Library Volume 2, Issue 4:
Resistance Reporter © XVII International AIDS Conference
Selections from the XVII International AIDS Conference (IAC); 3-8
August, 2008; Mexico City, Mexico
Section 1
TUAA02
Co-Chairs: Françoise Brun Vezinet, France, Osamah Hamouda, Germany
This session focused on the drug resistance surveillance of transmitted
HIV, with the goal of addressing this complex and potentially very
worrisome new aspect of the AIDS pandemic. As drug resistant HIV strains
become more or less prevalent among the populations of transmitted
viruses ("primary drug resistance"), the field focuses on monitoring
this phenomenon in various geographical and socio-economic settings,
increasing the performance (i.e., sensitivity and/or specificity) of the
relevant assays, and incorporating this knowledge into clinical
practice. In an interesting talk, Dr. Banks (Harare, Zimbabwe) explored
the potential discordance when drug resistant strains are investigated
at the level of plasma RNA versus cell-associated DNA. Drs. Hamouda and
Archibald described two epidemiological studies (from Germany and
Canada) a ~9% and ~14% incidence, respectively, of primary drug
resistance, which in the Canadian study was more common among B subtype
viruses. A similar trend towards lower incidence of primary drug
resistance in non-subtype B was observed by Dr. Diaz in a cohort of
South Brazilian HIV-infected individuals. Finally, Dr. Kato (Tokyo,
Japan) described a new, very sensitive PCR/mass spectroscopy-based assay
that would help quantify minor populations of drug-resistant viruses.
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TUAA03
Co-Chairs: Francoise Brun Vezinet, France, Luis Soto-Ramirez, Mexico
This session focused on current issues in drug resistance monitoring.
Birgit Dau, from Stanford University, showed that mutations in the
"connection domain" of RT are associated with diminished response to
HAART. However, he noted that it is too early to conclude on a direct
effect of these mutations, since they were also associated with
classical primary resistance mutations. Daria Hazuda (Merck) reported
that the integrase inhibitor raltegravir has comparable antiviral
potency against B and non-B HIV subtypes. Primary resistance mutations
in non-B subtypes included N155H and Y143R, which are also
characteristic of raltegravir resistance in subtype B. A difference may
lie in the pathway to resistance, which is preferentially initiated by
the Q148H/R/K mutation in subtype B, and by the N155H mutation in non-B
subtypes. L. Liao (China CDC, Beijing) presented a cross-sectional
survey of drug resistance in 2689 treated patients from China. Drug
resistance mutations were found in 17.6 % of patients, with a
predominance of NNRTI targeting mutations. Jose-Henrique Pilotto (IPEC,
Brasil) showed that women who received antiretroviral therapy to prevent
mother to child HIV transmission (PMTCT) and who stopped therapy after
delivery developed antiviral drug resistance mutations in 10% of the
cases. The authors noted that thse two studies emphasized the need to
implement HIV genotyping assays on a large scale. A. Maroszan (Progenics)
explained how a maraviroc resistant virus could be generated in vitro by
long-term culture in the presence of slowly escalating doses of the
drug. He also noted that the maraviroc resistant virus remained
susceptible to another CCR5 inhibitor, the monoclonal antibody Pro140.
Thus, he posited that an alternative anti-CCR5 therapy could be
considered in cases of maraviroc resistance without switch to X4
tropism.
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TUSY02
Chairperson:Douglas Richman, United States
The ability of antiretroviral drugs to suppress virus replication relies
on each drug's interaction with their specific HIV protein targets.
Variations in HIV genetic sequence may alter these specific
interactions, generating drug resistance and therefore a less effective
control of viral replication. This session focused on major recent
findings in the field of HIV drug resistance in a variety of settings.
Dr. Pillay's talk described the main complication in assessing the
presence of drug resistant HIV strains in resource-constrained countries
where, in absence of virological monitoring, changes in antiretroviral
therapy are driven only by signs of clinical failure. Dr. Kuritzkes
provided an excellent overview on the resistance to the newer classes of
antiretroviral drugs, i.e., CCR5 antagonists and integrase inhibitors.
He noted that the main reason for virological failure of CCR5
antagonists are (1) the emergence of CXCR4-using HIV from pre-existing
minority population, and (2) mutations in the V3 loop that allow the
virus to bind the drug-bound form of CCR5. For integrase inhibitor
drugs, specific mutations responsible for virological failure were
identified, with resistant viruses showing reduced fitness.
