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Weighted Genotypic Score Predicts Response to Maraviroc in MOTIVATE Trials
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7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm
Mark Mascolini
A score based on resistance mutations and type of antiretrovirals given in a salvage regimen predicted response to maraviroc in people enrolled in the MOTIVATE 1 and 2 trials of this CCR5 antagonist [1]. This result reflects findings of an earlier study in which a weighted phenotypic resistance score predicted response to maraviroc [2]. Nearly 80% of MOTIVATE participants randomized to maraviroc had a viral load under 50 copies at trial week 48 if they began treatment with more than 50 CD4s and had a weighted genotypic optimized background therapy susceptibility score (g-wOBTSS) indicating an active background regimen.
The g-wOBTSS ranked a background regimen antiretroviral as active or inactive depending on whether the ANRS genotypic algorithm interpreted mutation patterns as indicating possible resistance, resistance, or sensitivity. Drugs a patient continued from the pre-maraviroc regimen got scored 0, newly taken active nucleosides got scored 0.5, and newly taken active drugs in other classes got scored 1.0. Newly taken PIs for which the ANRS tool predicted possible resistance got scored 0.5. Summing scores for each patient, Charles Boucher and colleagues created three g-wOBTSS groups: less than 1, 1 to less than 2, and 2 or more.
MOTIVATE 1 and 2 enrolled people with CCR5-using HIV-1 who had taken or had resistance to three antiretroviral classes [3]. They got randomized to once- or twice-daily maraviroc or to placebo with an optimized background combination.
The new analysis excluded (1) people classified as nonvirologic failures in MOTIVATE 1 or 2, (2) people whose background regimen changed after trial screening, (3) people who began randomized treatment more than 7 days after their baseline visit, and (4) people with missing genotypic data or incomplete baseline information. As a result, the final analysis included 603 of 1049 MOTIVATE enrollees (57%). A comparison of pre-MOTIVATE virologic and CD4 numbers in the people included in and excluded from the final analysis showed no major differences.
Multivariate analysis in the 603-patient population found seven independent predictors of 48-week virologic success:
· g-wOBTSS 0 vs 2 or higher: odds ratio [OR] 7.2, P < 0.0001
· g-wOBTSS 0 vs 1: OR 2.9, P < 0.0001
· Baseline CD4 count under 50 vs over 200: OR 6.5, P < 0.0001
· Baseline CD4 count under 50 vs 101 to 102: OR 4.3, P < 0.0001
· Baseline CD4 count under 50 vs 50 to 100: OR 2.3, P = 0.043
· Baseline viral load over vs under 100,000: OR 1.8, P = 0.0056
· Placebo vs maraviroc: OR 5.0, P < 0.0001
After 48 weeks of treatment, a higher proportion of people taking maraviroc than placebo had a viral load below 50 copies regardless of g-wOBTSS group. Among people with a g-wOBTSS at or above 2 (those with a good background regimen), 71% in both maraviroc arms had a week-48 viral load below 50 copies, compared with 50% taking placebo. Among people with a g-wOBTSS of 1 to less than 2, more than 60% in each of the maraviroc arms had a 48-week load under 50 copies, compared with 24% in the placebo group.
Beginning the trial regimen with a CD4 count above 50 improved response rates. Among patients with a g-wOBTSS of 2 or more, 78% taking maraviroc once daily and 77% taking maraviroc twice daily had an undetectable viral load at week 48, as did 57% taking placebo. Respective response rates among people in the 1-to-2 g-wOBTSS range were 66%, 62%, and 24%.
Boucher also found that evolution of coreceptor use during the trial depended on background regimen activity. Among maraviroc-treated people, most failures in those with a g-wOBTSS of 2 or more came with CCR5-uing virus. But maraviroc failure in people with a g-wOBTSS below 2 came more often with CXCR4-using virus than with R5 virus.
Analysis of background regimen components in a 617-person viral outcome population determined that 155 people (25%) had no active drugs by g-wOBTSS, 102 (17%) had an active protease inhibitor and nucleoside, 80 (13%) had only an active protease inhibitor, 82 (13%) had only active enfuvirtide, and 65 (11%) had only an active nucleoside.
Boucher and coworkers concluded that g-wOBTSS is a robust predictor of response to maraviroc in the MOTIVATE trials.
References
1. Boucher C, Schapiro J, Llibre J, et al. A genotypic weighted OBT susceptibility score (g-wOBTSS) is a predictor of virological response <50 copies/ml at 48 weeks in Motivate-1 and 2
7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm. Abstract 112.
2. Valdez H, Lewis M, Delongne C, et al. Weighted OBT susceptibility score (wOBTSS) is a stronger predictor of virologic response at 48 weeks than baseline tropism result in MOTIVATE 1 and 2. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), October 25-28, 2008, Washington, DC. Abstract H-1221.
3. Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008;359:1429-1441.
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