Pulsed Therapy and Structured Interruptions of Treatment
Research has begun on two new strategies for long-term treatment of HIV disease. Although both theories involve taking people off treatment in some way, they have different goals and expectations. These two strategies are known as pulsed therapy and structured interruptions of treatment (sometimes called drug holidays).
The first approach, best described as a form of pulsed or intermittent therapy, aims at stimulating a stronger immune response against HIV. Researchers speculate that this will empower the person's own immune system sufficiently to control HIV replication without the continual use of anti-HIV drugs.
The second approach, a type of structured interruption of treatment (or drug holiday), can take a number of different forms. On one level, it can be little more than taking people off therapy, after successfully suppressing HIV for a year or more, to simply see what happens. On another level, it assumes that measurable HIV replication will begin again sometime after treatment is stopped but tests whether this is necessarily bad. This kind of therapy interruption compares the benefits and drawbacks of constantly staying on drug therapy against those of periodically taking time off.
While each approach is getting serious attention as a research project, no one suggests that we know enough to recommend these strategies for anyone's personal use. They are experimental strategies whose overall harm or benefits are simply not yet known.
The pulsed therapy approach assumes that people should always maintain viral loads below the limit of detection to be healthy. In this approach, a person who has been treated since the earliest stage of HIV infection is taken off all therapy once viral load remains undetectable for some pre-determined length of time, perhaps six months to a year or longer.
While off therapy, the person would be carefully monitored for the return of measurable virus. If and when viral load becomes detectable again, the person would be put back on aggressive antiviral therapy. Typically, this results in the rapid disappearance of measurable viral load for the second time. After another pre-determined period on therapy, the cycle is repeated -- taking the person off therapy while monitoring for return of measurable viral load.
An interesting phenomenon has been noted in a few cases of pulsed therapy, either as a structured experiment or simply as a matter of patient choice. The first time a person went off therapy, viral breakthrough (return of measurable levels of viral load) occurred after a relatively short period of time, ranging from a few days to a few weeks. After restarting therapy, viral load plummeted again, below the level of detection. Then after staying on therapy for varying periods, they stopped therapy a second time. This time, viral load remained undetectable for considerably longer than the first time, despite the lack of continued treatment.
A few people who cycled on and off therapy twice now have no return of measurable viral load, while off ther-apy, for periods ranging from 6 to 21 months. Researchers theorize that each cycle of pulsed therapy led to a progressively longer period for the body to fully control viral replication without the help of anti-HIV drugs. In a few cases, people treated with two or more cycles of pulsed therapy have been able to control viral replication with continued therapy for as long as two years (and still counting).
It is hard to draw any clear conclusions from these observations since nearly every patient involved has done something differently from others. For the most part, they were simply choosing to go on and off therapy for personal reasons. They each had varying times on and off therapy, and varied considerably in how quickly they returned to treatment when viral load reappeared. Researchers carefully studied the consequences of their actions, and were understandably surprised by the results.
What Is Going On Here?
Researchers at the Aaron Diamond AIDS Research Institute and the RIGHT group have proposed a theory: the periods in which a person is taken off therapy and viral replication is allowed to resume may be beneficial. They suspect that the returned viral load is acting somewhat like a vaccination. HIV is aggressively presented to the immune system once again, stimulating a more powerful immune response.
This makes some sense because we know when people use antiviral drugs that work for them, HIV is no longer being presented to the immune system. In theory this might allow the normal immune response against HIV to gradually decline. In turn, occasional interruptions in therapy as proposed here may reintroduce HIV into the immune system, thus stimulating a renewed immune response against the virus.
If this is indeed what is happening -- and there is promising initial evidence that it is -- this approach might be used to help people become less dependent on anti-HIV drugs and more reliant on their immune systems for control of HIV. Such a response might resemble the tiny percentage of HIV-infected people known as "long-term non-progressors." Such people appear able to control HIV replication without the use of anti-HIV drugs and usually have an abnormally strong immune response against HIV, very similar to that being seen in people who are treated with pulsed therapy.
Still, pulsed therapy is far more theory than reality at this point. The only thing known for sure is that a few people seem to respond in a way that resembles the theory, including the widely discussed "Berlin patient" reported by Dr. Franco Lori's group. Studies of many more people are necessary and already planned.
Even proponents of pulsed therapy warn that there is no evidence so far that this will work in typical, chronically infected people. The case reports noted have all come from people who began anti-HIV treatment extremely early after initial HIV infection. Such people are known to still be able to mount strong HIV-specific immune responses.
In contrast, many people with more typical chronic HIV infection (where treatment began six months or later after initial infection) frequently show no evidence of this kind of immune response. Some researchers believe that the natural capacity for this immune response is lost fairly early in the course of HIV infection. Thus, for now, the only realistic target for pulsed therapy research is in people treated from the earliest or acute stage of HIV infection, also known as primary infection.
Structured Interruptions of Treatment
The second strategy, structured interruptions of treatment, responds to a different set of goals and concerns. It assumes that people taken off therapy are likely to see a rebound of measurable viral load. What's not clear is how high the rebound will go and whether it will initially shoot up and then fall back to some lower "set point" level (a viral load level lower than that seen before the person began therapy).
In this approach, people are not automatically put back on antiviral therapy the minute viral load becomes detectable again. Instead, a person stays off drugs for awhile despite the presence of detectable viral load. So then a question begs to be asked: "Is the harm caused by a return of measurable viral load a greater or lesser danger than constant therapy, and all the attendant side effects and development of resistance to treatment?"
