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  22nd Conference on Retroviruses and
Opportunistic Infections
Seattle Washington Feb 23 - 26, 2015
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Early ART, continuous suppression, tied to lower HIV DNA in CHER trial children
  CROI 2015, February 23-26, 2015, Seattle, Washington
Mark Mascolini
Early versus deferred antiretroviral therapy (ART) and longer continuous viral suppression in HIV-positive infants enrolled in the CHER trial predicted lower HIV DNA in peripheral blood mononuclear cells (PBMCs) and a greater chance of attaining an undetectable DNA reservoir [1]. But only 5 of 247 children assessed reached an undetectable HIV DNA level in PBMCs.
CHER is the landmark trial that found early ART for HIV-infected infants reduced morbidity and mortality 75% compared with deferred treatment [2]. CHER enrolled South African infants younger than 12 weeks old and with a CD4 percent above 25%. Researchers randomized them to start ART immediately and take it for 40 weeks or 96 weeks, or to defer ART. Any child in the deferred arm or who suspended ART resumed treatment if clinical AIDS developed or CD4 percent fell below 20%.
CHER investigators collected PBMC samples every 12 weeks. This analysis focused on children who had taken ART for at least 24 weeks and had two consecutive plasma HIV RNA loads below 400 copies. The researchers measured HIV DNA in PBMCs with an assay that can detect as few as 1 provirus per 100,000 cells. Primary goals of this study were to determine the impact of early versus deferred ART on HIV DNA in PBMCs, to assess the impact of antiretroviral interruption, and to pinpoint factors that predicted a drop in PBMC DNA.
Proviral DNA in PBMCs was higher in the 45-child ART-deferred group than in the 73-child early-ART group at week 96, even though everyone had taken ART for at least 24 weeks at that point (log-scaled t test P < 0.0001). Median proviral DNA levels at 96 weeks measured 100 copies per 100,000 PBMCs in the deferred group versus 27 copies in the early group. At the 96-week point the deferred had spent a median of 81 weeks on ART compared with a median of 96 weeks in the early group (P < 0.0001).
Earlier age when ART began correlated with lower proviral DNA in PBMCs (r = 0.4, P < 0.0001), as did duration of continuous HIV suppression (r = -0.4, P < 0.0001). From study week 96 to week 248, proviral DNA levels remained stable in children on continuous ART but rose in those who interrupted therapy. At week 248 HIV DNA levels did not differ substantially between the original deferred arm, the 40-week early arm, and the 96-week early arm. The investigators proposed these findings suggest that the DNA-reservoir benefit of starting ART early "can be lost" by interruption. At 248 weeks both cumulative duration of ART and continuous HIV RNA suppression predicted levels of proviral DNA in PBMCs, regardless of original randomization.
Three factors independently predicted DNA PBMC reservoir decline and probability of attaining an undetectable DNA reservoir: early versus deferred ART (P < 0.0001), longer continuous HIV RNA suppression (P < 0.0001), and lower cytomegalovirus DNA at trial enrollment (P = 0.02). The CHER team wondered whether the last result suggests a role for treating CMV infection in such an infant population.
All children who interrupted ART had resurgent HIV RNA. Among 247 children assessed, only 5 (2%) reached an undetectable HIV DNA level--4 children in the early arm who took ART for 96 weeks and 1 child in the deferred group who started ART at week 14. The researchers stressed that undetectable HIV DNA in PBMCs does not mean HIV has been cured.
The CHER team believes their findings support the view that starting ART early and sustaining virologic suppression in newly diagnosed infants are critical to draining the HIV DNA reservoir in PBMCs. They noted that "early ART" in CHER was not "very early": For example, the four early-arm infants who reached an undetectable proviral DNA levels started ART at 6 or 7 weeks of age.
1. Payne HA Watters S, Hsaio M, et al. Early ART and sustained virological suppression limits HIV proviral DNA reservoir: CHER evidence. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 35.
2. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359:2233-2244. http://www.nejm.org/doi/full/10.1056/NEJMoa0800971