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  • Oral presentation
  • Open Access

O123. Short-term variation of HIV tropism readouts in the absence of CCR5 antagonists

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  • 1,
  • 1,
  • 1,
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Journal of the International AIDS Society201013(Suppl 4):O9

https://doi.org/10.1186/1758-2652-13-S4-O9

Published: 8 November 2010

Keywords

  • Assay Detection
  • Plasma Virus Load
  • Maraviroc
  • A4001029 Study
  • CCR5 Antagonist

Background

Spontaneous tropism changes (from R5 to non-R5 or vice-versa) were observed in approximately 10% of patients between screening and study baseline in the maraviroc (MVC) clinical trials. Little is known of the biology of these apparent short-term tropism fluctuations.

Methods

Population-based and "deep" V3-loop sequencing were performed in 53 MVC recipients in the MERIT, MOTIVATE and A4001029 studies who spontaneously changed tropism readout by the original Trofile assay between screening and baseline (~4-8 weeks) and 72 randomly sampled patients who did not change. Tropism was inferred by "geno2pheno" with previously defined cutoffs: 2% X4 prevalence with a 3.5% false-positive rate (fpr) for "deep" sequencing; 5.75% fpr for population-based sequencing.

Results

Patients changing Trofile readout from R5 to non-R5 had significantly higher screening non-R5 prevalence by "deep" sequencing than those who remained R5, and this increased slightly by the baseline timepoint (Table 1). Similarly, patients who changed tropism from non-R5 to R5 in the A4001029 trial had a lower percentage of non-R5 viruses at screening and baseline. Although there was no difference in total viral load, absolute CXCR4-using plasma virus load was higher in those who changed tropism at screening (2.7 vs. 0 log10 copies/mL, p=0.02 in MERIT; 3.1 vs. 0 log10 copies/mL, p<0.0001 in MOTIVATE) and baseline (3.0 vs. 0 log10 copies/mL, p=0.04 in MERIT; 3.8 vs. 0 log10 copies/mL, p<0.0001 in MOTIVATE). Non-R5 was reported at screening in 26% and 49% of patients who changed phenotype to non-R5 by population and deep-sequencing, respectively.

Table 1

 

# Genotyped

 

Screening X4% [IQR]

  

Baseline X4% [IQR]

  
 

No Change

Changed

No Change

Changed

p

No Change

Changed

p

MERIT

25

13

0 [0-0]

1.9 [0-3.3]

0.01

0 [0-0.1]

7 [0-16.3]

0.04

MOTIVATE

25

32

0 [0-0.1]

2.4 [0.1-21.3]

0.0001

0 [0-0.1]

9.1 [0.4-32.7]

<0.0001

A4001029

22

8

5.0 [0.2-91.5]

1.8 [0.4-30.6]

0.5

4.3 [0-76.6]

0.4 [0-47.5]

0.3

Conclusions

In most cases, the prevalence of non-CCR5 usage inferred from "deep" sequencing was stable over the short term between screening and baseline. Where apparent phenotypic tropism changes from R5 to non-R5 occurred, non-R5 virus was generally detectable at the screening timepoint by genotype, coupled with relatively small increases in non-R5 virus by baseline. Small variations in CXCR4-using HIV populations around the phenotypic assay detection limit, rather than coreceptor switch, contributed to apparent tropism switching from R5 to non-R5.

Authors’ Affiliations

(1)
BC Centre for Excellence in HIV/AIDS, Vancouver, Canada
(2)
ViiV Healthcare, Research Triangle Park, USA
(3)
Pfizer Global R&D, New London, USA
(4)
Pfizer Inc., New York, USA

Copyright

© Brumme et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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