PI Perspective #23

November 1997     View PDF     En español

On The Road Between Euphoria and Failure

Nearing the end of the second year of the “protease inhibitor era” patients, physicians and treatment activists are anxiously looking for clearer answers about the use of these new drugs. Thanks largely to the media, public expectations have been driven so high that no therapy could live up to the promises made for these drugs.

On the one hand, such optimism has brought a welcome renewal of hope. Carried to an extreme, however, it also contributes to a disturbing new carelessness about prevention, safer sex and the all too real risks still posed by HIV. It is disappointing indeed to realize that the improvements in AIDS therapy could so quickly lead to increased risk behavior and purportedly serious philosophical debates about such topics as “bare-backing.” In contrast to the optimism, however, are reports of high levels of treatment failure, leading pessimistic voices to renew their belief that all people with HIV remain doomed to an early death. From this perspective, it’s only a matter of time before all drugs fail everyone. Neither point of view serves as a useful basis for constructing effective long-term strategies against AIDS.

Those with the most optimistic views must come to recognize that even the best currently available therapies offer no cure and that they are not the ultimate solution to this disease. HIV-infected people should not assume that the current generation of drugs will work for the rest of their normal lifetimes, nor that these drugs can be used for decades without serious side effects, some of which we may not discover for years to come. The original hope of a few scientists that the drugs would result in eradication of HIV now seems unlikely, leaving only the option of life-time maintenance therapy—and no currently available drug or combination is good enough for that. In a broad sense, the present drugs will almost certainly fail over time. But this doesn’t mean that therapy, overall, is doomed to failure. Cheaper, less toxic and easier-to-use therapies must be developed before we can talk realistically about life-time management of HIV disease. Fortunately, such therapies will continue to be developed, at least as long as the pharmaceutical industry sees AIDS as a profitable market.

Whatever their limitations, the current generation of drugs represents a major advance over anything we’ve had before, and the full extent of their benefits has not yet been measured. In the optimal circumstances of controlled clinical studies and with careful adherence, the success of these drugs is surprisingly strong at two years out. Once people achieve truly “undetectable” levels of virus on the newer ultra-sensitive viral load assays, the development of drug resistance is dramatically delayed. We don’t know how long this can be sustained, but the duration is already being measured in years rather than months. Another unknown is the accumulation of long-term side effects. Recent findings about diabetes and other metabolic changes, such as redistribution of body fat, must be watched very carefully. However, despite widespread belief that these recently reported effects are associated with protease inhibitors, careful data collection is beginning to question this assumption. Preliminary analysis of several case studies suggests that the phenomena are not associated with any particular protease inhibitor, nor even with the class of drugs itself. Rather, it appears that these conditions may exist across the entire population of HIV-infected people.

Part of the dilemma for patients and physicians is that both sets of facts—the optimistic and the pessimistic—are true to varying degrees with different groups of people. But there is no way to predict how the matter is going to play out for any single individual.

Analyzing “Failure” Rate Reports
A few recent studies have reported “failure” rates on the new therapies as high as 53%, but such figures may be misleading if taken out of context. In the most widely quoted study, this percentage includes people who never responded in the first place and those who could not tolerate the associated side effects, as well as those who responded initially but later saw a return of detectable virus. It also includes a high proportion of people who reported difficulty adhering to the strict dosing regimens required by the drugs.

We’ve known all along that the drugs work much better in people who are just beginning treatment, compared to those who have been using therapy for years. We’ve known that it is difficult for many people to use the drugs precisely as prescribed and that any significant or repeated deviation from the prescribed program would contribute to hastened drug resistance. And it’s been clear from the beginning that side effects could interfere with peoples’ ability to use these drugs properly.

Considering all these things, it’s actually surprising that the drugs have worked as well as they have in so many people. Almost any AIDS hospital or practice in the country can confirm that the drugs have reduced death and disease rates dramatically.

When people report high “failure” rates in the context of such overwhelming evidence of success, it suggests that we need to take a very careful look at what is meant by “failure.” Typically, “failure” in recent studies simply means that a person using the drug either was unable to achieve “undetectable” levels of virus, or saw a return to “detectable” levels after initial success in making it “undetectable.” This is a very narrow and technical definition of “failure,” especially when it is accompanied by record low rates of new opportunistic infections and deaths. Failure is being defined solely as some degree of change in a laboratory marker, making no distinction between someone whose viral load reached 500 copies HIV RNA and someone whose viral load has soared to 5 million. It also doesn’t tell us if a person who failed one therapy was able to go on to some other therapy that brought viral replication back under control. It also doesn’t tell how many of the people in the studies had their best chances for successful long-term therapy wasted by early use of the original version of saquinavir. Use of this drug has now been clearly implicated as a cause of early failure on the drug itself and on subsequent, more potent protease inhibitors. In one study, prior use of the original version of saquinavir was identified as a primary predictor of failure for people using indinavir.

