GMHC Treatment Issues, Volume 9, Number 6 - June 1995 ----------------------------------------------------- The Gay Men's Health Crisis Newsletter of Experimental Therapies ----------------------------------------------------- Viral Resistance to Protease Inhibitors by Theo Smart Just a year or so ago, it was commonly held that HIV could not rapidly become resistant to protease inhibitors. Reports stated that the mutations could not occur within HIV's protease enzyme without reducing the enzyme's activity.[1,2] Even when a mutant but functional protease was created in the test tube that was resistant to one inhibitor, it remained susceptible to the other compounds.[3] Later, there were reports that HIV in some patients had become less susceptible to protease inhibitors after just a few months of treatment. Multiple mutations within the protease enzymes in HIV isolated from these patients enabled the virus to resist the drug's effect. The specific mutations, referred to as patterns of resistance, that occurred depended upon the drug being used, and it appeared that there were a couple of patterns that rendered the virus resistant to more than one compound. Worse yet, after continued therapy on one drug, Merck's MK-639, researchers discovered strains in a handful of patients that had decreased sensitivity to all other protease inhibitors in clinical development at the time.[4] Before panic sets in, remember that the degree of resistance can vary. One strain of HIV may be highly resistant to a drug in the test tube while a slightly higher concentration of drug may still suppress another strain. There also is next to no information on the relationship between drug resistance and physical response to the drug. What information that does exist is puzzling. For example, the pharmaceutical companies that make protease inhibitors have reported rises in CD4 cell counts that are sustained after the development of resistance and the corresponding rebound in viral load. But the CD4 cell counts do start to drop eventually. The Evolution of Resistance Some researchers believe that resistance occurs when strains of the virus that are less sensitive to a drug's effects exist prior to therapy. A second model maintains that resistance evolves during therapy, when there is less than enough drug available to completely shut down viral replication. The virus continues to reproduce somewhere in the body (perhaps in a cell type into which the drug does not penetrate) and over time, there is a chance that resistance could occur. Both mechanisms may play a role, particularly when a slightly resistant virus evolves into a highly resistant strain. HIV's reverse transcriptase enzyme is the root cause of resistance, whether pre-existing or acquired during therapy. The enzyme constructs new viral genetic material but often makes mistakes. About ten percent of the time the result is a virus with a genetic structure (genotype) that differs from the parent virus. Sometimes, these genetic variations are substantial enough to change the physical structure (phenotype) of viral proteins and enzymes. Some of these phenotypes are resistant to drugs currently being used in therapy. The higher the viral load, the more opportunities there are for resistant mutants to develop. However, drugs may also be inactivated by host resistance, which has nothing to do with viral load or changes in the virus. Host resistance occurs when, over time, the body begins to discriminate against the drugs, sometimes on the cellular level. This may occur in cellular factors responsible for converting the nucleoside analogues into their active form.5 For example, a loss of antiviral activity is often seen with drugs such as ddI long before the development of resistant virus is detected. Other factors may also be at work with different drugs. Resistance Data Merck's resistance data do sound quite frightening. After trial participants had been on several months of therapy, researchers isolated HIV that was resistant to MK-639, but within a year on continued therapy, the virus appeared to evolve ever-decreasing sensitivity to other protease inhibitors. The protease enzyme could successfully make multiple mutations, some of which were not even in the "active" parts of the enzyme -- the part that snips out the individual HIV proteins from a long string (see Treatment Issues, March, 1994, page 1). The authors concluded that a number of pathways to broad spectrum resistance appeared possible. However, the data came from only four individuals treated with MK-639 as a monotherapy. The virus from these patients seemed to develop increasing resistance that may have been caused by sub-optimal dosing. When low-level resistance was seen at the dose that was too low to be completely effective to begin with, the dose was raised, but it clearly was not raised enough. This happens to be a classical way to induce higher levels of resistance to a drug. A study from the Aaron Diamond Institute in New York City, presented at last January's Conference on Human Retroviruses, reported that high-level resistance to every protease inhibitor currently in clinical trials could be bred in the test tube. Investigators could do this by exposing the virus to drug levels that were not quite enough to completely suppress it. Once they produced a resistant strain of virus, they increased concentrations of drug just slightly. After repeated exposure to increasing concentrations of any single protease inhibitor, the researchers had produced phenotypes that were less sensitive to almost every known protease inhibitor.[6] But outside of an occasional clinical trial, no one administers drugs to people in this manner. It is unknown what will happen to people who start out on optimal doses of drug or who take protease inhibitors in combination with other drugs. Patterns of Resistance Aside from high-level cross-resistant phenotypes, data show at least three, and probably more, general patterns of resistance to protease inhibitors. One phenotype confers resistance to saquinavir, as well as decreased sensitivity to VX-478 (the Glaxo-Wellcome-Vertex compound), and SC-52151 (Searle's failed compound). Virus resistant to saquinavir is also three-to-five fold less sensitive to Agouron's AG1343, which has just been reported to show antiviral activity in people (see box, page 4). However, the initial HIV mutations that resist AG1343 in the test tube are not the same ones conferring resistance to saquinavir. Still another series of mutations reduces susceptibility to the Merck, Abbott, the NCI/Kyoto Pharmaceutical and DuPont Merck compounds. Other compounds on the horizon such as new drugs from Upjohn and Searle may induce other mutations. Data on the pattern of resistance to Upjohn's compounds seen in the test tube will be presented at an upcoming conference. There is now evidence that some resistant phenotypes may be pre-existing. Noel Roberts of Hoffmann-La Roche has reported that blood samples from nearly ten percent of the patients entering saquinavir studies already possessed HIV with mutations that are involved in resistance to the Merck/Abbott group of compounds, and some had mutations associated with reduced sensitivity to AG1343. He has not found pre-existing resistance to saquinavir, although after a year of therapy, half of the patients have HIV with mutations in response to saquinavir.[7] Saquinavir appears to lose its antiviral effect in people before the virus becomes resistant, though. It is unclear what causes this, but it may be host resistance, or a decrease in absorption of the compound over time. This may also happen to other protease inhibitors in development. Informed Treatment Decisions Up to now, the only access to protease inhibitors has been through clinical trials, but soon there will be limited expanded access programs (see page 3), and by the end of the year, saquinavir may even be approved. In light of the confusing information on resistance, it is difficult for people with HIV to make informed decisions about utilizing protease inhibitors in treatment regimens. Here is what we know: Resistance to protease inhibitors taken alone is possible. It happens faster in people with higher viral loads. If you become resistant to one drug, there are probably at least a few others to which you simply will not respond. There is also a remote possibility of insurmountable high-level cross-resistance to most or all protease inhibitors. Many researchers often compare HIV disease to tuberculosis as both HIV and the tuberculosis bacterium tend to become resistant to drugs. If they are right, the development of resistance to protease inhibitors -- the most potent antivirals yet seen -- is indeed cause for serious concern. When drugs were first being developed for TB, many were studied as monotherapies. Some worked well for a couple of months, but then resistance developed. Eventually, it was determined that combination therapy could permanently keep TB in check. Tragically, the people who had developed resistance to one of the available TB drugs derived less benefit from the early combinations. Protease inhibitors may face a parallel challenge from HIV. Taking one drug as a monotherapy may mean losing the opportunity to use that drug in the future in a potentially more effective combination strategy that extends the health benefits of available therapy. It must be the right combination of drugs since an inferior mix may have little effect or could be toxic. The right combination may significantly delay the development of resistance, but it may take an almost complete suppression of the virus to achieve this. The catch is that we do not know whether such a combination can be created from the current range of available drugs, whether protease inhibitors or others. It is unforseeable how long it will take to develop a really effective combination. And the longer an individual waits, the higher his or her viral load becomes and the greater the chance for drug- resistant HIV strains to arise. Protease inhibitors may indeed turn out to be a dramatic step forward in the treatment of AIDS. This is all the more reason to be careful about how they are used until clinical studies provide us with more information. References 1 El-Farrash MA et al. Journal of Virology. Jan 1994; 68(1):233-9. 2 Sardana VV et al. Biochemistry. Mar 1 1994; 33(8):2004-10. 3 Otto MJ et al. Eighth International Conference on AIDS Jul 19-24 1992;.1(abstract ThA 1505):Th66. 4 Condra et al. Nature. Apr 6 1995; 374(6522):569-571. 5 Antonelli G. AIDS Research & Human Retroviruses. Oct 1992; 8(10):1839-44. 6 Mo H et al. The Second National Conference on Human Retroviruses and Related Infections. Jan 29-Feb 2 1995; (abstract 188):89. 7 Noel Roberts, Personal Communication. Feb 2 1995. ************************************ The Next Wave of Protease Inhibitors Three of the newer protease inhibitors are particularly interesting in light of cross-resistance, either because they achieve levels in the blood that may overwhelm low-level resistance (Agouron's compound) or because data suggest that they will not be cross-resistant with compounds in current clinical trials (Searle and Upjohn's products). Agouron's AG1343 Data from a study of AG1343 in people with HIV is beginning to trickle in. The only information that the company has formally released comes from the first patient to complete a phase I study. "Patient 001" came into the study with oral leukoplakia, a CD4 cell count of 368 and a plasma HIV level around 40,000 copies per ml. After two weeks on drug, his HIV level had dropped by 99 to 99.7 percent, and his CD4 count went up by 120. At 28 days, patient 001's viral load was undetectable by current tests and his CD4 count was up by more than 300 cells. His oral leukoplakia had resolved. Agouron will not release surrogate marker data on other patients in the study, but Dr. Neil Clendeninn, Vice President of Clinical Affairs, did comment that: 1) some responses were more modest than what was seen in patient 001, although his response was not unique; and 2) he has yet to see resistance in people or any rebounds in viral load. Also, two patients had resolutions of severe seborrheic dermatitis and one patient's recurrent oral candidiasis went away. Researchers have not observed any serious side effects, Agouron claims. Searle's S338 Searle will not discuss the status of its compound or whether it is even still in the game since its first generation drug failed. Upjohn Upjohn's protease inhibitors are small molecules and should be much easier to manufacture than most other protease inhibitors. It is too bad that two of these compounds have already failed in preliminary clinical studies. The most recent compound was toxic to the liver. Extremely high doses (up to eight grams a day) were required because this class of compounds has a high affinity to the human blood protein albumin. This binding inactivates the drug and increases the blood levels needed to achieve an antiviral effect. The company hopes that a third, and reportedly much more potent, compound will be in human studies soon. It is undergoing toxicity testing in animals at present.- TS ********************************** Protease Inhibitor Expanded Access by Theo Smart The makers of the protease inhibitors furthest along in development insist their drugs are so difficult to manufacture that they barely have enough for their clinical trials, not to mention expanded access. Nevertheless, Merck and Hoffmann-La Roche have now announced small access programs (Roche's is the larger one with slots for 4,000 persons), while Abbott, whose drug supply problems are supposedly not as great, has refused. Abbott's stance finally provoked an activist response. Hoffmann-La Roche/Saquinavir Hoffmann-La Roche plans to open a worldwide 4,000-person compassionate use protocol of saquinavir in August, 1995. Slightly over half (2,280) of the participants will be in the U.S. Sixty percent of the slots will be for people with CD4 cells below 50. The remainder will be in people with CD4 cell counts between 50 and 300. Since the company anticipates more demand than supply, the slots will be distributed through a lottery system. Gail Levinson of Roche says the company hopes to increase the size of the study as more drug becomes available. Physicians who want to register patients can call 800/332-2144. The program is significantly different in Canada, which is only allotted drug for 96 people. It is open to anyone with HIV older than thirteen, regardless of CD4 cell count. A tier system will be implemented to distribute the drug first to those most ill. The first tier will be patients with less than 50 CD4 cells and two concurrent opportunistic infections. Interested Canadians can call 800/257-3741. The allocations of drug in both the U.S. and Canadian systems were devised with input from representatives of the respective AIDS communities. It is interesting to note the differences in priorities. Merck/MK-639 Merck initially claimed it would not have enough drug for expanded access, but the company unexpectedly found enough drug for 1,400 people. Merck's program is an adaptation of a 300-person study in individuals with less than 50 CD4 cells, which is starting this month (see table). A new study arm will be open-label MK-639 for patients who are intolerant to AZT or who have been on 3TC for an extended period (which is not defined). The first participants should receive drug sometime in August, and Merck plans to enroll at least 1,400 by end of the year. Abbott/ABT-538 Abbott has not announced plans for expanded access. The company is running a study in 900 people with less than 100 CD4 cells, and after four months on study, everyone will get ABT-538. This did not satisfy an ad hoc Protease Working Group (PWG), made up of representatives of major AIDS organizations including Treatment Action Group (TAG), GMHC, ACT UP/New York and ACT UP/Golden Gate. In May, the PWG called for a week-long fax zap of numerous Abbott officials. Jules Levin of the PWG said the company has since communicated that it is considering expanded access and should give the community an answer by July. Depending on the company's response, further action is contemplated. In the meantime, members of the community are still urged to contact Abbott and express their feelings about this matter. Fax Andre Pernet, Abbott Laboratories vice president for pharmaceutical research, at 708/938-1797. Others Most of the newer protease inhibitors, such as Agouron's, Upjohn's and Vertex's, are in early stages of development, but are reputedly much easier to manufacture than the older drugs. AG1343 has shown antiviral activity in people and seems poised for rapid clinical development. Representatives of Agouron have stated that the company intends to implement a program eventually, contingent on drug supply. Although Agouron is well funded, it owns no production facilities. The company is currently negotiating manufacturing arrangements with other companies. New and Improved Saquinavir Formulation Saquinavir is one of the most potent protease inhibitors in the test tube, but not in people. The poor bioavailability (absorption) of saquinavir is probably to blame. Roche now has a new "enhanced oral formulation" (EOF) that is reportedly seven times more bioavailable. "The 600 mg three times a day dose [of the current formulation] is probably not the optimal dose for monotherapy," according to Miklos Salgo, Roche's Director of Clinical Research and Virology. Why didn't Roche wait until the EOF was available? "We want to get the 600 mg dose approved first. If we had to wait for the EOF, we will be the number eight or number ten protease inhibitor." To get the EOF approved, Roche needs safety data on several hundred patients for six months. Initial dose-ranging studies will start in July. The next study will begin in November and evaluate the safety of the EOF combined with nucleoside analogues. **************** Washington Watch by Derek Hodel FDA Reform Floated in DC Legislative proposals to significantly reshape the mandate of the Food and Drug Administration (FDA) are now receiving serious attention in Washington. Many of the proposals capitalize on the current Republican drive to deregulate American industry and to reduce federal bureaucracy. Although such deregulation has long been a goal of the pharmaceutical and medical device industries, some of the changes now under consideration would, if implemented, reshape the agency to a greater extent than at any time since the Kefauver Amendments were passed by Congress in 1962. (This legislation first vested the FDA with the responsibility to ensure the efficacy of drugs in addition to their safety. It is the cornerstone of drug regulation today.) AIDS activists will occupy an unusual position in this debate, as much of the charged rhetoric now employed by the conservative right substantially echoes the arguments crafted by the activists themselves during past well publicized debates with the agency concerning the approval of AIDS drugs. Many activists are understandably ambivalent about rushing to the defense of the government agency that had been the focus of their ire only a few years ago. But most AIDS organizations also agree that their intention was never to debilitate the agency, and like many more traditional consumer groups, they are now worried that the so-called reform proposals would do just that -- and what is worse, might actually diminish the number of effective drugs developed in the future. Accordingly, many AIDS groups, including Gay Men's Health Crisis as well as ACT UP (New York and Golden Gate chapters), AIDS Action Council, American Foundation for AIDS Research, Human Rights Campaign Fund, National Minority AIDS Council, Pediatric AIDS Foundation, Project Inform and Treatment Action Group (TAG), have formed an ad hoc coalition to participate in the FDA reform debate. The group is drafting principles for evaluating FDA reform proposals from the standpoint of people with life-threatening disease. Although the FDA has always claimed a mandate to advance the public health, the responsibility to keep harmful products off the market has always taken precedence over ensuring that helpful products reach the market. Of course, the consequences of the former are also much more immediate and severe -- rarely do Congressional hearings or media exposŽs concern drugs that have yet to reach the market. Now the balance is starting to shift the other way. Many of the current suggestions for reforming the FDA would significantly alter its authority. To date, proposals have been advanced mainly by conservative think tanks and drug industry associations. Also, Rep. Ron Wyden (D-OR) has just introduced the "FDA Modernization Act of 1995" (HR-1742). Among the items under discussion are measures that would: * Shift more efficacy studies to a "post-marketing" setting. The FDA's determination of efficacy (whether a drug "works" or not) is, in some ways, a judgment call. Clinical trials after a drug is approved are called post-marketing studies. Most are designed to study side effects that occur so infrequently as to go unnoticed during clinical trials. By approving drugs earlier (when less efficacy data are available), many more people could take the drug, even though substantially less would be known about its effects. Pros: Drugs reach the market much faster, so more people have access sooner. Cons: The risks are greater, because many more people take drugs with even less data about the tradeoff between hazards and benefits in new drugs. * Utilize local Institutional Review Boards (IRBs) to review proposals for the early human testing (phase I clinical trials) of drugs. Presently, the FDA must approve an Investigational New Drug Application (an IND) before a manufacturer (or research scientist) can conduct studies in humans. Additionally, a local IRB (usually composed of scientists, physicians, ethicists, clergy and lay persons) must examine and approve the human subjects protections in all human research protocols. Current reform proposals would shift to local IRBs the whole responsibility to evaluate INDs. Pros: More than half of the INDs under review at the FDA are submitted by individual research scientists who are seeking to increase knowledge about a given drug. The considerable FDA resources allocated to these reviews could be diverted to more critical questions. Cons: IRBs are not currently constituted with appropriate expertise (animal toxicologists, for example) to evaluate critical data prior to commencing initial human studies. Additionally, local IRBs sometimes reach contradictory