START Antiretroviral Therapy ASAP

Guidelines for initiation of antiretroviral therapy, based primarily on CD4+ cell counts, have changed over the years. Early recommendations were to start when the CD4+ cell count fell below 500 cells/mL, based largely on the fact that 500 was halfway between zero and 1000 (a typical value for HIV uninfected persons). Subsequent recommendations were to start in most persons only when the CD4+ cell count fell below 200 cells/mL, the point at which most clinical infections and other HIV-related events occurred. Several commonly-held assumptions formed the basis for most of these recommendations:

1. Antiretroviral therapy itself was likely to be associated with some “risk” (eg, safety, adherence, and resistance concerns

2. The benefit of antiretroviral therapy would be immediate, such that delaying until there was a substantial risk of an event was a reasonable option

3. It was more important from a public health perspective and a resource allocation perspective to focus on the group of individuals, worldwide, who were at the greatest risk of morbidity and mortality from HIV (ie, those with the lowest CD4+ cell counts)

4. Years of ongoing HIV replication, resulting in HIV RNA levels typically in the 50,000 copies/mL range, were not likely to be of any substantial clinical significance as long as the CD4+ cell count remained in the “safe” range.

What was lacking in all of these recommendations were data--especially data from randomized clinical trials. In the last 5 or more years, data from large observational cohorts of HIV-infected persons did suggest that starting therapy “early” (eg, when the CD4+ cell count was above 350 cells/mL or 500 cells/mL) was better than starting later. Nevertheless, guidelines for initiation of antiretroviral therapy differed throughout the world, and the “strength” of the recommendation varied based primarily on the availability of randomized clinical trials data at various CD4+ cell count cut points.

In other words, while “expert opinion” and data from observational cohorts are great for generating hypotheses, data from randomized clinical trials are best for proving or disproving these hypotheses.

The NIH-funded START study opened in April 2009, and randomized 4685 HIV-infected persons with CD4+ cell counts above 500 cells/mL to immediate antiretroviral therapy with one of the Department of Health and Human Services (DHHS)-approved regimens versus delayed initiation until the CD4+ cell count fell to <350 cells/mL. The study was closed early by the Data and Safety Monitoring Board (DSMB) in December 2014, when the results became clear. The study has just been published in The New England Journal of Medicine.¹ I was one of the investigators enrolling HIV-infected persons into this trial, who came from 215 sites from 35 countries. Over 25% of the participants were women. Among the key findings:

• Median CD4+ cell count at study entry was 651 cells/mL, and median HIV RNA level at study entry was 12,759 copies/mL.
• Early initiation of therapy reduced the number of serious AIDS-related events by over 70%, and reduced the number of serious non-AIDS-related events by almost 40%.
• Of the 42 primary end points that occurred in the early initiation group, only 4 occurred before the initiation of antiretroviral therapy versus 68 of the 96 endpoints that occurred in the deferred initiation group.
• No safety concerns were identified in the study, and the number of serious adverse events were similar between early versus deferred initiation groups.
• HIV RNA levels were <200 copies/mL in 98% of particiapants at 12 months in the early initiation group, and remained at or around 98% through 60 months of follow up.
• CD4+ cell counts increased to around 900 cells/mL at 36 months in the immediate initiation group, compared to falling to about 630 cells/mL (from about 700 cells/mL in the deferred initiation group.
• Sixty eight percent of all primary endpoints occurred in persons with CD4+ cell counts above 500 cells/mL.

Taken together, these results show conclusively the advantages of initiating antiretroviral therapy as soon as an HIV-infected person enters care. In addition, the high CD4+ cell count level at which most of the events occurred suggests that ongoing HIV RNA replication, or some other factor (eg, pro-inflammatory cytokine excess), may be more directly related causally to the event than is immune status. Finally, the impressive adherence rates achieved in this trial, such that HIV RNA levels remained below 200 copies/mL at 5 years in 98% of the immediate initiation group, show what can be achieved when adherence to therapy is emphasized at every visit. As such, it makes the strategy of “therapy as prevention” more likely to be successful in reducing the numbers of new infections.²

References:

1. The INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic infection.  N Engl J Med. 2015;373:795-807.
2. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493-505.