Human Growth Hormone
by John S. James
On August 23 the FDA told Serono Laboratories, Inc. that it would give accelerated approval to Serostim(TM), its recombinant human growth hormone, for treatment of AIDS wasting. Accelerated approval means that the drug was approved based on medical tests indicating drug activity (mainly increase in lean body mass, in this case), and that the company will need to complete further studies to provide additional information and confirm the clinical benefit of the drug.
This growth hormone has already been available on a "treatment IND," a temporary program for early release before approval. A number of third-party payers, including MediCal (California's Medicaid) were willing to pay for the drug in treatment IND status, but many others were not. Approval should make it easier for the drug to be reimbursed. (Note: Other versions of recombinant human growth hormone have been approved in the U.S. for years. But they have not been used to treat wasting, partly because some companies chose not to research their products for AIDS-related uses, partly because human growth hormone has been tightly controlled to prevent abuse by athletes, and also because all these products have been very expensive. It is not known if the other products would be equivalent to the version just approved, as Serono's is derived from genetically engineered mammalian cells, and the others from non-mammalian cells.)
Serono plans to have its human growth hormone available in pharmacies by November. Until then, the treatment IND access program (explained below) will remain open, and will allow new enrollment. The price of Serostim has not been decided, but Serono has agreed to a price cap, under which no patient will be charged more than $36,000 per calendar year for the drug. There are plans for a patient assistance program, but details have not been worked out.
Physicians or people with AIDS can get more information by calling the Serono Access Line, 800/714-2437, Monday through Friday 8:30 a.m. to 5:00 p.m. Eastern time.
Wasting is a major problem in later stages of HIV disease, and is responsible for many deaths. It is very important to get medical attention early, when the condition is easier to treat. Inexpensive treatments work for many people, especially when treatment is started early; very expensive drugs such as human growth hormone can usually be avoided. (And growth hormone is unlikely to work in some cases, such as weight loss caused by an eating disorder or by severe malabsorption.) A major problem is that there is much denial by patients, and disregarding of the problem by physicians; therefore people do not get medical attention quickly when they start losing weight or lean body mass, or when they fail to regain weight lost during an opportunistic infection.
It is possible to have serious wasting without losing weight or looking thin, if lean body mass -- muscle and organs -- is replaced by fat. An inexpensive, non-invasive test called bioelectric impedance analysis (BIA) can warn of this development. BIA measures change in body composition by changes in the body's impedance to small electric currents. Other tests are also used for this purpose.
The first step in medical care is diagnosis. Some causes of weight loss or wasting (loss of lean body mass) may be easily treatable -- such as certain intestinal parasites or other infections, sores in the mouth or throat preventing intake of food, or problems in absorbing nutrients from the intestines, or other nutrient deficiencies. A number of different problems, treatable to varying degrees, may be contributing to loss of lean body mass in an individual. A number of treatment possibilities (many inexpensive) have been widely proposed; but due to the very expensive and profit-oriented drug development system in the U.S., these have not been approved by the FDA, nor submitted or considered for approval.
When anabolic drugs are needed, a popular low-cost regimen for some patients is testosterone plus nandrolone. Much more expensive (in the U.S.) is oxandrolone, an oral anabolic steroid which was first approved in the U.S. over 30 years ago, and recently became available here again. With a good medical management program, the most expensive treatments -- human growth hormone, and TPN (total parenteral nutrition) -- can often be avoided or minimized. It is important that they be available, however, for those patients who do need them.
Historical Note: Activists' Critical Role
Human growth hormone would not be approved or otherwise available today for treating AIDS wasting without the work of treatment activists. Three persons in ACT UP/Golden Gate -- Bill Thorne, Jeff Getty, and Matt Sharp, who were interviewed for this article -- have done major work on human growth hormone for the last three years. Others who have made major contributions include the Treatment Action Group (TAG), Project Inform, and AIDS Project Los Angeles.
Major treatment activist involvement started three years ago in San Francisco, when a 12-week trial of human growth hormone was unable to recruit patients. The main problem was that those using the most recent antiviral then available -- d4T -- were excluded, because d4T was officially "experimental" at that time, although it was widely available through an expanded access program of Bristol-Myers Squibb. Almost everyone with wasting severe enough to qualify for the trial was trying d4T, since other treatments had failed to stop the disease progression. At first the activists could not get through to Serono, but finally the company had to listen, because its trial was going nowhere. The d4T exclusion was lifted and the trial filled quickly, especially in San Francisco, where activists told others about the opportunity to enroll.