conclusions -- employing them to review INDs would subvert national coordination of drug trials. * Privatize certain drug safety reviews, by relegating them to independent testing or accrediting institutions. Many proposals would shift responsibility for determining a drug's toxicology (and thus safety), a critical early part of the review process, and other manufacturing standards to private vendors, much like Underwriter's Laboratory evaluates the safety of electrical appliances. Pros: Much of the backlog at the FDA is a result of these early, often technical reviews -- privatizing them could significantly speed the process. Cons: It is difficult to establish independence and avoid conflict of interest in for- profit organizations. * Permit the promotion of FDA-approved drugs for "off-label" uses. In general, drugs are approved by the FDA for a narrow range of use, specified in the so-called label indication. Doctors, however, are free to prescribe FDA-approved drugs for uses not described in the label or validated by the FDA. Such "off-label" use is not only common, but for many diseases represents the standard-of-care. Manufacturers are prohibited from promoting off-label uses of drugs, however, and must apply again to the FDA before modifying a label to include a new use. This prohibition prevents manufacturers from making unsubstantiated claims, but critics claim that doctors and patients are denied state-of-the-art information concerning the clinical application of drugs. Pros: Because manufacturers have an incentive to promote the use of their products, up-to-date information concerning innovative uses of approved drugs would become available much more quickly. Cons: As described earlier, the determination of efficacy is not absolute, but rather represents a subjective decision that balances risk and benefit -- leaving the decision in the hands of manufacturers seems to invite conflicts of interest. * Impose statutory time limits on FDA reviews. Most FDA reviews are already subject to statutory time limits, some of which the agency habitually misses. Most analysts agree that the problem is a result of insufficient resources, not statutory deficiencies. * Improve harmonization with international standards. Because the FDA maintains the highest standards for drug safety and efficacy in the world, drug approval in the United States is often out-of-sync with the international community. In a majority of cases, drugs are approved abroad before the FDA allows them in the United States. By agreeing with other countries to jointly review drugs, or to use common standards, the FDA could utilize safety and efficacy data generated overseas. Pros: The duplication of efforts in multinational drug approvals would surely diminish, speeding up the drug testing process and saving manufacturers money. Cons: The FDA rejects foreign data in part because it is unable to sufficiently monitor the quality of foreign clinical trials. International agreement would likely require extensive negotiations and oversight. * Remove export barriers for non-FDA-approved drugs. American companies currently are prohibited from exporting drugs that are not licensed by the FDA, regardless of whether they are approved for use in the country of import. Present proposals would remove these barriers. Pros: Business opportunities for American manufacturers would increase substantially. The United States would respect other countries' sovereignty in setting their own standards for safety and efficacy. Cons: There is a risk that the United States could be held to blame for dangerous drugs that are exported as a result of weak international standards. Although administrative agency reforms are all the rage in Washington, the authorizing committees in both the House and Senate seem to harbor particularly focused, long-standing resentments toward FDA Commissioner David Kessler. Kessler enraged many tobacco-state members (including Thomas Bliley, R-VA, now chair of the House Commerce Committee) by his attacks on cigarette manufacturers. Speaker Newt Gingrich clearly has the commissioner in his sights when he claims that the "FDA is the biggest job-killer in America." How far reforms go is still up in the air, but it is safe to say that insofar as AIDS activists sparked much of the discussion in the first place, we will continue to play a major role in the debate. Derek Hodel is GMHC's director of federal affairs. **************** Treatment Briefs by Dave Gilden A Monumental Struggle for Sufficient Nutrition As Treatment Issues went to press last month with a long section on therapies for AIDS-related wasting, a study appeared in the Journal of Acquired Immune Deficiency Syndromes (R.S. Hogg et al., June, 1995) that indicated just how desperate are the body's efforts to replenish its nutritional stores during HIV infection. The study was based on questionnaires filled out by HIV-positive gay men without clinical AIDS and HIV-negative ones participating in the Vancouver [Canada] Lymphadenopathy-AIDS Study (VLAS). The men were interviewed about their diet over the previous 24 hours. The HIV-positive men reported a 24-hour consumption of 2,239 calories versus 1,989 calories for the negative men. The distribution of calorie intake among protein, fat, carbohydrates and alcohol was the same for the two groups. Average weight was stable over the last year in the two groups, but at the time of the interviews, the HIV-positive men weighed five percent less than the HIV-negative men, and their body mass index, a measure of the lean tissue to fat ratio, was four percent less. There were no differences in food consumption or composition between men with less than or more than 200 CD4 cells per milliliter of blood. The authors concluded that the HIV-positive men should have weighed ten kilograms (22 pounds) more assuming that their reported diet had been the same over the past year. They considered the fact that they did not a sign of the increased basal metabolic rate that occurs during chronic HIV infection. These men also had already lost a disproportionate amount of their lean tissue despite adequate protein intake. Nutritionally, these relatively healthy men with HIV were precariously balanced. Any subsequent illness that made it hard to eat or absorb nutrients, or just placed additional metabolic demands on the body, could have disastrous consequences in terms of wasting. R U Ready for This? Cortisol is an important glucocorticoid hormone secreted by the adrenal gland to moderate stress. Among other things, glucocorticoids promote the breakdown of protein stores in the body to produce sugar (glucose) and can decrease the immune system activity. Cortisol levels are high in people with HIV infections, and the hormone has been implicated in wasting syndrome. In addition, blocking cells' glucocorticoid receptors was found recently to reduce the proliferation of Kaposi's sarcoma tissue (W.X. Guo and T. Antakly, American Journal of Pathology, March, 1995). Now a study has found that blocking these receptors also might inhibit HIV itself. The HIV study, by a group of University of Pennsylvania researchers (Y. Refaeli et al., Proceedings of the National Academy of Science, April, 1995) investigated the function of the Vpr protein, produced within cells by a relatively obscure HIV "accessory" gene. Vpr appears to mildly stimulate HIV replication by combining with the long terminal repeat genetic sequence at the end of the HIV gene set. The researchers have deduced that Vpr forms a complex with a cellular protein they call Rip and the intracellular receptors for glucocorticoids. The complex is able to transport Vpr into the cell nucleus where the HIV gene set resides. This process seems to be promoted by synthetic glucocorticoids such as dexamethasone. In laboratory cultures, HIV production was reduced 70 percent by a glucocorticoid receptor blocker -- RU486. RU486 is well known for its use as an abortion-inducer. Pressure from anti- abortion groups has delayed its availability in this country. To underscore the fact that nothing concerning HIV is ever straightforward, a group of French researchers reported in March (J.M. Andrieu et al., Journal of Infectious Diseases) on successful results from a preliminary trial of glucocorticoid therapy in HIV infection. Forty-four asymptomatic trial participants with CD4 counts between 200 and 800 took 25 to 40 mg of the drug prednisolone daily, depending on their weight. After one year, no major new disease had occurred. CD4 counts were up by an average of 119. Immune activation markers were down while tests of immune function held stable. Interestingly, HIV levels did not decrease in response to therapy but remained constant. The researchers noted a decrease in spontaneous cell death (apoptosis) in peripheral blood mononuclear cells (lymphocytes and macrophages). They felt this effect might be a major reason why glucocorticoid therapy had beneficial results in the face of unchanged HIV levels. ********************* Future of ICC Debated by Theo Smart The Inter-Company Collaboration for AIDS Drug Development (ICC) was created with great fanfare over two years ago. Its purpose is to foster cooperation between pharmaceutical companies with antiviral drugs in clinical development so as to more rapidly develop therapies for people with AIDS. At a meeting with community representatives on May 11, 1995, the ICC presented an update on the organization's recent activities, including advances in collaboration on basic research, a review of the ICC's current clinical trial program, and a discussion of alternative trial designs to rapidly find the more active antiviral combinations. Basic Science The companies of the ICC have made a commitment to extend their collaboration into basic research. They agreed that: 1) companies would share animal models they develop; 2) they will share biologic data (lab samples) for drug resistance studies; 3) they agree to exchange biochemical assays (drug screening tests); and 4) companies will share data on compounds that failed in pre-clinical development, to help keep other companies from repeating similar mistakes. Clinical program ICC-001 is the first of the ICC's proposed clinical studies evaluating the surrogate marker effect of two separate three- drug combinations, AZT/ddC/Invirase and AZT/ddC/nevirapine compared to AZT/ddC, in 225 patients. The rate of accrual has been very rapid, and the trial is now fully enrolled, although the number of female participants is quite low. Representatives from the community are forming a committee to find solutions for this problem. ICC-002 is scheduled to begin enrolling June 12. It compares AZT/ddI/nevirapine and AZT/ ddI/3TC to AZT/ddI, again in 225 patients. For the location of the nearest trial site, call the National AIDS Clearinghouse at 800/TRIALS-A. Alternative Trial Designs Two activists at the meeting were given an opportunity to propose clinical trial designs for the ICC's consideration. Jules Levin recommended that the collaborative run combination protease inhibitor studies, specifically of Merck's MK-639 and Roche's Invirase (saquinavir). Representatives from the two companies said they plan to do that, but not until the new formulation of saquinavir (designed to be better absorbed) is ready for clinical development (next year at the earliest). Bill Bahlman proposed that the ICC run open-label studies of a new three-drug combination in 30 patients every month in order to quickly discover more potent combination therapies. Each study would last six to ten weeks, and would include groups with CD4 cell counts greater than and less than 300. To be considered successful, a combination would have to be safe and show dramatic activity (reducing viral load, and boosting CD4 cells) in 70 to 90 percent of the study participants. The degree of activity that would be considered dramatic remains to be defined. The community members present were very supportive of the concept in principle. However, some voiced concerns that if a new three-drug combination is not compared to a two-drug combination, there would be no way of telling whether the addition of the third drug was helpful or harmful. Also, since it is unknown whether the magnitude or duration of antiviral effect is more important for clinical benefit, such short-term studies could reject important combinations with less effect on viral load but a longer period of activity than some other combinations. (The Treatment Action Group is now drafting a variation of this proposal that addresses these concerns.) David Barry, M.D., of the Burroughs Wellcome Co. (and chair of the ICC's clinical trials subcommittee) felt that Mr. Bahlman's concept could be accepted by the ICC with slight modifications, but only if it were run in people with HIV resistant to AZT. He said that he would draw up his proposal and present it to the ICC's members at the consortium's next meeting, slated for June. Dr. Barry also presented a proposal to establish an observational database that would gather data on every person with HIV under treatment by a physician. He suggested the creation of a standardized data collection form for use by AIDS care providers. Each patient could be given a fourteen digit code (to protect confidentiality) and his or her medical history entered into the national database. [Dr. Barry resigned from Burroughs Wellcome as Treatment Issues went to press. It is unclear how his departure will affect ICC plans.] **************** Reappraising d4T by Gabriel Torres, M.D. d4T (also known as stavudine or Zerit) may be getting a new lease on life with the recent release of new data showing its beneficial effects in patients with prolonged previous treatment with AZT. The FDA approved d4T (a nucleoside analogue like AZT) in June, 1994 as a second or third line agent for patients with a history of intolerance or failure on AZT therapy. The agency based its action on a preliminary analysis of a randomized trial comparing the two drugs, which showed a beneficial effect on surrogate markers (CD4 counts and HIV levels). The data available at the time may have underestimated d4T's value. Final Analysis of the 019 Study The final analysis of this trial, known as 019 and sponsored by the d4T's developer, Bristol-Myers Squibb (BMS), was recently announced at a meeting in San Francisco. This double-blind randomized trial enrolled 822 people with HIV and CD4 counts between 50 and 500 and at least six months of prior AZT therapy. The primary endpoint of the trial was treatment failure, defined as a drop in CD4 count to 50 percent of baseline, a new or recurrent AIDS-defining event or death. Ninety-two percent of the patients were followed for two years, even after the development of a clinical or CD4 cell endpoint. The trial participants who received d4T remained on the drug longer than those continuing to receive AZT (79 versus 54 weeks). The results of the comparative analysis demonstrated that the time to treatment failure was longer for those on d4T, as was the time to AIDS-defining events or death. This delay in clinical disease progression had not been seen in trials involving switching from AZT to ddI, ddC or combination therapy with AZT and ddC. Time to death (survival time) alone was prolonged by switching to d4T, although this difference was not statistically significant. The rates of peripheral neuropathy were higher for d4T (ten percent) than for AZT (four percent) as were the rates of liver enzyme elevations, but there were more cases of bone marrow toxicity (anemia and neutropenia) among those receiving AZT. No differences in the rates of pancreatitis were observed. In terms of quality of life, the group taking d4T scored better in all areas than those taking AZT. The daily functioning and well-being of those switched to d4T were improved, and they reported fewer drug reactions overall with less asthenia (weakness), anorexia, abdominal pain, nausea/vomiting and anemia in particular. Parallel Track Other important d4T data are those from the parallel track program which enrolled 12,551 patients between October, 1992 and May, 1994 by 1,244 physicians who enrolled patients from their offices. This large simple trial compared two doses of d4T (20 and 40 mg twice daily) and measured survival as its primary parameter. Participants were 94 percent males and only sixteen percent non-white, demonstrating again the lack of access of expanded access trials to women and minorities. The average CD4 count was 45 and the median duration of prior AZT therapy was 96 weeks. There was a non-significant survival trend favoring the higher dose of d4T, as well as more improvements in hemoglobin and neutrophil counts (indicating better recovery of bone marrow function), increased weight and fewer hospitalizations. The overall conclusion of this trial was that d4T can be administered safely to patients with advanced disease and that the higher dose may be slightly superior to the lower dose. Therapy-Naive Patients