The Positive Side

Spring/Summer 2005 

Treatments on Trial

On the road to better HIV therapies

(This article was updated April 2012.)

By Maia Joseph

“WE NEED CLINICAL TRIALS because we need new treatments for HIV,” says José Sousa, 43, from Montreal. Sousa, who was diagnosed with HIV in 1985, knows what he’s talking about: He’s the chair of the Canadian HIV Trials Network’s Community Advisory Committee and has participated in three clinical trials since the early 1990s.
Sousa has seen HIV research evolve over the years, but he knows the list of questions that still need answering is a long one. “We need drugs that are less toxic,” he says. “We need to determine the best way to treat HIV/hep C co-infection. We need to find ways to prevent HIV infection. And we need a cure. We can’t do any of this without clinical trials.”

Clinical trials, however, can’t run without participants. And with trial enrolment on the decline, researchers are having more and more trouble finding answers to those all-important research questions — answers that could prolong the lives of people with HIV/AIDS (PHAs) and improve the quality of those lives.

What is a clinical trial, exactly?

Clinical trials are carefully designed experiments that allow investigators to test their research questions on people. Of course, the testing of a new drug or other treatment never begins with humans — it starts in the lab, where investigators perform in vitro (test-tube) experiments to determine the effects of the treatment on animal and human cells. Eventually, if the treatment shows promise, investigators test it on living animals to get a better idea of how it will affect humans.

Ultimately, though, investigators will only know for sure whether a treatment is safe and effective by testing it on people — and that’s where clinical trials come into play. At first, the treatment is tested on a very small number of people. Then, if that test goes well, investigators conduct larger studies involving more participants. A drug will be approved for sale only after it has made it through the clinical stage.

Clinical trials offer information about a drug’s effect on humans that investigators can’t get from test-tube and animal experiments. They are the gold standard of treatment research.

The changing clinical landscape

HIV/AIDS clinical research has changed dramatically over the past two decades. In the early days, when the antiretroviral drugs that make up today’s standard regimens were still on the drawing board, PHAs participated in clinical trials simply to gain access to these lifesaving treatments. “I enrolled in my first trial in the early 1990s, and at that time it was all about access to drugs,” Sousa recalls. “There weren’t many treatment options approved for marketing, and clinical trials opened up possibilities for us. Researchers were still comparing most potential drugs to a placebo because there were no standard treatments to test against.”

Today, with seven classes of antiretrovirals approved for treatment in Canada and with opportunistic infections on the decline in the developed world, clinical research is starting to focus on other pressing issues. Hot new areas of research include treatment management, vaccines and microbicides for HIV prevention, therapeutic vaccines (to boost the immune response against HIV), treatments for co-infections, and new classes of antiretrovirals.

These days, though, the rush to participate in a clinical trial has died down to a trickle. In a sense, HIV research has become a victim of its own success: Potential trial participants have found treatments that do a fairly good job of keeping their HIV in check and, understandably, they don’t want to rock the boat by enrolling in a trial.

Some trials don’t have much trouble recruiting participants. For example, a Canada-UK therapeutic vaccine study of the Remune vaccine boosted with an agent called Amplivax has been enrolling steadily since it opened in mid-2004, likely because it presents an innovative new treatment option and PHAs do not have to alter their current drug regimens to participate. But recruitment success is becoming less common as more and more trials struggle just to get off the ground.

The recruitment rut

Trial recruitment is a thorny issue within clinical research circles — one that’s complicated by a range of factors. Perhaps most important is that clinical trials are a hard sell for PHAs who would have to interrupt a relatively effective treatment regimen in order to participate.

“Your primary reason for taking part in a trial should be to help others in the future,” Sousa says. Indeed, in the HAART era, altruism plays a major role in the decision to enroll in a clinical trial, because even though review boards make every effort to minimize risk, the treatments are still experimental and there are no guarantees that a particular trial will work for you.

For a growing number of PHAs who want to help their community but don’t want to sacrifice their fundamental right to personal health, the decision to enroll involves a careful balancing act. They must weigh the risks and responsibilities that participation in a trial might entail against the trial’s potential future benefit and their own desire to make a contribution. No two people face exactly the same situation — the same health concerns, treatment options, lifestyle and support network. “It’s always a completely individual decision,” Sousa emphasizes.

