Maraviroc: A Coreceptor CCR5 Antagonist for Management of HIV Infection

Raymond Yost; Timothy R. Pasquale; Eric G. Sahloff

Disclosures

Am J Health Syst Pharm. 2009;66(8):715-726. 

In This Article

Clinical Efficacy

Evidence for the clinical efficacy and safety of maraviroc in treatment-experienced patients was obtained from the analysis of two 48-week Phase IIb/III trials in Europe, North America, and Australia: MOTIVATE 1[9] and MOTIVATE 2.[10] In addition to these studies, maraviroc was studied in treatment-naive patients in the MERIT study.[11] While the MOTIVATE and MERIT studies focused on CCR5-tropic HIV, study A4001029 tested the potential role of maraviroc in dual or mixed tropic infection.[28]

MOTIVATE 1

In this randomized, double-blind, placebo-controlled Phase IIb/III trial conducted in the United States and Canada, subjects verified to have CCR5-tropic virus were enrolled in a 1:2:2 fashion into placebo, maraviroc once-daily, or maraviroc twice-daily groups.[9] All subjects received an OBR consisting of three to six antiretrovirals with or without enfuviritide selected according to treatment history and resistance testing. Darunavir could not be part of the OBR in this study. Due to drug interactions with concurrent PI use (excluding ritonavir-boosted tipranavir), a maraviroc dosage of 150 mg once or twice daily orally was used for subjects receiving a PI in the OBR. Maraviroc 300-mg doses were administered once or twice daily in all other subjects. Subjects were enrolled if they had CCR5-tropic HIV-1, had HIV RNA concentrations of ≥5000 copies/mL, had a stable antiretroviral regimen prestudy or no antiretrovirals for four or more weeks, were at least 16 years old, and had documented resistance against or class experience with each of three classes of antiretrovirals or two PIs for at least six months. The change from baseline HIV-1 RNA levels (≥1 log decrease from baseline) at 48 weeks was the primary virological efficacy endpoint, while secondary endpoints assessed the percentage of subjects achieving HIV-1 RNA concentrations of < 50 and < 400 copies/mL, immunologic response (change in CD4 cell count from baseline), and time to treatment failure.[9]

Baseline characteristics were similar among groups with mean HIV-1 RNA concentrations of 4.85, 4.86, and 4.84 log copies/mL for the groups receiving maraviroc once daily (n = 232), maraviroc twice daily (n = 235), and placebo (n = 118), respectively.[9] Median CD4 cell counts were not significantly different among the groups receiving maraviroc once daily, maraviroc twice daily, and placebo (168, 150, and 160 cells/mm3, respectively). The 48-week intent-to-treat analysis showed a significant decrease in mean HIV-1 RNA concentrations for subjects receiving maraviroc once daily (change, -1.66 log copies/mL; difference, -0.85; 97.5% confidence interval [CI], -1.22 to -0.49) and maraviroc twice daily (change, -1.82 log copies/mL; difference, -1.02; 97.5% CI, -1.39 to -0.66) compared with placebo (change, -0.80 log copy/mL). Mean CD4+ cell counts significantly increased by 113 and 122 cells/mm3 in the maraviroc once-daily and maraviroc twice-daily groups versus an increase of 54 cells/mm3 in the placebo (OBR only) group (p < 0.0001). Percentages of subjects attaining HIV-1 RNA concentrations of < 400 and < 50 copies/mL in the maraviroc once-daily, maraviroc twice-daily, and placebo groups were 50.9% and 41.8%, 57.5% and 46.8%, and 22.0% and 16.1%, respectively. The differences between the maraviroc-treatment and placebo groups were significant at 48 weeks (p < 0.0001). First-time users of enfuvirtide achieved HIV-1 RNA concentrations of < 50 copies/mL in 64%, 61%, and 27% of subjects in the maraviroc once-daily, maraviroc twice-daily, and placebo groups, respectively. Grade 3 or 4 adverse events were reported in 26%, 33%, and 32% in the maraviroc once-daily, maraviroc twice-daily, and control groups, respectively. Six percent of subjects in the maraviroc once-daily and placebo groups and 5% in the maraviroc twice-daily group discontinued therapy due to adverse events. Overall, no significant differences were noted among groups regarding toxicities.

MOTIVATE 2

MOTIVATE 2 was conducted in Europe, Australia, and North America.[10] Both MOTIVATE 1 and MOTIVATE 2 used the same inclusion criteria and assessed the same virological and immunologic endpoints. As in MOTIVATE 1, darunavir use was restricted. Mean baseline HIV-1 RNA concentrations were similar among groups: 4.89, 4.87, and 4.84 log copies/mL in the placebo (n = 91), maraviroc once-daily (n = 182), and maraviroc twice-daily (n = 191) groups, respectively. Median baseline CD4+ cell counts were similar for the placebo (174 cells/mm3), maraviroc once-daily (173 cells/mm3), and maraviroc twice-daily (182 cells/mm3) groups. The mean change in HIV-1 RNA concentration from baseline was -0.76 log copy/mL (placebo), -1.72 log copies/mL (maraviroc once daily), and -1.87 log copies/mL (maraviroc twice daily). An increase in mean CD4+ cells from baseline was noted for the maraviroc once-daily and twice-daily groups (increase of 121 and 128 cells/mm3, respectively) compared with the placebo group (increase of 69 cells/mm3). Significantly more subjects in the maraviroc-treated groups were able to achieve HIV-1 RNA concentrations of < 400 and < 50 copies/mL (53% and 45% in the maraviroc once-daily group, respectively, p < 0.0001; 55% and 46% in the maraviroc twice-daily group, respectively, p < 0.0001; and 23% and 17% in the placebo group, respectively). The percentage of subjects who discontinued maraviroc due to drug toxicity ranged from 4.4% to 5.2% across the three groups.[10]

MOTIVATE 1 and 2: 48-week Pooled Data Analysis

Since MOTIVATE 1 and MOTIVATE 2 used identical study designs and endpoints, the results of the two trials were pooled for further analysis.[29] The efficacy endpoints have been reported for each MOTIVATE study above. In regard to adverse effects, discontinuation attributed to toxicity was approximately 5-6% in all groups. Grade 3 or 4 adverse events were reported in approximately 29% in the placebo and maraviroc once-daily groups and 35% in the maraviroc twice-daily group. Grade 3 or 4 elevations in hepatic transaminase levels were seen in < 4% of subjects across all three study groups. The most common adverse effects reported in all groups were diarrhea (> 20%), nausea (> 15%), fatigue (> 10%), and headache (> 10%). Upper-respiratory-tract infections were reported in > 10% of the maraviroc once-daily and twice-daily groups and in approximately 5-6% of the placebo group. No statistical analysis of adverse events among groups was reported.

Causes of treatment failure in the MOTIVATE 1 and 2 trials have been assessed.[17] Maraviroc treatment failure occurred in 242 subjects (23%).[17] In each maraviroc-treated group, 7.5% of subjects who did not respond to maraviroc had CCR5-tropic virus at baseline but had non-CCR5-tropic virus at the time of virological failure, compared with only 1.9% in the placebo group. Approximately 4% of individuals in each maraviroc-treated group and 38% of subjects in the placebo group remained CCR5-tropic at the time of virological failure. The presence of non-CCR5-tropic populations at screening or baseline was considered as a potential cause of maraviroc failure, as non-CCR5 failure occurred an average of 30 days sooner than did CCR5 failure.[17] The rate of CDC category C AIDS-defining events was low in all treatment groups (< 7%).[29]

MOTIVATE 1 and 2: Once-daily Versus Twice-daily Dosing

Pooled 24-week data from MOTIVATE 1 and 2 were analyzed to assess the safety and efficacy of once-daily versus twice-daily maraviroc plus OBRs.[30] As with MOTIVATE 1 and 2, the primary efficacy endpoint was change in HIV-1 RNA levels from baseline to 24 weeks. Secondary endpoints included the percentage of subjects achieving HIV-1 RNA concentrations of < 50 and < 400 copies/mL. For further subgroup analysis, subjects were stratified by baseline HIV-1 RNA concentrations (> 100,000 copies/mL), CD4+ cell count, and number of active drugs in the OBR. A decrease of 1.88 log and 1.96 log copies/mL was reported for the maraviroc once-daily (n = 414) and maraviroc twice-daily (n = 426) groups, respectively, compared with 0.99 log copy/mL in the control group (n = 209). Significantly more subjects in the once-daily and twice-daily groups achieved HIV-1 RNA concentrations of < 50 copies/mL (44% and 45%, respectively) compared with subjects receiving placebo (23%) (p < 0.0001). In the subgroup analysis across baseline HIV-1 RNA and CD4+ strata, the maraviroc-treated groups were more likely to achieve HIV-1 RNA concentrations of < 50 copies/mL versus placebo. In a comparison of the maraviroc once- and twice-daily groups, a trend toward better virological efficacy was reported for the group receiving the twice-daily regimen compared with the once-daily regimen.

MERIT

This randomized, double-blind, Phase III noninferiority study conducted in North America, South America, Australia, and Europe compared maraviroc 300 mg twice daily to efavirenz 600 mg once daily in treatment-naive patients, with both groups receiving zidovudine 300 mg plus lamivudine 150 mg twice daily.[11] Patients were enrolled if they had CCR5-tropic HIV-1 and an HIV RNA concentration of > 2000 copies/mL. Exclusion criteria included an active and untreated opportunistic infection, current treatment for an opportunistic infection or an unexplained temperature of > 38.5 °C for more than 7 days, prior treatment with antiretroviral therapy for more than 14 days, suspected acute HIV infection, and genotypic or phenotypic resistance to efavirenz, zidovudine, or lamivudine.