In this trial, the activists learned that "the drug helps people recover. We clearly saw it working in our friends." During the three years since, they have pressured both Serono and the FDA to solve other problems:
So activists had to pressure both parties to reach the compromise which led to the recent approval: Serono would request accelerated approval (committing itself to further trials), and the FDA would accept the existing data for this purpose. But as recently as this summer, activists walked out of a meeting with the company, refusing to help it get approval unless it lowered its price, which at that time was going to be as much as $75,000 a year. In later negotiations in Oakland, with a company official flying in from Geneva for the purpose, Serono agreed to a price cap which would limit the maximum annual cost to a patient to about half of what it otherwise would have been. After this agreement, a series of meetings took place between Serono, the FDA, and activists, in which the agreements leading to the current approval were finalized. (This is the first time that accelerated approval has been used for a metabolic drug, which is handled by a different and more conservative staff at the FDA than the antivirals, which have often been given accelerated approval.)
Activist-company relations, while successful, remain difficult. At the Vancouver conference, Serono received one of five "Golden Urn" awards from ACT UP/Golden Gate for AIDS profiteering ("they earn, we urn"). An August 26 press release from ACT UP/Golden Gate, "celebrating" the approval, quoted Matt Sharp as follows:
"It has been an uphill battle from day one to get growth hormone approved. Now we can be satisfied that our ongoing pressure on Serono and the FDA will come to fruition by having this drug save thousands of lives."
ACT UP/Golden Gate can be reached at 415/252-9200 or 415/252- 9275, fax 415/252-9277, email email@example.com, web site http://www.actupgg.org . It has public meetings every Tuesday night in San Francisco.
For More Information
Probably the best overall single information source on wasting at this time is The Wasting Report (subtitled Current Issues in Research and Treatment of HIV-Associated Wasting and Malnutrition), by Tim Horn & David Pieribone, with a foreword by Donald P. Kotler, M.D. The Wasting Report is published by the Treatment Action Group, 200 East 10th St., #601, New York, NY 10003, phone 212/260-0300, fax 212/260- 8561. It was first distributed at the Eleventh International Conference on AIDS in Vancouver, July 1-12, 1996. You can get a copy from TAG at the above address for $10 (the price is waived in case of financial hardship). The report will soon be available on the World Wide Web at: http://www.aidsnyc.org/network/tag/tag.html.
ddI plus d4Tby John S. James
A study in 85 volunteers found fairly good viral suppression from a combination of ddI (didanosine, VIDEX(R)) plus d4T (stavudine, ZERIT(R)). This combination is interesting because the drugs have shown synergistic antiviral effect in laboratory tests, each drug alone has shown clinical benefit in large human trials, and for each drug viral resistance is relatively slow to develop. The combination appeared safe; however, the persons in this trial all had CD4 counts of at least 200 (the median was 325), and persons with more advanced illness who use the combination may be more likely to develop peripheral neuropathy or other side effects.
The volunteers all received both drugs, and were assigned to five different dosage arms:
with doses adjusted for body weight for persons under 60 kg (132 lbs).
The study is continuing, and blinded. Overall results of different dose groups were presented, but the doses received by individual patients were unknown to the researchers.
A 1.3 log viral load reduction, sustained to at least 52 weeks, was observed when the five dose groups were pooled together; for the individual groups, reductions were 1.1 to 1.8 logs at 52 weeks. By week 8, their average CD4 count had increased by about 80, and this increase was sustained until at least week 52. (This CD4 response varied greatly by dosage group, however, with the highest-dose group having an increase of about 140 at week 52, the lowest-dose group having no increase at that time, and the other three groups being in the middle, with CD4 increases of about 75.)
This study found the treatment well tolerated; no dose-related adverse events were found. There was only one case of peripheral neuropathy which required drug discontinuation, and therapy was later restarted successfully at a lower dose. Eight patients had liver enzyme elevations -- "some related to hepatitis A," but these were able to restart treatment at full dose, after resolution of the acute disease. There were some other cases of drug discontinuation.
