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Design and implementation of a randomized crossover study of valproic acid and antiretroviral therapy to reduce the HIV reservoir.

ABSTRACT: HIV reservoirs represent the major obstacles for eradication and are defined as a cell type that allows persistence of replication-competent HIV in patients on optimal long-term antiretroviral therapy (HAART). Several pilot clinical trials have been implemented to assess the value of experimental therapy to reduce reservoir size or eradicate HIV. In order to eradicate HIV, valproic acid was used as a new strategy to increase viral gene expression in the nucleus of infected cells with the expectation of generating a direct cell death or destruction by nearby cytotoxic cells. Previous pilot studies using VPA have showed conflicting results on the ability of VPA to reduce the size of HIV reservoirs.As the role of VPA on HIV reservoirs remains unclear, we conducted a multicenter clinical trial with a specific study design to obtain optimal information on reservoir changes while exposing the smallest number of individuals to the experimental medication.To this aim, a randomized, crossover design with 2 different treatment durations was implemented. By doubling the therapeutic period in one study arm, we were in a position to assess the impact of an extended duration of VPA on the size of the HIV reservoir and to evaluate the duration of treatment effects upon VPA withdrawal in the other arm. However, limitations for this type of study design included the logistical complexity of 2 uneven study arms and longer study duration.Despite the absence of demonstrable impact of VPA on reservoir size, such crossover study design should be considered in the early stage testing of novel HIV therapeutics targeted to reduce reservoir size or eradicate HIV.

SUBMITTER: Routy JP

PROVIDER: S-EPMC3815453 | biostudies-literature | 2012 Nov-Dec

REPOSITORIES: biostudies-literature

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Design and implementation of a randomized crossover study of valproic acid and antiretroviral therapy to reduce the HIV reservoir.

Routy J P JP Angel J B JB Spaans J N JN Trottier B B Rouleau D D Baril J G JG Harris M M Trottier S S Singer J J Chomont N N Sékaly R P RP Tremblay C L CL

HIV clinical trials 20121101 6

<h4>Background</h4>HIV reservoirs represent the major obstacles for eradication and are defined as a cell type that allows persistence of replication-competent HIV in patients on optimal long-term antiretroviral therapy (HAART). Several pilot clinical trials have been implemented to assess the value of experimental therapy to reduce reservoir size or eradicate HIV. In order to eradicate HIV, valproic acid was used as a new strategy to increase viral gene expression in the nucleus of infected cel ...[more]

PMID: 23195668

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Project description:BackgroundA major challenge to HIV eradication strategies is the lack of an accurate measurement of the total burden of replication-competent HIV (the "reservoir"). We assessed the association of anti-HIV antibody responses and the estimated size of the reservoir during antiretroviral therapy (ART).MethodsWe evaluated anti-HIV antibody profiles using luciferase immunoprecipitation systems (LIPS) assay in relation to several blood-based HIV reservoir measures: total and 2-LTR DNA (rtPCR or droplet digital PCR); integrated DNA (Alu PCR); unspliced RNA (rtPCR), multiply-spliced RNA (TILDA), residual plasma HIV RNA (single copy PCR), and replication-competent virus (outgrowth assay). We also assessed total HIV DNA and RNA in gut-associated lymphoid tissue (rtPCR). Spearman correlations and linear regressions were performed using log-transformed blood- or tissue-based reservoir measurements as predictors and log-transformed antibody levels as outcome variables.ResultsAmong 51 chronically HIV-infected ART-suppressed participants (median age = 57, nadir CD4+ count = 196 cells/mm3, ART duration = 9 years), the most statistically significant associations were between antibody responses to integrase and HIV RNA in gut-associated lymphoid tissue (1.17 fold-increase per two-fold RNA increase, P = 0.004) and between antibody responses to matrix and integrated HIV DNA in resting CD4+ T cells (0.35 fold-decrease per two-fold DNA increase, P = 0.003). However, these associations were not statistically significant after a stringent Bonferroni-adjustment of P<0.00045. Multivariate models including age and duration of ART did not markedly alter results.ConclusionsOur findings suggest that anti-HIV antibody responses may reflect the size of the HIV reservoir during chronic treated HIV disease, possibly via antigen recognition in reservoir sites. Larger, prospective studies are needed to validate the utility of antibody levels as a measure of the total body burden of HIV during treatment.

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Design and implementation of a randomized crossover study of valproic acid and antiretroviral therapy to reduce the HIV reservoir.

Publications

Design and implementation of a randomized crossover study of valproic acid and antiretroviral therapy to reduce the HIV reservoir.

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