With the introduction of highly active antiretroviral therapy (HAART), HIV is now considered a chronic and stable disease in effectively suppressed individuals on ART. Despite the fact that HAART can lead to undetectable levels of plasma HIV-RNA (<50 copies/ml), low-level viral replication persists in latently infected CD4+ T cells, which is believed to account for viral rebound on ART withdrawal [1, 2]. These viral reservoirs are a major challenge to HIV eradication. Research suggests that the CD4+ T cells harboring HIV are established early in the acute phase of infection and persist even with years of effective therapy [3, 4]. While the mechanisms responsible for HIV latency are poorly understood, the histone architecture within the latently infected T cell is believed to inhibit viral transcription, viral expression and the release of replication competent virus [5, 6]. In vitro, histone deacetylases (HDAC) inhibition has been shown to induce HIV-1 viral expression from resting CD4+ T cells . HDAC inhibition has therefore been proposed as a novel strategy to purge the HIV reservoirs in ART-treated individuals, in whom treatment prevents integration of the released virus into naïve T cells . Despite promising preliminary data using the HDAC inhibitor, valproic acid (VPA) , its role in the treatment of HIV-infected individuals remains unclear [9, 10], in part due to the small number of people studied and the varying treatments received. The CIHR Canadian HIV Trials Network (CTN) study 205 (CTN 205) was the first randomized controlled trial of VPA in HIV, undertaken to better characterize the effect of VPA on the HIV reservoir in ART-treated individuals. This multicentre study was initiated in 2006 and is now completed. The results of this randomized crossover study have recently been published . Herein, the design features of CTN 205 are considered within established criteria for crossover designs , as a methodological contribution to the study of HIV therapeutics. In addition, we also consider the methodological challenges of the crossover design in the context of the extended study duration and the added logistical complexity.