More importantly, it’s not clear what the clinical consequence is of seeing a return to measurable viral load. Evidence suggests that a rise in the HIV RNA level is not accompanied by an immediate return of symptoms or a loss of the improvement experienced in measures of immunity. It just means that the viral load has moved above a certain arbitrary threshold. Even though keeping viral levels “undetectable” is associated with the largest and longest lasting benefits from treatment, drugs and combinations which caused significant reductions in viral load (without achieving the goal of “undetectable”) were still associated with improved clinical condition and longer survival time.

We also don’t know how much of the reported “failure” is due to relentless, natural progression toward resistance, versus how much it is being hastened by non-adherence to the prescribed regimens. Without such data, it’s impossible to determine how applicable the reported “failure” rates are to people who are highly adherent. Clinical data suggest that people who can carefully adhere to “the program” have a much higher (though still not perfect) success rate.

Despite these uncertainties, we do know the answer to some questions about treatment failure and resistance. Most relevant are data from presentations at the Resistance meeting in the summer of 1997, in St. Petersburg, Florida. A key study there showed that when people achieved “undetectable” levels of virus on the new ultra-sensitive assays (measuring down to 50 or 20 copies of virus), they are very likely to have a long and successful run on their treatment regimen, probably measured in years. In contrast, those who never reached “undetectable” or, surprisingly, those who only reached “undetectable” on the older, standard viral load tests (measuring only down to 500 copies of virus), were likely to experience “drug failure” (rising viral load) within 6 to 12 months. The ability to reach “undetectable” status on either version of the test was greatly affected by the individual’s viral load prior to initiating therapy. If it was low to begin with, it was easy to keep it undetectable for long periods. The higher it was at the start, the tougher it was to reach “undetectable.”

What to Do?
What does this mean to people struggling to make wise decisions about the use of these new drugs? Here are a few questions people find themselves facing, and a few possible answers:

I’m doing OK for now, but am I doomed to see my drugs fail? How soon?
No currently available HIV treatment regimen is likely to last for a full normal lifetime and none has been shown to “eradicate” the virus. Until we can completely suppress viral replication, drug resistance is likely to contribute to treatment failure over time. How long it can be fully suppressed is uncertain. When people achieve undetectable levels on the new ultra-sensitive viral load tests, the durability of response is greatly enhanced and seems to produce a result beyond the initial expectations of most scientists. When the new therapies work and reach their goal, they seem to work remarkably well. If this is your experience, the message is clear: as long as you’re following the general “rules” about 3-drug combination therapy, just keep doing what you’re doing. If you’re one of the lucky few who at least temporarily achieve “undetectable” viral load on a 2-drug regimen, you might want to consider adding a third potent drug before your viral load starts to rise again. Since the new ultra-sensitive tests seem to be important for predicting durability of treatment effect, their availability must be hastened. Until that test becomes widely available, people can take some comfort in recent research that suggests that when people persist a year or longer at the “undetectable” level on the standard test, it’s quite likely they are also “undetectable” on the ultra-sensitive test. Your own adherence to your regimen will likely remain the most critical variable affecting the durability of your treatment.

What’s going to happen when the drugs fail?
We don’t know clinically when viral load returns to measurable levels, how quickly the immune system might be compromised again. We do know that it does not signal immediate decline to clinical illness or death. The rates of return to clinical illness and new opportunistic infections are nowhere near as high as the reported rates of “treatment failure.” There is plenty of evidence that even temporary success in suppressing viral load can lead to significant levels of immune restoration. The longer suppression of virus is maintained, the larger the improvement seems to be. It may be that clinical and immunologic decline simply lags behind the return of viral load by several months, but even if this is the case, it gives a cushion of time while awaiting new and better therapies.

