START at the Finish: A Top HIV Clinical Development of 2015
December 2, 2015
It is fitting to write about the START trial just after the New York City Marathon. Not entirely dissimilar from the hapless Italian runner who ended up on the subway, lost in the outer realms of Brooklyn, this study of when to start HIV antiretroviral therapy (ART) arrived at its conclusion years after guideline committees and clinicians had recognized that starting antiretrovirals earlier saved lives.
However, many hold that randomized controlled trials are the currency with which meaningful research results are bought, and it is undeniable that the START (Strategic Timing of Antiretroviral Treatment) study results are valuable, even if not groundbreaking, and serve as the final word on a debate that has raged for years. Moreover, among its main results are important findings that have received less attention -- that two-thirds of the adverse outcomes experienced in the deferred therapy arm occurred at CD4+ cell counts above 500 cells/mm3 suggests a benefit of antiretroviral therapy beyond simply the preservation of immune function.
A commonly held assumption was that a planned delay in the start of HIV therapy until counts reached 350 cells/mm3 would risk a drop in CD4+ cell counts and opportunistic conditions in the deferred arm -- and certainly for some, especially in areas where tuberculosis is endemic, this was the case. However, suppressing viremia alone was shown in this study to be protective, particularly from serious malignancies. In contrast, there was no difference between the two study arms in the rate of cardiovascular disease -- despite much promulgated theories regarding unchecked inflammation driving atherosclerosis.
The Bottom Line
I have been less than shy in my criticism of the START trial. The study team's and its supporters' vehement insistence that the trial go on despite mounting evidence of the benefit of early ART for personal and public health, and their own criticism of guideline panels that raised and then abandoned CD4+ cell count thresholds for ART initiation, smacked of self-serving defensiveness. Others have suggested that some of the adverse outcomes, including fatalities, that occurred in the deferred ART arm during the trial could have been avoided had the study been stopped earlier.
On the other hand, a number of experts expected that the trial would fail to show a difference between early and delayed ART initiation, given an inherent bias in the selection of participants (i.e., those with lower viral loads and stable CD4+ cell counts were more likely to be enrolled). That a difference in adverse outcomes was detected despite this bias is a significant finding.
Lastly, randomized clinical trials carry a lot of weight, and these results -- along with those from the TEMPRANO trial (a study that looked at when to start ART in patients in Cote d'Ivoire) -- have led to major changes in the World Health Organization's HIV treatment guidelines. Together, these trials give an important, final emphasis to this debate, even if it's not an exclamation mark.
What are some other top clinical developments of 2015? Read more of Dr. Wohl's picks.
David Alain Wohl, M.D., is an associate professor of medicine in the Division of Infectious Diseases at the University of North Carolina and site leader of the University of North Carolina AIDS Clinical Trials Unit at Chapel Hill.
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