A total of 721 patients were randomized to receive either maraviroc twice daily (n = 360) or efavirenz (n = 361); a trial of an additional 205 patients receiving maraviroc 300 mg once daily was discontinued after 16 weeks due to lack of noninferiority to efavirenz.[11] For this analysis, noninferiority was defined as a difference of no more than -10% (lower bound of 97.5% CI) between groups. Patients were stratified by baseline viral load and geographic location (Northern versus Southern Hemisphere). Primary endpoints included the percentage of subjects achieving HIV-1 RNA concentrations of < 50 and < 400 copies/mL at 48 weeks. The mean baseline HIV-1 RNA concentrations were 4.88 log copies/mL in the efavirenz group and 4.86 log copies/mL in the maraviroc group. Median baseline CD4+ cell counts were 254 and 241 cells/mm3 for the efavirenz and maraviroc groups, respectively. Maraviroc was found to be noninferior to efavirenz in achieving HIV-1 RNA concentrations of < 400 copies/mL at week 48 (73.1% versus 70.6% for efavirenz and maraviroc, respectively) (difference, -3.0%; lower bound of 97.5% CI, -9.5%). For the endpoint of HIV RNA concentrations of < 50 copies/mL, maraviroc was not noninferior to efavirenz (65.3% of patients treated with maraviroc versus 69.3% of patients treated with efavirenz) (difference, -4.2%; lower bound of 97.5% CI, -10.9%). In patients with baseline viral loads exceeding 100,000 copies/mL, HIV-1 RNA concentrations of < 50 copies/mL were achieved in 66.6% and 59.6% of patients in the efavirenz and maraviroc groups, respectively. In patients with baseline viral loads of < 100,000 copies/mL, 71.6% in the efavirenz group and 69.6% in the maraviroc group achieved HIV-1 RNA concentrations of < 50 copies/mL. At 48 weeks, maraviroc-treated patients achieved a significantly larger mean increase from baseline in CD4+ cell count (170 cells/mm3) compared with efavirenz (144 cells/mm3). While there was little difference in the Northern Hemisphere groups achieving viral loads of < 50 copies/mL, a notable difference was seen in the Southern Hemisphere groups (71% in the efavirenz group versus 62.1% in the maraviroc group). Overall, discontinuation rates were similar between groups (near 25%). Through the 48 weeks of the MERIT trial, more patients discontinued maraviroc due to lack of efficacy (43 of 360 patients, 11.9%) than discontinued efavirenz (15 of 361 patients, 4.2%). However, more subjects discontinued efavirenz due to adverse events (49 of 361 patients, 13.6%) than discontinued maraviroc (15 of 360 patients, 4.2%). Grade 3 or 4 adverse effects regarding liver function test values were reported in < 4% of either group. The use of efavirenz was associated with a slightly greater increase in lipids from baseline compared with maraviroc. Maraviroc is not currently approved for use in patients not previously treated with antiretrovirals.

Maraviroc in CXCR4 Dual- or Mixed-tropic HIV (A4001029)

The possibility of a shift to CXCR4-tropic virus due to selective pressure associated with the use of CCR5 antagonists, particularly in dual- or mixed-tropic populations, is concerning. The goal of study A4001029 was to assess the efficacy and safety of maraviroc in patients identified to have dual- or mixed-tropic R5/X4 HIV-1 populations.[28] In this ongoing, double-blind, placebo-controlled study, maraviroc 300 mg once daily and 300 mg twice daily plus OBR were compared with OBR alone. In addition to a viral load of > 5000 copies/mL and documented multiple-class experience or resistance, dual- or mixed-tropic HIV-1 virus had to be identified for patient inclusion in the trial. Detection of CCR5-tropic virus resulted in exclusion from this study. Study endpoints included HIV-1 RNA change from baseline, percentage of patients achieving viral loads of < 400 and < 50 copies/mL, and change in CD4+ cell count. A total of 167 subjects were identified with dual- or mixed-tropic virus at baseline. At 24 weeks, the mean change in viral RNA copies from baseline was similar among all groups at -0.91, -1.2, and -0.97 log copies/mL for the maraviroc once-daily, maraviroc twice-daily, and placebo groups, respectively. These values for maraviroc were neither superior nor noninferior to placebo for this endpoint. Statistical significance was only shown during post hoc analysis of CD4+ cell counts in which maraviroc twice daily showed a mean increase of 62.4 cells/mm3 versus a mean increase of 35.7 cells/mm3 in the placebo group (p < 0.05). For patients with dual- or mixed-tropic virus, there was no statistical improvement in the percentage of patients achieving undetectable HIV RNA concentrations (either < 400 or < 50 cells/mL).

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