title: CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions--review of the literature.
abstract: In the context of emerging resistance to antiretroviral agents in HIV medicine, the development of new drugs classes with a novel mechanism of action remains essential. The CCR5 co-receptor antagonists inhibit fusion of HIV with the host cell by blocking the interaction between the gp-120 viral glycoprotein and the CCR5 chemokine receptor. So far, four CCR5 antagonists have entered clinical evaluation, of which three are currently still in different stages of clinical assessment. In this review we compare the clinical efficacy in phase I and II as well as the long-term tolerability, pharmacokinetics and interactions of these new antiretroviral drugs entering HIV practice. Being the first CCR5 antagonist to be investigated in clinical trials, aplaviroc showed initial potent antiviral activity. However, after the occurrence of severe hepatotoxicity in several patients, its development had to be stopped in October 2005. The second CCR5 antagonist, maraviroc, has displayed promising results in phase I, II and III studies, showing a significantly greater decline in HIV RNA and CD4 cell increase compared to placebo, with no clinically relevant differences in safety profile and tolerability. The expanded access program for maraviroc was opened in June 2007 in several European countries. The FDA approved the use of maraviroc for antiretroviral therapy of HIV on the 7th of august, 2007. Finally, the third CCR5 antagonist vicriviroc also showed long-term potent viral activity in phase II studies as long as it was boosted with low-dose ritonavir, with no significant differences in grade 3 and grade 4 adverse effects compared to placebo. The phase II clinical trial amongst ART experienced individuals who received Ritonavir-boosted vicriviroc 10-15 mg qd was unblinded early because of the unexpected occurrence of malignant lymphoma and adenoma. However, no further malignancies occurred in the extended follow-up evaluation of this drug until today. Vicriviroc is currently entering phase III evaluation. Pharmacokinetics of maraviroc and vicriviroc may be influenced by coadministration of CYP3A4-inhibitors and -inducers, since both substances are metabolised primarily by the CYP3A4 system. This requires dose adjustments when combined with for instance protease inhibitors (with the exception of tipranavir/r), efavirenz, ketoconazole or rifampin. Concerns have risen about possible class-specific long-term adverse effects of CCR5 antagonists, particularly with regard to hepatotoxicity or malignancy. The pooled data from phase II and III however, so far show no new or added toxicity risk for maraviroc or vicriviroc compared to the respective placebo arms of the trials. Extended follow-up of the vicriviroc trials showed no further case of malignancy, reassuring the overall good tolerability profile of the drug so far.
authors.affiliation: Department of Medicine I, University Clinic Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Emmelkamp
authors.forename: J K
authors.initials: JK
authors.lastname: Rockstroh
mesh_terms: D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001565:Benzoates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists; D002986:Clinical Trials as Topic; D003510:Cyclohexanes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D054659:Diketopiperazines; D004347:Drug Interactions; D006801:Humans; D000077592:Maraviroc; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013141:Spiro Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: 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