Library Volume 1, Issue 6:
Resistance Reporter© Targeting HIV Entry from 3rd
International Workshop
Selection from the Targeting HIV Entry: 3rd International Workshop,
December 7-8, 2007, Washington, DC
Our expert staff, along with Resistance Reporter©'s highly-respected
editorial board, sorted through numerous recent journals for
articles related to HIV resistance and hand-picked 4
scientifically-important presentations plus one presentation from
Targeting HIV Entry: 3rd International Workshop to cover in this issue.
These selections have been grouped into two sections that provide
clinically-relevant information related to a certain topic. The
selections and summaries we have provided are of truly noteworthy
research; hot links to the abstracts and suggestions for related reading
makes broadening your existing knowledge on a complex topic
logical and
easy.
-
Section 1: Select articles related to the prevalence and
persistence of HIV drug resistance and its correlation with
virological failure
-
Section 2: Select presentations and articles related to new
agents and the diagnostic utility of tropism testing in the
strategic sequencing of CCR5 inhibitor use in HIV treatment
Select articles related to the prevalence
and persistence of HIV drug resistance and its correlation with
virological failure
Long-Term Persistence of Transmitted HIV Drug Resistance
in Male Genital Tract Secretions: Implications for Secondary
Transmission
J Infect Dis. 2007;196(3):356-360, Smith D et al.
Transmitted drug-resistant virus may persist
longer in the unique environment of the male genital tract than it does
in blood plasma. The current study included 5 individuals who were newly
infected with HIV carrying resistance mutations to nonnucleoside reverse
transcriptase inhibitors (NNRTIs) and assessed the decay of HIV
resistance in blood versus semen over time using population-based
pol sequencing. At enrollment, the individuals had an average age
of 37 years (range: 22-59 years). Three of the five individuals had
detectable NNRTI-resistant HIV present in both blood and semen
throughout the mean follow-up of 296 days (approximately 0.8 years)
after the estimated date of infection. These individuals have been
monitored for the shortest amount of time. The other two individuals had
persistent NNRTI-resistance that was detectable in both blood and semen
through 871 (2.4 years) and 1179 days (3.2 years) after the estimated
date of infection. In these latter two individuals, resistant virus was
still detectable in seminal fluid well after 3 years (at 1193 days and
beyond 1179 days of follow-up, respectively), even though it had
reverted back to wild type in blood plasma. Transmission linkage
analysis determined that one individual had acquired NNRTI-resistant HIV
from a source partner who developed drug resistance following
antiretroviral treatment. Analysis of another individual with primary
NNRTI-resistant HIV who remained antiretroviral naive showed that this
individual serially transmitted the drug-resistant virus to two sexual
partners. The investigators speculate that the male genital tract may
serve as a sanctuary site, thereby allowing prolonged persistence of
drug-resistant virus up to years after initial infection in select
individuals, which may allow for further transmission of drug
resistance.
Back to Top
This study retrospectively analyzed two
mutually exclusive cohorts of HIV-infected patients to identify the
prevalence and covariates of darunavir resistance-associated mutations (DRV-RAMs).
The clinic population included 1847 patients receiving treatment under a
managed-care program in Northern California, of whom 1175 had received 1
or more PIs. The database population included 11,697 patients in the
Stanford HIV Drug Resistance Database, of whom 2744 had received 1 or
more PIs. The DRV-RAMs assessed included V11I, V32I, L33F, I47V, I50V,
I54L/M, G73S, L76V, I84V, and L89V, which were previously defined in
other analyses. The prevalence of each DRV-RAM in PI treatment-naďve
patients was very rare, typically occurring in less than 0.5% of
patients in any of the 8 most common HIV subtypes. In contrast to their
almost complete absence in isolates from PI-naive persons, the 11
DRV-RAMs did occur in PI-treated persons:, 29.8% of the 1175 PI-treated
patients in the clinical cohort while 23.7% of the 2744 PI-treated
patients in the Stanford database had 1 or more DRV-RAM . Despite the
prevalence of these mutations, 96% of PI-treated patients in the
clinical cohort and 99% of PI-treated patients in the database cohort
had fewer than 3 DRV-RAMs, which portends a favorable response to
darunavir (DRV). In accord with prior reports, the number of DRV-RAMs
was significantly and independently predicted by the number of PIs
previously received (P<10-16) and with prior receipt of
amprenavir or fosamprenavir (P<10-16), which are structurally
very similar to DRV. The investigators also identified 17 additional
mutations that correlated with the presence of DRV-RAMs (L10I/F, G16A,
Q18H, K43T, M46I, F53L, K55R, I62V, L63P, C67F, A71V, I72L, G73C/T,
I85V, L90M). The authors noted that common mutations such as M46I and
L90M, which they found to be highly correlated with the number of
DRV-RAMs, may have an effect on virologic outcome despite not having had
a significant effect when added to a model that already contained 11
mutations with which they were highly correlated.
Back to Top
This study assessed the longitudinal risk of
developing extensive virologic failure to the three original
antiretroviral classes among a prospective cohort of 7916 patients being
followed in the UK Collaborative HIV Cohort Study. Virologic failure was
defined as HIV RNA > 400 copies/mL despite > 4 months of continuous use
of a specific drug. Extensive virologic failure to the PI class was
defined as virologic failure of at least one ritonavir-boosted PI, and
extensive failure of the NNRTI class was defined as virologic failure of
either nevirapine or efavirenz. Extensive failure of the nucleoside
reverse transcriptase inhibitor (NRTI) class was defined as virologic
failure of one drug within three subclasses: zidovudine or stavudine;
lamivudine or emtricitabine; and didanosine, tenofovir, or abacavir. All
patients initiated treatment with three or more antiretrovirals. At
baseline, patients had a median age of 36 years (range: 31-42), 25% were
female, 61% initiated treatment with an NNRTI-based regimen, the median
CD4+ cell count was 187 cells/mm3 (range: 90-282), and the
median viral load was 5.0 log10 copies/mL (range: 4.4-5.5).
