AIDS Treatment News
by John S. James
Today there is more optimism among leading experts about the prospects for controlling HIV infection than at any previous time in the AIDS epidemic. This change (illustrated by a recent conference, "Can HIV Be Eradicated from an Infected Individual," June 12-13 in Washington, D.C., organized by the University of Amsterdam and the journal ANTIVIRAL THERAPY -- and by a major page-one article in the June 14 WALL STREET JOURNAL) does not reflect any single breakthrough, but rather a number of clinical research findings, which together are strengthening an approach to treatment strategy which began coming into public view a few months ago. It is important to understand the limitations as well as the promise of this new approach.
In late January of this year, at the Third Conference on Retroviruses and Opportunistic Infections, early data from at least two small trials suggested that, under ideal conditions, certain drug combinations could reduce all evidence of viral replication to undetectable levels in most patients. And the proportion of patients achieving this success seemed to increase over time -- the opposite of previous experience with anti-HIV drug treatments, which quickly reached a peak of viral suppression and then steadily lost effectiveness.
Today there is more data, and from different kinds of patients, suggesting that:
The emerging view of experts today is that what counts is getting the viral load very low and keeping it very low, regardless of how this is achieved -- whether naturally in persons fortunate enough to be long-term nonprogressors, or by whatever antiviral combination works for the particular patient. The more advanced the illness, the higher the viral load is to start with, the more drug-resistant viruses the patient already has, and the more problems there are with continuing the drugs and using them as directed, the more difficult it will be to get the viral load low enough. To maximize potential benefit, the emerging treatment philosophy is "hit hard and hit early."
How low a viral load is low enough? No one knows for sure at this time. A viral load which is and remains below the limit of detection of the Hoffmann-La Roche Amplicor HIV-1 Monitor(TM) test -- the only viral load test currently approved by the FDA -- would seem to be a reasonable goal for now; for more information, see "HIV Viral Load Markers in Clinical Practice," published in NATURE MEDICINE, June 1996 (reviewed in AIDS Treatment News #248, June 7, 1996). [As we reported in our last issue, two free tests to establish a baseline are being offered to everyone with HIV in the U.S., but only for a 60-day period beginning June 17, 1996; for more information, call 1-888-TEST-PCR.]
Is Viral Eradication Possible?
If viral replication can be essentially completely suppressed for a long time, is it possible that the virus remaining in the body would eventually die, meaning that HIV was eliminated and the person could stop taking the drugs and would be cured? This is conceivable, but at this time there is no evidence that this is possible. Eventually some people whose virus is now being completely suppressed by antiviral drugs will try going off the drugs, and then we should find out quickly whether or not the virus comes back. (Two patients who had undetectable viral load for two months and four months did interrupt therapy, and the virus returned; this was reported by Dr. Luc Perrin, of Geneva University Hospital, at the recent HIV Eradication conference mentioned above.)
Although there is no evidence today that it is possible to eradicate HIV in an infected person, what is new is that the question is now open. Until recently, all drug regimens had been observed to fail with time; therefore, there was no possibility that any amount of those treatments could eliminate the virus. Today, with better treatments, we do not know. But even if it turns out that HIV cannot be eradicated just by suppressing it completely enough for long enough, the new results would still suggest that for many patients viral activity can be stopped for a long time, and drug efficacy maintained, with combinations of currently available drugs.
Comment: Practical Concerns
Most of the drugs being used in the new trials which appear to have largely shut off HIV replication in many patients are already widely available (in the U.S. and some other countries), by prescription or through expanded-access programs. The researchers running the trials have been unwilling to recommend particular combinations, since what counts is getting the viral load low enough, and the best drugs to use for this purpose will vary depending on the patient. Most of these regimens combine a protease inhibitor with at least two other antivirals. We will report results of particular drug combinations with particular patients as more information becomes available.
One of the practical difficulties in implementing the "hit hard and hit early" strategy, as the new results suggest, is that it means that people in early illness, who have no symptoms, are expected to begin long-term (possibly life- long) therapy with combinations of at least three drugs. All these drugs can have side effects -- and all are expensive, and often inconvenient to use (as most must be taken twice a day or more, some on an empty stomach, others with food, etc.) How many people will be able and willing to begin and stay on such multiple-drug treatment, when they feel completely healthy, and may understandably be inclined to leave well enough alone? How many will be able to pay for expensive treatment (especially when their insurers see that they appear entirely well)? The new results seem to suggest that everyone who is HIV-positive should be on aggressive treatment with multiple antiviral drugs. But how realistic is this?
