Chemokine coreceptor antagonist
Maraviroc received accelerated approval from the U.S. Food and Drug Administration (FDA) in August 2007 for use in treating adults with CCR5-tropic HIV-1 infection who have HIV strains that are resistant to multiple other antiretroviral agents and who have ongoing viral replication while receiving antiretroviral therapy. It received traditional approval in 2008, and in 2009 it received approval for use in initial therapy for adults with CCR5-tropic HIV-1 infection. Maraviroc was the first agent in the class of chemokine coreceptor antagonists to be approved by the FDA. It binds to CCR5, one of two possible coreceptors used by HIV to enter CD4+ cells, thus blocking entry of CCR5-tropic HIV into these cells.
Initial FDA approval was based primarily on 24-week results of 2 randomized, placebo-controlled Phase 2b/3 studies (MOTIVATE 1 and MOTIVATE 2) in patients with CCR5-tropic HIV-1, viral loads of >5,000 copies/mL, and prior experience with (or documented resistance to) at least 3 of the available classes of antiretroviral agents: nucleoside analogues, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors (specifically enfuvirtide). All subjects had CCR5-tropic HIV-1. Subjects were given either maraviroc or placebo, each with an optimized background regimen. At 24 weeks, the maraviroc groups had greater decreases in viral load and higher rates of HIV RNA suppression to <400 copies/mL and <50 copies/mL; these differences were statistically significant.(1,2)
| Clinical Use|
As with all antiretroviral medications, maraviroc should be used only in combination regimens. Maraviroc is a substrate of the cytochrome P450 enzyme system (CYP3A) and p-glycoprotein, and has therapeutically significant interactions with many medications, including other antiretroviral agents. Inhibitors of CYP3A such as protease inhibitors (other than tipranavir) substantially increase the serum concentration of maraviroc. Inducers of CYP3A such as efavirenz and etravirine may significantly decrease serum maraviroc concentrations if given without a strong CYP3A inhibitor. Nonantiretroviral medications that significantly alter maraviroc metabolism include the CYP3A inhibitors ketoconazole, itraconazole, clarithromycin, and nefazodone and the CYP3A inducers rifampin, carbamazepine, phenytoin, and St. John's wort. Dosage of maraviroc must be adjusted appropriately if it is taken with interacting medications.(3)
Information about drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated. Because the pharmacokinetic effects of multiple interacting medications have not been studied thoroughly and information on dosage adjustment of maraviroc in all combinations is not available, it is recommended that maraviroc be used cautiously for patients on complex regimens with multiple CYP3A inhibitors and inducers.
Maraviroc does not appear to cause clinically significant changes in concentrations of other medications.
For additional information, see Dosage Adjustments for ARV-ARV Drug Interactions and the Database of Antiretroviral Drug Interactions Database.
| Use in Initial vs Subsequent Therapy|
For initial treatment of HIV infection, adult and adolescent guidelines of the U.S. Department of Health and Human Services designate the combination of maraviroc + zidovudine/lamivudine as "acceptable" and maraviroc + 2 other nucleoside pairs as "may be acceptable but more definitive data are needed."
Maraviroc is effective only in persons with exclusively CCR5-tropic HIV. Tropism testing should be performed before initiating treatment with maraviroc, to verify that no CXCR4-tropic virus is present.
