891
Profiling Etravirine Resistance in Ugandan Children with Extended Failure of a NNRTI-inclusive Regimen as First-line ART
A Kekitiinwa1, D Friedman2, E Coakley3, Y Lie3, and Frank Graziano*2
1Mulago Hosp, Kampala, Uganda; 2Univ of Wisconsin Hosp and Clinics, Madison, US; and 3Monogram Biosci, South San Francisco, CA, US
Background: Etravirine (ETR), a NNRTI, is the first
FDA approved second-generation NNRTI demonstrating activity against K103N and
other NNRTI-resistance mutations. Indeed in one highly treatment-experienced
population reduced ETR susceptibility (fold-change >3, PhenoSense HIV,
Monogram Biosciences) was seen in approximately 1 of 4 samples with
approximately 1 of 3 samples demonstrating hypersusceptibility (fold-change <0.4).
This susceptibility profile may have clinical relevance to individuals failing
ART in resource-limited settings where NNRTI are generally used in first-line
therapy and where they may be maintained in the setting of treatment failure
for extended periods.
Methods: To explore the patterns of ETR resistance
in this clinical setting we retrospectively analyzed the genotypic and
phenotypic HIV resistance profiles (PhenoSenseGT) in 35 children attending the
Pediatric Infectious Disease Clinic (PIDC Mulago Hospital, Kampala, Uganda) who were experiencing clinical failure of an NNRTI-based first-line ART. All children had
been on the same ART regimen for ≥13 months which consisted of nevirapine
(NVP) or efavirenz (EFV) with lamivudine (3TC) and either zidovudine (AZT), or
stavudine (d4T).
Results: All isolates were subtype A, D, C, or a combination
of these. All samples demonstrated both phenotypic and genotypic resistance to
NVP, EFV, and 3TC. However, only 20% of samples had multiple ZDV/d4T associated
mutations and only 30% and 3% had reduced susceptibility to ZDV and d4T,
respectively. However, 35% of samples had phenotypic resistance to ETR (fold-change
>2.9) while no sample demonstrated ETR hypersusceptibility.
Conclusions: In this population with extended
failure of their first ARTV regimen, including NVP or EFV, reduced ETR susceptibility
was not uncommon (fold-change >2.9, 33%) and no samples demonstrated ETR hypersusceptibility
(fold-change <0.4). These findings may have been impacted by the relatively
low levels of NRTI resistance observed in this population. The data suggest
caution in anticipating specific patterns of ETR susceptibility in this
resource limited setting where non-B clade HIV is common. Further study is
warranted to more fully define the patterns of ETR susceptibility in this
setting.
|
