Background:  The CC-chemokine receptor 5 (CCR5) is an important host co-receptor involved in HIV-1 infection. Maraviroc (MVC) is a CCR5 antagonist currently in late-stage development for the treatment of CCR5-tropic HIV-1. Mean viral load reduction of 1.6 log₁₀ copies/mL occurred immediately following 10 days of MVC monotherapy in patients infected with CCR5-tropic virus. In a phase IIb safety study in 186 treatment-experienced patients infected with non-CCR5-tropic HIV-1, a clinically relevant increase in CD4 and CD8 cell counts, with no associated decrease in viral load, followed 24 weeks of MVC in addition to optimized background therapy compared with optimized background therapy alone. Despite the known promiscuity of CCR5 and its ligands, there is a theoretical risk of immunomodulatory effects due to prevention of binding and signaling by host endogenous ligands of CCR5 alone. A review of the immune function markers from 5 double-blind, placebo-controlled, multiple-dose studies and the complete differential blood counts from 13 multiple-dose studies was conducted.

Methods:  Markers of immune function (complete differential blood counts, immunoglobulin levels and lymphocyte subsets) were measured in 5 studies; 2 phase I studies of 10 to 11 days (n = 87, MVC ≤600 mg once daily), a phase I study of 28 days (n = 48, MVC 100 mg twice daily, 300 mg twice daily), and 2 phase IIa 10-day monotherapy studies (82 HIV-infected subjects with baseline CD4 count ≥250 cells/mm³) at doses ≤300 mg twice daily. For 8 additional multiple-dose phase I studies (n = 214, MVC ≤1200 mg once daily), the differential blood count was also reviewed. All reported infections and malignancies were monitored and reviewed until 28 days post therapy.

Results:  For both healthy volunteers and HIV-1-infected subjects, no clear effect on hematology parameters was observed. Immunoglobulin levels and lymphocyte subset data, including CD4 and CD8, did not indicate any changes related to MVC. There was no effect on frequency or severity of infections reported. All reported infections were typical of the population studied. No malignancies were reported.

Conclusions:  Following short-term dosing in a limited number of subjects at doses ≤600 mg once daily, the body of evidence from phase I and IIa data does not suggest that maraviroc has an effect on immune function. No increased frequency or severity of infections and no increase in CD4 or CD8 cell count was noted in this population.