STIs (structured treatment interruptions) involve going off anti-HIV therapy for periods of time in a structured and strategic fashion, typically guided by increased lab and health monitoring. In all, more than two dozen studies of STIs of varying types have been conducted since 1998. It is important to note that interpreting the results of STI research can be challenging. Some of the assumptions about HIV disease that led researchers to investigate treatment interruptions in the first place have yet to be proven conclusively. At least some of the research on STIs, however, has been promising and other research has made clear those areas where interrupting therapy is neither safe nor effective.
The discussion that follows will explore what is known about the following STI-related strategies where the goals were:
The primary rationale for studies of STIs to reinvigorate immune responses came from observations suggesting that HIV disease progression might be linked to the loss of a specific type of immune cell, called an HIV-specific cytotoxic lymphocyte (CTL). HIV-specific CTLs are cells that seek out and destroy other HIV-infected cells. Some findings indicate that long-term non-progressors -- those who remain well for many years despite HIV infection, without the use of anti-HIV therapy -- manage to maintain potent HIV-specific CTLs while people who progress more rapidly do not. Not all research supports that the loss of HIV-specific CTLs is responsible for HIV disease progression. Nevertheless, a number of studies including treatment during acute infection followed by STIs, or STIs combined with therapeutic vaccines to enhance immune responses against HIV, were planned or initiated.
The goal of this research is to enhance HIV-specific immune responses and thus improve the body's own ability to control HIV infection for the longer-term, preferably without anti-HIV therapy. In this context, anti-HIV therapy (with or without the use of an experimental therapeutic vaccine against HIV) was used to curb the destruction of cells by HIV. By starting and stopping therapy periodically, it was hoped that with each successive treatment interruption the immune system would demonstrate increasing ability to control HIV on its own. This approach is sometimes called autoimmunization, where it's hoped that modulating a person's exposure to virus can induce a more potent and effective response against the virus.
Ultimately the goal of this approach is to enhance and preserve HIV-specific immune responses in people with very, very early HIV infection, such that a person's immune system would better control HIV on its own for longer, perhaps indefinitely, without anti-HIV therapy. Or, for people with established HIV infection, the goal is to enhance or restore HIV-specific immune responses, such that those who have lost these responses might regain them and thus hopefully do better in the long-term.
The results of this research, however, were exactly the opposite of what was expected. People who had been infected longest were actually the most likely to carry a broader and more potent HIV specific CTL response. Those who had initiated anti-HIV therapy during primary infection had a fairly narrow and weak CTL response that could be boosted somewhat during a treatment interruption, but then tapered again back to lower levels after reinitiating treatment. Similar results have been found in several other studies of STIs in people with chronic, established HIV infection.
More recently, several studies began to combine STIs with immune modulating therapies such as IL-2 (Interleukin-2) or therapeutic vaccines. The hope is that these therapies, used in conjunction with an STI may provide the additional lift necessary to orchestrate a stronger immune response to HIV. Although several studies are still ongoing, the results reported so far have not been promising. As such, people who are hoping to "boost" their immune response to HIV should not look to STIs as a proven course.
There are, however, data that show it may be safe for people who started anti-HIV therapy early to go off of treatment safely. Many people who initially went on anti-HIV therapy early now wish to try going without it. The decision to simply stop anti-HIV therapy and then reinitiate therapy according to current Federal Guidelines is not an STI, per se. There have, however, been STI studies conducted in people who initiated treatment in the "hit it hard, hit it early" era of treatment. People in this population have been among the most likely to be able to discontinue anti-HIV therapy. On average, roughly one third to one half of people treated early in HIV disease who have participated in STI research have been able to go off of treatment and stay off for months at a time without virus levels climbing again. Some were able to achieve virologic control during the first treatment interruption; others required two or three treatment interruptions. The results of STIs in people who initiated treatment somewhat later (six months to several years after primary infection) have been less promising and consistent. Generally, however, people whose viral load was low and whose CD4+ cell counts were high before starting anti-HIV therapy are also the most likely to achieve long-term suppression of virus following an interruption.
For individuals who were treated early in HIV disease and who wish to attempt going off HIV medications, there are indications that it may be possible to do so safely. As reported in studies, however, treatment interruptions carry the risk even in people treated during primary infection of leading to loss of control of the virus. There is no particular STI protocol in this population that can be recommended over another. People who wish to go off their medications, should only do so with the full knowledge and assistance of their doctors. It is important to monitor CD4+ cell counts and viral load following a treatment interruption and to resume anti-HIV therapy in accordance with the Federal Guidelines ("Starting Anti-HIV Therapy"). Most doctors would recommend reinitiating anti-HIV therapy if CD4+ cells drop below 200 or viral load climbs and remains over 55,000. It is also important to remember that some people experience symptoms of acute infection in the first weeks following a treatment interruption. These symptoms are flu-like in nature and can include a fever, muscle aches, swollen lymph nodes, and a rash.
Treatment fatigue is when a person is simply "tired" of taking anti-HIV medicines. For people who wish to discontinue anti-HIV therapy due to treatment fatigue the data are somewhat conflicting. Perhaps the most hopeful data to emerge from the various STI studies is that some people can successfully take a break from treatment without developing drug resistance, treatment failure or symptoms of HIV disease progression. Moreover, several factors have emerged that help predict when a person may have a poorer outcome during their time off of treatment. These are:
There is a significant difference between studies looking at a single treatment interruption versus multiple treatment interruptions. There have been several studies that used CD4+ cell counts and viral load as a guide for when to restart therapy following a single treatment interruption. Nearly all of these studies were conducted in people who had achieved undetectable viral loads for at least the past twelve months and a CD4+ cell count above 350 for the past six months. In most studies, at least one third of volunteers were able to remain off of therapy for at least one year. The median time off therapy for the remainder of the study participants ranged from eight to twelve weeks.
