Persistence of PI-resistance Mutations among Children Undergoing a PI-targeted Partial Treatment Interruption
Usha Phillips*1,2, Usha Phillips*1,2, M Rosenberg1,3, M Rosenberg1,3, J Dobroszycki1,3, J Dobroszycki1,3, A Wiznia1,3, A Wiznia1,3, G Fennelly1,3, G Fennelly1,3, J Abadi1,3, and J Abadi1,3
1Albert Einstein Coll of Med, Bronx, NY, US; 2Montefiore Med Ctr, Bronx, NY, US; and 3Jacobi Med Ctr, Bronx, NY, US
Background: We previously described the stable medical
outcomes of a cohort of HIV-infected children who underwent a partial treatment
interruption of the protease inhibitor (PI) component of their combination ART.
In this retrospective study, we examined the genotypic drug-resistance profiles
of the subjects prior to and during the partial treatment interruption period.
We elaborate on the unexpected finding that many of these patients maintained
significant PI resistance despite the prolonged absence of PI drug pressure.
Methods: We identified 40 perinatally HIV-infected
children and adolescents among our clinic population who met the following
inclusion criteria: detectable viremia
(>1000 copies/mL) at baseline; receipt of a stable PI-containing regimen for
at least 3 months before baseline; stopping the PI either because of poor adherence,
reluctance to continue PI therapy, or toxicity; completed at least 6 months on
partial treatment interruption; and genotypic resistance testing had been
obtained before and throughout the partial treatment interruption period. We
catalogued mutational patterns affecting nucleoside, non-nucleoside, and PI
drug susceptibilities. We explored the number, type, degree of persistence, and
relationship between PI and RT resistance mutations; and speculate about the
influence of these mutations on viral fitness and disease progression.
Results: Gender and race distribution were 22 males
and 18 females, 15 African Americans, 11 Latinos, 4 Caucasians. Median age at
initiation of partial treatment interruption was 9.7 years (range 3 to 18
years). Median duration of partial treatment interruption was 45 months (range
8 to 79 months). All patients had evidence of genotypic RT and PI resistance at
baseline. Despite detectable viremia (median 4.05 log10 copies/mL)
in all subjects throughout the study period, accumulation of further RT
resistance was infrequent, while 80% of the cohort maintained 3 or more primary
PI resistance mutations. PI resistance waned predominantly in those children
who continued their partial treatment interruption beyond 40 months.
Conclusions: Significant genotypic PI resistance persisted
for an extensive time in this group of children who underwent partial treatment
interruption. Because PI and RT resistance mutations can be linked on the same
viral genome, this cohort demonstrated that maintenance of
triple-class-resistant viruses can be achieved with simplified, RT
inhibitor-based treatments. The reduced fitness of these resistant strains of
HIV may contribute to the overall disease stability characteristic of these