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CCR-5 Antagonists—Safety and Efficacy in Treatment-experienced Patients
or one boosted PI. HAART is successful at controlling HIV infection in the or placebo. The PI darunavir was not included in the OBT. Participants
short term; however, there are concerns relating to virus rebound from long- treated with OBT containing a PI (other than tipranavir) or delavirdine
term administration, particularly in treatment-experienced patients.
14–16
received a 150mg dose of maraviroc. Patients treated with tipranavir or
Therefore, new classes of ART are always being sought. other drugs received 300mg maraviroc QD or BID.
CCR-5 represents a good target for HIV treatment. Individuals who are After 24 weeks, results from MOTIVATE 1 demonstrated that administration
homozygous for the CCR-5 polymorphism known as the Delta32 mutation of 150/300mg of maravoric QD or BID was superior to placebo. Significant
are naturally resistant to HIV R5 infection due to the lack of CCR-5 surface improvements were reported in the reduction of viral load, number of
receptor.
17,18
Those heterozygous for Delta32 who become HIV-positive have patients with undetectable viral load, and mean changes in CD4+ cell
much slower disease progression because they express a lower number of count. The percentage of subjects with viral load <50 copies/ml was 25, 42,
CCR-5 receptors.
19
and 49% in the placebo, maraviroc QD, and maraviroc BID arms,
respectively. Furthermore, CD4+ cell count was up by more than 100
CCR-5 antagonists block viral entry by binding to the host cell’s receptor and cells/mm
3
in both maraviroc arms, compared with 52 cells/mm
3
in the
rendering it unrecognizable to the R5 strain. Before administration with a placebo arm.
25
CCR-5 antagonist, a tropism test must be performed to confirm that the
patient is infected with the HIV R5 strain. The most commonly used test is Combined analysis of MOTIVATE 1 and 2 after 24 weeks confirmed that
Trofile (Monogram Biosciences), which is a single-cycle molecular assay that maraviroc plus OBT demonstrated statistically greater efficacy than and
does not require co-cultivation of HIV particles in cell culture.
20
There are similar safety to placebo plus OBT. In selected sub-populations there were
other validated tests, although most clinical data have been collected for higher rates of virological suppression with maraviroc BID than with
Trofile. However, even with Trofile, the detection of minority variants is maraviroc QD, including patients with no active drugs in OBT, low CD4+ cell
limited; for all tests the detection limit is between 1 and 10%.
21
Several oral count (<50 cell/mm
3
) at baseline, or high HIV-1 RNA (>100,000 copies/ml).
26
CCR-5 antagonists have reached clinical development, but currently Interestingly, in patients receiving, for the first time, combined treatment
only maraviroc (Selzentry
®
, Pfizer) is approved. This article will focus on with PI inhibitor lopinavir/ritonavir or fusion inhibitor enfuvirtide and in
maraviroc and vicriviroc (SCH-D, Schering-Plough), which is currently in late- whom the virus was not resistant to these drugs, the treatment was
stage clinical development. Previous attempts to develop a CCR-5 associated with an increased likelihood of achieving undetectable viral load.
27
antagonist include aplaviroc (GlaxoSmithKline), the development of which
was terminated in 2005 following concern over hepatotoxicity. Final 48-week results for both MOTIVATE trials were also presented in 2007.
The mean change from baseline of HIV RNA copies/ml was -0.78, -1.68, and
Maraviroc -1.84 log
10
for the placebo, maravoric QD, and maravoric BID arms,
respectively, after 48 weeks. The maraviroc arms also had a superior
Efficacy response to all secondary end-points. The percentage of patients with viral
Maraviroc is a selective, slowly reversible, non-competitive CCR-5 load <50 copies/ml after 48 weeks was 16% in the placebo arm, 42% in
antagonist that has been demonstrated to have a broad spectrum of anti- the maraviroc QD arm, and 47% in the maraviroc BID arm. In addition,
HIV-1 activity and is available for patients with a viral load >1,000 more than twice the number of patients in the maraviroc arms had
copies/ml.
22,23
The phase IIa trials A4001007 and A4001015 both undetectable disease. Furthermore, CD4+ cell counts were higher in the
demonstrated a significant reduction in viral load >1 log
10
in patients maraviroc groups compared with placebo, demonstrating superior
treated with ≥100mg of maraviroc twice daily (BID).
24
The authors immunological efficacy. Once again, first-time use of enfuvirtide greatly
concluded that maraviroc potently blocks the CCR-5 receptor, which augmented treatment response.
28,29
represents a valid target for the treatment of HIV-1-positive patients.
Safety and Tolerability
Two phase IIb/III trials—MOTIVATE 1 and MOTIVATE 2 (Maraviroc plus The safety of maraviroc in HIV patients is under close scrutiny owing to the
Optimized background Therapy In Viraemic, Antiretroviral Treatment discontinuation of other CCR-5 antagonists in clinical development due to
Experienced patients infected with CCR-5-tropic HIV-1)—aimed to test the adverse events. Specific concerns were raised regarding the incidence of
efficacy of maravoric in triple-class-experienced and/or triple-class-resistant malignancy (including lymphoma), hepatotoxicity, and cardiac toxicity. In
HIV patients. The studies were of identical design, and differed only in MOTIVATE 1 and 2, maraviroc was reported to be generally well tolerated
geographical coverage: MOTIVATE 1 included 601 patients in the US and up to a dose of 300mg BID at 24 and 48 weeks.
25,30,31
Discontinuations due
Canada, while MOTIVATE 2 included 464 subjects in Europe, Australia, and to adverse events occurred in approximately 5% of patients in any group at
North America. Entry criteria were that patients should have only R5-tropic both 24 and 48 weeks. The most common side effects were diarrhea,
HIV-1 (as measured using the Trofile assay) and HIV-1 RNA >5,000 nausea, fatigue, and headaches, which occurred at similar rates in all of the
copies/ml. The primary end-point for both trials was the mean reduction in treatment arms.
HIV viral load over 24 and 48 weeks. Secondary end-points included the
number of patients achieving undetectable viral load, changes in baseline Combined data from MOTIVATE 1 and 2 at 24 weeks demonstrated no
CD4 cell count, and evaluation of tropism and resistance shifts. difference between the three groups in terms of the proportion of patients
who experienced grade 3 or greater increases in alanine transaminase (ALT),
All participants received optimized background therapy (OBT), and were aspartate transaminase (AST), or bilirubin levels, indicating no risk of
also randomized 2:2:1 to receive maravoric once daily (QD), maraviroc BID, hepatotoxicity from maraviroc; pooled analysis revealed no new or unique
US INFECTIOUS DISEASE 27
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