Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
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GMHC Treatment Issues, Vol. 10, No. 3 - March 1996
Dave Gilden and Theo Smart
The advisory committee worked on the assumption that there is a correlation between these two, that HIV level and physical health are closely linked. It ran into difficulties when that logical assumption was contradicted by the facts. Similarly, the committee assumed that combination antiviral therapy was better than single agent therapy and reacted with considerable consternation when it found that this is not always so.
Meanwhile, any assumption that all barriers to rapid drug approval were down in the agency was countered on March 1, when the metabolic and endocrinology committee voted to reject the Serono Laboratories application for recombinant human growth hormone as a therapy for AIDS-related wasting (see page 6). FDA reviewers' disparaging dissection of the company's trials derailed the approval process and underscored that the FDA considers anti-HIV drugs a special, urgent case.
The day after the Abbott protease inhibitor ritonavir (brand name: Norvir) received its approval recommendation, FDA officials announced that they had officially approved the drug. Two business days later, Abbott shipped its first lots, with a one year supply for an individual costing wholesale distributors $6,500 (leading to a retail price of about $8,000). Official approval for Merck's indinavir (brand name: Crixivan) came two weeks later, as that company prepared its distribution system (see box, page 4). Merck is "only" charging $4,380 wholesale for a year's supply.
Viral load testing, central to optimizing and occasionally adjusting treatment regimens in each person, now seems to be on the FDA fast track, too. The FDA's Blood Products Advisory Committee took up the Roche Amplicor PCR test for viral load on March 21. Roche was originally asking for only a diagnostic approval for this assay (to detect simply whether someone is HIV-positive or -negative). With the FDA's encouragement, the company expanded its request to include approval for monitoring plasma HIV levels for the purposes of predicting disease progression and measuring treatment benefit. Chiron filed for approval of its bDNA test this month, but at press time the advisory committee has yet to schedule a hearing on the application.
It was clear during the advisory committee's second day that ritonavir had a demonstrated ability to extend survival and delay new opportunistic infections in people with advanced disease, at least for six months. Lack of long-term safety or efficacy data, surprisingly meager drug interaction test data (ritonavir's package insert contains a long list of untested "potential" interactions) and the sparseness of the data in early disease strongly influenced the committee's recommendation. While accepting that ritonavir was eligible for full approval for people with advanced HIV infection, the committee recommended that the FDA grant only accelerated approval for use of ritonavir in patients with early HIV infection. It sought further studies to evaluate this patient population.
The case for ritonavir in early disease was not aided by the new and perplexing surrogate marker data in less advanced patients, which indicated that although ritonavir was better than AZT, the combination of ritonavir and AZT was no better than ritonavir monotherapy (see table). Worse, ritonavir alone suppressed viral load more than the combination arm, and this difference was statistically significant. Why might ritonavir monotherapy outperform combination therapy? Abbott believes that this was due to lack of compliance, (the study used the old nauseating liquid formulation of ritonavir, now succeeded by capsules) and that adding AZT -- which frequently also causes nausea -- made the drug even harder to tolerate. Plasma levels of ritonavir were 50 to 70 percent lower in the combination arm than in the monotherapy arm, presumably because the people already nauseated by AZT recoiled more from taking the foul elixir. Treatment discontinuation due to adverse events was extremely high in the combination arm, 38.8 percent.
The underlying problem with ritonavir is that its toxicities limit the allowable dose to 600 mg twice a day. This is probably not the optimum dose as far as anti-HIV effect is concerned -- 600 mg suppresses HIV more than 400 mg, and 800 mg could well be more active still, if it could be tolerated. Beside the mostly gastrointestinal side effects listed above, ritonavir is a very potent inhibitor of the liver enzymes that break down many other medications. Ritonavir's possible interactions with the other drugs worried the committee: the magnitude of many of the predicted drug interactions has not been measured in people, and their potential danger should not be underestimated. The committee also expressed concern about increases in liver enzymes and lipids (triglycerides) in the blood since such increases are often predictive of long-term damage to the liver and pancreas.
There are almost no data available on the safety of ritonavir past six months. Nor are there much data about durability of effect beyond this time period. The consensus of the committee was that the goal of therapy now is to safely suppress HIV, by as much and as long as possible, with either single or multiple agents. Higher and possibly more potent doses of ritonavir were too toxic to use in people. If the "tolerable" ritonavir dose turns out to be too low to support lasting antiviral activity, the emergence of ritonavir- resistant HIV could become a pitfall for the drug, particularly in those who begin treatment early.
