Rapporteur report
Track B: Clinical Research, Treatment and Care report by Nick Paton
Yves Levy outlined the now considerable body of data indicating that immune activation plays a pivotal role in disease progression. Immune activation early in disease and even prior to seroconversion predicts long-term outcome. CD4 count restoration is often incomplete and there is excess mortality compared to the general population until the CD4 count is sustained above 500 for several years. Observational data suggest that the quality of immune restoration is predicted by the immune status at the time of treatment initiation. All this suggests a benefit for early treatment, and Professor Levy concluded that this is an open question that should be subjected to a randomized controlled trial.
James Neaton outlined a paradigm shift in thinking about possible benefits of ART that has followed the recognition of the importance of serious non-AIDS conditions. In people with high CD4 counts these events occur 3 to 4 times more frequently than serious AIDS events at high CD4 counts. Professor Neaton also presented some intriguing new data from recent analyses of biomarkers in a subset of patients from SMART that showed that D-dimer, a well known marker of activation of the coagulation system, decreased after ART initiation. The potential clinical relevance of this was shown by a 12 fold increased risk of death for those in the highest level of D-dimer at baseline compared to those in the lowest quartile. This data provides further evidence of the potential wide-ranging benefits of ART in early infection.
Paula Munderi outlined the impressive success of the HIV treatment programme at her clinical site in Uganda. With increased voluntary counseling and testing, an increasing number of people are being identified with early disease. She felt that research on the optimal time to start ART would be feasible in that setting, and the immediate the priority would be to address the question of the benefit of ART in the range of 250 to 350. Resource constraints would limit the utility of research at higher CD4 counts, although the information would be useful for informing policy.
Julio Montaner discussed the effects of ART on transmission of HIV, drawing on data from various groups and populations that all point towards a benefit of ART on early transmission. Mathematical modeling in his group suggests that if coverage were to increase from the current 50% of eligible patients, this would have a major effect on decreasing new incident infections in British Columbia. Furthermore, if this potential prevention benefit were taken into account, early treatment would be highly cost effective.
Fred Gordin picked up on the theme of serious non-AIDS conditions to discuss the rationale for an early treatment study. A significant reduction in serious non-AIDS events was seen in the small group of SMART patients who entered the study off ART treatment and were randomized to start treatment. He argued that the definitive evidence would not come from cohorts, and the few ongoing randomized trials of early ART do not have sufficient focus on non-AIDS events. He outlined design of the START trial a randomized controlled trial of immediate versus deferred treatment for those with high CD4 counts, and asserted that the time was right to do it now.
By the end of this session few could have doubted the case for and the momentum behind a trial to definitively address the question of immediate versus deferred ART at high CD4 counts. Mark Harrington took the opportunity of securing from the session facilitator a commitment that the NIH was interested in and prepared to fund such a study.
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