GMHC Treatment Issues
Now There are Eleven,
by Dave Gilden
With the April 7 FDA approval of Pharmacia & Upjohn's delavirdine (brand name: Rescriptor), there are now 11 drugs marketed in the U.S. for suppressing HIV. Delavirdine, like nevirapine (Viramune®) before it, is a nonnucleoside reverse transcriptase inhibitor, or NNRTI. NNRTIs chemically combine with HIV's reverse transcriptase enzyme to block the virus' infection of new cells. Their role in HIV therapy has always been uncertain because HIV rapidly develops resistance when exposed to the current members of the class, at least when these drugs go up against HIV alone: The best bet seems to be as first-line therapy in combination with fresh nucleoside analogs. Then, the protease inhibitors could be saved for occasions when HIV levels are very high or stubbornly resist treatment with other drugs. But then again, maybe it is best to go to maximum suppressive therapy with the less resistance-prone protease inhibitors in the first place.
Reading delavirdine's package insert is a scary experience that will put off most people from trying the compound. In the first place, resistant HIV emerges within a few weeks of taking the drug, due to a single mutation. That mutation most often occurs at reverse transcriptase's amino acid 103. This same mutation also reduces HIV's sensitivity to Du Pont Merck's experimental and much more active NNRTI DMP 266. It would be a shame to lose some of the advantages of DMP 266 through previous use of delavirdine. Largely because of its resistance problem, delavirdine provided no statistically significant benefit in two of the three clinical trials that led to its approval. One of these, ACTG 261, involved participants who had no prior therapy or less than six months of AZT. Preliminary analyses of the viral load and CD4 count data in ACTG 261 indicate that AZT/ddI is virtually equal to AZT/ddI/delavirdine or ddI/delavirdine and decidedly better than AZT/delavirdine. In another study, the AZT/delavirdine combination did do better than AZT alone in a cohort with six months or less of prior AZT therapy. This improvement was not apparent when evaluating CD4 count changes, only in terms of viral load. (A further reduction in HIV levels of only about 0.1 log -- 20% -- after week eight could be attributed to delavirdine. At week four, this difference briefly reached 0.5 logs or 67%.)
Then there is the problem that delavirdine therapy requires taking four 100 mg pills three times a day. This comparatively large burden, of course, comes in addition to the other antiviral drugs with which delavirdine must be taken (delavirdine monotherapy is strongly advised against). With the recommended regimen, delavirdine blood levels vary considerably from person to person, and on average women achieve 31% higher levels than men. Delavirdine is metabolized by the liver and inhibits the same CYP3A hepatic enzyme that the protease inhibitor ritonavir does (though not to the same extent). Like ritonavir, delavirdine comes with a long list of warnings concerning drugs whose blood levels it raises due to this suppression of liver metabolism. Delavirdine also causes skin rashes, usually (but not always) temporary, in about 20% of patients. Finally, it causes birth defects in rats.
This is not a very attractive drug. Except, except... One of the pieces of information that led the FDA to OK delavirdine was some data from Paul Bellman, M.D., a New York City AIDS specialist in private practice. Taking advantage of the preapproval delavirdine expanded access program, Dr. Bellman added the compound to the regimens of 60 of his patients who were experiencing rising viral loads despite being on AZT/3TC/indinavir. (In some patients, the AZT was switched to d4T at the same time). Lo and behold, 15 of the 27 patients whose records have been made available experienced a rapid viral load decline amounting to more than one log (90%) by the second or third month. Dr. Bellman has no way of checking, but he thinks that the people failing the indinavir regimens were not achieving high enough blood levels of this protease inhibitor, possibly due to poor absorption in the digestive tract. Delavirdine conceivably could have raised the patients' average indinavir levels by two-fold or more, due to its effect on the liver, where 80% of indinavir is broken down.
Dr. Bellman observes, "Delavirdine added to nucleoside analogs does not have these benefits. But adding delavirdine, a potent drug, to indinavir makes it potent, too. So now there are two potent new drugs in the patient's antiviral combination."