Few studies of d4T are available in people without previous anti-HIV therapy, mostly because the sponsor delayed development of the drug in favor of its sister drug, ddI, which is also made by BMS. But a retrospective analysis examined AZT-naive individuals with CD4 counts below 300 who received d4T in Phase I/II and compared them to a similar matched group of trial participants who received AZT in an ACTG study (116A). The mean change in CD4 counts was higher and more sustained for 48 weeks in the d4T group. Though intriguing, these data from studies which were done with different groups of volunteers at different times have to be interpreted very carefully. Certainly they suggest that additional studies of d4T should be carried out to see if d4T indeed is a better drug than AZT in persons without previous anti-HIV therapy. Viral Load Analyses Viral load measurements are also generally lacking from d4T trials. In several small studies conducted at Yale University, d4T has been shown to reduce viral load, as measured by peripheral blood mononuclear cell cultures, by 90 to 99 percent, with a 90 percent reduction maintained up to five weeks. In contrast, a quantitative PCR assay found only a 70 percent reduction in blood plasma levels of HIV (viral load). In the BMS 019 study mentioned above, the plasma samples for the viral load assay were not handled and processed adequately at most of the participating sites. Only a small sample of assays was available for analysis, and this sample size was insufficient to ascertain whether viral load changes correlated with enhanced clinical health. Combination Studies Combination studies of d4T and AZT were completely stalled because of a report finding that the two drugs were antagonistic when used together in cell culture. Data from four laboratories subsequently indicated that both drugs can be synergistic or additive in their anti-HIV effects. An ACTG study due to begin enrolling patients in June 1995 compares d4T to ddI and the combinations AZT/ddI and AZT/d4T in patients with greater than six weeks of AZT and CD4 counts between 300 and 600 (ACTG 290). Another ACTG study will compare the combination AZT/d4T to either drug alone as first-time therapy for patients with CD4 counts of 300 to 600. The ddI/d4T combination also is under study in a pilot trial comparing high and low doses of both drugs. An interim analysis of the first 55 patients in this trial could not find a significantly higher incidence of predictable toxicities such as peripheral neuropathy, even in volunteers receiving the higher doses of both drugs together. The study remains blinded and will continue until 75 persons have participated. Finally, an analysis of the 114 patients in the parallel track program who reported taking AZT and d4T together indicated a survival benefit for those taking the higher dose (40 mg twice daily) of d4T, no increased incidence of adverse effects and a lower incidence of dementia. Resistance The information on the emergence of d4T-resistant strains of HIV is limited, but it appears that such resistance is slow to develop. In test tube experiments, Douglas Richman, M.D., from the University of California San Diego was able to isolate viral strains resistant to d4T. These were not cross- resistant to other nucleoside analogues. Bristol-Myers Squibb researchers reported last fall that of eleven individuals with eighteen to 22 months on d4T monotherapy, decreased susceptibility to d4T occurred in only two persons. The two had started d4T with HIV that was extraordinarily sensitive to the drug. No particular viral gene mutations were associated with d4T use. In this study, sensitivity to d4T was determined directly by viral culture, not indirectly by analysis of genetic mutations. The low frequency of clinical d4T resistance is encouraging although renewed declines in CD4 cells and rises in HIV levels are still seen with long-term d4T use. This loss of benefit may not be due to drug resistance as much as with AZT. CNS Affects The only data available on penetration of d4T into the brain comes from two small studies that measured blood levels of the drug in the cerebrospinal fluid (CSF). One study done in four children reported that drug levels 38 to 97 percent of those in plasma were attainable in the CSF, and the other one in nine volunteers observed levels 16 to 72 percent of those in plasma. These levels are significantly higher than those seen with ddI or ddC. No studies of d4T in demented patients have been done. In the BMS 019 study, no one in the d4T arm developed dementia, as compared to four persons on AZT, suggesting a protective effect. d4T's Potential D4T definitively seems to be superior to ddI or ddC in terms of both efficacy and toxicity given the results of the BMS 019 study of AZT pre-treated patients. But the paucity of data on AZT-naive persons or the use of d4T in combination is very disappointing. Some clinicians prescribe the drug as a first-line agent in naive patients who adamantly refuse to take AZT; others are combining it with 3TC in advanced patients who have failed or are intolerant to all other approved drugs. Scattered anecdotal reports of 99 percent or more reductions in viral load from d4T and 3TC in combination argue that this regime should be studied urgently. It remains to be determined how d4T will fare when combined with protease inhibitors or non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and loviride). A trial using d4T along with the Merck protease inhibitor is already in progress. Copyright (c) 1995 - GMHC Treatment Issues. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. 714.248.2836 * 8N1/Full Duplex * v.34+