INDICATIONS

• Used in combination with other antiretroviral agents in treatment-experienced adult patients infected with CCR5 (R5)-tropic HIV-1.

FORMS

*Costs (rounded to the nearest dollar) are based on usual adult dosing per day, are representative of "Average Wholesale Price" (AWP), and are current within the prior three months.

^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

• MVC 300 mg PO bid with or without food
• With PIs (except TPV/r) : MVC 150 mg PO bid. (use standard dose with TPV/r)
• With LPV/r + EFV: MVC 150 mg PO bid
• With SQV/r + EFV: MVC 150 mg PO bid
• With EFV: MVC 600 mg PO bid
• With NVP: no data, consider MVC 300 mg PO bid
• With DLV: MVC 150 mg PO bid

RENAL DOSING

ADVERSE DRUG REACTIONS

• MVC generally well tolerated in clinical trials, with similar rates of study discontinuation vs. placebo.

• Diarrhea, nausea, headache and fatigue, that occurred at rates similar to or less than those of placebo.

• Cough, fever and upper respiratory tract infection (pneumonia was uncommon)
• Rash
• AST/ALT elevation
• CK elevation
• Myalgia
• Abdominal pain
• Dizziness
• Orthostatic hypotension (dose dependent, uncommon at the recommended dose)

• Hepatotoxicity with allergic features (rash, eosinophilia, elevated IgE)
• Cardiac events related to coronary artery disease (1.3%)

DRUG INTERACTIONS

Drug-to-Drug Interaction

RESISTANCE

• MVC-resistant viruses that emerged in vitro contained amino acid substitutions/deletions in the V3 loop of the HIV-1 envelope (gp120), with the primary substitutions isolated being A19T and I26V. MVC failure can also be due to a tropism shift, leading to the emergence of X4 or dual/mixed-tropic virus that is not inhibited by MVC. Tropism shifts probably represent selection of pre-existing minority variants rather than true shift of R5-tropic virus.

PHARMACOLOGY

• Absorption: Rapid absorption with a 33% bioavailability.
• Metabolism and Excretion: 22% metabolized by CYP3A4 (N-dealkylation) and 11% hydroxylated. Both inactive metabolites and unchanged drugs are excreted via fecal route (>76%).
• Protein Binding: 76%
• Cmax, Cmin, and AUC: Cmax=266 ng/mL; Cmin=54 ng/mL; AUC=1681 ng h/mL
• T1/2: 14-18 hrs.
• Distribution: 194 L

COMMENTS

• MVC not recommended in pts with dual/mixed (D/M)- or X4-tropic virus due to lack of efficacy.
• Tropism assay should be performed prior to initiation of treatment with MVC. The Trofile™ (Monogram Biosciences, Inc.) co-receptor tropism assay is the only commercially available assay; it detectspresence of R5-, X4-, or dual/mixed-tropic virus.
• Tropism assay requires VL >1000, which means that MVC cannot be used to substitute for other drugs in a suppressive regimen.
• Sensitivity of tropism assay to detect D/M or X4-tropic virus is 100% when it comprises at least 10% of total viral population, and 83%when it comprises at least 5% of population. In MOTIVATE trials 7.6% of participants had R5-tropic virus at screening but had D/M-tropic virus at baseline (4-6 wks later), presumably representing failure of initial assay to detect D/M- or X4-tropic virus present at low levels.
• Samples can be sent to Monogram Biosciences for processing, either directly or by the processing laboratory. Practitioners should contact Monogram Biosciences, Inc. for further information on sample processing and reimbursement (http://www.trofileassay.com).
• Although MVC clearly has a role in the management of treatment-experienced pts, the lack of long-term safety data, non-viral target, high cost of the tropism assay, inconvenience of bid dosing, and failure to meet non-inferiority threshold compared to EFV for <50 threshold in the MERIT trial MVC is unlikely be used in treatment-naive pts in the near future.

References

1. 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 HIV1: Week 48 results of the MERIT study ; 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, 2007. Abstract WESS104 ; 2007; Vol.
   Comments:Over 700 pts with mean baseline VL4.8 logs and med. CD4 of approximately 250 were enrolled in this prospective randomized trial. Study participants received AZT/3TC with either EFV or MVC for 48 wks. MVC (dosed bid) was found to be non-inferior to EFV in viral suppression to </-400 (70.6% vs. 73.1%, respectively), but MVC did not meet non-inferiority threshold using </-50 assay (65.3% vs. 69.3%). Pts with baseline VL> 100,000 were less likely to achieve a VL<?50 with MVC than EFV (59.6% vs. 66.6%), although suppression was similar in those with VL <100,000(69.6% vs. 71.6%). Pts from the study sites in the Southern hemisphere, comprising almost half the study population, were less likely to achieve viral suppression to <50 with MVC (62.1%) compared to EFV (71.0%), whereas this difference was not observed in pts from Northern hemisphere sites (68.0% vs. 67.8%). Mean CD4 increases were 170 and 144 in the MVC- and EFV-treated pts, respectively. Overall discontinuation rates were similar between groups; however, pts on MVC were less likely than pts on EFV to withdraw from the study due to AEs (4.2% vs. 13.6%, respectively), but more likely to withdraw due to lack of treatment effect (11.9% vs. 4.2%, respectively). CNS side effects more common in the EFV-treated group.
   
   
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 from a phase 2b/3 study in the US and Canada. ; 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 104bLB, 27thFebruary, 2007 ; 2007; Vol.
   Comments:Heavily treatment-experienced pts who were failing their current ARV regimens, had at least 6 mos of prior treatment with at least 1 agent (2 agents for PIs) from 3 of 4 ARV drug classes, and/or documented resistance to 3 of the 4 ARV drug classes and VL >5000 were enrolled. Pts enrolled had a med.VL of 4.86 log and med. CD4 of 167. 41%? had baseline VL>100,000 and 58% had a baseline CD4 <200. Approximately 2/3 had an overall susceptibility score (OSS, the number of active drugs in the background regimen) of <3. The wk 24 ITT analysis in both studies demonstrated significantly greater reduction of VL from baseline in both MVC arms vs. placebo. Mean change in VL was -1.87, -1.96, and -0.99 login qd, bid, and placebo treated groups, respectively. VL suppression to <50 achieved in 44.0%, 45.3%, and 23.0% of respective groups. When stratified for ENF use in ENF-naive pts, mean VL reductions was significantly higher in ENF treated pts who had not previously used ENF [van der Ryst E, et al. 4th IAS Conference, Sydney, 2007, Abstract WEPEB115LB]. As expected, virologic response was better ifOBR contained active drugs. VL<50 achieved in 32.7%, 46.7%, 55.7%, and 59% of MVC-treated pts when they had 0, 1, 2, 3 active drugs in the OBR, respectively.