AIDS Treatment News
Nelfinavir (VIRACEPT®) Approved:
by John S. James
New AmFAR Directory: Best Quick Reference for
by John S. James
The January 1997 AIDS/HIV TREATMENT DIRECTORY, compiled and
published by the American Foundation for AIDS Research
(AmFAR), is an excellent reference for almost any treatments
for HIV in general medical use or in clinical trials in the
United States. It will be helpful to patients who are
involved in their own treatment, as well as to physicians and
Some uses for the directory:
1. You have heard the name of a treatment and want to find
out something about it.
2. You want to learn about the major treatments or
prophylaxis regimens for an opportunistic infection.
3. You want to learn about the major clinical trials for a
drug or opportunistic condition.
4. You need to find public or private programs that can
provide some drugs without charge. The directory has separate
a. Expanded access / compassionate use / treatment IND
programs for unapproved drugs;
b. State AIDS Drug Assistance Programs (ADAP), which offer a limited list of drugs, varying greatly from state to state, to persons with low income levels;
c. Patient assistance programs of pharmaceutical companies (which first try to find any programs which could pay for the drug, but then can supply free drug to persons with very low incomes who have no other possible way to get them).
The expanded access and patient assistance programs are listed alphabetically by drug; the ADAP listing is alphabetical by state.
Other sections in the directory:
The directory does have its shortcomings. Some of the page
numbers in the index are off by one -- so do not give up if
what you are looking for is not on the page listed; the index
probably did get you to the right section, which usually is
alphabetical. And the newsletter and resource lists need more
checking to make sure the listings are current.
Ritonavir: New Approval for Children
On March 14 the FDA approved ritonavir for children age two
to 16. While the drug was already available and could be
prescribed for children, official approval is important
because it means that a dosage recommendation has been
tested, and found to have comparable safety and
pharmacodynamics as in adults. Also, approval should help in
obtaining reimbursement from HMOs and other third-party
The University of California San Francisco has started a Web
site with authoritative information on treatment and other
major aspects of AIDS. While there are already hundreds of
Web sites with AIDS information, this one is distinguished by
being managed by leading experts in the field, at the UCSF
AIDS Program at San Francisco General Hospital, and the UCSF
Center for AIDS Prevention Studies (CAPS). Also, it has the
funding and staff to check with hundreds of experts every
month to keep the information peer reviewed and up to date.
The site is intended both for professionals and for persons
The medical section includes the AIDS KNOWLEDGE BASE (a 1600- page online textbook), a searchable database of clinical trials throughout the United States, treatment guidelines, case studies, and fact sheets. Other sections include Prevention, Social Issues, and Resources (organized by key topics, and also by a U.S. map).
The authoritative management of this site could make printouts especially useful in advocating for treatment or reimbursement.
This project was originally funded by the Henry J. Kaiser Family Foundation, with additional educational grants from Bristol-Myers Squibb, and from Merck, and with computer equipment donated by Sun Microsystems.
The Web address is http://hivinsite.ucsf.edu.
Two issues ago we reviewed an article reporting that
researchers had found an abnormally low level of
acetylcarnitine (also spelled acetyl-carnitine, acetyl-L-
carnitine, or L-acetylcarnitine) in persons with HIV who had
neuropathy which appeared to have been caused by ddI, d4T, or
ddC ("Drug-Related Neuropathy: Low Acetylcarnitine Levels
Found, AIDS Treatment News #265, February 21, 1997). We did
not know at that time but learned since that acetylcarnitine
is available in the U.S. through health-food distributors. We
have no information about these products.
Acetylcarnitine is being tested in the U.S. and elsewhere as a possible treatment for diabetic neuropathy, and for other conditions. Bristol-Myers Squibb is interested in working with a clinical research group to develop the first HIV- related clinical trial.
AIDS Treatment News would like to hear from anyone with information about use of acetylcarnitine by persons with HIV, for any purpose. Contact John S. James, email@example.com, or 415/861-2432, or by fax at 415/255-4659, or c/o AIDS TREATMENT NEWS, P.O. Box 411256, San Francisco, CA 94141.
