Library Volume 2, Issue 6:
Resistance Reporter© from Ninth International Congress on
Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow, UK
Resistance Reporter 2.6 (Glasgow): 5 summaries in 2 topical sections
Expert Commentary on YouTube™
Paul
E. Sax, MD,
discusses the dangers of misusing new agents.
Joseph
J. Eron, MD,
discusses management strategies for patients with long-term, low-level
viremia.
View the FULL POSTERS for the presentations summarized below by clicking
on the titles
Protease inhibitor resistance
Genotypic algorithms used to predict the
clinical efficacy of lopinavir/ritonavir (LPV/r) have included a range
of mutation lists and efficacy end-points. HIV clinical trials are
normally powered to detect a difference between treatment arms of 10-12%
for the end-point of HIV-1 RNA suppression <50 copies/mL. In this
analysis, baseline genotypic data from the TITAN trial (TMC114-C214),
which evaluated lopinavir/ritonavir (LPV/r) vs. darunavir/ritonavir (DVR/r)
in 595 treatment-experienced patients with HIV-1 RNA >1000 copies/mL,
were classified using seven genotypic resistance algorithms
(Click on title to view poster). Then, efficacy, defined as
HIV-1 RNA <50 at week 48, was correlated with the number of mutations
from each list to show the "efficacy advantage cut-off level" and the
number of mutations from each list associated with a difference in
efficacy between treatment arms of at least 12%. Multivariate analysis
identified lower than previously reported genotypic cut-off levels where
there was at least 12% lower efficacy for LPV/r versus DVR/r.
Furthermore, the analysis identified more sensitive cut-off levels for
several LPV genotypic algorithms, below those currently used. These new
cut-off levels also detect a higher percentage of patients with
virological failure (VF) than previous cut-off levels, and the authors
noted that the risk of VF is greater if LPV is used in people with
baseline PI resistance levels above these new thresholds. The author
also noted in the conclusion, among other things, that new breakpoints
for interpretation of genotypic information should now be based on full
HIV-RNA suppression <50 copies/mL rather than the previous cut-offs for
defining susceptibility to antiretrovirals based on analysis of
continuous log reduction in viral load and very early time points.
Patients failing a protease inhibitor
(PI)-based regimen at 40 US sites of the UTILIZE study were randomized
to have either a genotype or combined phenotype-genotype test to assist
with treatment decision-making (Click on title to view poster).
For this analysis, the investigators utilized data from both arms and
assessed the genotypic susceptibility to first-generation and second
generation PIs, but only the genotypic resistance data were evaluated to
assess PI cross-resistance. Of the 236 patients in whom resistance tests
results were available, a little over half (139; 59%), had evidence of
HIV-1 resistance to at least one PI. Of these, 28% of isolates were
resistant to all PIs, while 58% and 55% remained sensitive to the second
generation PIs, tipranavir (TPV) and darunavir (DRV), respectively. As
expected, the proportion of patients fully susceptible to each PI
decreased as the number of previous PIs taken increased, and
susceptibility to first-generation PIs was significantly lower than to
second generation PIs. However, 60% and 62% of patients who had taken
3-4 PIs retained full susceptibility to TPV and DRV, respectively,
making these PIs the most likely PIs to be active in those with ≥1 PI
mutation. Of those for whom TPV had failed, 43% were susceptible to DVR,
and conversely, 27% of those for whom DVR had failed remained
susceptible to TPV.
Back
to Top
The 595 treatment-experienced but lopinavir-naive
participants in this study included those with >1000 copies viral load (VL)
after at least 12 weeks on a stable failing regimen who received either
600/100 mg of darunavir/ritonavir (DRV/r) twice daily or 400/100 mg of
lopinavir/ritonavir (LPV/r) twice daily (in the old capsule formulation)
plus an optimized background regimen (Click on title to view
poster). Participants were fairly evenly divided into three
groups: protease inhibitor (PI) naives, those had taken one PI, and
those who had taken two or more PIs. In each of these groups, 10% had
>10-fold loss of susceptibility to LPV, whereas only 1% to 2% had more
than 10-fold resistance to DRV. Note that a fold change of <10 to LPV
does not necessarily signify full susceptibility to LPV, and patients in
each arm had a median number of 4 PI resistance mutations at baseline.
