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GMHC Treatment Issues
October 1996

Contents


When HAART Is Not Enough

by Dave Gilden

Despite all the publicity about "viral eradication" at this summer's International Conference on AIDS and at the ICAAC conference covered in this Treatment Issues, many people continue to fail on their current HIV medications, even if they are receiving one of the new triple combinations. (Such therapy is sometimes called HAART, for "highly active antiretroviral therapy.") Here are a few of the disappointing experiences that we at Treatment Issues have heard lately:

  • George was in an indinavir monotherapy trial and initially had great success reversing a sudden crash in CD4 count (it went from 250 to 70 and eventually to over 600). His viral load became undetectable (under 200 copies/ml) and stayed that way for 18 months. Now, even though he also has been taking d4T/3TC for nearly a year, HIV is again at 20,000.

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  • Darryl, conversely, had been stable on d4T/3TC when he added indinavir. His viral load went from 50,000 to below 1,000 for six months, while his CD4 count leaped from 250 to 450. Then suddenly, his viral load went up to 180,000, close to the figure in the days before d4T/3TC.

  • Michael was diagnosed with AIDS in 1989 but had been a long-term AZT success story. In the last few years, though, he has not done so well: He has had PCP, two cases of MAC and finally cryptococcal meningitis. Michael switched nucleoside analogs several times along the way with at most marginal improvement. Last winter he tried adding saquinavir -- it provided no evident benefit while causing frequent vomiting. He went on indinavir more recently, but too late to do much good given how ravaged his body had become. Michael died in August of bacterial pneumonia.

"I'm seeing treatment failures most commonly in patients with very high baseline viral loads -- over 100,000 -- and low CD4 counts. Those with low viral load and high CD4 counts in general are not crashing or failing" said Gabriel Torres, M.D., Treatment Issues' medical consultant, reporting on what he has encountered so far with the new antiviral combinations.

Aside from their tendency to have more advanced HIV infections, the people not responding to the new, improved anti-HIV regimens do not all fall into any particular pattern. Many doctors blame patient compliance for a treatment's lack of success -- after all, the HAART regimens require complicated schedules for taking the different drugs, and some medications need to be taken with food while others require an empty stomach. The number of side effects encountered might also discourage people from taking full and regular doses of particular drugs. But the experiences described above all involve very conscientious and knowledgeable people who swear they faithfully followed their prescriptions' instructions.

One does not need to blame the patient to find reasons for treatment failure: Some people may have gastrointestinal problems that prevent absorption of enough drug (this absorption problem arises for the great majority of people on the present version of saquinavir regardless of their digestive status). Others may have developed HIV resistant to most nucleoside analogs due to prior sequential therapy with these agents. Now protease inhibitor-resistant HIV is emerging in their bodies during ostensible combination therapy that is basically protease inhibitor monotherapy. Still others cannot tolerate the currently available agents -- they suffer from vomiting on ritonavir and saquinavir and kidney stones on indinavir. Finally, there are the odder cases, such as people with impaired livers that cannot process the current protease inhibitors without added hepatic dysfunction.

At this point, there are no reliable figures about the frequency with which the widely heralded HAART regimens are meeting defeat. But it seems to be a common, if not the predominant, experience. One estimate of its incidence comes from Agouron Pharmaceuticals, which interviewed several dozen doctors with large AIDS practices in an effort to determine the demand for an expanded access program offering the company's experimental protease inhibitor nelfinavir. (That program is now in operation -- see below.) Based on the doctors' responses, the company estimates that about 2,500 Americans with HIV and CD4 counts less than 50 already have failed or could not take all three protease inhibitors on the market. Agouron further estimated that 10,000 U.S. patients with CD4 counts under 200 have failed on or are otherwise unable to take at least two of the three protease inhibitors. By comparison, over 50,000 Americans are now taking Merck's protease inhibitor indinavir.

Ramon Seva, the marketing research official at Agouron who supervised the survey cautions, "These numbers are very rough. This was not the most controlled study because we needed answers within a week and a half. If I had had the time, I would have made the doctors look at their records for specific reasons people went off the protease inhibitors and for people who would go off drug if they had a replacement. I'd have asked 50 to 100 docs, and it would have taken a month."

The Limits of Antiviral Therapy

The eventual extent of treatment failure lay behind a persistent debate at the International Conference about the need for therapy that strengthens the body's natural immune defenses against HIV and the opportunistic infections that interfere with recovery during administration of HAART regimens. Current therapeutic strategies focus on essentially poisoning actively replicating HIV without trying to manipulate overall conditions in the body to make them more inhospitable to the virus. Several observations reported at the conference underscored the limits of anti-HIV treatment as currently conceived.

In particular, although CD4 cell counts rise sharply after the introduction of potent anti-HIV therapy (combination therapies that durably reduce viral load by 100-fold -- 2 logs -- or more), there usually is a general ceiling at 100 to 150 above the pretreatment CD4 count. This phenomenon was observed, among other places, in the striking pilot trial of triple combination therapy (AZT/3TC/nelfinavir) presented at the International Conference by Martin Markowitz, M.D.,1 of the Aaron Diamond AIDS Research Center in New York. In eleven volunteers who continued on the regimen (there was one drop- out), HIV levels were reduced to below the limits of detection with the most sensitive available assay (which detects down to 25 HIV RNA copies/ml of plasma). CD4 counts, which initially ranged from 37 to 557, exhibited a mean increase of 109 at week 16. (In this small study, there was no measurable correlation between the amount of CD4 increase and pretreatment CD4 count.)

It appears that as the pressure of the HIV infection is relieved, existing CD4 T-cells expand to their maximum capability, but the desperately needed new "naive" CD4 cells that would trickle out of the bone marrow via the thymus have yet to be observed in any quantity. This lack may occur because people's thymus glands are too damaged by HIV infection to allow the CD4 T-cells to mature, or it may be that our experience with potent antiviral therapy is as yet too limited, both in time and numbers of patients, to observe immune healing. It could take a while for the surviving thymus tissue as well as small surviving naive CD4 cell population in the blood and lymph to produce noticeable numbers of new cells.