On March 5 the FDA issued a warning letter to the U.S.
distributor of SPV-30 (The Health Connection, Ltd., of
Copiague, New York), effectively requiring them to stop
distributing the product. This dispute concerns "published
articles, study reports, news releases, and advertising
bulletins about SPV-30 that you provide to your customers."
The company plans to appeal the action to the FDA.
As far as we know, buyers' clubs and others have not been required to stop selling SPV-30, which is an herbal product prepared from the boxwood plant. However, it is unclear at this time whether they will be able to obtain new supplies.
For the latest information about availability of SPV-30, call the Boston Buyers' Club, 800/435-5586 (within Massachusetts, call 617/266-2223).
It's Time to Approve
by David Scondras, Search for a Cure, Boston
The FDA is approaching a decision that will affect every
person with HIV illness by deciding whether to use new
surrogate markers to evaluate a therapy that might help
restore the health of the immune system.
Across the country, drops in the death rate and clearing of opportunistic infections have been reported, making many feel that we have turned the corner in this disease.
However, we do not know how long the human body can tolerate daily doses of heavy antiviral artillery. And we're not sure how to repair the damage already done by the virus to the immune system, or help the 20 to 30 percent of people who fail the drug therapies.
A major factor limiting the development of new kinds of therapies is the paucity of accepted markers for improved immune function. Only two markers have been widely accepted as connected to disease progression and mortality in a causal fashion: CD4 T-lymphocyte levels and the amount of viral RNA in the blood (viral load).
However, they are rather crude. They do not give a full picture of the health of the immune system. For example, many people want to know if using IL-2 will help them protect their CD4-cell repertoire or whether it might hasten "aging" of their cells. But viral load data tells us very little about either.
The great immunological event that underlies the efforts to develop therapies that boost the immune system is the observation that the immune system works well in controlling the virus for so long.
We know that after initial infection, the virus grows out of control, making perhaps tens of billions of copies per day for a period of time. Then the immune system, through a mechanism not fully understood, gets the viral burden down as much as seven logs -- better than any antiviral to date -- and keeps it relatively low for many years. In the case of long-term non-progressors, the virus is kept under control for over 15 years. Even in the case of rapid progressors, the virus is usually contained for years. This powerful natural "antiviral" has never been identified, but over time it clearly weakens; in many ways it is the loss of this immune function that required we pay attention to HIV, and therefore led to the development of antivirals. After all, if the immune system kept the virus under control indefinitely, as it does so well for many years in the beginning, few of us would bother studying HIV because it would be a benign infection.
Some within the FDA recognize the need for the development of immune-based therapies, and the connection between this need and the evaluation of more surrogate markers. At a closed agency meeting to be held within the next few days, there will be a serious discussion of how to evaluate new therapies using immunological markers other than viral load and CD4 counts. It is clear that evaluating immune-based therapies cannot be done using markers designed to measure the effectiveness of antivirals.
There are a number of candidate immunological markers which seem highly correlated with disease progression, such as lymphocyte proliferation to antigens (the body's readiness to produce large numbers of cells to fight an illness when presented with pieces of the enemy pathogen), elevated levels of cytokines like gamma interferon, RANTES, MIP-1-alpha, and MIP-1-beta (substances that fight viruses that are secreted by cells when they are presented with the virus -- see "CD8 Cells: Suppressive Factors Discovered," AIDS Treatment News #238, January 5, 1996), DTH (delayed type hypersensitivity reactions, a test of the body's ability to fight an array of common illnesses that we have been vaccinated against or which we have been exposed to, like measles or polio, or HIV itself) and many others.
There are data that lead us to believe that effective immune- based therapies are possible with refinement of existing efforts. For example, ACTG 315 is a recent study which shows that roughly one third of people with moderately advanced disease (a CD4 count of 100-300) on antiviral therapy have a partial return of non-HIV-specific lymphocyte proliferation to some recall antigens, and enhanced levels of both memory and naive CD4-cells and naive CD8 cells. These findings lead one to hope immune-based therapies that restore these markers might help the body fight the damage done by the disease. But no markers have been accepted by the FDA for immune restoration, so the likelihood that the therapies will be rapidly developed is minimal.
