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48-Week Safety and Efficacy of Maraviroc in Combination with Optimized Background Therapy (OBT) for the Treatment of Antiretroviral-Experienced Patients Infected with Dual/Mixed-Tropic HIV-1
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Reported by Jules Levin
45th IDSA
San Diego, USA, October 4-7, 2007
Late Breaker
JM Goodrich1, M Saag2, E van der Ryst3, G Fatkenheuer4, B Clotet5, N Clumeck6, J Sullivan3, M Westby3, and H Mayer1
1Pfizer Global Research and Development, New London, USA; 2University of Alabama at Birmingham, USA; 3Pfizer Global Research and Development, Sandwich, UK; 4University of Cologne, Cologne, Germany; 5University Hospital Germans Trias i Pujol, Barcelona, Spain; 6St Pierre University Hospital, Brussels, Belgium
AUTHOR Summary of 48-Week Analysis
48-week results were consistent with 24-week findings:
Maraviroc (BID or QD) + OBT was generally well tolerated
-- The safety profile of MVC + OBT was similar to PBO + OBT
-- No new or unique safety findings emerged
-- Maraviroc + OBT was not associated with an increase in LFT abnormalities, Category C events, malignancies, discontinuations due to AEs, or deaths compared to PBO + OBT
--There was no evidence at Week 48 of an adverse effect on viral load or CD4+ cell counts when MVC (QD or BID) was added to OBT, compared to PBO + OBT, in treatment-experienced patients with D/M-tropic HIV-1 and advanced disease
BACKGROUND
Maraviroc, a CCR5 antagonist, is active against R5 but not X4 or dual-tropic HIV_1
A4001029 is a double-blind, placebo-controlled, Phase 2b study investigating the safety and efficacy of maraviroc in treatment-experienced patients with non-R5 HIV-1
At 24 weeks1, in treatment-experienced patients with D/M-tropic HIV-1 and advanced disease:
-- Maraviroc + OBT was generally well tolerated
-- HIV-1 RNA changes were not significantly different between either MVC + OBT group and PBO + OBT
-- Maraviroc + OBT was associated with greater increases in CD4+ cell count than PBO + OBT
OBT = optimized background therapy of 3-6 ARVs (PK boosting doses of RTV not counted as an ARV
D/M = dual/mixed
1. Mayer H et al. XVI IAC 2006; Abstract THLB0215
A4001029: Phase 2b Pilot Study Evaluating the Safety of Maraviroc in Patients with Non-R5 HIV-1. STUDY DESIGN
Patients randomized to MVC 150mg bid + OBT, MVC 150mg QD + OBT, or placebo + OBT.
Patient eligibility criteria:
• X4 or D/M-tropic HIV-1, or indeterminate tropism due to repeated assay failure
• At least one active drug in OBT
• HIV-1 RNA ≥5,000 copies/mL
• Stable pre-study ARV regimen, or no ARVs for ≥ 4 weeks
• Dual-class resistance and/or ≥ 3 months' experience with ≥ one ARV from three classes
Baseline Characteristics
Includes all treated patients with non-R5 virus at screening who received at least one dose of study medication
Baseline Characteristics-Primary Study Population
Includes all treated patients with D/M-tropic virus at screening who received at least one dose of study medication.
--Median CD4 count: 42 across all 3 arms; mean viral load: 5.01 log in placebo (100,000 c/ml); 5.03 log in MVC qd; 5.10 in MVC bid. Fuzeon use: n=30 (56%) in placebo; n=35 (61%) in MVC qd; n=29 (56%) in MVC bid. 2 or less active HIV drugs in OBT: n=30 (52%) in placebo; n=41 (72%) in MVC qd; n=27 (52%) in MVC bid.
