Maraviroc: The first CCR5 antagonist for the treatment of HIV

Maraviroc is the first CCR5 antagonist approved for the treatment of HIV-1 infection. The use of maraviroc is associated with significant decreases in HIV viral load and increases in CD4 counts in antiretroviral treatment-experienced patients with CCR5-tropic virus when used as an add-on to optimized antiretroviral treatment. In clinical trials, patients with dual- or mixed-tropic virus (which can infect cells using CXCR4 and/or CCR5 receptors) who were treated with maraviroc demonstrated no difference in HIV viral load compared with patients who received placebo. A recent study compared maraviroc plus lamivudine/zidovudine with efavirenz plus lamivudine/zidovudine; maraviroc did not demonstrate noninferiority when undetectable virus was defined as <50 copies/mL; however, maraviroc did meet noninferiority criteria when undetectable virus was defined as <400 copies/mL. Maraviroc is not recommended for patients with CXCR4-tropic, dual-tropic, or mixed-tropic virus; for antiretroviral-naive patients; or for..

Key Points


Approximately 40 million people worldwide are living with HIV; 4.3 million new cases of HIV and AIDS were diagnosed in 2006.1 The number of people affected by HIV continues to increase, in part because of increased survival likely resulting from improvements in antiretroviral medication regimens.1

In order for HIV to infect cells, the virus must attach itself to both a CD4 receptor and a G protein-coupled receptor (eg, a CCR5 or CXCR4 receptor). If the viral strain relies on the CXCR4 coreceptor only, the virus is considered CXCR4-tropic; if the strain relies on the CCR5 coreceptor only, the virus is considered CCR5-tropic. The virus may also use a combination of these coreceptors to infect cells; if both CXCR4 and CCR5 are used (the virus is both CXCR4-tropic and CCR5-tropic), the virus is considered mixed-tropic; if the viral strain can use either CCR5 or CXCR4 coreceptors to infect cells, the virus is considered dual-tropic.4

FDA approved maraviroc (Selzentry, Pfizer) on August 6, 2007, for combination antiretroviral treatment of adults with CCR5-tropic HIV-1.3 Maraviroc is the first CCR5 antagonist to be approved for the treatment of HIV; the drug is considered a fusion inhibitor and works outside the cell to prevent the entry of HIV into the cell.5


Maraviroc (exo-4,4-difluoro-N-[3-[3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1(S)-phenylpropyl]cyclohexanecarboxamide) has a 90% inhibitory concentration (IC90) of 2.03 nanomolar.5,6 Maraviroc's pharmacology is unique among FDA-approved antiretroviral agents; the drug inhibits the binding of HIV to the CCR5 receptors. Maraviroc's ability to block the CCR5 receptor is especially significant because CCR5 appears to be the coreceptor primarily used during the early stages of HIV.7,8 In later stages of HIV, approximately 50% of infected patients have HIV strains that may continue to use only CCR5; other patients may have viral strains that either switch completely to CXCR4 receptors or that replicate using a combination of both coreceptors.7,8

Maraviroc is administered orally and has good solubility within a pH range of 1 to 7.5.5 Most HIV medications have poor solubility, resulting in regimens that require high pill burdens daily for each medication. The high solubility of maraviroc makes a low pill burden possible; the recommended dosing regimen is 1 tablet BID.5


Because HIV can infect cells using CCR5, CXCR4, or a combination of receptors, researchers have sought to establish whether inhibition of CCR5 would cause the virus to begin to utilize the CXCR4 receptor. Many resistance studies have been conducted, both to assess whether this receptor switch would take place and to determine whether the virus would demonstrate resistance to maraviroc.9–12 One such study assessed resistance to increasing concentrations of maraviroc in 1 lab-adapted and 6 CCR5-tropic HIV virus strains.9,10 Two of the 6 CCR5 strains demonstrated resistance to maraviroc. Importantly, this resistance was not demonstrated as a switch to the use of CXCR4 receptors but instead as changes in the amino acid sequence of the virus.9,10 Specifically, the strains had the following mutations: in the first virus strain, CC1/85: mutations of A316T and I323V in the V3 envelope and T163K, N355Y, and S405A in other areas; and in the second virus strain, RU570: deletion of QAI at positions 315 to 317 in the V3 envelope with additional other mutations of D389N, N422K, and E509K.9,10 After additional passages of the virus in the absence of maraviroc for 20 weeks, all mutations (except for I323V from the first virus strain) reverted back to the original sequence.10 The authors suggested that the mutations that reverted were potentially associated with a less-fit virus.10