It has been known for some time that non-progressors have quite powerful HIV-specific immune responses which people who progress lack, such as lymphocyte proliferation and enhanced levels of chemokines such as RANTES and MIP-1-alpha and beta. We already have therapies which partially restore some HIV- specific responses, such as the Salk vaccine, but the existing crude markers cannot tell us their value without unrealistically large, long, and expensive trials.
While antivirals can block viral replication, it is unclear that they can strengthen the immune system's capacity to fight the virus. If a therapy can strengthen the body's ability to control the virus after antivirals have reduced the viral load, perhaps we could stop using antivirals for long periods of time. This would lengthen the usefulness of the drugs and improve people's quality of life. For example, if IL-2 followed by revaccination could restore the body's ability to fight diseases, it would greatly benefit those who must constantly use prophylactic regimens, notwithstanding antiviral therapy.
But we'll never know without FDA recognition of new markers, because the two now used tend to weed out any efforts except the refinement of antivirals.
The FDA needs to send a signal that it will look at new surrogate markers. In addition to its meeting next week, at which a discussion on surrogate markers to evaluate a particular immune-based therapy will occur, it should convene a joint session of its antiviral drug advisory committee and its biologic response modification advisory committee in a public session to identify those immunological markers which indicate improved health.
Convening these public bodies would send a signal to public and private bodies that would speed research and development of immune-based therapies.
AIDS Treatment Activism:
by John S. James
The tenth anniversary of ACT UP provides an occasion to look
into the past and into the future. What has the AIDS
treatment movement accomplished so far? How do we need to
change, in view of the very important changes happening
today? How can we be stronger and more productive?
What Has Been Done?
What AIDS treatment activism has accomplished must be seen in the historical context of patients and institutions in medicine.
For each disease, the traditional pattern is that those most affected had little or no real influence on the medical research or other institutional responses. Most patients start with little background in science, medicine, or public policy -- and no particular connections or working relationships with their fellow patients.
While patients may be involved for only a limited time, the professionals -- doctors, researchers, officials of corporations, foundations, government agencies and other institutions -- are likely to be working with the disease for years or decades. Whatever personal sincerity and commitment they may feel in their hearts, the real relationships that structure their work and their lives are with the other professionals. The result is a systemic power imbalance, with the professionals alone at the negotiating table where the real decisions are made, and therefore the deals ultimately reflecting their concerns and interests. The patients and their families and friends -- for whose benefit the whole enterprise ostensibly exists -- are in fact uniquely disenfranchised, the only ones who are affected but have no place at the table. The widespread image of medicine, of everyone being of good will and on the same team, does not replace this missing representation.
At the end of the day, the professionals go home the same whether they succeed or not. The fact that most of them try hard, and sincerely want to help, has not automatically created the needed institutional support for successful medical research. For example, if a clinical trial goes nowhere for months or years because it cannot recruit -- due to unrealistic design, such that those who could qualify for the trial would have no incentive to enter it -- who will fix the problem? Within the traditional structure, who could? Probably not the principal investigator -- because that would require renegotiating with the IRB, the FDA, corporate funders, and others, many of whom will have at least an ego investment (if not a financial one) in the failing design. And if not the principle investigator, then who? Possibly the research team as a whole could fix the study, but that would be a lot of work -- work which nobody is funded, mandated, or encouraged to do.
Activists have fixed such problems when the professionals alone have not, basically by providing the missing mandate. They identify and analyze the problem, then keep blowing the whistle so that it cannot slip quietly from attention. Then the researchers and other professionals need to respond -- which allows them to fix the trial without personally initiating the action and being seen as rocking the boat (which could hurt their careers by marking them to funders and others as troublemakers who are difficult to work with).
