AIDSWEEKLY Plus, 19 August 1996
Daniel J. DeNoon, Senior Editor
It says so right there in the patient-information section of the package inserts for the three U.S.- approved protease inhibitors: saquinavir (Hoffman-LaRoche's Invirase), indinavir (Merck's Crixivan), and ritonavir (Abbott's Norvir).
This remains true despite the widely held belief that people with HIV infection can indefinitely postpone disease by adding an HIV protease inhibitor to their treatment regimens.
There is solid evidence in support of this idea: as many as 90 percent of clinical-trial participants who receive a protease inhibitor plus zidovudine (AZT) plus lamivudine (3TC) have had their HIV burden reduced to undetectable levels. Other drug combinations which include protease inhibitors also appear to be effective.
This effect has been sustained for about a year in a number of trial participants and shows no sign of abating - as long as people continue to take the medications without fail.
There is every reason to be greatly encouraged by these findings. But there are substantial downsides. These are compliance, adverse effects, and cost.
In early trials of protease inhibitors participants received what are now known to be suboptimal dosages. HIV readily developed resistance to the new drugs. Once the virus became resistant to a protease inhibitor, even higher doses remained ineffective.
And there is in vitro evidence of cross resistance between these drugs, although the extent of cross resistance remains controversial.
The specter of resistance means that patients can neither miss doses nor reduce dosages.
"This is one of those cases where it's very important for the patient to take the drug religiously and to avoid drug holidays," said Jonathan Schapiro of Stanford University at the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.
Schapiro and colleagues found out that the reason why some people gradually stopped responding to saquinavir was that they were missing doses. This was not hard to do: the drug must be taken six times per day.
Indinavir must be taken three times daily and ritonavir twice daily. It is not known exactly how often a patient can slip, but New York University researcher Roy Gulick told AIDS Weekly that he suspects compliance issues are the reason why some patients did not respond to indinavir/AZT/3TC therapy.
Several clinicians interviewed for this article were openly worried about being able to communicate to their patients the extraordinary urgency of strict - or as Schapiro put it "religious" - compliance.
Compliance would be difficult enough if simply remembering to take the drugs were the only problem. But even relatively healthy patients can have problems tolerating some of the protease inhibitors and/or other drugs taken in combination.
Particularly severe side effects have been reported for ritonavir; these can include nausea, diarrhea, vomiting, anorexia, and circumoral and peripheral paresthesias. Indinavir is associated with the development of kidney stones, and patients are advised to drink large quantities of water.
Patients unable to tolerate protease inhibitors are advised not to scale down their dosages but simply to stop taking the drugs until the side effects pass and dosing can resume.
Abbott has been singled out by the patient advocacy group ACT UP for the high price of ritonavir (the company received the dreaded Golden Urn award, signifying actions believed to be hastening the deaths of people with AIDS). But all three protease inhibitors are extremely expensive, limiting availability.
AIDS is a disease of poverty. The vast majority of people with HIV infection will never receive a single dose of a protease inhibitor. The drugs' high cost also raises the ugly possibility that some people may have to stop taking the drugs when their money runs out.
One factor contributing to the expense is the high dosages of these complex molecules needed to overcome protein binding. The drugs must be taken daily in gram quantities.
According to Michael Seggev, manager of public affairs for Merck, indinavir is the least costly of the three drugs at a cost of $12 per day. This is 25 percent less than saquinavir ($15.89 per day) and 33 percent less than ritonavir ($17.80 per day) but still adds up to $4,380 per year not counting the costs of AZT, 3TC, or other drugs used in combination.
Seggev said Merck is preparing for a huge demand for indinavir. As of July 1996, the company was capable of manufacturing enough drug for 40,000 people. The company has retrofitted one production facility to produce the drug and is building another from the ground up.
By early 1997, Seggev said, the company will be able to manufacture 250,000 doses and by the end of 1997 expects to be able to meet all demands. This will represent 20 percent of the total drug volume for Merck.
Seggev said that indinavir is priced as fairly as is possible and that cost reductions are not anticipated.
Without doubt, new and improved protease inhibitors will come to market. A better saquinavir is already in the works, and the Glaxo protease inhibitor currently in clinical trials looks very promising, if not less expensive. Protease inhibitors with better pharmacokinetics could be given in smaller doses, thereby reducing cost and perhaps increasing compliance by reducing adverse effects.
If it turns out to be impossible to eradicate HIV infection with better protease inhibitors in better combinations, the question of how long HIV can be suppressed becomes important.
What will happen to patients who overcome the cost, side effects, and compliance issues and keep HIV at very low levels for many years?
One rumor making the rounds at the Vancouver AIDS conference may be relevant.
This anecdotal report holds that a chimpanzee experimentally infected with HIV nearly a decade ago suddenly developed high viral titers - after consistently exhibiting undetectable levels of virus - and had a precipitous drop in CD4 cells.
If true, there may finally be an animal model for AIDS - and, perhaps, a model of what might happen after years of HIV suppression by combination therapy with protease inhibitors.
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