Rapporteur reports
Track A: HIV Basic Science report by Eric Arts
The topic of this symposium was in general terms on HIV-1 drug
resistance, in particular resistance to CCR5 antagonists. John Moore highlighted the resistance
pattern and mechanism of resistance to the small molecule CCR5
antagonists, which now include maraviroc, vicroviroc, and
apliviroc. Studies by his group and research directed by the
developers of these compounds have stressed that resistance to CCR5
antagonists may be mediated through alterations in the interactions
with CCR5 rather than a co-receptor switch. However, as addressed
by Doug Richman in a later talk, CXCR4-tropic viruses can also arise during
maraviroc treatment. These CCR5 antagonists bind as allosteric
inhibitors and change the conformation of CCR5 in such a way that the
"wild type" HIV-1 envelope cannot interact for productive entry.
When resistance emerges, virus is capable of using both the free and
drug-bound form of CCR5, which effectively negates any possibility of
residual inhibitory activity. This "dual" binding property may be
related to an increased dependence on binding to the N-terminus of CCR5
rather the 2nd extracellular loop, which is in closer proximity to the
drug binding region. As a consequence, the possible continued benefits
in the face of resistance as observed with PIs (described by Steve
Deeks in the same session) would be very unlikely with CCR5 antagonists following the
emergence of resistance. Finally, resistance to these CCR5
antagonists does not appear to come at a cost to the virus.
Continuing in the theme of resistance pathways and mechanisms to new
drugs, Doug Richman highlighted several presentations from the most
recent HIV-1 Drug Resistance Workshop in Barbados. Much attention
at this meeting was again paid to resistance to maraviroc and to the
emergence/detection of CXCR4 tropic virus in the patient's virus
population (quasispecies). Is failure with an X4 variant
associated with new virus evolution in the patient or the presence of
pre-existing clones prior to maraviroc treatment? Evidence
suggests that the X4 clones pre-exist and are selected during treatment with CCR5 inhibitors. Current methods are not
yet sensitive enough to detect their presence or set a cut-off.
Dr. Richman also described recent studies with the new NNRTI inhibitor,
TMC125 and indicated low levels of resistance with Y181C but the
accumulation of secondary mutations in patients receiving treatment
will result in high-level resistance. The same observations holds
true with resistance to the integrase inhibitors Raltegravir and EVG. The N155H or Q148R mutations alone do not confer
high-level resistance but this is achieved with accumulation of secondary
mutations.
Steve Deeks addressed the reasons for the possible benefit of PI-based
treatment regimens not attaining full virus suppression. These
observations are well documented by the presenter but the same
observation does not appear to hold true with NNRTI-based treatment
regimens (although prospective clinical trials have not been performed
for this comparison). This finding has significant implications
for developing countries where NNRTI-based treatment regimens are the
norm. Statistical models exploring historic data on PI and
NNRTI-based treatment regimens in the US suggest that there is a
significant survival benefit of switching ARV treatment regimens early
(< 6 mo after treatment failure) versus late (>6 mo) if the
patient was on an NNRTI treatment regimen. In contrast, switching
early versus late after failure of PI-based regimen showed significant
survival benefit. So what are the reasons for this enhanced PI
benefit? The obvious and well-documented difference may be
related to lack of a significant fitness cost with NNRTI-resistance
mutations as compared to the significant fitness cost with
PI-resistance mutations. Another factor may be related to CD8+ T
cell activation which is higher in patients with a "reduced" benefit
after treatment failure. PI or PI-resistant virus appear to
reduce CD8+ T cell activation.
Track B: Clinical Research, Treatment and Care report by Nick Paton
The first 3 talks in this bridging session are covered in the Track A report, and for this Track B report I will focus on the entertaining and thoughtful perspective on the future of resistance testing given by Bernard Hirschel. He argued that the future of resistance testing will depend on two things: whether the frequency of resistance in populations increases or decreases over time, and whether the results of resistance testing actually have any effect on treatment outcomes. Now that patients initiate therapy with highly effective drugs and most people on treatment have undetectable viral load with low risk of transmission, you would expect that the level of transmitted resistance in populations would be declining over time. Professor Hirschel presented contrasting data from studies in Denmark and New York City, the former confirming a decline in resistance and the second finding the opposite. So from the perspective of whether we will have greater need for resistance tests to guide initial therapy, the data is controversial. As for whether resistance testing improves the outcome of ART, he presented a meta-analysis of data from the 6 randomized controlled trials of genotypic testing that suggested that they are of little use. Thus the two premises that he outlined for supporting the ongoing use of resistance tests are at best weakly supported. So why do we continue to use resistance tests? Partly out of comfort. Partly because we recognize that the randomized controlled trials of genotypic testing were done in an era before effective salvage regimens could be constructed. With the second generation protease inhibitors, new NNRTIs, and the drugs in the new classes it seems logical that genotypic testing will give us information that is likely to improve the outcome of therapy. On the other hand you could argue that in people who have not been exposed to darunavir, integrase and fusion or entry inhibitors the response to a new combination containing these drugs is so good that resistance testing is likely to be irrelevant. In summary we are likely to continue to use resistance testing in the future even though we lack good evidence that it confers benefit.
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