Project Inform - November, 1997

Perhaps the most important rule in such a situation is to seek highly potent, optimal uses of available therapies. This means it is often more important to wait to start two or more new drugs simultaneously than it is to take immediate action. In short, using HIV antiviral drugs correctly is more important than using them at any particular moment. Simply adding a single new or different drug is unlikely to help. The most recent information suggests that even adding two new drugs is seldom sufficient for people failing on previous regimens. Instead, the best chance of success may come from starting a completely new regimen. The earlier strategies also stressed the opportunity for people in this category to seek out clinical trials of truly new agents. Unfortunately, there often aren’t many clinical trials, or new drugs, to choose from.

Since the initial discussions of antiviral treatment strategies in PI Perspective #19 and #21, additional options have been identified; but there is only minimal data from clinical trials to support these approaches. In some cases, there are little or no data at all, but the following suggestions represent the weight of some degree of "expert" opinion or the case experience of primary care physicians. Since every case of "treatment failure" represents a unique medication history and different contributing factors, it is unlikely that any one approach will be universally successful.

In all of the following suggestions, emphasis is given to the choice of protease inhibitors and other highly potent agents, such as the non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine (Viramune®), delavirdine (Rescriptor®) and efavirenz (Sustiva®). These are likely to play the most important role because of their potency. Even though powerful new nucleoside analogue reverse transcriptase inhibitors (NARTIs), such as abacavir (1592), are becoming more available, existing evidence suggest they will offer little potency in people who have been heavily pretreated with other drugs of this type. Nonetheless, they may play some modest role in overall therapy when other drugs have failed. Preference should be given to those NARTIs which have been least used previously by the individual patient. If all NARTIs have had similar periods of use, a good strategy might be to give preference to the ones known to be slowest to develop resistance. At the top of this list are ddI (didanosine/Videx®) and d4T (stavudine/Zerit®).

Possible Approaches

Changing protease inhibitors (not very likely to be effective after drug failure). Assuming a person has developed true resistance to an existing protease inhibitor therapy, the likely effects of switching to any other protease inhibitor can be summed up in a few words. Such a switch is unlikely to result in significant or long-lasting additional suppression of virus. Switching protease inhibitors because of side effects or issues with taking the regimen is not the same as a switch due to resistance. Switching for reasons other than true resistance has a reasonable chance of success.

Studies have shown that neither indinavir (Crixivan®) nor the newly enhanced saquinavir (Fortovase®) is particularly effective in people previously treated with the original saquinavir (Invirase®). The same is likely to be true to switching to ritonavir (Norvir®) or nelfinavir (Viracept®). Similarly, only a very small percentage of people who switched from an existing protease inhibitor to nelfinavir in that company’s expanded access program experienced significant success. A more recent study showed that, contrary to the manufacturers claims, when nelfinavir fails after being used as a first protease inhibitor, people do not respond well to indinavir or ritonavir. Switching between ritonavir and indinavir is also unlikely to work in most cases. Project Inform has argued all along, people should assume that there will be significant cross-resistance between any of the currently available protease inhibitors, and there is little reason to choose one or another as the first therapy in hopes of avoiding cross-resistance. Clinical data now confirm this view across all possible sequences of the known protease inhibitors. There may be individual, but unpredictable, exceptions to this. As a general rule, people have only one good opportunity to use a protease inhibitor.

Combining protease inhibitors (not as easy as originally thought). The hope of combining two protease inhibitors for people who have developed resistance to an initial protease regimen is to overcome partial resistance by increased drug potency. However, little if any of the clinical experience has actually tested dual protease inhibitor combinations in this fashion. Most research has tested such combinations in people using protease inhibitors for the first time. Also, protease inhibitors have typically been combined at lower-than-standard doses in hopes of reducing toxicity, rather than at standard doses in hopes of increasing overall potency. Some specifics:

• ritonavir + saquinavir (Invirase® or Fortovase®) combination: While this is commonly used as a "salvage" strategy after failure of a first protease inhibitor, almost all the data supporting this combination comes from people who are just beginning their first use of a protease inhibitor. In the one known study tracking its use after initial protease failure, the combination was found to be effective only about 25% of the time, and even then, the results were not sustained for long. The potency of this combination should be the same whether using the old version of saquinavir (Invirase®) or the new version, because both result in the same levels of drug in the blood when used along with ritonavir.
• nelfinavir + saquinavir (Fortovase®) combination: Again, this is only supported by data in people using protease inhibitors for the first time. Its success in treating protease-resistant virus is unknown (and unlikely).
• ritonavir + indinavir combination: This is a very new avenue of clinical study, initially focusing on first-time users of protease therapy. The hope that might make this useful after initial protease failure is the sheer potency expected from combining two of the most powerful protease inhibitors, along with the fact that ritonavir should also dramatically increase the levels of indinavir. The proper or safe doses for this combination are not known and the risk is that when full doses of each drug are used, there may be significant side effects, similar to the effects of taking higher-than-standard doses.

Combining therapies for synergy (some anecdotal claims of success). This approach mixes drugs whose chemical properties or absorption into the body are enhanced when used together. The hope for this approach is to overpower partial resistance.