Dr. Bellman combines delavirdine with the standard indinavir dose of 800 milligrams three times a day. Upjohn, though, recommends that indinavir should be reduced to 600 mg three times a day when co-administered with delavirdine. The worry with high indinavir levels in the body is that some of the compound will end up in the kidneys as an extremely painful precipitate or sediment. Dr. Bellman says he has noticed no increase in this kidney stone problem, which strengthens his feeling that his failing patients had abnormally low indinavir levels to begin with.
The doctor's whole strategy rests on his personal intuition. He has not actually monitored the indinavir levels in any of his patients since such a test is not commercially available. His experience points out a gap in current research -- why people fail treatment regimens is not examined systematically. In particular, the drug levels achieved in patients are rarely looked at.
Merck, which developed indinavir, is now collecting blood samples from people who have not responded well to the compound. The reasons why people fail seem varied, according to Merck researcher John Condra. He says, "We don't have any evidence that failures have low blood levels. This is one possibility. Among the other explanations are drug resistance and inadequate compliance." If the problem is failure to take indinavir on schedule or to take it with food rather than on an empty stomach, this should be corrected first before adding delavirdine. If the problem is indinavir-resistant HIV and not low indinavir levels, the benefits and dangers of adding delavirdine are uncertain.
Adding to the mystery, Dr. Bellman notes that he has seen patients continue to fail when delavirdine was added to their indinavir regimen and then succeed on indinavir plus nevirapine. But nevirapine reduces indinavir levels rather than raising them.
Like the reasons for protease inhibitor failure, protease inhibitor/NNRTI combinations have suffered from lack of attention. Manufacturers in the past have tried to position their NNRTIs as substitutes for the more expensive protease inhibitors in combination regimens with nucleoside analogs. It nonetheless makes more sense to combine NNRTIs with protease inhibitors rather than nucleoside analogs since then two different HIV enzymes and points on the virus lifecycle are attacked rather than just one. In one small Vancouver trial, for people with AIDS who had failed all nucleoside analogs, the combination of 3TC, indinavir and nevirapine was surprisingly successful (see Treatment Issues, February 1997). Also, the two-drug combination of DMP 266 and indinavir in trials has suppressed HIV as effectively as most three drug combinations.
Dr. Bellman's results in his first patients are drawing increasing attention in New York City and elsewhere. The complete results are not in, though. For most of these initial patients, adding delavirdine to indinavir did not drive HIV down to undetectable levels (below 400 HIV RNA copies/ml of plasma). This leads to fears that long-term stability will not be maintained, given HIV's propensity to develop resistance to either of these two compounds when residual viral replication is possible during treatment. The clock may be set back, but usually it is still ticking; successful ways to recover from treatment failure need further elaboration.
Part of that solution appeared to be Upjohn's "spawn of delavirdine," a series of altered delavirdine compounds that the company tested in the lab and found to be active against delavirdine-resistant HIV. These compounds were described in a series of four papers over the past year, but Upjohn now says it has no attention of developing them further because they exhibited poor stability in animal studies. More recently, Upjohn has come up with a new set of NNRTIs, the "pryrimidine thioethers," which also are potent against delavirdine-resistant HIV as well as nonresistant virus. Their absorption and stability reportedly are excellent in rats, but Upjohn is still evaluating their future development. There is considerable speculation in the AIDS community that Upjohn is pulling back from HIV research. It will be interesting to see what the company does.
by Jill Cadman
Chiron Vision's Vitrasert eye implant for treating CMV was approved by the FDA in March of 1996 (see Treatment Issues, March 1996). The implant is an important breakthrough because it is able to deliver steady amounts of ganciclovir directly to the retina for months. Besides making massive daily infusions of ganciclovir unnecessary, it increases the drug's effectiveness by bypassing the blood-retina barrier and delivering high levels of ganciclovir to the localized site of CMV retinitis. A year's experience with Vitrasert has better defined its potential for treating CMV.
There were initial concerns about safety, especially regarding the risk of retinal detachments. Daniel F. Martin, M.D., in Atlanta, a major figure in the pre-approval implant trials, was among the first to voice these concerns. But CMV disease itself leads to retinal detachments in a large proportion of patients. Cumulative one-year risk ranges from 24% to 50%, according to various reports. Hence, it is not easy to pinpoint the cause of a detachment in an implanted eye.
