Ever since the first antiretrovirals were approved, one of the most vexing questions for patients and doctors has been when to start therapy. In the past two years, a host of new data has been released that is bringing us closer to a time when therapy can be offered to everyone with HIV. I would like to share with you the evolution in my own thinking which may help you make a decision.
When to start has been compared to a pendulum swinging back and forth, with higher and lower limits set for the decision on when to initiate antiretroviral therapy (ART). A pendulum, however, swings back and forth between fixed points. The debate about "when to start" has been more like a playground swing hanging from a decision framework made up of CD4 counts and viral loads. With one major exception, that swing has consistently moved higher, suggesting initiation of treatment earlier and earlier in the disease process.
Making the decision has meant weighing the pros and cons of treatment. On the pro side has been our desire to control and possibly cure the disease. HIV has been one of the only diseases in modern medicine that is not treated immediately upon discovery, one we wait years or even decades to treat.
On the negative side rest much heavier concerns, including drug toxicities, cost of medication, the need for perfect adherence, denial of access by insurance companies and governments, and lack of research data. For most of the last 25 years, the swing swung back towards waiting to start therapy. But while we waited, our thinking evolved.
When AZT was first available, it was only approved for patients who had experienced an opportunistic infection. After so many years without any therapy, it quickly became clear, however, that people who were suffering from other complications of HIV were going to demand access to the drug. In retrospect, most of the people getting it in those days had very, very low CD4 counts, probably less than 50. We all know now that any benefit from AZT was probably limited to a six-month increase in survival in those very advanced people. More drugs became available during the late 1980s and early 1990s and our comfort level in treating people increased. We progressed to treating everyone with fewer than 200 CD4 cells/mm3. In 1993, the case definition was changed so that a low CD4 count alone meant an AIDS diagnosis. Part of the impetus for this was to ensure access for people with low CD4 counts who weren't yet ill with infections.
The 200 CD4 limit remained for many years, and in fact, remained in place in the World Health Organization guidelines until 2010. In the U.S. and Western Europe, the 200 CD4 limit began to be called into question with the advent of highly active antiretroviral therapy (HAART) in the late 1990s. There was a great deal of excitement about the benefits we were seeing in those starting on the triple combination cocktail, despite the very serious side effects and complications of those early treatments. People with CD4 counts over 200 began wanting access to the medications. We also understood more about the dynamics of HIV infection. It became clear that rather than there being a "latent" period when the virus was controlled and nothing much was happening, HIV infection was, instead, a very dynamic process.
By the late '90s, studies were being initiated in people with higher CD4 counts and there was interest in treating early infection. We had clear-cut data from controlled clinical trials and observational studies that the 200 CD4 limit was important, but many of those caught in the middle (not in acute or early infection but above the 200 CD4 level) became increasingly uncomfortable with not being treated. There were serious discussions about moving the bar up to 500, with David Ho and others advocating that we "hit hard, hit early." Not waiting for studies to be completed, many patients, beginning with the activist community, put their bodies on the line to test this in practice. And so the swing got a push and swung upward.
By the turn of the century, the side effects and complications of HAART were becoming more clear, written in the wasted faces and growing bellies of so many patients. An increasing number of those who had chosen to start therapy when the swing swung toward 500 decided to go on extended drug holidays. I treated many of these patients who did well off medications, some maintaining low viral loads and improved CD4 counts for several years. This was the one instance that I can recall when the so-called swing actually swung back down.
Many providers who had been willing to treat people with higher CD4 counts were uncomfortable going back to waiting until 200. It was also clear that if one waited to initiate the conversation on starting until patients hit 200, by the time adherence and access issues were addressed, therapy was often not initiated until well below 200. So, many of us started talking about therapy with patients who had between 300 and 400 T-cells and were starting them on meds a little earlier. Observational studies at the time seemed to indicate that treatment appeared to improve outcomes in this range, but there was little evidence that it was having a big clinical impact above a count of 500.
In 2008, the first presentations were given of the NA-ACCORD trial, a huge retrospective review of some of the largest cohorts in the U.S. and Canada. The results were striking. There was a 70% decrease in all-cause mortality in patients who initiated therapy with a count between 350 and 500. A later analysis showed a 60% decrease in mortality in those who started at a count of 500 compared to those who waited until fewer than 500. This was paradigm-shattering as it really indicated clinical consequences to waiting to initiate therapy.
There are limitations to retrospective observational studies. It is possible that those who started therapy earlier could be longer-lived for reasons having nothing to do with when they started. Retrospective studies also tend to smooth over some big variations. As I mentioned earlier, in the late 1990s and early 2000s, there were large numbers of people who started therapy early but then stopped for extended periods. This was not accounted for and those people were considered throughout as "early starters."
In any case, data from other retrospective studies has supported the observations in NA-ACCORD. The ART Cohort Collaboration looked at the data a bit differently and there was a clear benefit up to a count of 400 CD4/mm3 but not above. A growing consensus emerged and in the 2009 U.S. Department of Health and Human Services (DHHS) guidelines, it was recommended that therapy should be initiated in all patients below 350 CD4/mm3 and that therapy should be considered between 350 and 500 CD4/mm3, especially in pregnant women and people who were symptomatic, including those with cancers.
By the time the guidelines were rewritten for 2010, many on the panel felt that the accumulated data was really showing a benefit to initiating treatment at 500. Less than 350 still had the most hard data behind it, but there was increasingly more observational data to show decreases in some of the secondary illnesses being observed as people lived longer with HIV -- things like cardiovascular disease and cancer.
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