During the question period at the Vancouver presentation, a leading HIV physician warned about serious problems with peripheral neuropathy, and a severe case of pancreatitis, which he had seen when using this combination in patients with more advanced disease (much lower CD4 counts).
Pollard R, Peterson D, Hardy D, and others. Stavudine (d4T) and didanosine (ddI) combination therapy in HIV-infected subjects: Antiviral effect and safety in an on-going pilot randomized double-blinded trial. XI International Conference on AIDS, Vancouver, July 7-12 [abstract #Th.B.293].
Pollard R, Peterson D, Hardy D, and others. Antiviral effect and safety of stavudine (d4T) and didanosine (ddI) combination therapy in HIV-infected subjects in an ongoing pilot randomized double-blinded trial. 3rd Conference on Retroviruses and Opportunistic Infections, Washington, January 28 - February 1, 1996 [abstract #197].
Ritonavir Plus Saquinavir:
by Mark Mascolini
Two studies of combination therapy with the protease inhibitors ritonavir (Norvir(TM)) and saquinavir (Invirase(TM)) were presented at the International Conference on AIDS in Vancouver, and they reached some dissimilar conclusions. One found that the combination substantially decreased levels of HIV RNA in plasma (viral load) through 6 weeks of follow-up, but the second detected viral load rebounds in several persons 9 to 13 weeks after therapy began. Differences in the size and disease stage of the populations studied, and in how the drugs were given, may explain the diverging results. No one in either study had taken protease inhibitors before.
The trial that got more attention, a multicenter study presented by William Cameron, M.D., of the University of Ottawa, found that two different doses of ritonavir and saquinavir decreased average viral load by as much as 99% and increased CD4 counts by an average 80 to 100 in 63 persons, more than 40 of whom had taken the drugs for at least 6 weeks. The starting CD4 counts of people in this study were between 100 and 500, and the average viral loads were 34,000 and 48,000 HIV RNA copies/ml in the two dosage groups.
But in a smaller study of 9 persons with more advanced HIV disease -- starting CD4 counts between 1 and 37, and average viral load of 107,000 copies -- Bernard Hirschel, M.D., of the University Hospital of Geneva, found that viral loads first declined by at least 90% but then rapidly returned close to or above starting levels in 2 of 5 individuals at 9 weeks and in 3 of 4 at 13 weeks. CD4 counts after 13 weeks were not significantly higher than at the start of therapy. Two people did not have an initial good response to the combination, possibly because they did not absorb the drugs well, according to Dr. Hirschel; both had diarrhea.
Interest in combining ritonavir with saquinavir came to light last fall when scientists at Abbott found that ritonavir substantially increases blood levels of saquinavir in rats. The poor absorption and resulting low levels of the current formulation of saquinavir limit its effectiveness. The Geneva study and two human drug interaction studies completed earlier this year showed that ritonavir also greatly increases blood levels of saquinavir in humans.
The response to ritonavir plus saquinavir in the multicenter trial suggests that resistance to the drugs did not develop early in that study. But resistance could eventually emerge. Although the Geneva group has not finished the work needed to confirm resistance in their patients, Hirschel assumes it caused the failures. If resistance did develop, it was not because patients skipped doses of their protease inhibitors, because they were taking the drugs under supervision.
Is the Difference in the Dosage?
Although many people are already taking--or considering taking--this combination outside of clinical trials, the diverging results of these two brief trials suggest how much remains to be learned about combining ritonavir and saquinavir. The key problem is finding the dose or dose range that is strong enough to suppress viral replication and prevent drug-resistant mutations, yet mild enough to be safe and tolerable. If the dose is too high, some fear liver toxicity could result.
Four doses are being studied in the ongoing trial Dr. Cameron reported. The results he presented were from people in the first two dosage groups: 400 mg of ritonavir twice daily plus 400 mg of saquinavir twice daily, or 600 mg of ritonavir twice daily plus 400 mg of saquinavir twice daily. Another two groups are now taking 400 mg of ritonavir three times daily plus 400 mg of saquinavir three times daily, and 600 mg of ritonavir twice daily plus 600 mg of saquinavir twice daily. People receiving the 600-mg twice-daily dose of ritonavir begin at lower doses and gradually increase the amount they take until they reach the full dose between days 7 and 14.