It seems to us that the widespread use of very early, very aggressive treatment will in practice usually wait until more evidence becomes available. Much more will be known by later this year. And it is possible that persons with a naturally low viral load might need less aggressive treatment to achieve the suppression required. It is also possible that after a period of suppression, maintenance therapy might not need to be as aggressive as the initial therapy. But this is only speculation until more is known.
Meanwhile, physicians and patients should re-think the unfortunately common practice of beginning HIV treatment with AZT alone, or with other regimens not strong enough to suppress the virus sufficiently. This approach is likely to lead to resistant viruses, which might make future treatment more difficult than if the inadequate treatment had never been started at all.
Internet Free Speech
by John S. James
On June 11 a U.S. District Court ruled that the key provisions of the Communications Decency Act of 1996 -- against placing "indecent" or "patently offensive" communications on computers where they might be accessible to minors -- are unconstitutional because they violate the First Amendment of the Bill of Rights. Even though it is not final because the government is likely to appeal to the Supreme Court, this 39,000-word decision is immensely important because it explains the issues and the technology in a way that the legal community can understand. (The current Supreme Court, while conservative in many areas, has generally defended free speech.)
The June 11 decision does not affect the laws against obscenity and child pornography, which remain illegal on the Internet as elsewhere. But the "indecency" standard is much more far-reaching and vague than obscenity. For example, unlike obscenity, indecency "has not been defined to exclude works of serious literary, artistic, political or scientific value" (quotation from the court decision). The new ruling essentially gives the Internet similar First Amendment protection to what books, newspapers and other print media now have, instead of imposing the much more restrictive standards now applied to broadcast radio and television, which the Communications Decency Act would have done.
The decision includes an excellent summary of the technology and history of the Internet; we learned much from it. Also impressive is its review of the recent history of the First Amendment, and explanation of the reasons free speech is important in our system of government and society. The court also noted that there are effective ways to keep unsuitable material away from children, without restricting communication among adults.
The decision took particular note of the "market failure" by which both broadcast and print media have largely become controlled by a few large institutions, with most peoples' participation being passive -- and how the Internet is fundamentally different, with much lower barriers for entry, and essentially the same low barriers for speakers as for listeners. The Court clearly understood that the new law would have a disproportionate effect on individual citizens and on small organizations, while large corporations could protect themselves through expensive legal defenses, and by limiting their material to the mainstream viewpoints that we now receive through the broadcast and major print media. (The Court also noted that the new law would have little effect on commercial pornographers, who already exclude children by requiring credit cards for access to their materials, and therefore would not be much affected by the CDA.)
The historic importance of this ruling cannot be overemphasized, as many experts suspect that computer communication will become as important as the printing press in human cultural development. The new law would have effectively required adults to limit their use of this medium to communications suitable for children.
The case which led to this decision was brought by dozens of organizations and companies (in two separate legal actions which were later combined), including the American Civil Liberties Union, American Library Association, American Society of Newspaper Editors, Apple Computer, Microsoft Corporation, America Online, CompuServe, The Microsoft Network, and Prodigy. AIDS organizations included AEGIS, Critical Path AIDS Project, and The Safer Sex Page.
The decision provided sound bites which were quoted again and again in the media:
"The Internet may fairly be regarded as a never-ending worldwide conversation. The Government may not, through the CDA, interrupt that conversation. As the most participatory form of mass speech yet developed, the Internet deserves the highest protection from governmental intrusion."
The full text of the decision is available at various Internet sites, including http://www.aclu.org. AIDS Treatment News followed the development of the CDA in issues # 227, 229, 236, 237, 238, and 240.
Azithromycin Approved for Once-Weekly
On June 14 the FDA approved azithromycin (Zithromax(R)), adult dose 1200 mg taken once weekly, for prevention of MAC (MYCOBACTERIUM AVIUM complex) disease in persons with advanced HIV infection. According to Pfizer Inc., the new 600-mg tablets will be available in pharmacies in several weeks.
Azithromycin has been approved in the U.S. for other uses since 1992. The new approval for MAC prophylaxis should help to educate physicians about this treatment option, and also help in getting reimbursement for the drug.
According to Pfizer, its drug "will be available at a lower cost than currently used MAC prevention therapies." The company has a patient assistance program to help some patients who need the drug and cannot afford it.
Nevirapine Recommended for Approval
On June 7 the FDA's Antiviral Drugs Advisory Committee recommended accelerated approval of nevirapine, an experimental antiretroviral currently available through an expanded-access program. The vote in favor of the drug was 8- 0. Official approval is almost certain; nevirapine will then be the first approved member of a new class of anti-HIV drugs (non-nucleoside reverse transcriptase inhibitors).
Nevirapine was recommended for use in combination with other antiretrovirals, because when the drug is used alone, viral resistance develops quickly. In triple combination with AZT plus ddI, it showed significantly greater improvement in CD4 count increase, and in viral load reduction, than AZT plus ddI plus placebo, lasting at least for the 48 weeks the trial was run.
In a separate one-year trial with previously untreated patients, those on the triple combination of nevirapine plus AZT plus ddI had an average CD4 increase of 138 at the end of the trial (computing the average increase from weeks 40-52), and the CD4 count was still increasing after one year. Without the nevirapine, those on AZT plus ddI had an increase of 81 in the same time period (weeks 40-52), and their counts were decreasing. The difference between the 138 increase and the 81 increase was statistically significant. Also, about two thirds of those receiving nevirapine plus AZT plus ddI had their viral load reduced to undetectable levels.
An in-depth article on nevirapine, by Jules Levin of the National AIDS Treatment Advocacy Project, looks in more detail at the nevirapine clinical trial results -- and at safety, drug interactions, viral resistance, status of approvals internationally, and contact information for the expanded access program. This article is available on the World Wide Web at http://www.aidsnyc.org/natap; if you do not have Internet access, you can reach Mr. Levin by fax at 718- 624-8399, or by phone at 718-624-8541.
Free Viral Load Tests:
In our last issue AIDS Treatment News published a toll-free phone number, 1-888-TEST-PCR, for patients or physicians to call for information about the availability of free viral load tests, using the Hoffmann-La Roche test newly approved by the FDA. Two tests are being offered to everyone in the U.S. with HIV, but only during the 60-day period starting June 17.
Some calls never reached the Roche hotline, but came to private homes and businesses instead. This happened because people did not dial the '1' to indicate a long-distance call; as a result, the first seven digits of the number were taken as a local call, and the last three digits were ignored.
The '888' area code represents a new toll-free phone number, presumably instituted because the familiar '800' numbers are running out. AIDS Treatment News normally does not publish the '1' in front of a long-distance number, since people know to dial it. The current confusion occurred because '888' toll-free numbers are new. We will include the '1' with '888' numbers we publish in the future.
On June 7 the U.S. Centers for Disease Control and Prevention (CDC) published revised guidelines for antiviral treatment to reduce the risk of HIV transmission due to occupational exposure, such as needlestick injury with HIV-positive blood in a hospital or laboratory. The new guidelines are provisional, as little data is available.
Because the risk of transmission is low -- only about 3 HIV infections per one thousand percutaneous exposures to HIV- infected blood, and because the antiviral drugs can have side effects, treatment is not recommended in very low risk situations (such as exposure to urine or saliva from HIV- positive persons). When treatment is recommended, it should be started very rapidly, preferably within one to two hours of exposure. The treatment suggested is indinavir (Crixivan(R)) plus AZT plus 3TC for four weeks; however, this regimen should be changed in certain cases, such as with a patient likely to be intolerant to one of those drugs or who is taking incompatible medications.
The previous recommendation for occupational exposure to HIV called for treatment with AZT. A case-control study found that this use of AZT alone was associated with a 79% reduced risk of seroconversion. There is no human data on the effectiveness of combination treatment in preventing infection due to occupational exposure to HIV (since it takes a long time to get such data, because cases of seroconversion are rare). But all that is known suggests that combination treatment will probably be more effective than AZT alone.
The complete guidelines were published in the June 7 MMWR (MORTALITY AND MORBIDITY WEEKLY REPORT, of the CDC). According to this publication, updated information about prevention of infection due to occupational exposure to HIV will be available in early 1997 from the CDC's Internet home page (http://www.cdc.gov), and also by fax and telephone.
AIDS and Alternative Medicine:
by John S. James
Remarks to AIDS and Alternative Medicine: Current State of the Science, Bastyr University, Seattle, April 28, 1996:
I started AIDS Treatment News 10 years ago, and the newsletter has now published 245 twice-monthly issues. When we started, we thought that AIDS Treatment News would focus mainly on alternative/complementary treatments -- thinking that physicians and patients were already flooded with mainstream treatment information from journals and from industry marketing departments.
