Library Volume 2, Issue 5:
Resistance Reporter© from 48th Annual ICAAC/IDSA
46th
Selections from the 48th Annual ICAAC/IDSA 46th
Annual Meeting; Oct 31-Nov 4, 2008;Washington, DC
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Section 1: Select presentation concerning raltegravir and
efavirenz first-line failures
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Section 2: Select presentation of results from Expanded Access
Programs: raltegravir + etravirne
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Section 3: Select presentation concerning evolving raltegravir
resistance
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Section 4: Select presentations related to HIV tropism analysis
Select presentation concerning raltegravir
and efavirenz first-line failures
A noncompleter-equals-failure analysis of
STARTMRK showed that 86% taking raltegravir and 82% taking efavirenz had
a viral load under 50 copies at 48wks, the trial's primary endpoint. The
study enrolled antiretroviral-naive people with a viral load above 5000
copies and with no resistance to efavirenz, tenofovir, or emtricitabine.
Researchers randomized 281 people to raltegravir (400 mg twice daily)
and 282 to standard-dose efavirenz, both with tenofovir plus
emtricitabine. The average age of participants in each arm was similar,
38 years in the raltegravir group and 37 in the efavirenz group. About
40% in each group were white. STARTMRK investigators reported 39
virologic failures with efavirenz versus 27 with raltegravir; all of
which had HIV RNA > 50 after 24 weeks or after confirmed suppression. Of
12 raltegravir failures with a viral load above 400 copies, no
raltegravir mutations were detected in 5 and they could not amplify the
integrase gene in 3. Four people had detectable integrase mutations, 2
with G120S plus Q148H/R; 1 with Y143H, L47M, E92Q, and T97A; and 1 with
Y143R. Among 8 efavirenz failures at a viral load above 400 copies,
efavirenz mutations could be detected in only 3 cases. The number of
patients with resistance in either arm was very small given the size of
the study. These results indicate that raltegravir is not inferior to
efavirenz for initial antiretroviral therapy. Time to virologic response
proved significantly shorter in the raltegravir group (P < 0.001),
though the clinical significance of this difference is unclear.
Select presentation of results from Expanded
Access Programs: raltegravir + etravirne
For some years, Expanded Access Prrograms (EAPs)
have provided HIV multi-treatment experienced patients with vital new
antiretroviral therapies prior to FDA approval. The concurrent
etravirine (ETR) and raltegravir (RAL) EAPs, conducted in a clinic
setting, provided an opportunity to examine the efficacy and safety of
ETR + RAL + background therapy (BT) in patients with limited or no
treatment options due to virologic resistance or intolerance to multiple
antiretroviral regimens: 53 mostly male participants were reported on;
all patients were NNRTI experienced, however prior to initiating ETR +
RAL + BT, more than half of patients had an ETR mutation score < 2. The
majority of these patients had mutations not associated with ETR
resistance such as K103N, V108I, and P225H. Conclusions described by the
authors included efficacy data: over 90% of patients achieved HIV-1 RNA
below the level of quantification after 24 weeks of therapy. When
comparing virologic outcomes by baseline versus cumulative resistance,
the additional historical mutations obtained from the cumulative
resistance did not appear to significantly change the observed response
in this limited data set. The authors stated that the high rate of
virologic success in this study population can be contributed to the use
of multiple active agents in the regimen, including ETR, RAL and/or a
boosted PI.
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Select presentation concerning evolving
raltegravir resistance.
Merck investigators used population
sequencing to search for integrase mutations in 64 people whose
raltegravir regimen failed in Benchmrk 1 and 2. They used standard
assays to determine susceptibility of mutant virus to raltegravir and
replication capacity of that virus. Identifying signature mutations at
three integrase sites in most patients with virologic failure (N155,
Q148, and Y143), the researchers monitored viral evolution in these
people over time. The Q148H emerged as the principal
resistance-conferring mutation, often replacing N155H in viral isolates.
The first genotype after raltegravir failure determined that 45% of
isolates from 64 patients had the N155H mutation, but only 18% of 51
people with a follow-up genotype had N155H. The first genotype detected
mutations at position 148 in 27% of 64 people. Follow-up genotypes in 51
people found position 148 mutations in 53%. Mixed mutation populations
declined from 19% of viral isolates in the first genotype to 10% of
follow-up genotypes. The study also documented steady emergence of
resistance mutations when a failing raltegravir regimen continued. On
the first genotype in 64 people, 30% had 1 mutation, 44% had 2
mutations, and 27% had more than 2 mutations. Follow-up genotypes in 51
people spotted 1 mutation in only 8%, 2 mutations in 45%, and more than
2 mutations in 47%. Emergence of integrase mutations in people whose
raltegravir regimen fails correlated with high-level resistance.
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Select presentations related to HIV tropism
analysis.
