The Bay Area Reporter - December 15, 1995
G'dali Braverman, ACT UP/Golden Gate Writers ' Pool

That single fact may serve as a clue as to why Saquinavir may be coming to market as a marginally useful therapy.

The advent of combination HIV therapy has grown out of a very basic principle: if a drug is good enough to take alone, than perhaps it will be even better when combined with existing therapies. Now the field is moving in the direction of approval of therapies that don't quite cut the mustard on their own.

This necessitates scientists, the government, and the patients taking a closer look at how such drugs work and why they stop working. Moreover, patients need to know that paying for a second drug correlates with some definable additional benefit, without unacceptable additional risks. Will T-cells go up, or viral load go down, more than they would have by simply trying some other "single" therapy for the first time? Will such benefits be sustained longer by adding this second therapy?

The data presented by Hoffmann LaRoche (the manufacturer of Saquinavir) are open to interpretation which may not clearly provide an answer of "yes" to the above questions.

Studying the AZT virgin

In the first study for which data was presented, Roche examined 92 AZT virgins: patients who had never before received anti-HIV therapy. The study was conducted in Italy and lasted 16 weeks. All patients had fewer than 300 CD4s (T-cells) prior to entering the study. Patients were randomly assigned to receive either AZT + Saquinavir (at one of three doses), Saquinavir alone at 600 mg. three times a day, or AZT alone. Based upon CD4s alone, the study demonstrated that Saquinavir was no better than AZT when taken as a monotherapy. The study was unable to statistically show a CD4 benefit for combo AZT/Saq over either monotherapy. Based upon reduction in viral load, the combo demonstrated a greater reduction at 16 weeks than either monotherapy. However, we have no data as to whether such a benefit was sustained post-study.

One shortcoming of the above mentioned study is that we now know that AZT is not the standard that should be used for comparison when considering patients who have never before been on an anti-HIV therapy. Recent NIH data shows that such patients are better off starting with either ddI or AZT/ddI combination therapy. While Hoffmann LaRoche can not be blamed for using AZT as the standard, a decision that reflected HIV standard of care when the study was first developed, patients and physicians do need to consider this fact in making treatment choices today.

To date there is no data to suggest that AZT/Saq is superior to ddI monotherapy or AZT/ddI combination therapy. Moreover, at $6,000 (wholesale) per year, Saquinavir provides a treatment option which, when used in combination with any other approved therapy, results in a minimum four-fold increase in cost over monotherapy. Fortunately, insurance companies don't force pharmaceutical companies to demonstrate that patients have a four-fold increase in CD4s. Hoffman LaRoche would face some major problems if this were the case.

Studies in the AZT-experienced

In the second study conducted by Roche, data on 423 patients who had previously been on AZT for greater than one year were presented. These patients were randomly assigned to receive 16 weeks of either Saq/ddC combination, Saquinavir monotherapy, or ddC monotherapy. It's important to note neither physicians nor activists consider ddC monotherapy a good treatment option. Curiously, while neither therapy demonstrated even a half log reduction in virus, ddC showed more virus reduction than Saquinavir. With respect to CD4 response, Saquinavir only demonstrated equivalence to ddC monotherapy. However, Saq/ddC combination therapy showed a mean T4-cell increase of 37 at 8 weeks into study.

Once again, doctors and patients will need to consider whether merely switching to or adding ddI might not be a better and cheaper option. There is more than 24 months of follow-up data on AZT pre- treated patients who were switched to or added ddI instead of remaining on AZT monotherapy.

Given Saquinavir's lackluster performance as a monotherapy, and the FDA recommendation that it be used in combination with an anti-HIV therapy to which the patient has not been previously exposed, it is difficult to feel fully confident that response to treatment reflects Saquinavir's "additive benefit."

Data from a third study only serves to make the matter more confusing, In this 24 week study 295 patients were randomly assigned to receive 24 weeks of either AZT/ddC/Saq triple combination or AZT/ddC or AZT/Saq. All patients had previously taken AZT for more than two years. Nearly 40% of patients had some previous ddC exposure. Despite the fact that participants had never been previously exposed to Saquinavir, patients receiving AZT/ddC combination had a greater reduction in viral load than those receiving AZT/Saq. Patients receiving the triple combination had a mean T4-cell increase of 34 at week eight. At 48 weeks about half of the triple combination group had T4 cells above the average T4 entry level.

Is a low dose, no dose?

While patients' treatment options are certainly broadening, it is difficult to feel excited about these less-than-dramatic advances. However, with respect to Saquinavir, one should not yet give up hope. There was a clear consensus at the November 7, 1995 FDA advisory committee meeting that this drug was being studied at a suboptimal dose. The committee was essentially stuck having to make a decision about a drug that might very well prove far more beneficial at higher doses. Studies are being conducted at Stanford University looking at up to four times the approved dosage.

Meanwhile, patients need to know that taking Saquinavir at 600 mg., three times a day, may very well mean that resistance will develop. Given data seen on other protease inhibitors, one could expect that such patients will not benefit from higher doses at some later date. This information might influence people at earlier stages of disease, who have not yet exhausted other treatment options, to delay the use of Saquinavir until either a new formulation or a higher dose of the existing formulation is made available.

What to know if you're choosing to take it now

For patients who have exhausted other options, or opt not to delay use of Saquinavir, the following information should be helpful. To get any absorption of drug, patients should be sure to take Saquinavir with a full heavy meal (not just a snack). Patients with malabsorption should be aware that studies of people taking Saquinavir in a fasting state showed no detectable levels of drug in blood.

The side effect of diarrhea should also be taken into account. Taking Saquinavir with grapefruit juice helps increase the level of drug in your blood. Conversely, taking with either Rifabutin or Rifampin significantly reduces the amount of Saquinavir in one's blood, This impacts one's choice of prophylaxis and treatment of MAC and TB. Finally, while Ketaconazole increases levels of Saquinavir, we have no data on the effects of Fluconazole.

ACT UP box:

ACTion UPdate:

As of December 7, 1995 Hoffmann LaRoche has established a reimbursement and assistance hotline for patients and physicians seeking to access Saquinavir. At this time the company appears to be ready to provide drug to those who are presently uninsured. At the price which the company has set for Saquinavir, all of us need to consider just how quickly we might reach our policy caps and join the ranks of the uninsured. If this drug is to be used at higher doses Roche may also be beckoning bankruptcy for the State AIDS Drug Assistance Program.

* Call (800) 282-7780 and let the company know the community will not tolerate such pricing. Remember, there are two other protease inhibitors just around the bend. Those companies are watching to see what the patients will swallow. Weigh the risks and benefits, don't be enticed by today's sweetened deals, and ACT UP, Fight Back, Fight AIDS and profiteering.

* ACT UP/Golden Gate meets every Tuesday at 7:30 at 592 Castro Street. Everyone is welcome.

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