AIDS TREATMENT NEWS Issue #235, November 17, 1995
John S. James

The issue is complex, because early data suggests that saquinavir even at the low dose may cause less resistance and cross resistance than the other protease inhibitors to which it has been compared. The bottom line is that nobody yet knows whether using the current dose of this drug could cause loss of opportunities to benefit from better treatments later. Sentiment in the community seems to be that persons with more advanced disease may choose to try new treatments as soon as they are available, while others might decide to wait for additional information and options. Fortunately, a small clinical trial could quickly address the immediate questions about saquinavir.

Background

When protease inhibitors were first tried against HIV, many researchers guessed that it would be difficult for the virus to develop resistance against them. The protease enzyme, the target of these new drugs, is fairly small (it consists of only 99 amino acids), and it has a critical function in the production of new copies of HIV. Researchers had assumed that if the HIV protease changed its structure in response to a drug, the viruses produced would be defective.

But in fact, resistance to protease inhibitors has turned out to be a serious problem -- and a complex one. At least 11 of the 99 amino acids in HIV protease can change and still produce a viable virus. And resistance develops very differently to the different protease inhibitors now being tested in people; there seems to be no consistent pattern.

Is cross resistance serious with low-dose saquinavir, the first protease inhibitor likely to be approved? Two of the major companies now developing protease inhibitors -- Hoffmann-La Roche with saquinavir, and Merck & Co. with indinavir (Crixivan(TM)) a rival drug -- publicly disagree about the risk. The bottom line, which came out two days before the FDA Antiviral Advisory Committee meeting (at a drug resistance workshop sponsored by Project Inform and the Gay Men's Health Crisis), is that both sides are guessing; no one knows the answer. But we DO know how to find out; there is widespread consensus that a small clinical trial, combined with the proper laboratory studies, could within a few months answer the practical questions about using saquinavir. The issue now is whether these companies which are bitter rivals can cooperate enough with each other, or with the National Institutes of Health, to conduct the studies -- when everyone agrees that they need to be done, and everyone agrees that we know exactly how to do them.

Resistance and Cross Resistance: What Is Known?

While much remains unknown, some facts about resistance are becoming clear. While this information does not answer all questions about practical treatment decisions, it can help to clarify some of the issues.

* Drug resistance can be more serious with HIV than with most disease-causing organisms, for at least two major reasons. First, unlike bacteria, HIV ordinarily is never completely cleared from the body; it keeps reproducing for years and making new mutants, some of which will be drug resistant in ever-changing ways. Also, HIV reproduces very rapidly and also inaccurately (since retroviruses, unlike human cells, cannot edit the errors which occur when they reproduce), allowing new variants to develop rapidly.

* A drug can stop working for different reasons -- not only because the virus has become resistant. For example, the body can change its metabolism to resist certain drugs. Unfortunately, this "host resistance" has not been studied enough, and is poorly understood.

* Conversely, a drug can sometimes still be beneficial even after HIV has become resistant to it. For example, when persons are given too low a dose of the Merck protease inhibitor indinavir the viral load first goes down greatly, and the CD4 count goes up. But then in a few weeks or months the viral load comes back up toward its baseline value, because the virus has become resistant and the drug can no longer stop it from reproducing. However, the CD4 count often stays up, for months or more after the viral load has returned to its starting value. No one knows why this happens; it is possible that the resistant virus is weaker in some way and causes less damage.

* New resistant variants cannot develop unless the virus is reproducing. Therefore, if it becomes possible to shut off viral reproduction almost completely -- by using better drug combinations -- it might be possible to stop the creation of new resistant variants. But so far, this strategy has been difficult for several reasons. First, the drugs available today are not good enough to shut off viral reproduction sufficiently. Also, there may be reservoirs of virus in the body, such as in the central nervous system, where certain drugs do not penetrate well. In addition, if patients miss doses or take a "drug holiday," the virus can take advantage of this opportunity to start reproducing again. And finally, a person with advanced HIV disease probably has millions of HIV variants already, including variants resistant to the treatments they are using; these then only need to be selected for by the drug, not created by new mutations.

* Resistant virus is usually (but not always) less "fit" for survival in the absence of the drug. Therefore, if a person uses a drug and develops a resistant virus, and then stops the drug, most of the virus will usually go back to its original form. However, it seems that the resistant virus is not truly gone, but remains at a low level, too low to be directly detected. Therefore, if the drug is started again, the resistant virus will probably come back quickly.

* As with tuberculosis, it is usually much harder for HIV to develop resistance to a well-chosen combination of drugs which are started together, than to develop resistance to the same drugs one at a time. For this reason, when someone decides to start antiretroviral treatment, it is probably a mistake to start with AZT alone. It seems better to start with a combination, although it is uncertain what combination is best. Persons who have already used AZT extensively may need different combinations than those who are treatment naive (or in some cases they might switch to a single drug such as ddI). Sequences of combinations may be necessary, and some sequences are likely to work better than others. Much more work needs to be done to find out which combinations are best for which patients. (Meanwhile, viral load tests can indicate which combinations are working well for an individual, allowing treatments to be determined by trial and error.)

* Some treatment combinations are inherently difficult for HIV to develop resistance to. For example, 3TC is especially effective against certain AZT-resistant viruses -- which helps to make this combination a good one. (Today, however, it is known that HIV can become resistant to both AZT and 3TC.)