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TUAB0105
Hosseinipour M, van OosterhoutJJ, et al
In this study 94 samples of 96 patients failing a first line regimen
(d4T or AZT-3TC-NVP) showed high rates of pan nucleoside resistance in
Malawi. Mean (sd) CD4 count, HIVRNA, and duration on ART were:
121cells/ml (131), 135984 copies/ml (201278), and 38 months (20.4),
respectively. Four samples did not amplify and 5 samples had no
mutations identified. Seven samples had M184V plus NNRTI mutations only.
NNRTI mutations 181C, 103N, 106M, 188L, 190 occurred with similar
frequency. The most common mutation pattern was M184V plus NNRTI
mutations with one or more TAM (most common = 215F/Y) which occurred in
55% of patients. The authors were surprised to note that 19% of patients
acquired NNRTI mutations (with or without 184V) plus either the K70E or
K65R mutations. 16% of the patients had pan-nucleoside resistance which
corresponded to K65R or K70E and additional multi-nucleoside resistance
mutations, most commonly the 151 complex and/or rarely 69 insertions.
All in all resistance to 3TC was present in 81%, to first generation
NNRTIs in 93%, and pan-nucleoside resistance in 17%. According these
data, between 22-50% of patients had no fully active drugs in the
recommended second line backbone, highlighting the need to re-evaluate
the definition of clinical or immunological criteria to change therapy
in low resources settings. For slides and figures, click
here
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TUPE0048
Haubrich R, Schapiro J, Vingerhoets J, et al.
For the first time in DUET, researchers performed a retrospective
analysis of 406 DUET enrollees not using enfuvirtide in their darunavir/etravirine
salvage regimen. The researchers also excluded anyone who quit the study
before week 24 for reasons other than virologic failure. All study
participants took darunavir/ritonavir (600/100 mg BID) plus etravirine
(200 mg QD) and background NRTI which was selected by the investigators
for each patient based on resistance testing. The study also evaluated
two mutational scoring systems for etravirine, the original with 13
etravirine mutations and a revised with 17 etravirine mutations. The
investigators classified -<50-copy response rates according to whether
patients had (1) 0, 1, 2, 3, or > 3 darunavir-associated mutations
before salvage and 0, 1, 2, 3, or > 3 etravirine-associated mutations
before salvage, or (2) < 10-fold, 10- to 40-fold, or > 40-fold decrease
in susceptibility to darunavir before salvage, and < 3-fold, 3- to
13-fold, or > 13-fold decrease in susceptibility to etravirine before
salvage. These analyses, which used an etravirine scoring system of 13
mutations, showed that at least 67% of people with no darunavir
mutations and up to 3 etravirine mutations had a viral load < 50 copies
at week 24, and at least 73% with no etravirine mutations and up to 3
darunavir mutations had a <50 response at 24 weeks. Thirteen of 14
people (93%) with 2 etravirine mutations and 1 darunavir mutation had a
24-week viral load under 50 copies. Among those with less than a 3-fold
change in susceptibility to etravirine and a 10- to 40-fold decrease in
susceptibility to darunavir (intermediate resistance), 65% had an
undetectable load at week 24. No one with more than 3 etravirine
mutations plus more than 3 darunavir mutations or 40-fold resistance to
darunavir plus more than 3-fold resistant to etravirine responded by
week 24 in this 406-person analysis. The authors noted that the 65%
response cutoff suggests that assessing response to a salvage regimen
may be improved by algorithms that can account for two of the agents in
the regimen.
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Additional Reading:
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Bacheler L, et al.
Exploring etravirine resistance among recent routine clinical
samples submitted for resistance testing.Antivir Ther 2008;3
Suppl 3:A120
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MacArthur RD, Novak RM, Peng G, et al.
A comparison of three highly active antiretroviral treatment
strategies consisting of non-nucleoside reverse transcriptase
inhibitors, protease inhibitors, or both in the presence of
nucleoside reverse transcriptase inhibitors as initial therapy
(CPCRA 058 FIRST Study): a long-term randomised trial. Lancet.
2006;368:2125-2135.
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Johnson JA, Li JF, Wei X, et al.
Baseline detection of low-frequency drug resistance-associated
mutations is strongly associated with virologic failure in
previously antiretroviral naive HIV-1 infected persons. Antviral
Ther 2006; 11:S79.
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Vingerhoets J, et al.
An update of the list of NNRTI mutations associated with decreased
virologic response to etravirine (ETR): multivariate analyses on the
pooled DUET-1 and DUET-2 clinical trial data. IHDRW 2008.
Abstract 24