Reanalysis of the MERIT study with the enhanced Trofile™ assay
ICAAC/IDSA Abstract H-1232a, Saag M, Heera J, Goodrich J, et al.
MERIT researchers presented a retrospective
reanalysis (MERIT ES) of their original data utilizing a new, more
sensitive version of the Trofile™ assay. In brief, MERIT included 721
ART naïve participants from both the Northern and Southern hemispheres;
29% were female. Participants were randomly assigned to receive either
300 mg twice-daily maraviroc (MVC) or 600 mg once-daily efavirenz (EFV),
both in combination with zidovudine/lamivudine (Combivir coformulation,
CBV) for 48 weeks; MVC+CBV was shown to be noninferior to EFV+CBV (See
tables). In MERIT ES, stored samples from the original MERIT study
participants were retested using the recently introduced enhanced
Trofile™ assay. This enhanced assay-can detect CXCR4-tropic or
dual/mixed HIV variants that make up as little as 0.3% of an
individual's total virus population, a 30-fold improvement in
sensitivity. Key 48-week study endpoints were reanalyzed after excluding
patients found to have non-CCR5-tropic virus using the new test. Among
other results,106 of 721 patients (14.7%) across both treatment arms
initially classified as having exclusively CCR5-tropic HIV were found to
have dual/mixed (D/M) virus using the new test, leaving 311 remaining in
the maraviroc arm and 303 in the efavirenz arm (1 person was initially
misclassified). Based on these findings, the investigators concluded
that the enhanced Trofile™ assay reclassified approximately 15% of
patients as having non-R5 HIV and identified approximately 52% of
patients who had DM virus at baseline or on study. [Editor's note: The
removal of 15% of the subjects with the Trofile ES renders MERIT no
longer a randomized comparison study, hence the results should be
interpreted with caution.]
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In order to better identify patients most
likely to respond to maraviroc (MVC), a post-hoc analysis of MOTIVATE 1
and 2 was undertaken. It examined the predictive value of both the
standard drug-counting approach to optimized background therapy (OBT)
scoring and the use of a weighted OBT sensitivity score (wOBTSS), an
alternative, simple weighted methodology. The full analysis set of
MOTIVATE 1 and 2 comprised all randomized subjects who received at least
one dose of study medication (N=1,049). A sub-population of the full
analysis set, the Virologic Outcomes (VO) population, was defined to
exclude both non-virologic failures and those whose baseline OBT score
did not accurately reflect the drugs received throughout their period of
randomized treatment. The findings: In this defined
treatment-experienced population the wOBTSS provided a better measure of
OBT activity than counting active drugs. The authors concluded that a
wOBTSS >/=2 and a baseline CD4+ cell count >50 cells/mm3 are the
strongest predictors of virologic response to a MVC-containing regimen.
Approximately 80% of subjects receiving MVC (BID or QD) with wOBTSS >/=2
and >50 CD4+ cells/mm3 at initiation had undetectable viremia at Week
48. The author also noted that these findings are consistent with
earlier data in treatment-experienced patients showing baseline CD4+
cell count, viral load, number of active OBT agents, and prior
experience of fewer ARVs as being strongly predictive of virologic
response on enfuvirtide.
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Additional Reading:
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Virologic Success of Different Strategies for Initial ART Regimens
Is Predicted by the Type and Detection Level of Minor Drug-Resistant
Variant Detected by Ultra Deep Sequencing: The CPCRA 058 FIRST Study
15th Conference on Retroviruses and Opportunistic Infections,
Boston, Feb 3-6, 2008. Abs 878, Huppler Hullsiek K, et al.
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Paredes R, et al.Presence
of Minor Populations of Y181C Mutants Detected by Allele-Specific
PCR and Risk of Efavirenz Failure in Treatment-Naïve Patients:
Results of an ACTG 5095 Case-Cohort Study. 15th Conference on
Retroviruses and Opportunistic Infections, Boston, Feb 3-6, 2008.
Abs 83,
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Roquebert B, Malet I, Wirden M, et al.Role
of HIV-1 minority populations on resistance mutational pattern
evolution and susceptibility to protease inhibitors. AIDS.
2006;20:287-289.
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Heera J, M Saag, et al.Virological
Correlates Associated with Treatment Failure at Week 48 in the Phase
3 Study of Maraviroc in Treatment-naive Patients. 15th
Conference on Retroviruses and Opportunistic Infections, Boston, Feb
3-6, 2008. Abs 40.
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Reeves JD, Han D, et al.Enhancements
to the Trofile™ HIV Co-receptor Tropism Assay Enable Improved
Detection of CXCR4-using Subpopulations and Earlier Detection of
CXCR4-using Viruses in Sequential Patient Samples. Targeting HIV
Entry: 3rd International Workshop, Abstract 11.
