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Early initiation of ART, sustained virological suppression reduced reservoir size

SEATTLE — Earlier initiation of ART and uninterrupted virological suppression were associated with a reduced viral reservoir size and an increased likelihood of developing an undetectable reservoir, according to data presented at CROI 2015.

To assess the impact of ART strategies on viral reservoir size in pediatric HIV, Helen A. Payne, MBChB, BSc, of the Institute of Child Health at the University College London, and colleagues measured HIV-1 proviral DNA from HIV-infected infants (n = 257) aged younger than 12 weeks with CD4 percentage of at least 25% who were randomly assigned to groups comparing early and deferred ART approaches.

In this substudy of the CHER trial, researchers examined data from infants randomly allocated to: deferred ART, immediate ART for 40 weeks or immediate ART for 96 weeks with successive treatment interruption. Criteria for ART initiation in the deferred group — or reinitiation of therapy after interruption in the other two groups — was a CD4 percentage of at least 20% or CDC severe stage B/C disease.

Payne and colleagues measured HIV-1 proviral DNA using DNA extracted from 384 cryopreserved PBMC samples taken 12 times weekly from 40 to 252 weeks after a minimum of 24 weeks of therapy; the effect on proviral DNA decline from early vs. deferred ART as well as ART interruption also were examined.

Researchers analyzed predictive factors for reservoir decline, including:

• ART duration;
• CD4 count at enrollment vs. CD4 count at 96 weeks;
• HIV serostatus and quantitative HIV-antibody at 84 weeks;
• baseline CMV viremia;
• immunological phenotypes;
• viral load at enrollment vs. viral load at 9 to 12 months before proviral DNA measurement; and
• total weeks of continuous suppression below 400 copies/mL.

In addition, Payne and colleagues noted the profiles of five children with undetectable proviral DNA measurements.

“We found there was a highly significant difference between early and deferred ART with the early treatment arm having a far lower HIV proviral DNA,” Payne said during a news conference. “What was also highly significant was that cumulative weeks of HIV suppression were predictive of a lower HIV proviral DNA and that interrupting ART, unsurprisingly, demonstrated an increasing reservoir.”

Payne and colleagues noted, however, that patterns of proviral DNA decline varied in spite of continuous ART and apparent virological suppression.

The researchers observed that ART interruption only slightly increased levels of proviral DNA (P = .03). Additionally, while HIV serostatus was not associated with reservoir size, higher CMV DNA levels at enrollment were linked to an increased HIV reservoir (P = .02).

Furthermore, Payne and colleagues highlighted that four of the children with undetectable proviral DNA were randomly assigned to the ART interruption group and subsequently experienced HIV-1 viral load resurgence during their interruption.

“At the end of the trial, between all three groups, there was no significant difference in the HIV profile DNA measurements, which suggests that the benefit of starting ART early can be lost if therapy is interrupted,” Payne said. – by Bob Stott

Reference:

Payne HA, et al. Abstract 35. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 23-26, 2015; Seattle.

Disclosure: The researchers report no relevant financial disclosures.