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Hardy et al J Acquir Immune Defic Syndr  Volume 55, Number 5, December 15, 2010 censored from the 96-week analysis. Those placebo recipients who had not reached a treatment failure endpoint were followed through week 96 for descriptive purposes but were not included in the efficacy analysis, as the studies became noncomparative after unblinding. Efficacy was assessed as the proportion of patients with plasma HIV-1 RNA ,50 copies per milliliter at week 48 who maintained virologic control through week 96. Virologic control was stratified as follows: (1) those who maintained ,50 copies per milliliter through week 96; (2) those with plasma HIV-1 RNAbetween 50 and 400 copies per milliliter at week 96; and (3) those with HIV-1 RNA .400 copies per milliliter at week 96 but who had not reached the criterion for virologic failure (on study, not failed). For the week-96 analysis, this failure criterion was specified as a rise in plasma HIV-1 RNA to at least 3 times the value at baseline. Safety Analysis This analysis includes all blinded data until EBT for study patients according to their original randomization. It does not include any open-label treatment data. Consistent with the change in study analysis plan at EBT, patient data could contribute to the efficacy analysis both before and after EBT; however, for the safety analysis, only data collected while patientswere receiving original blinded treatmentwere included. Hence, the safety analysis comprises a wide range of blinded exposure durations to maraviroc or placebo between week 48 and EBT. Safety data for both week 48 and EBT are presented. Due to the considerable differences in the range of exposures to blinded study therapy between the maraviroctreated and placebo-treated patients (Fig. 1B), the safety analysis examined both unadjusted and exposure-adjusted incidences of all-cause adverse events, AIDS-defining events (CDC category C), malignancies, and hepatic enzyme and function tests. Event countswere adjusted to 100 years of subject exposure, and if the same subject had more than 1 occurrence in the same event category, only the most severe occurrence was considered. Reported changes in hepatic transaminase and total bilirubin testswere limited to the occurrence ofmoderate-to-severe events (.3 3 ULN for transaminases and .1.5 3 ULN for total bilirubin) irrespective of baseline grading. Of note,MOTIVATE inclusion criteria allowed enrollment of otherwise eligible patients with mild-to-moderate elevations of transaminases (#5 3 ULN) or total bilirubin (#2.5 3 ULN). Statistical Methods Demographics and baseline characteristics were sum- marized using descriptive statistics. Unless otherwise noted, percentages are based on the total number of subjects initially randomized to the 3 study arms. Median change from baseline in CD4+ T-cell count at week 96 was calculated using the last available observation on each subject. The study was designed by the sponsor, Pfizer Global Research and Development, with input from the study investigators. Data were gathered by the study investigators and the sponsor, with data summaries provided by an independent statistician (Covance CAPS, Berkshire, United Kingdom) from the Statistical Data Analysis Center to the data and safety monitoring board for periodic review. All statistical 560 | www.jaids.com analyses were carried out by the study sponsor according to a predefined plan. One of the authors wrote the paper, with extensive input from the study team. The study teamconfirms the accuracy and completeness of the data and analysis as presented. RESULTS The combinedMOTIVATE 1 and 2 studies included 1049 randomized patients who received at least 1 dose of maraviroc every day (n = 414),maraviroc twice a day (n = 426), or placebo (n = 209). Patient demographic and baseline characteristicswere similar across the 3 treatment groups (Table 1). Two-thirds of enrolled patients received OBTs with 2 or fewer potentially active antiretroviral agents, assessed by the overall regimen susceptibility score.11 More than 40% of patients received enfuvirtide as part of their OBT; 59% of this group were receiving enfuvirtide for the first time. Less than 15% of subjects in MOTIVATE received tipranavir as a new protease inhibitor. The duration of study treatment exposure was sub- stantially greater for the maraviroc-treated patients (median 73 weeks, range up to 135 weeks) compared with those receiving placebo (median 20weeks, range up to 132weeks) at EBT (Fig. 1B). As expected, 47% of placebo patients had experienced treatment failure or drug intolerance and rolled over to openlabel maraviroc twice a day at EBT. In contrast, 58% of maraviroc every day patients and 61%of maraviroc twice a day patients had not experienced treatment failure or intolerance at EBT and rolled over to open-label maraviroc twice a day. Efficacy Analysis For study subjects assigned to maraviroc twice a day, whose treatment remained the same preweek and postweek 48, 41% had HIV-1 RNA ,50 copies per milliliter at week 96, compared with 46% at week 48 (Fig. 2A). For those assigned to maraviroc every day, for whom postweek 48 data included TABLE 1. Demographics and Baseline Characteristics Treated, n = 1049 Mean age, yrs (range) Female, n (%) White, n (%) Mean CD4+ cell count, (cells/mm3)a Mean HIV-1 RNA, (log10 copies/mL)b #2 active drugs in OBT, %c Enfuvirtide in OBT, % Enfuvirtide sensitive and first use, % Tipranavir in OBT, % Placebo + OBT, n = 209 MVC Every Day + OBT, n = 414 51 (12) 336 (81) 171 4.86 66.0 40.6 22.3 15.9 MVC Twice a Day + OBT, n = 426 46 (29–72) 46 (17–75) 46 (21–73) 24 (12) 178 (85) 171 44 (10) 363 (85) 167 4.86 66.0 43.5 28.0 13.9 4.85 69.7 42.7 26.0 14.8 MVC, maraviroc. acalculated for each patient as the mean of up to two pre-dose assessments (screening and baseline). bcalculated for each patient as the mean of up to three pre-dose assessments (screening, randomization, and baseline). caccording to overall susceptibility score at screening. Includes all patients who received at least one dose of study medication. q 2010 Lippincott Williams & Wilkins http://www.jaids.com

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