But the personal decision faced by many PHAs is just one factor — albeit a critical one — in the participant shortage. Some investigators are also finding it harder to make contact with potential trial participants, primarily because the HIV population has diversified. It’s more difficult to disseminate trial information to street youth and Aboriginal people living on reserves than to reach the close-knit, predominantly urban community of gay men. Add to this the fact that the PHA population is generally healthier than in the past — meaning fewer clinic visits — and it becomes clear that investigators face a significant communication hurdle.

Another key factor in recruitment is the increasing number of clinical trials. More studies mean more competition for participants among the wide range of stakeholders who fund clinical trials. Trials driven by individual investigators — which are usually funded by the government, universities and non-profit networks or organizations — compete head-on for participants with heavily funded trials sponsored by pharmaceutical companies. Such companies often have the means to run large, multi-site trials, while some investigators lobby for years just to get their trials funded at all.

The result? Well, the best trials (whether investigator- or company-driven) do tend to go ahead. That said, the potential for private pharmaceutical interests to undermine the interests of the public is great.

Clinical Catch-22

Researchers’ ongoing efforts to run trials on structured treatment interruptions (STIs) offer a revealing example of the recruitment issue’s complexities. These researchers want to determine whether a planned drug holiday will lead to resistance or other problems. Such information could improve the quality of life of PHAs, given the high toxicity and complex dosing schedules of many antiretrovirals. Drug holidays could also decrease treatment costs. [Updated April 2012: Since this article was first published, several large clinical trials have shown that stopping treatment comes with serious health risks, and so it is not recommended. For more information, check out CATIE's Practical Guide to Drug Treatment.]

Most pharmaceutical companies won’t touch the drug holiday issue. Results from a few publicly funded Canadian trials that have struggled to address the question are eagerly awaited but have been slow in coming because clinical opinion remains divided.

“The beliefs held by doctors on this topic are quite variable,” says Bill Cameron, MD, the Canadian principal investigator of the tri-national Options in Management of Antiretrovirals (OPTIMA) study, which compares different approaches to treatment management, including planned drug holidays. “About half advocate STIs and half do not, and within those groups there are other differences of opinion as to the type of treatment regimen a patient should be on, when and for how long an STI should take place, and so on.”

The fact that some physicians are skeptical about drug holidays means they’re less likely to recruit for a study like OPTIMA. Moreover, because of the division in clinical opinion, some PHAs worry about enrolling. The result is a Catch-22: Researchers can’t get the answers they need about drug holidays because they can’t enroll enough trial participants, and potential participants won’t enroll because researchers don’t have clear answers.

Dr. Cameron notes that answering treatment questions can take a long time, often owing to safety concerns. He points to an influential breast cancer trial from the 1970s and ’80s, which compared the then-standard surgical procedure for breast cancer, a modified radical mastectomy, to a lumpectomy — a new, less invasive procedure. Despite the fact that the trial results could potentially improve quality of life, enrolment was slow.

“Breast cancer is a lethal disease, and physicians thought they knew how to deal with it,” Dr. Cameron says. “Some felt they couldn’t, in good conscience, recruit for the trial because they worried that the new procedure would not be as effective as the standard. It took eight years to enroll enough participants.”

In the end, the results of the trial showed an absolutely equivalent survival rate between the two study groups. Today, lumpectomy is the most common surgical procedure for breast cancer.

Dial “T” for trial

What role can PHAs play in the complicated HIV research environment, where varied opinions and interests seem the order of the day? Staying informed and involved are paramount. PHAs who are active in clinical research circles can identify the trials that best cater to their needs and push to have those trials go ahead.

Lynn Stevenson of Nova Scotia is one such PHA. In search of treatment options, Stevenson enrolled in her first trial in the mid-1990s. Her experience was largely negative: She suffered a drug side effect that led to health complications. “You know there are no guarantees,” she says, “but you never actually think that something will happen to you.” Stevenson eventually left the trial and had the side effect treated, but she remained apprehensive about participating in another study.

