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CROI 2007; Los Angeles, Calif.; February 25-28, 2007

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The Body Covers: The 14th Conference on Retroviruses and Opportunistic Infections
Phase 3 Results of Two Key Trials of Maraviroc, the First-in-Class CCR5 Antagonist

February 27, 2007

Maraviroc (MVC, UK-427,857) is the first CCR5 antagonist and the first oral agent with a new mechanism of action to reach phase 3 development since the approval of the first protease inhibitors (PIs) in the late 1990s. During the process of viral entry, HIV uses a chemokine co-receptor known as CCR5. After HIV has attached to CD4 cellular receptor, it interacts with a chemokine receptor, either CCR5 or CXCR4, which facilitates viral conformational changes that lead to fusion and cellular entry. Individuals who lack the CCR5 receptor appear to have near-normal immune function and a high level of resistance to acquiring HIV. HIV's use of CXCR4, the alternative co-receptor, increases as a patient's CD4+ cell count declines and also possibly as the patient gains greater treatment experience.

Previously reported data with maraviroc suggest that this agent results in limited antiretroviral benefits but modest CD4+ cell count increases relative to placebo in individuals who have viral populations using both the CXCR4 and CCR5 co-receptors (called mixed or dual X4/R5 populations).1 Maraviroc is not anticipated to be active in rare individuals with HIV that exclusively uses the CXCR4 co-receptor.

The two phase 3 studies of maraviroc, known as MOTIVATE 1 and 2, screened individuals using the Monogram Biosciences Trophile™ assay to determine HIV co-receptor usage. Only individuals identified as having CCR5-tropic HIV were included in these studies.

The studies were of identical design and included individuals with resistance to and/or six months or more experience with at least one antiretroviral agent from the three approved oral drug classes and exposure to at least two PIs. MOTIVATE 1 enrolled 601 individuals mainly from North America, and MOTIVATE 2 enrolled 475 individuals mainly from Europe and Australia.

At entry, individuals were required to have a viral load of at least 5,000 copies/mL and had to be either off treatment for at least four weeks or on a stable but failing antiretroviral regimen.

Using the results of genotypic and phenotypic tests, a background regimen of approved antiretroviral agents was constructed by the treating physician (i.e., optimized background therapy [OBT]). Patients were then randomized to receive placebo, maraviroc 150 mg once daily or maraviroc 150 mg twice daily in a 1:2:2 manner. Individuals assigned to the maraviroc arms who were not receiving ritonavir (RTV, Norvir) as part of their OBT received maraviroc 300 mg, either once daily or twice daily.

The interim results from planned 24-week analyses of both trials were presented at the 14th Conference on Retroviruses and Opportunistic Infections.2,3

Safety data from both studies indicated that maraviroc was very well tolerated, with no clear adverse events associated with this agent. Specifically, no excess of malignancies or liver function abnormalities were observed in the maraviroc groups relative to placebo. There were also no differences in the rate of treatment discontinuation or the incidence of grade 3/4 adverse events observed across the arms in either study.

MOTIVATE 1

In MOTIVATE 1, 585 individuals received at least one dose of medication: 118 received placebo, 232 received maraviroc once daily and 235 received maraviroc twice daily.2 Participants were predominantly male (90%-91%) and predominately white (81%-84%).

For the placebo, once-daily and twice-daily groups, the median baseline CD4+ cell counts were 163, 160 and 150 cells/mm3, respectively, and the median baseline viral loads were 4.84, 4.85 and 4.86 log10 copies/mL, respectively. Enfuvirtide (T-20, Fuzeon) was included in the OBT for 42%, 43% and 46% of individuals in the three respective groups, with the majority of individuals in each group having two or fewer active agents in the OBT (66%, 69% and 76%, respectively).

Both maraviroc arms demonstrated dramatic improvements in virologic and immunologic parameters in comparison with the placebo arm. Moreover, all of these differences were highly statistically significant at P < .001.


Outcome at Week 24Placebo + OBT
(n = 118)
MVC QD + OBT
(n = 232)
MVC BD + OBT
(n = 235)
Mean change in HIV-1 RNA from baseline (log10 copies/mL)-1.03-1.82-1.95
HIV-1 RNA < 400 copies/mL (%)31.454.7*60.4*
HIV-1 RNA < 50 copies/mL (%)24.642.4*48.5*
Mean change in CD4+ cell count from baseline (cells/mm3)+52+107*+111*
BD = twice daily; QD = once daily.

* P < .001 in comparison with placebo.


MOTIVATE 2

In this study, at least one dose of study medication was received by 91 individuals in the placebo arm, 182 individuals assigned to maraviroc once daily and 191 individuals assigned to maraviroc twice daily.3 Similar to MOTIVATE 1, the majority of participants were male (84%-89%) and white (82%-87%). The median baseline CD4+ cell count ranged from 174 to 182 cells/mm3 for the three groups, while the baseline HIV-1 RNA level ranged from 4.84 to 4.89 log10 copies/mL. Enfuvirtide was included in the OBT for 37% to 45% of individuals, and 62% to 66% of individuals had two or fewer active drugs included in their OBT.

