Date: 19 Nov 1997 05:51:55 From: aidsnews@igc.org Subject: AIDS Treatment News #283 AIDS Treatment News Issue #283, November 21, 1997 phone 800-TREAT-1-2, or 415-255-0588 CONTENTS: FORTOVASE(TM) Approved: New Saquinavir Formulation 1592 Access: Larger Program Planned HIV Resistance Testing: More Questions Than Answers Drug-Resistant Herpes: Cidofovir Gel in Limbo. Interview with Jay Lalezari, M.D. Treatment in Developing Countries: New UNAIDS Pilot Program Geneva Conference Deadlines: Time to Start Planning ***** FORTOVASE Approved: New Saquinavir Formulation by John S. James On November 7 the FDA approved FORTOVASE, the new "soft gel" formulation of saquinavir, for treating HIV infection in adults, in combination with other antiretrovirals. The new formulation delivers much more of the drug to the blood than the older version, INVIRASE(R) (saquinavir mesylate). The main problem with INVIRASE has been that the amount provided by the approved dose is too low. FORTOVASE, which is taken three times a day with meals (or up to two hours after a meal), should be on pharmacy shelves within a week. The old saquinavir (INVIRASE) will remain in pharmacies for six months; after that, it will still be available on a limited basis to patients who want to continue using it, through a special distribution program. FORTOVASE has been priced to cost the same as INVIRASE, with a wholesale acquisition cost of approximately $5,700 per year. Developer Hoffmann-La Roche has a patient assistance program, for persons unable to pay for the drug. This program can also help patients who want to convert to FORTOVASE before their health plan approves it for reimbursement. A safety study with 442 patients who received FORTOVASE in the approved dose, for a median of 52 weeks, found that the main side effects were diarrhea, nausea, and abdominal discomfort. Eight percent of patients had to discontinue the drug due to side effects, mainly gastrointestinal; fewer than one percent discontinued because of laboratory toxicities. A large U.S. FORTOVASE trial now recruiting is comparing FORTOVASE in a three times a day vs. a twice a day dosing schedule (combined with other antiretrovirals), vs. FORTOVASE plus VIRACEPT plus a new reverse transcriptase inhibitor. This may be an attractive trial since everyone will receive a credible treatment; there is no "loser" arm which must do worse for the study to fulfill its purpose. For more information about this trial, call 800-TRIALS-A. Hoffmann-La Roche has established the following sources for information about FORTOVASE: * Healthcare professionals, call 800-526-6367. * Patients (outside of the Washington D.C. area), call 800- 910-4687. * Patients in the Washington D.C. area, call 202-442-2437. * For the Roche HIV Therapy Assistance Program, call 800-282- 7780. Or on the Web, see http://www.fortovase.com. ***** 1592 Access: Larger Program Planned by Linda Grinberg and John S. James Plans for a larger 1592 expanded access program, projected to start early in 1998, were discussed at an October 13 meeting attended by several treatment advocates and Glaxo Wellcome representatives. After the meeting, some community groups called off a boycott of Glaxo Wellcome products, which had been organized to protest serious difficulties in gaining access to the drug. Community representatives proposed the following design for the 1998 program: * No Arbitrary Limitation on Program Size. As neither the company nor community representatives could estimate the actual need for the drug, it was agreed from the outset that there should be no pre-established numeric limit on the total number of patients served by the program. Every effort should be made to allocate all available drug, not used for clinical trials, to the program. * Principle of Expanded Access/Eligibility Criteria. The underlying principle of the expanded access program should be to allow patients to construct a viable treatment regimen based on the current treatment guidelines. Unless required by the FDA, community representatives felt this definition eliminated the need to set arbitrary entry criteria such as viral load, CD4+ counts, or failure of specific drugs. (See "Expanded Access to Experimental Drugs: Activist Seek More Open Programs" in our last issue, AIDS TREATMENT NEWS #282.) * Initiation of Program. Glaxo agreed to make every effort to initiate a broader expanded access program as soon as possible in the 1st Quarter of 1998--without committing to a date certain. * Traditional Distribution. The new program should not be restricted to a small number of centers or physician practices, but should be a more traditional expanded access which would permit registration through a patient's primary care physician. * Flexibility. The program should be designed with enough flexibility that patients who need the drug as a treatment option will have access. * Community Meetings. Glaxo representatives should continue to meet with community treatment advocates and with physicians by holding future meetings in various cities to solicit