Mori et al11 further evaluated resistance in vivo. The investigators assessed isolates obtained from phase 3 studies investigating patients with CCR5-tropic, maraviroc-resistant virus. Specifically, resistance criteria for inclusion were either plateau <95% in maximal percentage inhibition (MPI), IC50 fold-change compared to reference virus (FC) outside the normal range (>1.95), or a >2-fold change in IC50 between baseline and on-treatment samples. Most of the identified resistance (occurring in 6 of 15 patients) was associated with the virus developing the ability to bind to CCR5 in spite of being bound to maraviroc, which was evidenced by plateaus of <95% MPI. These changes in the MPI plateaus were associated with amino acid mutations in the V3 region of the virus envelope.11 In addition to resistance being associated with MPI, 1 patient's isolate demonstrated a 3-fold increase in the IC50.

The incidence of tropism change was further evaluated in 64 HIV-positive patients with CCR5-tropic virus who received maraviroc as part of 10-day short-term efficacy and tolerability trials; 62 patients were included in the final study results.12 At Day 11, the investigators observed CXCR4-tropic virus in addition to the original CCR5-tropic virus in 2 of the 62 patients. Further analysis demonstrated that both of these cases were unlikely to be switches; the CXCR4-tropic virus probably developed from a small quantity of CXCR4 virus that existed before therapy was initiated. After maraviroc treatment was discontinued, 1 of the 2 patients with dual tropism reverted back to having CCR5-tropic virus only; the other patient continued to have mixed-tropic virus at Day 203.

Additional in vivo resistance data were obtained from phase 3 studies.13 The researchers identified CXCR4-tropic virus in 16 patients who received maraviroc and in 4 patients who received placebo. A total of 14 patients had emergent virus that appeared similar to CXCR4-tropic virus at baseline. This CXCR4 virus was initially present in 1% to 6% of 10 patients' virus and in >10% of 4 patients' virus. The isolates of the remaining 6 patients appeared to be distinct, with 7 to 17 mutations in the V3 portion of the envelope. Active treatment with maraviroc was associated with the suppression of the majority of CCR5-tropic virus but was not associated with suppression of CXCR4-tropic or mixed-tropic viruses among patients with dual- or mixed-tropic virus.13


The pharmacokinetics of maraviroc were investigated in both healthy and HIV-positive adults.5,14–18 Table 1 illustrates the pharmacokinetic properties demonstrated in HIV-positive patients receiving maraviroc 300 mg BID and in healthy men receiving maraviroc 100 mg BID.7,19 A comparison of ethnic pharmacokinetic differences demonstrated no differences between healthy Caucasian and Asian male volunteers.16 In clinical studies, peak concentrations occurred approximately 0.5 to 4 hours after dosing.5,14 Volume of distribution was estimated to be ~2.8 L/kg; approximately 75% of the maraviroc dose was bound to plasma proteins.5,17,18 The bioavailability of maraviroc ranged from 23% to 33% (lower for lower doses).5,7,18 The differences in bioavailability are thought to be related to saturation of P-glycoprotein.17 Approximately 65% of maraviroc was metabolized, primarily by CYP3A.5 Additionally, 26.4% of the drug was eliminated unchanged in the feces, and 8.3% was eliminated unchanged in the urine.5 Maraviroc concentrations may be decreased by ≤33% if the drug is taken with a high-fat meal, but no food restrictions have been recommended because this change in plasma concentration was not observed to affect viral load. Additionally, the decrease in concentration was minimized when maraviroc was taken in combination with cytochrome P450 (CYP450) inhibitors, which are commonly included in HIV treatment regimens.5,7


Phase 2a trials. The phase 2a studies A4001007 and A4001015 compared maraviroc with placebo in 82 asymptomatic patients with CCR5-tropic virus.7 Maraviroc was administered at doses of 25 to 600 mg/d (administered QD or BID) for 10 days. The use of maraviroc ≥200 mg/d was associated with decreases in HIV viral load >1 log10 in all patients with CCR5-tropic virus.

