Transient Relapses (“Blips”) of Plasma HIV RNA Levels During HAART Are Associated With Drug Resistance

Stuart, J. W. T. Cohen; Wensing, Annemarie M. J.; Kovacs, Colin; Righart, Maike; Jong, Dorien de; Kaye, Steve; Schuurman, Rob; Visser, Corjan J. T.; Boucher, Charles A.

doi:10.1097/00126334-200110010-00001

Cited by 63 publications

(14 citation statements)

References 31 publications

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“…2B), most of the viral load values were between 50 and 200 copies/ml (the percentage of patients with viral loads above 200 copies/ml was between 0% and 11% depending on the week of treatment). This result further supports the evidence of continuous virus evolution when viral loads are low but above 50 copies/ml, as has been documented by others [Wit et al, 1999;Cohen-Stuart et al, 2001;Le Moing et al, 2002].…”

Section: Nucleotide Sequence Analysessupporting

confidence: 91%

Long‐term suppression of plasma viremia with highly active antiretroviral therapy despite virus evolution and very limited selection of drug‐resistant genotypes

Pariente

Pernas

Rosa

et al. 2004

Journal of Medical Virology

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HIV-1 evolution and the possible emergence of mutations associated with resistance to antiretroviral inhibitors have been evaluated in a cohort of sixty-three patients successfully treated with highly active antiretroviral therapy (HAART). The patients under effective HAART were recruited in three different hospitals in Spain, and none of them had been treated (naïve) before entering this study. HIV-1 RNA levels, CD4+, and CD8+ T-cell counts were determined, and nucleotide sequences of proviral regions encoding protease and reverse transcriptase (RT) were obtained for longitudinal blood samples spanning a mean follow-up period of 88 weeks. Phylogenetic reconstructions and calculations of genetic distances among the different sequences of each patient were performed. All except one of the patients under study showed an early and sustained decrease in plasma HIV-1 RNA to levels that were below 200 copies/ml. The plasma viral decline paralleled a significant increase in the CD4+ T-lymphocyte counts. Amino acid sequence analyses revealed the occurrence of mutations associated with antiretroviral resistance in nine patients (14.3%) during HAART treatment, that in some cases could be attributed to excess G to A transitions. In six of the nine patients, the mutations conferred resistance to inhibitors administered in the treatment regime, although the mutations did not result in treatment failure. Sequence comparisons revealed viral evolution during the period of treatment in 47.5% of the patients. The results indicate successful suppression of HIV-1 under HAART for extended time periods, indistinguishable for patients in which evidence of virus evolution could or could not be documented.

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Section: Nucleotide Sequence Analysessupporting

confidence: 91%

Long‐term suppression of plasma viremia with highly active antiretroviral therapy despite virus evolution and very limited selection of drug‐resistant genotypes

Pariente

Pernas

Rosa

et al. 2004

Journal of Medical Virology

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“…By comparing the proportion of episodes occurring in patients who received or did not receive triple-drug therapy, it has been suggested that intermittent viremia might occur because of higher levels of viral replication [81], including selection of drug resistant variants [34]. Thus, there was concern that viral blips could represent viral evolution [73] through active virus replication and, thereby, signal imminent virological failure [67].…”

Section: Intermittent Viral Blipsmentioning

confidence: 99%

“…Thus, there was concern that viral blips could represent viral evolution [73] through active virus replication and, thereby, signal imminent virological failure [67]. However, in other studies viral blips were not associated with virological failure [81, 138, 147, 207], even though in some cases they were associated with the emergence of new drug resistant HIV variants [34, 131]. By comparing viral sequences derived from transient viremia with sequences from PBMC collected before and during HAART, Tobin et al [217] showed that viral blips could result from production of virus following immune activation and clonal expansion of latently infected cells.…”

Section: Intermittent Viral Blipsmentioning

confidence: 99%

Modeling HIV persistence, the latent reservoir, and viral blips

Liang

Perelson

2009

Journal of Theoretical Biology

217

185

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HIV-1 eradication from infected individuals has not been achieved with the use of highly active antiretroviral therapy (HAART) for a prolonged period of time. The cellular reservoir for HIV-1 in resting memory CD4 + T cells remains a major obstacle to viral elimination. The reservoir does not decay significantly over long periods of time but is able to release replication-competent HIV-1 upon cell activation. Residual ongoing viral replication may likely occur in many patients because low levels of virus can be detected in plasma by sensitive assays and transient episodes of viremia, or HIV-1 blips, are often observed in patients even with successful viral suppression for many years.Here we review our current knowledge of the factors contributing to viral persistence, the latent reservoir, and blips, and mathematical models developed to explore them and their relationships. We show how mathematical modeling can help improve our understanding of HIV-1 dynamics in patients on HAART and of the quantitative events underlying HIV-1 latency, reservoir stability, low-level viremic persistence, and emergence of intermittent viral blips. We also discuss treatment implications related to these studies.

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“…Investigations of intermittent viremia suggest that viral blips might originate from higher levels of active viral replication [23], including the selection of drug resistant variants [24]. By comparing viral sequences derived from transient viremia with sequences from peripheral blood mononuclear cells (PBMC) collected before and during HAART, Tobin et al [25] showed that viral blips could also result from production of virus following immune activation and clonal expansion of latently infected cells.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric division of activated latently infected cells may explain the decay kinetics of the HIV-1 latent reservoir and intermittent viral blips

Liang

Perelson

2009

Mathematical Biosciences

109

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Most HIV-infected patients when treated with combination antiretroviral therapy achieve viral loads that are below the current limit of detection of standard assays after a few months. Despite this, virus eradication from the host has not been achieved. Latent, replication-competent HIV-1 can generally be identified in resting memory CD4+ T cells in patients with “undetectable” viral loads. Turnover of these cells is extremely slow but virus can be released from the latent reservoir quickly upon cessation of therapy. In addition, a number of patients experience transient episodes of viremia, or HIV-1 blips, even with suppression of the viral load to below the limit of detection for many years. The mechanisms underlying the slow decay of the latent reservoir and the occurrence of intermittent viral blips have not been fully elucidated. In this study, we address these two issues by developing a mathematical model that explores a hypothesis about latently infected cell activation. We propose that asymmetric division of latently infected cells upon sporadic antigen encounter may both replenish the latent reservoir and generate intermittent viral blips. Interestingly, we show that occasional replenishment of the latent reservoir induced by reactivation of latently infected cells may reconcile the differences between the divergent estimates of the half-life of the latent reservoir in the literature.

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Transient Relapses (“Blips”) of Plasma HIV RNA Levels During HAART Are Associated With Drug Resistance

Cited by 63 publications

References 31 publications

Long‐term suppression of plasma viremia with highly active antiretroviral therapy despite virus evolution and very limited selection of drug‐resistant genotypes

Long‐term suppression of plasma viremia with highly active antiretroviral therapy despite virus evolution and very limited selection of drug‐resistant genotypes

Modeling HIV persistence, the latent reservoir, and viral blips

Asymmetric division of activated latently infected cells may explain the decay kinetics of the HIV-1 latent reservoir and intermittent viral blips

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