Extensive virologic failure to all three classes developed in 167
patients (2.1%) during 27,441 patient-years of follow-up. The majority
of patients (77%) who developed extensive triple-class failure had
previously had a viral load below 50 copies/mL. The estimated risk of
extensive triple-class failure was 3.5% (95% confidence interval [CI]:
2.9%-4.1%) by 5 years and 9.2% (95% CI: 5.0%-13.4%) by 10 years, and
these rates appear to have decreased over time (adjusted hazard ratio:
0.86 per each successive year; P = .006). The risk of extensive
triple-class failure at 10 years was markedly lower in patients who
initiated treatment with a CD4+ cell count of 200 cells/mm3
or more (5.5%; 95% CI: 3.5%-7.5%) compared with those who initiated
treatment with a CD4+ cell count below 200 cells/mm3 (12.1%; 95% CI:
5.1%-19.1%). In a multivariate analysis, independent predictors of an
increased risk of extensive triple-class failure included a low CD4+
cell count at the start of therapy (P < .0001), younger age (P
= .001), heterosexual risk of contracting HIV (P < .0001), and
initiation of treatment long ago (p=.006). Strikingly, 60% and 44% of
patients had one or two consecutive viral load measurements,
respectively, below 50 copies/mL after being diagnosed with extensive
triple-class failure. The risk of death from extensive triple-class
failure by 5 years was 10.6% (95% CI: 2.4%-18.8%; included 9 deaths).
The authors concluded that these findings illustrate that the
development of extensive virologic failure to the three main classes of
antiretrovirals occurs slowly and is associated with a relatively low
risk of death in routine clinical practice.
Back to Top
RELATED ARTICLES:
Back to Top
Select presentations and articles related to
new agents and the diagnostic utility of tropism testing in the
strategic sequencing of CCR5 inhibitor use in HIV treatment
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, Reeves J
The phenotypic TrofileTM assay is
typically used to screen patients prior to the administration of CCR5
inhibitors. The CCR5 inhibitor, maraviroc, was FDA approved in 2007, and
it is known that patients with dual/mixed- or CXCR4 (X4)-tropic virus
are unlikely to benefit from this agent or others in the CCR5 inhibitor
class. The standard TrofileTM assay is only 85% sensitive at
detecting minor X4-using variants present at 5% in a mixed-virus
population, and minor variants present at less that 5% can be missed
entirely, which may contribute to rapid selection of X4-using variants
if CCR5 inhibitors are administered. Several modifications were made to
the TrofileTM assay to enhance its sensitivity, including
varying virus input, varying coreceptor expression levels, and
optimizing transfection and infection conditions in the event that this
will further optimize selection of patients who may benefit from therapy
with entry inhibitors targeting CCR5. Compared with the standard TrofileTM
assay, these enhancements improved the detection of minor X4-using
variants in a mixed viral population 10-fold, enabled detection of
X4-using variants present at only 0.1% of a total mixed viral
population, and allowed for earlier detection of the emergence of
X4-using variants in longitudinal samples collected from
treatment-experienced individuals at various comparative time points.
Applying the enhanced assay to 258 sequential samples taken from a
cohort of 77 treatment-experienced individuals with incomplete virologic
suppression on therapy that had already been classified using the
standard TrofileTM assay resulted in reclassification of 20
of the samples (8%). Nineteen samples originally classified as CCR5
(R5)-tropic by the standard TrofileTM assay were determined
to be dual/mixed by the enhanced assay, as was one sample originally
classified as X4 tropic. This resulted in reclassification of HIV
coreceptor use for 14 of the 77 patients. Additional testing of the
enhanced TrofileTM assay in CCR5 inhibitor clinical trial
samples is planned to determine the clinical utility of this assay.
Back to Top
AIDS. 2007;21(14):F17-F24, Low A et al.
There is a desire to identify faster and
less costly methods to determine HIV coreceptor tropism to better
integrate CCR5 antagonists into clinical practice and exclude
individuals with X4-using HIV from receiving ineffective treatment. This
study compared the accuracy of six different V3 genotyping algorithms
for predicting HIV coreceptor usage with that of actual phenotypic
results. Genotypic information was obtained by bulk sequencing, whereas
phenotypic information was obtained using the Trofile™ assay. Matched
genotype and phenotype data were available for 920 clinical samples
collected from treatment-naďve individuals. Although specificity of the
genotypic algorithms was high, sensitivities were quite low for all six
algorithms: the 11/25 rule (93% specificity/31% sensitivity), a neural
network (88%/44%), a subtype-b position-specific scoring matrix (PSSM)
of syncytium-inducing to nonsyncytium-inducing virus (96%/34%), PSSM of
X4 to R5 virus (97%/24%), support vector machine (SVM) genomiac
(90%/22%), and SVM geno2pheno (89%/50%). The poor sensitivity of these
methods was attributed to the inability of bulk sequencing to reliably
detect minority X4-using virus present below 22% of the total
population. The investigators argued that the sensitivity of select
genotypic algorithms could be enhanced by optimizing cut-off methods, by
using a more sensitive sequencing technique, and/or by including
clinical data on CD4+ cell count. These findings indicate that current
coreceptor prediction algorithms that rely on genotype are inadequate
for accurately identifying X4-using HIV.
Back to Top
RELATED ARTICLES:
To order new educational programs that give unbiased, independent
information and hope to patients running low on treatment options, view
or download (FREE) Visionary Health Concepts' educational booklet,
"Are You Experienced? HIV and You©"at
www.freehivinfo.com.
