrolled in a phase 2a clinical study to test the efficacy of the novel CCR5 antagonist, UK-427,857; and to correlate any changes in the circulating virus populations during the course of the study with measured PK and PD parameters.

Methods:  Co-receptor tropism and phenotypic susceptibility of viruses to UK-427,857 was performed on baseline, day 11 and day 40 plasma samples using ViroLogic’s PhenoSense-HIV Entry Assay. Viable env clones from each time-point were also sequenced and assessed for co-receptor usage as above. Functional occupancy of the CCR5 receptor by the compound was measured using an ex vivo receptor saturation assay.

Results: This patient experienced no drop in viral load despite receiving UK-427,857 at 100 mg twice daily for 11 days. The patient’s PK was not significantly outlying and CCR5 receptor saturation was within the normal range of the responding patients. The circulating virus population at baseline had a dual tropic phenotype, with a predominance of R5 variants. The R5 variants were susceptible in vitro to UK-427,857 and appeared suppressed in vivo during treatment. This effect appeared to be reversible, as R5 virus again became the dominant circulating species following cessation of treatment.

Conclusions:  This is the first documented example of selective R5 virus suppression occurring in vivo in the absence of a measurable drop in virus load. Significantly, the patient’s circulating virus returned to be predominantly R5 tropic following cessation of treatment, indicating that treatment of this patient with UK-427,857 did not result in a permanent change in co-receptor tropism. The data presented is consistent with there being differential control of X4- and R5-virus replication in co-infected patients.

Keywords: entry; coreceptor; resistance