It did not turn out as expected. While some of our most important articles have been about alternative treatments -- for example, the September 1, 1995 interview with acupuncturist John Sinclair of the Immune Enhancement Project in San Francisco -- we have published many more articles about mainstream experimental treatments, or mainstream approved treatments, than about alternative approaches. Partly this is because the journals and pharmaceutical companies have done poorly in getting physicians the mainstream information they need, so most of our readers' questions concern mainstream treatments.
But also, there is much less research on alternative treatments, due to well-known funding difficulties. Research money, from government as well as from industry, is funneled preferentially into development of the most expensive treatment options -- a major though unrecognized upward pressure on the overall cost of medical care. Our reporting has been affected, because most of the new research findings have come from mainstream research. And we have felt compelled to focus on what is new, because no one has had the answer. Existing treatments, both mainstream or alternative, can be helpful, but most of the answers required to save lives will have to come from new research and development.
What has been lost from failing to research alternative treatments?
The big Vancouver international AIDS conference will happen in two months. After one of the earlier meetings, a physician from the developing world, who had just wandered through the high-tech exhibits and research reports, commented, "There is nothing for us here."
That is not surprising, since every medical tradition on Earth except for one has been excluded from any real role in developing new treatments. Only the corporate, high-tech, big-money, FDA-approved research process has been taken seriously. And this year at Vancouver there will be another issue: the unaffordability of the fruits of the big-money tradition, now that it is producing results arguably worth fighting for. Being excluded from AZT monotherapy seldom became a major concern.
But the loss is not only to the developing world, or to the excluded communities within the United States. For if there are important leads to new approaches within indigenous healing traditions -- and certainly there are -- we are unlikely to hear about them. Excluding almost everybody from the search for better treatments will slow that search greatly.
Major Problems in Drug Development
Some of the biggest problems in medical research and drug development affect mainstream and alternative alike. To simplify the recent history of drug development and approval, several years ago there were two major bottlenecks. One of them was obvious and painfully pressing, and has now largely been fixed, at least for AIDS. The other problem was more subtle, and it remains one of the major challenges for today.
When AIDS Treatment News started reporting 10 years ago, the obvious bottleneck was in the late stage of drug development -- the later steps leading up to FDA approval. It was clear that clinical-endpoint trials were going to be required -- and that if a drug did work, it would take years for all but a few people to get it. The drug had to already look good enough that hard-nosed companies would invest many tens of millions of dollars in its development. And people could read about the drug in the newspapers, but could not get hold of it. This bottleneck, of course, affected only mainstream treatments, since anything which gets that close to approval would be considered mainstream by definition.
In most cases we do not have this problem in AIDS today. The current FDA leadership has developed regulations for accelerated approval, which allows a drug to be approved based on easily measured markers like CD4 and viral load -- and encouraged various forms of expanded access, which allow companies to provide a drug to many people before approval. The FDA now goes out of its way to find official, legal ways to make available AIDS drugs that the medical community as a whole has good reason to want to get. There are still problems, however: for example, expanded access can work commercially for some large companies, but others are uninterested, and for small companies it may be out of the question.
But the other bottleneck, early in the drug development process, has not been solved -- and it affects mainstream and alternative treatments as well. This bottleneck, which I believe is the fundamental problem in drug development today, is the difficulty of going from early work to the first credible human data on possible activity or efficacy.
In the case of mainstream treatments, the early work is usually in the laboratory. Treatment leads which show promise commonly do get published in mainstream, peer-reviewed journals. They get published because publication is the lifeblood of academic careers, so the researchers will fight to reach this stage. But then, in almost all cases, development stops cold, no matter how promising the laboratory results may be. With no human data, no one will invest millions of dollars which current rules usually require to be spent before that human data is available.
For alternative treatments, the bottleneck occurs after the treatment is already in human use, sometimes widespread human use, but there are no generally accepted scientific studies or data to support its benefit. Usually those studies never happen -- despite the obvious public health importance of researching treatments which are in widespread use, whether they work or not.
Part of the tragedy is that if a new drug or other treatment approach or idea could reach the stage of early data -- the first credible showing of activity in humans, even if less than a controlled trial -- then the existing system of drug development might respond passably well. Pharmaceutical companies, physicians, academics, and others will start being interested, and the treatment will have the momentum to carry it into further stages of research. But before it has that first credible human data, there is no sufficient evidence, no momentum, to start the ball rolling. Laboratory results, biological plausibility, or popular interest and use, have usually not been enough.