feedback on the proposed framework for a wider program in 1998. Glaxo recently reported a total of 615 patients enrolled in the 1592 adult program, but as of October 10 only two children had been enrolled in the pediatric program. At the meeting concerns were raised about the pediatric viral load criteria being too restrictive. It was agreed this limit should be lowered, subject to FDA approval. Much of the current delay in access to 1592 and other experimental drugs is primarily due to local IRBs (institutional review boards), which often meet only monthly and do not understand the disease or the drug; they may make vital access programs wait in line behind more routine research projects. Glaxo set up a national IRB for the 1592 open label program, but when hospitals have their own IRB, they often require their physicians to use it instead of a national one. As of the October meeting ten sites had not enrolled any patients, as their own IRB approvals were still pending. Community representatives in attendance were encouraged by the general tenor of the meeting; they felt that a more constructive dialogue and spirit of working in cooperation had begun. They remain hopeful that Glaxo will use best efforts in its 1998 program to adequately address access for all patients who need the drug. ***** HIV Resistance Testing: More Questions Than Answers by Bruce Mirken Since the advent of Highly Active Antiretroviral Therapy (HAART) in early 1996, increased attention has been focused on the subject of HIV's ability to develop resistance to antiretroviral drugs. If a person's virus is already resistant to two of the drugs in a three-drug combination, his or her treatment is effectively reduced to monotherapy and is likely to fail. Given the large number of PWAs who have been treated with nucleoside analogs such as AZT and ddI prior to the introduction of protease inhibitors and non- nucleoside reverse transcriptase inhibitors, along with the possibility that some people might become newly infected with resistant strains, choosing an effective regimen can be difficult. Still, making the right choice means a greater chance of long-term success and a reduced possibility of developing resistance to the new drugs. One obvious answer to the problem would be a test that doctors could use before starting treatment to determine if a patient's virus is resistant to any drugs and again in the case of viral rebound to see if resistance has developed. Tests that seek to do just that have been available for some time, but serious questions remain as to their usefulness in day-to-day clinical practice. There are two broad types of tests that can be used to look at HIV drug resistance: phenotypic and genotypic assays. Phenotypic assays test the actual ability of the virus to replicate in cell culture when a drug or drugs is added. Genotypic tests, on the other hand, identify specific genetic mutations in the virus which correlate with phenotypic resistance. Both types of tests are used in research, but because today's phenotypic tests are cumbersome, time-consuming and expensive, there has been little effort as yet to make them commercially available for clinical use. The faster and less expensive genotypic tests have been available to doctors since last year, but their usefulness remains controversial. "When [genotypic resistance tests] started becoming available we ordered quite a few," comments San Francisco AIDS specialist Dr. Virginia Cafaro. But, she says, "they were not matching up clinically with what we found, so they were not all that useful." Cafaro still orders the tests occasionally as a source of additional information in particularly difficult or puzzling situations, but overall considers the tests "just not good enough" at this point for use as a regular part of clinical decision-making. New York AIDS physician Dr. Paul Bellman agrees, calling genotypic testing "disappointing" thus far. One problem is that although researchers have identified numerous specific HIV mutations associated with drug resistance, the exact interplay of those mutations remains somewhat unclear. This was underlined by several presentations at the June, 1997 International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication, held in St. Petersburg, in which the associations between known mutations and real-world drug failure were not found to be as clear-cut as might have been expected. For example, two mutations, G48V and L90M, have been associated with resistance to saquinavir. But when Stanford researchers analyzed the virus from 40 patients who had experienced treatment failure on long-term saquinavir treatment, one or both of those mutations was seen in just 58 percent of them, and 35 percent had mutations typically associated with resistance to other protease inhibitors. Strikingly, all who developed the G48V mutation--some of whom remained on saquinavir and some of whom switched to indinavir or nelfinavir--eventually went on to develop a second mutation associated with resistance to ritonavir and