CMV (cytomegalovirus) is a prevalent virus from the herpes family which can cause opportunistic infections in immune-compromised persons. It is estimated by the Centers for Disease Control (CDC) that one-third of all Americans are infected with CMV. The virus is transmitted through body fluids or transfusions. It is common for infected people to show no symptoms while CMV is inactive. There is a CMV antibody test commercially available for those wishing to know if they are infected. The risk of developing active CMV disease increases in persons with AIDS as CD4 counts decrease. Those with CD4 counts below 100 are at greatest risk and should begin ophthalmologic screenings for CMV retinitis. As CD4 cells drop below 50, screening should become more frequent. Screenings should continue even if CD4 cell counts increase due to antiviral therapy.
CMV is a systemic infection that can cause disease in many parts of the body in addition to the eye, including the brain, colon, esophagus and other organs. The most common manifestation is CMV retinitis, which causes lesions on the retina. Severity depends on the location of the lesion. Zone 1 disease causes damage in the highly sensitive central retina (the macula) and is most sight-threatening. Zone 2 includes the periphery of the retina. Infection there is less dangerous to vision, although it may spread to the central retina. CMV retinitis is frequently associated with CMV encephalitis, a severe brain disorder with multiple neurological complications (see Treatment Issues November 1996).
Treatment for CMV retinitis is given in two phases. An initial induction therapy consists of twice a day intravenous ganciclovir or foscarnet (or once weekly cidofovir) administered for two to three weeks. The purpose of induction therapy is to halt disease progression and prevent blindness. Induction is followed by maintenance therapy which consists of daily ganciclovir or foscarnet infusions, biweekly cidofovor infusions, or other treatments (see article) to prevent or delay reactivation of viral replication. It is difficult to completely suppress CMV, and if there is a reactivation, the patient will need "reinduction" via intravenous infusions.
Systemic medication can also be used as prophylaxis for persons with low CD4 counts who have never developed active CMV disease. There are indications that the choice of such therapy depends on a patient's CMV viral load. Those with very high plasma CMV burdens (over 50,000) may require preemptive intravenous (high dose) therapy, even when there is no evidence of active disease, while those with low CMV viral loads (below 50,000) may receive satisfactory results from a course of daily oral ganciclovir. (See Treatment Issues , September 1996).
Retinal detachment is a frequent complication of CMV infection. It occurs when a hole in the retina allows ocular fluid to seep behind, causing the retina to separate from the back of the eye (the choroid). The first symptom is often the appearance of small moving spots known as floaters. Surgery may be necessary to repair the hole and reattach the retina. The injection of silicone oil may also be used in the treatment of retinal detachments. Whatever the treatment, some loss of visual acuity can result. -- JC
With the advent of highly active antiretroviral therapy (HAART), some doctors hoped that improvements in CD4 counts would translate into lower risk for reactivation of CMV disease, calling into question the need for pre-planned implant replacement. However, increasing a patient's CD4 count through HAART does not always prevent CMV reactivation. Dr. Martin stated, "I stopped doing scheduled exchanges for awhile and was disappointed. I had some patients with very high CD4 counts and their CMV reactivated at about the same time I would have expected."
Dr. Martin advises those who have Zone 1 (central) disease to have scheduled replacements because they cannot afford to take a chance on loss of vision. For those with Zone 2 (peripheral) disease, Dr. Eviatar stated, "If the patient is doing better systemically and the lesion is not site-threatening, I think it's reasonable to wait and see how they respond. It may be that with the protease inhibitors, they are better able to control the CMV on their own or with oral ganciclovir."
Caution should be used when interpreting this small number of case reports. The first author of the letter and clinical director of the National Eye Institute, Scott Whitcup, M.D., stated, "We will need more information before recommending that all people with CMV retinitis and elevated CD4 counts stop their anti-CMV medications." Dr. Whitcup would not recommend coming off anti-CMV medication outside of a carefully picked patient population with extremely close supervision.
