Maraviroc for previously treated patients with R5 HIV-1 infection

Abstract

Background: CC chemokine receptor 5 antagonists are a new class of antiretroviral agents.

Methods: We conducted two double-blind, placebo-controlled, phase 3 studies--Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2--with patients who had R5 human immunodeficiency virus type 1 (HIV-1) only. They had been treated with or had resistance to three antiretroviral-drug classes and had HIV-1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy (OBT) based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks.

Results: A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV-1 RNA from baseline was greater with maraviroc than with placebo: -1.66 and -1.82 log(10) copies per milliliter with the once-daily and twice-daily regimens, respectively, versus -0.80 with placebo in MOTIVATE 1, and -1.72 and -1.87 log(10) copies per milliliter, respectively, versus -0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV-1 RNA levels of less than 50 copies per milliliter (42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P<0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo (increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups.

Conclusions: Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV-1 who were receiving OBT. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

Figure 1. Screening, Randomization, and Completion of Treatment

Exclusion from the studies for other reason included failure to meet all inclusion criteria or meeting one or more exclusion criteria — for example, patients with a screening HIV-1 RNA level of less than 5000 copies per milliliter, no evidence of triple-class experience or triple-class–resistant virus, or an excluded laboratory-test value. Lack of efficacy was assessed by the study investigator on the basis of protocol-defined criteria for treatment failure, as discussed in the Methods section. The analysis was limited to study patients who both underwent randomization and received at least one dose of the study drug. OBT denotes optimized background therapy.

Figure 2. Treatment Responses at 48 Weeks

HIV-1 RNA suppression (Panel A), the time to protocol-defined treatment failure (Panel B), and the change in CD4 cell count (Panel C) are shown as pooled data for MOTIVATE 1 and MOTIVATE 2. To review the same data for each individual study, see the Supplementary Appendix, available with the full text of this article at www.nejm.org. All patients received at least one dose of study treatment. The HIV-1 RNA value was defined as the baseline level if missing or if the patient discontinued treatment before the end of the 48-week study period. For the CD4 cell-count analysis, the last observation was carried forward. MVC denotes maraviroc, and OBT optimized background therapy.