In previously untreated patients, a randomized controlled study compared maraviroc with efavirenz, each drug being given in combination with zidovudine + lamivudine. All patients had only CCR5-tropic HIV according to the tropism assay available at the time of study entry. At 48 weeks, by intention-to-treat analysis, the maraviroc group had lower rates of virologic suppression to <50 copies/mL than the efavirenz group (65% vs 69%); this result did not meet the study's criteria for noninferiority of maraviroc.(4) However, researchers later reanalyzed the baseline tropism status of the study subjects using a more sensitive tropism assay and found that 15% were erroneously identified as CCR5 tropic; when these patients were excluded from the analysis, the rates of virologic suppression to <50 copies/mL at 48 weeks were essentially the same in the two groups, 68.5% in maraviroc recipients and 68.3% in efavirenz recipients; there also was no significant
difference between the treatment groups in patients whose baseline HIV RNA was >100,000 copies/mL.(5) The mean increase in CD4 count was greater in the maraviroc group (174 cells/µL vs 144 cells/µL for the efavirenz group).(5)
In patients with advanced HIV disease, prior exposure or documented resistance to at least 3 classes of antiretroviral medications, and ongoing viral replication, 2 randomized controlled Phase 2b/3 studies (described above in "Approval") compared maraviroc with placebo, each given in combination with a background regimen. All study patients had exclusive CCR5-tropic virus at screening, according to tropism assay. In pooled analysis, the groups that received maraviroc (dosed either twice daily or once daily) had superior virologic outcomes at 24 and 48 weeks. At 48 weeks, the group that received maraviroc twice daily had greater mean decreases in HIV RNA (1.84 log10 copies/mL vs 0.79 log10 copies/mL) and higher rates of viral suppression to <400 copies/mL (56% vs 22%) and to <50 copies/mL (45% vs 23%) than the group that received placebo. These differences were statistically significant (p < .001).(1,2,6) The efficacy of maraviroc-containing regimens correlated with the number of other active antiretroviral agents used concomitantly, indicating the importance of including at least 2 agents with potent activity in the antiretroviral regimen.(7,8,9) The mean increase in CD4 count was greater in the maraviroc groups (at 48 weeks, 124 cells/µL for the twice-daily dosing group) than in the placebo group (61 cells/µL), (p < .001). It is not known whether the superior virologic and CD4 cell count responses seen with the maraviroc recipients in these studies will result in improved clinical outcomes.
In a small group of treatment-experienced patients with virus that used both CCR5 and CXCR4 coreceptors at baseline (dual- and mixed-tropic HIV), treatment with maraviroc (either once or twice daily) plus an optimized antiretroviral background did not result in greater decreases in HIV RNA in comparison with placebo plus an optimized regimen at 24 weeks.(10)
| Factors Affecting Adherence|
Symptomatic adverse effects of maraviroc include cough, upper respiratory tract infections, muscle and joint pain, diarrhea, and sleep disturbance. Myocardial ischemia and hepatitis have been observed in patients receiving maraviroc; the role, if any, of maraviroc in causing these conditions is not yet known. Laboratory abnormalities seen in persons taking maraviroc include increases in hepatic transaminase levels.(1,2,3,10,11)
To date, no increased incidence of malignancy or serious infection has been observed in maraviroc recipients. The clinical implications, if any, of blocking a human cellular protein, CCR5, are the subject of ongoing investigation.
It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with maraviroc is initiated.
Maraviroc has not been studied thoroughly in pregnant women; it is classified as an FDA Pregnancy Category B drug.
Resistance to maraviroc is associated with one or more of several mutations in the V3 loop of gp120; however, these mutations do not appear to be consistent among various patients, and their role in causing resistance is not clear.(12) Phenotypic analyses in maraviroc recipients with virologic failure show a plateau effect in viral inhibition whereby increasing concentrations of maraviroc do not result in a corresponding percentage increase in inhibition of HIV replication. The significance of these findings and the mechanisms of maraviroc resistance have not been well defined; further investigations are under way.(12)
Virologic failure of regimens containing maraviroc may be caused not only by resistance but also (and perhaps more frequently) by emergence of non-CCR5-tropic virus or by changes in viral tropism; see "Special Considerations" below.(4)
| Implications of maraviroc resistance for treatment with other antiretrovirals|
It is unclear whether resistance mutations selected by maraviroc will confer resistance to other CCR5 antagonists now in development. Maraviroc mutations do not affect sensitivity to other classes of antiretroviral agents (nucleoside analogues, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitor, integrase inhibitors).
Further studies are needed to characterize maraviroc resistance and to assess its implications for subsequent treatment.
| Implications of resistance to other antiretrovirals for treatment with maraviroc|
In an in vitro study, resistance to the investigational CCR5 antagonist vicriviroc appears to convey cross-resistance to maraviroc.(13) Signature mutations that predict resistance to maraviroc have not been identified.
