Assessing theoretical risk and benefit suggested by genetic association studies of CCR5: experience in a drug development programme for maraviroc.
The proliferation of published gene association studies of the CCR5delta32 mutation is of relevance to drug development of a CCR5 antagonist for HIV, in highlighting potential safety concerns. We conducted an initial review of all non-HIV gene association studies of CCR5-delta32, followed by detailed meta-analyses in the three disease areas most commonly reported. Our review indicated no consistent evidence of increased risk of susceptibility to hepatitis C virus infection or multiple sclerosis among individuals with CCR5-delta32 mutation, and suggested treatment with a CCR5 inhibitor is unlikely to have related adverse effects. There was, however, evidence to suggest rheumatoid arthritis as a potential therapeutic target for a CCR5 antagonist. Clinical evidence would be required to confirm these findings.
Wheeler
Jeremy
J
Pfizer Research and Development, Sandwich, Kent, UK. Jeremy.wheeler@pfizer.com
McHale
Mary
M
Jackson
Vicky
V
Penny
Michelle
M
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000009:adverse effects*; D015195:Drug Design; D005260:Female; D005838:Genotype; D023581:HIV Fusion Inhibitors / Q000009:adverse effects*; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D006526:Hepatitis C / Q000139:chemically induced / Q000235:genetics; D006801:Humans; D008297:Male; D000077592:Maraviroc; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000235:genetics; D009154:Mutation; D010597:Pharmacogenetics / Q000379:methods*; D019713:Receptors, CCR5 / Q000235:genetics* / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D014230:Triazoles / Q000009:adverse effects*
D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc