Single and Multiple Dose Pharmacokinetics of Maraviroc in Saliva, Semen, and Rectal Tissue of Healthy HIV-Negative Men

Abstract

NCT00775294.

Lack of Prophylactic Efficacy of Oral Maraviroc in Macaques despite High Drug Concentrations in Rectal Tissues

“…MVC protein binding in plasma, rectal secretions, and vaginal secretions was determined by rapid equilibrium dialysis as previously described (rapid equilibrium dialysis device system; Thermo Scientific) (7). Briefly, a 100-l volume of plasma or secretions from treated animals was incubated for 10 h at 37°C in dialysis cartridges, followed by protein precipitation and measurement of total and free MVC concentrations.…”

“…MVC is not currently recommended for first-line therapy and resistance is rare, as opposed to TFV and FTC, which are widely used clinically and result in the emergence and onward transmission of drug-resistant viruses (6). MVC is also rapidly absorbed and penetrates very efficiently into cervicovaginal and rectal tissues, achieving high and sustained concentrations (7,8). A phase II, double-blind, randomized human clinical trial with daily MVC alone or in association with FTC or TDF is now assessing the safety and tolerability of MVC for PrEP in at-risk MSM (http://clinicaltrials.gov/).…”

“…The single-layer columnar epithelium of the rectum differs from the multilayered squamous epithelium that covers the vagina and has a unique immunological composition and CCR5 distribution that may influence early establishment and dissemination of infection (14)(15)(16)(17). In humans, MVC exposure after oral dosing also differs in rectal and vaginal tissues, likely due to differences in tissue vascularization, drug trapping in mucus, and protein binding (7,8). Therefore, it is important to define the prophylactic efficacy of oral MVC against rectal transmission using validated animal models.…”

Maraviroc-induced decrease in circulating bacterial products is not linked to an increase in immune activation in HIV-infected individuals

“…1 T cells coexpressing HLA-DR and CD38 tended to decrease during maraviroc intensification (from 10.2 [interquartile range, 6-22] to 10.0 [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18], P 5 .06, Figure 1B). Plasma levels of soluble CD14 did not increase (from 13 281 [interquartile range, 10 605-16 632] to 13 636 [10 646-16 249] pg/mL, P 5 .950).…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…Intensifying treatment in cART-suppressed individuals may help to further reduce residual viral replication and immune activation. Early intensification of treatment with the CC chemokine receptor 5 (CCR5) antagonist maraviroc may be of special interest not only because the viruses that are capable of establishing an infection generally use CCR5 as a co-receptor, but also because of the quick penetration and sustained concentrations of maraviroc in the rectal mucosa [235]. The addition of maraviroc to the antiretroviral regimen resulted in a faster reduction in newly infected cells [236], a decrease in microbial translocation markers [237,238] and a faster increase in CD4 counts [236,237].…”