MAJOR ARTICLE
A Double-Blind, Placebo-Controlled Trial of
Maraviroc in Treatment-Experienced Patients
Infected with Non-R5 HIV-1
Michael Saag,1 James Goodrich,2 Gerd Fätkenheuer,3 Bonaventura Clotet,4 Nathan Clumeck,5 John Sullivan,6
Mike Westby,6 Elna van der Ryst,6 and Howard Mayer,2 for the A4001029 Study Group
1
School of Medicine, University of Alabama, Birmingham; 2Pfizer Global Research and Development, New London, Connecticut; 3Universitätsklinik
Köln, Köln, Germany; 4Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, Spain; 5Le Centre Hospitalier Universitaire St-Pierre,
Brussels, Belgium; and 6Pfizer Global Research and Development, Sandwich, United Kingdom
Background. Maraviroc, a CCR5 antagonist, is active against R5 but not X4 or dual- or mixed-tropic strains of human
immunodeficiency virus type 1 (HIV-1). A phase 2b study was conducted to determine the safety and efficacy of maraviroc in
combination with optimized background therapy in treatment-experienced patients infected with dual- or mixed-tropic HIV-1.
Methods. Treatment-experienced patients with an HIV-1 RNA level 肁5000 copies/mL who had received 肁3
classes of drugs and/or were infected with virus resistant to 2 drug classes and were infected with non-R5 HIV-1 were
randomized to receive optimized background therapy plus maraviroc (once or twice daily) or placebo. The primary
end point was change in HIV-1 RNA level from baseline to 24 weeks.
Results. Among 167 patients infected with dual- or mixed-tropic HIV-1, baseline mean HIV-1 RNA levels were
⬎5 log10 copies/mL and median CD4⫹ cell counts were ⬍50 cells/␮L. From baseline to 24 weeks, patients who
received placebo demonstrated a mean decrease in HIV-1 RNA levels of 0.97 log10 copies/mL, compared with mean
decreases of 0.91 and 1.20 log10 copies/mL for those who received maraviroc once (P ⫽ .83) or twice (P ⫽ .38) daily,
respectively. Mean increases in CD4⫹ cell counts from baseline were 36 cells/␮L for patients who received placebo, 60
cells/␮L among patients who received maraviroc once daily, and 62 cells/␮L among patients who received maraviroc
twice daily. The incidences of serious adverse events were similar among groups.
Conclusions. In this exploratory study involving extensively treatment-experienced patients with advanced,
non-R5 HIV-1 infection, neither superiority nor noninferiority was statistically demonstrated for either maraviroc
dosage compared with placebo at 24 weeks of treatment.
Trial registration. Clinicaltrials.gov identifier NCT00098748.
Human immunodeficiency virus type 1 (HIV-1) strains
are categorized as R5 (CCR5 tropic), X4 (CXCR4
tropic), or R5X4 (dual-tropic strains that use both CCR5
Received 16 July 1008; accepted 22 December 2008; electronically published
7 May 2009.
Potential conflicts of interest: M.S. has received consultancy fees from Avexa,
Boehringer-Ingelheim, Bristol Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp
and Dohme, Monogram Biosciences, Panacos, Pfizer, Progenics, Roche, Tibotec, and
Virco and has received grant support from Achillion Pharmaceuticals, BoehringerIngelheim, Gilead Sciences, GlaxoSmithKline, Merck Sharp and Dohme, Panacos,
Pfizer, Progenics, Roche, Serono, and Tibotec. J.G. is an employee of Pfizer. G.F. has
received consultancy fees from Gilead, GlaxoSmithKline, Monogram, Pfizer, Roche,
Schering-Plough, Tibotec, and Bristol Myers Squibb; has received lecture fees from
Abbott, Boehringer-Ingelheim, Bristol Myers Squibb, Gilead, GlaxoSmithKline, Merck
Sharp and Dohme, Pfizer, Schering-Plough, and Tibotec; and has received grant support
from Pfizer. B.C. has received consultancy fees from Janssen, Merck Sharp and Dohme,
Gilead, and Bristol Myers Squibb and has received lecture fees from Janssen, Merck
Sharp, and Dohme and Gilead. N.C. has received consultancy fees from Gilead, Pfizer,
Abbott, and Merck Sharp and Dohme. J.S., M.W., E.v.d.R., and H.M. are employees of
Pfizer and hold stock options in Pfizer.
The Journal of Infectious Diseases 2009; 199:1638 – 47
© 2009 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2009/19911-0012$15.00
DOI: 10.1086/598965
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Saag et al.
and CXCR4) [1]. Patients infected with dual- or mixedtropic HIV-1 harbor a mixture of R5, X4, and/or dualtropic viruses [1]. Most extensively antiretroviralexperienced patients continue to be infected with only
R5 virus [2– 4].
CCR5 antagonists only inhibit R5 strains; X4 and
R5X4 strains (i.e., CXCR4-using strains) can infect cells
in the presence or absence of a CCR5 antagonist. Maraviroc, an oral CCR5 antagonist, has demonstrated potent activity in vitro and in vivo against R5 HIV-1, including variants that are resistant to multiple drug
classes [5, 6]. Analyses from 2 phase 3 studies of maraviroc involving treatment-experienced patients infected
Presented in part: XVI International AIDS Conference, Toronto, Canada, 13–18
August 2006 (presentation THLB0215).
Financial support: Pfizer Global Research and Development. Editorial support
was provided by Health Interactions and was funded by Pfizer.
Reprints or correspondence: Michael S. Saag, MD, Director of AIDS Outpatient
Clinic, University of Alabama at Birmingham School of Medicine, 908 20th St. S.,
Birmingham, AL 35294 –2050 ([email protected]).
with R5 virus have clearly demonstrated efficacy and safety during 48 weeks of treatment [7, 8]. Evaluation of the safety of a
CCR5 antagonist in patients infected with a mixture of viruses
that may include CXCR4-using variants is important, because
such patients could inadvertently receive a CCR5 antagonist. We
present results from a study evaluating the safety of maraviroc
treatment in patients infected with non-R5 virus and the efficacy
of maraviroc in patients infected with dual- or mixed-tropic virus.
METHODS
Study design and conduct. A4001029 is a randomized,
placebo-controlled, double-blind, phase 2b trial with a primary
end point at 24 weeks conducted at 76 centers in Australia, Europe, Canada, and the United States. Patients were excluded
from the study if they had only R5 HIV-1 detected during
screening (which was performed using the original Trofile assay
[Monogram Biosciences]). Eligibility criteria included HIV-1
RNA level 肁5000 copies/mL, resistance to 肁2 antiretroviral
drug classes approved at the time of study initiation (i.e., nucleoside analogues, nonnucleoside reverse-transcriptase inhibitors,
protease inhibitors, and fusion inhibitors) or 肁3 months experience receiving 肁1 agent from 3 of these drug classes, and detection of X4 or dual- or mixed-tropic HIV-1 or indeterminate
tropism at screening (indeterminate tropism was defined as assay results that failed to determine tropism in 3 consecutive tests
of the same specimen). Patients were excluded if, on the basis of
resistance testing results, enfuvirtide or 肁1 nonnucleoside
reverse-transcriptase inhibitors or protease inhibitors were not
available as active treatment options. Other criteria were identical to those of the MOTIVATE studies [7], as were the study
design, conduct, monitoring, and statistical analyses, except as
indicated. Written informed consent was obtained from all patients, and the protocol was approved by institutional review
boards or independent ethics committees at all study centers.
Patients were randomized 1:1:1 to receive maraviroc at 300
mg once daily, maraviroc at 300 mg twice daily, or placebo; all
patients received a selected optimized background therapy that
included 3– 6 antiretroviral drugs (with or without low-dose
ritonavir). Patients who were currently receiving potent
CYP3A4 inhibitors, such as protease inhibitors (excluding tipranavir) or delavirdine, received 150-mg doses of maraviroc.
After initiation of study treatment (baseline), study visits were
scheduled at weeks 4, 8, 16, 24, 32, 40, and 48. In addition to
measurement of CD4⫹ and CD8⫹ cell counts and HIV-1 RNA
level, study evaluations included physical examination; assessment of vital signs, symptoms, and adverse events; serum chemistry and hematology measurements; and review of concomitant
medications. A plasma sample was collected for determination
of HIV-1 coreceptor tropism from patients who experienced
protocol-defined treatment failure, from patients who had
HIV-1 RNA levels ⬎500 copies/mL at weeks 4, 8, 16, 32, and 40,
and from patients who discontinued treatment. HIV-1 RNA was
isolated from plasma for drug resistance testing only for patients
who experienced protocol-defined treatment failure. A fasting
metabolic assessment (i.e., measurement of total cholesterol,
high-density liprotein, low-density lipoprotein, triglycerides,
glucose, and glycosylated hemoglobin levels), 12-lead electrocardiogram, and orthostatic blood-pressure monitoring were
performed at baseline and at weeks 24 and 48, or at discontinuation.
Treatment failure was prospectively defined as reaching 肁1 of
the following 4 HIV-1 RNA measurement end points (confirmed by consecutive measurements meeting the end point
within 14 days): (1) an increase in HIV-RNA level to 肁3 times
baseline level, at or after week 2; (2) a decrease in HIV-1 RNA
level from baseline of ⬍0.5 log10 copies/mL, at or after week 8;
(3) a decrease in HIV-1 RNA from baseline of ⬍1.0 log10 copies/mL at or after week 8 in a patient who had previously
achieved a decrease from baseline of 肁2.0 log10 copies/mL; or (4)
an increase in HIV-1 RNA level to 肁5000 copies/mL in a patient
who had previously had levels ⬍400 copies/mL on 2 consecutive
visits. Subjects who discontinued treatment because of treatment failure or for other reasons were followed up according to
the study protocol until week 48.
The primary end point was the change in HIV-1 RNA level
(measured as log10-transformed copies/mL) in plasma from
baseline to 24 weeks. Secondary efficacy end points were identical to those used in the MOTIVATE studies [7]. For the primary
end point, the differences in least-square mean HIV-1 RNA levels and a 2-sided 97.5% confidence interval (CI) between groups
are presented. For secondary efficacy end points, 2-sided 95%
CIs between groups are presented. This study was part of a regulatory submission; therefore, the primary end point was adjusted for multiple comparisons to maintain an overall significance level of .05. Safety data were analyzed through 肁24 weeks
for all patients who received 肁1 dose of study medication, regardless of the result of HIV-1 tropism screening, with use of
methodologies identical to those used in the MOTIVATE studies [7]. Data were collected and analyzed by the study sponsor
according to a predefined statistical analysis plan and were reviewed periodically by a data and safety monitoring board.
Statistical analysis. The primary efficacy population included all randomized patients infected with dual- or mixedtropic HIV-1 at screening who received 肁1 dose of study medication. Based on the assumption that 79% of patients with
non-R5 virus would have dual- or mixed-tropic HIV-1 (the remainder having an X4 tropism result or an indeterminate tropism result), ⬃192 patients would have to be randomized to
include 150 patients infected with dual- or mixed-tropic HIV-1
in the study. Assuming a standard deviation of 0.8 with a 2-sided
significance level of .025 (using Bonferroni adjustment for multiple comparisons) and assuming 50 patients infected with dual-
Maraviroc in Patients with Non-R5 HIV Infection
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1639
or mixed-tropic HIV-1 per treatment group, there was 80%
power to detect a difference in HIV-1 RNA level (the primary
efficacy end point) of 0.5 log10 copies/mL between each maraviroc arm and the placebo arm. Using the same assumptions about
the study population with a 1-sided significance level of .0125
and assuming that maraviroc treatment groups would demonstrate decreases in HIV RNA levels that were 0.25 log10 copies/mL greater than that demonstrated by the placebo group,
there was 80% power to demonstrate noninferiority with a margin of 0.25 log10 copies/mL. An analysis of covariance model was
used, with HIV-1 RNA level at screening (randomization stratification factor), enfuvirtide use as part of optimized background therapy (randomization stratification factor), and treatment arm as the main effects. Efficacy data were analyzed using
an intention-to-treat approach. Change from baseline was imputed as 0 for patients who discontinued treatment for any reason and for patients for whom a baseline value was missing.
Further sensitivity analyses were performed using the primary
end point, including analysis with a last-observation-carriedforward approach to discontinuations and a nonparametric
analysis in which patients who discontinued treatment were
ranked lower than those who completed treatment.
The percentage of patients with an undetectable viral load
(⬍50 copies/mL) was summarized for the primary efficacy population; values for patients who had missing data or who discontinued treatment were imputed as 0. Subgroup analyses of the
proportion of patients with undetectable viral load, according to
randomization stratification criteria and by overall susceptibility
score at screening, were also conducted, imputing values of 0 for
patients who had missing data or discontinued treatment.
Least-squares mean change in CD4⫹ cell count from baseline
was analyzed using an analysis of covariance model, with baseline CD4⫹ cell count, enfuvirtide use, and treatment arm as the
main effects, and using a last-observation-carried-forward approach. Further sensitivity analyses were performed on CD4⫹
cell count data, including an analysis that imputed values of 0 for
patients for whom data was missing or who discontinued treatment.
Time to protocol-defined treatment failure was summarized
using Kaplan-Meier curves. The difference between each of the
maraviroc arms and the placebo arm was analyzed using a stratified log-rank test.
RESULTS
Study population. Of 190 patients who were randomized, 186
received 肁1 dose of study medication (figure 1). Demographic
and baseline clinical characteristics were similar across treatment arms (table 1). Mean time since receipt of HIV diagnosis
was 13.5 years (range, 2.2–23.8 years); 57 (31%) of 186 patients
had previously received enfuvirtide, and the median baseline
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Saag et al.
CD4⫹ cell count was ⬍50 cells/␮L, which is indicative of a population with advanced HIV infection.
At screening, 167 (90%) of 186 patients who had received 肁1
dose of study drug were infected with dual- or mixed-tropic
HIV-1 (the primary efficacy population). In addition, 1 patient,
who was randomized in error, had only R5 HIV-1 detected at
screening, and the remainder had either an X4 tropism result or
an indeterminate tropism result (table 1). Of the 167 patients in
the primary efficacy population, 98 (59%) had a overall susceptibility score of 聿2 at screening, and 94 (56%) received enfuvirtide as part of optimized background therapy.
Premature discontinuation and treatment duration. Among
the 186 patients who were randomized and treated, 38 (61%) of 62
patients in the placebo arm, 38 (60%) of 63 patients in the maraviroc once-daily arm, and 32 (52%) of 61 patients in the maraviroc
twice-daily arm discontinued study treatment (maraviroc or placebo) by week 24, which was the primary efficacy analysis timepoint. The most common reason for discontinuation in all groups
was lack of efficacy (determined by the investigator, guided by the 4
prespecified criteria for treatment failure). At week 24, the median
duration of treatment was 127 days for patients who received placebo, compared with 119 days for patients who received maraviroc
once daily and 176 days for patients who received maraviroc twice
daily. Time to protocol-defined treatment failure was not significantly different among groups (maraviroc once daily vs. placebo,
P ⫽ .75; maraviroc twice daily vs. placebo, P ⫽ .25) (figure
2A).
Efficacy. The least-squares mean HIV-1 RNA level in
plasma from baseline to week 24 decreased 0.97 log10 copies/mL
in the placebo group, 0.91 log10 copies/mL in the maraviroc
once-daily group (difference vs. placebo, 0.06 log10 copies/mL;
97.5% CI, ⫺0.53 to 0.64 log10 copies/mL; P ⫽ .83), and 1.20
log10 in the maraviroc twice-daily group (difference vs. placebo,
⫺0.23 log10 copies/mL; 97.5% CI, ⫺0.83 to 0.36 log10 copies/mL;
P ⫽ .38) (table 2). The statistical analysis did not indicate superiority or noninferiority for either maraviroc dosage, compared
with placebo. Results at week 48 were similar; mean HIV-1 RNA
levels decreased 0.84 log10 copies/mL in the placebo group, 0.62
log10 copies/mL in the maraviroc once-daily group (difference
vs. placebo, 0.23; 97.5% CI, ⫺0.35 to 0.81 log10 copies/mL), and
1.11 log10 copies/mL in the maraviroc twice-daily group (difference vs. placebo, ⫺0.26 log10 copies/mL; 97.5% CI, ⫺0.86 to 0.33
log10 copies/mL).
The sensitivity analyses yielded findings similar to those of the
primary analysis. Using the last-observation-carried-forward
approach, the least-squares mean HIV-1 RNA level in plasma
from baseline to week 24 decreased 1.20 log10 copies/mL in the
placebo group, 1.18 log10 copies/mL in the maraviroc once-daily
group (difference vs. placebo, 0.020 log10 copies/mL; 97.5% CI,
⫺0.539 to 0.579 log10 copies/mL), and 1.50 log10 copies/mL in
the maraviroc twice-daily group (difference vs. placebo, ⫺0.298
log10 copies/mL; 97.5% CI, ⫺0.870 to 0.273 log10 copies/mL).
Figure 1. Disposition of study participants at 24 weeks (primary efficacy analysis timepoint). *Number of patients who had a dual- or mixed-tropic
HIV-1 tropism result at screening (primary efficacy population). †Lack of efficacy as determined by the investigator, but guided by the 4 prespecified
criteria for treatment failure (see Methods for details). ‡A total of 7 deaths were recorded during the study, but only 5 of these deaths were listed by
investigators as the reason for discontinuation of study treatment.
The results of a sensitivity analysis that used a stratified Wilcoxon test, with patients who discontinued treatment ranked
below those who completed treatment, were consistent with the
results of the primary analysis.
A slightly higher proportion of patients in the maraviroc
twice-daily arm (14 [27%] of 52) achieved undetectable viremia
(HIV-1 RNA level ⬍50 copies/mL) at 24 weeks, compared with
12 [21%] of 57 patients in the maraviroc once-daily and 9 (16%)
of 58 patients in the placebo group; however, these differences
were not statistically significant (table 2; figure 2B). Similar results were observed at 48 weeks, with 27% of patients in the
maraviroc twice-daily arm, 18% of patients in the maraviroc
once-daily arm, and 22% of patients in the placebo arm achieving undetectable HIV-1 RNA levels.
The proportion of patients whose optimized background
therapy included enfuvirtide and who achieved undetectable viremia at 24 weeks was somewhat greater in the once- and twicedaily maraviroc arms (7 [20%] of 35 and 7 [24%] of 29 patients,
respectively) than in the placebo arm (3 [9%] of 34 patients),
although the numbers were small and statistically significant differences were not observed. Similarly, when analyzed by HIV-1
RNA level at screening, a somewhat greater proportion of patients with a lower viral load at screening (⬍100,000 copies/mL)
who were randomized to receive maraviroc achieved a viral load
⬍50 copies/mL at 24 weeks (7 [27%] of 26 and 8 [35%] of 23
patients in the once- and twice-daily arms, respectively), compared with those who received placebo (4 [15%] 26 patients).
The percentage of patients with HIV-1 RNA levels 肁100,000
copies/mL at screening who achieved HIV-1 RNA levels ⬍50
copies/mL ranged from 16%–17% in the maraviroc once-daily
and placebo groups to 21% in the maraviroc twice-daily group.
Just 1 patient with a overall susceptibility score ⬍2 at screening
(in the maraviroc once-daily group) achieved undetectable viremia
at week 24. The proportions of patients with an overall susceptibility
score of 2– 4 who achieved undetectable viremia were slightly
greater in the maraviroc once- and twice-daily groups (11 [31%] of
35 and 14 [36%] of 39 patients, respectively), compared with the
placebo group (9 [23%] of 40 patients).
Maraviroc in Patients with Non-R5 HIV Infection
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1641
Table 1.
Demographic and baseline clinical characteristics of all patients who received 肁1 dose of study medication.
Treatment group
Characteristic
All treated patients
No. of patients
Age, mean years (range)
Male sex
Racea
White
Black
Asian
Other
Duration since diagnosis of HIV-1 infection,
mean years (range)
Prior enfuvirtide experience
HIV-1 tropism at screening
Not phenotyped or not reported
R5
X4
Dual or mixed tropism
Treated patients with dual- or mixed-tropic HIV-1
at screening
No. of patients
HIV-1 RNA load,b mean log10 copies/mL
CD4⫹ cell count,b median cells/␮L
HIV-1 RNA level at screening
⬍100,000 copies/mL
肁100,000 copies/mL
Genotypic susceptibility score at screening
0
1
2
肁3
Missing
Phenotypic susceptibility score at screening
0
1
2
肁3
Missing
Overall susceptibility score at screeningd
0
1
2
肁3
Missing
PI and/or delavirdine in OBTe
Enfuvirtide in OBT
Placebo
Maraviroc once daily
Maraviroc twice daily
62
45 (23–65)
53 (85.5)
63
43 (16–59)
53 (84.1)
61
43 (16–62)
55 (90.2)
40 (64.5)
18 (29.0)
3 (4.8)
1 (1.6)
46 (73.0)
17 (27.0)
0 (0.0)
0 (0.0)
44 (72.1)
13 (21.3)
1 (1.6)
3 (4.9)
12.9 (2.2–20.3)
22 (35.5)
13.8 (6.0–20.9)
18 (28.6)
13.8 (5.2–23.8)
17 (27.9)
2 (3.2)
0 (0.0)
2 (3.2)
58 (93.5)
3 (4.8)
1 (1.6)
2 (3.2)
57 (90.5)
5 (8.2)
0 (0.0)
4 (6.6)
52 (85.2)
58
5.01
41.5
57
5.03
39.5
52
5.10
43.1
25 (46.3)c
29 (53.7)c
26 (45.6)
31 (54.4)
23 (44.2)
29 (55.8)
4 (6.9)
19 (32.8)
7 (12.1)
27 (46.6)
1 (1.7)
5 (8.8)
30 (52.6)
12 (21.1)
9 (15.8)
1 (1.8)
6 (11.5)
18 (34.6)
10 (19.2)
17 (32.7)
1 (1.9)
2 (3.4)
13 (22.4)
11 (19.0)
31 (53.4)
1 (1.7)
0 (0.0)
12 (21.1)
23 (40.4)
21 (36.8)
1 (1.8)
2 (3.8)
6 (11.5)
13 (25.0)
30 (57.7)
1 (1.9)
2 (3.4)
15 (25.9)
13 (22.4)
27 (46.6)
1 (1.7)
53 (98.1)f
30 (55.6)f
1 (1.8)
19 (33.3)
21 (36.8)
15 (26.3)
1 (1.8)
52 (91.2)
35 (61.4)
2 (3.8)
11 (21.2)
14 (26.9)
24 (46.2)
1 (1.9)
48 (92.3)
29 (55.8)
NOTE. Data are no. (%) of patients, unless otherwise indicated. All patients received optimized background therapy (OBT) in addition to study
medication. HIV, human immunodeficiency virus, PI, protease inhibitor.
a
Patients of Hispanic or Latino ethnicity (15.6% of patients) could be included in any of the 3 racial designation groups included in this table.
Baseline values for each patient were calculated on the basis of up to 3 measurements made before administration of study medication (i.e.,
at screening, randomization, and baseline visit).
c
HIV-1 RNA level stratification data were missing for 4 patients.
d
Susceptibility score was based on an algorithm that assigns a net assessment of phenotypic and genotypic information for each OBT
medication with use of a binary system.
e
The maraviroc dose was 150 mg for patients who were concurrently receiving a PI (excluding tipranavir) and/or delavirdine as part of their
OBT; otherwise, the maraviroc dose was 300 mg. Only data for patients receiving a PI other than tipranavir are included.
f
Data were missing for 4 patients.
b
1642
Figure 2. Treatment response in the primary efficacy population (i.e., all patients with dual- or mixed-tropic virus who received 肁1 dose of study
medication) over 24 weeks (primary efficacy analysis timepoint). A, Kaplan-Meier plot of time to protocol-defined treatment failure. HIV-1 RNA value
from baseline was imputed if data were missing or if patient discontinued before 24 weeks. B, Proportion of patients with HIV-1 RNA levels ⬍50
copies/mL. C, Mean change in CD4⫹ cell count from baseline (using last-observation-carried-forward approach). OBT, optimized background therapy.
1643
Table 2. Efficacy at 24 weeks (primary efficacy analysis timepoint) in patients infected with dual- or mixed-tropic human immunodeficiency virus type 1 (HIV-1) at screening (primary efficacy population).
Treatment group
Difference (95% CI)
Variable
Change from baseline in plasma HIV-1
RNA level, least-squares mean
log10 copies/mLa
HIV-1 RNA level ⬍50 copies/mL,
% of patientsc
Change in CD4⫹ cell count,
least-squares mean cells/␮Ld
All patients
Patients receiving blinded
therapy at week 24e
Patients who discontinued
because of treatment failuref
Placebo
(n ⫽ 58)
Maraviroc
once daily
(n ⫽ 57)
Maraviroc
twice daily
(n ⫽ 52)
Maraviroc once
daily vs. placebo
P
Maraviroc twice
daily vs. placebo
P
⫺0.97
⫺0.91
⫺1.20
0.06 (⫺0.53 to 0.64)b
.83
⫺0.23 (⫺0.83 to 0.36)b
.38
16
21
27
7 (⫺7 to 20)
36
60
62
24 (⫺1 to 49)
80
91
99
11
19
4
38
25
34
21
11 (⫺3 to 26)
.06
27 (1–52)
.04
NOTE. The maraviroc dose was 150 mg for patients who were concurrently receiving a protease inhibitor (excluding tipranavir) and/or delavirdine as part of
their optimized background therapy; otherwise, the maraviroc dose was 300 mg. CI, confidence interval.
a
b
c
d
e
f
Patients who discontinued the study at or before week 24 for any reason had their missing values imputed as baseline values.
97.5% CI.
Data were missing for 4 patients in the placebo group.
The last-observation-carried-forward analysis was used to impute missing values.
There were 24 patients in the placebo group, 23 patients in the maraviroc once-daily group, and 26 patients in the maraviroc twice-daily group.
There were 23 patients in the placebo group, 33 patients in the maraviroc once-daily group, and 21 patients in the maraviroc twice-daily group.
The change in CD4⫹ cell count from baseline was a secondary
end point. With use of the last-observation-carried-forward approach, the increase in CD4⫹ cell count from baseline to 24
weeks was greater for both maraviroc treatment groups, compared with the placebo group (table 2; figure 2C). Unadjusted for
multiple comparisons, the difference in the increase in CD4⫹ cell
count from baseline for the maraviroc twice-daily arm (62 cells/
␮L) versus the placebo arm (36 cells/␮L) was statistically significant (difference, 27 cells/␮L; 95% CI, 1–52 cells/␮L; P ⫽ .04).
The magnitude of the difference in increase in CD4⫹ cell count
from baseline between the maraviroc twice-daily (47 cells/␮L)
and placebo arms (32 cells/␮L) was lower when CD4⫹ cell count
values were analyzed using values of 0 for all patients who discontinued treatment or had missing data (difference, 14 cells/
␮L; 95% CI, ⫺11 to 39 cells/␮L).
Mean CD4⫹ cell counts increased slightly in all groups between weeks 24 and 48. By week 48, the increase from baseline
was 51 cells/␮L in the placebo group versus 65 and 78 cells/␮L in
the maraviroc once- and twice-daily groups, respectively (using
last-observation-carried-forward approach). At 48 weeks, there
were no statistically significant differences in CD4⫹ cell count
response between treatment groups.
A change in tropism result between screening and baseline
was observed in 18 (11%) of 167 patients with dual- or mixedtropic HIV-1 at screening. Sixteen patients had results change
from dual- or mixed tropic to R5, and 2 had results change to X4.
Most patients (140 [84%] of 167) did not have a result for
tropism tests at week 24, primarily because of discontinuation or
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having a viral load ⬍500 copies/mL. Of the 75 patients with
dual- or mixed-tropic virus at screening who experienced treatment failure and for whom a tropism test result was available, 31
(41%) had a different HIV-1 tropism result at the time of treatment failure. Patients who received maraviroc and experienced
treatment failure were more likely to have X4 HIV-1 at treatment failure (12 [36%] of 33 and 12 [57%] of 21 patients who
received maraviroc once and twice daily, respectively) than were
those who received placebo and experienced treatment failure (2
[9%] of 23 patients). Increases in CD4⫹ cell count from baseline
to treatment failure in this subgroup with X4 HIV-1 (48 and 33
cells/␮L for patients who received maraviroc once and twice
daily, respectively) were similar to the increase in CD4⫹ cell
count observed among maraviroc-treated patients who experienced treatment failure with dual- or mixed-tropic virus (34 and
14 cells/␮L for patients who received maraviroc once and twice
daily, respectively). These increases were similar to the mean
increase in CD4⫹ cell count at 24 weeks of 36 cells/␮L observed
among patients in the placebo group.
Safety. The most commonly reported adverse events that
occurred during treatment across all groups were diarrhea, fatigue, headache, nausea, injection site reactions, pyrexia, and
bronchitis; there was no clear pattern to their incidence (table 3).
Study drug–related discontinuation attributable to adverse
events was uncommon, and the rates were similar across groups
(3.2%, 0%, and 1.6% for the placebo, maraviroc once-daily, and
maraviroc twice-daily groups, respectively).
Table 3.
Treatment-emergent adverse events among all patients who received 肁1 dose of study medication.
Treatment group, no. (%) of patients
Variable
Experienced 肁1 adverse event (all grades)
All causality
Treatment related
Grade 2–4 adverse events occurring in 肁5% of patients
in any treatment group
Bronchitis
Diarrhea
Fatigue
Headache
Injection site reaction
Nausea
Pyrexia
Category C (AIDS-defining) adverse events
Esophageal candidiasis
Cytomegalovirus chorioretinitis
Herpes simplex virus infection
Histoplasmosis
Mycobacterium avium infection
Pneumocystis jiroveci pneumonia
Pneumonia
Encephalitis
Total number of events
Patients experiencing event
Maximum liver function test valuesa
Aspartate aminotransferase
Grade 3, ⬎5.0 to 10.0 ⫻ ULN
Grade 4, ⬎10.0 ⫻ ULN
Alanine aminotransferase
Grade 3, ⬎5.0 to 10.0 ⫻ ULN
Grade 4, ⬎10.0 ⫻ ULN
Placebo
(n ⫽ 62)
Maraviroc once daily
(n ⫽ 63)
Maraviroc twice daily
(n ⫽ 61)
55 (88.7)
38 (61.3)
54 (85.7)
28 (44.4)
56 (91.8)
30 (49.2)
0 (0.0)
5 (8.1)
3 (4.8)
3 (4.8)
2 (3.2)
5 (8.1)
2 (3.2)
1 (1.6)
8 (12.7)
4 (6.3)
4 (6.3)
1 (1.6)
1 (1.6)
3 (4.8)
4 (6.6)
5 (8.2)
3 (4.9)
3 (4.9)
4 (6.6)
1 (1.6)
4 (6.6)
1 (1.6)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (1.6)
1 (1.6)
3
2 (3.2)
0 (0.0)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)
3 (4.8)
0 (0.0)
0 (0.0)
7
6 (9.5)
2 (3.3)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (1.6)
0 (0.0)
0 (0.0)
3
3 (4.9)
2 (3.4)
0 (0.0)
1 (1.6)
1 (1.6)
1 (1.6)
0 (0.0)
2 (3.4)
1 (1.7)
1 (1.6)
0 (0.0)
0 (0.0)
0 (0.0)
NOTE. The maraviroc dose was 150 mg for patients who were concurrently receiving a protease inhibitor (excluding tipranavir)
and/or delavirdine as part of their optimized background therapy; otherwise, the maraviroc dose was 300 mg. ULN, upper limit of normal.
a
There were 58 patients in the placebo group, 63 patients in the maraviroc once-daily group, and 61 patients in the maraviroc
twice-daily group who had 肁1 observation for the given liver function test while receiving study treatment or within 7 days of receiving
the last dose of study medication.
None of the 9 serious adverse events reported in each of the
maraviroc arms and only 1 of the 10 reported in the placebo arm
was considered to be treatment related. Seven deaths were recorded. Three deaths occurred among patients in the placebo
group, which were attributed to (1) aggravated renal failure, ascites, hemothorax, and disease aggravation; (2) progressive multifocal leukoencephalopathy; and (3) multiple cerebral lesions.
Two deaths occurred among patients in the maraviroc oncedaily group, which were attributed to (1) pneumonia and possible chest mass and (2) HIV disease progression. Two deaths also
occurred among patients in the maraviroc twice-daily group,
which were attributed to (1) bacterial pneumonia and (2) pneumocystis pneumonia. None of the deaths were considered to be
treatment related. There were 3, 7, and 3 category C (AIDS-
defining) events that occurred among patients in the placebo,
maraviroc once-daily, and maraviroc twice-daily groups, respectively (table 3). During the treatment period, 1 patient in
each treatment group received a diagnosis of malignancy: basal
cell carcinoma (placebo), anal carcinoma (maraviroc once
daily), and bowenoid papulosis (maraviroc twice daily). No
cases of lymphoma were reported.
The overall incidence of grade 3 or 4 laboratory abnormalities
was similar across treatment arms: 17% in the placebo group,
19% in the maraviroc once-daily group, and 18% in the maraviroc twice-daily group. The incidence of liver function test abnormalities was low and similar between groups (table 3). No
new or unique safety findings emerged between the 24- and 48week timepoints.
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DISCUSSION
The findings of this exploratory study demonstrate that the addition of maraviroc to optimized background therapy in an extensively treatment-experienced patient population infected
with dual- or mixed-tropic HIV-1 does not confer a significant
additional reduction in plasma viremia, compared with placebo,
over 24 weeks (primary efficacy analysis timepoint) of treatment. Neither superiority nor noninferiority of either maraviroc
dosage versus placebo was statistically demonstrated with respect to the primary virologic end point (HIV-1 RNA levels).
This may reflect the fact that the variability in virological response was higher than had been assumed in the sample size
calculation.
