Phase 2 Study of the Safety and Efficacy of Vicriviroc, a CCR5 Inhibitor, in HIV‐1–Infected, Treatment‐Experienced Patients: AIDS Clinical Trials Group 5211

Gulick, Roy M.; Su, Zhaohui; Flexner, Charles; Hughes, Michael D.; Skolnik, Paul R.; Wilkin, Timothy; Gross, Robert; Krambrink, Amy; Coakley, Eoin; Greaves, Wayne; Zolopa, Andrew; Reichman, Richard C.; Godfrey, Catherine; Hirsch, Martin S.; Kuritzkes, Daniel R.

doi:10.1086/518797

Cited by 233 publications

(186 citation statements)

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“…The fact that immune activation in HIV patients upregulates CCR5 expression (35) suggests that RAPA will enhance VCV activity significantly in patients. For reference purposes, it is interesting that patient dosing with 10, 25, and 50 mg VCV yields C max values of 58, 150, and 304 nM, respectively, and potent viral suppression (8). In transplant patients RAPA plasma levels range from 1 to 10 nM.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…One mechanism by which this occurs is the use of the alternative HIV coreceptor, CXCR4. In vivo, this has most often been manifest as the outgrowth of R5/X4-tropic HIV isolates that were present in the patient's circulating viral swarm prior to therapy (17,27,55). A second mechanism of HIV resistance to CCR5 antagonists is the use of drug-bound CCR5 as a coreceptor for entry.…”

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confidence: 99%

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

Pfaff

Wilen

Harrison

et al. 2010

J Virol

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We previously reported on a panel of HIV-1 clade B envelope (Env) proteins isolated from a patient treated with the CCR5 antagonist aplaviroc (APL) that were drug resistant. These Envs used the APL-bound conformation of CCR5, were cross resistant to other small-molecule CCR5 antagonists, and were isolated from the patient's pretreatment viral quasispecies as well as after therapy. We analyzed viral and host determinants of resistance and their effects on viral tropism on primary CD4 ؉ T cells. The V3 loop contained residues essential for viral resistance to APL, while additional mutations in gp120 and gp41 modulated the magnitude of drug resistance. However, these mutations were context dependent, being unable to confer resistance when introduced into a heterologous virus. The resistant virus displayed altered binding between gp120 and CCR5 such that the virus became critically dependent on the N terminus of CCR5 in the presence of APL. In addition, the drug-resistant Envs studied here utilized CCR5 very efficiently: robust virus infection occurred even when very low levels of CCR5 were expressed. However, recognition of drug-bound CCR5 was less efficient, resulting in a Entry of human immunodeficiency virus (HIV) into target cells is a complex, multistep process that is initiated by interactions between the viral envelope (Env) protein gp120 and the host cell receptor CD4, which trigger conformational changes in gp120 that form and orient the coreceptor binding site (9,24). Upon binding to coreceptor, which is either CCR5 or CXCR4 for primary HIV isolates, Env undergoes further conformational changes resulting in insertion of the gp41 fusion peptide into the host cell membrane and gp41-mediated membrane fusion (8,15,26). Targeting stages of the HIV entry process with antiretroviral drugs is a productive method of inhibiting HIV replication, as demonstrated by the potent antiviral effects of small-molecule CCR5 antagonists and fusion inhibitors (23,35,49). As with other antiretroviral drugs, HIV can develop resistance to entry inhibitors, and a detailed understanding of viral and host determinants of resistance will be critical to the optimal clinical use of these agents.The coreceptor binding site that is induced by CD4 engagement consists of noncontiguous regions in the bridging sheet and V3 loop of gp120 (4,18,42,43,50). Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sul-

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“…1) [24] and vicriviroc, which are currently in Phase II clinical trials [25]. In our recent work, we have reported new 4-nitroimidazoles with their anti-HIV activity [26 -32]; meanwhile the efforts have been focused on developing inhibitors based on novel scaffolds, via a regioselective palladium(0)-catalyzed cross-coupling reaction [33,34].…”

Section: Introductionmentioning

confidence: 99%

Nitroimidazoles Part 8. Synthesis and Anti-HIV Activity of New 4-Nitroimidazole Derivatives Using the Suzuki Cross-Coupling Reaction

Al‐Soud¹,

Al‐Masoudi²,

Al-Suod³

et al. 2012

Zeitschrift Für Naturforschung B

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The development of new HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs) offers the possibility of generating structures of increased potency. To this end, a series of 1-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-4-(1,1 -biaryl)-4-yl-piperazine derivatives (6a-l) was synthesized via the Suzuki coupling reaction. Analogously, coupling of the acid derivative 5, prepared from 4, with various amino acid methyl esters in the presence of HOBt/DCC reagents afforded the benzamide derivatives 8-11. The newly synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. All compounds are inactive, except compound 6f which showed inhibition of HIV-1 with EC 50 = 2.60 µg mL −1 with a selectivity index (SI) of 9.

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Phase 2 Study of the Safety and Efficacy of Vicriviroc, a CCR5 Inhibitor, in HIV‐1–Infected, Treatment‐Experienced Patients: AIDS Clinical Trials Group 5211

Abstract: In HIV-1-infected, treatment-experienced patients, vicriviroc demonstrated potent virologic suppression through 24 weeks. The relationship of vicriviroc to malignancy is uncertain. Further development of vicriviroc in treatment-experienced patients is warranted.

Cited by 233 publications

References 17 publications

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

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

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

Nitroimidazoles Part 8. Synthesis and Anti-HIV Activity of New 4-Nitroimidazole Derivatives Using the Suzuki Cross-Coupling Reaction

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Phase 2 Study of the Safety and Efficacy of Vicriviroc, a CCR5 Inhibitor, in HIV‐1–Infected, Treatment‐Experienced Patients: AIDS Clinical Trials Group 5211

Abstract: In HIV-1-infected, treatment-experienced patients, vicriviroc demonstrated potent virologic suppression through 24 weeks. The relationship of vicriviroc to malignancy is uncertain. Further development of vicriviroc in treatment-experienced patients is warranted.

Cited by 233 publications

References 17 publications

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

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

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 + T Cells

Nitroimidazoles Part 8. Synthesis and Anti-HIV Activity of New 4-Nitroimidazole Derivatives Using the Suzuki Cross-Coupling Reaction

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HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells