HIV-1
interacts with a cell-surface receptor, primarily CD4, and through conformational
changes becomes more closely associated with the cell through interactions with
other cell-surface molecules, such as the chemokine receptors CXCR4 and CCR5.
48-week
Data from MOTIVATE trials
Maraviroc
was approved by the Food and Drug Administration (FDA) in August 2007 for use
by treatment experienced patients with drug-resistant HIV and past treatment failures.
Approval was based on 24-week data from the MOTIVATE 1 and 2 trials, which were
reported
at last year's Retrovirus conference.
This year, the researchers presented
combined 48-week results from the 2 studies (abstract 792). MOTIVATE 1 was conducted
in the U.S. and Canada, while MOTIVATE 2 enrolled participants in the U.S., Europe,
and Australia. In these identical randomized, controlled Phase IIb/III trials,
1049 heavily treatment-experienced subjects with documented CCR5-tropic HIV and
triple-class antiretroviral resistance were randomly assigned to receive oral
maraviroc at doses of 150 mg once-daily (QD) or twice-daily (BID), or else placebo,
in combination with optimized background therapy (OBT).
Participants in
all study arms were generally similar at baseline. About 90% were men, with a
mean age of about 45 years. The median CD4 cell count was 150-180 cells/mm3 and
the mean HIV viral load was about 65,000 copies/mL.
Results
•
At 48 weeks, maraviroc produced greater virological
response compared with placebo:
•
HIV RNA less than 50 copies/mL: 45.5% maraviroc
BID, 43.2% maraviroc QD, 16.7% placebo;
•
HIV RNA less than 400 copies/mL: 56.1%, 51.7%,
and 22.5%, respectively;
•
Mean viral load decrease: 1.84, 1.68, and
0.78, respectively.
•
CD4 cell gains were larger in the maraviroc
arms (124 cells/mm3 BID, 116 cells/mm3 QD) compared with the placebo arm (61 cells/mm3).
•
No new or unique safety findings turned up
at 48 weeks beyond those reported at 24 weeks.
•
Discontinuations due to any adverse events
(about 5%-6%), serious adverse events, or laboratory abnormalities, including
grade 3-4 transaminase (ALT and AST) elevations occurred with similar frequency
in the maraviroc and placebo arms.
•
Adverse events were slightly more common with
once-daily compared with twice-daily maraviroc.
•
AIDS-defining events were also balanced across
treatment groups.
•
Death rates were 2.1% and 1.4% in the BID
and QD maraviroc groups compared with 1.0% in the placebo arm, but no deaths were
judged to be related to the study drug.
The
researchers concluded that, "Maraviroc plus OBT demonstrated statistically
greater efficacy and similar safety compared with placebo plus OBT in this pooled
week 48 analysis. These results demonstrate that treatment with maraviroc plus
OBT provides sustained antiretroviral efficacy and tolerability in treatment-experienced
patients with [CCR5-tropic] virus."
Virological
Failure in Treatment-naive Patients
Maraviroc
is also being studied in previously untreated patients in the ongoing Phase III
MERIT trial. This study includes 721 participants (29% women) with documented
CCR5-tropic HIV receiving antiretroviral therapy for the first time (about 400
from the Northern hemisphere and 300 from the Southern hemisphere); just over
half were white and about 35% were black. The median baseline CD4 cell count was
about 250 cells/mm3 and the mean baseline viral load was about 700,000 copies/mL.
Participants were randomly assigned to receive either 300 mg maraviroc
twice daily or 600 mg efavirenz
(Sustiva) once daily, along with the Combivir
(AZT/3TC) fixed-dose combination pill for 48 weeks. A once-daily maraviroc
arm was halted early after interim data showed a higher rate of virological failure.
As
previously reported, maraviroc was not quite as effective as efavirenz, with
65.3% and 69.3%, respectively, achieving HIV RNA below 50 copies/mL; in particular,
rates of viral suppression were lower in the maraviroc among patients with a higher
baseline viral load. However, participants taking maraviroc had a larger CD4 count
increase than those taking efavirenz (170 vs 144 cells/mm3, respectively), fewer
discontinued due to adverse events (13.6% vs 4.2%), and lipid profiles were more
favorable.
At last week's conference, researchers provided further information
on virological failure and lipid parameters in the MERIT study.
In the
first analysis (abstract 40LB) HIV tropism for all participants was measured at
predetermined study visits using the Monogram Trofile assay. HIV can use 1 of
2 co-receptors, CCR5 or CXCR4. Some patients have a mixed population of CCR5-using
and CXCR4-using virus (mixed tropism), and some HIV strains can use both co-receptors
(dual tropism). Maraviroc only works against CCR5-tropic virus.
Resistance
to NRTIs and efavirenz was evaluated using the PhenoSense GT assay at screening
and at the time of failure. Resistance to maraviroc was evaluated using the PhenoSense
HIV Entry assay. Maraviroc plasma concentrations were determined using sparse
pharmacokinetics sampling at protocol-specified time-points and combined with
compliance data obtained from the study database.
Results
•
Of the 721 patients, 24 (3.3%) changed from
exclusively CCR5-tropic HIV at screening to dual/mixed (D/M) tropism at baseline
(that is, before they started taking maraviroc).
•
Response in this group was lower for both
maraviroc and efavirenz, with 7.1% and 54.6%, respectively, achieving HIV RNA
below 50 copies/mL at week 48.
•
Mean CD4 cell increases were greater in patients
who failed on maraviroc (101 cells/mm3) compared with those who failed on efavirenz
(44 cells/mm3), regardless of viral tropism at the time of failure.
•
CXCR4-tropic virus was detected at failure
in 10 of 32 patients (31.3%) in the maraviroc arm who had exclusively CCR5-tropic
HIV at baseline.
•
NRTI resistance was selected at failure in
all of these patients.
•
For the 13 patients who failed with CCR5-tropic
virus, maraviroc-resistant virus was selected in 2 patients and NRTI resistance
in 7.
•
NNRTI resistance was detected in 5 of 6 patients
failing efavirenz who had a valid tropism result at failure.
•
Patient race/ethnicity, sex, HIV clade, and
geographic region did not appear to be associated with increased risk of virological
failure of maraviroc.
•
Poor treatment adherence, however, was a significant
contributor to treatment failure.
"CXCR4-using
virus at baseline was an important predictor of failure on maraviroc in this study,"
the researchers concluded. "As seen with treatment-experienced patients,
failure with CXCR4-using virus is an important mechanism associated with virological
failure. In these patients viral replication in the presence of only NRTI[s] occurred,
resulting in selection of NRTI [resistance] mutations." Lipid
Profiles in Treatment-naive Patients
In
the second analysis (abstract 929), researchers looked at fasting serum lipids
of MERIT participants measured at the baseline and at week 24 and 48 visits or
at the time of early study discontinuation.
Between the study arms they
compared median maximum changes (in mg/dL) in total cholesterol (TC), high-density
lipoprotein (HDL or "good") cholesterol, calculated low-density lipoprotein
(LDL or "bad") cholesterol, TC-to-HDL ratio (TC:HDL), triglycerides
(TG), and the proportion of patients exceeding the borderline high threshold as
per the 2001 National Cholesterol Education Program (NCEP) guidelines.
Results
•
At baseline, lipid values and the proportion
of patients exceeding NCEP thresholds were comparable between the maraviroc and
efavirenz groups.
•
Median maximum changes from baseline in TC,
HDL, LDL, and TG were greater in the efavirenz group compared with the maraviroc
group:
•
The median decrease in TC:HDL ratio was greater
in the maraviroc group (P < 0.01).
•
Though the percentage of patients exceeding
NCEP thresholds were not different at baseline, they were highly statistically
different on therapy for TC and LDL (P < 0.0001), favoring the maraviroc arm.
"These
data demonstrate that maraviroc has minimal effect on lipid profiles and is at
least as lipid neutral as efavirenz," the researchers concluded.
Maraviroc
to Prevent HIV Infection
In
late January, Pfizer announced that it had granted the International Partnership
for Microbicides a royalty-free license to develop maraviroc as a microbicide
for prevention of HIV infection. While several microbicides under study work by
creating a physical barrier or attempting to inactivate HIV, maraviroc would prevent
the virus from entering host cells.
Maraviroc may also potentially be suitable
as an oral agent for HIV prophylaxis, according to a late-breaker presentation
(abstract 135LB) at the conference. Pfizer researchers described an open-label
study of maraviroc pharmacokinetics in the blood plasma and genital tract of 12
healthy HIV negative women. Study volunteers received 300 mg twice-daily maraviroc
for 7 days.
The researchers collected 8 paired plasma and cervicovaginal
fluid samples over a 12 hour interval on days 1 and 7, and at 24, 48, and 72 hours
after the final dose on day 7. Plasma and genital trough (lowest level) samples
were collected prior to the morning doses on days 2-6. Vaginal tissue biopsy samples
were collected once per subject at 2, 4, 8, or 12 hours post-dose on day 7 (3
subjects per time point).
Results
•
Maraviroc was detectable in genital fluid,
with concentrations reaching or exceeding plasma concentrations 4 hours after
a single oral dose.
•
Steady-state concentrations of maraviroc in
plasma and genital fluid appeared be reached by day 2 based on trough values.
•
The accumulation ratio based on area under
the curve (AUC) (day 7/day 1) was 1.3 for plasma and 2.4 for genital fluid.
•
On day 7, maraviroc was detectable in all
tissue biopsy samples.
•
The AUC in tissue biopsy samples was 1.9-fold
higher than in the blood plasma. After maraviroc was discontinued, genital fluid
concentrations declined in parallel to plasma concentrations.
Conclusion
"Maraviroc
exposures in cervicovaginal fluid and vaginal tissue biopsies were higher than
those observed in blood plasma," the researchers concluded. "These data
indicate that maraviroc has the potential to be studied as an oral agent for HIV
prophylaxis."
2/12/08
Sources
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Hardy, J Reynes, I Konourina, and others. 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. 15th Conference on Retroviruses
and Opportunistic Infections (CROI). Boston, MA. February 3-6, 2008. Abstract
792.
J Heera, M Saag, P Ive, and others. Virological Correlates Associated
with Treatment Failure at Week 48 in the Phase 3 Study of Maraviroc in Treatment-naive
Patients. 15th CROI. Abstract 40LB.
E DeJesus, S Walmsley, C Cohen, and
others Fasted Lipid Changes after Administration of Maraviroc or Efavirenz in
Combination with Zidovudine and Lamivudine for 48 weeks to Treatment-naive HIV-infected
Patients. 15th CROI. Abstract 929.
J Dumond, Kristine Patterson, A Pecha,
and others. Maraviroc (MVC) Pharmacokinetics (PK) in Blood Plasma (BP), Genital
Tract (GT) Fluid and Tissue in Healthy Female Volunteers. 15th CROI. Abstract
135LB.
Maraviroc
(Selzentry): 48-week Treatment-experienced Data, Failure and Lipids in Treatment-naive
patients, and Possible Use for Prevention 
