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Clinical, Virological, and Immunological Characteristics of Patients With Discordant Phenotypic and Genotypic (Ultra-Deep Sequencing) Tropism Test Results: Analysis of Tropism Calls in MOTIVATE and 1029
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Reported by Jules Levin
International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik, Croatia
D Chapman1, H Valdez1, M Lewis2, I James2, J Heera3, RA McGovern4, LC Swenson4,
PR Harrigan4
1Pfizer Inc, New York, NY, USA; 2Pfizer Global Research and Development, Sandwich, UK; 3Pfizer PGRD New London, CT, USA; 4BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada
- In summary, the majority of patients had concordant original Trofile and deep sequencing tropism results.
- 15.9% of patients with Trofile R5 results were reclassified as non-R5 by genotype. This is similar to the percentage of patients who were reclassified by the enhanced sensitivity Trofile assay in the treatment-naive MERIT study.
- Discordant R5 Trofile samples had significant proportions of non-R5 virus and these patients responded to MVC as poorly as those with concordant non-R5 results
- The small number of patients with discordant R5 results by deep sequencing had better virologic responses than those with non-R5 deep sequencing results.
1. Cooper DA, et al. J Infect Dis 2010; 201:803-813
1. Harrigan PR, et al. 5th IAS 2009. Abs WELBA101.
2.Swenson L, et al. 12th EACS 2009. Abs.PE3.3/2.
- 889 TE patients from the maraviroc Motivate and 1029 studies had paired original Trofile and deep sequencing tropism results available at screening.
- The Motivate studies enrolled patients with R5 virus while the 1029 study enrolled patients with non-R5 virus.
- Deep sequencing was conducted using a 454/Roche instrument using cutpoints that were previously defined by Swenson et al.
- V3 population sequencing data was also assessed in these patients.
1. Swenson L, et al. 12th EACS 2009. Abstract PE3.3/2; 2. Swenson L, et al. 47th IDSA 2009. Abstract 297
- 14 % of patients shown in the orange slice had discordant non-R5 results by Deep sequencing while 15 patients shown in the yellow slice had discordant R5 deep sequencing results
- This color scheme for representing the 4 groups will be continued throughout this presentation.
- This slide summarizes the BL characteristics of patients with concordant results (shown in the first and last columns) and discordant results (shown in the center 2 columns).
- Patient BL characteristics including age, gender, race, clade, and no. of active drugs were broadly similar across these groups.
- However patients with concordant R5 results had the highest baseline CD4+ cell count compared to patients in the other groups.
- The 2 columns to the left describe patients with R5 results by Deep sequencing, while the 2 columns to the right describe patients with non-R5 results by Deep sequencing
1. Valdez H, et al. 48th ICAAC/46th IDSA 2008. Abstract H-1221
- These graphs quantify the amount of non-R5 virus detected by deep sequencing on screening samples
- On the left is shown the absolute log counts of non-R5 virus and on the right is shown the percentages of non-R5 virus by deep sequencing.
- Discordant groups are represented by the 2 bars shown in the center of each graph
- Patients with concordant non-R5 results (shown in the red bars) had the highest proportion of non-R5 virus with a median of 47% non-R5 virus,
- Patients with discordant R5 results by Trofile (shown in the orange bars) also had a high median absolute non-R5 viral load comparable to that of patients with concordant non-R5 virus.
a0 copies/mL (untransformed).
b25th percentile = 0 copies/mL
- This graph splits out Trofile R5 results shown in green bars and Trofile non-R5 results shown in red bars by percent of non-R5 virus detected by deep sequencing shown along the x axis.
- Most (631/784; 80%) Trofile R5 results were associated with <1% non-R5 virus
- The highest proportion of non-R5 Trofile results (38/105; 36%) was seen at levels above 60% CXCR4 use
- Approximately one third (20/58; 34.5%) of samples with non-R5 virus present at levels above 60% returned an R5 Trofile result
aIncludes 7 patients with X4 virus by Trofile
- The majority of discordant Trofile R5 results had between 2-30% non-R5 virus by deep sequencing, while only 4.8% had >30% non-R5 virus.
- All patients with pure X4 virus by Trofile had a concordant non-R5 result, with most (6/7) displaying > 98% non-R5 virus.
- Most (631/784; 80%) Trofile R5 results were associated with <1% non-R5 virus
- The highest proportion of non-R5 Trofile results (38/105; 36%) was seen at levels above 60% CXCR4 use
- Approximately one third (20/58; 34.5%) of samples with non-R5 virus present at levels above 60% returned an R5 Trofile result
aIncludes 7 patients with X4 virus by Trofile
- Population sequencing results shown in the striped bars were highly concordant with Trofile and deep sequencing, with the majority of 80% having concordant results across all three tests.
- When deep sequencing was used as the reference standard for tropism calls, population sequencing detected approximately 13% more non-R5 virus than the original Trofile test.
- This graph shows virologic responses in terms of log change from baseline through 24 weeks
- Patients with concordant R5 results had the strongest virologic responses (shown by the green line),
- while those with non-R5 results by deep sequencing (shown in the red and orange lines) had similarly weaker responses irrespective of their Trofile results.
- The small number of patients with discordant R5 results by deep sequencing (shown in the yellow line) had better virologic responses than those with non-R5 deep sequencing results.
Last-observation-carried-forward
- In summary, the majority of patients had concordant original Trofile and deep sequencing tropism results.
- 15.9% of patients with Trofile R5 results were reclassified as non-R5 by genotype. This is similar to the percentage of patients who were reclassified by the enhanced sensitivity Trofile assay in the treatment-naive MERIT study.
- Discordant R5 Trofile samples had significant proportions of non-R5 virus and these patients responded to MVC as poorly as those with concordant non-R5 results
- The small number of patients with discordant R5 results by deep sequencing had better virologic responses than those with non-R5 deep sequencing results.
1. Cooper DA, et al. J Infect Dis 2010; 201:803-813
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