Title: Does short cycle antiretroviral therapy impact on inflammation immune activation thrombogenesis and CD4 cell dynamics?
Funder: Department of Health (England)

Abstract: Design: PENTA 16 is a prospective open multicentre randomised (1:1) controlled Phase II/III trial. Young people are being randomised 1:1 into two groups: continuous ART (as currently taken) or SCT. Young people randomised to the SCT arm will follow a cycle of 5 days on ART (Mon-Fri or Sun-Thurs) and 2 days off (Sat-Sun or Fri-Sat). Any young person with a confirmed VL >50 copies/ml is re-started on continuous therapy. All patients have regular monitoring of their VL CD4 counts and standard haematological renal and hepatic monitoring. In addition EDTA plasma and peripheral blood mononuclear cells (PBMCs) are being collected and stored. This sub-study utilises these stored samples for the analysis of markers of vascular damage inflammation and changes in haemostasis.Setting: 160 young people are being recruited from out-patients clinics in Europe Uganda Thailand the USA and the Ukraine.Target Population: 160 HIV-1 infected young people aged 8 to 24 years inclusive with viral suppression (HIV-1 RNA <50 copies/ml) for at least the prior 12 months on ART containing two nucleoside reverse transcriptase inhibitors (NRTIs) and efavirenz (EFV) and without previous virological failure on ART. Participants with previous first-line mono or dual therapy unless as prevention of mother to child transmission are excluded.Health Technologies Being Assessed: Stored plasma (at all sites n=160)) and PBMCs (at selected sites n=100) taken at baseline weeks 4 24 and 48 will be analysed from patients in both the short cycle therapy arm (SCT n=80) and continuous therapy arm (CT n=80). We will use a combination of ELISA Electrochemiluminescence detection flow cytometry and Flow – Fish to undertake an extensive analysis of immunological inflammatory and thomboregulatory indices in patients ransomised to coninute therapy CT or to interupt therapy SCT. We will measure indicators of inflammation (hsCRP serum Amyloid A IL-6 IL-8 IL-10 IL1Ra and TNFa) evidence of microbial translocation (sCD14 LPS Broad-range 16S rDNA-PCR) chnages in CD4 cell dynamics and activation (CD45RA/RO Ki67 HLA-dr telomere length) and disordered thromogenesis and vascular injury (thrombomodulin E selectin P-selectin VCAM-1 ICAM-1 MCP-1 VEGF angiopoietin and d-dimers).The arms will be compared to see if SCT alters these parameters as compared to CT.Measurement of cost and outcomes: The primary outcome measure of whether ART given as SCT is as effective as CT will be the differences in the change from baseline to week 24 in the markers between the 2 groups. Whilst there are some data in adults it is unknown how these markers change over time in adolescents interrupting treatment. There may be a possible sharp increase between baseline and week 4 which then stabilises or there could be a gradual increase over 48 weeks or there could be an increase followed by a decrease. Week 24 was chosen to balance these factors. However where there is evidence of a difference at 24 weeks random effects models with flexible time trajectories (e.g. natural cubic spline functions with change points informed by simple summaries of means) will be used. Adjusting for multiple comparisons (~20 outcome measures) by reducing the nominal alpha level 152 young people will provide 80% power to detect a difference of 0.63 standard deviations (two sided alpha = 0.0025). 160 young people (80 per arm) will be included to allow for 5% missing samples. Normality of the data will be assessed and either unadjusted or log10-transformed data will be used as appropriate for analysis (the study is powered to detect differences of 0.63 times the standard deviation where standard deviation is calculated either on the absolute or log10 scale). Project Timetable (including recruitment rate): Recruitment to PENTA 16 commenced April 2011 and aims to be completed by the end of June 2013. Samples are stored and will be analysed in batches until late 2014. Results will be analysed and disseminated in late 2014/early 2015.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;6.1 PHARMACEUTICALS
Health categories: INFECTION