Resistance to antiretroviral agents from other classes is not associated with resistance to maraviroc.
| Special Considerations|
Maraviroc is active against HIV that uses the CCR5 coreceptor exclusively. It does not appear to be active against HIV strains with CXCR4, dual, or mixed tropism.(7)
Substantial proportions of patients, particularly those with advanced HIV infection, are likely to have virus that is not exclusively CCR5 tropic. In the Phase 2b/3 studies discussed above, 44% of patients who were screened were found to have CXCR4 or dual/mixed-tropic virus and were excluded from the trials.(1,2)
Coreceptor tropism should be determined by specific testing before maraviroc is started, using the enhanced sensitivity tropism assay. There are several considerations about tropism testing: 1) in order to perform the tropism test, the HIV RNA must be >1,000 copies/mL; 2) tropism may shift with time and with disease progression, so the tropism assay ideally should be performed close to the time of planned CCR5 antagonist use; 3) the assay currently available for commercial use is highly sensitive and specific, whereas the first generation of tropism assays did not always reliably detect dual or mixed tropism. In the Phase 2b/3 studies in treatment-experienced patients, nearly 8% of those with exclusively CCR5-tropic virus at the time of screening were found to have dual- or mixed-tropic virus 4-6 weeks later, before treatment with maraviroc, either because of the emergence of previously undetected CXCR4 or because of tropism shifts.(1,2)
In the study of initial treatment, about 15% of subjects identified with exclusive CCR5 tropism using the original tropism assay were later determined by the more sensitive assay to have non-CCR5 tropism.(5)
The presence of non-CCR5 coreceptor tropism is associated with virologic failure in patients treated with CCR5 antagonists. Emergence of CXCR4 virus (either previously undetected or newly developed) appears to be a more common cause of virologic failure than the development of resistance mutations.(4,5) In Phase 2b/3 studies of treatment-experienced patients, dual/mixed or CXCR4 tropism was identified in nearly 65% of patients tested after treatment failure (compared with approximately 5% of placebo recipients with treatment failure).(1,2) Through week 24 in studies of treatment-experienced patients, shifts in tropism resulting from maraviroc therapy have not been associated with decreasing CD4 cell counts or clinical deterioration.(1,2,10)
|| ||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.|
|| ||Selzentry [package insert]. Pfizer Inc, New York.|
|| ||Lewis M, Simpson P, Fransen S, et al. CXCR4-using virus detected in patients receiving maraviroc in the phase III studies MOTIVATE 1 and 2 originates from a pre-existing minority of CXCR4-using virus. In: Program and abstracts of the XVI International HIV Drug Resistance Workshop; June 12-16, 2007; St. Michael, Barbados. Abstract 56.|
|| ||M Saag, J Heera, J Goodrich, et al. Reanalysis of the MERIT study with the enhanced Trofile assay. In: Program and abstracts of the 48th International Conference on Antimicrobial Agents and Chemotherapy; October 25-28, 2008; Washington, DC. Abstract H-1232a.|
|| ||Gulick RM, Lalezari J, Goodrich J, et al; MOTIVATE Study Teams Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008 Oct 2;359(14):1429-41. |
|| ||Gulick RM, van der Ryst E, Lampiris H, et al. Efficacy and safety of once-daily (QD) compared with twice-daily (BID) maraviroc plus optimized background therapy (OBT) in treatment-experienced patients infected with CCR5-tropic-HIV-1: 24-week combined analysis of the MOTIVATE 1 and 2 studies. In: Program and abstracts of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 23-25, 2007; Sydney, Australia. Abstract WEPEB116LB.|
|| ||van der Ryst E, Cooper D, Konourina I, et al. Efficacy of Maraviroc in combination with at least one other potent new antiretroviral drug: 24-week combined analysis of the MOTIVATE 1 and 2 studies. In: Program and abstracts of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 23-25, 2007; Sydney, Australia. Abstract WEPEB115LB.|
|| ||Fatkenheuer G, Nelson M, Lazzarin A, et al; MOTIVATE 1 and MOTIVATE 2 Study Teams. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med. 2008 Oct 2;359(14):1442-55.|
|| ||Mayer H, van der Ryst E, Saag M, et al. 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. In: Program and abstracts of the 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0215.|
|| ||Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: Week 48 results of the MERIT study. In: Program and abstracts of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 23-25, 2007; Sydney, Australia. Abstract WESS104.|
|| ||Mori J, Mosley M, Lewis M, et al. Characterization of maraviroc resistance in patients failing treatment with CCR5-tropic virus in MOTIVATE 1 and MOTIVATE 2. In: Program and abstracts of the XVI International HIV Drug Resistance Workshop; June 12-16, 2007; St. Michael, Barbados. Abstract 10.|
|| ||Tsibris AMN, Gulick RM, Su Z, et al. In vivo emergence of HIV-1 resistance to the CCR5 antagonist vicriviroc: findings from ACTG A5211. In: Program and abstracts of the XVI International HIV Drug Resistance Workshop; June 12-16, 2007; St. Michael, Barbados. Abstract 13.|