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Early ART and sustained virological suppression limits
HIV-1 Proviral DNA reservoir: CHER evidence (mortality increased 76% with early ART)
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Reported by Jules Levin
CROI 2015 Feb 23-26, Seattle, WA
"Early-initiation of ART and sustained virological suppression are key to reservoir reduction.....Benefit of starting ART early can be lost by ART-interruption.....Increased HIV Proviral DNA after ART-interruption"
Helen Payne
S Watters, M Hsaio, R Callard, K Otwombe, A Babiker, A Violari, MF Cotton, DM Gibb, NJ Klein
webcast:http://www.croiwebcasts.org/console/player/25555?mediaType=slideVideo&
As a brief reminder, the CHER trial examined the effect of early ART on clinical disease progression in HIV-infected children diagnosed <12wks with CD4% >25%.
411 children were randomised to 3 arms: deferred ART until clinical/immuological progression, or immediate ART for 40wks, or immediate ART for 96wks with the latter 2 groups interrupting their regimen until clinical/immunological progression.
As it is widely known Interim analysis of CHER data in 2007 demonstrated 76% reduction in mortality for early vs deferred ART - therefore early ART in infants henceforth became standard of care
At the trial end, after median 5 years follow up, Early Limited ART remained superior to delayed ART
When comparing deferred versus early ART at trial week 96, early ART
has unsurprisingly highly significantly lower proviral DNA.
(Time spent on ART by trial week 96 was significantly different in the two Arms
(median 81 [IQR 70.3-85.9] versus 96 [IQR 96-96] weeks, p<0.0001)
This is reinforced by the proviral DNA measurements which correlate significantly with the age of starting ART and weeks of continuous viral suppression at week 96 of the CHER trial
Moving on to the impact of ART-interruption on reservoir quantity... here we illustrate the change in proviral DNA using paired samples from individuals at both trial week 96 and 248, comparing continuous (ART-Def in red) with interrupted ART (ART-96W in blue where median interruption was 45 wks) demonstrating minimal change on continuous ART and unsurprisingly an increasing reservoir in the interrupted arm.
However, between all 3 arms at the end of the trial, where overall there was no difference between time off ART (i.e. in ART-Def at the trial start, ART-40W in year 1 and ART-96W in year 2), there appeared to be no significant difference in proviral DNA between the 3 groups. This suggests the benefit of starting ART early can be lost by interruption
Correspondingly, by the end of the trial cumulative duration of ART, AND cumulative continuous HIV-suppression also highly significantly correlates with HIV proviral DNA regardless of deferred start or ART-interruption
Numerous factors were explored to predict low levels of proviral DNA, as listed here.
And as we have shown in the previous slide, reduced reservoir size and probability of developing an undetectable reservoir were strongly associated with earlier ART-initiation and longer continuous HIV-suppression.
Interestingly, lower CMV DNA levels at enrolment were associated with lower proviral DNA - (?which might suggest a role for therapeutic treatment of CMV or other potential co-infections at ART initiation)
It should be noted that HIV serostatus did not correlate with reservoir size
Of 247 children explored, 5 children had one or more "undetectable" measures of proviral DNA
However, it is important to note that of the available viral loads at time of analysis, all children who interrupted their ART regime demonstrated viral load resurgence
I have summarised the profiles of the 4 children from ART-96W here - where blue illustrates CD4 count, red viral load, green the point of ART-interruption and the black diamond is the measurement of undetectable HIV proviral DNA
They all started ART 6-7 wks
All 4 underwent ART-interruption
All 4 exhibited HIV-resurgence during that interruption
3 had undetectable proviral DNA by 96 wks
Even though interestingly, child 2 had a "viral blip" at approximately 1 year of age)
However the first 3 remained off ART until trial end (~3yrs)
The final 1 had low proviral DNA by 40 weeks then interrupted at 96 weeks for 57 wks, yet became undetectable within ~2yrs
As you can see half were HIV-seronegative and half seropositive
The final child was from the deferred ART arm and began continuous ART from 14 weeks of age. After 90 weeks of ART she had 2 copies of proviral DNA and was undetectable by 4 years on 3 subsequent measures of proviral DNA.
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