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Being Alive

Getting and Using Protease Inhibitors: Problems and Questions




 

Being Alive 1996 Apr 5: 1

As a service to our readers, we are printing the Special Alert from Project Inform titled "Critical Information about the Availability and Use of Indinavir (Crixivan) and Ritonavir (Norvir)" (see page 4). Though this alert is not comprehensive, we believe its basic thrust is well-founded. It gives information as to where to find further and future answers. My only caveat is that Project Inform has always been strongly in favor of drug treatment for HIV infection, providing advice and critical commentary about the best possible drugs and combinations available. Those who tend to be more skeptical or slow about initiating "state-of-the-art therapy" may well want to add as many "grains of salt" as they find helpful, and balance or supplement P.I.'s opinions with other sources.

To that end, let me contribute, for what they are worth, nine points I have gleaned from other sources including Internet comments of smart people, experiences of my friends and initial conversations with a few HIV physicians. One valuable source is Jules Levin, of the National AIDS Treatment Advocacy Project (NATAP) in New York City. Jules has devoted most of the last two years to following protease inhibitor development very closely, writing about it and acting as a community advocate with government and industry sources. Being Alive and NATAP have organized a major all-day forum in Los Angeles on protease inhibitors, which unfortunately is due to occur a few days after we go to the printer. We will bring you new information in forthcoming issues.

Protease Inhibitors are works in progress: be prepared for an uncomfortable level of uncertainty. Critical information is lacking to make decisions which many of us have to make anyway before complete data are available. If you feel you need to act soon to incorporate these promising drugs in your life, you will have unanswered questions and will have to take risks. Some of these key uncertainties are amplified below. Those of us involved in treatment advocacy must work with others to demand the focused research as rapidly as possible, while continually putting forth the best of what we know at a given point. Keep up with the evolution of our knowledge.

Beware of drug-drug interactions. The most urgent caution is not to combine saquinavir (Invirase) and ritonavir (Norvir) on your own. In lab tests, ritonavir was found to increase the blood level of saquinavir by 290 times (29,000%)! This fact may prove to be very helpful in increasing the problematic bioavailability of saquinavir, but right now taking both at the recommended doses is dangerous. Critical Path AIDS Project reported last week calls from four Philadelphia PWAs who were given this combination by an insufficiently informed physician and developed serious and life-threatening reactions.

Secondly, ritonavir has potentially adverse reactions with dozens of other commonly-used drugs. These include Seldane, Hismanal, Rifampin, Halcion, Valium, Tranxene, Xanax and Versed, and many more too numerous to list. The package insert lists many of them, but not all are yet known. Abbott, the manufacturer, maintains an 800 number for both providers and patients that can give you the latest information on drug interactions: 800.441.4987. The Project Inform hotline can also provide their frequently-updated Drug Interaction Fact Sheet.

Indinavir can increase the blood availability of rifabutin, and should be accompanied by a rifabutin dose reduction to ward off possible eye problems. Indinavir may also require dose modification of anti-fungal medications like ketaconazole, itraconazole, and the like.

Saquinavir may require dose modifications in rifabutin, rifampin, and the same "azole" anti-fungals.

Short-term side effects can be horrible, but seem to become tolerable after a while for most people. Ritonavir has the worst buzz so far, but many are willing to try it because its use is supported by the best data that it actually prolongs survival. Activist Carlton Hogan of Minneapolis wrote on the "sci.med.aids" Internet forum, "I...had quite spectacular nausea and vomiting, numbness running all the way down my throat, and taste perversion. Of all the drugs I have ever taken, this one feels the most similar to toxic waste." The company is now distributing a different, gel cap formulation which may help. Others have found that tapering up the dosage to full strength over a few days helps reduce the side effects. Many people recommend taking it on a full stomach, after a high-protein, high-fat meal. Yogurt may help some. A little ibuprofen seems to help. Usually the symptoms go away in two weeks or less, but some have reported that it took up to three months for symptoms to go away "95%." Overall, as many as 25% of people who try it are not able to tolerate it.

Indinavir seems to be better tolerated, but causes gastro-intestinal problems in some people and may cause kidney stones. However, the relatively frequent reports of kidney stones in earlier studies may have been mostly attributable to dehydration in fairly sick people. Drinking a lot of water (or taking it IV if you have to) is essential with this drug.

Longer term toxicities, like liver function abnormalities, will have to be closely observed. As is too typical, we know too little about whether there are some gender differences in toxicities and side effects that may pose special cautions for women.

Use the experience of others, but don't rely on just one. In reading Internet exchanges and talking to friends, I realize that there are more individual differences than there are uniformities, especially in the experience of side-effects. Anecdotal experiences of friends and support-group members and waiting-room acquaintances can be very helpful in picking up tips of what to expect and what to do about it. The danger, however, is being put off trying something that may help you based on the experiences of someone else which may turn out not to apply to you.

Resistance and cross-resistance are problems. We know that resistance (growth of strains of HIV that are immune to the effect of a drug) will develop in all known protease inhibitors; we just don't know how soon, how severely and what is the best strategy to minimize or counteract it. We do know that protease inhibitors should only be used as part of combination therapy. (Of course that's not to say you shouldn't try monotherapy if you're desperate and can't take or benefit from anything else, but all evidence showing effectiveness of this class of drugs is based on combinations with other antiviral drugs.) The best combinations we don't yet know. Inform yourself and consult closely with your provider.

