HCG: New Kind of KS Treatment?by John S. James
Human chorionic gonadotropin (hCG) is a hormone which is
naturally produced in early pregnancy. Commercial
preparations of hCG, which are relatively crude extracts
prepared from the urine of pregnant women, have long been
available as an approved medical treatment for a variety of
conditions, in both women and men. For several years there
has been interest in the possibility that some hCG
preparations might be useful in treating Kaposi's sarcoma.|
On October 24, 1996, the results of two small trials (with 36 volunteers total) were published in the New England Journal of Medicine,1 along with an accompanying editorial.2 These results leave little doubt that this approach to treatment, which is very different from conventional chemotherapy, has important potential. But major questions still remain -- including how to obtain a reliable supply of the active ingredient (since it is now believed that it is not hCG itself, but some related substance, which is affecting KS -- and the commercial hCG preparations vary greatly from brand to brand and probably even batch to batch in anti-KS activity). Another critical question is the possible role of hCG in systemic treatment; these trials were designed to test treatment of individual lesions by intralesional injection of hCG, although there was also evidence of benefit to some lesions which were not injected.
Robert C. Gallo, M.D., one of the authors of theNew England Journal of Medicine research report, released a press statement on October 25 urging caution by physicians and patients until more research is done.,3,But since side effects are small, and the drug is readily available (although expensive), and research has been slow due to lack of commercial interest in this generic treatment for a limited market, it seems inevitable and appropriate that this experimental treatment will be tested in clinical practice as well as in formal trials, especially when conventional treatments are not satisfactory. Clinical practice, as well as trials, also produces new knowledge.
The New ResultsHere we will briefly summarize the results reported on October 24; for more information, see the original article.1 First, because of the great variation in activity of different preparations of hCG, four different commercial brands were tested in the laboratory against Kaposi's sarcoma cell lines. The most active of the four was A.P.L.(R), produced by Wyeth-Ayerst Laboratories.
Next, a dose-ranging study tested four different doses (250, 500, 1000, and 2000 IU, injected under the skin directly over a lesion, with a fine needle). In this study, the dose was administered three times a week for only two weeks. There were six patients in each dose group, and two lesions were injected in each patient -- with a third lesion in each patient injected not with the drug, but with the liquid used to dilute the drug, as a control. There was one complete response (a lesion flattened completely, and no evidence of KS found in biopsy) in one lesion at the lowest dose (of the 12 lesions treated), one complete response and two partial responses at 500 IU, one complete response and four partial responses at 1000 IU, and 10 responses at 2000 IU, five of which were tested by biopsy, with all five showing no evidence of KS. (The two lesions which did not respond at 2000 IU were in a patient who withdrew from the study after one dose because of pain at the injection site.)
Also, in the five patients who received more than one dose, four had their control lesions (which were injected, but without the active drug) flatten completely, although on biopsy they did not show KS cell death -- suggesting a possible limited systemic effect from treatment of two lesions. (The later controlled study, described below, found no effect at all from the control injections, in patients who did not receive any of the active drug.)
As a result of this dose-ranging study, the dose of 2000 IU intralesionally was chosen for a double-blind randomized controlled study, which was done next. This study also tested three injections per week for two weeks. It assigned six patients to receive hCG, and six to receive the control injection alone. In each patient, two lesions were injected (with the active drug, or with the control).
In this study, 10 of the 12 lesions showed responses; biopsies were done on six lesions, and five of them showed a complete response. None of the control-injected lesions responded.
After the two weeks of treatment, the five patients with complete responses were followed for varying periods no longer than five months. Two of the five lesions that had showed a complete response recurred, while the other three did not, during the followup period.
Also, five of the six who received the control injections were given open-label treatment later; all had lesions which flattened completely, although no biopsies were done in this group. In four of the five patients, none of the lesions recurred after four to five months (the fifth patient was lost to followup).
Microscopic examination of the biopsies, by blinded examiners, found that the treatment was killing the KS cells by apoptosis (programmed cell death) -- which is different from cell killing by conventional chemotherapy. Also, there was no evidence of immune-cell infiltration of the lesions, suggesting that the treatment was killing the cells directly, not by stimulating an immune response.
The intralesional treatment was found to be causing a systemic decline of two related hormones (FSH and LH). There were some increases in testosterone, but these were not statistically significant in this study.
