This strategy trial did not demonstrate a significant result in the primary outcome: an ordered categorical endpoint at one year that combines clinical and virologic outcomes. This combined outcome was chosen because we did not believe we would see a significant difference in the incidence of AIDS progression and/or death alone given our sample size and best estimates of progression rates in the HAART era. However, because the composite endpoint incorporated an assessment of viral load at 1 year, which was essentially identical in both arms, the differences between the groups were not significant on our primary combined outcome. In effect, the equivalent virologic outcomes at 1 year “diluted” the larger than anticipated positive impact of early ART on clinical outcomes.
There was a significant difference favoring the early treatment group in the secondary outcome of AIDS progression/death. The impact is seen primarily on morbidity and mortality events in the first 6 months (see ), suggesting that early improvement in immune responsiveness is critical to prevent clinical progression. Subjects in the early ART arm spent less time with CD4 counts <50 or <100 and therefore the “window of vulnerability” to additional AIDS-related complications was shortened by early use of ART. The idea that ART seems to have an early effect on the clinical course following an OI is supported by our finding that early ART was beneficial even though the difference in the time to initiation of ART following the OI was only about 1 month. The difference in outcomes could not be explained by differences in ART regimens used, adherence, adverse events or number of hospitalizations (which were similar in the two arms).
Because AIDS progression/death was not the primary outcome of our study, we recognize that our results should be interpreted cautiously. On the other hand, AIDS progression/death is an important (it could be argued the most important) outcome for ART trials, and our results are consistent with the biologic effects of ART treatment. These findings extend the results of landmark clinical trials that ushered in the first decade of effective ART in patients with advanced immunodeficiency but without active OIs. 
In retrospect, one would not expect that a 1 month difference in ART treatment would significantly impact viral load response at 1 year if the patient survives the period immediately following OI without further complications.
Surprisingly, IRIS was uncommon in this study (7%) although subjects had very advanced immunodeficiency, were receiving ART early in their OI treatment course, and had good increases in CD4 counts - all conditions that have been associated with IRIS. From published case series and clinical cohorts, the incidence of IRIS after ART initiation has ranged from 15% to 45% 
. It is not clear why the rate of IRIS was low in this trial. However, we do not believe it is because cases were being missed given the special efforts that the study team made to find cases including a team review of all subjects who received corticosteroids that identified no unreported IRIS cases. The use of predefined criteria and real-time review in this prospective study may have reduced case finding bias. In support of this is another recently published prospective study reporting a similar rate of IRIS in a South African population. 
Although IRIS has been reported for many AIDS-related OIs, the risk is likely to vary by OI and corticosteroid use. We conclude that IRIS is less frequently a complication of ART in the setting of the OIs included in this study– most particularly PCP - than has been the impression from retrospective studies to date. We don't believe that corticosteroid use influenced the overall incidence of IRIS but may have deferred its onset. However, other infections like TB may have higher rates of IRIS. TB at entry was excluded in this study but is being studied in a second ACTG study. At least for the spectrum of OIs included in this study, fear of IRIS should not be a reason to defer ART.
Initiating ART early required slightly more ART changes but this did not appear to have a deleterious impact on outcomes. On the positive side, starting ART early may better assure that patients have an opportunity to benefit from this life-saving treatment. In this study, all subjects in the early arm initiated ART, but 9% of the subjects in the deferred arm never did. This can be seen as another potential benefit to the strategy of initiating ART early. If ART is deferred there may be a “lost opportunity” to intervene (either because patients become progressively more ill or died or are lost to follow up medical care) and this effect may be even larger in the context of clinical practice as opposed to a clinical trial wherein additional resources are available and additional efforts are made to follow and treat subjects. Individuals who present to care with late stage AIDS without benefit of prior ART are often seen as being at high risk for non-adherence and poor medical follow up. However, we believe that given these study results practitioners should at least offer ART early in the treatment course of the OI to these patients.
An important strength of this strategy study is that it was designed to mirror most aspects of clinical practice. Physicians often treat on the basis of presumptive diagnoses. Had we limited our study to only the treatment of definitive diagnoses, it may not have generalized to the care of patients treated presumptively. Also, we allowed for a range of starting points in ART treatment within both arms because that too reflects the realities of clinical practice. Although AIDS progression/death was not the primary outcome of our study, it is an important standard by which to judge the outcome of ART trials. Our findings most directly reflect the spectrum of opportunistic and serious bacterial infections seen in the resource-rich countries where the majority of the patients were enrolled. These results also reflect a primarily ART naïve population, in patients with prior ART therapy and drug resistance the impact of early ART may be more attenuated. Additional randomized controlled studies are required for TB (ongoing) and cryptococcal infections given our lack of power to provide a definitive result in this study.
Our study can be viewed as demonstrating the efficacy of early ART since there was selection by treating clinicians for patients that were likely to be “good” clinical trial candidates. We have no way to know how much “pre-screening” of patients occurred but treating clinicians were instructed to use “best clinical judgment” in selecting patients for the study. Although there was likely some “pre-selection” of patients, this is no different than any other randomized clinical trial and since there were 40 participating sites across a wide spectrum of clinical settings in the US (and South Africa) we feel the study results are fairly generalizable. Studies of the effectiveness of this strategy in other populations who might be less-ideal clinical trial candidates -like injection drug users - may be required to further generalize our findings but even more challenging to conduct.
We would be cautious to generalize these results to resource-limited countries, even though patients in those countries are accessing ART with advanced AIDS and with some of these same OIs and BIs as seen in our study. None-the–less, it is reassuring that the results favoring early ART seem to be consistent across a variety of clinical categories ()
On the basis of these results, and although logistically challenging, we recommend that ART be started early in the setting of acute AIDS-related OIs if there are no major contraindications to doing so. Waiting to complete OI treatment before initiating ART appears to be associated with a higher risk of AIDS-related disease progression and/or death without any significant benefit in terms of safety or virological response. Initiation of ART in the setting of an acute AIDS-related OI will require a multi-disciplinary team approach with expertise in ART management to be sure that care for these critical ill patients is well-coordinated and effective. Although there are many potential clinical challenges in initiating ART early in patients with acute AIDS-related opportunistic infections the potential benefits to such patients appears to be substantial.