Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1

Abstract

We assessed the efficacy and safety of 10-d monotherapy with the orally administered CCR5 antagonist maraviroc in 63 HIV-1-positive individuals prescreened for the absence of CXCR4-using virus. Maximum reduction in viral load occurred at a median of 10-15 d, with a mean reduction of >or=1.6 log(10) copies/ml at all twice daily doses >or=100 mg. These results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach.

Emerging functions as host cell factors – an encyclopedia of annexin-pathogen interactions

“…However, CCR5 together with RANTES (CCL5), one of the several CCR5 agonists, appear to be involved in an antiviral response to other chronic infections (Schuh et al, 2002;Sanchooli et al, 2014). Therefore, refined antagonists that selectively target HIV-CCR5 binding without disrupting CCR5 activation by endogenous agonists might be safer therapeutic tools (Fätkenheuer et al, 2005). As listed above, extracellular annexins, and prominently AnxA2, were implicated in a vast amount of pathogen interactions with their target host cells.…”

Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development

“…As such, it is critical to understand the relationship between RO and downstream PD/clinical effects when dose prediction is based on RO. For antagonistic drugs that block cell surface receptors without depletion of cells, high level of RO is required for maximum blockade of down‐stream receptor signaling 4, 5, 13 and the RO level is usually proportional to therapeutic effects. As such, RO is highly relevant as a PD.…”

“…Both receptor occupancy (RO) and downstream signaling modulation can be appropriate measures for PD. Measurements of downstream modulation 9, 10 are generally preferred as they provide information pertaining to drug effects on target receptor activation, especially in cases where receptor activation is not in linear relationship with RO 11, 12, 13. However, assays that measure receptor signaling and other effects downstream of target engagement may not always be feasible.…”

Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

“…However, to date the three major groups of drugs being used in the clinical practice are the reverse transcriptase inhibitors (nucleoside/nucleotide, NRTI, and non-nucleoside, NNRTI) and the protease inhibitors (PI). In recent years, three additional drugs have been approved, each representing a new class of anti-retroviral inhibitors by targeting different steps of the HIV-1 life cycle: enfuvirtide, which binds to gp41 thus blocking the fusion process [60], raltegravir, targeting the viral integrase enzyme [61] and maraviroc, targeting the cellular HIV-1 entry co-factor CCR5 [62], see Table 1. The current therapeutic strategy, the so-called highly active anti-retroviral therapy (HAART), involves the use of agents from at least two distinct classes of antiretrovirals [63].…”