There were also several reports of increased appetite and weight gain. In one case, chronic diarrhea stopped when the treatment was started, then started again after the treatment was ended.
Side effects were described as mild, and affecting only a few patients.
All of the lesions injected in this study were relatively small.
CostA price of A.P.L., mentioned in the accompanying editorial by Susan E. Krown, M.D., in the New England Journal of Medicine2, was $264 per 20,000 IU vial (the drug is also supplied in 5,000 and 10,000 IU vials). While the editorial noted that the cost would be "astronomical" if the effect "requires sustained local concentrations in tumors of the magnitude achieved after the direct injection of 2000 IU," this seems unlikely, since there appeared to be some effect on untreated lesions when only two lesions in the body were treated. In the trial, the total amount of drug used at the 2000 dose was 12,000 units per lesion (three times per week for two weeks), which would prorate to more than $300 for this two-week therapy for the two lesions. It is not known how much drug would need to be used systemically, or how often treatment may need to be repeated.
Highly purified hCG has little anti-KS effect in laboratory studies; therefore, it is strongly suspected that the active substance in this treatment is not hCG itself, but probably a related substance (perhaps a fragment of the hCG molecule). Eventually, more efficient treatment should be possible. But the active ingredient will probably be a proprietary drug, so the price of treatment will likely remain high.
1. Gill PS, Lunardi-Iskandar Y, Louie S, Tulpule A, Zheng T,
Espina BM, Besnier JM, Hermans P, Levine AM, Bryant JL, and
Gallo RC. The effects of preparations of human chorionic
gonadotropin on AIDS-related Kaposi's sarcoma. New England Journal
of Medicine. October 24, 1996; volume 335,
number 17, pages 1261-1269.
Press Statement of Dr. Robert C. Gallo, Director, The Institute of Human VirologyDr. Gallo, listed as senior author on this study, released the following statement to the press on October 24:
Kaposi's sarcoma continues to be a significant contributor to AIDS mortality with current therapy options principally palliative in nature. In addition, the toxicities that arise from current treatments often interfere with the front-line antiretroviral agents that are the standard of care treatments for HIV disease.
The study published in the New England Journal of Medicine on the effects of treating dermatological KS with injections of human chorionic gonadotropin (hCG, a hormone found in early pregnancy) gives promise of a new treatment with potentially far less toxicity and no interference with standard of care antiretroviral therapies. It is clear that some commercial preparations of hCG induce a local tumor regression response through the mechanism of inducing cell death; more investigation is necessary to determine the precise agent inducing the beneficial effect. Studies are now underway to evaluate the systemic effects of hCG on KS tumors, which can include internal organs as well as the skin.
Since hCG is readily available to physicians, several cautions are in order at the stage of clinical research [emphasis in original]. While this study confirms that some preparations of hCG produce a dose-related antitumor response, it is crucial that the precise biochemical agent be identified conclusively, and that further clinical studies be completed before physicians and patients rush into unguided use of hCG. Currently available commercial preparations of hCG vary widely in terms of purity and ability to be effective as intralesional treatment for KS. The method of injection is also a key variable. It is also likely that hCG is not the effective molecule, but rather that the effective agent is an active degradation product. Confirming this must be a high priority in the next stage of this research.
Dr. Parkash Gill of the University of California School of Medicine and Dr. Philippe Hermans of the Universite Libre de Bruxelles in Belgium are to be commended for advancing this work into human trials. It builds on the work done in 1995 by Drs. Yanto Lunardi-Iskandar and Joseph Bryant, working with Dr. Robert Gallo, all presently at the Institute of Human Virology. These same investigators isolated (in laboratory tissue culture) the first neoplastic cell line from HIV-1- associated Kaposi's sarcoma, and subsequently identified chorionic gonadotropin as the active factor in inhibiting growth of the cells. (The former is in JOURNAL OF THE NATIONAL CANCER INSTITUTE 1995;87:974-981, and the latter study is in NATURE 1995;374:64-68.)
