1. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection The INSIGHT START Study Group Ben Andres Oct 15, 2015

2. Background ART reduces morbidity and mortality in HIV infected individuals There is clear data to show morbidity and mortality reduction in pts with CD4 count <350, even stronger when CD4 count <200

3. Background The benefits of early initiation of ART are less clear in pts with CD4 count of > 350 - most studies have focused on AIDS associated complications/mortality The risks of these are less in those with higher CD4 counts – however non AIDS related complications of untreated HIV infection as well as increased transmission should also be considered

4. Research question Do the benefits outweigh the risks in starting ART in pts with CD4 count > 500 vs deferring until CD4 count declined to < 350?

5. Study design Multi-center randomized controlled trial Subjects randomized to either immediate initiation of ART or deferred initiation of ART – Deferred initiation started ART when CD4 count declined to <350 or when another event occurred otherwise requiring initiation of ART (such as pregnancy) Primary end point was a composite of any serious AIDS-related event plus any serious non-AIDS-related event Secondary end points: above plus unscheduled hospitalizations and “grade 4 events” ART regimens used:

7. Study Subjects HIV+ pts > 18yo in “generally good health” No hx of AIDS Not pregnant or breast-feeding No prior ART therapy CD4+ counts > 500 twice at least two weeks apart within 60d of enrollment total of 4685 pts enrolled from 4/2009 to 12/2013 at 215 sites in 35 countries – Median age 36, 27% female, median cd4 count 651 – Mean follow up time of 3 years - 212 pts with unknown primary end point (lost to f/u for >10 mos)

8. Results At the conclusion of the trial, 98% of pts in immediate initiation group and 48% in the deferred group had started on ART Median CD4 count at the time of initiation in the deferred group was 408

13. Conclusions Results showed that there is a consistent benefit to initiating ART regardless of CD4 count The primary end point occurred in 42 patients in the immediate-initiation group (1.8%) and 96 patients in the deferred group (4.1%), HR of 0.43, 95% CI 0.3- 0.62, P<0.001 In 5/2015, study terminated on basis of interim analysis and pts in the deferred group offered ART Main limitation is length of f/u – 3 yrs for pts who will presumably need to be on ART indefinitely