indinavir. What this suggests, the researchers wrote, is that resistance to saquinavir "may provide a genotypic foundation for the development of resistance to other protease inhibitors." In other words, mutations that arise during saquinavir use may not directly cause resistance to other protease inhibitors but may increase the likelihood of future mutations that do cause resistance to those drugs. Numerous other presentations at the St. Petersburg meeting suggested similarly complex patterns--all of which are not fully understood as yet--by which resistance to various protease inhibitors develops. So even though testing can now give doctors a print-out identifying particular mutations, we may not have enough information yet to truly understand what those mutations mean. Ed Hurwitz, vice president and chief financial officer of Affymetrix, whose GeneChip genotyping system is presently being marketed only to researchers, says, "I guess our opinion is it's going to take two to three years of research" before the tests can be effectively used in "day-to-day disease management." The same concern was voiced in a May 24, 1997 commentary in The Lancet by San Francisco General Hospital AIDS researchers Drs. Steven Deeks and Donald Abrams, who argue that "there is little consensus among experts on the significance of most mutations." In a recent interview Deeks confirmed that his views on the subject "have not changed a bit." Another concern Deeks and Abrams raise is the sensitivity of the tests. According to Dr. Terry Robbins, director of clinical molecular biology for Specialty Laboratories, a Los Angeles firm now marketing genotypic testing to physicians, his company's assay can identify "the majority species of HIV present in an infected individual... If it was present at 25 percent [of a person's total virus population] we would see it." But Deeks and Abrams argue that "since drug-resistant strains can be rapidly selected by antiretroviral therapy," mutants present at much lower levels are likely to be significant. Robbins notes that there is an opposite danger as well: A too-sensitive test could "pick up random mutations" that are clinically irrelevant. Indeed, data from the St. Petersburg meeting suggested that such random, occasional mutations did not appear to have an influence on the outcome of treatment. The ideal level of sensitivity for genotypic resistance tests remains uncertain at this point, but in discussions at the recent Interscience Conference on Antimicrobial Agents and Chemotherapy some physicians argued that it will be necessary to detect mutants representing less than 10 percent of a person's virus population. Robbins, not surprisingly, is more upbeat than Deeks and Abrams about the current use of genotyping as a clinical tool. He argues that one key use of such tests, to determine if an increase in viral load is due to the development of resistance as opposed to other factors, doesn't depend on the ability to detect minor populations. Still, though he believes genotyping can be useful to physicians now, Robbins cautions that it shouldn't be the sole basis for treatment decisions: "If a physician is basing therapeutic changes on a genotypic pattern, it needs to be done in conjunction with the patient's past history. A therapeutic decision should not be based on a single test." Meanwhile, research and development of HIV resistance testing is continuing at a fairly rapid clip. Robbins notes that Specialty Laboratories is developing a multicenter clinical trial it hopes will validate clinical use of its test, while the CPCRA is also mounting a genotyping trial. At ICAAC a Canadian firm called Visible Genetics unveiled a new genotypic test--available only to researchers for the time being--which it claims can identify mutations others miss, and for which it is planning several clinical trials. South San Francisco based ViroLogic presented initial data on a new phenotypic assay that can produce a result in 8-10 days, nearly as fast as the genotypic tests. The ViroLogic test can detect mutants at "about 10 percent of the population," according to researcher Chris Petropoulos. That such research and development is moving ahead energetically is a positive sign, and there seems little doubt that HIV resistance testing will get increasing attention in future years as both the technology and scientists' understanding of how to use it improve. For now, though, the only clear consensus is that it represents an area with great potential and many unanswered questions. ***** Drug-Resistant Herpes: Cidofovir Gel in Limbo. Interview with Jay Lalezari, M.D. by John S. James Cidofovir, a drug active against many herpes viruses, has been approved for over a year in intravenous formulation (VISTIDE(R)) for treatment of CMV retinitis in patients with AIDS. Developer Gilead Sciences has also produced a 1% cidofovir gel called Forvade(TM), to test as a topical treatment for acyclovir-resistant herpes lesions, and perhaps also for warts or other viral skin infections. A multicenter study tested Forvade for treatment of acyclovir-resistant herpes, but in May 1997 the FDA found the data insufficient and turned down the drug for marketing. The study results were published in October.