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Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Treatment-experienced Patients Infected with CCR5-Tropic HIV-1: 48-Week Combined Analysis of the MOTIVATE Studies
David Hardy*1, J Reynes2, I Konourina3, D Wheeler4, S Moreno5, E van der Ryst3, W Towner6, A Horban7, H Mayer8, and J Goodrich8
1David Geffen Sch of Med, Univ of California, Los Angeles, US; 2Univ Hosp of Montpellier, France; 3Pfizer Global R&D, Sandwich, UK; 4Infectious Diseases Physicians, Inc, Annandale, VA, US; 5Hosp Ramon y Cajal, Madrid, Spain; 6Kaiser Permanente, Los Angeles, CA, US; 7Szpital Zakazny Centrum Diagnostyki i Terapii AIDS, Warsaw, Poland; and 8Pfizer Global R&D, New London, CT, US
Background: MOTIVATE
1 (USA, Canada) and MOTIVATE 2 (Europe, Australia, USA) are randomized, double-blind,
placebo-controlled phase III studies assessing the efficacy and safety of
maraviroc (MVC), a recently approved oral CCR5 antagonist, in treatment-experienced
patients with CCR5-tropic HIV-1. In both studies, MVC + optimized background
therapy (OBT), (once-daily/twice-daily) demonstrated significantly greater
virologic and immunologic efficacy and a similar safety profile compared with placebo+OBT
in the week-48 primary analysis. A planned analysis of pooled data from the 2
studies was conducted.
Methods: Patients with triple drug-class experience
or triple-class resistance, R5 virus, and HIV-1 RNA ≥5000 copies/mL were
randomized 2:2:1 to MVC once-daily or twice-daily +OBT (3 to 6 antiretrovirals ±
low-dose ritonavir; darunavir/r not permitted) or placebo+OBT. Efficacy endpoints
at week 48 included change from baseline (mean of all pre-dose assessments) in
HIV-1 RNA and CD4+ cell count, and proportion of subjects achieving <50
and <400 copies/mL. Superior virologic and immunologic efficacy of each MVC+OBT group vs placebo +OBT was demonstrated. Pooled analysis revealed no new or unique safety
findings at 48 weeks. Discontinuations due to adverse events, serious adverse
events, and laboratory abnormalities (including grade-3 or -4 transaminase
elevations) occurred with similar frequency between treatment groups. Category
C (AIDS-defining) events were also balanced across treatment groups.
Results:
|
Week 48
|
Placebo+OBT
(n = 209)
|
MVC Once-daily+OBT
(n = 414)
|
MVC Twice-daily+OBT
(n = 426)
|
|
Mean change in viral load from
BL† (log10 copies/mL)
Treatment difference vs placebo
(97.5%CI)
|
–0.78
N/A
|
–1.68
–0.89
(–1.17, –0.62)
|
–1.84
–1.05
(–1.33, –0.78)
|
|
% <400 copies/mL
p value vs placebo
|
22.5%
N/A
|
51.7%
<0.0001
|
56.1%
<0.0001
|
|
% <50 copies/mL
p value vs placebo
|
16.7%
N/A
|
43.2%
<0.0001
|
45.5%
<0.0001
|
|
Mean change in CD4+ from baseline‡
(cells/mm3)
p value vs placebo
(95%CI)
|
+61 (n = 206)
N/A
|
+116 (n = 407)
<0.0001
(+36, +74)
|
+124 (n = 418)
<0.0001
(+44, +82)
|
|
Discontinuations due to adverse events, n (%)
|
11 (5.3%)
|
24 (5.8%)
|
21 (4.9%)
|
|
Deaths§, n (%)
|
2¶ (1.0%)
|
6 (1.4%)
|
9 (2.1%)
|
†Discontinuations=no change from baseline
‡Last observation carried forward
§No deaths related to study drug according to
investigators
¶One patient received open-label MVC prior to death
Conclusions: MVC+OBT demonstrated statistically
greater efficacy and similar safety compared with placebo+OBT in this pooled week
48 analysis. These results demonstrate that treatment with MVC+OBT provides sustained antiretroviral efficacy and tolerability in treatment-experienced
patients with R5 virus.
|