The fundamental change with HIV disease is that persons living with the illness have obtained a place at the negotiating table, alongside the professionals, funders, regulators and others. This means that the real interests of those most affected can be represented. Patients' major concerns include workable access to care, and the productivity of the research enterprise.
Sometimes we may lose sight of how profound a change has occurred. About ten years ago I spoke with an AIDS worker who had come from a cancer career, and I outlined the need for a movement like the treatment activism which later developed. This person saw my world view as like that of cancer patients who were convinced that doctors were sabotaging medical research, so that they could keep making good money treating cancer. This preposterous conspiracy theory, which significant numbers of people do believe, shows the tragedy of decades of lack of leadership. Patients who were desperately ill could sense that something was deeply wrong, but had no language to describe the problems or articulate their concerns effectively.
Changing Needs Today and Tomorrow
The AIDS world is changing greatly today, and treatment activism must change in order to remain responsive and maintain public support.
We should realize that as treatments improve, there will be a lessening of the public's sense of urgency. The movement will also be weakened as medical improvements make it more possible for those with good health care to insulate themselves from the problems of others. Yet at the same time, the success of the protease inhibitor combinations has shown clearly that treatment improvement is possible -- which will stimulate research, and also create a more compelling case for access. We need to understand such changes so that we can plan effectively.
I believe that the key to the future success of treatment activism will be SERVICE -- the practical benefits that we can bring to people. Here is a partial list of some areas that especially need attention and work:
Access, Money Issues, and Standards of Care
Substandard and otherwise inadequate care has always been a major problem -- although often a quiet one, away from the high-profile cities. Now, as treatments get better but more expensive (although also more cost effective), and more persons with HIV want medical care, the money issues are becoming more critical. Effective treatment access for many people will have to combine public financing with price restraint by industry. This is because no conceivable lowering of current prices would enable the uninsured or inadequately insured to purchase care solely from personal funds -- but at the same time, Congress will not pay for drugs if the main result is to fatten already-exorbitant profits. We will have to work with industry to obtain adequate funding, where we have interests in common, such as ADAP -- while at the same time working with others to reduce profiteering, sometimes by the same companies.
The cost effectiveness of medical care -- compared to the expenses of hospitalization and disability -- will be a critical part of the case for public and other reimbursement.
Other huge access issues include private insurance, managed care, and discriminatory legislation which could discourage people from coming forward for testing and treatment.
A major new standard of care should be released soon by the Federal government, hopefully within a month. If it is successful, a new official standard will provide a major tool to help us advocate for adequate care. And advocacy will be needed to make the new standard effective.
Immune-Based Therapies, Markers, and Trial Design
For antivirals, viral load is already an entirely credible marker. But there are still regulations in place that require the ordeal of clinical-endpoint trials, even when they clearly do not answer the major remaining questions (especially long-term toxicity, which of course is not addressed by viral load).
There has, of course, been years of infighting among treatment activists over the need for clinical-endpoint trials. Disagreement is natural, but we must always be aware of what is serving our public and what is not. Fighting can easily take on a life of its own -- or become focused on proving who was right in the past.
In another treatment area, the development of immune-based therapies has been slowed greatly by the lack of knowledge and agreement on markers. The consequence of lack of widely accepted markers has been that there has been no way to test rapidly to see which drugs might be beneficial. (For a proposal in this area, see "It's Time to Approve More Surrogate Markers," by David Scondras of Search for a Cure, elsewhere in this issue.)
A New Role for "Alternative" Treatments.
Ten years ago, when ACT UP -- and also AIDS Treatment News -- began, mainstream AIDS research was largely useless; it was clear even at that time that each day that went by brought us no closer to treatments that could save lives. In those days, the main hope was for some unexpected breakthrough, which might start either as some chance laboratory or clinical observation, or as some "alternative" or folk medicine. There was little hope of getting such an outsider treatment through the drug-development and approval system of that time (or even seriously into the process at all); therefore, the much- criticized "drug of the month club," which developed later, was in fact the best research system available, the most likely to produce results.