Much of the advance of medicine comes from lucky accidental discovery, in which the unexpected is allowed to reveal itself. Today's system poisons this well of potential discovery, by making research so cumbersome and expensive that it can only test ideas which already have widespread support in advance.
What Can Be Done?
How might research be organized to overcome this particular gap between widespread use of an alternative treatment, and widely credible data showing possible activity or effectiveness? We see several possible approaches. They are relevant not only to researchers, but also to physicians, patients, advocates, public officials, and potential donors who might support research.
For mainstream treatments, and sometimes for nutritional approaches as well, a flurry of calls usually means that research just published in a high-status journal was reported by major newspapers or TV networks. What is driving this interest is scientific discovery.
But behind a flurry of calls about an alternative treatment, in most cases, is not a scientific advance, but a marketing campaign to make money for someone. A new incarnation of some old pill or machine is being pushed.
Recently we used the Internet's World Wide Web to do computer searches on alternative treatments. We used a search engine called Alta Vista (described below), which immediately checks over 20 million existing Web pages for whatever words we specify, and returns results immediately. About 4,000 pages include the phrase "alternative medicine." But a great many of them were listings of health-food type products for sale. When we asked the search engine to eliminate all those that contained the word "product" or "products," we got the total down to a more manageable 2,000.
The fact that a product is commercially promoted does not mean it doesn't work. But it can make it hard for us to get a sense of whether it works or not. We do not know the people behind the campaign; do they believe in their own product? Do they have evidence, and are they evaluating it well? Or are they only pursuing a marketing challenge, in which their goal is to sell as much as they can, without any need to know whether or not it works?
Occasionally a flurry of phone calls or letters results not from a commercial promotion, but from activities of a true believer. Here the credibility problem is largely the same. It is hard to tell what you can trust and what you cannot.
The pharmaceutical-industry mainstream deals with this problem by having third parties, usually academic or clinical research physicians, conduct its research. While the company pays the money, the researcher's career depends only slightly if at all on whether there are positive results -- but depends centrally on a continued reputation for objectivity.
Perhaps the alternative-treatment world could borrow this system, too. The difference would be that we will never have the money that pharmaceutical companies have, and therefore must find research strategies which are far less expensive. This is possible, since most alternative treatments are already in frequent human use, so trials are much safer than those testing a new chemical entity which no human has ever encountered before.
But the history so far is not always promising. Often academics are misused in a way which constitutes a sale of their name for use in a marketing campaign. Hungry researchers or institutions which have a public reputation are hired to do some laboratory test or other piece of the research on an alternative product -- a test which has little or nothing to do with whether the product works as claimed. The academics do their job competently, but meanwhile their name is plastered on ads or promotional articles, to make the product appear to have credibility it would not otherwise have had. This practice complicates the search for methods to do the research right.
Ultimately, to make knowledge widely transportable and useful, we will need to find credible ways of testing proposed approaches. But these ways need to be developed in collaboration. It will often not work to bring in a preconceived piece of scientific methodology developed in other contexts and for other purposes.
One potential resource for starting this learning process is ExtraMED, a new database created by the World Health Organization, of over 200 medical journals in developing countries. These journals are excluded from Medline, Embase, and other major bibliographic databases, and therefore largely unknown to researchers in the developed world. (For more information about ExtraMED, see below).
Appendix: ExtraMED Database
ExtraMED is a database of over 220 biomedical journals selected by the World Health Organization as among the best in the developing world. But almost all of these journals are not indexed in Medline, Science Citation Index, or any other Western indexing service. Therefore most researchers never find out about this published research.
An eye-opening article in the August 1995 SCIENTIFIC AMERICAN, "Lost Science in the Third World" by staff writer W. Wayt Gibbs, compiles appalling statistics on the exclusion of developing-country research from the world's scientific literature. A handful of indexing services have come to serve as gatekeepers of whose work can reach the scientific community. They have allowed only two percent participation in science from 80 percent of the world. And the numbers have become seriously worse during the last ten years.
ExtraMED, now in its second year, claims particular strength "in such topics as AIDS, tropical medicine, communicable diseases, emergency conditions, and traditional medicine." The database is distributed on CD-ROM, which stores the complete text of all pages of all articles as high-quality images -- together with a cumulative index which allows all disks to be searched with one command.
ExtraMED costs $1800 a year for 10 disks (50% less in the developing world). For more information, contact DV Trimmer, Informania Ltd., P.O. Box 1359, London W3 0ZU, England; fax 011-44-1730-265398, email email@example.com.