Structured interruptions of highly active antiretroviral therapy in cycles of 4 weeks off/12 weeks on therapy in children having a chronically undetectable viral load cause progressively smaller viral rebounds

Palacios, Gerardo C.; Sánchez, Luz María Sánchez; Briones, Evangelina; Ramirez, Teresa J.; Castillo, Hugo del; Rivera, Lydia G.; Vázquez, C; Rodríguez‐Padilla, Cristina; Holodniy, Mark

doi:10.1016/j.ijid.2009.03.003

Cited by 6 publications

(13 citation statements)

References 32 publications

(95 reference statements)

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“…One reason for our observed shorter TI is that our CD4% criterion for ART restart was higher (25%) to align with later WHO recommendations[22], while PENTA-11 and CHER used CD4% of 20% eligibility for ART restart. Small pediatric TI studies have observed CD4% increase following initial decline as HIV-1 specific immunity increases in response to viremia emerging after TI [23]. Lower CD4% criteria for ART re-start may permit time to develop HIV-specific immunity to contain virus and regain immune reconstitution.…”

Section: Discussionmentioning

confidence: 99%

Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy

Wamalwa

Benki-Nugent

Langat

et al. 2016

Aids

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Objective Treatment interruption (TI) has been safe and durable in some pediatric studies but none have compared TI to continued antiretroviral treatment (ART) following ART initiation in early HIV. The objective of this study was to compare outcomes in TI versus continued ART among early-treated infants. Design Randomized trial (OPH-03; NCT00428116) Methods The trial included HIV-infected infants who initiated ART at <13 months of age, received ART for 24 months, and, if eligible (CD4>25%, normal growth), were randomized to TI vs. continued ART. Children in the TI group re-started ART if they met WHO ART-eligibility criteria. During 18-months post-randomization, primary outcomes were incidence of serious adverse events (SAEs) and growth. CD4, viral load, morbidity, and growth were compared. Results Of 140 infants enrolled, 121 started ART, of whom 75 completed ≥24 months ART and 42 were randomized (21 per arm). ART was initiated at median age 5 months and randomization at 30 months. Among 21 TI children, 14 met ART re-start criteria within 3 months. Randomization was discontinued by DSMB due to low TI durability. At 18 months post-randomization, growth and SAEs were comparable between arms; hypercholesteremia incidence was higher in the continued arm (p=0.03). CD4% and VL did not differ between arms (CD4% 35% and median VL undetectable (<150 c/ml) in both arms, p=0.9 for each comparison). No infants had post-treatment viral control. Conclusion Short TI did not compromise 18-month CD4%, viral control, growth, or morbidity compared to continued ART among infants who started ART in early HIV infection.

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Section: Discussionmentioning

confidence: 99%

Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy

Wamalwa

Benki-Nugent

Langat

et al. 2016

Aids

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“…Recently, evaluation of Structured Treatment Interruptions (STI) has been proposed as an alternative therapeutic strategy to reduce complications associated with continuous HAART administration [ 1 ]. Based on the establishment of treatment periods followed by drug-free periods long enough to allow significant viral rebound but with a controlled maintenance of the viral replication [ 2 ], STI could induce an increase of the HIV-specific immune response and, consequently, progressively smaller viral rebounds [ 3 , 4 ]. However, information available about STI in pediatric patients remains limited and such information in adults is still controversial.…”

Section: Introductionmentioning

confidence: 99%

Mutations Related to Antiretroviral Resistance Identified by Ultra-Deep Sequencing in HIV-1 Infected Children under Structured Interruptions of HAART

et al. 2016

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Although Structured Treatment Interruptions (STI) are currently not considered an alternative strategy for antiretroviral treatment, their true benefits and limitations have not been fully established. Some studies suggest the possibility of improving the quality of life of patients with this strategy; however, the information that has been obtained corresponds mostly to studies conducted in adults, with a lack of knowledge about its impact on children. Furthermore, mutations associated with antiretroviral resistance could be selected due to sub-therapeutic levels of HAART at each interruption period. Genotyping methods to determine the resistance profiles of the infecting viruses have become increasingly important for the management of patients under STI, thus low-abundance antiretroviral drug-resistant mutations (DRM’s) at levels under limit of detection of conventional genotyping (<20% of quasispecies) could increase the risk of virologic failure. In this work, we analyzed the protease and reverse transcriptase regions of the pol gene by ultra-deep sequencing in pediatric patients under STI with the aim of determining the presence of high- and low-abundance DRM’s in the viral rebounds generated by the STI. High-abundance mutations in protease and high- and low-abundance mutations in reverse transcriptase were detected but no one of these are directly associated with resistance to antiretroviral drugs. The results could suggest that the evaluated STI program is virologically safe, but strict and carefully planned studies, with greater numbers of patients and interruption/restart cycles, are still needed to evaluate the selection of DRM’s during STI.

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“…These treatment strategies have received increasing attention in recent years, but their efficacy and safety have been controversial. Many studies have considered specific STI strategies involving different interruption intervals and decision rules for stopping and initiating therapy [17,20,23,28]. Tang et al [28] use a piecewise model of HIV dynamics to explore STI strategies guided by CD4+ T cell counts.…”

Section: Introductionmentioning

confidence: 99%

“…Tang et al [28] use a piecewise model of HIV dynamics to explore STI strategies guided by CD4+ T cell counts. Palacios et al [20] examine the viral, immune, and clinical impacts of a STI program in three cycles of 12 weeks on and 4 weeks off on children infected with HIV.…”

Section: Introductionmentioning

confidence: 99%

“…There are some evidences that the HIV specific cytotoxic T lymphocyte response (CD8+ immune effector cells) activity increases in patients experiencing a viral rebound [20,27]. Therefore, a number of studies have developed methods that can boost immune effector cells through vaccine or treatment interruptions once patients have suppressed the viral replication [30].…”

Section: Introductionmentioning

confidence: 99%

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Hybrid on-Off Controls for an Hiv Model Based on a Linear Control Problem

Jang¹,

Kim²,

Kwon³

et al. 2015

Journal of the Korean Mathematical Society

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Abstract. We consider a model of HIV infection with various compartments, including target cells, infected cells, viral loads and immune effector cells, to describe HIV type 1 infection. We show that the proposed model has one uninfected steady state and several infected steady states and investigate their local stability by using a Jacobian matrix method. We obtain equations for adjoint variables and characterize an optimal control by applying Pontryagin's Maximum Principle in a linear control problem. In addition, we apply techniques and ideas from linear optimal control theory in conjunction with a direct search approach to derive on-off HIV therapy strategies. The results of numerical simulations indicate that hybrid on-off therapy protocols can move the model system to a "healthy" steady state in which the immune response is dominant in controlling HIV after the discontinuation of the therapy.

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Structured interruptions of highly active antiretroviral therapy in cycles of 4 weeks off/12 weeks on therapy in children having a chronically undetectable viral load cause progressively smaller viral rebounds

Cited by 6 publications

References 32 publications

Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy

Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy

Mutations Related to Antiretroviral Resistance Identified by Ultra-Deep Sequencing in HIV-1 Infected Children under Structured Interruptions of HAART

Hybrid on-Off Controls for an Hiv Model Based on a Linear Control Problem

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