Representatives from the FDA, clearly poised to approve ritonavir immediately, worked late into the night with Abbott officials to hash out an accord. The next day, when announcing the formal FDA approval of ritonavir (which conformed with the advisory committee's mixed accelerated/full approval vote), David Feigal, head of the FDA's antiviral division, read a letter from Abbott vice- president Andre Pernet making the following commitments: 1) continued long-term follow-up of both the late and early stage disease studies to gather long-term clinical efficacy and safety data, 2) the launching of a clinical study in pediatrics and 3) the establishment of a ritonavir/saquinavir study evaluating safety and duration of antiviral effect out to at least a year or a year and a half.
Actually, the company had already mentioned plans for the second and third points during its presentation to the advisory board the previous day. During that session, the Pediatric AIDS Foundation bitterly denounced Abbott for its neglect in investigating ritonavir for children (with the one small children's trial having enrolled no one under two). As for ritonavir/saquinavir, an initial two-week study in HIV- negative volunteers already is over. The study found that taking ritonavir along with saquinavir increased the body's exposure to saquinavir twenty-fold (in terms of "area under the curve" (AUC), a measure of how well drug levels persist over time). Dr. Feigal of the FDA also noted that the company had expressed a "strong interest" in a ritonavir/ddI/d4T study the day before, but this was not included in the letter.
The advisory committee had less trouble with indinavir on March 1, and smoothly voted to recommend granting it broad accelerated approval for people with HIV infection. Although the application included no results on delay of actual disease progression, Merck provided impressive safety and surrogate marker data for indinavir alone or in combination with nucleoside analogs in both early and late stage disease. Merck's trials included both AZT-experienced and -naive participants, and the studies have had a longer observation period than ritonavir's. Over 2,000 people have taken indinavir, 600 have been on indinavir for more than six months and 250 for more than one year, with some on treatment for as long as two years.
Most of the indinavir studies have been reported previously in Treatment Issues (see February 1996, pages 2, 4-5, and October 1995, pages 5-6). New preliminary surrogate marker data were presented from two studies testing indinavir versus AZT versus the combination -- one a clinical endpoint study in Brazil in AZT-naive people with CD4 cell counts between 50-250, and the other a large surrogate marker study in AZT- naive people with 50 to 500 CD4 cells in the U.S. (see table).
Neither study can yet confirm that indinavir plus AZT is superior to indinavir monotherapy. Participants in these studies started out at low HIV levels, and thus, the viral load assay's limit of detectability (500 viral particles per milliliter of plasma) served as a barrier to comparing the profound reductions in viral load experienced on single agent and combination therapy. By week 24 in both trials combined, viral load had gone down to below detectable levels in 39 percent of the participants on indinavir alone and in 42 percent of the people on indinavir/AZT.
Resistance to monotherapy also may take longer to occur in people with lower viral loads. Other studies have shown that once resistance to indinavir does occur, viral load rebounds. In further follow-up of the indinavir/3TC/AZT study (see last month's Treatment Issues), the median viral load in 20 people on indinavir monotherapy for 24 weeks was returning to baseline (the peak viral load decrease of 1.6 log below baseline, attained at week twelve, slipped to 0.7 log below baseline at week 24). Meanwhile, the nineteen patients on combination therapy to reach week 24 had sustained viral load reductions of more than 2 log (99 percent) below baseline. Ironically, even though Merck has said more about HIV protease cross-resistance to various inhibitors than any other company, neither the FDA nor Merck brought up the issue during the indinavir hearing. Previously, in hearings on ritonavir and Roche's saquinavir, cross-resistance was considered a serious subject for discussion.
Nuke A + Nuke B = Nuke A
Compared to the Antiviral Drugs Advisory Committee's deliberations on the two protease inhibitors, its discussion February 28, the first day of hearings on new approvals for ddI and ddC might seem anachronistic. The advent of the protease inhibitors taken up in the following two days makes it less likely that ddI or ddC will continue to be used alone or in combination with just AZT. Consideration of ddI and ddC also took place with no account taken of the relative merits of 3TC or the AZT/3TC combination, nor of d4T/ddI or other newer and possibly more potent nucleoside analog regimens. Yet, the committee deliberations established a pattern of using viral load reductions when evaluating therapeutic regimens. And the committee's dismay at not being able to simply follow the logic of viral load (the deeper the drop, the better) are symptomatic of the problems yet to be resolved.
