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No adverse safety or virological changes 2 years following vorinostat in HIV-infected individuals on antiretroviral therapy.

ABSTRACT: To determine the long-term effects of vorinostat on safety and virological parameters in HIV-infected individuals on suppressive antiretroviral therapy (ART).Prospective longitudinal observational extended follow-up of 20 HIV-infected individuals on ART previously enrolled in a clinical trial of daily vorinostat 400?mg for 14 days. Extended follow-up included visits at 6, 12, 18 and 24 months postenrolment in the initial clinical trial.Cell-associated unspliced HIV RNA, total HIV DNA and plasma HIV RNA were quantified by PCR, and CD4 and CD8 T cells quantified by flow cytometry. Changes over time in each parameter were assessed using the Wilcoxon matched pair signed-rank test and generalized estimating equations for trend modelling.We recorded a total of 31 adverse events (26 grade 1 and five grade 2) in all study participants (n?=?20). There were no significant changes in the number of CD4 or CD8 T cells or plasma HIV RNA over time. In 12 participants for whom baseline samples were available, there were no significant changes in total HIV DNA, cell-associated unspliced HIV RNA, plasma RNA or CD4 and CD8 T cells at 6, 12, 18 or 24 months.Extended follow-up for 24 months did not reveal any long-term toxicity or changes in markers of HIV persistence or transcription in participants on ART who had received 14 days of vorinostat.

SUBMITTER: Mota TM

PROVIDER: S-EPMC5496768 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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No adverse safety or virological changes 2 years following vorinostat in HIV-infected individuals on antiretroviral therapy.

Mota Talia M TM Rasmussen Thomas A TA Rhodes Ajantha A Tennakoon Surekha S Dantanarayana Ashanti A Wightman Fiona F Hagenauer Michelle M Roney Janine J Spelman Tim T Purcell Damian F J DFJ McMahon James J Hoy Jennifer F JF Prince H Miles HM Elliott Julian H JH Lewin Sharon R SR

AIDS (London, England) 20170501 8

<h4>Objective</h4>To determine the long-term effects of vorinostat on safety and virological parameters in HIV-infected individuals on suppressive antiretroviral therapy (ART).<h4>Design</h4>Prospective longitudinal observational extended follow-up of 20 HIV-infected individuals on ART previously enrolled in a clinical trial of daily vorinostat 400 mg for 14 days. Extended follow-up included visits at 6, 12, 18 and 24 months postenrolment in the initial clinical trial.<h4>Methods</h4>Cell-associ ...[more]

PMID: 28301423

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Project description:BackgroundThe challenges of identifying acute HIV infection (AHI) have resulted in a lack of critical information on early AHI that constrains the development of therapeutics that are designed to eradicate HIV from the infected host.MethodsAHI participants were recruited from the Thai Red Cross Anonymous Clinic in Bangkok, Thailand into the RV254/SEARCH010 protocol and categorised according to Fiebig stages as follows: Fiebig I (HIV-RNA+, p24 Ag-, HIV IgM-) and Fiebig II-IV (HIV-RNA+, p24 Ag + or -, HIV IgM- or +, Western blot- or indeterminate). Proviral and viral burden and immune activation levels were compared between Fiebig stage groups at the time of AHI. CD4 and CD4/CD8 ratio were also compared between groups before and up to 96 weeks of ART.ResultsMedian age was 27 years and 96% were male. Fiebig I individuals had lower median HIV-DNA in mononuclear cells from blood (3 vs. 190 copies/106 cells) and gut (0 vs. 898 copies/106 cells), and lower HIV-RNA in blood (4.2 vs. 6.2 log10 copies/mL), gut (1.7 vs. 3.1 log10 copies/mg) and cerebrospinal fluid (2.0 vs. 3.8 log10 copies/mL), when compared to Fiebig II-IV individuals (all P<0.01). Median plasma sCD14 level was lower (1.1 vs. 1.6 μg/mL) in Fiebig I individuals as was the frequency of CD8+HLADR+CD38+ T cells in blood (7.6 vs. 14.9%, both P<0.05). The median plasma interleukin 6 levels were similar between stages (0.6 in Fiebig I vs. 0.5 pg/mL in Fiebig II-IV, P>0.05). The frequencies of CD4+HLA-DR+CD38+ T cells were also similar between these stages (2.1 vs. 2.6%, P>0.05). Median CD4 count and CD4/CD8 ratio were higher in Fiebig I: 508 vs. 340 cells/mm3 and 1.1 vs. 0.7, respectively (both P<0.001). After ART, CD4 cell count normalised by week 24 in Fiebig I and week 48 in Fiebig II-IV. However, CD4/CD8 ratio was lower in both groups after 96 weeks of ART compared to healthy Thais (P=0.02).ConclusionsCompared to later AHI stages, Fiebig I was associated with lower HIV burden in blood and tissue compartments, lower immune activation and higher CD4 and CD4/CD8 ratio. ART in Fiebig I-IV resulted in normalisation of CD4 cell count within the first year, supporting the benefit of early ART. However, the CD4/CD8 ratio was not normalised after 2 years of ART in all AHI stages, suggesting some degree of persistent immunological dysfunction even when ART was instituted as early as Fiebig I.

Dataset Information

No adverse safety or virological changes 2 years following vorinostat in HIV-infected individuals on antiretroviral therapy.

Publications

No adverse safety or virological changes 2 years following vorinostat in HIV-infected individuals on antiretroviral therapy.

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