Cross-resistance means that if you take one protease inhibitor, you can become resistant to a second protease inhibitor without ever having taken the second drug. Both Abbott and Merck agree that prior treatment with either ritonavir or indinavir will cause a large degree of cross-resistance to the other. If you use either one for a significant period, you may not benefit from later use of the other one, based on what we now know.

The story with saquinavir is more controversial. Roche (maker of saquinavir) and Merck (maker of indinavir or Crixivan) disagree. Merck believes that if one has used saquinavir first, one may develop resistance to indinavir more quickly. Roche says it ain't so. At FDA and community insistence, the two companies have agreed to conduct a special study to answer this question.

The same problem may occur with saquinavir and ritonavir, but for now establishing the safety of this combination is the first order of business in current studies. Ritonavir's manufacturer Abbott believes that the two drugs may have complementary resistance profiles that will produce a synergistic benefit in using them in combination, once they figure out the best and safest doses.

There is a potential for reversing resistance to protease inhibitors, as is believed to occur with the AZT/3TC combination (where it is believed that 3TC may reverse resistance to AZT which occurred earlier). Some reports say that another protease inhibitor in particular, one being developed by Glaxo-Wellcome, may have this ability. We will have to see, and to push Glaxo to investigate this possibility quickly and soundly.

When should you start taking a protease inhibitor? The answer is clear for those with high or rising viral loads as well as others no longer getting benefit from current regimens: as soon as possible. In earlier stages of disease, one has to go on the beliefs of you and your provider because they haven't yet been well-studied in people with higher T-cell counts (the clinical trials used for FDA approval were in people with no higher than 300 T-cell counts, usually much lower). A logical scientific argument can be made for including a protease inhibitor in a combination regimen started as early as possible, but this remains to be proven in the concrete. Other physicians recommend starting with other combinations and saving protease inhibitors for later. Whichever path is chosen, use of viral load tests can help you and your provider decide early on if your regimen seems to be working.

Other protease inhibitors are in the pipeline. Agouron's Viracept has been getting good reviews from many observers and the company may file for FDA approval this fall. The Glaxo-Wellcome Vertex protease inhibitor is also interesting. Pharmacia/Upjohn, among others, is also still hopeful about its candidate. You may want to hold off for further choices and more experience with the various drugs, if you are doing well with whatever you are taking (or not taking) right now.

Access: how can we all get 'em if we want 'em? The timing is a bear. These promising (if problematic) new drugs come out just as special funding for AIDS care has topped out and begun its decline, and all other forms of health care funding are under attack or being "downsized and economized." NATAP's Jules Levin has crystallized it well. The wholesale prices for a year's supply of these drugs are ritonavir-$6300, indinavir-$4380 (Merck decided to come in with a lowball price), saquinavir-$5800. This compares to a price range of $2000 to $3000 a year for each of the older, nucleoside analog drugs (AZT, ddI, ddC, d4T, 3TC). If one takes three-drug combination therapy that is now recommended, the cost easily exceeds $10,000 a year. Even with competition, the retail markup adds another 15-40%. Monitoring, especially with the new viral load tests that are expected to be FDA-approved very soon and thus widely available at $200 or more a pop, will add another two or three thousand a year at least.

About 30% of people with HIV are not insured and another 40% are covered under Medicaid (Medi-Cal in California). The AIDS Drug Assistance Programs (ADAP) serves about 20% of people in care for HIV, those uninsured or whose insurance does not pay for any or all drugs. Both Medicaid and ADAP are under attack; some state ADAP programs are already bankrupt and nearly all others are threatened. It is estimated than an additional $200 million will be needed for just the next fiscal year for adding protease inhibitors to the regimens of those who now use ADAP. Clinton has asked for an additional $52 million, which has passed the Senate but faces rougher sledding in the House. At the state level, Pete Wilson is refusing to ask for or release more funds for ADAP (it's about half state-funded and half federally funded). Good ol' Pete hasn't heard enough noise from us yet.

Some Medicaid and HMO formularies are refusing to add protease inhibitors until more is known about their optimal use or unless some other drugs are removed from the formulary (which means an approved list of drugs that a physician can prescribe and the patient can obtain, in a particular system or institution). We obviously have to fight for access or else a big chunk of us will never have the option of figuring out the best individualized drug therapy.

Get involved and keep yourself and others informed. Our efforts to provide the latest information to our community will be greatly assisted if you will send in your own experiences, observations and ideas about how to get and use protease inhibitors. We can then compile the information of our own direct constituency as well as that of researchers and advocates nationwide. Also, there are numerous urgent targets for public policy advocacy right now. We at Being Alive are gearing up our own unique advocacy voice and apparatus. Please call me or the office if you are interested.

P.S. I hope I haven't discouraged too many of you with all these problems and uncertainties. There is, of course, the possibility that the hope of protease inhibitors will turn to ashes, or be no more real in the long run than the hopes for AZT when it first came out. I don't think so, but we have to do the work implied above if we are to give these (and future) new drugs a chance to prolong our lives and energies.



 




Information in this article was accurate in April 5, 1996. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.