Mark Jacobson, M.D., and colleagues at the University of California San Francisco presented a study at the Fourth Conference on Retroviruses and Opportunistic Infections (abstract 353) representing the other end of the spectrum. The Jacobson study looked at five patients who had CMV retinitis diagnosed despite a CD4 count of 200 or more. Four to 24 weeks before the diagnosis, all patients had CD4 counts below 85, and four to eight weeks before the CMV diagnosis, all patients had initiated HAART. The researchers then examined data from 76 consecutive patients enrolled in a treatment trial for CMV retinitis. During the period from July, 1995 through February, 1996, only one patient out of 27 had CD4 counts above 50 and zero out of 27 patients had CD4 counts above 100. From March, 1996 (when HAART became widely available) through August, 1996, 14 out of 49 patients had CD4 counts above 50 and seven out of 49 had CD4 counts above 100. The investigators concluded that the immunological benefits of HAART may not fully protect against CMV retinitis, which may occur more commonly now in patients with CD4 counts above 50.
The authors of the JAMA letter suggest that such cases of CMV may be due to subclinical (asymptomatic) CMV retinitis existing prior to the onset of HAART. Dr. Whitcup notes that retinitis developed in patients in the Jacobson study shortly after initiation of HAART and feels that CMV would have eventually emerged in these patients in any case. Dr. Whitcup has seen his own patients develop such symptoms of CMV retinitis as vitreous floaters shortly after starting on HAART. It is possible that HAART cannot immediately protect a patient who already has a subclinical case of retinitis, but it may be protective against CMV progression over the longer run no matter what the initial status of the disease.
Dr. Whitcup said, "I have yet to see someone develop CMV retinitis who has been on HAART for over three months and whose CD4 counts are over 50 -- although I think there may be cases out there where that occurs." Of course those who have been on combination therapy for extended periods may experience "HAART failure" and subsequent CD4 count declines. Once CD4 counts fall below 50, there will be renewed risk for CMV progression.
The National Eye Institute is seeking to recruit AIDS patients with non sight-theatening CMV retinitis for further study at the NIH. A small 12-person trial will attempt to provide further insight into when it is appropriate to discontinue CMV treatment in patients on HAART. Anyone interested in this trial should contact Cheryl Perry at 301/435-4559.
There also is room for improvement in oral ganciclovir for maintenance therapy to prevent CMV reactivation. The current standard three-gram dose is not as effective as IV ganciclovir. Raising the daily dose of oral ganciclovir to 4.5 grams works better (see Treatment Issues, September 1996), but requires even more pills and expense. Roche's ganciclovir prodrug (RS-79070) is much more absorbable in the gut than the present version of ganciclovir and breaks down into the active form once in the body. The prodrug's oral bioavailability is about 61%, compared to about 8% for the current oral formulation. Data presented by Roche this past winter at the Fourth Conference on Retroviruses and Opportunistic Infections (abstract LB19) demonstrated that the same levels of serum ganciclovir can be achieved with the prodrug as with IV ganciclovir.
Providing that the pharmaceutical companies move forward, the future standard of care might employ Vitrasert II to treat the local manifestation of CMV retinitis for two years and one pill of ganciclovir prodrug per day to control extra-ocular disease. This treatment strategy would avoid what Dr. Martin calls "the emotional roller coaster of going back and forth from induction to maintenance therapy," which is the current experience of most people with CMV retinitis.
As this article was being readied for press, Hoffmann-La Roche announced that it was deferring development of the ganciclovir prodrug -- see box.
Roche had planned three clinical trials for the prodrug: one for treatment, one for prevention and one for induction therapy. Two of those three trials are now on hold. According to a company letter sent to investigators, "A decision has been taken within Roche to reassess the development of the ganciclovir prodrug. This action has been precipitated by an apparent decrease in the incidence of new CMV disease which may be attributed to the wide availability of highly active antiretroviral therapies (HAART)."
The induction trial (Protocol WV 15376B) is currently the only one to go forward. About 20 sites across the country are now seeking to enroll a total of 70 participants. The trial will compare three weeks of intravenous ganciclovir induction therapy (two two-hour infusions a day) and one week of IV ganciclovir maintenance therapy (one two-hour infusion a day) with three weeks of prodrug induction therapy (two pills a day) and one week of prodrug maintenance therapy (one pill a day). After four weeks all participants will receive the prodrug.