All the same, Stevenson stayed active in clinical research: As a registered nurse and AIDS activist, she served on hospital and community advisory committees, where she helped review trial protocols. She was able to see her side effect documented and to help set higher ethical standards for clinical trials.

This window into the institutional side of clinical research gave Stevenson added confidence in the process. Being informed about the benefits of clinical research also kindled her desire to participate in a second trial when the right one came along.

Stevenson’s decision to try another trial was partly motivated by altruism, but personal concerns also played a role. She liked, for instance, the fact that participating in a trial meant that her health would be monitored more often: “Suddenly you feel like you’re the centre of attention. The clinicians and nurses are all there explaining the trial to you and trying to make you feel comfortable. And throughout the trial you make more clinic visits, you get more care.”

“With the trial I chose,” she adds, “I was confident that, given the extra monitoring, any problems would be caught early enough to be addressed. My decision involved very practical considerations. I felt that, for me, the risk was pretty minimal.”

When asked if she can pinpoint a turning point on the road to participating in a second trial, Stevenson responds: “It’s an ongoing experience. On the first page of every protocol review, each member of the committee must answer questions about the study. The last one always asks, ‘If you were eligible, would you enroll in this trial?’ If I can’t answer yes to that question, then I have to ask, ‘Why not?’ And that brings me back to a safety issue or another fundamental issue that makes the trial seem inappropriate. Finally, I have to put my money where my mouth is.”

Stevenson, like José Sousa, stresses that the decision to participate in a trial belongs to each individual and that it requires careful consideration. But it’s also a decision that potential participants need to make — not avoid — because clinical trials are critical to advancing HIV care. “It’s really important that trials go ahead,” Stevenson says. “In the end, we need to know this information.”

Maia Joseph is a project coordinator and editor for the Canadian HIV Trials Network’s Communications and Information Programme.

Photograph: Andrei Tchernov, iStockphoto

Informed Consent: 10 things to know

  • Considering enrolling in a clinical trial? Your doctor should provide you with an informed consent form and discuss the trial in detail with you. Before signing on the dotted line, here’s what you should know:
  • You must give informed consent in order to participate in a clinical trial.
  • Informed consent is a process whereby the risks, benefits and requirements of a trial are clearly explained to participants.
  • The informed consent form should describe the trial in plain language.
  • Before you sign the form, consider all the factors involved in the trial, including your responsibilities, the time commitment, the benefits and the possible risks.
  • Your doctor should be willing to answer any questions you have about the trial.
  • You have the right to discuss the trial with anyone you wish.
  • You have the right to take as much time as you need to make your decision.
  • If you sign the informed consent form, you are considered enrolled in the trial.
  • After signing the form, you still have the right to leave the trial at any time.
  • Informed consent is an ongoing process: The investigator must continue to inform you of any new information that might affect your health or influence your decision to participate in the trial.

Stages of Trial Participation

Participating in a clinical trial involves a time commitment, but the payoff for many participants is the extra attention they receive from their doctors. If you enroll in a trial, you can expect to take part in many or all of the following stages:

  1. Informed consent: You sign a form stating that you understand the trial and are willing to participate.
  2. Screening visit: You are asked questions about your health and treatments and then given a physical exam, along with lab tests. The investigator then decides whether you meet the entry criteria for the trial.
  3. Randomization: You are randomly assigned to a treatment group.
  4. Waiting period: You may have to wait for the trial to begin. The investigator will monitor your health during this period.
  5. Washout period: You may have to stop taking a certain medicationand wait for a period of time. This allows the body to get rid of traces of the medication.
  6. Treatment period: The period during which you are on a study treatment before researchers evaluate its effect (usually 12, 24 or 48 weeks).
  7. Follow-up visits: Throughout the study you will be asked to come to the clinic for regular visits. The frequency of these visits is usually higher than for routine care.
  8. End of study: The study usually ends when all participants have completed either the treatment or follow-up period.

The booklet Clinical Trials: What You Need to Know is available through the CATIE Ordering Centre. Info on clinical trials enrolling in Canada is also available at through the CIHR Canadian HIV Trials Network, (www.hivnet.ubc.ca, 1.800.661.4664), or at CATIE (www.catie.ca, 1.800.263.1638).