These primary analyses of two ongoing phase 3 studies show that in previously treated patients infected with R5 HIV-1 only (as shown by a co-receptor-tropism assay) who are receiving optimized background therapy, the addition of maraviroc, as compared with placebo, is associated with a significantly greater reduction in the level of HIV-1 RNA and a greater increase in the CD4 cell count. The efficacy of maraviroc over placebo was further supported by the finding that 42 to 47% of patients taking maraviroc had HIV-1 RNA levels of less than 50 copies per milliliter at 48 weeks, as compared with 16% and 18% of those taking placebo.
Although the short-term efficacy of maraviroc was first shown in two phase 2 monotherapy studies in patients infected with R5 HIV-1,17
the MOTIVATE studies show that longer-term efficacy can be achieved by blocking a host protein, rather than a viral protein, with a small-molecule CCR5 coreceptor antagonist taken orally. These results are similar to those reported in studies evaluating other new drugs that target HIV directly28–33
and show that antiretroviral agents that target host and viral proteins can be used together to achieve virologic suppression in previously treated patients with HIV-1 infection. These results also support current antiretroviral treatment guidelines that recommend a new regimen with two (or preferably three) fully active agents from multiple drug classes for previously treated patients.4
The virologic response rates in the placebo groups in the current studies were notably higher than those seen at 48 weeks in the control groups of similarly designed studies — for example, the T-20 versus Optimized Background Regimen Only studies (TORO) involving patients with extensive previous treatment (HIV-1 RNA, <50 copies per milliliter overall in 17% vs. 8% of patients, respectively).31
This result is probably due to improvements in the drugs available to construct an optimized background regimen, including the use of enfuvirtide itself as part of the regimen in the MOTIVATE studies. In the recently completed studies of raltegravir — Blocking Integrase in Treatment Experienced Patients with a Novel Compound against HIV, Merck (BENCHMRK) — that allowed use of darunavir, even higher response rates (31 to 35%) were achieved in the placebo groups.32,33
The DUET studies of etravirine that mandated use of darunavir resulted in a response rate of 40% in the placebo groups.29,30
In the MOTIVATE studies, investigational agents (e.g., darunavir, etravirine, and raltegravir) were not permitted because no information on drug–drug interactions was available at the time, and only 15% of patients received tipranavir. Given the current availability of these newer antiretroviral drugs, combination regimens with maraviroc could be even more effective.
Treatment-related adverse events, study-drug discontinuation related to adverse events, AIDS-defining events, and deaths did not differ significantly across the three study groups, with the exception of esophageal candidiasis, which was more common in the group that received maraviroc once daily than in the placebo group or the group that received maraviroc twice daily. However, this difference must be interpreted cautiously, since the analysis was post hoc and was not adjusted for the duration of treatment exposure or for multiple testing. There were no significant differences between the maraviroc groups and the placebo group with respect to severe hepatotoxic effects, lymphoma, or other cancers, as reported in prior studies of other CCR5 antagonists.34,35
Given the relatively limited clinical experience with maraviroc to date, careful, longer-term safety monitoring would be prudent.
In general, studies of people with the CCR5
delta32 deletion show some immunologic effects. For example, the CCR5
delta32 mutation is associated with fewer signs and symptoms of rheumatoid arthritis36
but is also associated with more severe infection and increased mortality from West Nile virus in certain groups of patients.37
There are also data indicating that this host genetic deletion is associated with fewer cancers in patients with HIV infection.38
A congenital absence of CCR5 receptors, however, may not be equivalent to blocking of the CCR5 receptor with a small-molecule inhibitor; this again underscores the need for careful, longer-term safety monitoring is warranted.
These studies have several limitations. Although they were conducted on three continents, only about 10% of enrollees were women and less than 20% were nonwhite, which means that the generalizability of the results to other populations may be limited. The coreceptor-tropism assay used may not detect minority populations of X4 virus at baseline; the virus may emerge either before or during CCR5-antagonist therapy and may ultimately lead to reduced virologic responses. An enhanced tropism assay that better detects minority viral populations is now available.39
Use of newer antiretroviral drugs in the study regimens was limited (tipranavir) or prohibited (darunavir, etravirine, and raltegravir) because of the lack of data on drug–drug interactions with maraviroc or lack of availability of these investigational agents at the time. Safety comparisons were conducted post hoc and were not adjusted for treatment duration and multiple comparisons. Finally, although maraviroc, as compared with placebo, had superior virologic activity and resulted in higher CD4 cell counts with a similar safety profile in these 48-week studies, further follow-up is required to assess longer-term virologic and immunologic responses and drug-related side effects.
In summary, the results of these studies show that in previously treated patients with R5 HIV-1 infection only (as shown by a coreceptortropism assay), maraviroc, together with an antiretroviral regimen optimized on the basis of treatment history and drug-resistance testing, is effective and generally tolerated for at least 48 weeks.