When to Start Treatment

New findings presented at this year's Conference on Human Retroviruses and Opportunistic Infections were overshadowed by public discussion of a change in the U.S. Guidelines on the Use of Antiretroviral Therapies. The changes represented something of a correction, or some say, a repudiation of the "hit hard, hit early" approach promoted at the International AIDS Conference in Vancouver in 1996. Researchers whose views were considered "state of the art" in 1996 were now all but hiding from the press. As usual, the truth wasn't quite that simple nor are the changes as dramatic as some think. They do, however, offer an important clarification on the use of treatment.

The issue of when to start anti-HIV therapy has been debated since 1986. While there are good theoretical reasons to support early treatment of HIV, doing so means coping with a complex interplay of drugs, HIV evolutionary processes (resistance), short- and long-term side effects and issues of personal choice. If there is any clear message from the last fifteen years of research, it is that there is no single treatment strategy that is "best" for everyone, no matter how much people might wish to have one. The decision to start treatment is a personal choice that can be informed -- but not dictated -- by the available scientific and medical evidence.

Although there were various opinions on when to start therapy prior to the use of Highly Active AntiRetroviral Therapy (HAART) in 1996, the availability and success of protease inhibitors led to a wide swing in favor of early treatment. Talk of the potential of "eradicating" HIV led many physicians to believe that everyone should be placed on treatment without regard for clinical symptoms or how long a person was infected. A careful examination of what researchers were saying, however, showed that they were only raising the hope of eradication in people who started treatment literally within a few weeks or months of first being infected. Nonetheless, the media translated the call to "hit hard, hit early" into a mantra that was interpreted to mean "treat everyone."

During this period, the Federal government called together a panel of experts to draw up "official" recommendations for the use of anti-HIV therapy in adults. They recommended then that people with CD4+ cell counts below 500, and/or with a viral load of 5,000 to 10,000 copies, should be "offered" treatment, and that treatment should be strongly encouraged for people with CD4+ counts below 200. The Guidelines never said that people "should take treatment" -- only that it should be discussed and offered. For people with CD4+ cell counts above 500, the Guidelines concluded that treatment was a matter of personal choice and opinion since there were no data either supporting or firmly discouraging its use. Still, many physicians interpreted the Guidelines as recommending that everyone should be on treatment, regardless of lab values or stage of disease.

The Outcome -- Four Years Later

There are several possible long-term consequences of the "hit hard, hit early" era of therapy, many of which were not initially recognized.

1. It may cause people who had no urgent need for therapy to be unnecessarily exposed to drug side effects.

2. It may cause people to begin cycling through the list of the available drugs earlier than necessary. No drug lasts forever and most are eventually weakened by the development of resistance. By starting treatment earlier, people may have begun using up their treatment before the drugs were capable of providing a meaningful benefit.

3. Pressure to start therapy too early may discourage some from taking treatment altogether. Those who felt healthy before starting treatment suffered through rigorous daily regimens, disrupted eating and sleeping habits, and side effects like nausea, diarrhea and liver damage. These people may later oppose or fear the use of treatment when they need it most.

4. Many who start "early therapy" might become careless in their adherence or use of the drugs because they feel little if any pressure from the disease. They feel fine, with or without treatment.

With factors complicating the use of early therapy becoming more apparent over time, the U.S. Federal Guidelines Panel revisited their recommendations, as had their European counterparts and the International AIDS Society. Though there really aren't any new data regarding the potential benefits of early treatment, there are now a lot of data about the potential risks. After a year-long review, the new Federal Guidelines now recommend that physicians discuss and "offer treatment" to people with CD4+ cell counts below 350 or viral loads over 30,000 to 50,000 copies. Some newly available data continue to suggest that most people will fare well even if they wait until the CD4+ cell count falls to around 200, though this provides little safety margin to accommodate individual differences or the differences seen between men and women on some lab tests.

Therefore . . . ?

For HIV-positive people and their doctors who wish only to read the charts of the new Federal Guidelines but not the accompanying text, things sound very simple: just put everyone on treatment when their CD4+ cell counts fall below 350 or when their viral load exceeds 30,000 to 50,000. Following such a rule, however, might still result in a good deal of inappropriate use of drugs because the health of a person's immune system cannot be described solely by the CD4+ cell count or viral load, nor can their response to treatment be predicted.

Studies cannot predict how any individual will respond to treatment, or how they would fare without it. All a study can do is report the average response seen in the groups studied. Some of the people in those studies will indeed have the "average" response described by the study analysis, but many others will do much better or worse. While it is true, for example, that there is a serious risk of getting pneumocystis carinii pneumonia (PCP) when a person's CD4+ cell count falls below 200, some people get the infection with a CD4+ cell count of 300 or even 400, while others coast along with counts below 50 CD4+ cells without any infections. Monitoring not just lab values, but also overall measures of general health including weight, minor symptoms, and your overall sense of well-being can provide important clues as to your individual risk of disease progression and help you decide if intervening with therapies is right for you.