It should be noted, however, that people who interrupted treatment had significant drops in their CD4+ cell counts (on average dropping 50%) compared to people who remained on treatment. Without appropriate preventive medicine against opportunistic infection, these CD4+ cell count decreases could be dangerous for people whose counts drop below 200 during an interruption. Also, the majority of the studies were unable to consistently measure significant or meaningful improvements in cholesterol and triglycerides in people taking an STI versus people on continuous therapy. Study dropout rates also tended to be higher among those taking STIs compared to those who received continuous therapy in most of these trials, indicating that treatment interruptions may actually be more difficult to manage than taking pills every day.
For people with treatment fatigue, who wish to take a break from anti-HIV therapy, there are certain guidelines that may be followed. Because of the risks for disease progression and opportunistic infections, careful monitoring by your doctor is critical. People should check their healthcare benefits (whether through private insurance or public assistance) to ensure that additional viral load and CD4+ cell counts will be covered if needed. In situations where additional tests are not covered, it can be argued that the cost of additional tests will be far less than the costs associated with remaining on most anti-HIV therapy regimens.
A viral load test and CD4+ cell count should be taken before interrupting therapy and at least three months following the interruption. You and your doctor should decide in advance what factors will indicate that you should resume anti-HIV therapy. At minimum, most people would recommend using the Federal Guidelines for anti-HIV treatment (i.e., CD4+ cell counts that drop below 200 and/or a viral load count that settles above 55,000) as a basis for reinitiating therapy.
Your doctor may also wish to check your CD4+ cell count sooner if your counts were near 200 before stopping therapy, you had less than 200 cells before starting your last regimen or you have previously had an opportunistic infection. Federal Guidelines for preventing and treating opportunistic infections should absolutely be followed. Whenever CD4+ cell counts drop below 200, preventive treatment for opportunistic infections is highly recommended.
Another form of STIs studied were those designed primarily to reduce the amount of time a person spent on treatment. The first attempt, which directed volunteers to go on and off therapy every fourteen days, resulted in several people in the study developing drug-resistant virus and losing control of their viral load. Another small study of continuous cycles of seven days on and then seven days off therapy resulted in improvements in side effects and quality of life issues for people attempting STIs versus people on uninterrupted therapy. As well, virus levels were well controlled. A larger study in the US is ongoing. A similar study in Thailand had conflicting results, however, so it is impossible to state conclusively whether STIs of this type are likely to work.
When a person is attempting to construct a new regimen that may contain specific medications that had previously failed, the combination is often referred to as a third-line or salvage regimen. Because salvage also means, "to save," others sometimes call salvage regimens, "rescue therapy". For the purposes of this article, the term third-line therapy will be used to describe a new regimen that typically contains four or more different anti-HIV drugs, some of which a person's virus may carry resistance for.
The theory behind treatment interruptions in settings where a person wishes to start a third-line regimen is the hope that time spent off therapy may enhance the virus' susceptibility to treatments to which it had previously become resistant. Studies conducted in the early days of anti-HIV treatment found that when a person goes off a therapy to which the virus has become resistant, the newly emerging virus will rapidly revert to what is called wild-type. Wild-type virus is one of the many strains of HIV that exist in the bodies of people living with HIV. It is the strain of virus that reproduces most easily and is sensitive to anti-HIV therapy. The earlier studies found that when the wild-type virus takes over as the dominant form existing in the body, a therapy that had stopped working could sometimes regain some of its earlier potency.
For this reason, several studies have now been conducted examining the impact of treatment interruptions in third-line settings. One study from Barcelona found that a three-month treatment interruption did not provide any additional advantages before starting a third-line regimen compared to starting immediately. The GIGHAART study from France, which used a shorter interruption, did show that people taking a treatment interruption had larger reductions in virus when they started their next regimen than those who started their next regimen immediately. More recently, researchers in San Francisco conducted a similar study comparing a group of patients who were given a four-month treatment interruption before starting a salvage regimen to another group who started the new regimen immediately. Unfortunately there were no benefits in viral response to treatment in the group who underwent the treatment interruption. In fact, people who had interrupted treatment for four months were more likely than the other group to develop an opportunistic infection or die. Although the authors of this study concluded that treatment interruptions should not be attempted in people with lower CD4+ counts and drug-resistant virus, it may be fairer to say that they should certainly not be attempted in this population without proper medication and follow-up to prevent the development of opportunistic infections. It may also be that four months is too long to wait before resuming anti-HIV therapy.
It is critical for people to be monitored closely by their doctors when attempting a treatment interruption in this setting. Guidelines for preventing opportunistic infections are a must. Additionally, expert guidance in interpreting the results of drug resistance tests should be sought in constructing a third-line regimen (see "Third-Line Anti-HIV Therapy Strategies)."
While the results of the STI studies conducted so far have not been what anyone might have hoped, they are also not a reason to be discouraged. Based on what has been learned from the various studies, there may still emerge a new strategy that will successfully allow people to spend more time off treatment without problems. The prospect of time off treatment and the chance for a reduction in side effects have been tantalizing enough that a number of people living with HIV are still eager to enroll in STI trials or to attempt them on their own. There simply isn't sufficient data to say that any trial conducted so far or currently ongoing will offer a benefit to those attempting an STI. We do, however, know now that it is safe for at least some people to take a break from treatment for awhile. We also more clearly understand the conditions wherein breaks from treatment can result in problems. As stated in the lead article of PI Perspective #36, there are reasons to remain hopeful and to examine every piece of new information as the possible thread that will lead us one day to a cure.