What is the harm of constant therapy? Even if viral load remains undetectable for long periods, there are many possible long-term consequences to constant therapy. The risks of cumulative side effects and tissue damage are perhaps the greatest concerns. This encompasses problems such as fat redistribution (lipodystrophy), high cholesterol and triglycerides, diabetes, heart disease and liver problems. These come in addition to the side effects of the older generation of drugs, such as pain in the feet, legs, and/or hands (peripheral neuropathy), red and white blood cell suppression (anemia), pancreatitis, rash, etc.
Suppression of viral load through anti-HIV drug therapy can produce improvements in overall health and prolonged survival. The challenge is to find the best possible balance -- to get the most from therapy without experiencing its down sides which includes the emergence of possible long-term negative effects. For some, this might mean periodically structuring time away from the drugs, for the body to recover from side effects. Some researchers believe that periodic interruptions of therapy may not only be possible, but necessary to help people live out a normal lifetime with HIV disease.
Since we only have about three years of experience treating people with today's potent three- and four-drug combinations, it remains highly uncertain just how long people will tolerate constant use of the drugs. Few researchers, however, have enough confidence in the drugs to believe that people could use them continually for the 20 to 50 years needed to live a normal life span.
In contrast, we have long known that most people can tolerate long periods of untreated HIV infection without irreparable harm. On the average, people using no treatment at all can usually go for roughly ten years without progression to AIDS. For some, this period is longer, for others it's shorter. Part of the goal of treatment interruptions is to give some of this time back to people, in effect letting them coast along with the virus for awhile. They then return to medication only when signs of disease progression become apparent. Similar strategies employing periodic interruptions of treatments are routinely used for other chronic illnesses that require long-term therapy.
Another concern caused by constant therapy is simply the weariness it causes people. The longer many people remain on constant therapy the more likely they begin to miss doses or take short unstructured drug holidays. That can do harm by encouraging development of viral resistance. If structured interruptions of treatment can be offered to people in ways that are unlikely to hasten resistance, with little or no downside, commitment to proper use of therapy may increase during those periods when people use the drugs. This approach offers a compromise, but hopefully one that will provide long-term benefits.
Since we know that short or frequently repeated drug holidays speed the development of viral resistance, the model here focuses not on casual weekend holidays but rather on carefully planned, structured interruptions. An additional benefit already demonstrated in initial studies is that the break from drugs may help a person's virus increase its sensitivity to some previously used drugs. In theory, this might restore their ability to use drugs to which they had developed resistance. This would greatly enhance their options for future therapy.
Structured Treatment Interruption Research Programs
Treatment interruption programs are just beginning and plan to start with people who have undetectable levels of HIV for six months to a year or more (though this may change after more experience is gained). After that, the approaches vary. Four are outlined below.
Some plan to take people off therapy and monitor them, but not immediately restart therapy if viral load reappears. These seek to determine whether viral load will rise to and maintain a high level peak, perhaps even higher than before the person started therapy. Or they may find that such a peak is followed by a gradual reduction back to a lower and stable level (a set point). If viral load comes back down to a modest set point, researchers may choose to withhold therapy as long as viral load remains stable with no major decline in CD4+ cell counts. Such a study is planned at the NIH.
Still another approach, perhaps targeted to people with more advanced disease or those who have developed resistance to most available drugs, will keep people off therapy, regardless of viral load, for a period of a few to several months. At some fixed point, anti-HIV therapy will be restarted. The hope of this approach -- sometimes called a washout period -- is to see if the time off allows the virus to return to its natural state (often called wild-type virus) and regain sensitivity to previously used drugs. Restarting therapy with a mix of old and new drugs might then kick off another long period of effective viral control.
Another approach takes people off therapy for a fixed period, such as two to six months or longer. This is done to let the body heal from drug side effects and rest from the constant rigor of daily therapy. Either at a fixed point in time, or after some permissible level of CD4+ cell count decreases and/or viral load increases occur, the person may be put back on anti-HIV therapy. If successful, this could theoretically be repeated over many years or even throughout a normal lifetime. The hope is that the mix of time on and off therapy might lead to the increased tolerance of therapy and the longest possible life expectancy for HIV-infected people, short of an outright cure.
Many important new strategies for the use of anti-HIV therapy must be tested. Until recently, most research focused only on how well individual drugs worked over a period of a few months to a few years. Many people are already coming to the end of the hope offered by such narrowly defined, product-driven strategies.
Today, new strategy research on pulsed therapy or structured interruptions of treatment may well be what's needed. Such research may extend our knowledge of how to best get HIV-infected people through a lifetime, or at least well into the new millenium and not just the next few years. These strategies should not yet be considered recommendations for medical practice, nor should the fact that they are being tested encourage people to try them on their own.
We don't have enough information to know whether these procedures will help people live longer or instead cut precious time off what a person has left. If we knew, there would be no need for the research. The right approach is in the context of well-designed studies. Self experimentation seldom leads to knowledge, since there is never a way to know whether what happens to an individual is due to the strategy or drugs used, or whether it is a mere coincidence.
The next several months will see a rash of new strategy studies asking whether and how it might be possible for people to get off therapy, at least temporarily. The more people who volunteer to participate in these studies, the sooner we will know what is and isn't possible.
This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.