Paper # 849 
Incidence of Early Virological Failure and the Evolution of Antiretroviral Drug Resistance Mutations in Ugandan Children
Jane Achan*1, T Ruel2, P Li2, E Charlebois2, T Liegler2, M Kamya1, D Havlir2, and J Wong2
1Makerere Univ, Kampala, Uganda and 2Univ of California, San Francisco, US
Background: With limited access to virologic testing
and ARV-switch guidelines based on CD4/clinical criteria, African children are at
increased risk for unrecognized virologic failure and the development of high
level ARV resistance. There are limited longitudinal data about the evolution
of resistance in non-subtype B HIV+ children. Using banked specimens
from an observational cohort of Ugandan children, we sought to determine the incidence
of early virologic failure (EVF), the evolution of ART-mutations, and the
potential impact on second line therapy options.
Methods: Cases of EVF, defined as HIV RNA >1000
copies/mL 6 to 9 months after ARV initiation were selected from all children
with plasma HIV RNA data in that period. Available banked plasma specimens were
used for population sequencing of HIV-1 pol. Composite discrete
genotypic susceptibility scores (dGSS) scores were calculated using the
standard Ugandan second-line regimen and tested by time with Spearman rank
correlation.
Results: Of 126 children with median 746 follow-up days
beyond 6 months of ARV, 18 (14%) experienced EVF; all had viremia that
persisted throughout follow-up. Genotypic resistance testing was successful in 40
samples from 14 children. First-line ARV regimens for children were zidovudine/lamivudine
(53%) or stavudine/lamivudine (47%) plus nevirapine (NVP). With increased time,
lower dGSS scores predict worsening compromise of current (r = -0.44, P =0.004)
and standard second-line therapies (r =-0.41, P =0.008).
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Months of failure
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|
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0-5
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6-11
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12-17
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18-23
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24-30
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NRTI
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|
|
|
|
|
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1 TAM
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0
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0
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3
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4
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3
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≥2 TAM
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0
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0
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0
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1
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1
|
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M184V
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9
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7
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9
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8
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6
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|
|
|
|
|
|
|
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NNRTI
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|
|
|
|
|
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ETR, 1*
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5
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5
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4
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2
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2
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ETR, 2*
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0
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1
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2
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2
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3
|
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NVP/EFV
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5
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4
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4
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4
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5
|
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N=^
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(10)
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(7)
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(9)
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(8)
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(7)
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TAM: Thymidine-associated
mutation; NVP/EFV:mutations affecting both; ETR:Etravirine; *ETR-related
mutations, none had 3. ^: total # of children with data in time-period.
Conclusions: A significant portion of children
starting ARV in Africa experience EVF and quickly develop ARV mutations. Most
have M184V and NNRTI-mutations within 6 months, TAM’s after 12, and 2 ETR-mutations
by 30 months. With persistent and unrecognized viral replication, African
children with non-subtype B HIV EVF are likely to require more expensive and
less easily accessible second-line drugs. These data underscore the need for affordable
methods to identify viral failure and drug resistance in this population.
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