The doses were different in the Geneva study. Ritonavir was either started at 600 mg twice daily or introduced gradually at 300 mg twice daily for 2 days, 400 mg twice daily for 2 days, 500 mg twice daily for 2 days, then the full dose. Saquinavir was added only after 7 days at a dose of 200 mg twice daily. After another week, this dose was increased to 600 mg twice daily. These dosing schedules may have contributed to the failure of the combination among many of the people in Dr. Hirschel's study, all of whom had HIV infection that was much more advanced than those in Dr. Cameron's study. Dr. Hirschel noted that saquinavir blood levels reached in his study were lower than those expected on the basis of earlier Abbott studies in HIV-negative volunteers.
Whether starting the two protease inhibitors simultaneously would have improved the outcome in Dr. Hirschel's study (if that had been possible in these individuals) is an unanswered question and will remain so. Now Dr. Hirschel is changing his strategy for studying this combination. He is planning a trial involving 100 persons with CD4 counts below 250 and is adding a third drug, possibly d4T.
Other unanswered questions are how many people will be able to afford this high-priced combination if its safety and efficacy are confirmed, and what will happen to this strategy if the new formulation of saquinavir turns out to be more effective than the current drug and replaces it on the market. At the very least, new drug interaction studies will be needed. In fact, Abbott told AIDS Treatment News that it is about to start testing ritonavir with the new formulation of saquinavir in healthy HIV-negative volunteers.
One point on which the two studies did not differ was safety. Dr. Cameron and Dr. Hirschel both reported the side effects that are now expected with ritonavir: Tingling around the mouth and nausea were the principal side effects in the Geneva study, while tingling and diarrhea affected about 75% of participants in the multicenter trial. But the side effects were generally transient or tolerable in both studies: No one stopped taking the protease inhibitors because of these effects in the Geneva trial, and only 2 of 65 had dropped out of Dr. Cameron's study at the 6-week point.
Future Protease Combination Studies
Neither study team could provide additional data beyond what they reported in Vancouver. And no updates are scheduled for a September meeting in New Orleans where many AIDS researchers will gather. So the next most likely time for new information is the Retroviruses conference scheduled for January 1997. Because of the preliminary nature of the results reported here, people who are considering this combination will want to check with their physician as new findings emerge. In the meantime, a detailed account of Dr. Cameron's study (but not of Dr. Hirschel's) is available at the Web site of the National AIDS Treatment Advocacy Project (http://www.aidsnyc.org/natap/drug/ritsaq.html).
Continuing study of ritonavir/saquinavir, and of other protease inhibitor combinations, seems inevitable. Dr. Cameron noted that ritonavir also increases blood levels of at least three other protease inhibitors: indinavir (Crixivan), nelfinavir (Viracept), and VX-478 (the Glaxo/Agouron drug). He suggested that ritonavir/saquinavir may be studied in combination AZT plus 3TC, d4T plus ddI, or d4T plus 3TC. Such four-drug combos, he said, may be evaluated in people with acute infection, in patients with advanced disease, and as a strategy to prevent transmission of HIV.
CKR-5 -- Understanding the Newsby John S. James
A major discovery about how HIV infects cells and causes disease was made simultaneously by two independent research groups, and reported in recent articles in leading scientific journals,1,2 and relayed in August 9 press reports in The New York Times and other newspapers. What most caught the public's attention is that a few people in some racial or ethnic groups but not others may be very resistant or even immune to HIV infection through sexual transmission. What is probably more important is that this discovery opens many new doors for scientific progress in understanding HIV pathogenesis, and may lead to the creation of a new class of anti-HIV drugs.
It has long been known that HIV cannot infect cells unless those cells have the CD4 receptor -- a certain protein molecule which appears on the cell's surface (there are about 10,000 copies of the molecule per cell). The CD4 receptor (and there are a number of other kinds of receptors as well) causes the cell to perform certain functions in the immune system. Unfortunately HIV has evolved to use the CD4 receptor to enable it to enter the cell.
But it has also been known that the CD4 receptor by itself is not enough to allow a cell to be infected. It was suspected that there was another receptor which also had to be present, which served as a co-receptor for HIV, meaning that the virus had to use both to infect the cell. Recently a co-receptor called fusin was discovered on CD4-positive T-lymphocytes (the T-cells which are counted when one has a CD4 count done).
