CCR5 antagonists in the treatment of treatment-naive patients infected with CCR5 tropic HIV-1.
A new class of antiretroviral drugs is now available to the HIV provider: The CCR5 Antagonists belong to a group of entry inhibitors with a novel mechanism of action. While these antagonists do not directly interfere with any of the steps of HIV replication, they block the CCR5 receptor, one of the co-receptors HIV uses to enter its target cell. Thus CCR5 antagonists are able to prevent infection of the cell and represent a new and unique mechanism for the treatment of HIV. There is great interest in utilizing this new drug class in early treatment of HIV to prevent infection of large cell pools; CCR5 antagonists even may be useful tools in the various settings of exposure prophylaxis. Maraviroc is now approved in both the European Union and the United States for the treatment of HIV infection. This is the first medication belonging to the new class of CCR5 antagonists, and the first approval of an orally available drug in a new class since 1996. Aplaviroc, maraviroc, and vicriviroc are small molecule inhibitors of CCR5 that block HIV-1 infection in vitro and reduce plasma HIV-1 RNA in HIV infected subjects by approximately 1.5 log10 copies/mL over 10-14 days when given as single agents. Very limited data is available on the use of CCR5 antagonists in treatment naive patients due to early termination of many trials because of inferior performance or toxicity and at the time of this writing in August 2007 there is only one ongoing non-inferiority trial in the naive patient population. The 48 week interim results of this trial using twice daily maraviroc were reported at the International AIDS Society meeting in July 2007. Maraviroc compared to efavirenz was non-inferior in regards to percentage of subjects reaching viral loads below 400 copies/mL, but not so for the analysis of subjects reaching viral loads below 50 copies/mL. On the other hand maraviroc had a superior side-effect profile, fewer adverse events and a greater increase of CD4 cell count than efavirenz. These data will revitalize the interest in CCR5 antagonists as a treatment option for the treatment-naive patients. In order to be used as first line drugs, CCR5 antagonists face a number of challenges: They will have to be proven to be as potent, durable, safe, and convenient as current available options. Important questions unique to this new class will have to be answered: What are the mechanisms and risks of tropism change? What is the role and needed frequency of tropism testing, and what efficacy is seen in patients with dual-tropic/mixed infection in the long term? Clearly until we have answers to these questions CCR5 antagonists should be reserved for the treatment-experienced patient population with limited treatment options.
Bredeek
U Fritz
UF
University of California, Los Angeles, Division of Infectious Diseases, School of Medicine, Olive View UCLA Medical Center, 14445 Olive View Dr. 2B182, Sylmar, CA 91342, USA. Fritz@doctor.com
Harbour
Michael J
MJ
D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000627:therapeutic use; D054659:Diketopiperazines; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D013141:Spiro Compounds / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
D019380:Anti-HIV Agents; D001565:Benzoates; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D054659:Diketopiperazines; D010879:Piperazines; D011743:Pyrimidines; D013141:Spiro Compounds; D014230:Triazoles; C499671:aplaviroc; D000077592:Maraviroc; C486781:vicriviroc