Strategies and Goals for Attempting Structured Treatment Interruptions
January 2005

Introduction

Structured treatment interruptions (STIs) involve going off anti-HIV therapy for periods of time in a strategic way, typically guided by more frequent lab and health monitoring. In all, more than two dozen studies of STIs of various types have been conducted since 1998.

It's important to note that understanding the results of STI research can be challenging.
Some of the assumptions about HIV disease that led researchers to study STIs have yet to be proven conclusively. At least some of the research, however, has been promising. Other research has also made it clear when interrupting therapy is neither safe nor effective.

This publication explores what is known about the following strategies where the goals were Using an STI to Reinvigorate the Immune Response
The main reason for this type of STI study came from observations that suggested HIV disease progression may be linked to the loss of a type of immune cell, called an HIV-specific
cytotoxic lymphocyte (CTL). These are cells that seek out and destroy HIV-infected cells.

Some findings indicate that long-term non-progressors -- those who stay well for many years despite HIV, without therapy -- maintain these potent CTLs while people who progress more rapidly do not. Not all research supports that the loss of these CTLs is responsible for disease progression. Nevertheless, several studies (including treatment during the first few weeks or months after infection followed by STIs, or STIs combined with therapeutic vaccines to enhance immune responses against HIV) were planned or started.

Ultimately the goal of this approach is to preserve and enhance the body's natural immune responses in people with very early HIV infection. In theory, this would help a person's immune system better control HIV on its own for longer, perhaps indefinitely, without therapy. Or, for people with established HIV infection, the goal is to enhance or restore immune responses, so that those who have lost these responses might regain them, hopefully doing better in the long-term.

In this context, anti-HIV therapy (with or without a 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 STI the immune system would become more able to control HIV on its own. This is sometimes called autoimmunization, where it's hoped that enhancing a person's exposure to HIV in a controlled manner can create a more potent and effective response against it.

The results of this research, however, were exactly the opposite of what was expected. People living with HIV the longest were actually more likely to carry a broader and more potent CTL response. Those who had started therapy just before or after developing antibodies to HIV had a fairly weak CTL response that could be boosted somewhat during an STI, but then decreased again back to lower levels after restarting treatment. Similar results have been found in several other STI studies in people with long-term infection.

More recently, several studies began to combine STIs with immune therapies, like IL-2 (Interleukin-2) or therapeutic vaccines. The hope here is that they may, when used with an STI, provide the needed lift to orchestrate a stronger immune response to HIV. Although several studies are still ongoing, the results so far have not been promising. As such, people who hope to "boost" their immune response to HIV should not look to STIs as a proven course of treatment.

There are, however, data that show it may be safe for people who started therapy early in their infection to go off treatment safely. This is something that many people now wish to try. The decision to simply stop anti-HIV therapy and then restart it according to current Federal Guidelines is not an STI, per se. However, there have been STI studies done in people who started 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 stop anti-HIV therapy. On average, roughly one-third to one-half of people treated early in their disease who participated in STI research have been able to go and stay off treatment for months at a time without their HIV levels climbing again. Some were able to control their HIV levels during the first interruption; others needed two or three STIs.

For people who started treatment somewhat later (six months to several years after 9 ( infection), the results have been less promising and consistent. Generally, however, people whose HIV levels were low and CD4+ cell counts were high before starting anti-HIV therapy are also the most likely to reach long-term suppression of their HIV after an STI.

For people who were treated early in their HIV disease and wish to try going off meds, it may be possible to do it safely. As studies report, however, STIs may lead to the loss of control of HIV even in people treated during early infection. No one specific STI protocol can be recommended over another for this population. Those who wish to go off their meds should only do so with the full knowledge and support of their doctors. It's important to check CD4+ cell counts and HIV levels after an STI and resume anti-HIV therapy according to the Federal Guidelines. (For more information, read Project Inform's publication,

"Strategies for When to Start Anti-HIV Therapy.")

Federal Guidelines recommend that a person should start (or restart) anti-HIV therapy if their CD4+ cell count drops below 200 or HIV level climbs and stays over 100,000. It's also important to remember that some people feel symptoms of acute infection in the first weeks after an STI. They are flu-like in nature and can include fever, muscle aches, swollen lymph nodes and rash.

Using an STI to Help People Who Feel Treatment Fatigue
Simply put, treatment fatigue is when a person is "tired" of taking anti-HIV medicines. For people who wish to stop their therapy due to treatment fatigue, the data are somewhat conflicting. Results from the various STI studies show that some people can successfully

take a break from treatment without developing drug resistance, treatment failure or symptoms of disease progression.

Moreover, several factors have emerged that help predict when a person may have a poorer outcome during their time off treatment. These are:

low CD4+ count (below 200) before starting anti-HIV therapy,

high HIV level (above 55,000) before starting anti-HIV therapy,

poorer control of virus while on therapy or other signs of drug resistance, and earlier opportunistic infection (OI).

There's a significant difference between studies looking at a single STI than at several of them. Numerous studies used CD4+ cell counts and HIV levels as a guide for when to restart
therapy after a single STI. Nearly all of them were done in people who had reached undetectable HIV levels for the past twelve months or longer and CD4+ cell counts above 350for the past six months.

In most studies, at least one-third of volunteers were able to stay off therapy for at least

one year. The average time off therapy for the other participants ranged from 8-12 weeks. It should be noted, however, that people who interrupted their treatment had major drops in their CD4+ cell counts (on average dropping 50%) compared to people who stayed on treatment. Without proper preventive medicine against OIs, these decreases could be dangerous for people whose counts drop below 200.

Also, most studies were unable to consistently measure meaningful improvements in cholesterol and triglycerides in people taking STIs than in people on continuous therapy.

Dropout rates also tended to be higher among those on STIs in most of these trials. This indicates that STIs may actually be more difficult to manage than taking pills every day.

For people with treatment fatigue, who wish to take a break from therapy, there are certain guidelines that may be followed. Because of the risks for disease progression and OIs, careful monitoring by your doctor is critical. People should check their healthcare benefits (both private insurance or public assistance) to ensure that the cost of additional lab tests would be covered if needed. In cases where these tests are not covered, it can be
argued that the cost of extra tests will be far less than the cost of staying on most anti-HIV therapy.

Testing your HIV level and CD4+ cell count should be done before the STI and at least three months after it. You and your doctor should decide in advance what factors will indicate when you resume therapy. At a minimum, most people would recommend using the Federal Guidelines for anti-HIV treatment (i.e., CD4+ cell counts that drop below 200 and/or an HIV level that settles above 100,000) as a basis for restarting therapy. Also, drug resistance testing when HIV levels are at their highest should be conducted to determine whether a person should change to a new anti-HIV combination when and if they resume treatment.

Your doctor may also wish to check your CD4+ cell count sooner if your counts were near 200 before stopping therapy, if you had under 200 cells before starting your last regimen, or if
you have previously had an OI. Federal Guidelines for preventing and treating OIs should absolutely be followed. When CD4+ cell counts drop below 200, preventive treatment for OIs is highly recommended.

The prospect of time off treatment and fewer side effects have been tantalizing enough that some people living with HIV are still eager to enroll in STI studies or try them on their own.

We now know that it's safe for at least some people to take a break from treatment for a while. We also more clearly understand the conditions when taking breaks from treatment can result in problems. However, there simply aren't enough data yet to say that any study will offer a benefit to those attempting an STI. Still, there are reasons to remain hopeful and to examine every piece of new information as the possible thread that will lead us one day.

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