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Repeated Supervised Treatment Interruption with Progressive Increases in "Off-Treatment" Duration Results in Enhanced Virologic Control in a Subset of Pediatric Individuals
William Borkowsky*1, E McFarland2, R Yogev3, P Muresan4, L Frenkel5, T Fenton4, J Moye6, E Capparelli7, P Harding2, N Ellis8, and the Pediatric AIDS Clinical Trials Group 1015 Team
1New York Univ Sch of Med, NY, US; 2Univ of Colorado Hlth Sci Ctr, Denver, US; 3Chicago Children's Memorial Hosp, IL, US; 4Frontier Sci & Tech Res Fndn, Harvard Sch of Publ Hlth, Boston, MA, US; 5Children's Hosp and Med Ctr, Seattle, WA, US; 6Natl Inst Child Hlth and Devt, NIH, DHHS, Bethesda, MD, US; 7Univ of California, San Diego, US; and 8Univ of Washington, Seattle, US
Background: We performed a study to determine whether a
series of supervised treatment interruption (STI) intervals among pediatric
patients with ART-induced aviremia would induce
HIV-specific immunity that controlled their viremia.
Methods: For 14 children with suppressed plasma viremia (<400 copies) for >1 year and <50 copies
at baseline, we began a prospective nonrandomized STI protocol with
progressively increasing periods off therapy, starting with a 3-day STI during
cycle 1, STI increased by 2 days for each subsequent cycle. T cell percentage,
inactivated HIV, as well as Gag, Env, RT, and Nef-specific IFN-g
spot-forming-cells (SFC)/106 peripheral blood mononuclear cells (PBMC),
lymphoproliferative responses (LPR), and viral
genotyping are monitored. For personal reasons, 2 discontinued. Of the
remaining 12, 8 became viremic and reached cycle 13
(STI of >27 days) are analyzed. To compare RNA during later cycles with RNA
levels at comparable times off HAART during early cycles, RNA was measured
midway as well as at the STI end, beginning at C16. Replication capacity was
measured in 5 of 8.
Results: Median plasma RNA peaked at cycle 7 (4.4 log)
and declined at cycle 9, 12, and 15 (3.9, 4, 3.7 log), despite a longer
interval off treatment. By contrast, median change from baseline for IFN-g
SFC increased with sequential STI with 288, 1411, 1283, 2235 SFC at C7, C9,
C12, and C15. Subjects with HIV-specific LPR increased from 50% at baseline to
75% at cycle 9 and 12. CD4% declined slightly (median 40.5 to 36.5) while CD8%
increased (24 to 29.5). New mutations were seen in 1 of 8, 2 of 14 additional
subjects developed early mutations removing them from further STI. A subset of
5 who have reached cycle 17 had median RNA 3.4 log. Midcycle
RNA at C18 (16 to 18 days off treatment) was 0.32 to 2.1 (median 1.3) log lower
than at comparable days off treatment (17 to 18 days) at C8. IFN-g
SFC in the month preceding the STI was 4- to 30-fold higher pre-cycle 18 than cycle
8 in 4 of 5. Early and late replication capacity values did not significantly
change in 4; the subject who developed a resistance mutation showed a marginal
decline in replication capacity with time.
Conclusions: A subset of pediatric patients undergoing
progressively lengthening STI demonstrated improved virologic
control despite longer periods off therapy. This effect is seen in those who
have had ≥13 interruptions, resulting in STI that eventually exceed 27
days in length. Enhanced HIV-specific immune responses may have played a role
in this phenomenon. Selection of less replication competent virus may have
played a role in one of the individuals.
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