Schlecht et al Two subgroup analyses are of particular note. Among subjects with baseline viral loads 100,000 copies/mL EFV and maraviroc had similar rates of suppression to 50 copies/mL (71.6% vs 69.6% respectively). However, EFV was superior to maraviroc when baseline viral load was 100,000 copies (proportion with viral loads 50 copies/mL, 66.6% vs 59.6%). The two geographic regions also demonstrated a difference in response. Higher rates of response were observed with EFV in subjects from the Southern hemisphere (proportion with viral loads 50 copies/mL, 71.0% vs 62.1%) while similar rates of response were observed in subjects from the Northern Hemisphere. No underlying mechanism(s) has been clearly identiﬁed for this difference though clade variation between hemispheres may play a role. Rates of study drug discontinuation were similar in the two groups (26.9% for maraviroc and 25.2% for EFV) though reasons did differ. Subjects receiving EFV were more likely to stop due to adverse events (13.6% vs 4.2%; typically neuropsychiatric side effects such as abnormal dreams and dizziness) while subjects receiving maraviroc experienced higher rates of virologic failure (11.9% vs 4.2% in the EFV arm). Subjects taking maraviroc had fairly more frequent cases of bronchitis, and nose and throat infections. Further safety analyses demonstrated similar proportions of severe adverse events as well as severe (grade 3 or 4) liver enzyme disturbances, which were infrequent in both groups but nevertheless helped prompt an FDA “black box” warning regarding potential hepatotoxicity. Rates of new malignan- cies also did not differ between the treatment groups, which is a reassuring ﬁnding after initial concerns regard increased risk of malignancy with vicriviroc and potentially all CCR5 antagonists. Overall, maraviroc performed very well in the MERIT study but fell just short of rivaling EFV, an agent considered by some to be a standard worth embracing (Deeks 2006). Two identical studies, MOTIVATE 1 and MOTIVATE 2, are investigating maraviroc in treatment-experienced CCR5-tropic HIV-1 positive patients (Lalezari et al 2007; Nelson et al 2007). Identical in design, these phase IIb/III studies included subjects with: resistance to and/or 6 months experience with at least one antiretroviral agent from each of the three approved oral drug classes (at least 2 agents for protease inhibitors), HIV-1 viral load of 5,000 copies/mL and either off treatment or on a stable but failing antiretroviral regimen for at least four weeks. Subjects were stratiﬁed by enfurvitide use as well as viral load or 100,000 copies/mL. Applying genotypic and phenotypic test results, subjects were randomized to receive OBT plus placebo, maraviroc once daily or maraviroc twice daily (subjects receiving a PI other than tipranavir and/or delavirdine in their OBT received 150 mg while remaining subjects received 300 mg) in a 1:2:2 ratio. Interim results from planned 24-week analyses of both trials were very similar (see Table 1). MOTIVATE 1 enrolled 601 subjects mainly from North America, while MOTIVATE 2 enrolled 475 individuals mainly from Europe and Austra- lia. In each study the vast majority of subjects were male (84%–91%) and predominately white (81%–87%). Baseline characteristics were similar across treatment groups in both studies. Median baseline CD4+ cell counts ranged from 150 to 182 cells/mm3, median baseline viral loads from 4.84 to 4.89 log10 copies/mL, enfuvirtide (T-20, Fuzeon) use from 37% to 46% of subjects, and the majority of subjects had 2 or fewer active agents in their OBT (66%–76% and 62%–66% in MOTIVATE 1 and 2, respectively). Maraviroc arms in both studies demonstrated highly statistically signiﬁcant virologic and immunologic beneﬁts compared with the placebo groups. Maraviroc was very well tolerated, with no differences observed in the rate of study discontinuation or grade 3/4 adverse events across treat- ment arms. Importantly, no excess of cancer diagnoses or liver function abnormalities were observed in the maraviroc groups compared to placebo. Combined analysis of the two studies was performed to assess maraviroc’s contribution to viral suppression. As Table 1 24-week results of phase III maraviroc studies in CCR5-tropic subjects (Lalezari et al 2007; Nelson et al 2007) 24 week outcome MOTIVATE 1 and MOTIVATE 2 Results respectively Placebo + OBT MVC once daily + OBT Mean change in HIV-1 viral load from –1.03, –0.93 –1.82, –1.95 baseline (log10 copies/mL) HIV-1 viral load 400 copies/mL (%) 31.4, 23.1 54.7*, 55.5* HIV-1 viral load 50 copies/mL (%) 24.6, 20.9 42.2*, 40.8* Mean change in CD4+ cell count +52, +64 +107*, +112* from baseline (cells/mm3) *p 0.001 in comparison with placebo. Abbreviations: MVC, maraviroc; OBT, optimized background therapy. MVC twice daily + OBT –1.95, –1.97 60.4*, 61.3* 48.5, 45.6* +111*, +102* 480 Therapeutics and Clinical Risk Management 2008:4(2)