December 9, 2015
Infants who began antiretroviral therapy (ART) within 12 weeks of perinatal infection had a six-fold smaller proviral HIV DNA reservoir than infants who started ART later, according to results of a 23-child study. Treatment interruptions led to a "dramatic" jump in reservoir size, and this replenishment may be irreversible.
HIV resists attempts at eradication because an impervious proviral reservoir becomes established in resting CD4+ cells soon after infection. Unlike older children and adults, infants infected before or during delivery sustain a high viral load in the first years of infection if untreated. Yet neonates may be the best candidates for prompt antiretroviral intervention to prevent or limit establishment of a proviral reservoir because their infection can be diagnosed in the first days of life. But even though starting ART soon after delivery appears to prevent a proviral reservoir from forming -- as in the case of the Mississippi baby -- occult HIV can persist and trigger new rounds of replication if ART stops.
To inform the design of interventions in infants diagnosed with HIV in the first year of life, researchers at several Spanish centers conducted a retrospective analysis of 23 vertically infected infants: 14 given ART within 12 weeks of birth, and nine treated between 12 weeks and one year. The research team analyzed plasma and peripheral blood mononuclear cell samples collected after at least one year of viral suppression, defined as a plasma viral load at or below 200 copies/mL. They used droplet digital PCR to measure CD4+ cell-associated total HIV DNA (the proviral DNA reservoir).
When ART stopped in three children treated within 12 weeks of infection, the median size of their latent reservoir rose from 25 to 199 copies/million CD4+ cells, even though they had all maintained viral control in plasma for at least one year. The slope of this increase (0.29) was statistically significant (P = .0005), whereas the slope in nine children who never stopped ART barely changed (-0.02, P = .68). One child treated immediately after birth had a proviral reservoir of 3.8 copies/million CD4+ cells when ART stopped. Plasma viremia rebounded within one week to 500,000 copies/mL, then decreased rapidly when ART resumed. The proviral reservoir increased approximately 50-fold when ART stopped and remained at that level for the next three years after ART resumed.
The researchers believe their findings highlight the importance of starting ART within the first 12 weeks of life when possible in perinatally infected infants, because prompt treatment curtails seeding of the long-lived proviral DNA reservoir. They also believe the study "casts doubt on the ability of a small viral reservoir to limit viral rebound after [ART] discontinuation (as observed in the case of the Mississippi baby)."
The case of the child in their study with a sustained 50-fold increase in proviral reservoir size after ART interruption, the authors add, indicates that "treatment interruptions should be undertaken with caution, as they might lead to fast and irreversible replenishment of the viral reservoir."
Mark Mascolini is a freelance writer focused on HIV infection.
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