(1) Forvade--very important for a small number of patients--now faces an unclear future. It would be difficult to enroll another trial today, since improved antiretroviral therapy has greatly reduced the number of opportunistic infections, including cases of drug-resistant herpes. The published study tested Forvade, vs. a weaker formulation (0.3% gel), vs. placebo, in 30 patients treated once a day for 5 days. Half of those who received drug had either complete healing or a partial response; none of those on placebo did. Herpes virus shedding stopped in 87% of those receiving treatment, vs. none of those on placebo. All measurements used--lesion healing, viral cultures, and pain relief--were consistent, and statistically significant compared to placebo. Side effects were minor, and no drug (or almost none, in patients who had the largest lesions) was absorbed into the circulation. We interviewed Jay Lalezari, M.D., who has an HIV practice in San Francisco and is director of Quest Clinical Research. Dr. Lalezari is one of the most experienced physicians in the country in treating acyclovir-resistant herpes. AIDS TREATMENT NEWS: Why is Forvade (cidofovir gel) important? Dr. Lalezari: This was a double-blind randomized placebo- controlled study, and all of the measured efficacy parameters including healing, pain relief, and virologic outcome point to a clear, consistent, and statistically significant benefit of this drug. In my experience, these lesions are among the most painful, disabling, and difficult to treat complications of AIDS. For such patients the pressing issue is pain relief, and the clear benefit in this trial has been one of my most gratifying experiences in AIDS research. Although the infection has become less common, cases continue to occur, and treatment options are urgently needed. What is surprising is how much benefit we saw with only five days of once-daily topical therapy. Cidofovir is one of the most potent antiviral drugs that has ever been developed. Its long tissue half life may also help explain why it worked as well as it did. And there was no down side. The drug is not absorbed into the circulation, and therefore there was no systemic toxicity. There have been reports about local toxicity using a higher concentration of the gel, 3%, in treatment of warts; it has been associated with some local ulcerations. But we did not see any in this study. ATN: What happens now? Dr. Lalezari: Gilead is working with the FDA to determine what additional studies it wants. But the bottom line is that this condition is so infrequent that it would be extremely difficult to accrue a new study. It took us two years to enroll 33 patients in the original study--in the era before protease inhibitors, so there was still a small but significant number of patients who had acyclovir-resistant herpes who were desperate for treatment. Therefore it was possible to enroll the study; we enrolled half the patients in this office. But to do that now would be extremely difficult--not because there are no patients, but because they are very spread out. So I think that if the FDA insists on additional studies, it effectively kills the development of this drug. What is not clear is what are the politics behind that decision, at the FDA and in turn at Gilead. Fortunately, Gilead has said that it will continue its compassionate use program. But no company can do that indefinitely if the drug is not being developed. This is not a make-or-break issue for thousands of patients, but there are probably at any given time in this country ten to 50 patients with this problem. ATN: There was a dose response in viral culture negativity, but the high dose was not better than the low dose in lesion healing or pain relief. Do you know why? Dr. Lalezari: It appears that patients in the low-dose group took more pain medications, which tended to mask the pain response. Tissue healing is very complex. It involves many factors, including nutritional status--not just eradicating the virus. What is important is that there was clinically significant tissue healing (50 percent or better reduction in lesion size), in half of the treated patients, vs. none of those on placebo. And there were more patients on the high-dose group who had complete lesion healing. The results we saw were statistically significant, and were clinically meaningful, in a disease for which there are very few other treatment options. ATN: Could the IV formulation (VISTIDE) be used topically? Dr. Lalezari: I doubt it. You need something to keep the drug on the lesion, to allow for gradual absorption. If you just pour on the IV fluid, it runs off. ATN: Why do you think the FDA denied permission to market the drug? Dr. Lalezari: I do not know. There was just one study with a fairly small number of patients. But this is a very benign treatment intervention, with