Virtual Monotherapy: Can It Be Avoided?

Twenty years ago, participating in a clinical trial was usually the only way to access an experimental HIV drug. Doctors who kept up with new developments worked hard to get their patients on drugs as soon as they became available. Unfortunately, many doctors and patients ended up adding one new drug at a time. We soon learned -- painfully for many patients -- that this type of "sequential monotherapy" usually has only short-term benefits. And it has the primary effect of burning through all available antiviral drugs, helping the virus accumulate additional mutations that reduce the efficacy of any future regimen.

The official Department of Health and Human Services Guidelines recognize the importance of having more than one active drug in a treatment regimen. The current version states:

  • Use the [patient's] treatment history and past and current resistance test results to identify active agents (preferably at least two fully active agents) to design a new regimen. A fully active agent is one likely to demonstrate antiretroviral activity on the basis of both the treatment history and susceptibility on drug-resistance testing.

  • If at least two fully active agents cannot be identified, consider pharmacokinetic enhancement of protease inhibitors with Norvir (ritonavir) and/or re-using other prior antiretroviral agents to provide partial antiretroviral activity.

  • Adding a drug with activity against drug-resistant virus (e.g. a potent Norvir-boosted PI) and a drug with a new mechanism of action (e.g. HIV entry inhibitor) to an optimized background antiretroviral regimen can provide significant antiretroviral activity.

  • In general, one active drug should not be added to a failing regimen because drug resistance is likely to develop quickly. However, in patients with advanced HIV disease (e.g. CD4 <100) and higher risk of clinical progression, adding one active agent (with an optimized background regimen) may provide clinical benefits and should be considered. (Emphasis added.)

In 2006, we're in relatively good position in terms of the drug pipeline. There are promising new agents, including some that appear to be effective against HIV that is resistant to existing drugs. And drugs are showing up in new classes: attachment and fusion inhibitors, integrase inhibitors, and maturation inhibitors. A new class of drugs carries the strong hope of a lack of cross-resistance with older classes of drugs -- an extra boost to its ability to fight HIV. And yet, many patients are still risking their future treatment options by participating in clinical trials where they may only receive one new, active agent to add to their failing treatment regimen. What factors contribute to this situation? Why are people with HIV putting themselves at risk?

Clinical Trial Design

The FDA has long been aware of the risks of monotherapy in testing new drugs. In 1999 they wrote to manufacturers indicating that more than one investigational agent could be used in the same clinical trial. The FDA was very supportive of "factorial designs" where more than one agent at a time could be studied. For example, the following is an example of a factorial design (Note: OBR means "optimized background regimen," or the best combo that can be put together with existing drugs.)

  • OBR plus new drug A

  • OBR plus new drug B

  • OBR plus new drugs A & B

  • OBR alone

But unless your OBR includes at least one "active" agent -- a drug to which your virus is not yet highly resistant -- then the only arm that doesn't expose you to monotherapy is OBR plus A + B. And of course, the whole point of a randomized trial is that you can't choose which arm you get into.

The Lessons of Fuzeon and Aptivus

Two recent drug approvals were supported by large clinical trials that highlighted the benefits of having more than one active drug available.

The key clinical trials supporting the approval of Fuzeon (enfuvirtide) were the TORO trials. These trials generally studied a regimen that included a boosted protease inhibitor, with or without Fuzeon. When people in the TORO studies were given phenotype tests, one study found that people with 3 to 4 active drugs had an average viral load drop of 2.3 logs (99.5%) after 6 months -- an impressive result. But those who had only one other drug available achieved only a 0.2 log drop (37%). The TORO studies showed that Fuzeon works best in people who have two other active HIV drugs available, and some ADAP programs require this before they will pay for Fuzeon, the most expensive HIV drug yet approved.

The newest protease inhibitor to be approved is Aptivus (see article in this issue). An analysis of the RESIST clinical trials provided clear support for the benefits of additional active drugs in the background regimen: Almost 55% of people taking Aptivus had a treatment response if they had 3 or more active drugs available. But this number dropped to 46% when only two other drugs were available, 37% with one other drug available, and 13% with no other active drugs.

The TORO and RESIST trials clearly support the value of active agents in the treatment regimen, but they also leave open a key question: the role of a new class of drug. In both sets of trials, patients who took Fuzeon did better. Was this because it was "one more active agent" or because it was a drug in a totally new class? Would another fusion inhibitor (of course, there aren't any right now) or a drug in one of the other classes being developed (attachment inhibitors, integrase inhibitors, maturation inhibitors) have the same benefits? We won't know the answers to these questions until some of these newer drugs are tested.

Research vs. Treatment

That puts us squarely in the middle of the dilemma of how to test new drugs. From the manufacturer's point of view, the goal of a clinical trial is to provide key data to achieve FDA approval. The best way to do this is to show higher response rates with their new drug than without it. But this often conflicts with the best way to optimize treatment for an individual patient.

So -- what restrictions should be put on patients entering clinical trials to protect them against the risks of getting only one active drug? Should more than one experimental drug be tested in a single clinical trial? From a manufacturer's point of view, combining experimental drugs in a trial design is challenging and risky. What about legal issues? Will the manufacturer of the other new drug cooperate? Have interaction studies been done between the new drugs, and with existing drugs? Are they safe for people with kidney problems or liver impairment (such as with hepatitis B or C)? And when the trial is over, will anyone be able to sort out the contribution of Drug A versus Drug B to treatment success?

Of course, from a patient's point of view, allowing more than one experimental agent in a trial increases the possibility of constructing a regimen with active agents, raising the chance that the regimen that will control HIV, and avoiding real or "virtual" monotherapy.

It's also been common for clinical trials of new drugs to include an initial period of monotherapy. The benefit is being able to see the impact of the new drug by itself. The risk is that HIV will quickly develop resistance and the new drug will become useless.

Asking the Right Questions

If you're considering participating in a clinical trial, talk with your doctor about the following: Do we have current resistance testing results for me? If not, does it make sense to get them done now? What active drugs do I still have? Which approved medications still have a chance to contribute to control of HIV? (Remember that resistance is not "all or nothing" -- you may get some benefit from drugs that show partial resistance.)

What clinical trials are available for new drugs? What phase are these trials? How much is known about the drugs being studied? What are the treatment arms in the clinical trial? Would any of them expose me to monotherapy, real or virtual? Would any of them expose me to untested dosages? What are the anticipated side effects? Is there any other way to access experimental drugs? Are there expanded access or open-label safety studies that could provide access?

Informed consent is a process intended to protect people who enter clinical trials. There are always some risks, which must be weighed against the potential benefit. Unfortunately, the clinical trials system can be slanted toward the completion of the trial, and informed consent can sometimes be less thorough than is needed. Before entering any clinical trial, it's important to check it out with your healthcare provider, and to look for info from other sources, like an AIDS treatment organization or other people with HIV.

Where Do We Go From Here?

Clinical trials are not done to provide optimal care to trial participants. They are done to answer specific research questions about the effectiveness and safety of new drugs. On the other hand, clinical trials have always been a way for people with HIV to gain access to these new drugs. Unfortunately, most manufacturers won't let you access their new drugs through early access programs if you meet the criteria for their clinical trials. Exceptions are sometimes made for people who live too far from a trial site, but this is difficult to do. Activists have pushed for years to allow people with very low CD4 counts to get new drugs without risking being randomized in a clinical trial, but have not had much success.

When someone has highly resistant HIV and a falling CD4 count, the lure of a new drug -- especially if it's in a new class of drugs, such as attachment inhibitors -- can be impossible to ignore. But we have to remember that there is a risk/benefit ratio to calculate before deciding to enter a clinical trial. What happens if you get assigned to the placebo arm? What is the potential risk to your health? What if the experimental drug doesn't work as well as hoped? Where will you be after 6 months in the trial? What is the risk of developing resistance to the new drug? What is the risk of waiting?

There are no clear answers to these questions. The answers have to come from the clinical trials themselves. The real issue is for people with limited treatment options. As grim as things may look, overall, they're much better than a few years ago. At that time, the goal of salvage therapy was just to keep the patient alive for a few more months. Now, we talk about suppressing the virus, even for highly treatment experienced patients.

Recent studies suggest that going off all protease inhibitors -- while staying on nukes -- may be a good "holding" pattern. This avoids the accumulation of new protease inhibitor mutations, and appears to do a fairly good job of maintaining CD4 counts. In fact, many physicians leave Epivir (3TC) in a patient's regimen even if HIV has developed resistance to it, because Epivir resistance may actually enhance the activity of other nukes. If you still have two or three effective drugs that you can tolerate, ask your health care provider it you should switch to them. But if you have only one new treatment available, you have to balance any short-term benefit you might get against the value of preserving future treatment options. Check out web sites dealing with salvage therapy such as: (click on "Your Health Info" and then "Salvage Treatment");;; and

Some studies show that the decline in CD4 cells is slower in people with highly resistant virus because the virus may be less "fit" (meaning it is less able to infect CD4 cells). Can you afford to wait until the trials reveal more information about a new drug? Is your doctor willing to jump through the paperwork hoops necessary to enroll you in a compassionate access or expanded access program? Ultimately it's a personal decision -- so be sure it's an informed decision. Don't count on clinical trials alone to offer you the best care for your individual situation -- be aware of all your options.

Bob Munk is a long-time AIDS activist and the Project Coordinator of