Some virologists also believe that the highly mutated form of virus that evolves to resist the drugs is in many ways not as “fit” or destructive as the original “wild type” virus that most people started with. The virus has to pay a price, perhaps a high price, for accumulating all those mutations it needs to become resistant to the drugs. Collectively, those mutations may make fundamental changes in the virus and its capabilities. It may still be capable of replicating, but it may be diminished in other ways, such as its ability to damage the immune system. At worst, things would only be back to where they were before the advent of the protease inhibitors, with new drugs on the way.

When these drugs fail, will anything help?
Yes, there is hope that other things may help, but we need to be especially realistic on this point. Few people will have a good response on a second protease inhibitor after the first one succumbs to resistance. There is significant cross-resistance between all the protease inhibitors released thus far, no matter what drug company representatives claim. But when there is only a modest return of measurable virus, we needn’t think of resistance as a simple, on-off thing. It comes in degrees from high level resistance, which will cripple a drug, to low level resistance, which might be overcome by increased doses of the drug or changes in the companion drugs. Some level of resistance might be low enough to be overcome by a quick change to more aggressive therapy. Sometimes it can be overcome simply by finding two or more new, highly potent drugs that aren’t cross-resistant. And sometimes, viral load only reappears temporarily, likely in response to a secondary infection, and soon becomes undetectable after the infection has been cleared.

Beyond these points, there are a number of new drugs in the pipeline, some of which might be useful despite current resistance. For example, two new protease inhibitors in early clinical trials (GW141 in Phase II/III from Vertex/Glaxo Wellcome and PNU-140690 in Phase I from Pharmacia and Upjohn) are different from all current protease inhibitors and might offer the potential of being active despite resistance to the earlier drugs. Also, efavirenz (Sustiva, previously known as DMP-266), a powerful new non-nucleoside reverse transcriptase inhibitor which seems to work particularly well with protease inhibitors, is already available in small expanded access programs and should become generally available next year. There are also several new classes of drugs now in clinical trials. These include: T20 (a fusion inhibitor which has already shown activity against protease inhibitor resistant virus), integrase inhibitors and zinc finger inhibitors. Some new research is also re-emphasizing the potential of combinations which employ hydroxyurea. Of course, there’s also the whole field of immune restoration which should not be forgotten in our battle against this disease.

Is There a Bottom Line?
For those just contemplating therapy or currently using it successfully, the bottom line is to resist any tendency to swing back in the direction of hopelessness. Instead, this is a time to re-emphasize the importance of adherence and using therapy aggressively enough to fully suppress viral replication. Maintaining a positive attitude and taking decisive, informed and effective action are the only proven ways to get the greatest possible benefit from the available therapies.

For those already facing the prospect of “treatment failure,” however one chooses to define it, the bottom line begins with a staunch commitment to hope. It must include an aggressive pursuit of new options and inventive uses of old ones (see the article Strategies for Protease Inhibitor Failure). It means never succumbing to the defeatist notion that “there’s nothing I can do.” There is always something you can do—new therapies, new combinations, new trials and new outlooks. We may or may not ever find a true “cure” for HIV disease, but with each passing year, it is increasingly reasonable to expect to see successful lifetime management of the disease achieved within the current generation.

For the general public, HIV-infected or not, the bottom line here must be to take realistic stock of the imperfect but still advancing state of AIDS research. Everyone must understand that AIDS is not cured, not one person has seen his or her virus “eradicated,” and the fight is bound to go on for many more years. Excessive optimism and overselling the current state of therapy can harm people just as surely as HIV disease itself. It can diminish public support for research and funding for care. It can invite reckless behavior by people who falsely perceive the threat of HIV to be reduced. It can diminish the willingness of the pharmaceutical industry to invest in new and better solutions. And it can drive people to despair when all they hear is how well everyone else is doing, while their personal experience isn’t so rosy. Even when the new therapies work well, they add great challenges to the lives of those who must use them. Dealing with AIDS is far from simply taking pills.

Finally, until lasting and universal solutions are found, we must all recommit to prevention, which has at times been left on the sidelines in the wake of talk about “undetectable virus” and “morning after medications.” Those who today have come to think HIV disease “isn’t so bad” have an awful shock coming should they ever let such a misguided belief cause them to cross over the line to HIV sero-positivity.

Perhaps this new awareness of the limitations of treatment will be a good thing. It may ultimately help us get on with the business of making sure that better, safer and easier to use therapies become available as quickly as possible, and that everything that can be done to prevent new infections is being done.

LAST      NEXT

Strategies for Protease Failure