positive, believable results, in patients who have very limited options. It took us two years to find all those patients. I cannot imagine having done a study much bigger. And the size should not matter as long as the results were statistically significant. There may also be concern about the adequacy of the photographs. We took photographs of geographically complex lesions, and did the best we could. There are different focal planes, so not all the lesions are clear in all the photos. Even if the photographs were not adequate, the virology data is clear and objective. And there is no way to argue with the fact that there was clinically significant resolution of the lesions, and reduction in pain. These patients have advanced disease, and do not generally have a long life expectancy. All that really mattered was improving their quality of life, by eliminating the herpes virus, and reducing pain and lesion size. It made their quality of life significantly better. I do not know what the politics are between Gilead and the FDA. The other possible concern is potential carcinogenicity; a study in rats found an increase in mammary tumors associated with subcutaneous administration of cidofovir. This did not prevent approval of the injected drug, but if the gel were approved for acyclovir-resistant herpes, there may be concern at the FDA that it might be used much more broadly. People might start choosing it instead of acyclovir to treat less serious herpes, and the FDA may have concerns about possible long-term risk. Drug-resistant herpes in advanced AIDS is a miserable disease. For these people, going to the bathroom can be excruciating. This drug works in drying up the lesions; in some cases there was complete healing. You do not see that in the natural history of this disease, or in the placebo group. So the drug works. And since there was no down side, I cannot imagine why it would not be approved. It is a shame that the needs of these patients are not being given appropriate consideration. References 1. Lalezari J, Schackter T, Feinberg J. and others. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. THE JOURNAL OF INFECTIOUS DISEASES. October 1997; number 176, pages 892-898. ***** Treatment in Developing Countries: New UNAIDS Pilot Program by John S. James On November 5 the Joint United Nations Programme on HIV/AIDS (UNAIDS) announced the UNAIDS HIV Drug Access Initiative, a pilot program to develop ways of making AIDS-related treatment more available to the 90% of people with HIV who live in developing countries and have little or no access to modern treatments today. This program is a collaborative effort between pharmaceutical companies (including Glaxo Wellcome, Hoffmann-La Roche, and others) and health officials in developing countries. It was designed with the realization that money is not the only obstacle to effective treatment access, as there are also major training and infrastructure issues. The current pilot phase will operate in four countries--Chile, Cote d'Ivoire, Uganda, and Viet Nam--to develop procedures and knowledge that can then be used in many other countries. In each country, two new entities will be created: * A national HIV/AIDS drugs advisory board, under the Minister of Health. This board, which will include representatives of local medical, public health, and HIV communities, will devise a coordinated national policy for the provision of HIV-related drugs. * A nonprofit company which will be a clearinghouse for placing orders and receiving drugs on behalf of the government. Drug price subsidies will be negotiated separately between each country and the pharmaceutical companies. This initiative will include not only HIV drugs, but antimicrobials to prevent and treat opportunistic infections, and antibiotics to treat other sexually transmitted diseases, which increase the risk of HIV transmission. This effort will be funded from a variety of sources. UNAIDS itself will provide $1,000,000 for oversight, evaluation, and dissemination of the recommendations. "This program will provide the information we need to determine whether HIV/AIDS-related drugs can be obtained and distributed effectively in developing countries," said Dr. Joseph Saba of UNAIDS, coordinator of the initiative. "Armed with this information, countries will then be able to mobilize the necessary resources to treat infected individuals, and to help control the global epidemic." More information is available in a 12-page background document distributed by UNAIDS, October 1997. A detailed summary is available at http://www.unaids.org. ***** Geneva Conference Deadlines: Time to Start Planning by John S. James The 12th World AIDS Conference will be held at the Palexpo Conference Centre in Geneva, June 28 - July 3, 1998. It is important to begin planning early because: (1) Conference deadlines start as early as February 2. (2) Hotel rooms will be tight. Of the seven different zones where conference hotels will be located, only one is in Geneva; three are in France. Travel times to some of the hotels