In order to better understand the results of these studies, it is helpful to review the focus of STI research and what previous studies have shown. Interest in STI research is driven by four different and sometimes overlapping goals:
The following is a brief overview of the rationale for each goal and what research to date has shown.
The goal of one STI approach is to preserve and enhance the body's natural immune responses against HIV infection. In theory, this would help a person's immune system better control HIV on its own for longer, perhaps indefinitely, without therapy. In this context, anti-HIV therapy curbs the destruction of cells by HIV while treatment interruptions are employed to modify the immune response. By starting and stopping therapy periodically, it was hoped that with each successive treatment interruption, the immune system would become more able to recognize and 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 hoped. People living with HIV the longest were actually more likely to have more potent CTL response. Those who had started therapy soon after being infected with HIV had a fairly weak CTL response that could be boosted somewhat during an STI, but then decreased again after restarting treatment. Similar results have been found in several other STI studies in people with long-term infection.
Several studies have combined STIs with immune therapies, like IL-2 (Interleukin-2, Proleukin) or therapeutic vaccines. The hope 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 strategy.
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 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.
A recent and highly publicized study, called SMART, compared several thousand people who used constant therapy to others who stopped treatment whenever their CD4+ cell counts rose above 350. Those who took therapy "breaks" restarted treatment when their CD4+ cell counts fell to 250 or below. Overall, the study showed that people who used continuous treatment were less likely to experience death or disease progression.
Additionally, the study did not show any reduction in drug side effects in the people who cycled on and off therapy as directed by CD4+ cell counts. While this seems to argue against the use of STIs, it is important not to overstate the findings of the SMART trial. What gets lost in the observation that people on continuous therapy did better overall, it is also a fact that a great majority of those taking therapy interruptions fared well too. The actual number of people suffering disease progression or death was quite small in both groups. Perhaps the biggest surprise of the study, though, is that neither CD4+ cell counts nor viral load were able to predict who would experience problems as a result of treatment interruption.
Another unfortunate aspect of the study was that it did not call for patient volunteers to use preventive therapy against the most common opportunistic infections when their CD4+ cell counts fell to levels considered risky. Consequently, the study doesn't tell us anything about the possible role of preventive therapy as part of an STI strategy.
One important observation from SMART is that no matter what its conclusions, it will not stop people from using STIs in many situations. Treatment is still routinely interrupted when a person experiences certain major infections. It is interrupted because of drug side effects. And it will continue to be interrupted by people who suffer serious treatment fatigue. For such people, certain guidelines may be followed. Careful and increased monitoring by your doctor is critical due to the risks for disease progression and OIs. 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.
Lipodystrophy is an umbrella term for three conditions related to how the body regulates and stores fat (lipids). First is the accumulation of fat, usually in the abdomen, the breasts, and around or behind the neck. This is called lipohypertrophy. The second concern is the loss of fat, usually in the arms, legs, buttocks and face. This is called lipoatrophy. The third problem is elevations in two kinds of fats -- called cholesterol and triglycerides -- circulating in the blood. This is called hyperlipidemia.
Studies looking at the connection between anti-HIV drugs and all three kinds of lipodystrophy have yielded somewhat confusing results. While all three problems are more common in people who have taken anti-HIV drugs, they are all sometimes seen in people with HIV who have never taken anti-HIV drugs. To date there are no studies that have shown that STIs affect the risk of lipodystrophy.
A growing set of data show that people with HIV, especially those taking anti-HIV drugs, are at a slightly higher risk of heart disease. A particularly important study on this subject was the DAD study, which found an increased risk of coronary artery disease in people on all types of anti-HIV therapy. Importantly, the DAD study also found that some of the risk was lowered when people stopped taking their anti-HIV drugs.
STIs have been studied to reduce short-term side effects and improve quality of life as well. The studies have shown conflicting results. The first attempt, which had volunteers go on and off therapy every 14 days, resulted in several people developing drug-resistant virus and losing control of their HIV levels. Another small study of continuous cycles of seven days on and seven days off therapy resulted in fewer side effects and better quality of life for people on STIs than for people on continued therapy. HIV levels were well controlled as well. However, a similar study in Thailand had conflicting results, so it's impossible to state for certain whether STIs of this type will be safe.