CKR-5, which like fusin was described in publications earlier this year, is a second co-receptor, which together with the CD4 receptor allows HIV to enter a cell. CKR-5 is found on macrophages and related cells. (The name 'CKR-5' stands for "chemokine receptor 5"; sometimes it is called 'CC CKR-5', where the 'CC' is an abbreviation related to the chemical structure of the chemokines that bind to this class of receptors. It is often abbreviated 'CCR-5' instead of "CKR-5." Incidentally, 'CD-4' is an abbreviation for "cluster designation 4.") It is likely that there are also other co-receptors for HIV.
It has also been known that some strains of HIV infect T-lymphocytes, and others preferentially infect macrophages and related cells. Now it appears that the biological basis for this difference is that some strains of HIV need fusin in addition to CD4 in order to infect a cell, while others need CKR-5 in addition to CD4.
Each person has, in each cell in the body, two copies of the gene which can make the CKR-5 receptor molecule (usually the gene is turned off, however, which is why most human cells do not have the CKR-5 receptor). But in a minority of people, one copy of the gene (or both copies) has a certain defect -- a missing part of the gene, always the same missing section -- which prevents the gene from making the receptor. If someone has only one defective copy, the other good copy can make the receptor, although in smaller amounts. But if a person's cells have two defective copies of the gene, none of their cells can make a functioning CKR-5 receptor at all. Usually such a double copy of a defective gene would cause a hereditary illness. But in this case the researchers were surprised to find that persons without the CKR-5 receptor had no apparent illness or any other identifiable characteristic resulting from the missing receptor.
The occurrence of this genetic defect varies greatly among different human populations. In persons of Western European ancestry, about 20% had one defective gene, and about 1% had both genes defective. (These ratios are consistent, since about 4% (20% of 20%) of this population would have both parents with one defective gene, and one out of four of their children -- 1% of the population -- would by chance get both copies.) But in some population groups tested -- Japanese, some Central and West Africans, and a group of Venezuelans -- no copy at all of the defective gene was found, even though hundreds of people were tested. The prevalence of the gene in other population groups is not known, since they have not been tested yet.
There might also be other defects in the CKR-5 gene, which would be expected to give similar protection if they prevented a functional receptor from being formed. These might be present in any population groups. But no one has looked for them yet.
One of the research groups was approached by two people who reported that they had had unsafe sex many times, but had never become HIV-positive. They were tested, and both of them were found to have both copies of the gene defective. In laboratory tests, their macrophages could not be infected, even by very high concentrations of virus. Their T-cells could be infected, however (by strains of HIV which use the fusin receptor to enter those cells).
This and other evidence has led the researchers to believe that sexual transmission of HIV, and initial establishment of the infection, takes place primarily or only through macrophage-type cells. This virus which is transmitted is known as NSI virus (non syncytium inducing, as it does not cause infected T-cells to merge with other T-cells into large clusters, called syncytia, in laboratory tests). Later in HIV disease, the virus may evolve the ability to use the fusin receptor to infect T-lymphocytes; this virus is SI virus (syncytium inducing), and its appearance in a patient is associated with worse disease prognosis (possibly because the virus is worse, or possibly because then there are two viral populations targeting two kinds of cells, instead of only one). However, the NSI virus seems clearly most important in HIV transmission, and in early HIV disease.
New Directions for Research
Could drugs which blocked the CKR-5 receptor be a new kind of treatment for HIV? Companies are working now to develop such compounds. Since people who are born without this receptor appear healthy, a drug which blocks it might not be harmful. It is not known if this approach would work in advanced HIV infection, however, after the virus had evolved the ability to use the fusin co-receptor instead of CKR-5.
It will now probably be possible to develop small animals, such as mice, which are normal in most respects but which can develop HIV disease. This could greatly speed the testing of new antiretrovirals, and also allow rapid comparison of combinations of approved and available drugs. (Mice have already been given the human CD4 receptor.)
Testing more people for the defective CKR-5 gene could answer the question of whether persons with two copies of the defect are completely or only partially protected against HIV infection.
Could the CKR-5 gene be involved in the rare cases of persons who are HIV negative, but show immunological evidence of having been exposed to HIV and probably infected in the past? One theory is that persons with both genes defective might be infected by SI virus, but that the infection might not be able to sustain itself, since it could not enter the macrophages.