IL-2: Controlled Trial by John S. James
A controlled trial of IL-2 in 60 patients increased CD4
counts from an average of 428 at baseline, to an average of
916 at month 12 -- while in the control group which was not
given IL-2, the average decreased from 406 at baseline to 349
during that year. All patients entering this trial had a CD4
count over 200, and all were given standard antiretroviral
therapy. This research, at the National Institute of Allergy
and Infectious Diseases, was published October 31 in THE NEW
ENGLAND JOURNAL OF MEDICINE.1|
The IL-2 was given for five consecutive days every two months. Side effects were substantially less than in previous studies in which higher doses of IL-2 were used. Still, five of the 30 volunteers assigned to IL-2 had to withdraw due to side effects.
Five volunteers in the control group either developed a new AIDS-related condition or died, compared to only two assigned to the treatment group (during the 14-months study or during long-term followup after 14 months). These numbers are too small to be statistically significant, however (meaning that the difference could easily have happened by chance).
A new trial is being planned to test IL-2 in patients with CD4 counts below 200 who are using protease inhibitors. In the past, IL-2 has not worked well in those with counts under 200, probably because the drug stimulated growth of the virus. Now that better antivirals are available, it is possible that IL-2 might have usefulness in later disease.
CommentIt has been known for some time that IL-2 can greatly increase CD4 counts in some patients. But this increase in the count does not automatically prove that the treatment is beneficial, since it is possible that some kinds of CD4 cells are missing, or that for other reasons the new cells will not work as well as the cells of those who have a high CD4 count without this treatment. For these reasons, a larger trial is being planned to confirm that IL-2 treatment does have clinical benefit.
1. Kovacs JA, Vogel S, Albert JM, and others. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. THE NEW ENGLAND JOURNAL OF MEDICINE. October 31, 1996; volume 335, number 18, pages 1350-1356.
NTZ for Cryptosporidiosis: by Sally Cooper
[Note by JSJ: The experimental drug nitazoxanide (NTZ)
appears to be the first good treatment for cryptosporidiosis,
an infection which causes severe diarrhea and is responsible
for many deaths (see coverage of NTZ in AIDS Treatment News
issue #239, January 19, 1996, and #250, July 5, 1996). But
getting pre-approval access for those who need NTZ has been a
continuing struggle, even though there is no manufacturing or
economic reason for a shortage.
The PWA Health Group, New York's oldest and largest AIDS "buyers' club," has been the central advocate for the AIDS community in this struggle. It has not only supplied the drug to individuals (despite Federal seizure of one shipment in June), but has also created pressure on Unimed Pharmaceuticals, Inc. and on the FDA to make formal access arrangements. We asked Sally Cooper, executive director of the PWA Health Group, to explain the current status of NTZ access to our readers. Her article follows.]
I. No Numerical Limit on Expanded AccessOn October 15, Unimed Pharmaceuticals, Inc., the U.S. licensee of NTZ, announced that it had received permission from the FDA to end the numerical limit on the number of medically qualified persons who could enter its open label trial for NTZ. Unfortunately, persons who called Unimed in the few days after the press release were told to call back the following week, as the person handling enrollment was away on vacation [see Unimed's reply, below]. She is back now, and can be reached at 800/864-6330 x3032.
This trial is open to all who qualify. But when a new government-funded ACTG (AIDS Clinical Trials Group) phase III trial starts, the Unimed program will be closed to persons living in cities with ACTG trial sites, unless they cannot participate in the ACTG trial.
Everyone entering the Unimed program will get NTZ, but will be randomly assigned to receive either 1000 mg/day or 2000 mg/day for the first month. The dose can be escalated at monthly intervals, up to 3000 mg/day. Persons who also have intestinal CMV, MAC, or KS are still excluded, as well as those taking azithromycin or clarithromycin; but persons with microsporidiosis in addition to cryptosporidiosis are allowed. There is no limit to the amount of time people can receive drug once in this trial.
II. Federal Action against PWA Health GroupDuring the same week in October, the U.S. Customs Service notified the PWA Health Group in New York that they were fining the group $1000 for a shipment of NTZ seized by Customs late in June. The NTZ was released to the group on October 25, with a Customs escort for re-importation back into Mexico. Attempts to negotiate with the FDA to bring the drug back into the United States failed, despite appropriate personal use documentation and prescriptions, since this case was being used as "an example to buyers' clubs." Meanwhile the PWA Health Group has other NTZ in stock for persons with prescriptions who are waiting to get it, or who are unable to get into Unimed's open-label trial.
