The MOTIVATE trials: maraviroc therapy in antiretroviral treatment-experienced HIV-1-infected patients

Abstract

Although the use of combination antiretroviral therapy has resulted in spectacular improvements in morbidity and mortality of HIV-1 infected patients, a need for the development of antiretroviral compounds with new mechanisms of action remains. Maraviroc (Celsentri(®); ViiV Healthcare, Middlesex, UK) is the only drug of the class of chemokine (C-C motif) receptor 5 antagonists registered for treatment for HIV-1-infected antiretroviral therapy-experienced patients. Registration was based on the MOTIVATE-1 and -2 studies, which compared the efficacy and tolerability of maraviroc in combination with optimized background therapy with placebo. The aim of this paper is to review the MOTIVATE studies and to discuss issues related to maraviroc therapy in clinical practice such as assessment of HIV-1 coreceptor tropism.

Entanglement of CCR5 and Alzheimer’s Disease

“…The promising development of CCR5 receptor inhibitors is largely based on CCR5’s identity as a necessary pathway for AIDS infection. The only first-generation CCR5 antagonist that the Food and Drug Administration (FDA) approved, Maraviroc, was well tolerated and showed excellent repression of viral load in patients whose highly active antiretroviral therapy (HAART) failed but not in treatment-naïve patients(Lieberman-Blum et al, 2008; Sierra-Madero et al, 2010; Van Lelyveld et al, 2012). The high efficacy of maraviroc has set the tone for second-generation CCR5 antagonists, which account for the failures of aplaviroc and vicriviroc in clinical trials (Gulick et al, 2007; Leeson and Springthorpe, 2007; Stupple et al, 2011).…”

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

“…This drug demonstrates a long plasma half-life ( t 1/2 15–23 h) [41] to support a convenient once-a-day dosing schedule [42,43] and exhibits broad-spectrum antiviral activity across several R5 isolates including 200 clinically derived HIV envelope pseudo-viruses with an average IC 90 of approximately 14 nM [21]. Data collected from clinical trials (MOTIVATE (Maraviroc Therapy in Antiretroviral Treatment-Experienced HIV-1-Infected Patients) 1 and 2) indicate that MVC is generally well tolerated and significantly repressed viral load in R5-infected HAART-treatment-experienced patients; however, MVC is also hepatotoxic and is not recommended for treatment-naive patients or individuals infected with X4- or dual-tropic R5X4 virus [44–46]. The M/R5-tropic requirement of prequalification for MVC administration led the drug sponsor to develop a suitable test to determine viral population tropism within patients.…”

Developments in HIV-1 immunotherapy and therapeutic vaccination

“…The CCR5 antagonist Maraviroc is used for HIV-1 entry blockade in combination with ART [31] but also acts as an immune modulator. In a recent study on the impact of Maraviroc intensification, Maraviroc normalized HIV-1-associated CD8 + T-cell skewing and reduced the number of CD38- and human leukocyte antigen (HLA)-DR-expressing CD4 + T cells [32].…”