Subgroup Analyses of Maraviroc in Previously Treated R5 HIV-1 Infection

Fätkenheuer, Gerd; Nelson, Mark; Lazzarin, Adriano; Konourina, Irina; Hoepelman, Andy I. M.; Lampiris, Harry; Hirschel, Bernard; Tebas, Pablo; Raffi, François; Trottier, Benôit; Bellos, Nicholaos C.; Saag, Michael S.; Cooper, David A.; Westby, Mike; Tawadrous, Margaret; Sullivan, John; Ridgway, Caroline; Dunne, Michael; Felstead, Steve; Mayer, Howard; Ryst, Elna van der

doi:10.1056/nejmoa0803154

Cited by 304 publications

(293 citation statements)

References 28 publications

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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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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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“…In phase 3 clinical trials (MOTIVATE 1 & 2), randomly assigned patients, who had exclusively CCR5-tropic HIV-1, received 300 mg Maraviroc once or twice daily or placebo, together with an optimized background regimen. In combined analysis, the mean reduction of viral load at week 48 was 0.9-and 1.05-log10 copies/mL greater in Maraviroc once and twice daily groups, respectively, than that in placebo group, together with higher frequencies of patients whose viral load had been suppressed to less than 50 copies/mL and of CD4 + count increase (Fatkenheuer et al, 2008;Gulick et al, 2008). In another phase 3 clinical trial (MERIT), treatment-naïve patients were recruited and the efficacy and safey of Maraviroc as a first-line regimen were investigated.…”

Section: Small Molecule Entry Inhibitorsmentioning

confidence: 86%

“…The emergence of pre-existing CXCR4-tropic HIV-1 that failed to be detected in pre-treatment screening was related to virologic failure (Fatkenheuer et al, 2008;Cooper et al, 2010). CCR5-tropic Maraviroc-resistant strains have also been reported (Fatkenheuer et al, 2008), and the in vivo acquisition of Maraviroc-resistance was also a result of V3 sequence changes, similar to that from in vitro selection (Tilton et al, 2010 (Fig. 3F) .…”

Section: Small Molecule Entry Inhibitorsmentioning

confidence: 99%

Closing the door to human immunodeficiency virus

2013

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The pandemic of human immunodeficiency virus type one (HIV-1), the major etiologic agent of acquired immunodeficiency disease (AIDS), has led to over 33 million people living with the virus, among which 18 million are women and children. Until now, there is neither an effective vaccine nor a therapeutic cure despite over 30 years of efforts. Although the Thai RV144 vaccine trial has demonstrated an efficacy of 31.2%, an effective vaccine will likely rely on a breakthrough discovery of immunogens to elicit broadly reactive neutralizing antibodies, which may take years to achieve. Therefore, there is an urgency of exploring other prophylactic strategies. Recently, antiretroviral treatment as prevention is an exciting area of progress in HIV-1 research. Although effective, the implementation of such strategy faces great financial, political and social challenges in heavily affected regions such as developing countries where drug resistant viruses have already been found with growing incidence. Activating latently infected cells for therapeutic cure is another area of challenge. Since it is greatly difficult to eradicate HIV-1 after the establishment of viral latency, it is necessary to investigate strategies that may close the door to HIV-1. Here, we review studies on non-vaccine strategies in targeting viral entry, which may have critical implications for HIV-1 prevention.

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“…However, the sensitivity of the original commercially available assay was compromised with respect to the detection of low abundance (minority) CXCR4-using variants. As a result, a number of subjects were misjudged to have R5 virus at screening, whereas they actually harbored Dual/Mixed (D/M) virus populations when they entered clinical trials of CCR5 inhibitors; these patients appeared to have a blunted virologic response and high rates of early virologic failure [152][153][154]. Application of an enhanced-sensitivity Trofile assay or "deep sequencing" and re-analysis of the data showed that virologic failure in a significant proportion of these patients stemmed from the expansion of pre-existing minority CXCR4-using variants that went undetected during the first round of testing [155][156][157].…”

Section: In Vivo Resistance: Potential Expansion Of Pre-existing CXCmentioning

confidence: 99%

Chemokine Receptors as Therapeutic Targets in HIV Infection

Anastassopoulou¹

2012

Immunodeficiency

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Subgroup Analyses of Maraviroc in Previously Treated R5 HIV-1 Infection

Abstract: Subanalyses of pooled data from week 48 indicate that maraviroc provides a valuable treatment option for a wide spectrum of patients with R5 HIV-1 infection who have been treated previously. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

Cited by 304 publications

References 28 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

Closing the door to human immunodeficiency virus

Chemokine Receptors as Therapeutic Targets in HIV Infection

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