HIV This Week

Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, Horban A, Nadler J, Clotet B, Karlsson A, Wohlfeiler M, Montana JB, McHale M, Sullivan J, Ridgway C, Felstead S, Dunne MW, van der Ryst E, Mayer H; MOTIVATE Study Teams. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008; 2;359(14):1429-41.

CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. Gulick and colleagues conducted two double-blind, placebo-controlled, phase 3 studies—Maraviroc versus Optimized Therapy in Viraemic 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 millilitre. 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 based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks. A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per millilitre, and the median CD4 cell count was 169 per cubic millimetre. 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 millilitre 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 millilitre, 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 millilitre (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 millimetre, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimetre, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups. 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 optimized background therapy.

Editors’ note: Current antiretroviral treatment targets one or more of three HIV-1 proteins: reverse transcriptase, protease, and glycoprotein envelope subunit gp41. People with a delta-32 deletion of the CCR5 gene are relatively resistant to HIV infection (if both gene copies have the deletion) or have slower disease progression (if one gene copy has the deletion, resulting in fewer CD4 cells expressing chemokine receptor 5 [CCR5] on their surface). When the predominant virus population is R5 tropic, the virus is looking to dock on the CCR5 receptor. It cannot bind if Maraviroc blocks the site. Inhibiting a host cellular immune function rather than a viral function, Maraviroc is a welcome addition to the treatment chest. More study is needed of its interactions with other new antiretroviral drugs and to determine the optimal timing of its introduction into a regimen. The logistical and financial burden of having to test the tropism (R5 or X4) of the virus that a patient has is an important impediment to its use for treatment but would not affect its use in a preventive product such as a microbicide.