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HIV and AIDS CCR-5 Virus
analyses showed no unexpected adverse events. There was no difference failure will be minimised. Of note, where such ‘switch’ occurs, reversion to
between the placebo and maraviroc groups in rates of discontinuation due R5 virus occurred once maraviroc was discontinued. Resistance to CCR-5
to adverse events (around 6%) or in serious adverse events (grade 3–4) inhibitors has been described
32
and appears to result from a conformational
(around 17%). In MOTIVATE 2, 48-week data showed that 45% of patients change in the virus that enables binding in the presence of CCR-5 blockage
in both the once-daily and twice daily maraviroc groups had viral load below rather than via the ‘traditional’ route of genotypic change that prevents
50 copies/ml compared with 18% in the placebo group. For patients with antiviral activity.
33
The significance and detection of such resistance will no
viral load below 100,000 copies/ml at baseline, 64% taking maraviroc once doubt be further elucidated as these agents are used more widely, although
daily and 56% taking maraviroc twice daily achieved viral load below 50 initial data suggest that there is likely to be cross-resistance between all
copies/ml compared with 25% of those taking placebo.
30
Pooled data from CCR-5 inhibitors currently in development.
34
Antiviral synergy has been
MOTIVATE 1 and 2 found that in the twice-daily maraviroc arm 61% of observed between the CCR-5 monoclonal antibody PRO 140 and the small-
patients with no previous history of T-20 use who included the drug in their molecule CCR-5 antagonists,
35
but the clinical role of these agents has yet
OBT had viral load below 50 copies/ml at week 48, compared with 32% of to be proved.
patients who had previously used T-20. Of note, in both MOTIVATE studies
the number of treatment discontinuations was broadly similar in all three Summary and Conclusions
arms, and a similar low number (between two and 17) of patients in the CCR-5 inhibitors provide a potentially useful addition to HIV treatment.
three arms of both studies developed new AIDS-defining illnesses. Arguably Current data and licensing indications suggest this will be predominantly
of most clinical importance, aside from upper respiratory tract symptoms, for those with CCR-5-tropic virus determined by tropism testing and who
there was no apparent increase in adverse events associated with maraviroc are heavily treatment-experienced. There remains some theoretical
use. Treatment failure while on maraviroc has been reported in some concerns regarding CCR-5 inhibition, particularly whether CCR-5
individuals and seems to be associated with an unmasking or expansion of a antagonists will promote tropism switching
36
and therefore accelerated
pre-existing minority of X4 virus as a result of R5 suppression. In a phase IIa disease progression and susceptibility to as yet undetermined diseases
monotherapy study of maraviroc in ART-naïve patients with only R5 HIV-1 (such as West Nile Virus or lymphoma). However, large studies with
detectable at baseline, X4 variants were detected in two of 63 patients after maraviroc and extensive surveillance thus far suggest that this is not the
10 days. Further analysis of HIV clones suggest that CXCR-4-using variants case. Whether CCR-5 inhibitors will become more widely used in earlier
were derived from pre-existing CXCR-4 using reservoir and not through co- stages of therapy depends on further research. While improved tolerability
receptor switching.
31
This finding has been supported by analysis of to the conventional gold standard – efavirenz – has been noted, this may
individuals failing on maraviroc with CXCR-4 virus in the MOTIVATE trials. It be at the cost of reduced efficacy until tropism testing is optimised. There
is likely that, as methodology for tropism determination and the sensitivity for is also a potential role – currently being investigated – of CCR-5 inhibition
detection of non-CCR-5-tropic virus improves, this reason for treatment as a preventative method, such as in microbicides. ■
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64 EUROPEAN INFECTIOUS DISEASE 2007
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