CD4 cell-guided scheduled treatment interruptions in HIV-infected patients with sustained immunologic response to HAART

Maggiolo, Franco; Airoldi, Monica; Callegaro, Annapaola; Martinelli, Canio; Dolara, Alberto; Bini, Teresa; Gregis, Giampietro; Quinzan, Giampaolo; Ripamonti, Diego; Ravasio, Veronica; Suter, Fredy

doi:10.1097/qad.0b013e328321b75e

Cited by 40 publications

(40 citation statements)

References 24 publications

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“…Treatment interruption was well tolerated in most participants, in agreement with other therapeutic vaccine and treatment interruption trials. 5,15,19,20 However, one placebo recipient did experience a fatal myocardial infarction during cART interruption, which the investigator could not exclude as possibly related to study participation since previous studies have linked cART interruption to increased levels of infl ammation and increased risk of cardiovascular events; 15 however, the measured infl ammatory marker (high-sensitivity C-reactive protein) was not raised in this case.…”

Section: Discussionmentioning

confidence: 58%

“…20 published reports of clinical trials assessing various HIV therapeutic vaccine approaches, all of which included a "structured" or "analytical" cART interruption phase, were identifi ed. 4,5,11,12,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] These investigations have included various HIV-specifi c peptide approaches delivered either directly or through viral vectors (eg, adenovirus, canarypox, fowl pox, modifi ed vaccinia Ankara), DNA plasmids, or even as peptide loaded dendritic cells. Many of these clinical studies have been done in small sample sizes (ie, ≤30 participants), 19,21,24,26,27,29,33,34,36 and often in a non-controlled manner, 11,21,24,33,34 making defi nitive conclusions diffi cult.…”

Section: Panel: Research In Contextmentioning

confidence: 99%

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Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4×: a phase 2 randomised, double-blind, placebo-controlled trial

Pollard

Rockstroh

Pantaleo

et al. 2014

The Lancet Infectious Diseases

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SummaryBackground Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the effi cacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24Gag , in adults infected with HIV-1.

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Section: Discussionmentioning

confidence: 58%

Section: Panel: Research In Contextmentioning

confidence: 99%

Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4×: a phase 2 randomised, double-blind, placebo-controlled trial

Pollard

Rockstroh

Pantaleo

et al. 2014

The Lancet Infectious Diseases

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“…Aiming to maintain CD4 cell counts higher than 350 cells/ and HIV virus loads less than 100,000 copies/ , Ruiz et al designed an experiment to evaluate the safety of CD4 cell and HIV virusguided STIs [13]. Many works have been done to compare the STIs with the continuous antiretroviral therapy (ART), but conflicting results have been reported [7,11,[13][14][15][16][17]. In particular, Maggiolo et al made a conclusion that the structured treatment can result in the similar benefits for the patients with the continuous therapies [7], while the SMART study group found that STIs may also endanger the patients' life if their immune responses are not sufficiently stimulated [18].…”

Section: Introductionmentioning

confidence: 99%

“…Structured treatment interruptions (STIs), the alternative strategies, have been designed to effectively achieve sustained specific immunity for early therapy in HIV infection. Indeed, STIs are beneficial for some chronically infected individuals who may need to take drugs throughout their lives as well as the reconstruction of patients' immune system when they are not taking the drugs [7].…”

Section: Introductionmentioning

confidence: 99%

Global Dynamics of a Virus-Immune System with Virus-Guided Therapy and Saturation Growth of Virus

Xiao

2018

Mathematical Problems in Engineering

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We considered a piecewise virus-immune dynamic model to investigate the effectiveness of the HIV virus loads-guided structured treatment interruptions (STIs). To better describe the biological reality, we extended the existing models by taking the carrying capacity of the virus loads into consideration to indicate the saturated growth of virus loads. We initially investigated the sliding dynamics of the proposed model and then obtained the global dynamics of the proposed model. Our main results showed that the system can exhibit very complex and diverse dynamic behaviors including a globally asymptotically stable equilibrium, bistable equilibra, and tristable equilibria, depending on the dynamics of the subsystems and the threshold level. In particular, an interesting result indicated that, with a proper threshold condition, the virus-guided therapy policy can successfully control the virus loads far below its carrying capacity and maintain the activity of the immune system for the case that the effector cells always go to zero without therapy or with continuous therapy. The finding suggested that the optimal strategy should be individual-based due to coexistence of multiple stable steady states, depending on the threshold conditions and the initial levels of viral loads and effector cells of the patients.

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“…In the LOCF-d analysis, we carried the last value forward for individuals whose data were missing due to skipped visits or administrative dropout. We assumed that other individuals with missing data -those who dropped out for reasons related to efficacy or tolerability -would see a decline in CD4z cell count similar to that seen in randomized trials of structured treatment interruptions [27][28][29] (3 cells/mm 3 per week).…”

Section: Introductionmentioning

confidence: 99%

Missing CD4+ cell response in randomized clinical trials of maraviroc and dolutegravir

Cuffe

Barnett

Granier

et al. 2015

HIV Clinical Trials

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Background: Missing data can compromise inferences from clinical trials, yet the topic has received little attention in the clinical trial community. Shortcomings in commonly used methods used to analyze studies with missing data (complete case, last-or baseline-observation carried forward) have been highlighted in a recent Food and Drug Administration-sponsored report. This report recommends how to mitigate the issues associated with missing data. We present an example of the proposed concepts using data from recent clinical trials. Methods: CD4z cell count data from the previously reported SINGLE and MOTIVATE studies of dolutegravir and maraviroc were analyzed using a variety of statistical methods to explore the impact of missing data. Four methodologies were used: complete case analysis, simple imputation, mixed models for repeated measures, and multiple imputation. We compared the sensitivity of conclusions to the volume of missing data and to the assumptions underpinning each method. Results: Rates of missing data were greater in the MOTIVATE studies (35%-68% premature withdrawal) than in SINGLE (12%-20%). The sensitivity of results to assumptions about missing data was related to volume of missing data. Estimates of treatment differences by various analysis methods ranged across a 61 cells/mm 3 window in MOTIVATE and a 22 cells/mm 3 window in SINGLE. Conclusions: Where missing data are anticipated, analyses require robust statistical and clinical debate of the necessary but unverifiable underlying statistical assumptions. Multiple imputation makes these assumptions transparent, can accommodate a broad range of scenarios, and is a natural analysis for clinical trials in HIV with missing data.

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CD4 cell-guided scheduled treatment interruptions in HIV-infected patients with sustained immunologic response to HAART

Abstract: The two strategies may be considered clinically equivalent. CD4 cell-guided STIs seem a possible alternative for chronically infected individuals responding to HAART provided that CD4 cell decrements would be steadily maintained above a safe threshold.

Cited by 40 publications

References 24 publications

Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4×: a phase 2 randomised, double-blind, placebo-controlled trial

Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4×: a phase 2 randomised, double-blind, placebo-controlled trial

Global Dynamics of a Virus-Immune System with Virus-Guided Therapy and Saturation Growth of Virus

Missing CD4+ cell response in randomized clinical trials of maraviroc and dolutegravir

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