Initiation Of Continuous Therapy Research Articles

Early Short-Term Antiretroviral Therapy Is Associated with a Reduced Prevalence of CD8+FoxP3+T Cells in Simian Immunodeficiency Virus-Infected Controller Rhesus Macaques

Regulatory T cells contain a mix of CD4 and CD8 T cell subsets that can suppress immune activation and at the same time suppress immune responses, thereby contributing to disease progression. Recent studies have shown that an increased prevalence of CD8(+)FoxP3(+) T regulatory cells was associated with immune suppression and diminished viral control in simian immunodeficiency virus (SIV)-infected rhesus macaques. Preventing an increase in the prevalence of CD8 T regulatory subsets is likely to lead to a better long-term outcome. Here we show that short-term antiretroviral therapy initiated within 1 week after SIV infection was associated with lower viral set point and immune activation after withdrawal of therapy as compared to untreated animals. Early short-term treated controller animals were found to have better SIV-specific immune responses and a significantly lower prevalence of immunosuppressive CD8(+)FoxP3(+) T cells. Lower levels of CD8(+)FoxP3(+) T cells coincided with preservation of CD4(+)FoxP3(+) T cells at homeostatic levels, and significantly correlated with lower immune activation, suggesting a role for viral infection-driven immune activation in the expansion of CD8(+)FoxP3(+) T cells. Interestingly, initiation of continuous therapy later in infection did not reduce the increased prevalence of CD8(+)FoxP3(+) T cells to homeostatic levels. Taken together, our results suggest that early antiretroviral therapy preserves the integrity of the immune system leading to a lower viral set point in controller animals, and prevents alterations in the homeostatic balance between CD4(+) and CD8(+) T regulatory cells that could aid in better long-term outcome.

FINAL HEIGHT ATTAINMENT IN NORMAL CHILDREN WITH SHORT STATURE TREATED WITH GROWTH HORMONE

The mandate of the ITF was defined in order to determine the outcome in terms of final height attainment in short normal children of normal birth weight who have been treated continuously with GH for at least three years. After considerable discussion, the ITF developed a questionnaire for this purpose, which was provided to all investigators who had indicated by preliminary survey that they had data that could be made available for analysis. Several significant issues were recognized that would make data collection and analysis difficult. These included the limited number of children who have attained final height, the influence of puberty onset occurring during GH therapy, the enormously variable protocols that have been employed with both pituitary-extracted and biosynthetic growth hormone, the absence of a suitable control group that would span the genetic heterogeneity of the study populations, and the interruption of therapy in some children as a result of the CJD crisis in 1985. Data analysis will include initial bone age (BA) and mid-parental height to assess genetic potential, one-year pre-treatment growth velocity (GV) to determine height SDS at onset, height attained at two years after initiation of continuous therapy, and final height attained after at least a total of three years of GH therapy (BA fused and/or GV < 2 cm/yr.). Historical controls will be developed from untreated normal short stature children who have reached adult height by analysis of databases in several countries, including Germany, Sweden, and Denmark. A comparative analysis will also be made of those children with the diagnosis of GHD that have been treated with GH and attained final height, but who retest as ‘normal’ following discontinuation of GH therapy. It is anticipated that this task force will be able to provide at least a preliminary final height outcome statement in regard to short children who have received growth hormone for a significant period of their childhood. It will also recommend that a similar analysis be conducted in the future in regard to psychological and educational outcome variables in these children.