Hicks.qxp 19/5/08 4:56 pm Page 30
HIV and AIDS CCR-5 Virus
cell surface.
15,16
The average 50% reduction in cell surface expression levels of However, to put this into context, current HAART regimens routinely suppress
CCR-5 in heterozygotes
17,18
is associated with significantly delayed disease HIV RNA levels to undetectable levels for long periods of time, with overall
progression.
19
Individuals homozygous for the Delta32 mutation are highly success rates of more than 80%. This is a high efficacy hurdle for the
protected against R5 infection
15,16,19
and, in the few reported cases where treatment-naïve population. In contrast, there are no standard regimens
homozygotes have been infected with HIV-1, the patients have all exhibited for treatment-experienced salvage populations, where CCR-5 antagonists were
low viral loads and infection with X4 rather than R5 strains of HIV.
20
compared with placebo; the barrier to showing effectiveness is therefore much
The immunological importance of CCR5-∆32 is shown in studies of lower.
36
Clinical studies for antiretroviral-experienced patients continue; recent
immunologically mediated conditions such as rheumatoid arthritis and organ results from the phase IIb trial performed by the AIDS Clinical Trials Group 5211
transplantation, where homozygous individuals have improved outcomes.
21,22
showed six cases of malignancy in patients receiving vicriviroc compared with
However, these points are counterbalanced by evidence that CCR5-∆32 two cases among those receiving placebo, one of whom received the drug
homozygotes have a six-fold increased risk for severe West Nile infection and prior to the malignancy diagnosis.
37
However, no causal relationship between
a five-fold increased mortality risk,
23
as well as a greater susceptibility to the risk of malignancy and vicriviroc or other CCR-5 inhibitors has been
tickborne encephalitis.
24
Nevertheless, in terms of day-to-day living, this natural established. The phase IIb Victor-E1 (Vicriviroc In Combination Treatment with
polymorphism appears safe. As CCR-5-tropic HIV-1 is very common and Optimized antiretroviral therapy Regimen in experienced subjects) trial
necessitates the gp120–CCR-5 interaction, this has led to the development of evaluated treatment with vicriviroc in 116 triple-class-experienced patients. The
targeted antiretroviral therapies against CCR-5. The development of CXCR-4 doses used were either vicriviroc 20 or 30mg QD or placebo. There was a
antagonists is unlikely to be successful for a number of reasons. First, there are significant difference between the decline in HIV RNA achieved by patients in
no naturally occurring models of CXCR-4 deficiency. Second, the natural the vicriviroc arms compared with placebo, and significant improvements were
CXCR-4 ligand SDF-1α is a player in numerous cellular processes, including also seen in terms of CD4+ cell count.
38
organogenesis, stem cell localization, and T-cell trafficking.
25–27
Mouse embryos
in which either CXCR4 or SDF-1α are knocked out are not viable due to Maraviroc
obvious hematopoietic, cardiac, and cerebellar defects.
28
Maraviroc is the only FDA-approved CCR-5 inhibitor on the market indicated
for use in treatment-experienced patients with infection due to CCR-5-tropic-
CCR-5 Antagonists only HIV. A 10-day monotherapy study of maraviroc in R5-only-infected
There are several orally bioavailable small-molecule CCR-5 antagonists either in subjects, in which patients were randomized to receive maraviroc at doses of
development or on the market. Several of these -viroc (viral receptor 25, 100, or 300mg QD or BID or placebo, saw more than a 1.6 log
10
reduction
occupancy) antagonists, including aplaviroc (GlaxoSmithKline) and vicriviroc of plasma HIV RNA.
39
The large-scale phase IIb/III Efficacy and Safety of
(Schering-Plough), have been tested up to at least phase IIb clinical trials, but Maraviroc plus Optimized background Therapy In Viremic ART-Experienced
only maraviroc has received US Food and Drug Administration (FDA) approval. patients infected with CCR5-tropic HIV-1 (MOTIVATE) 1 and 2 studies
These compounds act as non-competitive allosteric antagonists of CCR-5 and randomized patients to optimized background regimen plus maraviroc 300mg
bind a cavity formed by structural elements in the co-receptor.
29–31
Also in QD or BID, or placebo; if the background regimen included a PI (other than
development are monoclonal antibodies directed against CCR-5, such as tipranavir) and/or delavirdine, the maraviroc dose was reduced to 150mg QD
PRO140 and CCR5mAb004, and other small-molecule inhibitors. or BID. Regardless of dosing frequency, maraviroc treatment significantly
decreased viral load with a greater percentage of patients achieving
Aplaviroc undetectable HIV viral loads and increasing CD4 counts compared with the
Early short-term monotherapy studies showed minimal toxicities associated placebo arm.
40,41
The Maraviroc versus Efavirenz Regimens as Initial Therapy
with the antiviral activity of aplaviroc. Patients treated with varying dosages of (MERIT) trial randomized antiretroviral treatment-naïve patients to receive
aplaviroc over a 10-day treatment period experienced a 1–1.6 log
10
reduction maraviroc or efavirenz in combination with zidovudine/lamivudine. The primary
in viral load.
32
However, the development of the compound was terminated end-point was the percentage of patients with HIV RNA <400 and <40
during phase IIb trials after aplaviroc was found to be associated with possible copies/ml at week 48. The 300mg BID arm showed comparable efficacy to the
drug-induced hepatitis, as manifested by elevations of alanine and aspartate efavirenz arm in achieving HIV viral loads <400 copies/ml (70.6 and 73.1%,
aminotransferase levels.
33
respectively), but failed to demonstrate non-inferiority in attaining <50
copies/ml (65.3 and 69.3%, respectively). A QD arm was discontinued because
Vicriviroc of inferior efficacy.
42
Although patients in the maraviroc arm were more likely
An initial 14-day monotherapy of 10, 25, or 50mg of vicriviroc twice daily (BID) than those in the efavirenz arm to discontinue treatment due to lack of efficacy
in HIV-infected adults saw an average decline of plasma HIV RNA by at least (11.9 versus 4.2%), patients treated with maraviroc were less likely than
1.5 log
10
.
34
A phase II study administering vicriviroc to treatment-naïve HIV efavirenz-treated patients to report adverse effects or have these adverse
patients—in which all subjects also received zidovudine plus lamivudine effects lead them to withdraw from the study (4.1 versus 13.6%).
(ZDV/3TC) as a fixed-dose combination—was discontinued when subjects
experienced increased rates of virological failure compared with the control Overall, maraviroc appears to be well tolerated; notably, the frequency of grade
arm, which received efavirenz-based antiretroviral treatment.
35
There are 3/4 elevations of alanine aminotransferase (QD 4.4%, BID 2.6%) or aspartate
concerns about the study design, however. Subjects in the vicriviroc arms aminotransferase (QD 3.9%, BID 4.8%) reported in the MOTIVATE trials was
received an initial 14-day period of vicriviroc monotherapy prior to the addition modest.
43
In considering the adverse event profile of maraviroc relative to that
of ZDV/3TC. There is also evidence that the dosing of vicriviroc was too low: seen with other CCR-5 inhibitors whose development has been affected by the
genotypic analysis demonstrated that virus from all subjects who experienced incidence of adverse events in early studies (such as malignancy and
virological breakthrough developed the M184V mutation for 3TC resistance. hepatotoxicity), a comparison is instructive. Clinical trials have not associated
30 US INFECTIOUS DISEASE
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76