People with the same CD4+ cell counts and same viral load do not all have the same risk of disease progression. By itself, the CD4+ cell count doesn't tell us enough. It's a good starting point, nothing more, nothing less. It's perhaps most useful when looked at over time, in the context of general trends. Other factors that should be considered in making a decision to start treatment include:

• CD4+ percentage: No test measures the exact number of CD4+ cells in the blood. Instead, laboratories measure the number of white blood cells and then roughly determine what percentage of a person's white blood cells (WBC) have a marker called "CD4+." That percentage is then multiplied by the number of white blood cells, giving us a calculated number called the "absolute" CD4+ cell level. But this number is anything but absolute. This process makes the count of the CD4+ cells dependent on the number of white blood cells, and that WBC fluctuates widely over time, usually for reasons that have nothing to do with the health of the immune system. Every time the WBC goes up or down for any reason, the "absolute" number of CD4+ cells circulating in the blood moves up and down with it, sometimes producing a very misleading number that can either frighten people or cause them to overlook a developing problem. In short: a high WBC results in an artificially elevated CD4+ cell count, while a low WBC causes an artificially suppressed CD4+ cell count. Because of this, many physicians also track the CD4+ percentage, which is provided by the same lab tests. The advantage is that the CD4+ percentage does not fluctuate along with the WBC and therefore reflects a more realistic picture of the balance of cells in the immune system. Many physicians recommend checking the CD4+ percentage as well as the absolute CD4+ before taking any action, as it filters out the fluctuations in cell numbers.

• CD4+ change over time (or trajectory): If the CD4+ cell absolute count rapidly declines from one test period to another, a fall below 350 might be a very important warning of danger to come. But if the number is largely stable over time and perhaps just moves a little above or below 350 (or is contradicted by the CD4+ percentage), treatment may not be critical at all. For some, a count of 350 might represent a brief step in a rapid decline from 400 or 500 to 200 or below. In this latter case, a test result of 350 CD4+ cells might be an important warning sign. Rapidly declining cell numbers are probably a more important warning sign than any particular threshold number or percentage of cells.

• Presence or absence of symptoms: A person who experiences repeated symptoms associated with HIV disease progression, such as frequent skin infections, difficult to control thrush (candida) infections, mouth or skin infections, etc. might be wise to consider therapy earlier than standard recommendations might imply. Conversely, someone who shows no symptoms and generally robust health might be safe to wait for the later extremes of CD4+ cell count decline. Almost everybody recommends anti-HIV treatment when CD4+ cell counts fall below 200, But even in this situation, personal choice can be a factor in decision-making.

• Personal needs, beliefs, and preferences: The fact that we currently lack proof of the benefit of treatment when CD4+ cell counts are above 350 or even 500 does not prove that starting treatment early is wrong. Scientists have changed their views a number of times already, and may well change them again when new data or new drugs become available. Some people prefer to try to halt any decline of their CD4+ cell counts, even if this means starting treatment with a high CD4+ cell count. There is nothing irrational or unscientific about trying to preserve one's immune system or to prevent any loss of cells of their functions. In fact, if drugs didn't produce side effects and people didn't have to worry about resistance, physicians would probably favor the earliest possible treatment. Some people would rather take their chances with side effects than with any permanent damage to their immune system. There is in fact some evidence that very early treatment -- starting within the first month or two after infection -- preserves some aspects of the immune system that are almost always lost when treatment is delayed.

• Personal situation: Some jobs, such as working in an office or driving a cab or a truck, might make it very difficult to cope with a drug that produces diarrhea as a side effect. For such people, delaying treatment as much as safety permits might seem a reasonable choice. Similarly, people unable or unwilling to share knowledge of their condition with family members may prefer the greatest possible delay. Women and men who are victims of domestic violence or who must hide their HIV status may find that their home life makes adherence or even regular access to medications difficult. None of these situations represents an insurmountable barrier to starting therapy, but each requires more planning and preparation and may factor into a decision to start therapy now or defer.

• Personal readiness: It makes little sense to force a person who fears anti-HIV treatment or its potential complications to start a treatment regimen. While some degree of fear of therapy may be normal, it's important to explore the extent and roots of those fears. Unless the person has come to grips with the situation and the necessity of treatment, that person may not use a treatment wisely. They may have great difficulty with adherence, leading to rapid development of drug resistance. Such a person may be better off to wait and continue preparing for treatment than to rush into something he or she isn't yet prepared for. This may be true even if it means waiting until after reaching the critical "200 CD4+ cell count" level. People can still be protected against most major opportunistic infections through simple, preventive medications before committing to anti-HIV therapies.

Commentary

HIV-positive people and their doctors must understand that the U.S. Federal Guidelines or the International AIDS Society Guidelines -- anyone's guidelines -- are not meant to be rigid formulas that dictate the practice of medicine. They are just a generalized starting point for making decisions about treatment. There is no one "right" time for starting treatment that will work for everyone, and no planned or possible study will ever result in a precise universal recommendation. Over time, studies may add to our knowledge about how the various factors affect the decision to start treatment. They will help clarify matters, but they too will never lead to a "cookbook" solution that fits everyone and every circumstance.

In deciding when to start, many factors should be considered, including a mix of all we have learned from studies, and all that is known about the individual and his or her life situation. Once this is understood, it is generally easier to find the "right" time for an individual to start therapy.

While there may be no one "right" time to start anti-HIV therapy, there is certainly a "right" time to start managing HIV disease. Learning about and lining up benefits and support systems; improving diet, exercise and general health habits; choosing and developing a relationship with a doctor; setting up routines of regular health check ups, including Pap smears for women, (quarterly and twice yearly, respectively); learning about HIV disease and treatment options; and cultivating a philosophy of well-being are ways to intervene in HIV disease and take charge of one's health that can start today. There is no question that starting these activities earlier rather than later is beneficial. Project Inform has resources to help people consider these approaches to health and well-being.

Back to the Project Inform Perspective March 2001 contents page.