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Being Alive
Developing Long-Term Treatment Strategies A Report from Project Inform

October 5, 1996
Being Alive 1996 Oct 5: 7

Studies of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) have begun to answer key questions about the treatment of hiv infection. It is tempting to wish for precise, cook-book style instructions, such as exactly when to start therapy, which are the best drugs to combine, and when therapy should be changed or stopped.

The history of medicine suggests that there will never be universal answers to these questions. There will always be individual differences in how people respond to specific therapies and how aggressively people choose to fight illnesses. The right answer for one person will not always be right for another, however similar their conditions may seem. Medicine is both an art and a science. Physicians and patients need guidelines and general strategies, not rigid rules. Earlier in the epidemic, loose strategies dictated by study designs were seen as "rules" of medicine or standards of care. This led many physicians to insist that everyone with CD4 counts below 500 be treated, while others just as rigidly chose to wait for counts to fall below 200. We now know that both approaches are sometimes right, sometimes wrong.

People with similar CD4 counts do not always have similar rates of disease progression or life expectancy. Studies of viral load have given us a clearer picture of disease progression and have shown that viral markers can be more predictive than CD4 counts alone. Even these do not tell the whole story for every individual. With this in mind, the new International AIDS Society guidelines for using viral load tests suggest that physicians assess multiple factors in treatment recommendations. They do not imply a rigid formula, recognizing that two physicians might easily interpret the same situation and lab markers quite differently. There is always a need for judgment and weighing of personal factors.

A few principles are becoming clearer from the protease inhibitor studies. Factors influencing medical strategies include what we know about managing other infectious diseases, like tuberculosis, as well as our growing understanding of viral resistance and hiv pathogenesis. Any discussion of strategy is, and is likely to remain, a mix of hard facts, judgment and opinion. Several factors and beliefs underlie the general strategies proposed here. They are an attempt to combine what has been learned in clinical trials with a core logic from the general treatment of diseases. Critics may argue that not all of these points are the subject of hard proof, but that is not a useful criterion for evaluation. Insisting that we know only what is considered absolutely proven is as short-sighted as pretending that we already know everything about hiv. It is important to take what is known from clinical trials and disease pathogenesis, combine it with the beliefs and expectations of experts and generate reasonable strategies for making treatment decisions. Some key factors and beliefs which drive the strategies suggested here include:  Achieving long-term successful use of therapies is more important than short-term gains. It is possible to get short-term benefits while ignoring or wasting potential long-term benefits.

 Reducing viral load as low as possible, preferably below the level of detection with the current tests, is the appropriate goal of anti-hiv therapy.

 Partially effective treatment is an engine which drives the development of viral resistance. Whenever possible, treatment which reduces viral load but still permits a continuing measurable level of viral activity should be avoided. Such treatment is bound to fail over time while leaving viral resistance in its wake. It makes sense to try to fully suppress viral replication if this can be done with a reasonable quality of life. When this goal cannot be achieved, people should realize they can still benefit from therapy and that long-term solutions may open up for them when additional therapies are available.

 People who are being treated for the first time have the greatest number of options. It is critical to think of the long-term picture when choosing from among those options. Failure to take a long-term view can result in rapid loss of options. A strategy should provide long-term benefits from the chosen therapies while preserving options for future use. An example of an ineffective strategy would be one which began therapy using single drugs or modest combinations which merely reduce, but do not fully suppress viral replication.

 The question of whether everyone should be treated immediately is not yet fully answered.

Many researchers argue that it is best to "hit it hard and hit it early"-an aggressive strategy of early intervention. They believe this preserves immune function, suppresses the development of drug-resistant viral mutations, and has the best chance of giving long-term benefits. This belief is reasonable based on knowledge of hiv biology. Yet others argue that the potential benefit must be balanced against unknown side effects of long-term therapy, long-term interference with quality of life, and the risk of using up options prematurely. This last concern has diminished with recent discoveries about slowing viral resistance and the rapid development of new therapies. An individual's ability to take the medications correctly also impacts on this strategy. Both the "very aggressive" approach and the "less aggressive" approach can be determined and supported as matters of reasonable personal choice. For now, neither has been proven "right" for all situations.

 Lessons from treating tuberculosis tell us that it is important to change or add two new therapies at the same time. The rule of "change by twos" is designed to best combat the development of viral resistance.

 Just adding a protease inhibitor on top of a therapy regimen which has been used for a few months or longer is unlikely to produce the highly potent benefits seen in clinical trials. The best results reported in clinical studies have always come when two or more new drugs are started together at the same time. It may be possible to achieve the necessary degree of viral suppression simply by adding a protease inhibitor in some situations, but this produces far less consistent results than changing at least two drugs simultaneously. It is unknown whether it is feasible to combine protease inhibitors with NNRTIs such as nevirapine and delavirdine.

 Drugs and combinations of drugs which have a larger, more consistent, and longer-lasting effect in reducing viral loads and increasing CD4 counts are likely to produce larger and long-lasting clinical and survival benefits. This has been repeatedly demonstrated in clinical studies.

Considerations When Selecting a Protease Inhibitor The three available protease inhibitors are radically different drugs. Each has a unique blend of activity, side effects, and drug interactions and must be selected carefully.

 Only ritonavir and indinavir should be considered as first-line protease inhibitors. Due to a formulation problem, the current version of saquinavir (Invirase) is not in the same class as these two drugs. Because it is very poorly maintained in the bloodstream, using the drug is equivalent to using a protease inhibitor at one fourth to one fifth the desired dosage. This is likely to produce significant and negative consequences in any long-term strategy.

