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J Acquir Immune Defic Syndr  Volume 55, Number 5, December 15, 2010 patients compared with those receiving placebo.3,4 In addition, the adverse event profile of maraviroc was similar to that of placebo with similar incidences of both all-cause and treatment-related adverse events, AIDS-defining events (CDC category C), non–AIDS-defining malignancies and grade 3 or 4 hepatic transaminase elevations.3,5,6 As with any novel class of medication, concerns regarding maraviroc’s long-term safety and durability of virologic efficacy must be addressed. Will altering the conformation of CCR5, an important part of the human chemokine system, have untoward, downstream immunologic consequences? What about adverse events seen with other agents in this class (eg, elevated liver enzymes and increased incidence of malignancies)7–10 or ones potentially resulting from maraviroc novel mechanism of action (eg, new, unusual, or reactivated infections)? These concerns warrant continuing evaluation and report of long-term clinical data with this new agent. To this end, we report the 96-week safety and efficacy analyses from the combined MOTIVATE studies. METHODS Study Subjects and Design The design and enrollment criteria of the MOTIVATE 1 and 2 studies have been described in detail previously (Fig. 1A).3 Briefly, both studies enrolled patients aged 16 years or olderwith only R5 HIV-1 detected at screening using the original Trofile assay (Monogram Biosciences, South San Francisco, CA), plasma HIV-1 RNA .5000 copies per milliliter and experience with or resistance to at least 3 antiretroviral drug classes. Patients were randomized 2:2:1 to receive maraviroc twice a day or every day or identical placebo combined with an investigator-selected optimized background therapy (OBT) of 3–6 other antiretrovirals based on treatment history and viral resistance testing at screening (Phenosense GT, Monogram Biosciences). Of note, agents that were investigational at the start of the study, such as darunavir, etravirine, and raltegravir, were excluded from the OBT. Patients receiving potent CYP3A4 inhibitors (ritonavirboosted protease inhibitors other than tipranavir or delavirdine) received 150 mg of maraviroc every day or twice a day, whereas others received 300 mg dosed identically. As the 2 studies had identical designs, similar enrollment demographics and baseline characteristics, pooled analysis of their data was conducted. Patients received their double-blinded, randomized study treatment until the last enrolled patient reached the week-48 visit. At this point, all patients’ study therapy was unblinded, and maraviroc every day and twice a day recipients who had not experienced treatment failure during the study were offered open-label maraviroc twice a day. Thus, therewas a wide range of study drug exposure at the end of blinded treatment (EBT), depending on when a patient was enrolled into the study. Placebo recipients with a history of treatment failure or drug intolerance were also offered open-label maraviroc twice a day. Treatment failure was defined as 1 of 4 virologic endpoints confirmed by a second consecutive measurement within 14 days as follows: (1) increase in HIV-1 RNA to $3 times the baseline level at or after week 2; (2) decrease of,0.5 log10 8; (3) decrease of ,1.0 log10 copies per milliliter at or after week copies per milliliter at or after q 2010 Lippincott Williams & Wilkins FIGURE 1. A, Study design, and B, duration of blinded study treatment. A, Patients were stratified by enfuvirtide use and HIV-1 RNA , or . 100,000 copies per milliliter. Patients without treatment failure at end of blinded therapy (last patient week-48 visit) were given the option to roll over to open-label MVC twice a day. Week 96 efficacy analysis included all patients Post week 48. Safety analysis included only patients on blinded randomized therapy between individual week 48 visit and end of blinded therapy. B, Median (bars) and range (lines) of study treatment duration at indicated study time point. week 8, after a decrease of$2.0 log10 copies per milliliter; and (4) increase in HIV-1 RNA to$5000 copies per milliliter after a decrease to ,400 copies per milliliter had been recorded on 2 consecutive visits. The study protocol was approved by the institutional review board or independent ethics committee at each study center. Written informed consent was obtained from all participants. The studies were performed in accordance with International Conference on Harmonization Good Clinical Practice guidelines and applicable local regulatory requirements and laws. Efficacy Analysis Patients receiving maraviroc (twice a day or every day) without a history of treatment failure or intolerance and plasma HIV-1 RNA ,50 copies per milliliter at their week-48 visit were followed through week 96. Data between weeks 48 and 96 were derived from a mixture of blinded and unblinded therapy that varied due to individual differences in the duration of blinded therapy between week 48 and EBT. In this analysis, patients were categorized according to their originally randomized treatment assignment irrespective of subsequent change to open-label maraviroc twice a day. Placebo recipients who began open-label maraviroc twice a day at EBT were www.jaids.com | 559 Maraviroc 2-Year Safety and Efficacy http://www.jaids.com

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