GMHC Treatment Issues, Volume 10, Number 5 - May 1995
Dave Gilden

Zero plus Zero Equals One

On May 7, Hoffmann-La Roche released the final clinical data on its North American trial NV14256. Preliminary surrogate marker (viral load and CD4 count) from this 1,000-person trial were presented to the FDA last fall as part of the package supporting marketing approval of the drug (see Treatment Issues, November 1995, page 2 and December 1995, page 2). The trial tested saquinavir plus the nucleoside analog ddC (also a Roche drug) against either drug alone in volunteers previously treated with AZT. The initial surrogate marker data made the combination look only slightly better than saquinavir or ddC monotherapy. This observation was a big disappointment considering that protease inhibitors are supposed to be a powerful new drug class whereas tolerable doses of ddC have weak antiviral activity even compared to other nucleoside analogs. At the time, Treatment Issues concluded, "Saquinavir's main advantage is that it is a relatively benign way of slightly boosting the mediocre performance of nucleoside analogs--but the retail price is $7,200 per year!"

The new data on progression to AIDS and deaths (final surrogate marker data have yet to be released) document the extent to which saquinavir supplements nucleoside analog therapy. Once again, ddC and saquinavir monotherapies came out nearly the same, but the combination therapy results exhibited greater superiority over monotherapy than one would expect from the available surrogate marker data (see table).

The ddC/saquinavir combination produced an immediate, sustained median viral load reduction of about 0.6 log (75 percent), compared to little to no long-term reduction for either drug alone. As was the case in a previous trial of AZT plus delavirdine (see Treatment Issues, January 1996, page 6), a threshold leading to significant clinical approval may have been crossed when the induced drop in HIV levels exceeded 0.5 log.

A major limitation of the NV14256 trial is that one still cannot tell how saquinavir plus ddC stacks up against the more potent nucleoside analog combinations (for example, d4T plus 3TC or ddI or AZT/3TC) in the advanced, AZT-experienced population under examination. The ongoing international trial comparing AZT/saquinavir to AZT/ddC to the triple combination in treatment-naive volunteers will partly fill this gap. Roche has developed a new "soft gel capsule" formulation of saquinavir that is much better absorbed by the stomach. It is hoped that this improved version will help the compound fulfill the anti-HIV potential it displayed in the lab. A 400 person, 48-week trial of the soft gel capsule plus participants' choice of nucleoside analogs is now fully recruited. The saquinavir dose used in this trial (1,200 mg three times daily, twice the current recommended dose of the present formulation) achieves peak blood levels eight times that attained by the current regimen with the marketed formulation.

A trial combining saquinavir with ritonavir is also in progress (see last month's Treatment Issues). Adding ritonavir inhibits breakdown of saquinavir by the liver and can raise saquinavir blood levels ten-fold. Combining the two protease inhibitors probably would allow for reductions in the recommended dosing of one or both drugs while enhancing their anti-HIV efficacy.

Both Gay Men's Health Crisis and Project Inform have written Roche asking the company to stop promoting and pricing the saquinavir now on the market as if it were equivalent to other protease inhibitors instead of just a "kinder, gentler ddC." At the same time, they asked that the company accelerate its efforts to bring its protease inhibitor up to the original expectations for it.

Roche officials profess great optimism about saquinavir's future. Franz Humer, the head of Roche's pharmaceuticals division, told Financial Times (London) that saquinavir would become a blockbuster drug for the company, according to the paper's May 7 edition. He predicted that annual sales of saquinavir would reach $160 to $400 million within five years and that total sales of all Roche HIV-related treatments would be as much as $800 million at that time.

The Incredible Shrinking Markup

One of the fears about widespread use of suboptimal saquinavir is that such exposure will start HIV on the evolutionary pathway to resistance to both higher doses of saquinavir and to other, more potent protease inhibitors, specifically Merck's indinavir (Crixivan). Merck, which just started selling indinavir at the end of March, reported that 13,000 people were taking the drug by mid-May. Rapid emergence of indinavir-resistant HIV would threaten what is becoming a very popular product.