The observation that the population with a low median baseline CD4⫹ cell count who received maraviroc twice daily experienced a statistically significantly greater increase in mean
CD4⫹ cell count at 24 weeks than those who received placebo
was unexpected, although this finding should be interpreted
with caution, because the difference was not corrected for multiple comparisons and was not apparent at 48 weeks. The reason
for the unexpected increase in CD4⫹ cell counts among maraviroc recipients remains undetermined, but a possible explanation
may be that the suppression of R5 virus is an important factor in
determining immunologic recovery. Alternatively, a decrease in
immune activation as a result of a CCR5 blockade, above and
beyond that caused by antiviral activity, may be responsible for
the release of CD4⫹ cells from lymphoid reservoirs into plasma.
The increase in CD4⫹ cell population resulted mostly from an
increase in total lymphocyte count rather than a specific effect on
CD4⫹ lymphocytes per se (data not shown), which suggests that
maraviroc has an effect on inhibiting adhesion molecules elaborated within lymphatic tissue, resulting in the release of lymphocytes into the circulation. This premise is supported by recent work of Silvestri et al. [9], which demonstrated reduced
CCR5 expression in gut-associated lymphoid tissue and reduced
immune activation in several species of nonhuman primates
with chronic, nonprogressing simian immunodeficiency virus
infection. This hypothesis needs to be further validated. A third
possibility is that CCR5 blockade may lead to prolongation of
the lifespan of CD4⫹ cells attributable to a reduction in apoptosis
or other mechanisms.
More patients in the maraviroc arms had X4 virus at time of
treatment failure, compared with placebo recipients, which is
consistent with the selective suppression of R5 virus in these
patients. However, X4 virus did not appear to be associated with
an adverse immunologic outcome in this patient population,
because CD4⫹ cell count increases for patients in the maraviroc
arms did not differ with regard to tropism results at the time of
treatment failure.
Contrary to previous hypotheses, we saw no evidence of synergy or additive effects of maraviroc and enfuvirtide in this study
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Saag et al.
population. Rather, maraviroc-enfuvirtide combination regimens perform as all other antiretroviral regimens, with activity
linked to the number of active drugs in the regimen [10].
The adverse event profile of maraviroc was comparable to that
of placebo in this study. Serious adverse events (including
deaths), grade 3/4 adverse events, and discontinuations attributable to adverse events occurred with similar frequency across the
3 treatment arms. In spite of the advanced level of disease in the
study population, only 13 new category C (AIDS-defining)
events were reported. Concerns have been raised previously
about the risk of developing lymphoma for patients receiving
CCR5 antagonists [11]. It is therefore reassuring that, in this
24-week study and in the 48-week follow up, no cases of lymphoma were reported among these severely immunocompromised patients who were at high risk of lymphoma.
Analyses from the MOTIVATE studies of maraviroc in
treatment-experienced patients, which were based on a similar
design to A4001029 but enrolled only patients infected with R5
virus at screening, demonstrated that the addition of maraviroc
to optimized background therapy provided significant virologic
and immunologic benefit and a similar safety profile to optimized background therapy alone in the patient population [7,
8]. Notably, when evaluating the tropism results at screening
and baseline in these studies, ⬃8% of the 1042 patients infected
with R5 virus at screening had a different tropism result at baseline [8]. The original Trofile assay used in these studies had a
reported 100% sensitivity for detecting CXCR4-using variants
present at the 10% level and 85% sensitivity for variants present
at the 5% level [12]. The ability to detect CXCR4-using viral
subpopulations will therefore depend on the proportion of these
minority strains in the total virus population, which can vary
over time and may at times be below the limit of detection of the
assay [13]. These observations reinforce the importance of the
study reported here, which indicates that treatment of patients
infected dual- or mixed-tropic HIV-1 with a maraviroccontaining regimen does not result in a negative virologic or
immunologic outcome.
This study has important limitations. Postdiscontinuation
data were not consistently available, and it was not possible to
control for the treatment regimen or the quality of patient care
after the study. Therefore, any adverse events that became apparent after discontinuation may not have been fully evaluated.
Second, because more than one-half of the patients in the maraviroc arms discontinued treatment prior to week 24, the mean
duration of maraviroc exposure was 4 and 6 months for the
once- and twice-daily arms, respectively. Finally, this study evaluated the efficacy of maraviroc in patients with dual- or mixedtropic virus. The low incidence of obligate CXCR4 use by HIV-1,
even in advanced disease, precludes the evaluation of efficacy in
patients with X4 HIV-1. The few patients who had an X4 tropism
result at baseline in this study had viral load and CD4⫹ cell count
responses that were within the ranges observed for the primary
efficacy population.
In conclusion, this study demonstrates that maraviroc combined with an optimized background regimen in treatmentexperienced patients with dual- or mixed-tropic HIV-1 confers
little to no virologic benefit but has no apparent adverse effect on
clinical outcome. Administration of maraviroc to patients infected with dual- or mixed-tropic virus did not result in a decrease in CD4⫹ cell count; rather, overall CD4⫹ cell counts increased in both the maraviroc arms. Furthermore, this study
indicates that maraviroc combined with optimized background
therapy is generally well tolerated in patients with non-R5 virus,
with no evidence of safety concerns when compared with placebo. Results at week 48 were consistent with findings at week 24.
Acknowledgments
We thank the study participants, study investigators, and study site staff.
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