How will CCR5 antagonists influence the recommendations for the antiretroviral treatment of HIV-1 infection

Abstract

The new antiviral CCR5 antagonists have proven to be highly efficient in treatment experienced patient populations with multiple drug failure. Maraviroc is the most advanced compound in clinical development representing this new class of entry inhibitors. The favourable toxicity-, resistance- and pharmacokinetic profile of the drug has been proven in phase III trials in treatment naive and experienced patients. In the latter population, maraviroc had superior antiviral efficacy and immunological activity compared to OBT+placebo alone in the control group. The antiviral responses after 48 weeks were comparable to results obtained from phase III trials with raltegravir and other previous salvage regimens including, darunavir, tipranavir and enfuvirtide. Due to its unique mode of action with exclusive activity against CCR5 tropic strains, viral tropism testing will be mandatory before using CCR5 antagonists in the clinic. The corresponding tests are established and will be further validated. Results from clinical trials indicate that approximately half of the treatment experienced patients will predominantly harbour CCR5 tropic quasispecies and will thus qualify for treatment with CCR5 antagonists. In treatment naive patients maraviroc so far formally failed to prove its non-inferiority to a standard regimen consisting of AZT/3TC+efavirenz after 48 weeks. However, further 96 weeks data will be analysed from this study as well as antiviral efficacy in distinct patient subpopulations. Therefore, it is likely that maraviroc will be recommended in early stages of salvage therapy at present and might replace more inconvenient drugs like enfuvirtide in later lines of therapy. The drug class has also the potential to enter first line therapy but this has to be proven in future trials. Special patient populations like primary HIV infection (PHI), pre- and post exposure prophylaxis, co-infection with tuberculosis and hepatitis B may show special clinical benefit but this is also awaiting confirmation from prospective trials.