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Virological Correlates Associated with Treatment Failure at Week 48 in the Phase 3 Study of Maraviroc in Treatment-naive Patients
J Heera1, M Saag2, P Ive3, J Whitcomb4, M Lewis5, L McFadyen5, J Goodrich1, H Mayer1, E van der Ryst5, and Mike Westby*5
1Pfizer Global R&D, New London, CT, US; 2Univ of Alabama at Birmingham, US; 3Univ of the Witwatersrand, Johannesburg, South Africa; 4Monogram Biosci, South San Francisco, CA, US; and 5Pfizer Global R&D, Sandwich, UK
Background: Maraviroc in Treatment-naive Patients (MERIT)
was designed to compare the safety and efficacy of maraviroc (MVC) 300 mg twice daily vs efavirenz (EFV) 600 mg once daily, each administered with Combivir, in
treatment-naive patients. Analysis of week-48 data demonstrated that 65.3% of
patients receiving MVC achieved an HIV-1 RNA of <50 copies/mL compared to
69.3% for EFV. More patients discontinued from MVC for lack of efficacy
compared to EFV (11.9% vs 4.2%), whereas fewer patients discontinued MVC due to adverse events (4.2% vs 13.6%). The aim of this analysis was to understand the
virological correlates of failure.
Methods: For all patients tropism was measured at
predetermined study visits throughout the study using the Trofile™ Assay
(Monogram Biosciences). Resistance to NRTI and EFV was evaluated by the
PhenoSense GT assay at screening and time of failure. Resistance to MVC was evaluated using the PhenoSense HIV Entry assay, with plateaus in dose–response as a
marker of resistance. MVC plasma concentrations were determined using sparse pharmacokinetics
sampling at protocol-specified timepoints and combined with compliance data
obtained from the study database.
Results: Of 721 patients, 24 (3.3%) changed from CCR5
(R5) at screening to dual/mixed (D/M) at baseline. The response in this patient
group was lower for both EFV and MVC groups, with only 54.6% and 7.1% patients
achieving <50 RNA copies/mL at week 48, respectively. CXCR4-using virus was
detected at failure in 10/32 (31.3%) MVC patients with R5 virus at baseline. NRTI
resistance was selected at failure in all of these patients. For the 13
patients who failed with R5 virus, MVC-resistant virus was selected in 2
patients and NRTI resistance in 7. In contrast, NNRTI resistance was detected in
5 of 6 patients failing EFV who had a valid tropism result at failure. Race,
clade, geographic region, and gender did not appear to be associated with
increases in virological failure to MVC, but poor treatment adherence was a
significant contributor to failure. Mean CD4+ cell increases from
baseline were greater in MVC failures (101 cells/mm3) compared to EFV
failures (44 cells/mm3), regardless of tropism at time of failure.
Conclusions: CXCR4-using virus at baseline was an
important predictor of failure on MVC in this study. As seen with treatment-experienced
patients, failure with CXCR4-using virus is an important mechanism associated
with virological failure. In these patients viral replication in the presence
of only NRTI occurred, resulting in selection of NRTI mutations.
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