There were many myths this summer about the U.S. Customs
seizure of our NTZ. One was that the NTZ was in a car without
license plates (sorry, Mexican rental cars do have license
plates). Many people asked us why the product had not been
declared (an uncalculated mistake on our part), but as Tom
Gardine, of FDA Regulatory Affairs, said, "we would have
seized it anyway." In other words, that was never the real
question, just a smokescreen to divert attention from the
central issue: that this is an approved medication in Mexico,
and was brought in with legal prescriptions -- something that
AIDS buyers clubs have done for years to help persons with
AIDS who cannot get to Mexico on their own. Emphasizing the
failure to declare also ignores another key aspect of
underground access: it provides fantastic leverage to push
laggard companies who are dragging their feet about
compassionate use and effective trials.
International Treatment Access and by John S. James
The recent International Conference on AIDS in Vancouver
demonstrated a greatly increased interest of U.S. AIDS
activists in access to medical treatment for people
throughout the world. At stake is not only the life and
health of the 90% of persons with HIV who now cannot get
modern medicines, but also the best possible care for those
who do have access. This is because effective treatment in
the developing world will require scientific testing of
traditional and accidentally discovered treatments; and if
any of them are found to be effective (as has happened
frequently in the history of medicine) they would become
available for use together with pharmaceutical-industry
On September 30 AIDS Treatment News interviewed Peter Piot, M.D., executive director of the Joint United Nations Programme on HIV/AIDS (UNAIDS), which brings together six UN agencies in a common effort against the epidemic, on what can be done to improve treatment access throughout the world, and improve research on natural and traditional medicines.
AIDS Treatment News: What is UNAIDS doing to make AIDS treatments more accessible?
Dr. Piot: There is now a major shift in international AIDS work. Until very recently, the programs have focused exclusively on prevention, with hardly anything being done on care. Some programs still maintain this policy. We are trying to change it; we advocate with governments, and with AIDS programs in the countries we work with, that they not deal only with prevention. That is the first step. With over 22 million people infected today, it would be obscene not to pay any attention to care. And successful prevention programs have been linked with care and support for people living with HIV and patients with AIDS.
Our staff is now covering 80 countries in the developing world, and that is part of their priorities, to put AIDS care and access to drugs higher on the agenda.
We must be realistic in what we can achieve. In the least developed countries, the newest antiretrovirals will not be a feasible option, if they have sometimes only ten dollars per year per person for health care in general.
There are other countries -- such as Brazil, Thailand, South Africa -- that are near the top of the income distribution of developing countries; there, access to the latest new antiretrovirals and other drugs is not a naive dream. We are working with the governments to try to negotiate lower prices, by bulk procurement for example. Also, we are supporting some local initiatives with non-governmental groups, community organizations, to set up a buyers' club, for instance.
Most of what we are doing is to promote wider access to generic drugs, to many drugs that are affordable for prevention or treatment of opportunistic infections, or palliative care. Even this is not being done; I believe that about 90% of people with AIDS in the world do not even have access to this kind of standard of care. We learned that preventive therapy for tuberculosis, the number one killer of AIDS patients in Africa, costs about $15 per year. It is affordable to people either if they have to pay themselves, or if the government or some organization budgets for it.
How to we improve this kind of access? We work with the governments, the ministers of health, pushing them to put it on their budgets. Also we work with the private sector, the non-governmental sector, which is becoming a bigger part of the healthcare system.
One of the biggest obstacles to good care is inadequate training of the doctors. They are overwhelmed, they have to deal with so many other major problems; therefore we need to invest more in their training, to help them with very simple ways of diagnosing opportunistic infections, and alerting them, for example, that patients should be on TB prophylaxis. This educational effort with healthcare personnel has not happened in most countries.
ATN: What can be done to develop less expensive treatments by improving research on traditional and natural medicines? People call and write us about proposed herbal remedies which might be antiviral; it would be easy to test them in a few people and see if their viral load went down. How could such research be organized?
Piot: Such treatments are often country-specific; they are being used in one country but not elsewhere, or nobody has heard of the treatment outside of a country. Our representatives first check what it's all about, because a lot of this is not in good faith. If the interest does look serious, if it is not just someone trying to make money out of the misery of others, we try to bring them in contact with individuals who could do some preliminary assessment. You do not need to start with big trials. But we have not done much in this difficult and diverse field. India or China, for example, have a very long tradition with these medicines. We hope to work with institutions like the Chinese Academy of Traditional Medicine.
