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Timing and T-Cells: The Evolution of When to Start Treatment Through One Doctor's Eyes

By Howard A. Grossman, M.D.

March/April 2013

Timing and T-Cells: The Evolution of When to Start Treatment Through One Doctor's Eyes

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.


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In the Beginning

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.


HAART Arrives

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.


Data Swings Toward 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.

"The idea was ... that everyone was going to need drugs in a few years anyway, so why not move it up? I didn't buy it."

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.

Treatment Reduces Transmission

I have to admit that I was skeptical. Starting in 2008, there was increasing evidence that treating HIV-positive people decreased viral transmission in the population. There was increasing discussion of inflammatory markers and the role that inflammation might play in HIV. The idea was also expressed that everyone was going to need drugs in a few years anyway, so why not move it up? I didn't buy it. I failed to see clear-cut evidence of benefit over 500 CD4s and I did not see how to convince individual patients that there were benefits for them in the idea that lowering their viral loads served the public good. Many drugs still had significant side effects, we had seen the difficulties when patients developed resistance and had few options, and the last time we pushed the starting line higher it had not been a good idea. This was a very uncomfortable place for me to be -- it was the first time I had ever found myself thinking more conservatively than the guidelines panel. I wondered if I had been at this too long.

Over the last couple of years the lines of thinking mentioned above have become more firmly established and the evidence for them continues to grow. Rates of HIV infection in the U.S. have continued at the same levels for almost two decades now. In my own practice, I have seen so many young men become positive in the past two years. We have seen high rates of STDs for years, but much of it seemed to be coming from oral sex. In the last two years, I have seen more anal gonorrhea and Chlamydia than I remember seeing in a long time. Some men are looking for any excuse to stop using condoms, the most effective method we have of preventing transmission for people having sex (although pre-exposure prophylaxis, PrEP, adds another tool). It has become very clear that our prevention messages are failing to help people maintain changes in behavior that would lower transmission rates. For young people today, the horrors of the AIDS epidemic are just things they learn about in history books, and the fear of HIV doesn't last beyond the next hook-up. The right wing in the U.S. has destroyed sex education in many places and the level of ignorance about STDs is appalling.

"The reality is that we are experiencing a new kind of apartheid based on viral load status."

The CDC and other public health authorities have undertaken a powerful campaign for treatment as prevention. I think it becomes increasingly clear that reducing viral load across communities by treating as many people as possible may be our only real chance of bringing this epidemic under control. So government is clearly moving to support universal treatment, thus guaranteeing coverage and access, removing another obstacle on the "con" side of the argument.

As a primary care provider however, one has to be able to convince the patient that the therapy being offered is of benefit to him or her. For those in a relationship with someone of the opposite serostatus, treatment as prevention does serve the interest of increasing the chance that the negative partner will stay uninfected. But the reality is that we are experiencing a new kind of apartheid based on viral load status. Over and over I hear from patients that they are questioned by potential partners about their viral load. If they are on meds and undetectable, they are acceptable sex partners. If they are not on meds, they get rejected. This has pushed some to start therapy earlier.


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Trending Toward STRs

For real personal benefits to be seen, however, powerful trends needed to come into play. First has been the development of truly tolerable and easy-to-take medication regimens. We have had Atripla for quite a few years now and its once-daily dosing made it easy. But many people still experienced side effects. The development of more once-daily regimens, of two more once-daily fixed dose combinations, the approval of several twice-daily, well tolerated meds in new classes -- all of these have suddenly presented us with more options, not just for initial therapy but for sequential regimens as well. And we expect to see a number of new once-daily and fixed dose combinations in new formulations -- PIs and entry inhibitors without nucleosides, new integrase inhibitors with next generation nukes, and many others. This is truly the first time in fighting HIV that, as a provider, I can say to a patient that he or she will most likely not have any side effects from the medication I'm prescribing.


Inflammation

The third area of growing consensus has been in regard to the importance of inflammation as a cause of disease. This is a trend across the entire field of medicine. Inflammation appears to play important roles in aging, in the development of cardiovascular disease, in neurologic disease, as well as in rheumatology, endocrinology, and virtually every other area. People with HIV at every CD4 count have shown elevated levels of inflammation and immune activation, as well as heightened risk for a myriad of diseases from blood clots to early heart attacks. By the time of the International AIDS Conference in Washington, D.C. last year, the evidence for the deleterious effects of inflammation and the positive impact of ART on markers of immune activation was becoming overwhelming. Data continues to accumulate rapidly. As I wrote this article, two new studies appeared in the New England Journal of Medicine which showed significant benefit for patients started on medications very early in the disease process.

The 2012 guidelines gave a stronger recommendation than previously to treating all patients with fewer than 500 CD4/mm3. There also appeared to be a growing consensus of expert opinion leading to more universal treatment.


Jumping Off

For me, the meeting in D.C. brought a kind of epiphany. It finally seemed that the scales had shifted. The things on the negative side of the scale -- the side effects, complicated regimens, drug access issues, and lack of documented benefit -- seemed to be lightening if not absent. And the side of the scale in favor of treatment was becoming heavier and heavier with reasons to start early. In fact, it appears to me that it is time to jump off of the swing at the highest point of its arc, to stop using CD4 count as a parameter in deciding when to start, and to offer treatment to all patients who are infected with HIV. I have begun to do this with overwhelming acceptance by many of my patients. Hopefully, we'll land on our feet.




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