HIV dynamics and T-cell immunity after three structured treatment interruptions in chronic HIV-1 infection

Ruiz, Lı́dia; Carcelain, Guislaine; Martínez-Picado, Javier; Frost, Simon D. W.; Marfil, Sílvia; Paredes, Roger; Romeu, Joan; Ferrer, Esther; Morales-Lopetegi, Kristina; Autran, Brigitte; Clotet, Bonaventura

doi:10.1097/00002030-200106150-00001

Cited by 137 publications

(104 citation statements)

References 33 publications

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“…After the cessation of therapy, HIV p24-specific CD4 ϩ T cell frequencies were not maintained in the group with the higher pretreatment VL. Such transient increases in HIV-specific CD4 ϩ T cell responses have also been described in other studies of STI (21,24,34,35). This result is in contrast to the patient group with lower pretreatment VL who maintained, and even increased, levels of HIV p24-specific CD4 ϩ T cells after the cessation of therapy.…”

Section: Lack Of Correlation Between Plateau Vl and Magnitude Of Hiv-supporting

confidence: 71%

“…In a few studies, STI has been shown to have an overall effect on viral doubling times; with increasing rounds of treatment interruption showing an increase in viral doubling times (21,22). In a substudy of SSITT, including 13 patients with frequent sampling, such an increase in doubling times was also seen (29).…”

Section: Resultsmentioning

confidence: 98%

“…In some of these preliminary studies, HIV-specific CD8 ϩ T cell responses were boosted by reexposure to autologous virus; in the case of HIV-specific CD4 ϩ T cell responses, such increases were transient. However, marked interpatient heterogeneity and small cohort sizes reached inconclusive and conflicting results and precluded statistically meaningful analysis (21)(22)(23)(24)(25). In contrast, STI after ART initiated during primary HIV-1 infection seems to have a beneficial effect on viremic control when ART is subsequently withdrawn (15).…”

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confidence: 99%

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Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection

Oxenius

Price

Günthard

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

190

159

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Potent antiretroviral therapy (ART) suppresses HIV-1 viral replication and results in decreased morbidity and mortality. However, prolonged treatment is associated with drug-induced toxicity, emergence of drug-resistant viral strains, and financial constraints. Structured therapeutic interruptions (STIs) have been proposed as a strategy that could boost HIV-specific immunity, through controlled exposure to autologous virus over limited time periods, and subsequently control viral replication in the absence of ART. Here, we analyzed the impact of repeated STIs on virological and immunological parameters in a large prospective STI study. We show that: (i) the plateau virus load (VL) reached after STIs correlated with pretreatment VL, the amount of viral recrudescence during the treatment interruptions, and the off-treatment viral rebound rate; (ii) the magnitude and the breadth of the HIV-specific CD8 ؉ T lymphocyte response, despite marked interpatient variability, increased overall with STI. However, the quantity and quality of the post-STI response was comparable to the response observed before any therapy; (iii) individuals with strong and broad HIVspecific CD8 ؉ T lymphocyte responses at baseline retained these characteristics during and after STI; (iv) the increase in HIV-specific CD8 ؉ T lymphocyte frequencies induced by STI was not correlated with decreased viral set point after STI; and (v) HIV-specific CD4 ؉ T lymphocyte responses increased with STI, but were subsequently maintained only in patients with low pretreatment and plateau VLs. Overall, these data indicate that STI-induced quantitative boosting of HIV-specific cellular immunity was not associated with substantial change in viral replication and that STI was largely restoring pretherapy CD8 ؉ T cell responses in patients with established infection.

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Section: Lack Of Correlation Between Plateau Vl and Magnitude Of Hiv-supporting

confidence: 71%

Section: Resultsmentioning

confidence: 98%

mentioning

confidence: 99%

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Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection

Oxenius

Price

Günthard

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

190

159

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“…Using patient data from the AutoVac study [19], we have used Bayesian estimation techniques (specifically, the MCMC method) to identify parameters from this model. The AutoVac study took viral load measurements at 1-day intervals during a series of on-off treatment switches for a number of patients.…”

Section: B Parameter Estimationmentioning

confidence: 99%

“…A method which is highly sensitive to model inaccuracies would be useless in practice. We have used a distribution of model parameters generated using Bayesian estimation techniques from patient data from an interruption trial reported in [18], [19]. This distribution was used for Monte-Carlo analysis of the performance of our algorithm using nominal parameter values.…”

Section: Introductionmentioning

confidence: 99%

Modeling-error robustness of a viral-load preconditioning strategy for HIV treatment switching

Luo

Piovoso

Zurakowski

2010

Proceedings of the 2010 American Control Conference

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In previous work, we have developed optimal-control based approaches that seek to minimize the risk of subsequent virological failure by "pre-conditioning" the viral load during therapy switches. In this paper, we use Monte-Carlo methods to evaluate the sensitivity of an open-loop implementation of these approaches to modeling errors. To account for hidden parameter dependencies, we use parameter distributions obtained from the convergence of Bayesian parameter estimation techniques applied to sets of clinical data obtained during serial therapy interruptions as the distribution from which the Monte-Carlo method samples.

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Structured Treatment Interruptions for the Management of HIV Infection

Friedman

Lisziewicz²

2001

JAMA

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Antiretroviral drugs constitute a milestone in the treatment of human immunodeficiency virus (HIV) infection; however, emerging problems limit their long-term use, and an increasing number of patients interrupt the prescribed continuous drug therapy for short or long periods. Some patients appear to benefit from structured treatment interruptions (STI), involving monitored repetition of on-and-off cycles of drugs; however, it is unclear whether patients and/or physicians should consider STI as a treatment option. This review is intended to provide a comprehensive update on the use of STI in clinical settings, and to carefully evaluate the advantages and potential risks for patients infected with HIV. We used a MEDLINE search to find all English-language articles published January 1999 to August 2001 regarding patients treated with highly active antiretroviral therapy for whom treatment interruption was investigated. Priority was assigned to peer-reviewed sources, when available. Otherwise, abstracts from authoritative international conferences were selected through the AIDSLINE database. Results from various studies with respect to type of drug treatment, baseline patient status, number of treatment interruptions, duration of treatment and interruption, changes in viral load, and immune system parameters were analyzed. Patients could be categorized into 3 distinct clinical scenarios: acute infection, chronic drug-suppressed infection and virological drug failure. The STI approach may offer more benefit during acute infection when the patient's immune system remains nearly intact. It is yet to be determined whether STI will facilitate the long-term management of chronic infection by decreasing drug-associated toxicity and improving quality of life without jeopardizing the efficacy of the treatment. Results from randomized controlled trials and more definitive means of gauging the status of the patient's immune system must be available before this treatment method is extended beyond the research setting. Ultimately, a safer approach using therapeutic immunization or vaccination would be preferable for stimulating vigorous T-cell-mediated immune responses and control of HIV during treatment interruption.

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HIV dynamics and T-cell immunity after three structured treatment interruptions in chronic HIV-1 infection

Abstract: The increase in the control of viral replication, and positive effects of STI on immune responses in this population should encourage the further development of HIV-specific immune-based therapeutic strategies.

Cited by 137 publications

References 33 publications

Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection

Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection

Modeling-error robustness of a viral-load preconditioning strategy for HIV treatment switching

Structured Treatment Interruptions for the Management of HIV Infection

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