There are numerous issues to be considered before going on a clinical trial, writes PETER WATTS.

Jim* arrived at my door and asked, “what does the term ‘treatment naïve’ mean?” I explained it means you’ve never taken HIV treatment before.

“Phew!” he replied. “I thought it meant I didn’t understand much about treatments!”

He elaborated further: his doctor had suggested he enrol in a clinical trial and had told him it was a ‘treatment naive study’. He waved an information sheet at me about the STALWART trial.

Jim wanted to know why he might consider going on this (experimental) trial versus starting standard, approved antiretroviral treatments.

I explained that he did not have to go on this or any other clinical trial, but that the decision to participate had to be his own, voluntary, choice. I also reminded Jim that reading the full details of the trial information sheet (the ‘consent form’) was an important part of making that choice, and that he should ask questions about any information he was not sure of. He was doing that with me, in the hope he could have a better understanding when talking further to his doctor about his decision.

Wet behind the ears: starting treatment

First, we talked about the current guidelines for when to start treatments. These guidelines have changed from time to time but at the moment the accepted approach is that people with a CD4 (T-cell) count lower than 200, or anyone with significant symptoms of HIV infection (regardless of CD4 count) should start treatment.

Above 200 and up to 350 Tcells, treatment is also recommended – the guidelines say it ‘should be offered’ following a discussion of the pros and cons.

For people with CD4 counts over 350, the usual approach is to defer treatment. Some physicians will recommend starting treatment if the patient’s viral load is very high (over 100,000) but the general aim is to try to defer starting treatment for as long as safely possible to avoid exposing the patient to drug toxicities.

This discussion was important in Jim’s case since he didn’t quite meet the current guidelines to start standard treatment. With a CD4 count of 380 and a viral load of about 5000, I pointed out that he could start if he wanted to but that he should also be aware that starting too early could increase his long term exposure to treatments and potential for unnecessary side effects.

The absolute need for (or benefit of) starting treatment has been demonstrated in trials only for people with CD4 counts less than 200, unless they have HIV symptoms. At this point, doctors will strongly recommend starting treatment because once the CD4 count falls below 200 the risk of developing opportunistic infections increases. For people with between 200 and 350 Tcells, there is little risk of disease progression in the short term, however most doctors would suggest thinking about going on treatment once the CD4 count falls below 350, as doing so can help to better preserve your natural immunity and possible future options. Jim was close to this 350 threshold, but with low viral load and feeling well.

Drying off: considering options

Jim was not sure if he should wait until his CD4 count fell within the range recommended in the guidelines or try a completely different (and experimental) option by joining the STALWART trial. This is an international trial for people who have never taken treatments and who have a CD4 count of 300 or above. As Jim fitted the criteria for joining the trial, his doctor had suggested he think about volunteering.

With Jim unsure about whether he wanted to start treatment now or wait a little longer, I pointed out that the way the trial works might even relieve him of the need to decide. “You see”, I said to Jim, “the thing about the STALWART trial is that one of the groups within the study that you could potentially be placed into (at random) won’t be taking any treatment at all.”

This group is called the comparison group (or control arm). It’s set up to compare whether there is a difference between the people who don’t take any treatment versus the people who do.

Different clinical trials have different structures; in the case of STALWART, three trial ‘arms’:

• Arm A (the control arm), who won’t take any treatment;
• Arm B, who will take the drug the trial is studying, called interleukin-2 (more on this below); and
• Arm C, who will take interleukin-2 and standard antiretroviral therapy.

Interleukin-2 (IL-2 for short) is an ‘immune-based therapy’, so-called because it stimulates CD4 cells rather than controling the virus like standard anti-HIV treatments. IL-2, which used to be known as ‘T-cell growth factor’, boosts levels of CD4 immune cells. It’s given by injection under the skin, in this trial the dose is twice daily for five consecutive days every eight weeks.

IL-2 is a chemical which occurs naturally in our bodies, and has the effect of stimulating production of CD4 cells. People with HIV have low levels of natural IL-2, and some studies have shown that it can boost CD4 counts, sometimes quite substantially.

Other studies are looking at whether IL-2 beneficially boosts CD4 counts in people who are already taking treatment (‘treatment experienced’), but where treatment alone is not working as well as it could for them, having CD4 counts below 300 (the SILCAAT trial).

Another trial called ESPRIT is also trying to determine if an increased CD4 count from IL-2 slows down HIV disease or not.

Although IL-2 is not currently an approved treatment for HIV, the idea behind this trial is to see if it can durably (for a long time) increase CD4 counts (and therefore improve health and immunity) without giving HIV more cells to chomp on (infect) – which could possibly increase viral load. Also, the study is trying to see if giving IL-2 in combination with anti-HIV drugs (in Arm C) may produce a greater increase in CD4 counts compared to Arm B.

Being nervous: obligations or choices

Jim asked whether it was fair that one third of the trial participants wouldn’t get any treatment. I explained that in this case because the CD4 count entry point to the trial (300 or above) is higher than when standard treatment would normally be mandated, then it is just the same as safely deferring treatment when you don’t meet the current standard approved treatment guidelines.

All trials have special safety protocols to ensure that, as far as possible, no one who participates in the trial is disadvantaged or endangered medically.

If someone were participating in this trial and he or she wanted or needed to drop out to start treatment, there’s nothing to stop them, I explained. Participation in this and all clinical trials is strictly voluntary and you can opt out at any time.

On trial: the pros and cons

I mentioned to Jim that there are risks to participating in clinical trials in that they are experimental. However, some trials are more experimental than others. In this trial there is a lot of accumulated evidence already for using IL-2 to benefit CD4 counts, mostly in treatment experienced people. Jim asked about side effects.

The main side effect of IL-2 in other trials was a flu-like feeling including muscle aches, fever, chills and feeling very tired. In some people this side effect can be very pronounced. The side effects are often helped with paracetamol to reduce the symptoms, but the trial nurse and doctor will advise about this and keep a close watch on side effects and help you with them. Most people find the flu-like feeling lasts only a few days or a week after the five-day cycle is done.

People running clinical trials are required to be very vigilant for the development of more serious side effects and if they occur the trial can be halted. If anyone participating in a trial feels the side effects of the medication are more than they can or want to deal with, they are of course free to withdraw from the trial.

In the STALWART trial participants will know which of the three arms they have been assigned to – this is called an open-label trial – and of course there’s nothing to stop you from withdrawing if you don’t get assigned to the arm you want, I explained. But it is best to enter a trial with the intent of completing it.

Another type of clinical trial is the ‘double-blind’ trial, in which no-one – neither the participants nor the researchers – knows who is in which arm until the trial is over.

I said to Jim, “If your circumstances change during then trial then you have the right to change your mind then. If you truly want no treatment at the moment, you would be best to wait until you need to take current approved treatments.”

Being gallant and stalwart: risks and rewards

One of theses risks is that this trial is looking at a type of structured treatment break, in that the treatment (either IL-2 or IL-2 plus HAART) is taken in cycles every eight weeks. That can have benefits, in that you don’t have to take treatments every day, but it is a treatment approach which is strictly experimental. There is the potential benefit that if the IL-2 works and results in an increase in your CD4 count, then there may be no need to take standard treatments for some time in the future.

Finally, if after the two-year trial is completed the results show that there is a proven benefit for using IL-2 in this way, then you will have helped the advancement of science to find a better way to start treatment. Science itself would be less ‘naive’ then!

As Jim left my room he said he’d consider enrolling in the trial.

* — not his real name

Peter Watts is the Health Promotion and Treatments Officer for Queensland Positive People.