One research group reported data suggesting that the much larger number of persons with only one copy of the defective gene may be about one third less likely to be infected by HIV than those with both copies of the normal gene. Do these people tend to progress more slowly? Answering this question might be helpful in making therapeutic decisions. (The research test for the defective gene has not yet been developed for large-scale use, and is not generally available.)
1. Liu R, Paxton WA, Choe S, and others. Homozygous defect in HIV-1 Coreceptor Accounts for Resistance of Some Multiply-Exposed Individuals to HIV-1 Infection. Cell. August 9, 1996; volume 86, number 3, pages 367-377.
2. Samson M, Libert F, Doranz BJ, and others. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. August 22, 1996, volume 382, pages 722-725.
HIV Sensitivity Testing:
Interest is growing rapidly in laboratory tests of an individual patient's HIV, to determine its resistance or susceptibility to available antiretrovirals. Such testing -- which has long been routine for certain bacteria, but is more difficult with viruses -- could greatly help physicians and patients make better decisions about starting and changing therapies.
There are two kinds of susceptibility testing: phenotypic, which grows virus in the presence of drugs, and genotypic, which tests for certain mutations associated with drug resistance. No test of either kind has yet been approved by the FDA; however, some experimental tests are in limited use in clinical practice. We plan to review this area in a later issue of AIDS Treatment News.
An activist group in the Community Advisory Board of the AIDS Clinical Trials Unit at New York University is organizing for faster development and greater availability of such testing. They would like to hear from others who are interested. If you might be able to help, contact Gus Vianna Biehler, CAB Chair, at 718/832-6465 or by fax at 718/832-6820.
Register to Vote:
Voter registration requirements vary by state. In California, the last day to register to vote in the November 5 election is October 7.
In California you can receive a voter registration form by mail, by calling the voicemail number 800/345-VOTE; a Spanish phone service is available at 800/232-VOTA. Also, registered California voters can vote absentee if they want to; they do not need to have a reason for being unable to get to the polls. For more information, contact your local Registrar of Voters.
At least two California propositions in this election could directly affect people with AIDS: Proposition 215 in favor of medical marijuana, and proposition 214 against HMO "gag rules" (rules which prohibit physicians from telling patients about treatment options the plan does not want to pay for).
A high voter turnout of persons concerned about AIDS will go a long way in furthering humane and rational government policies in Federal, state, and local governments.
AIDS TREATMENT NEWS Associates
by John S. James
AIDS Treatment News Associates, a new nonprofit organization to provide AIDS treatment information to underserved populations, received its Federal 501(c)(3) status in June, 1996. It has also received California tax exemption.
ATNA will provide treatment information to persons who cannot afford subscriptions due to low income and/or to high medical bills -- and also to prisoners, and to service organizations in developing countries. ATNA is organizationally separate from AIDS Treatment News, which began in January 1987 as a sole proprietorship entirely owned by this writer.
Current board members of ATNA are Claire Rappoport (president), Denny Smith (secretary), Kevin Farrell (treasurer), Carol Brosgart, M.D., Leonore Herzenberg, Ph.D., and Leonard Herzenberg, Ph.D.
AIDS Treatment News has never denied treatment information or this newsletter to persons who could not afford to pay for a subscription. We are now providing approximately 600 free subscriptions by first-class mail, and many others on a sliding scale which is less than our fulfillment cost. We also give free information and referrals to callers, without asking if they are subscribers. In the last two years the number of free subscriptions has tripled -- while the number of paying subscribers has changed little. Our basic price of $100 per year has not changed since we began, and we have no plans to raise prices now.
Since AIDS Treatment News has no income except for subscriptions and occasional unsolicited gifts, the cost of providing free subscriptions and other services has become increasingly burdensome, and is starting to impact the work we can do. Instead of raising prices, we plan to transfer some of our unpaid work to AIDS Treatment News Associates. (We decided not to turn AIDS Treatment News itself into a nonprofit, to avoid any risk to the editorial independence or even survival of this newsletter, which has worked well as a sole proprietorship for ten years.)
ATNA welcomes contributions. Tax-exempt donations can be made to AIDS Treatment News Associates, 584-B Castro St., San Francisco, CA 94114-1465. For more information, call Kevin Farrell, 415/241-0413, or Denny Smith, 415/750-4852.