What has happened, of course, is that mainstream research and development have vastly improved since then. Now it is mainstream science and medicine that are saving lives, completely overshadowing what alternative treatments can do.
But alternative treatments still have a role, though a smaller one, and are still very much worth attention. (By "alternative" we mean treatments which are safe enough, available enough, and inexpensive enough to be in popular use, although they have not been formally developed and therefore are seldom prescribed or recommended by mainstream health professionals.)
The new role for alternative treatments is for potential therapy of particular problems or conditions resulting either from HIV disease itself, or from drugs used to treat it -- problems such as itching, or neuropathy, or certain drug reactions. Recent possibilities we have covered include NAC (which might have a role in preventing or reducing Septra- type reactions), and acetylcarnitine (in human testing for certain non-HIV neuropathy -- and also sold today by health- food distributors). Other such possibilities we have reported include nutritional approaches for itching, and acupuncture/Chinese medicine for certain HIV-related problems. Note that some of these treatments, especially those that are nutritionally based, may (if they work at all) be offering not just symptomatic relief, but may ameliorate underlying problems.
Mainstream research, in the U.S. at least, is largely unable to develop an inexpensive treatment. Since there is seldom big money in a low-priced item, industry is not interested. Government and the nonprofit world seldom pick up the ball, since without corporate interest, an area is not conducive to career development and does not become professionally hot; no matter whom they work for, researchers gravitate elsewhere. Most doctors are too busy to do independent, unsponsored research -- and usually they are strongly discouraged from doing so.
For these reasons, it is likely that there are important treatment opportunities which will remain largely untried and unused -- unless activists force the issue and bring them to wider attention. Alternative treatments, therefore, do provide an important opportunity for activists to be of service to people with HIV, both in the U.S. and around the world.
A New Issue: Answering Treatment Rejectionists
Despite the recent improvements in AIDS treatments, and their great benefit to many, growing numbers of people with HIV are now dropping out of almost all medical care, because they believe the ideology that HIV is not the cause of AIDS, and that almost all mainstream AIDS organizations, activist organizations, and physicians are part of a huge conspiracy "worse than Lysenko" to defraud the public of billions of dollars. Different groups with varying viewpoints are promoting such ideas, but the common theme is that persons with no medical training are getting some people with HIV to reject their doctors' advice completely.
People should only use medical drugs to get through a particular infection, it is stated, but otherwise should avoid doctors, listen to their bodies, take common-sense steps to healthy living, and take responsibility for pulling their lives together. This poisonous mix of good advice plus deadly advice is being pushed by strong, charismatic leaders, often excellent debaters who have spent years learning how to argue this viewpoint persuasively. The result is that there are people now rejecting all antiretroviral therapy, and sometimes prophylaxis as well -- based on advice from totally unqualified persons, who have an enormous axe to grind and who give the same medical advice to everyone, regardless of their individual condition or situation.
What should we as a community do about this? Clearly the treatment rejectionists have a Constitutional right to speak. But it is sad that people, often new to AIDS and facing life- threatening illness, are getting only one side of the story; they seldom hear any specific refutation or answers. The AIDS world has been largely silent, because people do not want to be targeted, or to be forced to spend time debating what they consider nonsense. But unless some part of the AIDS community will take on the job of researching, preparing, and communicating adequate replies, we will have been derelict in our duty, and people with AIDS will continue to be abandoned, quietly dropping out of the system and losing critical opportunities to extend or save their lives.
It will not be easy to answer the treatment rejectionists, because their ideology consists of dozens if not hundreds of half-truths and false or misleading statements, each carefully if not professionally crafted to persuade. Each artful deception could require a small research project and an article to explain the real situation. The result would be a book-length reply, which few would be motivated to read.
But the hundreds of distortions do largely seem to cluster into a few major points -- probably no more than about 15 of them. By addressing these major issues, we could produce replies which are communicable. And we must be fully ready to point out where the rejectionists' critique is legitimate and important. (It has been said that a half truth is like half a brick -- you can throw it farther. If nothing these people said was true, no one would put their lives into their hands.)
