Maraviroc is an investigational entry inhibitor in the emerging class of chemokine coreceptor antagonists. It blocks CCR5, one of two types of chemokine coreceptors (the other is CXCR4) to which HIV binds as a necessary step in entering CD4 cells. As with other CCR5 antagonists now in development, maraviroc inhibits entry of CCR5-tropic HIV into CD4 cells but is not effective against viruses with exclusive CXCR4 tropism or viruses with dual or mixed tropism. However, it does not have cross-resistance to other classes of antiretroviral (ARV) drugs. The data presented here, from paired studies called MOTIVATE 1 and 2, represent planned 24-week interim analyses of maraviroc in treatment-experienced patients.(1,2) Methods
The MOTIVATE trials are two ongoing randomized, double blind, placebo-controlled phase 2b/3 studies, one in the Canada and United States (MOTIVATE 1), and one in Europe, Australia, and the United States (MOTIVATE 2). Study participants were required to have exclusively CCR5-tropic HIV virus, an HIV RNA viral load of ≥5,000 copies/mL (either on a stable regimen or off ARV therapy for ≥1 month), resistance to (or ≥6 months of treatment with) at least 1 drug in each of 3 classes of ARVs, and at least 2 protease inhibitor (PI) mutations. The 1,049 subjects were randomized 1:2:2 to one of the following treatment arms: placebo + optimized background therapy (OBT), once-daily maraviroc + OBT, or twice-daily maraviroc + OBT. The maraviroc dose was 150 mg for subjects whose OBT included delavirdine or a PI other than tipranavir, and 300 mg for the others. All groups in the two studies had similar baseline characteristics. The median baseline CD4 count was approximately 150-180 cells/µL, and the mean HIV RNA viral load was 4.85 log10 copies/mL. Roughly 65% of subjects were predicted by resistance testing to have ≤2 active agents in their background regimens. Results
At 24 weeks, by intention-to-treat analysis, rates of virologic suppression and CD4 increases were significantly greater in the maraviroc groups than in the placebo groups:
| ||Placebo + OBT||Maraviroc QD + OBT||Maraviroc BID + OBT||Placebo + OBT||Maraviroc QD + OBT||Maraviroc BID + OBT|
|HIV RNA <400 copies/mL (% of patients)||31.4||54.7*||60.4*||23.1||55.5*||61.3*|
|HIV RNA <50 copies/mL (% of patients)||24.6||42.2*||48.5*||20.9||45.6*||40.8*|
|Mean CD4 increase (cells/µL)||52||107*||111*||64||112#||102#|
Preplanned subgroup analysis within each MOTIVATE study showed that maraviroc recipients had comparable decreases in HIV RNA whether their baseline viral load was ≥100,000 copies/mL or <100,000 copies/mL, with no significant differences between once-daily and twice-daily dosing groups. Surprisingly, no differences in rates of HIV RNA suppression were seen in patients who received enfuvirtide as part of their OBT and those who did not, though no data were given on patients who had no previous exposure to enfuvirtide. In combined analysis, subgroups of patients with ≤2 active drugs in the OBT had significantly higher rates of virologic suppression if they received maraviroc rather than placebo; for subjects with 1 active drug in the OBT, 43% of the maraviroc group vs 3% of the placebo group had HIV RNA viral loads of <50 copies/mL at 24 weeks. In most analyses, maraviroc appeared similarly effective whether it was dosed once or twice daily; the only difference between maraviroc dosing groups was seen in patients with 0 active ARV drugs in the OBT; in this small subgroup, the maraviroc twice-daily recipients had higher rates of HIV RNA viral loads of <50 copies/mL.
Adverse effects and laboratory abnormalities were similar in the maraviroc and placebo groups. Compared with the placebo groups, the maraviroc groups had somewhat higher rates of upper respiratory symptoms. There were no differences between treatment groups in the incidence of malignancy; lymphoma was diagnosed in 3 maraviroc recipients and 2 placebo recipients.
Of patients with virologic failure on maraviroc, approximately two thirds had CXCR4-tropic virus at the time of failure, whereas about one third continued to have exclusive CCR5 tropism. No signature resistance mutations were identified. Conclusions
The preliminary results of the MOTIVATE trials confirm that maraviroc is potent and tolerable in patients with resistance to multiple ARV medications. These studies are ongoing and subjects will have to be followed to 48 weeks and beyond for a fuller assessment of efficacy and safety of this compound. A number of issues require further clarification. Some of these are specific to maraviroc (such as dosing and the role of other active agents) and some are related to the class of CCR5 antagonists. Among the latter are the following:
- The CCR5 antagonists are the first ARVs to act on a human cellular target; thus, concern about their safety is particularly elevated. Although the MOTIVATE studies thus far have not shown increased rates of adverse effects, an AIDS Clinical Trials Group study of a different CCR5 antagonist, vicriviroc, found a high incidence of malignancy in vicriviroc recipients; it is unknown whether the drug is causally related to the malignancies.(3)
- The lack of cross-resistance to other classes of ARVs makes CCR5 antagonists attractive for use in treatment-experienced patients. However, patients with more advanced disease states are less likely to have exclusive CCR5-tropic virus and thus are less likely to benefit from this class (only 56% of subjects screened for the MOTIVATE studies had exclusive CCR5 virus). The role of CCR5 antagonists in initial therapy has not been clarified.
- The implications of emergent resistance to CCR5 antagonists are unknown, including the clinical significance of a shift in tropism from CCR5 to CXCR4 or dual/mixed tropism. CXCR4 HIV has been associated with disease progression, but it is not known whether tropism shift is responsible for worsening clinical status.
The new CCR5 antagonist and integrase inhibitor classes of medication are expected to give patients with extensive drug resistance significantly better options for effective treatment. And, the arrival of these new classes may soon shift treatment paradigms both for experienced and for treatment-naive patients. Maraviroc currently is available in the United States through expanded-access programs. References
- Nelson M, Fatkenheuer 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. Abstract 104aLB.
- 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. Abstract 104bLB.
- Gulick R, Su Z, Flexner C, et al; ACTG Study Team. ACTG 5211: phase II study of the safety and efficacy of vicriviroc in HIV-infected treatment-experienced subjects. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006. Abstract THLB0217.