Fatkenheuer_EU_Infectious.qxp 29/1/08 17:45 Page 65
HIV and AIDS CRR-5 Virus
Chemokine (C-C Motif) Receptor 5 Antagonists –
Safety and Efficacy in Treatment-experienced Patients
a report by
Gerd Fätkenheuer
Head, Division of Infectious Diseases, University Hospital of Cologne
HIV is a retrovirus, part of a family of lentiviruses that also includes The HIV Armamentarium
simian and feline immunodeficiency viruses. Lentivirus infection is The first ART, a nucleoside reverse transcriptase inhibitor (NRTI), was
typified by a failure of the host’s immune system to prevent approved in 1987. Since then there has been a steady stream of approvals
continuous infection. HIV infects important immune system cells that of new drugs, and occasionally new classes. The first protease inhibitor (PI)
display the CD4 receptor including monocytes, macrophages and T was approved in 1995, and the first non-nucleoside reverse transcriptase
lymphocytes. While good progress has been made in the last 20 years inhibitor (NNRTI) in 1998. These days, HIV treatment is in the form of
in terms of developing new antiretroviral treatments (ARTs) to keep highly active ART (HAART) and consists of a combination of three drugs
HIV in check and prevent or delay the development of AIDS, the highly from different classes. However, while HAART can hold HIV in check for a
mutational nature of HIV means that new classes of intervention are short time, no combination has been found that offers long-term
always required. However, in contrast to the first ARTs, which were protection, and new drugs and classes are always being sought.
often quite toxic, new treatments face higher barriers to approval in
terms of efficacy and safety because of the extant armamentarium. One of the newer classes of compounds is CCR-5 antagonists, which aim to
This paper will investigate the latest results from the class of prevent viral entry. By targeting host cells rather than the virus itself, these
chemokine (C-C motif) receptor 5 (CCR-5) antagonists in this group of agents represent not just a new class but a whole new paradigm in ART. They
treatment-experienced patients. have advantages over those drugs that aim to disrupt the viral replication
process as they do not depend on cellular uptake mechanisms, nor do they
The Nature of HIV need to be activated once inside the cell. Furthermore, they are unlikely to
HIV infection is a complex, multistep process. First, the virus binds to CD4 have any cross-resistance problems with existing intracellular drugs. The first
and one other receptor on a host cell’s surface. This double binding causes (and as yet only) approved agent in this class is orally available small-molecule
the viral glycoprotein (gp)120 to change shape and the two cells to inhibitor maraviroc (Celsentri
®
, Pfizer), which received US Food and Drug
fuse. The virus then delivers its core into the host cell. This package contains Administration (FDA) and European Medicines Agency (EMEA) approval in
RNA and all of the enzymes (such as transcriptase and integrase) that HIV 2007. Other CCR-5 inhibitors include: vicriviroc (Schering Plough), in late-
needs in order to take advantage of the host cell’s own nucleotides and get stage clinical development; INCB9471 (Incyte), in phase I/II; PRO-140
its genetic material into the cell’s nucleus to be replicated. There are two (Progenics Pharmaceuticals), a monoclonal antibody (MAb), in phase I/II; and
major species of HIV. In most of the world, HIV-1 is the most common and HGS004 (Human Genome Sciences), also a MAb in phase I/II.
also the most virulent. Thus, this article will address this species.
Only patients with HIV-1 strains that are CCR-5-tropic will benefit from
HIV Tropism these drugs. The relationship between HIV-co-receptor tropism and
The tropism of HIV-1 is determined by the co-receptors it uses to clinical and virological outcome was investigated in 40 heavily pre-treated
enter a cell. There are two major co-receptors – CCR-5 and chemokine patients in the clinic by Lehman et al.
5
They found that co-receptor use
(C-X-C) receptor 4 (CXCR-4) – and all HIV-1 strains use one or both was stable in 87% of patients and CCR-5 tropism remained, indicating
of them. Therefore, the strains of HIV-1 are R5 (CCR-5-tropic), X4 that CCR-5 antagonists may be a valuable treatment option even in
(CXCR-4-tropic) or D/M (dual/mixed-tropic).
1
HIV-1 tropism is patients with repeated HAART failure.
determined using a phenotypic recombinant virus assay. The most
commonly used test is Trofile™ (Monogram Biosciences), a single-cycle Maraviroc
molecular assay that does not require co-cultivation of HIV particles in The large randomised, double-blind, placebo-controlled phase IIb/III study
cell culture.
2
There are other validated tests, although most clinical of maraviroc was called Maraviroc plus Optimised background Therapy In
data have been collected for Trofile. However, even with Trofile
detection of minority variants is limited. For all tests the detection limit
Gerd Fätkenheuer is Head of the Division of Infectious
is between 1 and 10%.
3
There are some individuals who are naturally
Diseases at the University Hospital of Cologne and
resistant to HIV infection, and some who contract HIV but have very Professor of Internal Medicine and Infectious Diseases at
slow disease progression. These individuals have been found to be
the University of Cologne. He has served as a principal
investigator and co-investigator in numerous multicentre
either homozygous or heterozygous for a polymorphism known as
clinical trials and has published extensively on various
delta-32 deletion, which results in no – or severely reduced –
aspects of HIV infection and other infectious diseases in
expression of CCR-5 but no obvious ill effects.
4
Thus, blocking CCR-5
peer-reviewed journals.
and therefore the ability of HIV to bind to it has been shown to be a
E:
g.faetkenheuer@uni-koeln.de
valid therapeutic approach.
© TOUCH BRIEFINGS 2007 65
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