Even very immune-suppressed people, if they are treatment-naive and have a drug-susceptible virus can, with time and diligence, hope to recover immune competency to a point where prophylactic medication may safely be stopped. And many people in the U.S. still discover their diagnosis at that late stage. But for an increasing number of individuals who have been on therapy long enough to have run the gamut of available drugs, constructing a treatment regimen when there are no good options increasingly starts to feel like a salvage operation.
Any occasion for a burst of viral replication while on antiretroviral therapy can lead to another, more worrisome, source of virological failure. Loss of susceptibility to antiretroviral therapy, also known as drug resistance, can occur whenever a viral mutation arises capable of replicating despite the presence of drugs. Since resistance allows replication and replication breeds resistance, there is a critical need to find new ways to fight viral strains that have become resistant to multiple HIV drugs. When an individual experiences immunological failure subsequent to loss of viral suppression, the need for a "salvage" strategy can become urgent lest clinical failure follow.
A more aggressive strategy, sometimes called "Mega-HAART," advocates piling on five, six, or more drugs, both approved and experimental, to beat the virus into submission. Usually, these intense regimens will include an agent to boost the blood levels of one of the other drugs.
Unfortunately, second and third regimens rarely work as well as the first one, and the toxicity of such intense drug regimens can become intolerable. Although "salvage patients" are often the most willing to attempt demanding regimens, they are also those least able to tolerate them.
A few novel strategies for addressing this problem are being tested. One approach proposes removing drug pressure with a structured treatment interruption in order to allow a switch in the dominant viral population from drug resistant to drug susceptible. This, in fact, can occur. But, unless a new drug from an untried class is added when treatment is restarted, attempts to suppress the shifted virus in a durable and sustained fashion using formerly used drugs have been disappointing.
Another concept already practiced by some clinicians, but not yet tested in a clinical trial, is to place patients with multi-drug resistant virus on a simple HAART regimen that suppresses wild-type virus at the expense of allowing a moderately unsuppressed MDR strain to survive. The theory here is that the MDR virus is less able to replicate and infect new cells than its ancestral "wild-type" strain. If this is true, then an individual would be better off with an unsuppressed amount of "crippled" virus. Studies have shown that "failing" drug regimens may continue to have significant antiviral activity that contributes to keeping MDR virus in check. This approach is also supported by observational reports that individuals who remain on "failing" regimens and receive careful medical management can have relatively few clinical problems.
Since none of the above are excellent options, there is an urgency for new drugs with unique resistance profiles to move through the development pipeline.
Since a single new drug added to failing background therapy will be the only active agent against the dominant viral strain, this situation is virtually the same as being treated with only one drug. Single drug therapy, or monotherapy, has long been recognized to give only temporary benefits. Although a single drug may provide a short-term reduction of viral load, viral replication can continue under monotherapy and viral mutations often arise that soon render the new drug useless. Adding one drug at a time has led many patients down a path of serial monotherapy, eking out a small benefit from each new agent before giving in to resistance. Patients who have been on multiple drug regimens over the years may have developed resistance to virtually every drug in every class. Many of these individuals find themselves chronically looking to the next new drug in the pipeline for hope.
One way to proceed would be to hold off switching regimens until two novel agents are available, then start them both at the same time. But because the drug development process is so sluggish, at any time there might be one new drug available through an expanded access program with another expected to come to market "any day." So constructing an optimum regimen when all else is failing requires patience and a steady flow of new drugs.
Another possibility for some is to get access to new drugs through a clinical trial. But what kind of trial design can provide an optimized regimen to every participant? The risks of serial monotherapy have also been recognized in the research setting. If a clinical trial is comparing one new drug to placebo -- each on top of an optimized background regimen -- then individuals on the treatment arm may experience temporarily lowered virus levels, but at the price of becoming resistant to the new drug. Those on the placebo arm may have unchanged viral levels yet retain susceptibility to the new drug for future use. Who's better off?
The problems of designing trials for "salvage therapy" reflect the problems of constructing regimens for multiple treatment experienced individuals. One solution is to offer more than one experimental drug to everyone in the trial.
In January 2001, the Federal Food and Drug Administration (FDA) convened a meeting of researchers, drug sponsors and community members to discuss the problems of developing drug trials for "salvage" populations. In sponsoring the meeting, the FDA was signaling their acknowledgment that data from trials leading to the approval of new drugs conducted in exclusively drug-naive populations are no longer as compelling as they once were and that trials with treatment-experienced individuals are not only acceptable for registration but are welcome.
Information from controlled trials about the use of drugs for heavily treatment-experienced patients would be extremely valuable to have. But for the pharmaceutical manufacturers, these studies pose difficult problems and hold significant risks. The rate of adverse events in "salvage" trials are likely to be relatively high since the participants have advanced disease and may be clinically less stable -- and a high rate of adverse events can make a drug look bad. For the same reason, drugs in these trials are also unlikely to show comparable efficacy to that seen in a treatment-naive population. Yet with sixteen antiretroviral drugs on the market, individuals with MDR virus are those most in need of new options.
In 1999, the FDA removed one obstacle to these trials by declaring that multiple investigational agents in a trial may be acceptable. In the past it had been presumed that more than one experimental drug would "muddy the waters" to such an extent that the FDA would reject any data from such a trial. The change was a big step forward, yet old beliefs lingered and some in the industry were slow to accept the shift in policy.
But allowing two experimental drugs in a study doesn't eliminate all problems. Imagine a situation where all participants in a trial receive optimized background therapy that includes one previously untried or experimental drug. Add to this either the study drug or a placebo. Those on the treatment arm may benefit from substantial viral suppression because they are getting two new drugs, but those on the placebo arm risk developing resistance to the single new drug in the background regimen.
One way past the "virtual monotherapy" problem is to offer every participant two experimental drugs in the background regimen, then randomize the third between placebo and the experimental drug the manufacturer is trying to have approved. This means that every participant will receive at least two new drugs with novel resistance profiles -- the minimum thought necessary to sustain suppression of MDR virus for more than a few months -- and some will receive three.
The complications are daunting. Interactions between HIV drugs are common and one drug may unexpectedly affect the blood levels of another. The source of common adverse events may be difficult to attribute to a particular experimental drug. Worse, an unforeseen serious toxicity might emerge that permanently taints every drug in the complicated combination.
Even with a green light from the FDA, the problem of gaining cooperation between multiple manufacturers remains. An experimental drug can only be provided by its manufacturer; it can't simply be purchased. This means that the sponsors of each experimental, but non-study drug, must agree to participate in the trial and supply their agents for free. So far it hasn't happened. Given the incentives for pharmaceutical developers to keep a tight rein on how their drug candidates are used, and the risks inherent in developing drugs in the MDR population, the barriers to launching optimal "salvage" trial designs are steep.
This is an expedient plan for rapidly bringing drugs to market and a plan favored by drug company representatives at the FDA meeting. Yet the risk of developing resistance during the short period of monotherapy worries community critics like Carlton Hogan of the Coalition for Salvage Therapy (CST). The CST has pressed for minimizing reliance on these studies, asking that periods of monotherapy be kept as short as possible.
One point was affirmed by all sides at the FDA meeting: Those in need of "deep salvage," -- those with absolutely no other options -- should not have to depend on clinical trials to get drugs. Compassionate use programs and expanded access should be widened to ensure that no one is left without hope of rescue.
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