 Indinavir has relatively few and infrequent side effects but can be complex to use. It must be taken three times daily, one hour before or two hours after eating. This requires people to plan their day and meal schedules around the drug. For some, this is quite intrusive. Taking indinavir with ddI is particularly difficult because of complicating food restrictions of both drugs.

 Ritonavir is easier to use for many people but creates difficult problems of side effects and drug interactions. It is an easier choice for people with busy schedules because it is used only twice a day and can be taken with food. This is offset by a very high rate of initial side effects (nausea, vomiting, diarrhea, numbness, etc.) which can also complicate life for people, whether busy or not. Many people who choose this drug abandon it within 60 days. Ritonavir and indinavir are highly cross-resistant (resistance to one causes resistance to the other) and partially cross-resistant to saquinavir.

 Claims that there is no risk of cross-resistance between saquinavir and other protease inhibitors are inaccurate. Data from the manufacturers indicate that at least 15% of the people who become resistant to saquinavir will have immediate high level resistance to indinavir and ritonavir. Anecdotal experience in the community suggests the risk may be higher. Even when it does not result in immediate cross-resistance, saquinavir use may, in theory, result in more rapid development of resistance to the other protease inhibitors once they are used. Of even greater concern are data from recent studies of high doses of saquinavir which have begun to show patterns of resistance similar to those of indinavir and ritonavir. Earlier studies suggested that saquinavir had a different pattern of resistance than other protease inhibitors.

Considerations When Selecting Nucleoside Analogues There are no mutations proven to cause resistance to d4T. This does not mean, however, that the drug will not fail. But it does suggest that it is unlikely to have problems of cross-resistance. Resistance to 3TC occurs almost universally in people who use it for 2 months or longer (except when it is initiated along with a potent protease inhibitor). Once resistance sets in, the drug remains useful only because the mutation which causes the resistance conversely increases the effectiveness of AZT and perhaps other nucleoside analogue drugs. Once resistance is present, 3TC loses its ability to directly produce large reductions in viral load.

The best results from combinations using AZT, protease inhibitors and 3TC only occur in people who initiate 3TC for the first time when they start the protease inhibitor. In this context, suppressing viral load below the limit of detection appears to prevent the development of resistance to 3TC. People in such studies have usually been AZT-resistant from the start. Thus, we are seeing the potent activity of 3TC combining with the very potent activity of indinavir or ritonavir. 3TC's impact on AZT is probably lost in this context as it is based on the development of a specific 3TC mutation which no longer occurs or is greatly depressed in the presence of indinavir or ritonavir. Such a therapy may only be acting as a 2-drug combination (protease plus 3TC). However, if indinavir or ritonavir is simply added to an existing regimen of AZT and 3TC (where 3TC resistance is already likely), the direct antiviral activity of 3TC may be lost due to 3TC resistance. Thus, such a combination is unlikely to give the suppression seen in the best studies.

Quality of Life Issues Tolerance is as least as important as the potency of a drug. If you can't take a drug consistently as prescribed, it is irrelevant how potent it is. Whatever the cause, lack of adherence to the protocol will quickly contribute to the development of drug-resistant mutations of hiv. When choosing a combination, consider how many total pills must be taken each day (antivirals and everything else), when they will be taken, whether they can be taken with other medications and whether they can or cannot be taken with food.

It is easiest to combine drugs which require similar conditions for their use (with food, without food, etc.) Otherwise, one's life becomes quickly dominated by drug schedules. Also, it is generally best to avoid mixing drugs with similar side effects, though sometimes this is impossible. And it is critical to learn about possible drug interactions before mixing any of these drugs. Qualify of life might benefit if the gains from new combination therapies improve the immune system enough to make it possible for people with advanced disease to eliminate their use of prophylactic medicines, such as septra or dapsone for PCP, etc. But current clinical experience suggests this represents an unwarranted risk-for now, prophylaxis must be maintained. Commentary Ideal combination strategies call for the use of fresh new drugs started at the same time. This is readily achievable for people beginning therapy for the first time. It is far more difficult for those who have used many therapies. Existing therapies can sometimes be juggled to achieve the desired effect. At other times, this is impossible. For some people, the best choice might be to delay using protease inhibitors or other new therapies until there are enough new drugs available to initiate an ideal combination. For most people, such a moment is seldom more than a year away. Several new therapies are on the near horizon which should make this possible. But getting there will require some people to resist the instinct to jump to each new drug as soon as it is available. Those who have fresh combinations at hand needn't hesitate to use them. Those who don't must consider the long-term implications of choices they make today. This shift toward long-term thinking is the true hallmark of this second decade of anti-hiv therapy. It must become a part of everyone's thinking. The alternative is the perpetuation of the short-term benefits and long-term failures characteristic of the last decade's approach to therapy.

All of this emphasizes the importance of a recent study which showed that people who received their medical care from physicians with a great deal of experience treating hiv infection actually lived longer than those who saw less experienced physicians. The complexity of treating AIDS has changed dramatically in the last year and the demands on the knowledge of physicians have increased proportionally. Whatever medical strategy a person chooses, it should begin with finding a physician who is experienced in treating hiv and who is wise enough to continue studying and learning from new developments in AIDS research.

(This information was provided by Project Inform. For more information contact the Project Inform Hotline, 800.822.7422.)