A Double‐Blind, Placebo‐Controlled Trial of Maraviroc in Treatment‐Experienced Patients Infected with Non‐R5 HIV‐1

Saag, Michael S.; Goodrich, James; Fätkenheuer, Gerd; Clotet, Bonaventura; Clumeck, Nathan; Sullivan, John; Westby, Mike; Ryst, Elna van der; Mayer, Howard

doi:10.1086/598965

Cited by 128 publications

(129 citation statements)

References 12 publications

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“…This finding supports the fact that an antiretroviral effect is necessary to observe the specific immune effects of MVC in relation to these markers. Thus, MVC will not have any immunomodulatory effect on patients who are insensitive to the drug, at least on the parameters studied herein, a finding which is in contrast to what has been previously suggested (23). Surprisingly, the MVC-specific effect after 8 days was an increase in CD8 ϩ T-cell activation and senescence levels.…”

Section: Discussioncontrasting

confidence: 78%

“…Thus, it is important to explore whether new drugs can have an impact on HIV progression-related biomarkers. Maraviroc (MVC) (7), the first CCR5 (R5) antagonist approved for the treatment of HIV-1 infection, has been proposed as a drug with an immunomodulatory effect independent of its antiviral activity (1,23,25). Moreover, it has been recently suggested that MVC-containing cART can facilitate a greater reduction in immune activation and inflammation markers than conventional cART (10).…”

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confidence: 99%

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Effect of Maraviroc on HIV Disease Progression-Related Biomarkers

Romero-Sánchez

Machmach

González‐Serna

et al. 2012

Antimicrob Agents Chemother

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The potential effect of blocking the CCR5 receptor on HIV disease progression biomarkers is not well understood. We showed that an 8-day maraviroc (MVC) monotherapy clinical test (MCT) can be used in selecting patients to receive MVC-containing combined antiretroviral therapy (cART). Using this MCT model, we assessed the effect of MVC on several HIV disease progression biomarkers during the MCT (MVC-specific effect) and following short-term (12-week) cART. We compared 45 patients on MVC monotherapy with a control group of 25 patients on MVC-sparing cART. We found that MVC did not modify any biomarkers in patients that had no virological response after the MCT. MVC-specific effects in patients with virological responses included increased CD8 ؉ T-cell activation and senescence levels, preservation of an increase in soluble CD14 (sCD14), and a decrease in D dimer levels. After 12 weeks, MVC-containing cART increased CD8 ؉ T-cell counts and preserved CD4 ؉ T-cell senescence levels compared with MVC-sparing cART. Moreover, there was a decrease in sCD14 levels in patients that received MVCcontaining cART. In conclusion, effects compatible with CD8؉ T-cell redistribution in peripheral blood were observed after MVC therapy. However, MVC was associated with a favorable profile in HIV disease progression biomarkers only in patients with a virological response. These results support a potential clinical benefit of a therapy which includes MVC in HIV-infected patients.

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Section: Discussioncontrasting

confidence: 78%

mentioning

confidence: 99%

Effect of Maraviroc on HIV Disease Progression-Related Biomarkers

Romero-Sánchez

Machmach

González‐Serna

et al. 2012

Antimicrob Agents Chemother

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“…Moreover, our results are also consistent with the data from the A4001029-study, a Phase 2b clinical trial, where patients carrying non-R5 viruses were treated with maraviroc-containing regimen. This study has indeed shown the suppression of viremia below 50 copies/ml in 27% of patients with D/M-tropic viruses at week 48 of a maraviroc-containing regimen (Saag et al, 2009). In particular, a marked decrease of viremia (close to that achieved in patients carrying R5 virus) at week-12 was observed in patients with a rate of X4-tropic viruses <10% (Swenson et al, 2009).…”

Section: Discussionmentioning

confidence: 80%

HIV-1 dual/mixed tropic isolates show different genetic and phenotypic characteristics and response to maraviroc in vitro

et al. 2011

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“…This was done in order to determine the sensitivity and reproducibility of conventional sequencing results as this nonhomogeneous clinical sample is representative of samples which are the most difficult to detect by conventional sequencing approaches. Samples from the phase 3 clinical trials of maraviroc, the MOTIVATE and A4001029 studies (7,25), which had both population-based sequence data and matched deep-sequencing data (26) in both the forward and reverse direction, were used as a wider data set for comparison (n ϭ 1,521 samples). Two independent samples of peripheral blood mononuclear cells (PBMC) from 39 patients from the MOTIVATE study and from 62 patients from the A401029 study were also sequenced.…”

Section: Methodsmentioning

confidence: 99%

Factors Influencing the Sensitivity and Specificity of Conventional Sequencing in Human Immunodeficiency Virus Type 1 Tropism Testing

et al. 2013

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bHuman immunodeficiency virus type 1 (HIV-1) V3 loop sequence can be used to infer viral coreceptor use. The effect of input copy number on population-based sequencing of the V3 loop of HIV-1 was examined through replicate deep and populationbased sequencing of samples with known tropism, a heterogeneous clinical sample (624 population-based sequences and 47 deep-sequencing replicates), and a large cohort of clinical samples from phase III clinical trials of maraviroc including the MOTIVATE/A4001029 studies (n ‫؍‬ 1,521). Proviral DNA from two independent samples from each of 101 patients from the MOTIVATE/A4001029 studies was also analyzed. Cumulative technical error occurred at a rate of 3 ؋ 10 ؊4 mismatches/bp, without observed effect on inferred tropism. Increasing PCR replication increased minority species detection with an ϳ10% minority population detected in 18% of cases using a single replicate at a viral load of 1,072 copies/ml and in 44% of cases using three replicates. The nucleotide prevalence detected by population-based and deep sequencing were highly correlated (Spearman's , 0.73), and the accuracy increased with increasing input copy number (P < 0.001). Triplicate sequencing was able to predict tropism changes in the MOTIVATE/A4001029 studies for both low (P ‫؍‬ 0.05) and high (P ‫؍‬ 0.02) viral loads. Sequences derived from independently extracted and processed samples of proviral DNA for the same patient were equivalent to replicates from the same extraction (P ‫؍‬ 0.45) and had correlated position-specific scoring matrix scores (Spearman's , 0.75; P Ͻ Ͻ 0.001); however, concordance in tropism inference was only 83%. Input copy number and PCR replication are important factors in minority species detection in samples with significant heterogeneity.

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A Double‐Blind, Placebo‐Controlled Trial of Maraviroc in Treatment‐Experienced Patients Infected with Non‐R5 HIV‐1

Abstract: Clinicaltrials.gov identifier NCT00098748 .

Cited by 128 publications

References 12 publications

Effect of Maraviroc on HIV Disease Progression-Related Biomarkers

Effect of Maraviroc on HIV Disease Progression-Related Biomarkers

HIV-1 dual/mixed tropic isolates show different genetic and phenotypic characteristics and response to maraviroc in vitro

Factors Influencing the Sensitivity and Specificity of Conventional Sequencing in Human Immunodeficiency Virus Type 1 Tropism Testing

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