To move treatment access forward, one has to work with a number of stakeholders. For example, in July we made plans for what UNAIDS would do in improving access to drugs, working with persons from government, from community groups, groups of people living with HIV, to get a better sense of what is possible. How can we learn from AIDS activism in the Western world? How can some of its approaches be used in some developing countries, especially where a very high proportion of the adult population is infected? The political issues in this work are as difficult as the technical problems.
ATN: Where do we go from here in developing worldwide AIDS activism? What could activist organizations do in the U.S. and other countries? What can individuals here do to help?
Piot: The first issue is awareness that there is a very important international impact of this epidemic. Activists in North America or Western Europe often have an agenda that is purely domestic or local; this is understandable as there are many problems. But also there is much to offer to our colleagues in developing countries. So raising the awareness among the domestic activist community that AIDS has a global dimension, that there is a role to be played for local activists in the whole international arena, is really important. That can only come from within. People like Eric Sawyer from Housing Works in New York, Paul Boneberg and GAAN (Global AIDS Action Network), and the National Council for International Health are trying to do this; much more has to be done.
AIDES in France, the very big AIDS service and support organization, has developed partnerships with AIDS activist groups and NGOs (non-governmental organizations) in neighboring countries, mainly Algeria and Morocco, but also in Poland. There are many migrants from North Africa living in France. Perhaps you could do something similar in the U.S., linking up with groups in Mexico, the Caribbean, where a large proportion of the population is coming from, and support them. Not necessarily with money, but also lessons learned; shortening the learning curve on how to be effective in activism is very important. I'm not sure that enough is happening at that level in the U.S. We in UNAIDS would be very open to working with such initiatives. Linking up with colleagues in other countries makes it concrete, not limited to theoretical discussions about international AIDS work.
ATN: How did AIDES get started in this?
Piot: I believe that it is the vision of Arnaud Marty- Lavauzelle, the chairman of AIDES and also a member of the governing board of UNAIDS, that made this possible. In the last two years they developed more and more international work. It is not their primary mandate, of course. But because they are confronted with people living in France who are from various other countries, they started working in the countries of origin of these people. That is a concrete link, and very helpful in doing a better job, since there is a big service component; it is not only an activist group, it has counseling centers, and provides home care and other services. That has been a very successful program. For those working in New York and Miami, it is clear that linking up with the Caribbean would be an obvious thing to do.
ATN: Few if any U.S. organizations have made it part of their mission to work with NGOs in the countries of origin of their clients. It would be a natural step to take.
Piot: It's concrete, and it would be very helpful for people in these countries -- working with community organizations for prevention, and also for access to care and drugs. The U.S. is surrounded by countries where standards of care for people with HIV are not where they should be.
From UNAIDS headquarters in Geneva, we are supporting networks of groups -- GNP+ (the Global Network of People Living with HIV), ICASO (International Council of AIDS Service Organizations), ICW (the International Community of Women Living with HIV/AIDS) and others; and within countries, we are pushing that activist groups, NGOs, community groups, be involved in development of national policies. This is not now the case in most countries, although it is in a few, like Brazil.
Today the gap is immense between people with HIV who are rich or living in a rich country, and the overwhelming majority who can only dream of the new treatments. There is a need for a strong strategic alliance -- even more, I believe, after the Vancouver conference and the recent breakthroughs with protease inhibitors and other drugs.
Retroviruses Conference --
The 4th Conference on Retroviruses and Opportunistic
Infections, January 22-26 at the Sheraton Washington Hotel in
Washington, D.C., will probably be the most important AIDS
conference in the U.S. in 1997. The number of scholarships
available is not known at this time. AIDS Treatment News
received the following notice on September 25:|
Community Scholarship ProgramA limited number of scholarships are available to attend the 4th Conference on Retroviruses and Opportunistic Infections.
Eligibility Criteria:The program is designed to provide travel support for AIDS treatment community activists and people with and affected by AIDS to attend the conference. The eligibility criteria are:
Application Process:Submit a letter of application outlining your eligibility and include a resume. Applications will be peer reviewed by the Community Liaison Subcommittee.