The SMART trial also weighed in heavily on this issue with surprising and clear findings. Much to the surprise of many, people who interrupted therapy actually had a worse experience with drug side effects, much as they did with the occurrence of opportunistic infections. This is believed to be due to the way the immune system reacts when a person cycles on and off therapy. Whatever the reason, the SMART trial certainly didn't support the use of STIs as a way to reduce drug side effects.
The SMART study's Data Safety and Monitoring Board (DSMB) -- a group of scientists not connected to the study and researchers charged with protecting the safety of study participants -- halted enrollment due to a higher rate of disease progression, death and other serious health problems in the STI group compared to those on continuous therapy. Further, they advised that volunteers in the STI group switch to continuous therapy due to the safety concerns that emerged from interrupting therapy.
The first public presentation of the data that led to the DSMB's decision was at this year's CROI. The researchers found higher rates of disease progression or death (2.15 times), serious AIDS-related events (5.82 times), and non-HIV related events like heart attack, liver disease (1.6 times) and death (1.6 times) among those interrupting therapy. These results led the DSMB to decide that the STI strategy used was too risky. In addition to closing enrollment, the researchers recommended that everyone who had stopped taking anti-HIV drugs restart them.
It is important to remember, as stated above, that the actual incidence of disease progression and death remained low overall. An increase of 2.15 times might sound impressive, but if it is 2.15 times a low number, then the result is still a low number and a low percentage of people suffering progression. This aspect of the SMART data has been largely overlooked. We point it out here in hopes that people who are using STIs and doing well need not feel overly frightened by the reports from the SMART trial. The trial significantly adds to the data that people can use in making their decisions about STIs. It does not conclude that everyone taking an STI faces imminent danger of death or disease progression as some reports have seemed to imply.
While many expected there would be more disease progression and AIDS-related problems in people on STIs, the higher rates of non-HIV health problems -- especially heart disease -- surprised many. In fact the researchers who designed SMART believed they would see fewer such problems in the STI group.
There are two broad lines of thinking on the SMART findings. Some question the CD4+ parameters used to start and stop therapy in the STI group, arguing that 250 might be too low and 350 might be too close to 250. Others speculated on the role that HIV itself might be playing in heart and kidney disease. These doctors and scientists wondered what role inflammation due to unchecked HIV replication might play in the higher rates of these problems seen in the people on STIs.
Perhaps the biggest difference between this trial and others like SMART was how the researchers chose to describe their results. Most trials focused on the rates of increased risk associated with treatment interruption. The reports from WINDOW instead focused on the overall levels of disease progression, rather than the difference between the treatment arms. Both points can be (and are) true of many of these studies.
Some of these results, especially those from WINDOW and ACTG 5170, support the idea that while STIs carry some known risks; they can be done safely for some people. A careful analysis of other studies, including SMART, shows the same thing, though it is not emphasized by the study investigators. It appears that STIs are safest for people who have never had very low (under 200) CD4+ cell counts and who were able to reduce viral load to undetectable levels while on anti-HIV therapy, though even this was questionable in the SMART study. None of these studies looked at the question of reinvigorating the immune response, nor have any yet examined the overall cost of therapy.
Taken together, many of these studies show that interrupting therapy carries with it some increased risk of disease progression. People considering an STI may discuss the relative risks with their doctors and develop a strategy for increased monitoring of their health while off anti-HIV treatment. Certainly no one is encouraging treatment interruption when CD4+ cell counts are below 200, whatsoever. Also, there is no support for discontinuation of OI preventive or maintenance therapy when those therapies are indicated. Also, while individuals might have interest, outside of studies, to experiment with STIs, the trade off for interrupting therapy is increased monitoring. Community experience has shown time and again those who wind up in the most troubling and dire health situation are those who stop therapy and don't increase monitoring of their health, CD4+ cell counts and HIV levels.
While the results of some STI studies have not been what many had hoped, a compelling need to continue studies on this subject remains. The prospect of non-stop, life-long anti-HIV therapy is daunting for many. The possibility that this long-term treatment can contribute to a higher risk of heart disease, diabetes and other troubling health consequences also supports the need for more research.
The high hopes for STIs may have indeed faded, but the questions are far from fully settled. Some people with HIV will still want to take time off their HIV meds. This might be to reduce exposure to the drugs and their toxicities, or just due to treatment fatigue. It is vital that doctors and scientists continue to study this important topic, to better understand the safest and most helpful ways for people with HIV to interrupt their treatment.