Slow enrollment in this trial was another factor in Roche's decision to hold off on the other two studies. The induction trial is due to be fully enrolled by the end of July, but not all sites were ready to enroll participants until April. Quick enrollment now may cause Roche to reconsider its position. Anyone interested in participating should call 800/TRIALS-A for more information.
The induction trial is too small to be decisive in the FDA approval process. Unless Roche makes a stronger commitment to the development of the prodrug, approval will be delayed indefinitely, and the drug will not reach the market any time soon.
Aside from being unconscionable, the decision to delay the prodrug's development is based on little hard information and runs counter to prevailing medical opinion. Although HAART may delay CMV emergence by slowing AIDS progression, most experts fear that this is only a temporary reprieve. Some clinicians feel that CMV incidence is already rebounding. As people with AIDS are living longer, the occasion to administer CMV medications for prophylaxis, induction or maintenance and the length of time on such medications may well increase.
Therapies that are easy to administer are vital to successful management of AIDS and HIV infection The dosing requirements of the current oral and intravenous formulations of ganciclovir make them unsuitable for extended use. The prodrug would improve the quality of life of many people. Roche needs to look beyond its own short-term profit margins to the larger picture. --JC
Happiness Reigns in the Drug Marketplaceby Karen Kuller
A new trend is changing the face of AIDS. Increasingly, information on HIV treatment options is gaining exposure through drug companies' marketing tactics -- specifically, mass-advertising. A two-page ad in this month's issue of GQ depicts a mountain-climber who struggles to make his way up a rocky cliff, and ends up on top. The ad, which also appears in Esquire and Details magazines, is for Merck's protease inhibitor, Crixivan. Initially distributed exclusively through the Pittsburgh-based Stadtlanders Pharmacy, Crixivan will be sold at more than 25,000 pharmacies nationwide starting in May.
Once lured to court AIDS and gay community groups because of their wide consumer reach, drug companies are resorting to more traditional methods of direct-consumer marketing as competition among the protease inhibitors heats up. The market's dominant player, Merck, has felt this pressure the most.
Its newest and fiercest rival, Agouron, launched an aggressive campaign to publicize Viracept's low toxicity and ease of use upon its approval in March. Only one month later Viracept represented 23% of new protease inhibitor prescriptions, according to one analyst report.
With an estimated 10,000 new prescriptions being filled each month, drug companies are becoming more and more anxious to get the message out that theirs is the superior product by whatever argument they can advance. The irony is that the messages conveyed about HIV through the media continue to reduce the disease to mere imagery, even as treating it grows more medically complex. Such imagery includes the notion of a war being waged in the blood where billions of T-cells are destroyed every day, says Joseph Sonnabend, M.D., and that "now we have drugs that can stop it all." In Merck's ad, phrases like "battle against HIV" and the tagline "focus on the rest of your life" are typical of ideas feeding the popular perception that AIDS is a manageable, even curable disease. Roche's tagline "consider a protease inhibitor you can live with," which accompanies pictures of happy, smiling people, strikes a particularly ironic chord: though perhaps tolerable, the product in its present formulation and dose does little to reduce viral load.
All ads include the highly technical patient package insert as required by the FDA. The duality of advertisements, where self-promotional imagery juxtaposes objective information, is reflective of the larger issue that is at stake with this approach to disseminating information on the treatment options available to people with AIDS. "Maybe these companies are reaching people who aren't getting this information elsewhere, and maybe they're giving them very useful treatment information," says Spencer Cox of the Treatment Action Group, "On the other hand, these people may be getting information that is not accurate or which they can't evaluate within the appropriate informational context."
Indeed, if raising awareness about HIV and combination therapy among the public-at-large can be construed as one advantage of mass-advertising, then the consequences of increased brand-name recognition should be construed as a disadvantage. Given the highly complicated regimens that characterize triple-combination therapy, using potent imagery and slogans to describe a protease inhibitor can seem oddly inappropriate. "This is not Rogaine or an antihistamine," says Jeanne Bergman, a policy analyst at Housing Works, "I find it peculiar to see ads for such heavy, heavy drugs."
With this comes the fact that combination therapy is still a matter of choice best addressed through active dialogue between a patient and his or her physician. Brand-name recognition should carry no clout in a decision-making process that involves individual considerations for physician and patient alike, including patient history and ease of use. As Spencer Cox put it, "I'm not sure that engendering consumer confidence is the most effective way to ensure the best healthcare." Rather, says Mark Snyder, M.D., an infectious disease specialist with the Mid-Atlantic Permanente Medical Group in Washington, D.C., the advertising can do more harm than good by "creating the belief that one drug is superior to the others when, in fact, it is not."
But creating that impression seems to be what the pharmaceutical industry is focusing more of its efforts on doing. With analysts predicting that the protease inhibitor market will exceed $2 billion by 1999, protease inhibitors are becoming a promising commercial enterprise indeed (Alex Brown Report, April 29, 1997). Concerns about cross-resistance are further supporting the ambitions of companies like Merck, Abbott, Roche, and Agouron to make their protease inhibitor first in line for inclusion in triple combination therapy. Drug resistance is a completely unsettled field that lends itself to widely different spins by the various protease inhibitor manufacturers.
The AIDS community has been insisting that drug companies proactively communicate information about their products since the beginning of the epidemic. "PWAs revolutionized the way medicine is practiced in our country," says Joy Schmitt of Agouron, "They are our most educated consumers, and the industry has responded to that." Yet information about just how these new drugs will affect the future of people with AIDS or HIV remains scarce. HIV therapy has come a long way since the introduction of AZT and ddI. Today, the only thing that is definite about HIV treatment is the dissenting medical opinion on when to initiate therapy, and the plethora of possible combination protocols. Observes Harold Grossman, M.D., "The truth is always somewhere between what all the companies tell you."
As Abbott, Agouron, Merck and Roche ponder their response to each other's latest ads, the bottom line is that clinical data remain the sole basis for judging the value of their products. Generating solid, clear information on potency and durability of effect is the best marketing technique there could be, whether that information is communicated through patient education material, community groups -- or ads.
Roche Brings New Formulation
by Jill Cadman
On May 12, Hoffmann-La Roche announced that it was applying to the FDA for approval of the long awaited "soft gelatin capsule" formulation of saquinavir. The soft gel capsule contains the protease inhibitor saquinavir blended with a proprietary lipid mixture that raises intestinal absorption of the compound to 12% of the total drug available, three times the abysmally low 4% observed with the hard capsule.
The recommended dose of the new version is 1,200 mg three times a day (TID), compared to 600 mg TID for the hard capsules. Taking this much will require 18 saquinavir soft gel capsules per day and provide eight to ten times the drug exposure of the current formulation. The eight-week dose-ranging study (NV15107) that identified 1,200 mg TID as the preferred dose recorded a respectable, though hardly record-breaking, 1.43 log (96.3%) drop in viral load among 22 volunteers on saquinavir monotherapy.
The safety study (NV15182) showed few adverse side effects with the new formulation, but caution should be advised for those with a history of liver disease. In addition to the safety data, the FDA has recently requested a head-to-head activity study comparing the two formulations to prove that the soft gel is an enhancement over the hard capsule. Sixteen-week activity data from this study (NV15355) should be available by mid-summer and will be submitted to the FDA during the review process. Roche expects to receive the FDA's go-ahead to market the improved saquinavir by the end of this year.
Community activists have raised concerns about the continuation of Roche's aggressive marketing campaign which is advertising saquinavir as "a protease inhibitor you can live with." The hard capsules are administered at 600 mg TID, a suboptimal dose that may breed resistance to both the new formulation and other protease inhibitors by failing to have much impact on HIV replication. At a community meeting in May, activists asked Roche to pull the campaign until the soft gel capsules are available. Tammy Lewis, Product Director for saquinavir, conceded that the best way to use the current formulation is in combination with the protease inhibitor ritonavir, which raises blood levels of saquinavir ten-fold by blocking the drug's metabolism in the liver. But the saquinavir/ritonavir combination has not been reviewed, much less approved, by the FDA, and Roche is prohibited from promoting it.
Roche is now pursuing approval of an expanded indication of saquinavir for use in combination with other protease inhibitors. Approval is not likely within the next 12 months and would probably be limited to specific drug combinations initially (in particular, 400 mg saquinavir plus 400 mg ritonavir), rather than a broad saquinavir/other protease inhibitor indication. Discussions have already taken place between Roche, Abbott and the FDA regarding registration trials in Europe for saquinavir/ritonavir.
Another long-standing community complaint is the current price of saquinavir. At $5800 per year wholesale, the hard capsule saquinavir is at least as expensive as the other protease inhibitors even if it is the weakest. Ms. Lewis says it is "premature" to comment on the pricing of the soft gel capsule. Especially at the preferred 1,200 mg TID dose, the soft gel could prove much more costly than the present version.
No Attrition in Research
by Dave Gilden
One of the most prevalent and dangerous conditions in AIDS and HIV disease has been chronic wasting, in which people progressively become so depleted of lean tissue and protein stores that their bodies can no longer perform basic functions. In this new era of highly active antiretroviral therapy (HAART), is it still a major concern? Kathleen Mulligan, M.D., who has studied AIDS wasting extensively at San Francisco General Hospital answers in the affirmative: "There're lots of anecdotes -- people proclaiming the end of wasting syndrome," she says, "but I'm not knocked out by what I see here. I don't think we're out of business."
It may be that once the conditions for wasting exist, the syndrome persists even when HIV levels decline. Several small surveys presented at April's Nutrition and HIV Infection conference in Cannes, France found that about a fifth to a quarter of those on aggressive antiviral therapies continue to lose weight or lean body mass. One of the studies observed that there was little correlation between viral load response to therapy and changes in weight. Serono Laboratories has made similar findings in an ongoing survey it is conducting. And the initial results from a study at Tufts University indicate that over the first seven to nine months on HAART, patients gain significant amounts of weight as they eat more, but it is all fat. (presented by Sherwood Gorbach, M.D., at the NIH Conference on AIDS Wasting Syndrome, May 20-21, 1997).
An inability to restore lean body mass (muscle in particular) after acute or chronic weight loss has been the hallmark of wasting syndrome. That inability remains even when a person recovers from an opportunistic infection that triggered the weight loss episode. Another on-going study at Tufts University is observing that, at least in people with high HIV levels, even strenuous exercise programs do not improve body composition. Trial participants did increase their weight by an average 3.8% after eight weeks, but the percent increase in fat and lean tended to be the same (presented by Ronenn Roubenoff, M.D., at the NIH Conference on AIDS Wasting Syndrome, May 20-21, 1997).
(A more definitive word on recovery after successfully suppressing viral load may come from the weight gain substudy that is part of the recently concluded ACTG 320, a trial of AZT (or d4T) plus 3TC with or without indinavir. The substudy will try to determine whether adding the protease inhibitor and obtaining greater reductions in viral load result in greater increases in lean body mass, and whether increased lean body mass is associated with changes in appetite and the body's pro-inflammatory agents (such as TNFa, see below). Until now, drug companies have either not collected or refused to release much information on weight changes in their protease inhibitor trials.)
It seems that in addition to potent antiviral therapy, an anabolic (muscle-enhancing) or anti-inflammatory agent may be necessary to reset the body's chemistry after chronic HIV plays havoc with it. Developments in this area continue to make news. December 2 marked the introduction of Serono's brand of human growth hormone (Serostim), which was granted accelerated approved for treating AIDS wasting system in August after a rough ride through the FDA. (For the details of the FDA's critique of Serostim, see Treatment Issues, March, 1996 and August, 1996.)
Glaxo's Parsimonious Compassion1592U89 is a new nucleoside analog from Glaxo Wellcome that promises to be a marked improvement over present analogs such as d4T or 3TC. In early trials, it was shown to reduce HIV viral loads on its own by up to 1.8 logs (98.4%), and in lab tests, it has strong residual potency against mutant, drug-resistant HIV. Because of this exceptional activity, 1592 is very appealing as salvage treatment for people who are not responding to the antiviral drugs currently on the market.
Discussions between Glaxo and community activists have taken place sporadically for over a year concerning some sort of expanded access program to supply such people while 1592 is under development. On April 28, the company announced the impending commencement of a limited compassionate use program. But this program is so restricted that it has touched off a tidal wave of community criticism.
Glaxo's proposal consists of three programs: a pediatric compassionate use for children who have failed one nucleoside analog, a program for people with "severe" AIDS dementia, and a general adult program. Entry to the general adult program would be restricted to people with viral loads over 50,000 and CD4 counts under 100 after having failed at least two nucleoside analogs and one protease inhibitor. The total worldwide availability will have a ceiling of 2,500 people, which by itself has been cause for a considerable outcry: "We will lose another five to six thousand people in the next year who could be saved by 1592," commented Jeff Getty of ACT UP/Golden Gate.
The enrollment criteria generated a whole slew of objections. Requiring adults to fail two nucleoside analogs and one protease inhibitor before receiving 1592 means that there will be little if anything left to combine the new drug with, given the implications of cross-resistance. To ensure adequate viral suppression and durability of treatment effect, people should take 1592 in combination with other drugs still active against the HIV in their bodies. Preferably that combination would include a protease inhibitor, which 1592 cannot replace. At the very least, the requirement to fail a protease inhibitor should be eliminated. (An alternative would be to undertake a joint expanded access program with Glaxo's experimental protease inhibitor 141W94, which lab studies indicate could be active against HIV resistant to the protease inhibitors on the market.)
Glaxo in addition is forcing both adults and children to wait until they have very high viral loads and low CD4 counts before they can receive 1592. Waiting until that point allows irreparable damage to be done as patients' CD4 cells are decimated and HIV replicates to levels that are hard to bring down. It would have been better to define treatment failure as either an upward trend in viral load or stable, but high HIV levels.
A similar concern arises in relation to the dementia program: Why require that dementia be "severe"? Full recovery may no longer be possible at that point.
Glaxo has responded to these objections by saying that the current supply of 1592 is low and that there is a need to collect extra safety and efficacy data before more broadly releasing the drug. To facilitate this data collection, the general adult compassionate use program will take place at "geographically dispersed centers" rather than the usual central mail order operation. This raises the question as to how people in remote areas will obtain the drug. According to a company announcement, instituting a network of separate sites is part of Glaxo's attempt to build within compassionate use an "open label study which allows for collection of safety and efficacy data... in a broad population of people in addition to that which is being collected through our clinical trials."
It is true that testing has been slow, but the supply problems that supposedly held up trials have been resolved. If Glaxo expects to market 1592 in a year, it must now have the capacity to make commercial-size batches of the substance for the traditional 12-month shelf-life test that new drugs go through. It could use that capacity for a true expanded access program, too.
The company does promise to institute a larger expanded access program next winter, but that will be only a few months before Glaxo anticipates receiving FDA approval for 1592. In the meantime, Glaxo's AZT and 3TC have been the best-selling HIV drugs. Although 1592 will steal some of that market , it can be expected to sell exceedingly well, too. The present demand for immediate access can only bolster its future sales. There is little reason for the miserly expedience that would divert compassionate use from an emergency distribution program into a stop-gap trial.
A Welcome and an Apology
Starting with the last issue, you may have noticed a new person on TI's bylines and masthead. Treatment Issues welcomes Jill Cadman as its new associate editor. Jill formerly was assistant coordinator of GMHC's Health Care Advocacy Department. She brings to this publication considerable practical experience resolving GMHC clients' problems with the healthcare system. That experience will be very useful in realistically appraising medical therapies. Jill also is an assiduous investigator who will further Treatment Issues' critical analysis of HIV/AIDS treatment developments.
You also may have noticed that Treatment Issues has been very late this spring. We are very sorry. TI editor David Gilden has been working two jobs lately -- in addition to his regular duties, he has been acting director of GMHC's Treatment Education and Advocacy Department. His temporary tenure in that position is now over, and with him back on the job full-time and Jill Cadman settling in, TI should resume its normal schedule -- or maybe not. All GMHC is moving next month, and who knows what chaos will ensue.
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