To gauge the extent of this threat, Merck is planning a trial of indinavir's efficacy in individuals with at least one year's prior saquinavir therapy. This six-month open-label study will test indinavir versus both old and new formulations of saquinavir. Merck is also planning dose- ranging and safety trials of indinavir and saquinavir combined. Other upcoming studies include the effect of taking indinavir with meals (currently not recommended), twice daily dosing versus thrice daily (the present recommended schedule), maternal-fetal HIV transmission and indinavir for early HIV infection (CD4 count over 500). Trials in infants are being held up by Merck's inability to produce a palatable liquid formulation.

The rapid growth of indinavir sales has raised the threat that supplies will run out for new patients attempting to obtain the drug. Until full-scale production facilities build up an adequate inventory (expected by the end of this year), Merck will fill prescriptions for only about 30,000 Americans, to whom it will guarantee continuing drug availability. The final 2,500 of these slots are reserved for people with CD4 counts below 50, on the assumption that this is the population with the most urgent need for a new and potent therapy.

To ensure a steady supply of indinavir to its clientele, nearly all prescriptions are being filled through Stadtlanders' pharmacy, a mail-order firm based in Pittsburgh, Pennsylvania. In addition to filling orders, Stadtlanders' is supposed to monitor supply, make sure customers receive refills in a timely fashion, and arrange with insurance companies and other third-party payers for direct reimbursement.

After some start-up troubles, the system is operating fairly smoothly, most people report, although the turnaround time for orders is at least four days, and can be several weeks, not the 48 hours Merck originally envisioned. The biggest controversy has been the price Stadtlanders is asking. Merck's wholesale price for a year's supply of indinavir is $4,380, and Stadtlanders originally wanted $6,022.50 retail for the same amount of drug. This exceptionally high 37.5 percent markup was a disappointment considering that Merck seemed to be intentionally limiting its per unit profit in order to create a larger total market for indinavir. The retail price sparked wide protests and calls for a boycott especially from ACT UP chapters in New York, Philadelphia and San Francisco (ACT UP/Golden Gate) as well as the PWA Health Group, also in New York City. Stadtlanders immediately argued that 80 percent of patients on indinavir were receiving a substantial discount due to negotiations with their reimbursers (HMOs, Medicaid, etc.).

Stadtlanders eventually agreed to provide similar discounts to cash customers who hold a discount card from the Community Prescription Service -- another mail-order pharmacy. (Call 800/842-0502 to obtain the card, which costs $18 annually.) With the addition of this measure, most people will be charged a retail price representing a more normal fifteen percent markup. The main exception is purchasers with traditional medical insurance whose carriers pay Stadtlanders directly. Those insurance companies will still pay full price. (If the purchasers pay Stadtlanders and then apply on their own for insurance reimbursement, they could receive the discount.)

Stadtlanders maintains it has to preserve the high official price as a benchmark for the discounts many third-party payers customarily receive. While Stadtlanders made sure it received an adequate return for the temporary distribution program, it lost considerable good will in the process.

There remains the issue of side effects experienced by the general population, rather than the more restricted cohorts in clinical trials. In a posting on the Internet's "Crixivan E-mail Discussion List," Kiyoshi Kuromiya, director of the Critical Path AIDS Project in Philadelphia, commented on his own personal experience as well as that of others. He wrote, "I think. . . that the incidence of 'flank pain,' crystalluria, and kidney stones is much higher than the three percent that Merck predicts. . . It can happen within hours of taking the Crixivan with insufficient water. It can lead to pain (that resembles acute appendicitis or severe gas pains) which may resolve after a few hours (ten in my case) on its own. Or it can lead to problems over a few days or weeks or months." To prevent the precipitation of indinavir in the urine, Mr. Kuromiya recommends ingesting the medication with several glasses to a quart of water.

