expected, with an increasing number of active agents in the OBT, the greater the likelihood of reaching an undetectable viral load. Subjects in the maraviroc arms achieved a much higher proportion of complete viral suppression when two or fewer active agents were present in the OBT in comparison with the placebo arm. This is consistent with numerous prior studies demonstrating that two active agents are keys to a successful salvage regimen. More recent combined 24-week analyses demonstrated results similar to the individual studies (see Table 2; Gulick et al 2007d). While the studies were not designed for a formal comparison of once daily and twice daily maraviroc dosing, higher rates of virologic suppression were observed with twice-daily maraviroc than with once-daily maraviroc in several important subgroups: subjects with viral loads 100,000 copies/mL at screening, and also subjects with baseline CD4 counts 50 cells/mm3. With such robust data, the makers of maraviroc requested and received accelerated approval by the FDA for treatment-experienced patients with inadequate control of multidrug resistant, CCR5-tropic HIV-1. In conjunction with maraviroc’s approval, the single- cycle recombinant virus tropism assay (Troﬁle®, Monogram Biosciences South San Francisco, CA, USA) also began its commercial availability (Coakley et al 2005). While the approval of maraviroc is for the treatment of patients with CCR5-tropic virus, its potential in patients with D/M-tropic virus has also been evaluated. Pﬁzer study A4001029 is a double-blind placebo controlled study in sub- jects with D/M-tropic virus who were randomized to OBT including at least one sensitive drug, plus either maraviroc once daily, maraviroc twice daily, or placebo (Goodrich et al 2007). 186 subjects with D/M virus and advanced immunodeﬁciency, approximate median CD4 cell count of 42 cells/mm3 and HIV viral load of 5.1 log copies/mL within each cohort, were enrolled across the study. After 48 weeks, the mean viral load decreases were 0.62 log copies/mL in the once-daily maraviroc group, 1.11 log CCR5 antagonists of HIV-1 infection copies/mL in the twice-daily group, and 0.84 log copies/mL in the placebo group. These differences were not statistically signiﬁcant and there was also no substantial difference across study cohorts in the proportion of subjects who achieved an undetectable viral load. However, despite a lack of antiretroviral beneﬁt, CD4 cell counts did rise in both maraviroc cohorts, by 65 cells/mm3 in the once daily arm and 78 cells/mm3 in the twice daily arm, whereas the placebo cohort CD4 cell count increase was only 51 cells/mm3. This ﬁnding has generated interest in the possibility that maraviroc, or CCR5 antagonists in general, may have an effect on elevating CD4 cell counts independent of antiviral activity. Similar rates of adverse effects and deaths were observed, while no cases of lymphoma or adenocarcinoma occurred. Thus, in addition to further reassurance of maraviroc’s safety proﬁle, the lack of HIV progression in the D/M group was quite signiﬁcant and deserves additional investigation as concerns linger regarding the impact of X4-tropic virus. Consequences of CCR5 antagonist treatment A number of concerns, some unique and others general, are germane to the potential use of CCR5 antagonists in patients. As previously discussed, targeting CCR5 leaves a patient without the role of the CCR5 receptor in innate immunity. However, the natural example of the ∆ 32 CCR5 allele and the redundancy of chemokine receptor function provide signiﬁ- cant reassurance that blockade should be tolerable. Whether untoward consequences of the iatrogenic loss of the CCR5 receptor’s function, including an undue number of severe West Nile virus infections in WNV endemic areas, is a central question that will prove important to CCR5 antagonist use. Also, just as with all antiretrovirals to date, the issue of viral escape has attended the development of CCR5 antago- nists. This concern takes on more substance with CCR5 antagonists than other agents as failure of HAART using a CCR5 antagonist may result in co-receptor switching to 3 9 19 3 55 Abbreviations: MVC, maraviroc; OBT, optimized background therapy. Table 2 Contribution of maraviroc at 24 weeks to viral suppression based on overall susceptibility score of phase III maraviroc studies (Gulick et al 2007d) Combined analyses of MOTIVATE 1 and MOTIVATE 2 results at 24 weeks Number of active agents HIV-1 viral load 50 copies/mL (%) in OBT based on overall Placebo + OBT MVC once daily + OBT MVC twice daily + OBT susceptibility score 0 1 2 29 43 53 58 18 43 52 61 Therapeutics and Clinical Risk Management 2008:4(2) 481