Application Deadline: December 2, 1996
Applicants will be notified of the disposition of their application by December 20.
Submit Application To:
Scholarship Program - 4th Retroviruses Conference,
Starting and Changing
A free interactive telephone call, "New Guidelines for
Starting or Changing Treatment for HIV Infection," will be
presented by the San Francisco AIDS Foundation on Tuesday,
November 5, at noon Pacific Time, 1:00 Mountain, 2:00
Central, 3:00 Eastern Time. To join the conference (allowing
you to ask questions of the experts), you need to register in
advance, by calling 800/707-BETA. But no registration is
required to listen to a recording of the call afterwards;
call 800/847-8912 and follow the voicemail prompts.|
Guest experts will be Michael Saag, M.D., Roy Gulick, M.D., and Kathleen Squires, M.D. The call is moderated by Ron Baker, Ph.D., editor of BETA, the treatment newsletter of the San Francisco AIDS Foundation. It is supported by an educational grant from Hoffmann-La Roche.
The cover article in the October TREATMENT ISSUES, the
newsletter of the Gay Men's Health Crisis, looks at new
therapeutic approaches which may be useful for patients who
have failed protease inhibitors (as well as in other
therapeutic situations). "When HAART Is Not Enough," by
editor Dave Gilden, looks at approaches for "establishing an
immune environment hostile to HIV." (The title word "HAART"
is an acronym for "highly active antiretroviral therapy" --
referring primarily although not only to combination therapy
with protease inhibitors.) This article focuses on research
approaches for future therapies, not on treatment options
widely available now.|
To obtain a copy, call Chuck Sock, 212/337-3613, or contact Dave Gilden, GMHC Treatment Education and Advocacy, 129 West 20th St., New York, NY 10011, fax 212/337-3656, email DAVE_G@gmhc.org.
AIDSACT, New Email List
AIDSACT, a new electronic mailing list for AIDS activists,
"provides a means of communication for AIDS activists who
address AIDS as a political crisis." Persons who subscribe to
the list will receive all email later sent to the list.
Subscribers can send email to the list; but to prevent
irrelevant communications, messages need to be approved by
the list manager before they go out.|
AIDSACT grew out of an earlier list, which ACT UP chapters and other organizations and activists used to plan actions at the Eleventh International Conference on AIDS in Vancouver.
To subscribe to AIDSACT, send a message to:
with no subject and a one-line message body in the form
subscribe AIDSACT First Last
where "First" and "Last" are your first and last names.
If you just want to get more information about AIDSACT, without subscribing at this time, send email to the same address, but instead of the "subscribe" line, say
Hepatitis C: Protease Structure of
Two companies, Agouron Pharmaceuticals Inc. and Vertex
Pharmaceuticals Inc., have determined the chemical structure
of the protease enzyme of the hepatitis C virus. Both
published papers about their work in the October 18, 1996
issue of CELL. Both companies used X-ray crystallography to
determine the structure of the enzyme.|
This discovery could lead to a new class of protease inhibitor drugs which target the hepatitis C virus -- similar to the development of protease inhibitors which now target HIV.
Bioethics: Major Meetings in by John S. James
The International Association of Bioethics will hold its
III World Congress of Bioethics in San Francisco, November
22-24, 1996. This meeting occurs every two years. It is
presented by the Pacific Center for Health Policy and Ethics
(at the Law Center at University of Southern California), on
behalf of the International Association of Bioethics and the
American Association of Bioethics. |
Several other bioethics meetings are also happening in San Francisco around that time:
The headquarters for the Congress and related meetings is the Crowne Plaza Parc Fifty Five Hotel in San Francisco.
Detailed programs and other information are available at http://www.usc.edu/dept/law-lib/bioethics/world-congress.html . For a brochure of the Bioethics Congress, call the Pacific Center at 213/740-2541.
Comment: There are few AIDS-related sessions (there are sessions on gay issues), and few AIDS activists in San Francisco know about these meetings. Somehow the two communities of AIDS and bioethics are surprisingly separate. At the least, this situation represents lost opportunities, as there are many issues (around access to treatment, for example, or clinical trials, or the press and medical/scientific journals) which could use more ethical review. At worst, this apparent disconnect could be dangerous, as there are efforts to roll back patient empowerment in favor of more authoritarian approaches to public health.