The next phase 2b/3 studies were the Efficacy and Safety of Maraviroc plus Optimized Background Therapy In Viremic, ART-Experienced Patients Infected With CCR5-Tropic HIV-1 (MOTIVATE) 1 and 2 studies, which included a total of >1,000 patients. Both studies were double-blind, randomized, controlled trials that evaluated the efficacy of maraviroc plus optimized background therapy in viremic antiretroviral-experienced patients with CCR5-tropic HIV.22–25 The difference between the studies was location. MOTIVATE 1 was conducted in the United States and Canada; MOTIVATE 2 was conducted in Australia, Europe, and North America. In both trials, patients were randomized 2:2:1 to maraviroc QD, maraviroc BID, or placebo. Maraviroc was administered at a dose of 300 mg QD or BID unless the patient was receiving delavirdine or a PI (except tipranavir/ritonavir), in which case patients were administered 150 mg per dose. The optimized antiretroviral background therapy included 3 to 6 medications (PIs [except daurinavir], NRTIs, NNRTIs, and fusion inhibitors) that best treated the patient's virus. Inclusion criteria for MOTIVATE 1 and 2 included patients who were triple-class-experienced, exhibited only CCR5-tropic virus, and who had viral loads ≥5,000 copies/mL.

The primary end point of both studies was a mean change in HIV viral load at 24 weeks.22,23 Secondary analyses included the percentage of patients with undetectable viral load (<400 copies/mL or <50 copies/mL) at 24 weeks and the efficacy of maraviroc when combined with other antiretroviral medications as measured by mean change in CD4 count.24,25 Individual study results are illustrated in Table 2.20–23,26 Baseline characteristics were similar between groups and included CD4 counts of 150 to 182 cells/mm3 and HIV viral loads of 4.84 to 4.89 log10 copies/mL.22,23 Overall, treatment with maraviroc QD or BID was associated with significant decreases in viral load from baseline, higher percentages of patients achieving undetectable HIV viral loads, and significant increases in CD4 counts compared with placebo.22,23 A subgroup analysis demonstrated that a greater number of patients with no other active drug (ie, resistant to background therapy), low initial CD4 counts, or high baseline HIV viral loads achieved undetectable viral loads when treated with maraviroc BID compared with QD.24 Combination therapy with maraviroc plus either lopinavir/ritonavir or enfuvirtide as active drug (ie, not resistant) and as a first-time exposure increased the likelihood of achieving undetectable viral loads.25

The most recent phase 3 trial was the Maraviroc Versus Efavirenz Regimens as Initial Therapy (MERIT) study, which was a multicenter, randomized, double-blind, noninferiority evaluation that compared maraviroc plus lamivudine/zidovudine with efavirenz plus lamivudine/zidovudine.26 This was the first study to evaluate maraviroc in antiretroviral-naïve patients, defined as patients with virus that demonstrated susceptibility to all study medications. Patients in both groups had similar baseline median CD4 counts (maraviroc, 241 cells/mL; efavirenz, 254 cells/mL) and HIV viral loads (median, 4.9 log10 copies/mLin both groups). The primary objective was to determine whether maraviroc plus lamivudine/zidovudine was noninferior to efavirenz plus lamivudine/zidovudine with regard to the percentage of patients who achieved HIV viral loads <400 copies/mL or <50 copies/mL. At Week 48, maraviroc demonstrated noninferiority to efavirenz in achieving HIV viral loads <400 copies/mL but not in achieving HIV viral loads <50 copies/mL. Patients in the maraviroc group were more likely to discontinue treatment because of lack of efficacy compared with patients receiving efavirenz (11.9% vs 4.2%); however, maraviroc-treated patients were less likely to report a grade 3 or 4 adverse event or withdraw from the study because of adverse effects compared with patients receiving efavirenz (4.1% vs 13.6%).