Maraviroc for Previously Treated Patients with R5 HIV-1 Infection

Gulick, Roy M.; Lalezari, Jacob; Goodrich, James; Clumeck, Nathan; DeJesus, Edwin; Horban, Andrzéj; Nadler, Jeffrey P.; Clotet, Bonaventura; Karlsson, Anders; Wohlfeiler, Michael; Montana, John B.; McHale, Mary; Sullivan, John; Ridgway, Caroline; Felstead, Steve; Dunne, Michael; Ryst, Elna van der; Mayer, Howard

doi:10.1056/nejmoa0803152

Cited by 684 publications

(622 citation statements)

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“…The identification and characterization of cellular cofactors represent a promising alternative. Indeed, the use of cellular genes as targets for antiviral drugs is already becoming a reality, as shown for the CCR5 coreceptor and its antagonist, maraviroc [40,41]. Targeting multiple host cell gene products would minimize the acquisition of drug resistance and provide long-lasting blocking of virus replication.…”

Section: Discussionmentioning

confidence: 99%

ZNRD1 (Zinc Ribbon Domain–Containing 1) Is a Host Cellular Factor That Influences HIV‐1 Replication and Disease Progression

et al. 2010

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Section: Discussionmentioning

confidence: 99%

ZNRD1 (Zinc Ribbon Domain–Containing 1) Is a Host Cellular Factor That Influences HIV‐1 Replication and Disease Progression

et al. 2010

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“…Drugs from new classes are now available in high-income countries [22][23][24] , and encouraging results have been obtained in clinical trials. However, they all have limitations in routine clinical practice: integrase inhibitors are somewhat prone to lose efficacy due to resistance development 25 , enfuvirtide requires injection, and CCR5 antagonists are only active against R5 strains of virus.…”

Section: Discussionmentioning

confidence: 99%

Triple-Class Virologic Failure in HIV-Infected Patients Undergoing Antiretroviral Therapy for Up to 10 Years

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Lodwick²,

Costagliola³

et al. 2010

Archives of Internal Medicine

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“…Thus, therapy with a CCR5 antagonist may select for pre-existing X4 strains but does not seem to induce evolution of R5 to X4 strains. Moreover, preliminary results show absence of immunological deterioration in patients who have detectable X4 strains and do not respond to maraviroc treatment, suggesting that more pathogenic viruses are not be selected under antagonist pressure (38,39). In any event, it is likely that a drug regimen containing RAPA and VCV will be effective in preventing the emergence and replication of X4 strains, because RAPA inhibits both R5 and X4 viral gene expression (40).…”

Section: Discussionmentioning

confidence: 99%

Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

Heredia

Latinovic

Gallo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Vicriviroc (VCV) is a chemokine (C-C motif) receptor 5 (CCR5)antagonist with potent anti-HIV activity that currently is being evaluated in phase III clinical trials. In the present study, donor CCR5 density (CCR5 receptors/CD4 lymphocytes) inversely correlated with VCV antiviral activity (Spearman's correlation test; r ‫؍‬ 0.746, P ‫؍‬ 0.0034). Low doses of the transplant drug rapamycin (RAPA) reduced CCR5 density and enhanced VCV antiviral activity. In drug interaction studies, the RAPA/VCV combination had considerable antiviral synergy (combination indexes of 0.1-0.04) in both multicycle and single-cycle infection of lymphocytes. The synergy between RAPA and VCV translated into dose reduction indexes of 8-to 41-fold reductions for RAPA and 19-to 658-fold reductions for VCV. RAPA enhanced VCV antiviral activity against both B and non-B clade isolates, potently suppressing clade G viruses with reported reduced sensitivities to VCV and to the licensed CCR5 antagonist maraviroc. Importantly, RAPA reduction of CCR5 density in lymphocytes sensitized VCV-resistant strains to VCV, inhibiting virus production by ϳ 90%. We further demonstrated the role of CCR5 density on VCV activity against resistant virus in donor lymphocytes and in cell lines expressing varying CCR5 densities. Together, these results suggest that low doses of RAPA may increase the durability of VCV-containing regimens in patients by enhancing VCV viral suppression, by allowing the use of lower doses of VCV with reduced potential for toxicity, and by controlling emerging VCV-resistant variants.chemokine receptor 5 antagonists ͉ coreceptor density ͉ HIV resistance ͉ vicriviroc resistance ͉ maraviroc H ighly active antiretroviral therapy (HAART) has improved treatment of HIV-1 infected individuals considerably (1). However, the success of current therapies is limited by the emergence of drug-resistant strains, the need for sustained adherence to complex regimens, and the potential for drug toxicity (2, 3). The two new antiretroviral classes of integrase and entry inhibitors may help overcome some of the current limitations of HAART (4, 5). Entry inhibitors are especially attractive because they target HIV at the earliest step of the viral cycle and are effective against strains resistant to inhibitors of protease and reverse transcriptase. Entry inhibitors interfere with HIV binding to CD4 receptor (attachment inhibitors) or chemokine (C-C motif) receptor 5 (CCR5)/chemokine (C-X-C-motif) receptor 4 (CXCR4) coreceptors (coreceptor antagonists) or by preventing fusion between cellular and viral membranes (fusion inhibitors) (5). Currently, the fusion inhibitor T-20 (enfuvirtide) and the CCR5 antagonist maraviroc (Selzentry) are the only licensed entry inhibitors (6, 7). The CCR5 antagonist vicriviroc (VCV) presently is in phase III clinical trials (8). Coreceptor CCR5 antagonists inhibit CCR5-tropic HIV-1 (referred to as ''R5 HIV-1'') strains, which are responsible for most transmissions and generally are present throughout the course of infection. In nor...

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Maraviroc for Previously Treated Patients with R5 HIV-1 Infection

Abstract: BACKGROUND-CC chemokine receptor 5 antagonists are a new class of antiretroviral agents.

Cited by 684 publications

References 30 publications

ZNRD1 (Zinc Ribbon Domain–Containing 1) Is a Host Cellular Factor That Influences HIV‐1 Replication and Disease Progression

ZNRD1 (Zinc Ribbon Domain–Containing 1) Is a Host Cellular Factor That Influences HIV‐1 Replication and Disease Progression

Triple-Class Virologic Failure in HIV-Infected Patients Undergoing Antiretroviral Therapy for Up to 10 Years

Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

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