2. Background Appropriate time to start HAART is still debatable 1995: “Time to hit HIV, early and hard” Eradication thought to be possible Early regimens had a lot of toxicity: CD4 200 Not 500, not 200, 350 than.

3. Study outline Study Design: cohort/observational Patients stratified according to CD4 count at baseline. Two groups of interest CD4 350-500 and CD4 > 500. Early –therapy: HAART started within 6 months of CD4 count within prespecified range Deferred-therapy: HAART started after transition into lower CD4 count range

4. Study outline Setting: Patients from 60 sites managed by 22 research groups based in Canada and US Participants: 17,517 asymptomatic patients with HIV infection who received care during the period of 1996-2005 and were therapy naïve. Data Collection: methods are not uniform. Some site collect prospectively, others retrospectively. Main Outcome: death from any cause

5. Results

6. Patients in deferred groups more likely to have HCV and hx of IVDU. Patients with CD4 > 500 that deferred Rx were less likely to have HIV RNA < 500 copies/ml 12 after initiation of Rx.

7. Results Adjustments also made for HCV status and Hx of IVDU Analysis done with exclusion of data from each cohort

8. Results

9. Strengths Feasible study design/External validity Death from all causes as end point Sample size Good vital systems: decrease in ascertainment bias Data available before intervention: decrease in lead time bias All strategies possible tested: interruption is bad Sophisticated analytical methods

10. Weaknesses Is intervention a marker for good outcome? Differences in exposure to health care and follow-up not addressed Health-seeking behavior (e.g., dif in viral suppresion) “Good Dr.” effect ~45% did not change CD4 stratum and not analyzed= slow progressors? Cause of death known in only 16% No KM curve. Lack of central lab Effects of resistance and long term toxicity not addressed (and maybe not possible addressed)

11. Preliminary discussion points: Making decision on treatment based on observational data: The HRT example When decision to treat is marker for good outcomes or a marker for bad outcomes Can we or should we have a RCT for each and every intervention?