Examination of HIV-1 Subtype and Response to ART in Ugandan Children
Addy Kekitiinwa*1, P Kasirye1, D Friedman2, E Coakley3, Y Lie3, and F Graziano2
1Mulago Hosp, Kampala Uganda; 2Univ of Wisconsin Hosp and Clin, Madison, US; and 3Monogram Biosci, South San Francisco, CA, US
Background: Subtypes A and D are the predominant
HIV-1 clades found in Uganda. There is evidence that ART developed against
HIV-1 subtype B has activity against the non-B subtypes that predominate in
areas of the world where other HIV clades are common. Few data comprehensively
examine the relationship between viral subtype and resistance
(genotype/phenotype), replication capacity, and viral tropism in individuals
with non-B subtypes treated with ART. With this in mind, the objective of this
study was to examine this relationship in Ugandan children failing their first
Methods: A retrospective evaluation was performed on
36 children attending the Pediatric Infection Disease Clinic, Mulago Hospital, Kampala, who failed their first ART. Stored blood (–70°C), drawn at the time of ART failure, was evaluated for viral
load, CD4 count, subtype, genotypic and phenotypic resistance, replication
capacity, and viral tropism. Among these children, 74% received nevirapine (NVP)/stavudine
(d4T) or zidovudine (AZT) -based therapy and 26% received efavirenz (EFV)/d4T
or AZT-based therapy. All children received lamivudine (3TC).
Results: Of the children, 41% were subtype A and 36%
subtype D. Subtypes C and recombinant subtypes A/D, A/C, C/D were also represented.
Replication capacity was greater in children failing therapy with subtype DOf
all children failing therapy, 61% had a dual mixed (R5X4) tropism, 32% were R5,
and 7% X4. Genotypically, all children failing therapy had M184V and NNRTI
mutations (K103N, G190A, Y181C predominated). One child had a Q151M mutation at
first failure. All AZT/d4T mutations were observed but M41L and L210W had a low
representation in this population of children (one child had M41L and one had
L210W). Phenotypic resistance mirrored the genotypic pattern, except that only
one child (Q151M mutation) had phenotypic resistance to d4T.
Conclusions: As the use of ART grows in Africa and failure of ART regimens appears more often in these resource-poor settings, it
will be critical to understand the relationship between viral subtype and
response to ART medications.