The investigators defined virologic failure (VF) as rebound from <400
copies or never reaching <400 copies after week 16. Overall failure rate
in those taking LPV/r was 26%, and in those taking DRV/r, 14% (P <
0.001). In those with ≤10-fold resistance to LPV at baseline, 23% had VF
in the LPV group and 13% in those taking DRV (P < 0.01). More LPV-treatment
limiting mutations and virologic failure occurred in those taking LPV
(21%), compared with DVR (12%), and these occurred whether participants
had used one or no PIs before the trial (P < 0.05). In every analysis,
cross resistance to other PIs proved significantly less common after DVR
failure than after LPV failure. The rates of emergent nucleoside
mutations were also less in the DRV group (23%) than in the LPV group
(6%) (P < 0.05).
Back
to Top
Etravirine expanded access programs (Europe
and Canada).
Antiretroviral treatment use and HIV-RNA suppression rates for 941
European patients in the etravirine expanded access programme
Florence E, et al. Abstract P36.
Expanded access programs (EAPs) provide
vital new drugs to highly treatment experienced patients. Patients who
were recruited from 10 countries in Europe and Canada received
etravirine (ETR) 200mg twice daily with a range of background
antiretrovirals (ARVs). By May 2008, there were 941 European patients
with data available (Click on title to view poster):
21% were female, 87% were Caucasian, with a mean age of 46 years. At
baseline, the mean CD4 count was 299 cells/uL (range 0-1647) and the
mean HIV-RNA was 4677 copies/mL, a range of 40 - 3,263,277, and drug
resistance was not assessed. Over three quarters of patients used at
least one PI (76%), of which most (91%) used DRV/r, and a little less
than a third (29.2%) did not use NRTIs at all in the background regimen.
In the 70.8% of patients who used NRTIs, the most commonly used were
lamivudine or emtricitabine (91%), tenofovir (69%), zidovudine (20%) and
abacavir (18%); other ARVs used included raltegravir (54%) and maraviroc
(15%). The percentage of patients with HIV-RNA <50 copies/mL was 51% at
week 4, 70% at week 12, and 74% at week 24 (observed data analysis). CD4
counts rose by a mean 79 cells/uL at week 12 and by 101 cells/uL at week
24. In the overall cohort (941), the percent of patients with HIV RNA
<50 copies/ml increased from 15% at baseline to 74% at week 24 (observed
data). (To review the USA etravirine EAP data presented at ICAAC 2008,
go to
Resistance Reporter Vol 2, Issue 5.)
Back to Top
The injectable fusion inhibitor, enfuvirtide
(ENF), has been an integral part of salvage regimens for several years.
However, with the advent of the newer antiretroviral therapies (ARVs),
switching from ENF to more convenient, less costly alternatives has been
explored within the context of expanded access programs (EAPs). This "as
treated" analysis (Click on title to view poster) is of
data from 37 very treatment experienced patients in the TMC125-C214
trial (global etravirine expanded access program) from Europe and Canada
with undetectable HIV-RNA levels (<50 copies/mL) who were permitted to
switch from ENF to etravirine (ETR) and followed for 24 weeks. At the
time of the switch, patients could also optimize other parts of their
background regimen: darunavir/ritonavir (DRV/r) was used in 36 (97.3%)
patients, raltegravir (RAL) in 23 (62.2%), maraviroc (MVR) in 6 (16.2%),
and 33 (89%) used NRTIs. Of the drugs added, many were new to the
participants with 19 (51.4%) using DVR, 12 (32.4%) using RAL, and 5
(13.5%) using MVR for the first time. The switch from ENF to ETR
appeared to maintain viral suppression in some patients. After the
switch, the percentage of all patients with HIV-RNA levels <50 copies/mL
was 86% at week 12 and 95% at week 24. Of those who were not below 50
copies/mL at week 12, there were four hovering just above the limit of
detection (50, 52, 52, 58), one with 217 copies/mL, and another patient
with 5,070 copies/mL. The mean CD4 count at baseline was 351 cells/uL
(range 90-935), and it remained above baseline through week 24. (To
review the USA etravirine EAP data presented at 48th Annual ICAAC/IDSA
46th Annual Meeting (2008), go to
Resistance Reporter Vol 2, Issue 5.)
Back to Top
Additional Reading:
