Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial

Rasmussen, Thomas A; Tolstrup, Martin; Brinkmann, Christel R.; Olesen, Rikke; Erikstrup, Christian; Solomon, Ajantha; Winckelmann, Anni; Palmer, Sarah; Dinarello, Charles A.; Buzón, María J.; Lichterfeld, Mathias; Lewin, Sharon R.; Østergaard, Lars; Søgaard, Ole Schmeltz

doi:10.1016/s2352-3018(14)70014-1

Cited by 547 publications

(557 citation statements)

References 30 publications

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“…Although all investigated LRAs showed increased virus transcription, no changes in the latent-reservoir size were detected after the use of LRA in vivo (14,(18)(19)(20) or in vitro (24). One reason could be the short time during which LRAs were given to ART patients (ranging from 8 weeks for panobinostat to 3 weeks for romidepsin and 3 days for disulfiram), making the detection of reservoir decay problematic.…”

Section: Resultsmentioning

confidence: 99%

“…An increase in plasma HIV RNA was seen with panobinostat (19), romidepsin (20), and disulfiram (14), although in the panobinostat trial (19) this was demonstrated by a nonquantitative assay. Changes in HIV transcription have been demonstrated in all trials by showing an increase in the level of cell-associated HIV RNA (CA RNA) in total and resting CD4 ϩ T cells (21).…”

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confidence: 92%

“…Various latencyreversing agents (LRAs) have been investigated, including drugs that trigger the NF-B activation pathway, such as prostratin (10) and bryostatin (11) analogues; BET inhibitors enhancing the binding of the viral Tat protein to the HIV TAR element (12); disulfiram (13,14); and histone deacetylase inhibitors (HDACi), like valproic acid (15,16), vorinostat (17,18), panobinostat (19), and romidepsin (20), that act as epigenetic modifiers. The HDACi were the first compounds to enter clinical trials, given the extensive data on their toxicity from studies in individuals with malignancy.…”

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confidence: 99%

“…The HDACi were the first compounds to enter clinical trials, given the extensive data on their toxicity from studies in individuals with malignancy. However, all clinical trials of HDACi have demonstrated no decline in the frequency of latently infected cells (15,(18)(19)(20).…”

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confidence: 99%

“…We use the results of the panobinostat (19) and romidepsin (20) trials to illustrate the effect of the interplay of the HIV reactivation rate and death on the US HIV RNA level. For example, although the CA RNA tripled in the presence of panobinostat, our model suggests that the frequency of transcription activation in time increased by less than 10%, while the much larger increase in the number of cells with reactivated HIV was caused by their long life span.…”

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confidence: 99%

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Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Petravic

Rasmussen

Lewin

et al. 2017

J Virol

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Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latencyreversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3-to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life Ͼ 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment.IMPORTANCE Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.KEYWORDS latency, reactivation, human immunodeficiency virus C ombination antiretroviral therapy (ART) suppresses plasma HIV RNA below the detection limit of laboratory assays and restores the immune systems of infected patients by preventing new rounds of productive infection. However, ART cannot eradicate the infection, and virus replication starts again within weeks of ART cessation

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Petravic

Rasmussen

Lewin

et al. 2017

J Virol

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Current Status of Approaches to EradicateHIVInfection

Wolkenberg

Marrouni

Converso

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Direct acting antiretroviral therapy is highly effective in suppressing viremia and preventing progression of human immunodeficiency virus ( HIV ) to acquired immunodeficiency syndrome ( AIDS ), but requires strict adherence to lifelong treatment. Upon cessation of therapy, viral rebound is observed within two to four weeks. Recently, significant effort has focused on the development of a finite drug regimen capable of providing sustained virologic response for years or decades; that is, an HIV cure. This review will provide an update on the strategies being pursued and summarize advances in the medicinal chemistry of individual targets.

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Connecting HIV‐1 integration and transcription: a step toward new treatments

Lucic

Lušić

2016

FEBS Letters

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Edited by Wilhelm JustThanks to the current combined antiretroviral therapy (cART), HIV-1 infection has become a manageable although chronic disease. The reason for this lies in the fact that long-lived cellular reservoirs persist in patients on cART. Despite numerous efforts to understand molecular mechanisms that contribute to viral latency, the important question of how and when latency is established remains unanswered. Related to this is the connection between HIV-1 integration and the capacity of the provirus to enter the latent state. In this review, we will give an overview of these nuclear events in the viral life cycle in the light of current therapeutic approaches, which aim to either reactivate the provirus or even excise the proviral DNA from the cellular genome.

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Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial

Cited by 547 publications

References 30 publications

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Current Status of Approaches to EradicateHIVInfection

Connecting HIV‐1 integration and transcription: a step toward new treatments

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