Highly significant virologic and immunologic benefits of maraviroc were reported for the MOTIVATE 2 study, similar to those observed in MOTIVATE 1.


Outcome at Week 24Placebo + OBT
(n = 91)
MVC QD + OBT
(n = 182)
MVC BD + OBT
(n = 191)
Mean change in HIV-1 RNA from baseline (log10 copies/mL)-0.93-1.95-1.97
HIV-1 RNA < 400 copies/mL (%)23.155.5*61.3*
HIV-1 RNA < 50 copies/mL (%)20.945.6*40.8*
Mean change in CD4+ cell count from baseline (cells/mm3)+64+112*+102*
BD = twice daily; QD = once daily.

* P < .001 in comparison with placebo.


Combined Analyses

A further analysis was presented describing the proportion of individuals with a viral load less than 50 copies/mL at week 24 according to the number of active drugs in the OBT. For all arms, the greater the number of active drugs in the OBT, the greater the likelihood of achieving complete viral suppression. It is important to note, however, that a much higher proportion of individuals in the maraviroc arms achieved complete viral suppression when two or fewer active agents were present in the OBT in comparison with the placebo arm.


Number of Active Agents in OBTHIV-1 RNA < 50 copies/mL (%)
Placebo + OBTMVC QD + OBTMVC BD + OBT
031829
194343
2195253
>3556158


Changes in Tropism

Changes in viral tropism were rarely observed during the course of the study, although a higher proportion of individuals in the maraviroc arms who experienced treatment failure during the 24 weeks of study showed the emergence of CXCR4-tropic virus, either alone or as a dual/mixed population, relative to placebo.

The proportion of treatment failures in each group included 46% (97 of 209) placebo recipients, 16% (68 of 414) maraviroc once-daily recipients and 18% (77 of 426) maraviroc twice-daily recipients. The majority of placebo recipients who failed treatment had CCR5-tropic virus at baseline and the time of failure, whereas a large proportion of patients on maraviroc showed the emergence of CXCR4-tropic virus at failure. This shift in tropism for maraviroc-treated patients was associated with a diminished increase in CD4+ cell count.


Outcome at Week 24Placebo + OBT
(n = 209)
MVC QD + OBT
(n = 414)
MVC BD + OBT
(n = 426)
Patients with treatment failure, n (%)97 (46.4)68 (16.4)77 (18.1)
   • CCR5 tropism at baseline and failure80 (82.5)18 (26.5)17 (22.1)
   • CCR5 tropism at baseline, dual/mixed or CXCR4-topic virus at failure4 (4.1)31 (45.6)32 (41.6)
Mean CD4+ cell count changes, cells/mm3
   • CCR5 tropism at baseline and failure+15+61+138
   • CCR5 tropism at baseline, dual/mixed or CXCR4-topic virus at failure+67+37+56


Of note, approximately 8% of individuals screened as having only CCR5-tropic virus demonstrated the emergence of some CXCR4-tropic virus by the time treatment was commenced four to six weeks later. The response to maraviroc in these individuals who were no longer only CCR5-tropic at baseline was consistent with the results previously reported at the International AIDS Conference in 2006 on the A4001029 study performed in individuals with dual/mixed tropic virus.4

Summary

Maraviroc is the first-in-class CCR5 antagonist. The preliminary MOTIVATE data demonstrate that both once-daily and twice-daily maraviroc is highly effective in individuals with CCR5-tropic virus. When combined with other active agents, maraviroc substantially increases the proportion of individuals achieving an optimal virological response and leads to substantial and significant increases in CD4+ cell counts. The inclusion of maraviroc in a new treatment regimen does not appear to increase the frequency of adverse events. Differences in outcome between once-daily and twice-daily maraviroc were not reported, although trends in most analyses suggested that there was a slight advantage to twice-daily dosing. Although treatment failure was less common with maraviroc relative to placebo, a higher proportion of individuals who failed maraviroc-containing therapy were found to have the emergence of a subpopulation of CXCR4-tropic virus. Moreover, these individuals tended to have more blunted CD4+ cell count responses than individuals who remained CCR5-tropic at failure.

Footnotes

  1. Mayer H, van der Ryst E, Saag M, et al. Safety and efficacy of MARAVIROC, a novel CCR5 antagonist, when used in combination with optimized background therapy for the treatment of antiretroviral-experienced subjects infected with dual/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0215.

  2. Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 study in the US and Canada. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Oral 104bLB.

  3. Nelson M, Fätkenheuer G, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-week results. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Oral 104aLB.

  4. H Mayer, E van der Ryst, M Saag, and others. Safety and Efficacy of Maraviroc (MVC), a Novel CCR5 Antagonist, when Used in Combination with Optimized Background Therapy (OBT) for the Treatment of Antiretroviral-Experienced Subjects Infected with Dual/Mixed-Tropic HIV-1: 24-Week Results of a Phase 2b Exploratory Trial. 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract THLB0215.



  
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