The MERIT Study of Maraviroc in AntiretroviralNaive Patients With R5 HIV1: 96Week Results

1
The MERIT Study of Maraviroc in
Antiretroviral-Naive Patients With R5 HIV-1
96-Week Results

• Heera J, Ive P, Botes M, DeJesus E, Mayer H,
  Goodrich J, Clumeck N, Cooper D, Walmsley S,
  Craig C, Reeves J, van der Ryst E and Saag M

2
Study A4001026 (MERIT) Phase 3 Trial Design
Double-blind, double-dummy study of 5-year
duration with investigators/patients unblinded
after last patient reached week 96
Randomization 11
Efavirenz (EFV 600 mg QD) Combivir (ZDV3TC)
Maraviroc (MVC 300 mg BID) Combivir (ZDV3TC)
Screening(6 weeks)
0
96 wk
48 wk
First patient visit Nov 2004
Primary analysis

• Patient eligibility criteria
• 16 years of age
• Treatment naive
• R5 HIV-1 infection

• HIV-1 RNA 2,000 copies/mL
• No evidence of resistance to EFV, ZDV, or 3TC

• Patients stratified by
• HIV-1 RNA lt and 100,000 copies/mL at screening
• Geographic location northern hemisphere and
  southern hemisphere

MVC QD arm discontinued at end of phase 2b (week
16) for failure to meet protocol-defined criteria
to continue (205 patients completed 16 weeks)
Patients experiencing toxicity to zidovudine
(ZDV) or lamivudine (3TC) were permitted to
substitute an alternative nucleoside reverse
transcriptase inhibitor (NRTI)
Saag M, et al. 4th IAS 2007 Sydney, Australia.
Abstract WESS104.
3
MERIT Study Enhanced Trofile Reanalysis
(MERIT-ES) Baseline Characteristics Were
Similar to Original MERIT Analysis
Reanalysis of MERIT patients who re-screened
with R5 virus using the more sensitive Trofile
assay (Monogram Biosciences) introduced in 2008
to replace the original assay used for MERIT
enrolment
All patients who received at least one dose of
study medication (modified ITT)
CBV, Combivir (zidovudine lamivudine)
MERIT
MERIT-ES
4
Similar Percentages of Patients Maintained HIV-1
RNA lt 50 Copies/mL Through Week 96
Only patients with an R5 screening result by
enhanced Trofile assay are included
100
90
EFV CBV
MVC CBV
80
70
62.4
60
58.5
Patients lt 50 copies/mL ( )
50
40
30
20
10
0
0
24
48
72
96
12
4
8
16
20
32
40
60
84
Time (weeks)
EFV n 303 279 267 261 249 250 242
238 233 228
213 209 203
203 MVC n 311 293 291 280
278 263 262 253 240
234 227 219
215 210
MERIT-ES
5
Similar Percentages of Patients Achieved lt 50
Copies/mL at Week 96 Overall and by Screening
HIV-1 RNA
Time-to-loss-of-virologic-response (TLOVR)
analysis
100
100
Treatment difference 0.3 Lower bound of
97.5 confidence interval 7.9
90
90
Screening HIV-1 RNA
lt 100,000 copies/mL
100,000 copies/mL
80
80
63.8
70
70
63.4
60.7
60.5
56.7
56.0
60
60
Patients lt 50 copies/mL ( )
Patients lt 50 copies/mL ( )
50
50
40
40
30
30
20
20
10
10
0
0
N 303 311
N 183 177 120
134
Adjusted for randomization strata Includes all
patients with R5 virus at screening by enhanced
Trofile assay who received at least one dose of
study medication missing values classified as
failures/non-responders MERIT-ES per-protocol
analysis (MVCCBV N285 EFVCBV N268) lt 50
copies/mL difference 0.029 (10.7)
MERIT-ES
6
Similar Proportions of Overall Discontinuations
at Weeks 48 and 96 in the Maraviroc and Efavirenz
Arms
Analysis includes all patients who received at
least one dose of study medication
Only patients with an R5 screening result by
enhanced Trofile assay are included 12 of
patients on MVC and 9 on EFV switched to other
NRTI backbones over 96 weeks Includes one death
in the MVC arm at week 48 and two deaths each in
the MVC and EFV arms at week 96 At week 96, 45
patients in each treatment group (15 and 14 in
the EFV and MVC groups, respectively) had
experienced a serious adverse event (compared to
34 11 and 32 10 patients at week 48)
MERIT-ES
7
Similar Proportions of Virologic Responders with
HIV-1 RNA lt 50 copies/mL Through Week 96
TLOVR analysis, censoring all non-responders
(virologic failures, rebounders 50 copies/ml
and discontinuations) over time
MERIT-ES
8
Maraviroc-Treated Patients Showed Significantly
Greater Increases in Mean CD4 Cell Count at
Weeks 48 and 96
41 cells/mm3 (95 CI 17, 65)
250
30 cells/mm3 (95 CI 10, 51)
212
EFV CBV
200
174
171
MVC CBV
144
150
CD4 Cell Changes From Baseline (per mm3)
100
50
0
Week 48
Week 96
Week 48 or 96 mean value adjusted for
randomization strata Last observation carried
forward blinded therapy values only. Includes
all patients with R5 virus at screening by
enhanced Trofile assay who received at least one
dose of study medication
MERIT-ES
9
Incidence of AIDS-Defining Infections at Week 96
Analysis includes all patients who received at
least one dose of study medication
MERIT
10
Malignancies at Week 96
Analysis includes all patients who received at
least one dose of study medication
MERIT
11
Patients at Week 96 Whose Lipid Values On
Treatment Exceeded Cutpoints for Considering
Lipid-Lowering Therapy
Total cholesterol
Triglycerides
LDL cholesterol
200 mg/dL (5.2 mmol/L)
130 mg/dL (3.4 mmol/L)
160 mg/dL (4.1 mmol/L)
200 mg/dL (2.3 mmol/L)
LDL, low-density lipoprotein
At one or more on-study assessments (fasting
lipoprotein profiles were obtained for each
patient at week 24 and week 48, or at early
termination) As defined by NCEP
guidelines P-values are for comparisons of
proportions (Pearsons chi-square test)
MERIT
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MERIT Study 96-Week Summary

• A similar percentage of patients on MVC and EFV
  achieved HIV-1 RNA lt 50 copies/mL at Week 96
• The lower bound of the one-sided 97.5 CI for the
  96-week treatment difference between MVC and EFV
  was above 10 for the lt 50 copies/mL
  time-to-loss-of-virologic-response analysis
• Analysis of percentage of patients with
  undetectable viremia over time continues to show
  only small differences between EFV and MVC
  through week 96 without further separation
  between the two treatment groups
• The difference in CD4 cell count increases
  favoring MVC was maintained through week 96
• In the MERIT-ES reanalysis the percentage of
  patients discontinuing from the study through
  week 96 was similar in the MVC (33.1) and EFV
  (34.0) arms
• Fewer patients experienced malignancies in the
  MVC arm than in the EFV arm
• Maraviroc had a more favorable impact on lipids
  than EFV

MERIT
MERIT-ES