David Ho, M.D., director of the Aaron Diamond Center, reported to the International Conference2 that his colleagues have in fact noted a gradual secondary increase in CD4 counts after the initial burst, although it remains too early to determine this secondary rise's frequency or significance in terms of immune recovery. Emilio Emini, who directs antiviral research at Merck Research Laboratories, has some of the most extended data on patients' response to protease inhibitors from the trials of his company's indinavir. Once again he can only give his impression, which is that the second phase immune system improvement mentioned by Dr. Ho is mostly seen in people with less advanced disease: "Some patients with late stage disease show no CD4 increase," Dr. Emini notes. "Some go up 100 and are stable, and some go further down." Aside from limits to the CD4 response, there is the question of the durability of the viral load response to a therapy that consists solely of antiviral compounds to which HIV can develop resistance. Dr. Emini notes that there have been "some" breakthrough HIV infections -- a return to measurable HIV levels (in this case above 500 copies/ml) -- among people whose viral loads dropped to undetectable levels during the early indinavir monotherapy trials. These people, most of whom have added other antiretrovirals to their regimen some time ago, are precisely some of the people who have been on indinavir the longest, up to two years. Sequentially adding antiviral agents, starting with nucleoside analogs and then adding on one of the new protease inhibitors, is a more common experience than giving three new drugs to people without prior exposure to any anti-HIV therapy as in the Aaron Diamond trial. It is possible that many people have used up their benefit from the available nucleoside analogs one by one and now will be going through the protease inhibitors in similar fashion.

The Merck-sponsored study of AZT/3TC/indinavir in a group with a median 31 months prior AZT did show that adding two new drugs (3TC and indinavir) can produce a major response: Plasma HIV levels were still down by a median of 99 percent and CD4 counts were up by 130 at 36 weeks.3The trial's principal investigator, Roy Gulick, M.D., notes that it will be of great interest to see what happens to the trial participants in the AZT/3TC control arm when they start receiving indinavir at the end of the trial. Dr. Gulick noted, "This is more like a common real world situation, where people first took AZT, then got 3TC, and are now receiving indinavir too."

Another limitation in current therapy is that usually when drugs are used to treat a disease, therapy is reinforced by the immune system which is able to destroy at least whatever residual microbes survive the administered medications. People with progressive HIV infection clearly do not have any intrinsic effective way to cope with treatment-resistant mutant HIV as it arises. The further along in the course of the disease they are, the more likely it is that their population of CD4 cells that respond specifically to HIV infection have been killed off by the virus, which preys preferentially on the CD4 cells activated to defend against infection. Their immune response, which was not entirely effective in the first place, can only get weaker and weaker. There is considerable hope that the new antiviral therapies will do better than just reestablish the old equilibrium. By controlling viral load better than the body ever could do on its own, aggressive anti-HIV treatment might make everyone have the viral loads of long-term nonprogressors with the life expectancy to match. Although the analysis of several clinical trials indicate that treatment-induced reductions of viral load do improve patients' prognosis (see the newly published report on ACTG trial 175, for example4), it is not clear that they create conditions mimicking strong immunological control.

Robert Coombs, M.D., of the University of Washington, asks, "Does a person with a viral load of 100,000 that is subsequently suppressed by drugs down to 10,000 have the same outlook as a person who naturally has only 10,000? Probably not, because immunologically, these latter people are totally different. This is a fundamental flaw in the current argument."

Such considerations led Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases to declare during his address in the opening session of ICAAC that, "We need to use our knowledge to create effective treatment by attacking host factors as well as the virus."

Environmental Warfare

Establishing an immune environment hostile to HIV may not necessarily require creating an active HIV immune response. Some of the most exciting and quickest-paced research in the past year concerns the so-called second receptor on cell walls to which HIV virus particles bind along with the CD4 receptor as they fuse to and enter uninfected cells. The hubbub started with an article last winter by a team from the National Cancer Institute led by Robert Gallo, M.D5 This article reported that three members of a class of immune regulatory substances known as CC-chemokines (specifically RANTES, MIP-1a and MIP-1ß) prevent HIV from infecting new cells. (See Treatment Issues, January 1996.) The discovery was surprising in that the chemokines previously had been known as compounds that attracted white blood cells to the sites of infection. Acting on this lead, several groups of researchers soon found that CCR-5, a cellular receptor that interacts with all three of these CC- chemokines, was necessary for cell entry by the macrophage- tropic or NSI ("non-syncytia inducing") strains of HIV prevalent in early infection. (See Treatment Issues, June/July 1996) Shortly before this, another cell receptor, known as fusin (more recently designated CXCR-4), was revealed as the co-receptor necessary for cellular entry with the highly pathogenic T-cell tropic or SI ("syncytia inducing") strains of HIV sometimes found in late-stage disease. Just recently it was discovered that fusin binds to a chemoattractant called SDF-1.6Other chemokine receptors may also be used by HIV on some occasions.

Why is all this plethora of initials important? Just before the International Conference on AIDS, researchers reported on two individuals who had apparently been exposed to HIV many times through unprotected sex yet remained uninfected.7 Immediately after the conference, the same research group reported that these two individuals were missing a segment in their genes for CCR-5 so that the receptors did not appear on their white blood cells at all.8In spite of this defect, these two persons were absolutely healthy. Other cell receptors seem to be able to take over the work of the missing CCR-5. Almost simultaneous to this report, a Belgian team seconded these findings in other exposed but uninfected persons. A genetic survey of this group conducted of the prevalence of this CCR-5 genetic defect found it in 1% of 704 HIV-negative persons and in none of 723 HIV-positive persons. These are the figures for people who received the defective CCR-5 gene from both parents (homozygotes). Those who possess one normal gene and one defective one (heterozygotes) were less frequently represented in the HIV-positive group compared to the HIV-negative one (16% vs. 11%), indicating that those with a discordant gene pair have some difference in numbers or structure of this cell surface receptor than those whose pair of CCR-5 genes is completely normal. A final paper published in Septembe9did not find that the heterozygotes were less likely to be HIV-positive, only that HIV infection progresses more slowly in such individuals. Based on data from samples collected from some long-standing cohorts of U.S. males (either homosexual or hemophiliac), about half the people with HIV and two normal CCR-5 genes have an AIDS diagnosis ten years after contracting HIV. For those with a discordant gene pair, only about 30% have AIDS. (This gap narrows in the second decade after infection, but does not close completely.) As for the homozygotes with absent CCR-5 receptors, once again none could be found among the HIV-positive men (1,343 individuals), although 17 of 512 HIV-negative men were homozygous.

At the International Conference itself, presenters confirmed that the CC-chemokines act as suspected, by blocking their CCR-5 receptor so that HIV cannot enter the cell.10 Hints for possible nontoxic therapies are emerging here. Ian Clark- Lewis of the University of British Columbia, who is an expert on chemokines, not HIV, told Treatment Issues, "This is a very encouraging field. Chemokines seem to be hangovers from the past and seem to be predominately involved in unwanted effects, when the body attacks its own tissues. Though there are some positive effects, there are so many chemokines that they can compensate for each other if you disrupt the functioning of some of them."

In looking at the chemokine/second receptor/HIV interaction, scientists have happened upon a situation where nature has done many of the needed experiments for them. People with no CCR-5 receptors are healthy but apparently protected against HIV. Those with fewer or altered CCR-5s also seem somewhat protected. It should be possible therefore to safely block CCR-5 in people with normal receptors and protect them against HIV. The problem is to find molecules that bind to CCR-5 without stimulating the cell. Whether people with normal, intact receptors will be able to compensate for the virtual disconnecting of CCR-5 from the intercellular signaling pathway remains to be seen. One caution has already appeared in the form of a brief report that natural chemokines appear to stimulate HIV replication in test tube cultures of pure macrophages.11 It may yet turn out to be safest to try to use molecules that bind to the part of the gp120 molecular unit of HIV's envelope that connects to CCR- 5. But exactly what region on gp120 is involved in this process has not been determined, so the feasibility of targeting HIV rather than the cells is unknown.

Then there is the question of how HIV would evolve in the face of such treatment. The virus might merely mutate into a more pathogenic T-cell tropic variant that uses fusin as its second receptor if CCR-5 suddenly became unavailable. While this does not seem to be what happens in people with heterozygous genes for CCR-5, who are slow progressors, the effect of anti-CCR-5 treatment in someone with a firmly established, high viral load HIV infection might be different. At the least, any anti-binding therapy along these lines would have to include compounds that block binding to fusin and other possible HIV co-receptors as well as CCR-5.

Treatments that take advantage of the newly gained knowledge of the HIV interaction with cell walls may appear fairly soon. According to David Ho, M.D., who directs the Aaron Diamond AIDS Research Center at which many of the experiments on CCR-5 were conducted, "Many companies have looked at compounds that bind to seven transmembrane receptors [the family of receptors that includes CCR-5 and fusin] to treat neurological and cardiac problems. Many companies already have compounds but no one is talking about it."

One team that is talking about it just published a letter in Nature.12This French/Swiss/Canadian group had already been experimenting with truncated chemokines that would block CCR- 5 and similar receptors without activating the cells. Researchers were initially looking for allergy and arthritis therapies, but after the Gallo and other papers appeared, they found that one of their products, a version of RANTES missing one end, inhibits HIV very well in the test tube. The effective concentrations are ten-fold greater than natural RANTES, though. As to be expected, the truncated RANTES was ineffective against a T-cell tropic HIV strain utilizing the fusin receptor. According Ian Clark-Lewis, who was one of these researchers, "I'd like to make this molecule ten times more powerful. The next step is to try it out in animal models to see if it does anything. Also, we should try to develop a small non-protein molecule that does the same thing as the truncated RANTES since that would be cheaper and more stable."

Another potential therapy is already entering human trials. British Biotech will try out BB 10010, a MIP-1a analog, on 15 HIV-positive volunteers for one week at a London hospital. Allowable CD4 counts range from 50 to 500. This analog, which only differs from MIP-1a by having one less amino acid, was originally developed for use in cancer therapy and bone marrow transplantation.

Chilling Out the Immune System

These attempts to block chemokine receptors comes on the heels of a long line of proposals to benignly obstruct aspects of immune function that supposedly help HIV more than the body. It is apparent that this overall concept can have considerable power from comments Anthony Fauci made concerning interleukin-10 (IL-10) during his lectures at ICAAC and the International Conference. Single injections of small amounts of this anti-inflammatory intercellular messenger (cytokine) can have dramatic effects on a patient's plasma HIV levels. In the eight volunteers tested so far, using amounts ranging from one to 25 micrograms per kilogram of body weight, one quick infusion sent viral loads crashing down toward or below undetectable levels (200 copies of HIV RNA per milliliter of plasma in this case) for a short period of time. Pretreatment viral load values were not regained for one to three days, depending on the dose. It almost looked as if HIV replication had switched off momentarily.

Phase II trials with multiple IL-10 infusions are now under consideration. Dr. Fauci seems almost diffident about IL-10's therapeutic potential, though. "Am I excited? I've been in this business too long to be excited!" he said in an interview. "IL-10 proves that tweaking the cytokine balance can influence the virus, but we have to proceed very cautiously in studying its therapeutic value. IL-10 is very immunosuppressive. It could possibly increase viral load over the long run -- but let's do the trials and not speculate."

There are some solid grounds for caution because like the many other cytokines that immune system cells exchange, IL-10 has complicated, even contradictory effects. The broad- ranging activity of interleukin-10 causes cells to go from an active to quiescent state, which does not support HIV replication. Dr. Fauci's lab has found that in particular, IL-10 suppresses cellular production of IL-1, IL-6 and tumor necrosis factor-alpha.13 These three are immune stimulating cytokines are present at unusually high levels during HIV infection. and they also specifically activate HIV replication. But IL-10 itself is present at increasingly elevated concentrations as HIV infection progresses. The Fauci lab further found in test tube experiments that if IL-6 or TNF-a are present in conjunction with IL-10, then IL-10 acts with either of the two stimulators to further increase HIV's activity.14 In the body, a parallel situation could arise if IL-10's suppression of production of stimulatory cytokines turns out to be incomplete at tolerable doses. Such situations probably are avoidable by using IL-10 in conjunction with aggressive HAART drug combinations and perhaps not administering it to people whose HIV infections are far advanced.

Then there is the worry that it could turn out that "the operation was a success, but the patient died." Long-term IL- 10 therapy might result in merely trading one type of immune deficiency for another. But then, a French study with the anti-inflammatory corticosteroid prednisolone has been following its 43 HIV-positive participants for up to three years at last report15 without finding anything particularly disturbing.

Rather, an overall long-term stability in CD4 count was noted in people with baseline viral loads below 100,000 after initial CD4 jumps of 250. People with higher viral loads deteriorated after the initial CD4 increase. Due to its small, informal design the exact study results should not be taken with complete confidence. Also, prednisolone's mechanism of action differs from that of IL-10. Nonetheless, there is an indication that lengthy, generalized immune suppression is endurable by people with HIV and could be beneficial, at least in people with lower viral loads.

One Nonresponder Has the Last Laugh

Finally, here is an example of "the operation failed, but the patient thrived." Jeff Getty was having no success on his AZT/3TC/indinavir regimen (as judged by a series of opportunistic infections including PCP and bacterial pneumonia plus and an unbudging CD4 count of 30) when he received a widely criticized (and publicized) baboon bone marrow transplant last January. The transplant was an effort to create a reservoir of functioning immune cells in his body that were unaffected by HIV. Many of the skeptics did not expect him to survive the experiment for a variety of reasons, including the possibility that the baboon cells would attack the human cells in his body (graft versus host disease is a common problem even in human-to-human bone marrow transplants).

Instead, Mr. Getty's CD4 count increased to 70 before stabilizing around 50, the highest in four years. At the same time, his viral load slipped from 22,000 to undetectable levels before stabilizing at under 1,000 by the second month. He also gained 12 pounds and his chronic sinusitis and asthma disappeared. "I haven't felt this good in a long, long time - I'm now off antibiotics, which I used to eat like candy," commented Mr. Getty, who continued his AZT/3TC/indinavir regimen during and after the transplant experiment. (He also has been receiving growth hormone therapy except in the period around the transplant procedure.)

But there is no evidence that the baboon cells took root in Mr. Getty's body. An alternative explanation for his improvement lies in the mild cyclosporine and radiation therapy he received to eliminate more of his own immune system, and hence a great deal of HIV and its target CD4 cells, so as give the transplanted cells a chance to engraft. At least one similar response to such immune system "ablation" plus continued antiviral therapy during bone marrow transplantation has been reported.16 In that case, the patient died after 47 days, due to a relapse of his lymphoma, and long-term results were not available.

The cyclosporine and radiation may have "set the clock back" on Mr. Getty's HIV infection as well as reduced counterproductive immune over-stimulation. But it would be miraculous to expect permanent HIV inhibition from one immune suppressive treatment, especially in people with very advanced HIV infections. Indeed, Mr. Getty's viral load is now creeping upwards (it was 20,000 in September), although he still free of physical illness or weakness.

He also landed in the hospital at the end of August due to severe kidney stones from the indinavir he has been taking. He switched to a ritonavir/saquinavir combination, but severe nausea and diarrhea, probably from the ritonavir, made that regimen intolerable. He also was not seeing any improvement in his viral load. The latest word is that he is switching to nelfinavir through the expanded access program and looking for some new nucleoside analogs.

Mr. Getty also hopes to get another course of ablative therapy through a new pilot study in San Francisco that will look at chemotherapy plus radiation in people with advanced HIV. This study will provide some confirmation of the putative benefits of this immune suppressive approach. Meanwhile, the chief lesson in Mr. Getty's story is that something can be done for people failing the new combination therapies -- there is life after HAART failure.

Coming next month: IL-2, therapeutic vaccines and cells that inhibit virus infection -- rather than turning off various aspects of the immune system to subvert HIV, can we train the immune response to be more effective?

Reference

  1. Markowitz M et al. XI International Conference on AIDS. July 7-12, 1996; abstract LB.B.6031.
  2. Ho D. XI International Conference on AIDS. July 7-12, 1996; presentation We.A.502.
  3. Gulick R et al. XI International Conference on AIDS. July 7-12, 1996; abstract Th.B. 931.
  4. Katzenstein D et al. New England Journal of Medicine. Oct. 10, 1995; 335(10):1091-98.
  5. Cocchi F et al. Science. Dec. 15, 1995; 270(5243):1811-15.
  6. Bleul C et al. Nature. Aug. 29, 1996; 382(6594):829-33. Oberlin E et al. Nature. Aug. 29, 1996; 382(6594):833-35.
  7. Dragic T et al. Nature. June 20, 1996; 381(6584):667-73
  8. Liu R et al. Cell. Aug. 9, 1996; 86(1).
  9. Dean M et al. Science. Sept. 27, 1996; 273(5282):1856-61
  10. Dragic T et al. XI International Conference on AIDS. July 7-12, 1996; abstract Mo.A.275.
  11. Schmidtmayerova H et al. Nature Aug. 29, 1996; 382(6594):767.
  12. Arenzana-Selsdedos F et al. Nature. Oct. 3, 1996; 383(6599):400.
  13. Weissman D et al. AIDS Research and Human Retroviruses. Oct., 1994; 10(10):1199-1205.
  14. Weissman D et al. Journal of Acquired immune Defiicency Syndromes and Human Retrovirology. Aug. 15, 1995; 9(5):442-9.
  15. Andrieu, JM. HIV Immune-based Therapies Workshop. Clinical Immunology Society. Jan. 26-28, 1996.
  16. Holland HK et al. Annals of Internal Medicine. Dec. 15, 1989; 111(12):973-81.


Anti-HIV Agents at ICAAC

by Theo Smart

After satiation at the International Conference in Vancouver, the usually informative yearly Interscience Conference on Antimicrobial Agents and Chemotherapies (ICAAC) held in New Orleans, September 15-18 seemed to offer only Cajun-spiced bread crumbs to many seeking information on new anti-HIV treatments. The optimism evidenced at Vancouver, though, had been a once-in-a-lifetime distillation, brewed from an improved understanding of the dynamics of viral replication and resistance, as well as the potency of the new anti-HIV drugs. During the opening plenary ICAAC, leading virologist Douglas Richman, M.D., of the University of California, San Diego, noted that what happened at Vancouver was a " shift in treatment strategy, from palliation with sequential monotherapy to complete suppression" with potent combination therapy.

Dr. Richman reviewed how the development of viral mutations that confer resistance to antiretroviral drugs has given the virus an upper hand in the battle against it. He believes that while single mutations that confer resistance to one drug generally exist before treatment with that drug is initiated, multiple mutations are required to defeat protease inhibitors and combination therapy. This resistance must evolve over time, which requires that a low level of viral replication continue in the presence of therapy. To keep the virus in check indefinitely, there needs to be truly complete suppression of the virus in all the body compartments in which the virus finds a home.

The growing number of reports of people who experience a rebound in viral load while on combinations that include a protease inhibitor indicate that this complete viral suppression is not being accomplished in all patients. The failure of the combinations to contain the virus may be due to heavy pretreatment with nucleoside analogs. It also should be remembered that nucleoside analogs often fail to suppress the virus even in the absence of mutations conferring resistance. This may be because natural processes in cells need to alter these nucleoside analogs before they become active against HIV, and this intracellular activation may decrease over time. Or perhaps treatment fails because the adverse effects of drugs such as ddI, AZT, d4T and ddC understandably lead patients simply to stop taking the pills over time. Resistance to the combinations also may evolve because they just do not penetrate every part of the body in which the virus resides, or because they are not quite bioavailable or potent enough (see the HAART articlein this issue by Dave Gilden).

ICAAC did offer a few new leads that may push us a little closer toward finding a truly optimal combination of drugs, or at least providing options to switch to after failing indinavir/AZT/3TC, or whatever cocktail one is currently ingesting. The new data include a further follow-up report on the combination of ritonavir and saquinavir, a report on the antiviral activity of the Glaxo Welcome/Vertex protease inhibitor 141W94, test-tube data on novel protease inhibitors from Ciba-Geigy and Gilead, plus the first antiviral data on the combination of a non-nucleoside reverse transcriptase inhibitor with a protease inhibitor (in this case DuPont Merck's DMP 266 plus indinavir).

141W94

The safety and antiviral activity of 141W94, the protease inhibitor that Glaxo Wellcome licensed from fledgling biotech Vertex, has been under investigation in a dose-ranging study that started last November. The time it has taken for the company to release data on the compound is longer than usual and rumors of the drug's activity or lack thereof have flourished. The interest in this drug is particularly intense because of preclinical reports that, in contrast to the other protease inhibitors, levels of this drug in the brain tissue of animals was equal to or greater than levels of the drug in the blood (170%), suggesting that this drug would reach viral reservoirs in the brain. Also, Glaxo Wellcome has made claims that the drug may be active against most, though not all, viral strains resistant to indinavir or ritonavir, making this drug an appealing option for anyone who has failed on those treatments.

The long-awaited data were meager, but did confirm that the drug has an antiviral effect which increases with the dose (abstract LB7a). Four-week data were available for the first four doses studied: 300 mg two or three times a day and 900 or 1,200 mg twice a day. Around ten people were enrolled in each arm, with a median baseline CD4 count of 282 cells and viral load of 4.83 logs. The lowest dose only reduced viral load by 0.58 log at peak, the next two highest doses were significantly more potent at peak, but the effect for all three lower doses lessened by week four at around a half a log below baseline. The highest dose reduced viral load by almost 99 percent (1.95 log reduction). This drop was sustained through the fourth week.

It is not clear that the lower doses are failing due to the development of resistance. The reduced antiviral effect may be because there are decreased levels of drug in the blood after the first couple of weeks on therapy, due to the way 141W94 is metabolized by the liver. The same phenomenon has been observed with ritonavir.

CD4 counts increased by a range of 35 to 110 cells over the four week study. Side effects were mostly mild, although two patients discontinued the study due to serious rash and one person quit because of worsening of colitis. Nine of the study's total of 42 enrolled patients had loose stools (similar to what has been reported for nelfinavir).

Three people bravely elected to undergo lumbar punctures so that the researchers could gauge the level of drug that reached the CSF, which was found to range between 0.45 to 1.3% of what was seen in the blood. The study's presenter, Chip Schooley, M.D., said that these were " very preliminary data that we decided to present in light of the early reports of very high levels of the drug in [the brains of] animals." Dr. Schooley says that two of these patients were on lower doses in the study. Also, in contrast to the animal studies that measured the drug levels in brain tissue at various timepoints (with the peak occurring five hours post-dosing), these were measurements of drug concentrations in the CSF at one timepoint two hours after dosing. Since protease inhibitors bind to protein, and cerebrospinal fluid has low levels of protein in relation to brain tissue, it could be expected that drug levels would be lower in the CSF.

Nevertheless, Dr. Schooley notes that the level of drug that reaches the brain is " clearly not 170% of what is seen in the plasma." Even so, he believes that the levels in the brain may still be adequate to treat the virus. Such antiviral concentrations were found in the patient with the highest CSF drug level. This patient also had very high blood levels of the drug, though.

In a meeting with activists, Glaxo Wellcome detailed its ongoing and planned studies for 141W94. The present dose- ranging study is evaluating four other dosing regimens. The company also is planning dose-ranging studies of 141W94 in combination with the other protease inhibitors. Pivotal clinical endpoint studies are slated to begin in the first quarter of 1997. Activists have been working to convince Glaxo Wellcome to commit itself to an expanded access program at roughly the same time.

Ritonavir/Saquinavir

The data from the ongoing study of ritonavir and saquinavir presented at ICAAC were similar to what was reported at Vancouver (see the August Treatment Issues, page 5). The antiviral effect now seems to be increasing with time, and there also are newly collected six-week data on the more recently initiated higher doses (abstract LB7b).

The study has enrolled at least 136 patients split into four groups receiving either 1) 400 mg ritonavir plus 400 mg saquinavir each twice a day, 2) 600 mg ritonavir plus 400 mg saquinavir, again, both twice daily, 3) 400 mg ritonavir plus 400 mg saquinavir each three times a day, or 4) 600 mg ritonavir plus 600 mg saquinavir both twice daily. The mean baseline viral loads between the arms ranged from 4.29 to 4.72 logs, and CD4 counts were between 278 to 313 at baseline.

Each arm had a profound effect on viral activity. By week twelve, doses one and two reduced viral load by 2.74 and 3.06 logs, respectively. Doses three and four dropped viral load by 2.09 and 2.19 log respectively by week six, which is very similar to (actually less than) the 2.43 log reduction after six weeks for group one reported at Vancouver. CD4 cell count increases for groups one and two at week 12 were 80 to 100 cells, and at six weeks 60 to 70 cells for groups three and four. None of these differences are statistically significant.

Circumoral paresthesia (numbness around the mouth and tongue), nausea, diarrhea and fatigue continue to be the most common toxicities. Elevated triglyceride levels have been observed as well, although this has not been associated with any physical effects. All doses seem to be equally well tolerated except for the three times daily dosing regimen. Although the drug-related adverse events do not seem to be more common on this arm, they may be more severe since they have led eight people to discontinue treatment (with only four discontinuing on the other three arms combined).

Other Protease Inhibitors

At least three other companies presented laboratory findings on protease inhibitors that may be effective against viral strains resistant to both indinavir and ritonavir. Pharmacia & Upjohn's compound was scheduled to be in dose-ranging studies by now, but these trials have been put off for several weeks because of a temporary shortage of one of the drug's primary ingredients (abstract I5).

In several ways, the protease inhibitor development programs at Gilead and Ciba-Geigy share much in common. Each company has a very potent protease inhibitor poised to enter human studies that would be much simpler to manufacture and therefore, one hopes, less expensive than the currently marketed drugs. It is too bad that these two protease inhibitors show dramatically reduced activity against virus that is resistant to ritonavir and indinavir.

Meanwhile, both companies have other compounds, also very potent and relatively simple to make, that are active against ritonavir/indinavir resistant virus (abstracts I3 and I5 for Gilead's compounds, and I6, I7 and I156 for Ciba-Geigy's). Ciba-Geigy's drug may be the more interesting, as the company has demonstrated that its protease inhibitor is also active against virus resistant to saquinavir and 141W94 as well. Each company realizes the advantage these compounds would have since there will soon be a large group of people who have failed or become resistant on the Merck and Abbott drugs. Both companies would prefer to quickly move these agents into human studies. The hitch is that in certain animal studies their drugs seem to be poorly absorbed by the digestive tract. So for the time being, each company is slowly proceeding with their first class of protease inhibitors while trying to quickly solve the bioavailability problem that limits the potential of the second generation drugs.

DMP 266

The first data on the activity of a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with a protease inhibitor were presented at ICAAC (abstract LB8a). DuPont Merck's DMP 266 is a unique NNRTI in that HIV seems slower to develop resistance to it than to delavirdine or nevirapine. The study randomized eleven patients to DMP 266 (200 mg a day) alone and five patients to placebo for two weeks. All patients were then given indinavir as well for an additional 12 weeks. Baseline mean viral load was 5.1 log (126,000 thousand copies/ml), and the mean CD4 cell count was 249. At the end of the second week, DMP 266 lowered viral load by more than 98% (1.68 log) and boosted CD4 cell counts by 96 cells. After the addition of indinavir to DMP 266, viral load dropped by a mean of 3.2 logs (more than 99.9% and surprisingly similar to what is seen with ritonavir/saquinavir).

These results may appear more dramatic than than for other antiretroviral combinations, but other trials count 400 copies/ml as the minimum viral load. The DMP 266 study included the less reliable viral load figures that fell below 400. Such a maneuver can have a dramatic effect when you consider that a reduction to 4 copies/ml is 2 logs greater than a reduction to 400 copies/ml.

Still, there was a strong trend for the reduction in viral load to be superior to the reduction seen with indinavir alone. Eighty percent of those on combination had " undetectable" viral loads (below 400 copies/ml) at the combination's peak effect, but by week twelve only 55% were below the limit of the assay's detection, which still compared favorably to the 20% below the limit of detection on indinavir monotherapy. CD4 cell counts jumped by more than 100 from baseline in all patients treated with indinavir.

The most commonly reported adverse events were rash, headache, dizziness and diarrhea, but none of these events was severe enough to lead any participant to quit the study. One potential "adverse event" of DMP 266 was that it lowered blood plasma levels of indinavir by 37%. This could mean that the blood levels of indinavir are too low to suppress HIV over the long term. The added antiviral effect of DMP 266 could counter the reduction in indinavir levels since resistance can only occur when there is enough residual replication to allow for it to evolve. The lower levels of indinavir may also reduce the potential for kidney stones. Nevertheless, preferring to err on the side of caution, the study investigators are expanding this study and investigating higher doses of both drugs.

A few other clinical trials of DMP 266 are currently enrolling participants. Two are evaluating different doses of the NNRTI in combination with AZT/3TC. One study will enroll people with at least two months of experience on AZT/3TC, and one is for treatment-naive patients. Another opening this month will compare DMP 266/indinavir/AZT/3TC to indinavir/AZT/3TC in 330 patients who are naive to DMP 266, 3TC or protease inhibitor and have CD4 cell counts between 50 and 500, with viral loads of at least 20,000. For information on sites near you, call 800/877-8899.


Nelfinavir Expanded Access Program

On September 16, Agouron Pharmaceuticals opened a program to provide expanded access to its experimental protease inhibitor nelfinavir (brand name: Viracept). The program is open to anyone with HIV and CD4 cells below 50 who is unable to use any of the three approved protease inhibitors " because of intolerance, contraindication or prior failure." These criteria were established with an eye toward limiting enrollment in the expanded access program to 500 persons per month, the maximum Agouron says its nelfinavir supply can accommodate. The entry restrictions may loosen if fewer than the expected number of people apply. Doctors, health care providers or patients interested in the program can call 800/621-7111 for further information.

It is not clear how effective nelfinavir may be in people that harbor virus resistant to ritonavir and/or indinavir. Most virus that has become resistant to either of these two is resistant to nelfinavir as well.

Also, taking nelfinavir in combination with another new drug (or two) offers the best chance of enjoying a sustained antiviral effect. It is unfortunate that no company has had the foresight to conduct a drug interaction study with nelfinavir in combination with delavirdine or nevirapine. These two newly available drugs usually can be added with advantage along with nelfinavir to antiviral regimens since few people have as yet been exposed to them.-TS


Cidofovir Warning

Following new reports of severe kidney damage, Gilead Sciences, has inserted a black-bordered warning box into the package insert for its new anti-CMV retinitis drug cidofovir (brand name: Vistide). The box declares that it is of utmost importance that clinicians closely follow new guidelines for safe usage of this drug. Even when the treatment is discontinued, the product labeling notes elsewhere that the kidney damage may be permanent. There have been cases in which kidney dialysis was required to compensate for the kidney damage. This damage even proved fatal on one occasion. The drug's usage guidelines now clearly state that cidofovir should not be used at the same time as other drugs that are toxic to the kidneys or in patients with impaired kidney function (as indicated by serum creatinine levels above 1.5 mg/dl, a creatinine clearance of 55 ml/min. or less, or a urine protein level above or equal to 100 mg/dl). Laboratory tests for kidney malfunction must be undertaken both before and 48 hours after starting cidofovir. If cidofovir causes serum creatinine to rise by more than 0.3 to 0.4 mg/dl over a patient's pretreatment reading, or if 2+ proteinuria occurs, the dosage of cidofovir should be reduced. If serum creatinine increases by more than 0.5 mg/dl, or 3+ proteinuria develops, the patient should be taken off cidofovir altogether.

In addition to these warnings, the labeling dictates that people who have been on other kidney-toxic drugs must terminate those drugs at least a week before starting cidofovir. (Among such drugs is foscarnet, a drug many people with CMV retinitis may have used before switching to the only recently approved cidofovir.) Also, the guidelines mandate strict adherence to the schedule for administering probenecid and intravenous hydration on the day of the cidofovir infusion. To protect the kidneys, two grams of probenecid must be taken three hours before the cidofovir infusion, one gram two hours after the infusion and again eight hours that. Intravenous hydration with one liter saline solution should take place over a one-to-two hour period immediately before the cidofovir infusion. If the patient can tolerate a second liter, it should be infused over a one-to-three hour period, either in a period overlapping the 60 minute cidofovir infusion or immediately afterwards.

Although Gilead has gone to great effort to inform clinicians of the proper usage of cidofovir, sending out letters to over 35,000 HIV-treating physicians, the clarity of the new guidelines is perhaps overdue. Studies have shown that the drug can be safely and effectively used, but the close monitoring that participants in drug trials receive is rare in general medical practice. When cidofovir was being considered for approval by the Food and Drug Administration last summer, many activists were concerned that " in the real world, patients would not be followed rigorously enough, resulting in adverse event rates not seen in the cidofovir trials" -TS


ICAAC's Future Fungal Fighters

by Theo Smart

Although there have been many changes in the treatment of certain opportunistic infections such as CMV over the last year, little has changed in the treatment of fungal infections since the introduction of fluconazole and itraconazole. At the same time, the rate of azole resistance has increased dramatically. The central role that these two azoles play in the treatment of fungal infections and fear that resistance will develop to the drugs has led a number of clinicians to be cautious about over using them as prophylaxis or for mild cases of candidiasis. When azole- resistant fungal infections crop up, there are few alternatives available.

The toxicity and inconvenience of amphotericin B make it the treatment of last resort. Meanwhile, controlled clinical data on the easier-to-tolerate liposomal formulations of amphotericin and nystatin have been long awaited. Liposomal formulations involve surrounding medically active compounds with tiny fat globules that allow the drugs to reach their targets with fewer adverse effects on other tissues. Information on the use of these drugs is beginning to trickle in (see below), but even if safer, these liposomal compounds still must be intravenously administered and this limits their usage to acute infections. But a note of optimism is emerging: The large number of presentations at ICAAC on new agents that attack fungi in new ways suggest that the treatment of fungal infections will undergo major changes over the next few years.

AmBisome vs. Amphotericin B for Cryptococcal Meningitis

There have been a number of case reports suggesting that Fujisawa and Vestar's AmBisome can effectively treat cryptococcal meningitis, even in patients who have failed on amphotericin B. At ICAAC, Dutch researchers presented the first placebo-controlled study comparing the two intravenous treatments (abstract LM35). Twenty-eight volunteers were randomized to receive three-week induction therapy with AmBisome (4 mg per kg a day) or amphotericin B (0.75 mg per kg per day). The median time to clearance of the infection from the cerebrospinal fluid was 14 days for AmBisome and more than 21 days for amphotericin B, which was statistically significant. The median time to improvement of meningitis symptoms was not significantly different, though.

Amphotericin B was significantly more toxic to the kidneys, although those on AmBisome did experience some increase in levels of serum creatinine (greater than 50%). Two patients on amphotericin B stopped treatment due to toxicity compared to no discontinuations on AmBisome. The study's presenter, Dr. Leeanders of the University Hospital in Rotterdam, concluded that "in a larger study, AmBisome may lead to a sooner response. [It] is probably the most effective available treatment for those with cryptococcal meningitis" AmBisome has yet to be approved in the U.S. even though it has been marketed in Europe and Mexico for several years. Fujisawa is now running studies evaluating the drug in neutropenic patients and in people with HIV and cryptococcal meningitis.

New Azoles

At least two new azole antifungal drugs similar to fluconazole and itraconazole have entered into human studies. Azoles block the spread of the fungi by slowing the synthesis of sterols needed by the fungus to grow. Voriconizole, made by Pfizer (abstracts F81-F86) and Schering-Plough's SCH 56592 (abstracts F87-F103) both purportedly are active against fluconazole-resistant candida, and have dramatically improved activity against other fungal organisms such as aspergillosis and histoplasmosis. In light of the history of the azole drugs, though, it seems likely that with increased use over time, the new azoles will also demonstrate increased cross- resistance with fluconazole and itraconazole. For example, despite early hopes, itraconazole has not proven to be particularly effective against fluconazole-resistant fungal infections.

Both voriconazole and SCH 56592 now have been evaluated in dose-ranging studies. Phase II clinical studies of voriconazole are complete, although the data are yet to be released. Three phase III clinical endpoint studies of voriconazole for invasive aspergillus, serious candida, and as empiric therapy for invasive fungal infections in neutropenic patients are anticipated to begin in Europe by the end of the year, and to expand into the U.S. in the beginning of 1997.

Meanwhile, Schering-Plough refuses to discuss with Treatment Issues where or in what population the clinical trials for SCH 56592 are being conducted, saying only that the oral form of the drug was in international early phase studies for " serious systemic infections." The company president and CEO Richard Kogan, though, has publicly said that the trials began in April, and that the drug was " orally active" (see SCRIP June 11, pg. 8).

Pradimicin

Bristol-Myers has a new antifungal, pradimicin, derived from a bacteria. Some antifungals, such as amphotericin B, kill fungi by punching holes in the fungal cell wall. Pradimicin works in a similar way but by binding to sugars in the fungal cell wall, which disrupts the membrane's integrity. Other studies previously have reported that this class of compounds also has both anti-HIV activity and anti-PCP activity. Unfortunately, these compounds do not appear to be absorbed orally.

Laboratory and animal studies presented at the conference documented that pradimicin is active against aspergillosis, candida and cryptococcus (abstracts F179-F183). Although no pradimicin-associated toxicity was observed in rabbits or mice, some possibly drug-related liver enzyme elevations have been noted in dose-ranging human studies of intravenous pradimicin. Bristol-Myers currently is reviewing the data from these early studies before deciding whether to move ahead with this compound or one of its more than 200 analogs.

The Echinocandins

Two members of a new class of antifungal drugs known as echinocandins have entered clinical trials. One, L-724,872, is owned by Merck, and the other, LY303366, by Lilly. As opposed to the antifungal azoles, which merely block growth of fungus cultures, echinocandins kill the fungi by interrupting the synthesis of ß-1,3 glucan, an integral part of the fungal cell wall. This cell wall component is not found in mammalian cells, raising the hope that the drug will prove less toxic than amphotericin B, which can cause channels to form in the walls of both fungal and mammalian cells.

In laboratory and animal studies, the echinocandins show activity against histoplasma, difficult-to-treat aspergillosis and azole-resistant candida. By themselves, the echinocandins do not seem to be active against the fungi that cause cryptococcal meningitis, but one study noted that L- 743,872 was synergistic with amphotericin B and fluconazole against this disease (abstracts F36, S25).

In one poster at the conference, evaluating the use of L- 743,872 in mice, an echinocandin was shown to have activity against Pneumocystis carinii during one stage of its life cycle (abstract F42). It is unclear whether these drugs will prove useful as a treatment of acute PCP, since they kill only the cyst form of the parasite (which can be thought of as the egg) but not the active parasitic form found during acute infection.

Merck's L-724,872 has been well tolerated in phase I dose- ranging studies. Unfortunately, the drug is not absorbed orally and must be given as a once-a-day intravenous infusion. This requirement will reduce the drug's use in clinical practice. Currently L-724,872 is in phase II non- U.S. studies in patients with people with HIV and esophageal candidiasis.

Lilly's LY303366 is bioavailable when taken orally. A dose- ranging study reported at the meeting showed that the drug is very well tolerated, causing mild-to-moderate diarrhea and abdominal pain only at very high doses (abstract F50). Much lower doses achieved blood levels of the drug more than adequate to suppress candida. The drug has a very long half- life that will allow for once-a-day dosing. Lilly is currently conducting a dose-ranging study of LY303366 in 160 people with HIV and oral candidiasis.

Other Compounds

The above is just a short list of some of the more advanced compounds. There were many other compounds in earlier stages of development. Shaman Pharmaceuticals reported on an antifungal, Nikkomycin Z, that blocks the synthesis of fungal chitin, used in making the fungal microorganisms' exoskeletal structure (abstracts F189 and 190). XOMA Corp. reported on a synthetic peptide, Mycoprex, that also kills the fungus by increasing the permeability of the fungal cell wall but that acts earlier in the fungal lifecycle than amphotericin B (F185, 186 and 187). Many of these presentations noted synergy with other available antifungal drugs.

The development of another class of well-tolerated oral antifungals could ultimately reduce the incidence of azole- resistance or provide a feasible option for instances when such resistance arises. There is also the possibility that antifungal medications could be combined for hard-to-treat infections. Appropriate drug combinations also could create less invasive and less toxic induction therapy for conditions such as cryptococcal meningitis. If a drug also proves active as a prophylaxis for PCP, it could provide an alternative for those intolerant to sulfa drugs, or reinforce prophylaxis in the substantial number of patients with breakthrough infections on Bactrim/Septra during late-stage disease. But it is too soon to say whether any of these drugs will be effective in humans. Further information, no doubt, will be available at upcoming conferences -- certainly by next year's ICAAC.




  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 

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