Merck officials profess to be mystified by such remarks, which they consider exaggerated. (It remains, though, that Merck advises people taking indinavir to drink an extra two quarts of water a day to preclude indinavir deposition in the kidneys, which can cause considerable pain.)

Ritonavir Plus Other Drugs

Abbott, with the most expensive protease inhibitor of them all ($6,500 a year wholesale) claims to have a similar number of protease inhibitor clients as Merck does. Despite speculation that a price cut is imminent, the company says no such move is planned. The only hope Abbott publicly holds out for lessening ritonavir's cost is that it might eventually be possible to combine it with saquinavir. This still highly experimental combination might allow some reduction in the standard ritonavir dose, but saquinavir is nearly as expensive as ritonavir. The final cost of this combination cannot be predicted at this time and could well be more than ritonavir alone (though the benefits might be greater, too). Some data on ritonavir/saquinavir will be presented at the International Conference on AIDS this summer.

Officially, about twenty percent of those who start ritonavir therapy discontinue it. The main reason is nausea and diarrhea. In addition, the problem of ritonavir's interactions with other drugs has confused and troubled many care providers and patients alike. Abbott has sent at least two different cards to practitioners outlining drug-drug interaction information. It also has a 27-page document on the subject for investigators taking part in ritonavir clinical trials.

The table on page 6 summarizes the feared interactions. Of particular concern is ritonavir's effect on most antidepressant drugs, whose blood levels ritonavir probably increases, and on estrogen-containing birth control pills, whose blood level is reduced by 40 percent (all other steroid hormones, including progesterone-based birth control, testosterone, anabolic steroids and corticosteroids, are probably increased).

Most of these interactions are theoretical, as actual studies have been conducted with only a handful of compounds. The information in the table is largely derived from predictions based on ritonavir's mostly inhibitory effect on different metabolic pathways in the liver and on other drugs' breakdown via these pathways. In particular, drugs broken down by the CYP3A or CYP2D6 pathways, which ritonavir blocks, have increased concentrations in the body, requiring careful monitoring for toxic effects. Conversely, blood levels of some medications are raised somewhat because they are broken down by liver enzymes whose activity ritonavir induces. Such drugs may require dose increases to maintain their effectiveness.

Coming Up: Does One plus One Equal One?

The problems with ritonavir promise to become a less serious issue upon the arrival of the second generation protease inhibitor Abbott now has under development. Known as ABT-378, the compound is said to be more powerful than any of the current protease inhibitors and to be relatively unaffected by the HIV mutations conferring resistance to the ones currently on sale. Human testing is scheduled for later this year, with the first information on any in vivo improvements in toxicity and efficacy available in December. (Merck, too, has an active second generation protease inhibitor program.)

Finally, more early clinical trial data were released in May on Agouron's experimental protease inhibitor, nelfinavir (brand name: Viracept). After 16 weeks on nelfinavir monotherapy, twenty volunteers experienced average viral load drops of 81 to 99%, depending on dose (the reduction at four weeks was 95 to 99%). CD4 counts went up by an average of 115 to 170. In a 36-person study of nelfinavir plus d4T, average viral load drops over 98% were observed for each of the three nelfinavir doses at 60 days, while CD4 count increases averaged 105 to 130. These data may sound impressive, but numbers of trial participants and duration of follow-up are small. The current larger trials eventually will provide sounder information. Although the present figures allow no definitive conclusion, it is curious that nelfinavir with or without d4T yielded substantially the same results. One plus one seems to equal one in this case.

A marketing application for nelfinavir is expected to be filed with the FDA early next year. With a variety of other protease inhibitors also on the way, we can expect that our lessons in protease inhibitor arithmetic will continue.

Table 1. Final Clinical Data from NV 14256 - AIDS-Defining Events

Regimen	or Death	Death Alone
ddC	85	28
Saquinavir	77	34
Saquinavir plus ddC	46*	9*

*statistically significant compared to the two monotherapies characteristics of participants:

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