* There is probably no cross resistance between nucleoside analogs (AZT, ddI, ddC, d4T, 3TC, etc.) and protease inhibitors (saquinavir, indinavir, ritonavir, etc.) This is because these two drug classes act entirely differently, on different genes in different parts of the virus. When additional classes of drugs such as integrase inhibitors are developed, they also will not be cross resistant to the existing drugs.

* Because of the very different resistance patters of different protease inhibitors, new protease inhibitors may still be effective even if resistance develops to all the known ones. And sometimes the development of resistance to one protease inhibitor can make HIV more sensitive to another.

* The three protease inhibitors which are furthest along in human trials have very different patterns of viral resistance. With the Merck drug, the virus needs at least three (and preferably five) mutations to show resistance in laboratory tests. With saquinavir, resistance seems to depend on only one or two mutations, but these tend to develop slowly; after one year, most patients do not have virus with the genes known to cause the resistance. Both a higher dose of saquinavir, and use of that drug in combination with other antiretrovirals, seem to reduce the rate of mutation.

The saquinavir mutations are not the ones important for resistance to the Merck drug; whether there is significant cross resistance between these drugs is controversial (Merck says maybe, Roche says no). With the Abbott drug (ritonavir), many different mutations can cause resistance, but one in particular seems likely to develop first. Since that mutation seems to be inconsistent with the major saquinavir mutation, it is possible that combining these drugs could make it hard for HIV to develop resistance. (Caution: people must NOT combine these two drugs until a scientific trial is done, because it is likely that the dose of saquinavir will have to be drastically reduced, probably by many times, because ritonavir greatly raises blood levels of saquinavir by preventing it from being eliminated by the body. Today no one knows how much the dose must be reduced.)

Saquinavir Dose and Formulation

The saquinavir dose now being used in the major Roche clinical trials, and in the Roche lottery (600 mg three times a day, for a total of 1800 mg per day), is the only dose which the FDA could approve at this time. While it is widely agreed that this dose is too low, no one knows what the best dose might be, because the safety and other studies have not been done. About 20 people have taken twice the current dose (total 3600 mg/day), and 20 others have taken four times the current dose (7200 mg/day), in a small trial in Stanford University. The "maximum tolerated dose" has not yet been reached, meaning that the best dose might be even higher. The low dose was chosen at least two years ago, due to manufacturing supply and cost; a higher dose would have delayed the large phase III clinical trials, because of the time required to manufacture enough saquinavir to supply those trials at the high dose. Also, the high dose would have cost so much to manufacture that people could not have afforded the drug.

More recently, Hoffmann-La Roche has developed a new formulation of saquinavir, which is more efficiently absorbed when given orally, making higher blood levels feasible. This new version of saquinavir is now starting dose-ranging trials, which will determine the optimum saquinavir dose. Unfortunately, current plans call for the large clinical trials to continue with the existing small dose; there is even talk of adding more people to these trials (at the wrong dose), because without more volunteers the trials might not get statistical proof that low-dose saquinavir is beneficial at all. (It has been suggested that everyone in the trials could be switched to a higher dose with the new formulation of saquinavir, once a new dose is determined.)

The immediate practical question facing patients and physicians is whether this low saquinavir dose might cause more harm than good by helping HIV more quickly develop resistance to saquinavir, and possibly cross resistance to other protease inhibitors. With the Merck drug, the answer to this question would clearly be yes; too low a dose causes resistance to develop rapidly, and then the person cannot get the benefit of the higher starting dose even if they shift to that dose, and in addition they have become resistant to most other protease inhibitors. But saquinavir is very different from the Merck drug; resistance develops much more slowly even at the low dose (perhaps because the mutations which cause resistance are harmful to the virus in other ways), and it is unclear if much cross resistance develops. Also, laboratory studies have not shown cross resistance between saquinavir and the Merck and Abbott drugs. (There is cross resistance between saquinavir and AG1343, the experimental protease inhibitor from Agouron, probably because of chemical similarities between the two drugs.)

The FDA Antiviral Advisory Committee, at its meeting on November 7, recommended that saquinavir be approved only for use in combination with one or more nucleoside analog antiretrovirals -- and with the suggestion that these nucleoside drugs should preferably be ones the patient has not used before. Which drugs to use, and when to start treatment, are always individual decisions; some people do not have time to wait but need to start antiretroviral treatment immediately, and may choose to include saquinavir; those who have time may decide to wait until later, when there is more information, and perhaps better protease treatments (either from higher doses of saquinavir, or from other drugs or combinations).

The decision whether or not to use saquinavir will be much easier when a study is done to find out whether people who have been treated with low-dose saquinavir are more likely to be resistant to the Merck or other protease inhibitors -- or likely to develop resistance more rapidly -- than those who have never received saquinavir. As we noted above, there is no mystery about how to do this study. Also, it will not cost much, because it does not need to be a big "clinical endpoint" trial; instead, viral load testing can quickly show in a few volunteers if people who have used low-dose saquinavir are resistant to the Merck drug or not. At the November 7 meeting, spokespersons for both companies promised FDA Commissioner David Kessler that they would do this research, and would cooperate with each other when necessary. Treatment activists can make an important contribution by continuing to follow this issue, and pushing when necessary to make sure that the study gets organized rapidly.

[Note: For more information about protease inhibitors, and their potential when used properly, see "Protease Inhibitors and Prevention of Cross Resistance," by Jules Levin, AIDS TREATMENT NEWS #232 (October 6, 1995).

[You can contact the Protease Inhibitors Working Group by calling Jules Levin, 718/624-8541.]

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