The other key to effectively countering the rejectionists is to be aware of the real concerns and motives of those who are persuaded by them. How can someone be convinced by what appears to be nonsense, to the extent that they will risk their life for it?
Part of the answer, we believe, concerns the closed nature of most establishments -- in this case, the AIDS mainstream. Establishments often become ingrown and define a world which offers little opportunity for entry of new people, very bleak options for their involvement. When such an establishment tightens its grip on the definition of legitimate thoughts, statements, and actions, people who are facing an intolerable situation (such as a deadly, permanent epidemic) are trapped. They naturally want to act, but all courses of action open to them are, to a greater or lesser extent, designed for failure. In this situation, they have the choice of giving up, or of breaking out of the box by going to war against the system which constrains them. This is the energy which the treatment rejectionists are now learning to tap. By improving our understanding of this kind of dynamic, we can help develop better options for people.
Demos, Zaps, and the Future
What do we see as the future role of street demonstrations, phone/fax zaps, affinity actions, and other such protests? Here we have less to say, because demonstrations have not been our element -- although we realize that they have been essential to the success of ACT UP. In this country at least, reasonable positions are seldom news; it can be hard to accomplish much if those making the decisions simply have no reason to listen or to relate.
For example, a few years ago the emerging breast-cancer movement could get non-pharmaceutical corporate support beyond the dreams of AIDS organizers when the AIDS movement was at a similar stage. But at the same time the activists who could get this support had trouble having their calls returned by government agencies. Without the issue of homophobia, the fight against breast cancer was an attractive vehicle for corporate public-relations contributions. But without a tradition of demonstrations, there was still a problem getting a foot in the door elsewhere.
Why do demonstrations work? The main reason, we believe, is that organizations are afraid of bad publicity. (A lesser reason is that some individuals are afraid of the intense, unstructured situation -- where a momentary misjudgment or mistake can have lasting consequences for one's professional status or reputation.) Historically, the major result of ACT UP demonstrations has been to get activists inside the doors, where the community's work, experience, and knowledge can stand or fall on its merits.
Today we are facing harder issues, like drug pricing. Pricing is difficult because it has long been a major issue for millions of people, yet has not been satisfactorily resolved. But pricing is not impossible, as shown by a number of successes by AIDS activists on this issue.
As the issues become more difficult, we need to improve our tools. We see two major ways to improve the effectiveness of ACT UP's demonstrations.
First, actions need more strategic analysis when they are designed. What often happens is that an action with strong emotional appeal is first proposed and then voted for in one meeting, with no committee work -- sometimes because nobody wants to be in the position of voting against it, even if they are not convinced that the particular target and timing are the best. In retrospect, most actions have worked quite well -- because the strong emotion does indicate a real need, and because bright and experienced people are able to shape the action before it takes place, and after. Still, more attention during the decision process would help.
Second, the focus on a single action might evolve into a larger focus on a continuing campaign, especially a media campaign (which can and usually will include one or more traditional ACT UP demonstrations). Since what the target organizations fear is not the action itself but the media exposure which results, why not design the exposure directly? This would include street or affinity actions as now, but also: statements by experts, celebrities, and respected organizations; the placing of human-interest stories (such as reports on persons who cannot afford the company's expensive drug) into major news media; research to contact other people who have grievances against the company or other target; financial investigations and publicity; and when appropriate, official complaints and actions which would themselves be publicized. Sometimes the information needs to be targeted to significant groups or individuals, such as members of a board of directors.
The reason for thinking carefully before doing this is that such campaigns would tend to be negative -- like the negative campaigns used in politics, which have long been excessive and have now become unpopular; they may still be effective, but they degrade the overall quality of public life. Is negative campaigning really what we want to do? In any case, we should at least consider the possibility of improving our clout by moving beyond the single-climax action design which has often been our model in the past.
Other Major Issues
Here are some concerns which we can only mention briefly: