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GMHC Treatment Issues
May 1996

Contents


Viral Entry Discovery 
Suggests New Treatments

by Theo Smart

A central mystery surrounding the infection of CD4 cells by HIV appears to have been solved by Edward Berger, M.D., and colleagues at the National Institute of Allergy and Infectious Diseases (NIAID). Scientists have long known that the envelope protein of HIV binds to the CD4 receptor on certain types of white blood cells. But that action by itself was not adequate to fully explain how the virus fuses with and inserts its genetic material into a cell. In fact, non-human cells altered to bear the human CD4 receptor were not infectable with the virus. There had to be an unidentified co-factor on human cells to which the virus clung, and investigators have spent a decade searching for it.

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The NIAID investigators now have identified the co-factor as a cell surface protein they call fusin due to its pivotal role in helping HIV fuse to CD4 cells. Their discovery reportedly rapidly has been confirmed by a number of other labs. The discovery of fusin is considered a breakthrough not only because it reveals a new target for anti-HIV drugs but because it may lead to the first true animal model for HIV infection.

Gene Libraries

Dr. Berger's team already had a model for HIV fusion using mouse cells modified to carry CD4 receptors. But, again, merely having a CD4 cell receptor did not make the mouse cell susceptible to HIV infection. To find the fusion cofactor, the researchers introduced a series of genes from a human CD4 cell line into the genetically engineered mouse CD4 cells and fusion occurred. Certain that one of these human genes was making a protein that allowed fusion, the researchers used a process of elimination to isolate the gene responsible for the fusin protein.

The fusin gene proved to be a member of the gene family that produces "G protein-coupled" cell receptors, often exploited by other viruses when entering cells. In contrast to the protruding CD4 receptor, G protein-coupled receptors weave in and out of the cell membrane. They form a depression that usually contain these receptors' critical binding region. If HIV binds to such a receptor on CD4 cells, it is already partially inside the cell.

Fusin as an Antiviral Target

To see whether fusin protein was required for infection of human CD4 cells, the researchers mixed CD4 cells with antibodies to fusin and effectively blocked infection of the CD4 cells. Antibodies to the V3 loop on the HIV envelope protein molecule gp120 also blocked fusion, suggesting that HIV binds to fusin via this highly conserved loop, although this has yet to be demonstrated. A number of other researchers have also observed that antibodies to the V3 loop neutralize the virus and block fusion.

Besides underscoring that fusion could not occur without fusin, the antibodies' antiviral activity raised the prospect that compounds interfering with this protein may block infection of CD4 cells.

But if this cofactor plays a role in the infection of CD4 cells, it would seem that simple drug screening tests would have picked up fusin blockers long ago, even if no one understood exactly how the drug worked. Indeed, other researchers screening potential anti-HIV drugs have found a few compounds believed to inhibit viral entry other than by blocking gp120 binding to the CD4 receptor. These chemicals include Rhône-Poulenc Rorer's betulinic acid derivatives, distamycin analogs from Pharmitalia, and the bicyclam compounds owned by Johnson Mathey.

"It is possible that some of these compounds actually interfere with fusion," says William Rice, Ph.D., head of the Laboratory of Antiviral Drug Mechanisms at the National Cancer Institute (NCI). It is conceivable, too, that these compounds bind to the part of the gp120 V3 loop that may attach to the fusin receptor. A recent laboratory study of the bicyclams found that HIV reacted to these compounds precisely by acquiring resistance-conferring mutations in the V3 loop.

None of these substances have made it into human studies, and Rhône-Poulenc says it has stopped research into betulinic derivatives due to poor "pharmacodynamic properties." Rice thinks that many pharmaceutical companies have a bias against drugs that act at this stage of the infection process: "It's very hard to push forward surface-active agents [drugs that prevent the virus from entering the cell]," he says, "because of the problems with dextran sulfate and some of the other sulfated polysaccharides." These drugs blocked infection by coating the surface of the cell, but they also caused hemorrhaging in clinical trial participants.

According to Dr. Rice, the NCI currently is planning clinical trials of one of the Pharmitalia compounds, which has recently shown anti-HIV activity in an animal model. Dr. Rice believes that the discovery of the fusin protein will lead to the development of more precise laboratory tests more capable of detecting more fusion-specific inhibitors. Meanwhile, Johnson Mathey wants to launch phase I studies of JM3100 within the year. This company's biomedical group is small, though, so the company is trying to get help to run the studies from the AIDS Clinical Trials Group.

One problem with developing drugs that directly block fusin, is that no one yet knows what human protein normally binds to it. Antivirals that work by blocking fusin may interfere with its natural function. The part of the natural ligand that binds to fusin also may share homology with sequences from the V3 loop of HIV. Some researchers have found similarities between segments of the V3 loop and parts of MHC-II proteins, involved in antigen presentation to CD4 cells.

The Chemokine Connection

Another potential shortcoming of anti-fusin drugs is that the researchers found that although the protein seemed necessary for the infection of CD4 cells, anti-fusin antibodies had no effect on the infection of macrophages. Drugs that are too specific to fusin may not block infection of macrophages. [Last minute note: Anne Bousseau, Rhô4ne-Poulenc's AIDS Program Director, told Treatment Issues that betulinic derivatives also block HIV entry into macrophages. These compounds interact with gp120 outside the V3 loop and produce an effect more general than mere inhibition of V3 loop-fusin would produce.]

Dr. Berger's team observed that fusin closely resembles a receptor for IL-8, one of the chemokines involved in directing lymphocytes to infected tissue. The group believes that a different but possibly related cofactor allows the HIV to fuse to macrophages. This suspicion is strengthened by reports that the V3 loop of gp120 determines cell tropism -- strains of HIV that infect macrophages more efficiently have slightly different V3 loops than the HIV that concentrates on CD4 lymphocytes. Given the similarity between fusin and the IL-8 chemokine receptor, the fusin-like protein on macrophages may be the receptor for Dr. Robert Gallo's anti-HIV chemokines: Rantes, MIP-1a and MIP-1b (see Treatment Issues article HIV Suppressors Found in Cells; January 1996, pages 10-12). The evidence for this association is circumstantial at present.

Animal Models

Even if this breakthrough in basic science does not lead to any new therapies, it may have one other practical implication: the development of a small animal model for HIV. The lack of the fusion co-factor had made this impossible. Scientists could alter mouse or rabbit cells to carry human CD4 cell receptors, but these cells could not be infected with HIV. Now, with the same gene altering techniques that the team used to isolate the fusin gene, they could genetically modify animals to have lymphocytes with both human receptors. Such an animal model would speed the identification and development of the most promising anti-HIV compounds.


Protease Inhibitor New Math

by Dave Gilden

Two months have passed since three protease inhibitors became commercially available in the United States. In this period, the three corporate sponsors, Abbott, Merck and Roche, have jockeyed for market share, with varying degrees of success. Each of the companies' products, respectively ritonavir (brand name: Norvir), indinavir (Crixivan) and saquinavir (Invirase), have encountered various controversies stemming from the conditions under which each compound is manufactured and administered. In each case, a peculiar brand of mathematics has been employed to resolve seeming contradictions. We review below these new developments, both pharmaceutical and mathematical.

Zero plus Zero Equals One

On May 7, Hoffmann-La Roche released the final clinical data on its North American trial NV14256. Preliminary surrogate marker (viral load and CD4 count) from this 1,000-person trial were presented to the FDA last fall as part of the package supporting marketing approval of the drug (see Treatment Issues articles, FDA Triple Header,November 1995, page 2 and A Kinder, Gentler ddC... For &7,200 a Year, December 1995, page 2). The trial tested saquinavir plus the nucleoside analog ddC (also a Roche drug) against either drug alone in volunteers previously treated with AZT. The initial surrogate marker data made the combination look only slightly better than saquinavir or ddC monotherapy. This observation was a big disappointment considering that protease inhibitors are supposed to be a powerful new drug class whereas tolerable doses of ddC have weak antiviral activity even compared to other nucleoside analogs. At the time, Treatment Issues concluded, "Saquinavir's main advantage is that it is a relatively benign way of slightly boosting the mediocre performance of nucleoside analogs... but the retail price is $7,200 per year!" The new data on progression to AIDS and deaths (final surrogatemarker data have yet to be released) document the extent to which saquinavir supplements nucleoside analog therapy. Once again, ddC and saquinavir monotherapies came out nearly the same, but the combination therapy results exhibited greater superiority over monotherapy than one would expect from the available surrogate marker data (see table below).

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

A major limitation of the NV14256 trial is that one still cannot tell how saquinavir plus ddC stacks up against the more potent nucleoside analog combinations (for example, d4T plus 3TC or ddI or AZT/3TC) in the advanced, AZT-experienced population under examination. The ongoing international trial comparing AZT/saquinavir to AZT/ddC to the triple combination in treatment-naive volunteers will partly fill this gap.

Roche has developed a new "soft gel capsule" formulation of saquinavir that is much better absorbed by the stomach. It is hoped that this improved version will help the compound fulfill the anti-HIV potential it displayed in the lab. A 400 person, 48-week trial of the soft gel capsule plus participants' choice of nucleoside analogs is now fully recruited. The saquinavir dose used in this trial (1,200 mg three times daily, twice the current recommended dose of the present formulation) achieves peak blood levels eight times that attained by the current regimen with the marketed formulation.

A trial combining saquinavir with ritonavir is also in progress (see Treatment Issues article, Matching Up Ritonavir with Saquinavir, Apr. 1996, page 8). Adding ritonavir inhibits breakdown of saquinavir by the liver and can raise saquinavir blood levels ten-fold. Combining the two protease inhibitors probably would allow for reductions in the recommended dosing of one or both drugs while enhancing their anti-HIV efficacy.

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

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

Final Clinical Data from NV 14256

AIDS-Defining Events
Regimen or Death
Death Alone
ddC
85
28
Saquinavir
77
34
Saquinavir plus ddC
46*
9*
*statistically significant compared to the two monotherapies


Characteristics of participants:
number: 978
CD4 counts: 50-300 (median of 160-180 depending on the treatment)
prior AZT: at least 16 weeks (median of 18 months)
time on assigned therapy: ddC -- 43 weeks; other two -- 56 weeks
median follow-up: 73-74 weeks

The Incredible Shrinking Markup

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

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

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

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

After some start-up troubles, the system is operating fairly smoothly, most people report, although the turnaround time for orders is at least four days, and can be several weeks, not the 48 hours Merck originally envisioned.

The biggest controversy has been the price Stadtlanders is asking. Merck's wholesale price for a year's supply of indinavir is $4,380, and Stadtlanders originally wanted $6,022.50 retail for the same amount of drug. This exceptionally high 37.5 percent markup was a disappointment considering that Merck seemed to be intentionally limiting its per unit profit in order to create a larger total market for indinavir. The retail price sparked wide protests and calls for a boycott especially from ACT UP chapters in New York, Philadelphia and San Francisco (ACT UP/Golden Gate) as well as the PWA Health Group, also in New York City. Stadtlanders immediately argued that 80 percent of patients on indinavir were receiving a substantial discount due to negotiations with their reimbursers (HMOs, Medicaid, etc.).

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

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

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

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

Ritonavir Plus Other Drugs

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

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

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

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

Coming Up: Does One plus One Equal One?

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

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

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


How Ritonavir 
Affects the Body's Processing 
of Concurrent Medication

Except for the last table, the interactions listed here are all theoretical predictions based on the way the liver is thought to metabolize the listed drugs and ritonavir's known inhibiting and inducing effects on that metabolism. The simple two-drug interactions in the table do not take into account other drugs a patient may be receiving (interactions between three or more drugs), nor does the table allow for interpersonal biochemical variations, especially abnormal liver function. The adequacy of the proposed drug substitutions has not been established, nor is their safety assured. Their levels may be altered by ritonavir, and individuals could experience undesirable changes in these drugs' toxicity and activity. (This issue has been raised in particular about Prozac, whose blood levels ritonavir may increase.) Direct monitoring of blood concentrations is frequently advisable. Drugs whose blood levels can be tested readily are marked with a ¤.



Never use concurrently with ritonavir:
(narrow therapeutic window)

Drug Class Drug Names Possible substitutions

analgesic

Demerol, Feldene, Darvon

Tylenol, aspirin, Percodan

antihistamine

Hismanal, Seldane

Claritin

antimycobacterial

rifabutin (see below)

clarithromycin (see below), ethambutol

cardiovascular
(antiarrhythmic)

Cordarone, Enkaid, quinidine,Tambocor,
Rythmol

safe alternatives unidentified; little clinical experience

cardiovascular
(calcium channel blocker)

Vascor

little clinical experience
(see below)

gastrointestinal

Propulsid

little clinical experience

psychotropic, antidepressant

Wellbutrin

Prozac¤, desipramine¤
(see below)

psychotropic,neuroleptic

Clozaril, Orap

little clinical experience

psychotropic,sedative/hypnotic

Ambien, Dalmane, Halcion, Restoril, Ativan Prosom, Tranxene, Valium,Versed, Xanax

(blood levels decreased by ritonavir)


Other notable predicted effects:

Drug Predicted Effects

analgesic

Ritonavir is predicted to greatly raise levels of fentanyl and methadone (monitor effects, reduce methadone dose by half) but may reduce levels of many opiates (including codeine, Dilaudid, heroin, morphine and Vicodin).

antibiotic

Erythromycin and Flagyl levels may increase substantially.

anticancer

Tamoxifen levels may increase very greatly.

anticonvulsant

Monitor blood levels. Phenobarbital¤and Dilantin¤ may reduce ritonavir levels.

antidepressant

Levels of most antidepressants¤ may increase substantially (monitor effects).

antifungal

Sporanox and Nizoral levels may increase substantially.

antimycobacterial

Rifampin levels may increase very greatly. Also, liver function test elevations observed -- reduce dose and monitor.

cardiovascular

Levels of most calcium channel blockers may rise greatly.

gastrointestinal

Lomotil levels may decline; the effect on Imodium is unknown. Marinol levels may rise.

immunosuppressant

Cyclosporine and FK-506 levels may increase very greatly.

steroid hormone

Levels of most anabolic steroids (including testosterone) and corticosteroids may increase substantially. Megace is probably unaffected.

thalidomide

Levels may rise substantially.


Results of actual drug interaction studies:


Concurrent Drug

Finding

Bactrim/Septra

20% decrease in total exposure (as measured by "area under the curve, "or AUC). No dose adjustment needed.

clarithromycin

77% increase in total exposure ( AUC). No dose adjustment in people with normal kidney function.

desipramine¤

145% increase in total exposure (AUC). Consider dose reduction.

ddI (Videx)

13% decrease in total exposure (AUC). Stagger administration by 2.5 hours.

ethinyl estradiol(the estrogen component
of many birth conrol pills)

40% decrease in total exposure (AUC). (the Increase dose or substitute another contraceptive.

fluconazole (Diflucan)

15% increase in total exposure (AUC) to ritonavir.

indinavir (Crixivan)

Eight-fold increase in total exposure (rat study). Coadministration not advised.

saquinavir (Invirase)

50- to 100-fold increases in total exposure observed. Coadministration not advised at this time. (There are some undocumented reports of severe liver toxicity from this combination.)

theophylline¤

43% decrease in total exposure (AUC). Consider dose increase.

AZT (Retrovir)

25% decrease in total exposure (AUC). No dose adjustment needed.
*Source of information and recommendations: Abbott Laboratories, "Drug Interactions with Norvir" (no date) and "Information for Clinical Investigators: Ritonavir Attachment No. 1 to the Protocols -- Version 3" (April 3, 1996).


Contracting Out the FDA: 
An Update

by Derek Link

Over the last six months, "FDA reform " bills have progressed at a slow but steady pace through both houses of Congress (see January's Treatment Issues, pages 1-5). The Senate Labor Committee passed in late March an amended version of S.1477, Sen. Nancy Kassebaum's (R-KS) FDA bill, S.1477, now awaits consideration on the Senate floor, a debate which has not yet been publicly scheduled. The House Commerce Committee introduced its FDA reform proposal in late March too. No action has been taken on the House FDA plan, although a subcommittee vote could occur soon.

The Senate bill passed the Labor Committee with nine amendments. Several of these, particularly the ones offered by Sen. Dan Coats (R-IN), came as a surprise assault. The bill had gradually evolved into a moderate proposal, but the Coats amendments undid much of the consensus building. They would force the FDA to immediately contract with private consultants for the review and approval of all medical devices, broaden the grounds for privatizing FDA's other key responsibilities, and dramatically lower safety, purity and effectiveness standards for drugs, devices and foods.

Patient advocates opposed Coats' amendments on the grounds that the regulatory system must be built on sound public health principles and rigorous, objective clinical research. Privatization should therefore proceed cautiously, in these advocates' view. There is no private sector industry immediately capable of taking on FDA's tasks. Even if Congress rushes ahead with farming out FDA activities, it will take time for this new industry to develop. Immediate privatization risks slowing drug development by throwing the entire system into chaos.

Also, drug and device makers could hire a private concern to review their products under the Coats plan. This builds conflict of interest into the regulatory system. Reviewers would have an incentive to approve products based on potential future business rather than on an objective examination.

The House Commerce Committee, after keeping its FDA proposals secret for months, released them in late March with much fanfare. At a bizarre media spectacle held in its ornate chambers, the Commerce Committee released three FDA bills -- a bill for drugs and biotechnology products, a bill for foods and a bill for medical devices. Several enthusiastic private citizens, whom the committee brought to the ceremony and described as victims of the FDA bureaucracy, provided a facade of popular support for the measures. Committee members even brought out a cake and sang a sweet song through teary eyes for a heart disease patient from New Jersey. The Committee also announced it had formed an FDA task force of four to guide the bills through the legislative process.

The House bills go far beyond S.1477, even with the Coats amendments. They privatize virtually all of FDA's functions, ranging from the inspection of drug-making facilities and blood banks to the review and approval of all drugs, devices, blood and biotechnology products. The House bill lowers safety and effectiveness even more than the Senate bill, allowing drugs to be sold with no clinical research whatsoever. The bill also allows higher levels of pesticides in food and restricts the FDA's ability to inform the American public about the dangers of products on the market.

AIDS organizations, and GMHC in particular, have helped lead the public opposition to the Republican FDA proposals. A growing array of groups -- patients, seniors, unions, women, minorities, environmentalists and consumers -- have now joined to defeat these bills. But the coalition is coming together in a frenzied and ad hoc manner that is limited both organizationally and financially. Discussions are now taking place as to how to form an aggressive, independent and organized public health lobby for the FDA.

Whether Congressional leaders can pass the FDA bills in both chambers, reconcile the substantial differences between House and Senate proposals, and secure assent from President Clinton remains a matter of much speculation. The growing opposition to the FDA bills, a dwindling legislative year and an intensifying electoral campaign make the likelihood of swift, easy passage decline from day to day. This year may prove to be just a dress rehearsal for future showdowns.


Making Inroads on PML

by Theo Smart

Progressive multifocal leukoencephalopathy (PML) can paralyze, blind, mute and kill people with AIDS within weeks. According to some estimates, the incidence of the condition has doubled in the last several years. This disease of the central nervous system presently occurs in around six percent of AIDS cases and the rate is expected to increase as people with AIDS live longer with low CD4 cell counts (partly due to improved prophylaxis and treatment of other opportunistic infections)(1). Although there is still no treatment for PML, a number of compounds that have shown potential in the laboratory, such as topotecan and cidofovir, are closer to being studied in people with PML. There have also been advances in diagnosis and basic science research which may lead to improved treatment and ultimately prevention.

The JC Virus

PML is caused by the JC virus, which infects and kills oligodendrocytes. These brain cells produce the myelin that surrounds and protects nerve cells. The virus, named after the first patient with PML in whom it was isolated, belongs to a family of viruses that also includes wart viruses.

The JC virus is common. By middle age, 80 percent of adults have been exposed to it. The primary illness that it causes is unknown, but a case of meningoencephalitis has been observed in an otherwise healthy teenage girl with rising JC antibody titers(2).

After acute infection, the virus can remain latent in the kidney, lymphoid organs, bone marrow and circulating B lymphocytes, but most researchers believe that the virus is not latent in the brain or central nervous system (CNS). A number of factors such as immune suppressive chemotherapies (most commonly, cyclosporine and methotrexate), and other viruses, including HIV and CMV can stimulate the virus out of latency. After reactivation, the researchers think that virus is transported to the brain by circulating B-cells. If this indeed is the case, early treatment of people with reactivated JC virus -- which has not yet taken up residence in the CNS -- possibly could prevent PML, should an effective anti-JC drug be discovered.

Once the virus enters the brain, treating it may become more difficult since the parts of the JC virus genome that drive reproduction are prone to mutation. A number of studies report that JC virus associated with PML lesions has unique genetic sequences in the part of the virus' genome that drives replication. These genes frequently differ from the genes of the JC virus found in the kidneys of the same patients(3). The genes in the "neurotropic" JC virus bear a strong resemblance to genes involved in making myelin and other neural proteins(4). Exactly how the virus adopts these changes is unknown, but these mutations may allow natural processes in the brain to accelerate spread of the virus there. This suggests yet another reason to treat before the virus invades the CNS. It also suggests that drugs being considered as possible treatments for PML should show activity against the neurotropic strain of the virus.

Improvements in Diagnosis

Although a brain biopsy is still considered the standard for definitive diagnosis in some cases, PML can be diagnosed without undergoing this invasive procedure. Many clinicians rely on axial computed tomography (CT) or magnetic resonance imaging (MRI). The MRI is more sensitive, and also can reveal the number and extent of lesions. With either technique, the pattern and enhancement of the PML lesions usually can be easily distinguished from toxoplasmosis, lymphoma and HIV encephalopathy.

Viremia (detectable virus) in the cerebral spinal fluid (CSF) is increasingly being used in diagnosis. A recent study by Dawn McGuire, M.D., and colleagues in San Francisco looked for JC virus in the CSF of 26 patients with PML plus 114 HIV-positive controls and sixteen HIV-negative controls (5).Using a very sensitive PCR test that could detect one copy of JC virus in 50 microliters of cerebrospinal fluid, the researchers found the virus in 24 of the 26 patients with PML, ten of the HIV-positive patients (who will be closely monitored for development of the condition) and one HIV-negative participant with neurologic abnormalities. An ongoing ACTG study of the treatment of PML (see below) should confirm the utility of JC virus PCR for diagnosis.

Viremia also may prove to be a prognostic tool. A team of French investigators has tested over 165 people with HIV along with 65 HIV-negative immune compromised persons and found that the incidence of detectable JC virus in peripheral blood leukocytes was almost twice as high in people with HIV (28.9 percent versus 16.4 percent in the HIV-negative patients)(6). The individuals with both HIV and JC virus are being followed to ascertain the predictive value of the tests. Clearly, 28.9 percent of people with HIV do not develop PML, however, the study may determine whether a higher JC viral load or certain strain of the virus distinguishes those people more likely to develop the condition.

Limitations of Present Therapies

As there is no accepted treatment, patients with PML frequently are subjected to experimentation with toxic agents. These experiments have yielded a number of case reports claiming improvements in response to treatments such as cytarabine, alpha interferon, vidarabine (adenine arabinoside) and idoxuridine. Treatment with AZT has been reported to lead to stabilization, but it is unclear whether improvement was due to an anti-JC viral effect or treatment of the underlying HIV infection(7).In another study, three months of intrathecal treatment with AZT failed to improve the status of two patients with PML(8).

Perhaps the most influential PML study was by Carolyn Britton, M.D., which reported clinical improvement in eight of thirteen patients (mean CD4 cell count of 106) treated with intrathecal cytarabine (ARA-C).(9). One must view such clinical improvement with skepticism -- spontaneous remission of PML can occur in the absence of treatment, particularly in patients with higher CD4 cell counts. A number of other case reports and open label studies recount the failure of cytarabine(10), as well as every other drug that has shown activity in other case reports. One review of the published case reports even noted that people treated with cytarabine died faster. There is at least one published case of cytarabine causing PML in a person with cancer (by suppressing the immune system)(11). On top of that, the drug is extremely neurotoxic. Nevertheless, because of Britton's open label studies, and because they have no other treatments to offer, many doctors and clinics administer cytarabine to patients with PML.

Cytarabine is being put to more rigorous challenge in ACTG 243, the first well controlled clinical trial for PML. The trial compares high-dose antiretroviral drugs alone to high doses of both intravenous and intrathecal cytarabine. The endpoints will be survival and changes in neurological condition. The mixed reports for these therapeutic approaches give few researchers faith that this study will advance treatment, though it will yield data on using JC viremia as a diagnostic tool.

New Leads

Camptothecin derivatives -- in particular, camptothecin, topotecan and irinotecan -- can suppress the neurotropic JC virus in glial cultures (12).These compounds are chemotherapeutic agents that work by inhibiting topoisomerase I, an enzyme that uncoils strands of DNA, a necessary step in transcription, and ultimately cell replication. These drugs are known to cause bone marrow suppression, diarrhea, nausea and other side effects.

A number of patients now have been treated with topotecan(13). Two end-stage patients failed to respond. Another patient experienced lesion remission and symptomatic improvement. Despite the bone marrow suppression that topotecan caused (in response to which the patient was given the growth-factors G-CSF and EPO), the patient's CD4 cell count increased. This patient had initiated therapy with a protease inhibitor six weeks earlier, though, which suggests that this response could have been due to the antiretroviral.

Nevertheless, the case has led SmithKline Beecham to design a study that should start next month in Los Angeles, San Francisco, Miami, and possibly New York City or Baltimore and a site in France. The study will enroll at least fifty volunteers with biopsy-proven PML who have been on stable antiviral therapy for six weeks. Trial participants will be randomized to treatment with topotecan or observation (no treatment). All in the latter study arm will be crossed over to the treatment arm after eight weeks -- or after only four weeks if there is progression in disease, defined as growth in PML lesions of at least 25% detected on MRI. For information on study enrollment call Sharyn Arnold at 215-751-7074.

A paper by a team of Belgian researchers, led by Erik de Clercq, M.D., at the Thirty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapies reported that cidofovir, a drug soon to be approved for the treatment of CMV retinitis, has activity against a murine (mouse) polyomavirus, which is very closely related to the JC virus(14). At a Japanese conference in May, the same group reported even greater activity against SV40, a more closely related simian polyomavirus that causes a condition similar to PML in immunosuppressed monkeys with SIV(15).

They then treated one PML patient with 3 mg per kg of cidofovir once every ten days(16). Although after the second infusion there was a reduction in the size of the lesion, there was continued neurologic deterioration. Treatment was discontinued after the fourth infusion, and the patient died two months later. As there was change in the size of the lesion, the Belgian team concluded that the treatment had potential but that further studies should use more frequent dosing.

Researchers in London are planning a controlled clinical study that should begin by August. The dosing regimen in this study will be the same as used for the treatment of CMV retinitis -- 5 mg per kg per week for the first two weeks, and then every other week.

Treating PML by Treating HIV

Topotecan and cidofovir may prove to be more effective treatments than cytarabine, which again, has been shown to cause PML. Still, the most significant advance against PML may turn out to be the new treatments for AIDS. There are numerous anecdotes of people with PML experiencing lesion remission after starting treatment with protease inhibitors. These drugs may do a much better job of salvaging the immune system than treatments of the past, and improvement of PML is fairly common in people with higher CD4 cell counts. Although anti-HIV therapy may only work temporarily, people with PML should certainly be offered the best available antiretroviral agents before turning to unproven toxic chemotherapies that may actually aggravate their condition.


1. Major E and Ault G. Current Opinion in Neurology. June, 1995; 8(3):184- 190.
2. Blake K et al. Archives of Disease in Childhood. Jul, 1992; 67(7):956-7.
3. Loeber G and Dorries K. Journal of Virology. May, 1988; 62(5):1730-1735.
4. Amemiya K et al. Journal of Biological Chemistry. Jul 15, 1992; 267(20):14204-14211.
5. Major E and Ault G. Current Opinion in Neurology. June, 1995; 8(3):184- 190.
6. Dubois V et al. AIDS. April, 1996; 10(4):353-358.
7. Conway B et al. Reviews of Infectious Diseases. May-June, 1990; 12(3):479-82.
8. Allegre T el al. 9th International Conference on AIDS. June 6-11, 1993; 9(1):423 (abstract PO-B16-1727).
9. Britton CB et al. Eighth International Conference on AIDS. Jul 19-24, 1992; 8(1):Th67 (abstract ThB1512).
10. Antinori T et al. AIDS. July, 1994; 8(7):1022-4.
11. Hwang TL et al. Journal of Neuro-Oncology. 1986; 3(4):335-9.
12. Kerr DA et al. Virology. Oct, 1993; 196(2):612-618.
13. Broom, C. Personal Communication, April 22, 1996.
14. Snoeck R et al. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20, 1995, abstract H49, pg 188.
15.Andrei G et al. Ninth International Conference on Antiviral Research, May 19-24, 1996.
16. Snoeck et al. Ninth International Conference on Antiviral Research, May 19-24, 1996.


Free Introductory Offer 
for Viral Load Tests

by Theo Smart

As Treatment Issues went to press, FDA marketing approval was imminent for Hoffmann-La Roche's Amplicor HIV-1 Monitor test kit. Approval will make the test, based on polymerase chain reaction (PCR), the first commercial method for measuring HIV in the blood, or viral load. The Amplicor kit will receive the FDA go-ahead for use in determining a patients prognosis and as an aid in assessing response to anti-HIV treatment. The latter indication is very important as it will allow much more frequent use of the test. In recent weeks, AIDS activists have put considerable pressure on the FDA to support such treatment monitoring.

Roche in partnership with a number of clinical laboratories is offering to provide two free baseline tests to all comers for the first 60 days Amplicor is on the market. To enroll in what is being termed the Amplicor Access Program, call toll-free 888/AMPLICOR (888/267-5426) This program will give Amplicor a head start over Chiron's competing bDNA test, whose approval also should come soon. Persons with baseline viral load by Amplicor should stay with that brand since it is not completely interchangeable with bDNA.

The company will use the 60-day period to convince Medicaid and other third party reimbursers to pay for the test. Roche is not committed to launching an indigent patient program for those who cannot afford viral load testing after the first 60 days. The company should be able to gauge the need for such assistance since those who enroll in its baseline testing giveaway will be asked about their insurance coverage. But any support Roche could give is complicated by the fact that much of the testing fee -- expected to be $150 or more initially -- goes to the commercial laboratories that perform it, not Roche itself.


Treatment Briefs

Glaxo, Merck and ADAP

Responding to a campaign by Project Inform and the company's own Community Advisory Board, Glaxo Wellcome has broadened the financial assistance program for its new popular antiviral 3TC. Previously, Glaxo refused to provide free or discounted 3TC to anyone covered by a state ADAP (AIDS Drug Assistance Program) that refused to include the drug in its formulary. (ADAPs, which serve 62,000 people nationwide, pay medicine costs for uninsured people with HIV of low or moderate income.) Glaxo refused to be the reimburser of last resort, but that stance left people without access to 3TC in the eleven states whose ADAPs did not include 3TC. With ADAPs across the country facing a financial crunch (see Treatment Issues article, ADAP Faces Financial Abyss; February 1996, pages 11-12), these people were unlikely to obtain 3TC any time soon, no matter how much pressure Glaxo's policy put on the states.

In announcing the change, Glaxo vice president Steve Skolsky noted that Glaxo will not necessarily back up everyone eligible for state ADAPs, only those who also meet Glaxo's criteria for financial assistance.

Merck & Co. has also come under sharp criticism for a similar policy in regard to financial assistance for indinavir. Only three ADAPs (Maryland, North Dakota and Washington) now pay for this protease inhibitor, and only seven others were expected to add it soon.

Fortunately, as part of the Ryan White Care Act extension passed by Congress in May, an extra $52 million will be available this year for ADAP expenses. New York and California ADAPs have already decided to cover protease inhibitors starting in July. Funding is still short, though, and it remains to be seen how well the ADAPs can keep up with the costs of the new anti-HIV treatments.

DMP 266: Keep the Drug but Dump the Trial?

"DMP 266" is a nonnucleoside reverse transcriptase inhibitor (NNRTI) like nevirapine or delavirdine that was originally created by Merck but languished when that company decided to concentrate on its protease inhibitor program. It was recently bought by DuPont Merck, a joint venture owned by DuPont and Merck. In its first human trials DMP 266 by itself reduced plasma HIV levels (viral load) in 20 volunteers by a median of over 1.4 logs, or greater than 96 percent.

Such figures make DMP 266 one of the most potent anti-HIV agents ever tried in humans. But previous NNRTIs are notorious for the speed with which HIV develops resistance to them, through a single point mutation in the virus's reverse transcriptase enzyme. The duration of DMP 266's effect remains unknown. Several mutations in reverse transcriptase appear necessary for high-level resistance to emerge. Researchers hope HIV strains resistant to DMP 266 are less likely to exist prior to treatment and will be slower to evolve after therapy commences. To ensure stability of response, though, future trials will test the compound only in combination with other drugs except for short two-week intervals.

Two new trials are about to begin: One tests DMP 266 in combination with indinavir while the other is a study of DMP 266 plus AZT and 3TC. Details on the second trial have yet to be released, but the first study is a fourteen-week, placebo-controlled trial taking place at ten East Coast sites. The 360 participants must have CD4 cell counts of between 100 and 500 and viral loads exceeding 20,000.

The DMP 266/indinavir trial is a step toward creating simpler, more "compact" drug combinations that strongly suppress HIV while having fewer toxicities and simpler dose schedules than current combination therapies. But this trial has already aroused some criticism in the AIDS community: over 100 participants in the trial's control arms will receive indinavir monotherapy (800 or 1,000 mg three times a day) for twelve to fourteen weeks.

Indinavir monotherapy is generally not advised for fear that HIV resistant to it will easily evolve, especially in people with high baseline viral loads. Volunteers assigned to this therapy risk not being able to receive full benefit from indinavir and other protease inhibitors that trigger similar resistance mutations -- ritonavir, for example.

PMPA Beats SIV Again

Gilead Sciences' drug PMPA can prevent mucosal transmission of simian immunodeficiency virus (SIV) and potently reduce SIV burden in infected macaques, according to data presented at the Ninth International Conference on Antiviral Research, held in Japan on May 19 to 24. These studies follow earlier data showing that administering PMPA could protect uninfected macaques against injected SIV (see Treatment Issues article, A Shot a Day Keeps the SIV Away; December 1995, page 3).

In the treatment study, ten macaques infected with SIV were injected for four weeks with two different daily doses of PMPA. Levels of the virus in the monkeys were reduced 100- to 1000-fold while viral load increased in two untreated macaques. Viral load became undetectable in eight out of ten of the treated monkeys, although SIV DNA (a measure of infected cells rather than free virus) was still detectable in most. After four weeks, treatment was discontinued and SIV levels rebounded to baseline.

There appeared to be no toxicity at the low dose, but the higher dose caused slight reductions in red blood cells, hemoglobin and phosphates, all of which reversed when treatment stopped. Studies of PMPA's effect in humans are expected to begin sometime this year.

Researchers in the transmission study treated four monkeys with an intravaginal topical gel containing ten percent PMPA. After intravaginal inoculation with SIV, the team performed weekly viral detection tests to see whether the macaques had become infected. All remained free from infection. After eight weeks of follow-up, the monkeys were still SIV- negative. Similar studies with microbicides such as the commercially available nonoxynol-9 have found that only one-third of treated monkeys 20 were protected from SIV exposure.

Oxymetholone Adds Weight

People with HIV experienced dramatic weight gains in a recently published German study of the oral anabolic steroid oxymetholone and the antihistamine ketotifen (see the British Journal of Nutrition, January 1996; 75(1):129-38). Ketotifen is thought to increase weight by lowering the body's production of tumor necrosis factor (see Treatment Issues article, Other Therapies for Wasting; May 1995, page 7), but it seemed to add nothing to the observed benefit from oxymetholone. Marketed in Europe, both drugs are available in the United States only through unofficial channels.

The 60-person, 30-week study followed volunteers who had lost more than ten percent of their body weight within the previous four months. Persons who had had an active opportunistic infection in the previous six months were excluded, as were those whose weight loss due to chronic fever and diarrhea with no known cause.

Thirty trial participants were randomized to two treatment arms. One group received 50 mg of oxymetholone three times a day. The other took the same dose of oxymetholone plus 50 mg twice a day of ketotifen. The remaining 30 participants went untreated and served as controls.

Within four weeks, those on both treatments began to gain weight. At thirty weeks, treated volunteers had increased their weight by ten percent whereas untreated volunteers had lost four percent. By the crude Body Mass Index, treatment led to an increase in lean body mass. Appetite and quality of life improved in the treated patients. Both agents were well tolerated.

Anti-CMV Drug Trials Back On-Line

Fomivirsen (formerly ISIS 2922) is an antisense RNA molecule designed to attack CMV. It is under study as an intraocular injection for CMV retinitis. Last year, Isis Pharmaceuticals placed fomivirsen trials on hold when the dose under evaluation, 330 mg, was found to cause a loss of peripheral vision in twenty percent of the patients with early stage disease (see Treatment Issues article, The Changing Treatment Options for CMV Retinitis; July/August 1995). This side effect only occurred in one out of forty patients with more advanced retinitis, though, so the company continued testing fomivirsen in that population.

The company then performed a dose escalation study in twelve patients with early stage retinitis, starting with a 75 mg dose. There was no toxicity and little treatment effect, so the researchers increased the dose to 150mg. This dose has produced none of the undesirable effects, and the company claims it has produced prolonged responses in a larger percentage of patients (although it is vague about both the number of responders and the duration of benefit).

Isis has now reinstated trials at the lower, safer dose in persons with early, non-sight threatening (peripheral) CMV retinitis. The study compares the time to progression in patients who are immediately treated to that of patients who do not receive treatment until after progression. Enrollment has not been rapid due to the earlier problems. The same is true of a second trial that compares fomivirsen plus oral ganciclovir to induction therapy with intravenous ganciclovir followed by oral ganciclovir maintenance therapy. (Adding oral ganciclovir to the intraocular fomivirsen injections addresses the threat of CMV breakthrough in the other eye or elsewhere.)

Two other studies have been opened. One is for patients with advanced CMV retinitis and compares two different dosing regimens. The second is for patients who have failed the other antiviral therapies and have no remaining therapeutic options. One of fomivirsen's key selling points is that there is no cross-resistance to other anti-CMV drugs, so there is a possibility that the drugcan offer benefit in otherwise untreatable patients. For information about the location of trial sites near you, call 800-679-4747.




  
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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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