The day started with a review of various recently completed large trials comparing the effect of different nucleoside regimens on progression of disease symptoms and death (clinical endpoints) as well as viral load and CD4 cell count. All the adult studies, ACTG 175, Delta and CPCRA 007 (NuCombo), have been recapitulated before in these pages (see Treatment Issues, October 1995, pages 2-4 and February, 1996, page 6). The newly analyzed results from ACTG 152, a pediatric trial, are described in this issue (see pages 7-8). These trials mostly compared AZT to the AZT/ddI and AZT/ddC combinations. ACTG 175 included a ddI monotherapy arm, as did ACTG 152, which did not test AZT/ddC. Except for ACTG 152 and ACTG 175, trial participants were people with relatively advanced disease.
FDA statistician Paul Flyer, Ph.D., summarized the four trials' results in a statistical analysis of the pooled clinical endpoint data. In the four trials as a whole, AZT/ddC was better than AZT alone only in patients without previous therapy. ddI performed better than AZT while AZT/ddI once again did no better than monotherapy, in this case with ddI rather than protease inhibitor. How can two drugs be no better than one, especially when the effect of the two together on viral load is considerably stronger? The committee could only conclude this time that ddI was potent enough to cover up the modest antiviral contribution of AZT in the AZT/ddI combination. So, if you are taking ddI, why take AZT too? On the other hand, if you cannot tolerate ddI, you can enhance AZT's effect by including ddC. AZT/ddC presumably does not distinguish itself in AZT-experienced people because their virus has developed resistance to AZT and it is up to the relatively weak ddC to accomplish most of the HIV suppression on its own.
After much agonizing, the committee unanimously recommended approving ddI monotherapy as an initial anti-HIV treatment (it now is approved only to succeed AZT) but could not explicitly endorse AZT/ddI. The vote on AZT/ddI was accompanied by an informal sense of the committee that the preponderance of evidence supports approval of this combination since it seems more effective than AZT or AZT/ddC, a sentiment reflecting the committee's inability to find consistency in the trial data it was reviewing. The advisory panel voted in favor of full approval of AZT/ddC but only in people with no prior therapy. This recommendation was especially confusing because the combination now has accelerated, or conditional, approval for patients with CD4 cell counts from 150 to 300 whether or not they have had prior AZT. (Below 150, approval is limited to people without past AZT exposure.)
Treatment with ddI will now become more common if the FDA follows its advisors' thinking. Another factor that will increase ddI's popularity is the new, smaller, orange- flavored chewable tablet approved by the FDA on February 27. This tablet is easier to ingest than the older "hockey puck," allowing patients to follow ddI's dosing schedule more rigorously.
The New Era
The FDA imperative around HIV apparently stems from a growing conviction that a four-drug combination will be highly effective in suppressing the virus. Researchers, like David Ho, are arguing that three drugs will provide long-term suppression of HIV infection but a fourth drug is needed for extra insurance against breakthrough infections. This additional agent, could be a new nonnucleoside reverse transcriptase inhibitor like delavirdine or nevirapine (both soon to be considered by the FDA) or another protease inhibitor. Besides the medical considerations, the FDA is also under considerable political pressure due to the FDA reform movement in Congress. To stave off dilution of its authority, the agency needs to demonstrate that it can act quickly when the situation calls for it.
The more potent combinations now becoming available will no doubt stand out from the single and double nucleoside analog combinations currently available. Precisely how much better the new therapies perform in complex real-life conditions remains to be seen. A treatment's success in individual patients depends on their ability to comply with treatment, the side effects they experience, how their bodies metabolize the compounds, and the susceptibilities of their personal HIV strain to the drugs.
By urging the release of the HIV treatments under consideration with the broadest possible indications, the committee has allowed doctors and individual patients to work out the best therapies on a case by case basis. Viral load monitoring may help make these decisions. One can only hope that using viral load assays will prove more straightforward with the new combinations than it did on February 28 with the traditional antiviral regimens.
Ritonavir Financial Assistance
Abbott Laboratories, like Merck (see page 4), has a financial assistance program for those who cannot obtain ritonavir (Norvir) for economic reasons. Eligible applicants must be nonhospitalized and have no health insurance or Medicaid coverage. They also must meet financial status guidelines. Note that assistance is limited to nine months and that patients must reapply to receive each three-month supply of drug. For further information and to receive an application, call 800/659-9050.
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Copyright © 1996 - Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, Inc. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011 fredg@gmhc.org http://www.gmhc.org
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