Reseeding of viral reservoirs may explain poor response to HAART interruption

Faith Reidenbach, for

The poor response of patients with chronic HIV infection to supervised treatment interruption, compared with responses in acutely infected patients, may be due to the emergence of different viral variants with each interruption, according to study results published in the Journal of Virology for February.

Dr Simon D Frost, of the University of California at San Diego, and colleagues formed their hypothesis after analysing data from a study conducted in Spain, which involved 12 HIV-1-infected patients who had at least a two-year history of viral suppression during highly active antiretroviral therapy. The patients stopped treatment for up to 30 days, then resumed it for 90 days, for four cycles.

The researchers measured viral load very frequently, at a median interval of two days. They say that because of this and their development of a novel Bayesian model, they were able to “obtain good estimates of the viral growth rate, the time for virus to rebound to detectable levels, and residual error even when there are many viral load measurements below the limit of detection.”

Overall, the level of circulating CD4+ T cells did not decrease between the first and fourth treatment interruptions. There was a significant decrease, by about half, in the average viral reproductive rate over the course of the four cycles, with extensive between-patient variation. Still, the research team says, the average time between treatment interruption and viral rebound was approximately the same in the first and fourth interruptions.

“One possible explanation for this discrepancy is that the growth rates above and below the limit of detection were the same, but the viral load present at the beginning of the interruption increased over successive structured treatment interruption cycles,” the authors suggest.

“An increase in the viral load present prior to interruption could be due to the reseeding of viral reservoirs,” they continue. “Any new drug resistance mutations that emerge during treatment interruptions may be archived in these reservoirs, which could lead to the rapid emergence of a resistant viral population in response to subsequent treatment.”

“This may boost the immune response less than repeated exposure to the same viral antigens,” Dr Frost pointed out in an interview with Reuters Health. “We are currently studying how the virus evolves during therapy interruption.”

Based on these and other findings, Dr Frost’s group draws three conclusions about the dynamics of viral replication during treatment interruption: “Multiple, short interruptions may be desirable to reduce exposure to drug, while minimizing the risk of viral rebound; a single, long interruption may be required to allow sufficient replication for the reversion of resistant virus to wild type; and multiple interruptions of intermediate length may be required to allow sufficient rebound of virus to stimulate immune responses, while minimizing the risk of damage to the CD4+ compartment.”

“Given that therapy interruption is also associated with risks — letting the virus replicate can result in drops in CD4+ count and increases the chance that drug resistance will emerge — it is important to emphasize that treatment interruptions remain an experimental regimen,” Dr Frost cautioned.


Frost SD, Martinez-Picado J, Ruiz L et al. Viral dynamics during structured treatment interruptions of chronic human immunodeficiency virus type 1 infection. J Virol 2002; 76:968-979.

Abstract at: PubMed&list_uids=11773372&dopt=Abstract

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