• delavirdine + indinavir combination: Although delavirdine has not been proven very effective in any clinical trial to date, it can effect the absorption of other drugs and increase their potency, much like ritonavir. It does a good job of increasing the levels of indinavir. A number of physicians report anecdotal success with this combination in people who have failed initial protease combination therapy. The two drugs are typically taken at their standard doses, though it is unclear what affect this has on toxicity. Particular care should be taken to watch for an increase in potential liver toxicity and kidney toxicity. Proponents of this approach report a fair degree of success in returning patients to undetectable viral load and sustaining this for 6 months or longer, even after initial failure on indinavir.
• efavirenz + indinavir combination: Studies in people first initiating protease inhibitor therapy have found this combination to be highly effective in suppressing HIV RNA levels. Although it hasn’t yet been tested in people with protease resistant HIV, the high potency offers the hope that it might be capable of overcoming partial resistance. It is likely that efavirenz will combine usefully with almost any other protease inhibitor as well.
• nevirapine + a previously unused protease inhibitor or dual protease combination: When employed along with one or two additional nucleoside analogue drugs, this approach seeks to overpower partially resistant virus.
• ddI + hydroxyurea + single or dual protease inhibitor combination, with or without a NNRTI (nevirapine, delavirdine, or efavirenz): Small studies have continued to confirm that the ddI/hydroxyurea combination offers unique properties and might work even in people with highly drug resistant virus. Of the NARTI drugs, ddI is perhaps the slowest to develop resistance and there is no known pattern of resistance affecting hydroxyurea. Some researchers also believe that d4T is slow to develop resistance and combines particularly well with ddI and hydroxyurea.

Experimental Approaches

• GW141 (a new Glaxo Wellcome/ Vertex protease inhibitor) plus abacavir (1592, a new Glaxo Wellcome NARTI) plus efavirenz (a new Dupont Merck NNRTI). A small nationwide clinical trial of this combination will begin before year’s end, targeting people who have failed all existing therapies. In laboratory studies, GW141 does not demonstrate cross-resistance with other protease inhibitors, and abacavir shows only partial cross-resistance to 3TC and ddI. Thus, this combination theoretically offers hints of good potential, even in a protease inhibitor resistant population. However, an early pilot arm of this study combining just the GW141 and abacavir did not appear to work well. Only time will tell if adding the third new drug, efavirenz, will change the outcome.
• AR177 (Zintevir®, an integrase inhibitor from Aronex) plus adefovir (Preveon®, a new type of RT inhibitor from Gilead Sciences) plus efavirenz. While this approach sounds intriguing because it combines two new classes of drugs (an integrase inhibitor and a nucleotide analogue), neither AR177 nor adefovir has shown much potency as individual therapy. Nonetheless, the overall combination still warrants careful study.

A Final Word

Virologic failure doesn’t necessarily mean clinical failure. Were this the case, we should already be seeing a great reduction in the clinical benefits of treatment, but this is not the case. Rates of new opportunistic infections and death remain at an all-time low, despite the growing incidence of virologic treatment failure. Many people assume that when they run out of options capable of completely suppressing viral load, they might as well go off their current antiviral therapies. Some even believe this will be helpful, based on the theory that this will permit their virus to regain sensitivity to the drugs. Most researchers dispute this view, pointing out that once resistance occurs, some quantity of virus with the resistant properties will always be retained and will quickly reassert itself. Many researchers also believe it is a mistake to discontinue therapy even when all possible combinations no longer seem able to suppress viral load below pre-treatment levels. They argue that even when all available therapy options have failed to suppress virus, it may still have an important effect. In this situation, therapy continues to shape or control the pool of virus, permitting only the growth of the mutated, resistant strains while blocking growth of more potent "wild-type" virus. The "wild type" is the natural state of HIV, the condition it prefers and in which it is most potent. Virologists believe that for each mutation a virus accumulates in the body, it pays a "price," forcing it to deviate from its preferred, natural state. While highly mutated virus may still be able to replicate to some degree, it is not clear that it is still as capable of harming the immune system.

However, other virologists worry that continuing on therapy when it appears to be "failing" virologically, may encourage the accumulation of even more mutations. This could make it more difficult for future drugs of the same classes to work, should such drugs come along. These arguments make sense only if new drugs of the same classes come along which aren’t cross-resistant to existing drugs. So far, in protease inhibitors, this has never been the case. In situations like this, people are forced to make a gamble, choosing between effects of the known, available drugs and the unknown effects of future drugs. Just which choice results in the longest survival is unknown.

There is considerable initial evidence that people retain immunologic benefits from therapy long after losing the battle for complete viral suppression. Also, some virologists suspect that when patients see only a modest and stable return of measurable virus, without returning to the pretreatment levels, the PCR test may be measuring defective, mutated copies of virus rather than productive virus capable of reproducing itself. For any of these reasons, it may be important to continue to use therapy to keep virus in its "unhappy" state. True loss of virologic control still does not imply complete return to the devastation of AIDS. In short, even when all options "fail" (by today’s definitions), hope is not lost.

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The original of this article can be found at http://www.projinf.org/pub/23/pifailure.html