can be as much as 90 minutes each way, although average time is probably closer to 45 minutes. [However, our travel agent tells us that there are rooms in Geneva available at this time, without going through the conference, starting at $115 per night.] (3) The best way to get low-cost air tickets is usually to buy them in sales which occur during the winter months. When setting travel dates, note that community and other satellite meetings usually occur before the international AIDS conference, not after. The earliest meeting now in the official schedule is the Community Rendez-Vous, starting Friday June 26 at 5:30 p.m.; however, many events have not been set yet, and some may be earlier. Since air and hotel reservations may not be changeable, we like to arrive a couple days early, giving time to rest and prepare for the conference--or to be available for meetings that otherwise we could not attend. Conference Deadlines February 2 is the deadline for: Abstract submission (must be received at the conference organizer in Stockholm, Sweden, on the form provided, *not* by fax); Scholarship applications (also not accepted by fax); Early registration fee; NGO booth requests; and Satellite meeting requests. April 1 is the deadline for accommodation requests (subject to hotel availability after this date). May 1 is the deadline for the standard registration fee, and for child care requests. June 1 is the deadline for late-breaker abstracts. Early registration is advised. There might or might not be onsite registration, depending on space available. Costs As this issue went to press, the cheapest regular fare from the San Francisco area to Geneva was $1070 round trip; however, there are charter flights to Paris for $398 round trip, and the train from Paris to Geneva takes 6 hours and costs $98 each way. Travel in Europe is crowded during the summer, and expensive; if one is flying into another city and taking a train to Geneva, it can help to go a day early to rest, and leave time to assure connections. Another option is a group fare, which a travel agent may be able to arrange if you have enough people flying from the same city. [Thanks to Tim James of Uniglobe Majestic Travel in Lafayette, California for this information.] Hotel prices for accommodations obtained through the conference organizer are in six categories, ranging (in Swiss francs) from CHF 80 to CHF 435 per day for a double room ($1.00 = CHF 1.35 in November 1997). The regular conference registration fee is CHF 940 (CHF 590 student) before it goes up after February 2. For media registration, see the Second Announcement and Call for Abstracts (described below). Miscellaneous A valid passport is required for citizens of all countries to enter Switzerland; a visa is required from residents of about two dozen countries (not including the U.S. or Canada). No vaccinations are required, and there are no HIV-specific restrictions. Be sure to check travel requirements of other countries you are traveling through--and for France if you are assigned to a hotel there. (U.S. citizens can enter France as tourists for up to three months without a visa, but "the expiration date of your passport must exceed by six months the last day spent in France.") Documentation requirements may change, so check with a travel agent or other expert. Geneva is in the French-speaking part of Switzerland. English is widely understood. The electricity is 220 volts, 50 cycles. For More Information For more information, see the Second Announcement and Call for Abstracts, which has been widely distributed to AIDS organizations and those who have attended previous conferences. There is also a Web site, below, but most of the information in the Second Announcement is not on the Web at this time. Also, the Second Announcement includes the abstract and other required forms. The conference organizer (for participants, exhibitors, media, scholarship applications, abstracts, and satellite meetings) is: Congrex Sweden AB AIDS 98 P.O. Box 5619 Linnegatan 89A SE-11486 Stockholm Sweden Phone: +46 8 459 6600 Fax: +46 8 661 8155 Email: aids98registration@congrex.se, or aids98@congrex.se Web: http://www.aids98.ch There are also separate addresses in different cities for program planning, accommodations and tours, and sponsorship and corporate relations; these are listed on the inside cover of the Second Announcement. Media inquiries can be directed to Ogilvy Adams & Rinehart in New York, 212-880-5231, ask for AIDS98. ***** AIDS TREATMENT NEWS Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews@aidsnews.org Editor and Publisher: John S. James Associate Editor: Tadd T. Tobias Reader Services: Tom Fontaine and Denny Smith Operations Manager: Danalan Richard Copeland Statement of Purpose: AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U.S. funds: personal check or bank draft, international postal money order, or travelers checks. VISA, Mastercard, and purchase orders also accepted. ISSN # 1052-4207 Copyright 1997 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.