Data missing for four patients
Data missing for one patient in each treatment group
Mean Change in HIV-1 RNA from Baseline
Week 24:
-0.97 log - placebo
-0.91 log - MVC qd
-1.20 log - MVC bid
Week 48:
-0.84 log - placebo
-0.62 log - MVC qd
-1.11 log - MVC bid
HIV-1 RNA value imputed as baseline if patient discontinued before 48 weeks
*Treatment difference vs PBO + OBT
1. Mayer H, et al. IAC 2006; Abstract THLB0215
Percentage of Patients with Undetectable HIV-1 RNA Over 48 Weeks (Jules: there is no difference in viral load changes between placebo & MVC arms although MVC bid appears to perform better than both other arms)
MVC bid: 31% <400 copies and 27% <50 c/ml at weeks 24 and 48; no change in % <400 or <50 between weeks 24 & 48.
MVC qd: 25% <400 at week 24 and 21% at week 48; 21% <50 at week 24 and 18% at week 48.
Placebo: 24% <400 at week 24 and 22% at week 48; 16% <50 at week 24 and 18% <50 at week 48.
HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 48 weeks
* MVC QD + OBT; PBO + OBT
Subjects with Viral Load <400 copies/mL and <50 copies/mL at Week 48 by OSS* at Screening
(Jules: There is no difference in this table between placebo and MVC arms).
*OSS - overall susceptibility score, a reflection of the number of active drugs in the OBT.
Patients with OSS of 0 did not do well: 0% <400 or <50.
Patients with OSS of 1: 0 on placebo had <400 or <50 while patients on MV qd had 11% (2/19) <400 and 5% (1/19) <50; patients on MVC bid: 9% (1/11) had <400 & 0 (0/11) <50.
Patients with OSS of 2: 38% (5/13) on placebo had <400 & 38% (5/13) had <50; patients on MVC qd: 38% (8/21) had <400 and 24% <50; MVC bid: 43% (6/14) had <400 & 33% (8/24) <50.
Patients with OSS of 3 or more did not do as well, this happened in Merck integrase study too (patients numbers small), patients with OSS of 3 didn't do as well as patients with OSS of 2. Placebo: 36% (9/25) <400 & 32% <50; MVC qd: 33% (5/15) had <400 & 33% <50; MVC bid: 38% (9/24) <400 & 33% (8/24) <50.
Mean Change from Baseline in CD4+ Count
(Jules: CD4 increases at weeks 24 and 48 were greater for MVC groups than placebo)
Mean CD4 increase in placebo group was +36 at week 24 and +51 at week 48. Meand CD4 increases were +60 & +62 for MVC qd & MVC bid at weeks 24 & 48. And for MVC bid CD4 increases were +62 and +78 at weeks 24 & 48.
Last observation carried forward
*Treatment difference vs PBO + OBT
Data missing for four patients
1. Mayer H, et al. IAC 2006; Abstract THLB0215
Summary of Week 48 Safety Results
There are no differences between placebo & MVC arms in any category listed below including malignancies (2% in each group)except 'patients with Category C events: 3% placebo; 8% MVC qd, 7% MVC bid.
No deaths or malignancies were related to study drug according to the investigator
Number of Category C Events
Numbers of patients with Category C events: 2 patients (3.2%) on placebo: 1 encephalitis; 1 candidiasis; 5 patients (7.9%) on MVC qd: 1 cytomegalovirus chorietinitis; 3 pneumocystis jiroveci pneumonia; 4 patients (6.6%) on MVC bid: 3 with candidiasis; 1 pneumonia.
--No Category C malignancies (Kaposi's sarcoma or Hodgkin's lymphoma) were reported
--Patients who experienced a Category C event had a lower median CD4+ count and slightly higher median HIV-1 RNA at baseline vs those who did not
Incidence of Adverse Events Occurring in ≥10% of Patients in Any Group, Unadjusted for Exposure (Jules: no apparent real differences between placebo and MVC groups).
Maximum Liver Function Test Values Over 48 Weeks Without Regard to Baseline
(Jules: no differences in grade 3 and 4 ALT, AST and bilirubin events between study arms).
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