AIDS Treatment News
Merck Protease Inhibitor:
by John S. James
Our last article on the 3rd Conference on Retroviruses and Opportunistic Infections (January 28 to February 1, Washington D.C.) focused on results of the Abbott protease inhibitor, ritonavir (Norvir(TM)), especially the proof that the drug substantially reduced the death rate in late-stage AIDS. The other highest-profile result from the same meeting concerned the Merck protease inhibitor, indinavir (Crixivan(R)), and its effect on viral load, especially in combination therapy.
The indinavir results must be viewed in context of their limitations, however. The two combination trials which attracted much attention at the Retroviruses conference have a total of 78 volunteers each; one is a six-month trial, the other will last one year but has not been completed yet. Also, there are no results today on clinical outcome, since trials to get that proof are ongoing, and no data are yet available.
The following outlines the major indinavir reports at the Retroviruses conference (and also includes information from elsewhere):
This study mainly looked at the percentage of the volunteers whose viral load dropped to an undetectable level (below 500 copies per ml., in the test which was used). Emphasizing this outcome -- instead of the more usual number of logs (factors of 10) that the viral load dropped -- is justifiable, because there is a problem with reporting the average log drop: since the lower limit of detection was 500 copies, it would be mathematically impossible for anyone who started with under 50,000 copies to record as much as a two-log drop, meaning that this study could not show a drop bigger than about two logs, even if it occurred. (Merck also reported the median viral load drop, despite this problem, which tends to make the drug look less active than it really is.)
At 16 weeks, 24 of 26 volunteers taking indinavir plus AZT plus 3TC had undetectable viral load -- compared to 13 of 26 on indinavir alone, and none of 26 on AZT plus 3TC. (Merck gave us this 16-week data after the Retroviruses conference; at that meeting, Merck presented 12-week results, which were comparable.)
Only a few of the volunteers have yet reached the 24-week point, since the trial is still ongoing. But the percentages at that time do suggest that the results may be sustained; at 24 weeks, six of seven volunteers in the triple combination arm, four of nine using indinavir alone, and none of eight in the AZT plus 3TC treatment arm, had undetectable viral loads.
Median CD4 increases for the triple combination were 79 at 12 weeks and 146 at 24 weeks; the latter figure is less reliable because it is based on a small number of patients.
At 20 weeks, 59% of those on the triple combination had an undetectable viral load.
The maximum median decline in viral load with the triple combination was 3.1 logs. (This may seem impossible if the starting median was 5 logs and no value under 2.3 logs (200 copies) could be recorded, but computations with medians can give unexpected results. Those with over 200,000 copies at the start of the trial could record drops of over three logs.)
The median CD4 increase for the triple combination therapy was 90 at 24 weeks.
Indinavir might continue to have some benefit even after resistance develops. In the early low-dose studies, while the virus had come back by 24 weeks, CD4 count increases of a median of 80 to 100 were maintained for at least 52 weeks. It is possible that the resistant viruses are defective in some way and may cause less damage than the patients' original viruses, but this is not known for sure.
At the conference, results were presented from mathematical modeling of the changes in CD4 count before and after patients received indinavir [abstract #148]. This research suggested that "CD4 return is determined in large part by starting CD4 count."
d4T Plus ddI Antiviral Results
A combination of two approved drugs showed encouraging viral suppression results in a one-year clinical trial [3rd Conference on Retroviruses and Opportunistic Infections, abstract #197]. The results are preliminary, however, as the trial is still continuing; it will not end until October 1996. Also, this trial was primarily designed to test the safety of the combination regimen, not to see how well it worked.
A total of 92 volunteers have entered the trial and were randomly assigned to one of five different dose combinations; the lowest-dose group received half the standard dose of ddI and a quarter the standard dose of d4T, while the highest- dose group combined the full dose of both drugs. Note that everyone received some of each drug. Also, since the trial is ongoing the dose assignments are still blinded, so dose- response information on antiviral activity is not yet available.
The volunteers had CD4 counts between 200 and 500, and no previous HIV therapy; note that these are persons who are more likely to show a strong response to treatment than those who were more advanced, or had extensive prior antiretroviral treatment.
Most of the volunteers had a viral load of at least 1000 at baseline; they were selected for a study of viral load changes. (Those with a very low viral load at the beginning were not included, since they could not show much of an antiviral effect even if it were there, as the viral load tests could not have recorded much decrease). Preliminary data from the ongoing study showed a median viral load decrease of about 1.2 logs (16 fold), and a median CD4 increase of about 60 to 80; these increases appear to be sustained for at least a year, but it is not possible to be sure yet, as only 14 patients in the viral-load substudy have completed the full year.
Six of the volunteers discontinued the trial due to adverse events which might have been caused by the drug; however, these events did not seem to be dose related. [The eight events which led to drug discontinuation in six people were grade 2-4 lipase elevation (3 cases), abdominal pain (2 cases), and one case each of grade 4 liver transaminase elevation, grade 3 neutropenia, and grade 3 depression.] Only one volunteer had to interrupt therapy due to peripheral neuropathy, and he was able to go back on treatment at a lower dose.
The next report from this study is likely to be at the Vancouver conference in July -- although the trial will still not be finished by then.
Note: A separate, laboratory study reported at the Retroviruses conference compared the antiviral activity of the d4T plus ddI combination with that of the two drugs individually (abstract 294). The combination showed additive antiviral effects in one test (meaning that the combination worked as well as would be expected by adding the activities of the separate drugs), and synergistic (better than additive) activity in another test, depending on the cells and viruses used.
One of the most critical research tasks now is to learn which combinations of drug tend to work well together. Small trials like this, with about ten to 20 volunteers per arm and measuring viral load for at least six months, may be the most feasible way to test combinations which have some clinical, laboratory, or theoretical rationale. The main challenge will be getting different pharmaceutical companies to work together; that was not a problem with d4T plus ddI, since both are marketed by the same company, Bristol-Myers Squibb, which funded this clinical trial.
This trial focused on the safety of the drug combination; its design is less than ideal for looking at drug activity. For example, only one viral load baseline measurement was used; and there were provisions for replacing volunteers in the study arms, instead of analyzing everyone assigned to treatment and/or everyone treated. There is a need to develop realistic consensus guidelines for small drug-activity trials -- based on the realization that physicians will use the results in making treatment decisions, and that with the great number of potential combination treatments available today, "definitive" phase III trials for most of them will never be run.
Growing Crisis in Paying for Careby John S. James
How will the rapidly emerging new standard of care -- antiretroviral combinations usually including a protease inhibitor, and viral load tests to tell which combinations are working for a patient -- be paid for? This question is rapidly becoming perhaps the most critical AIDS issue in 1996 and beyond.
Total antiretroviral costs will also rise as physicians use combination treatments earlier in HIV disease -- and as many patients who rejected AZT come to accept the new drugs. But other major costs, including hospitalization, should decline as improved treatment prevents HIV-related illnesses.
Access to Medicaid is also threatened by proposals to turn the program into a block grant to states, with few Federal standards on how the money is spent. Under these plans, state legislatures could define eligibility, formulary, and other rules to largely exclude HIV treatment from Medicaid.
The move to force Medicaid and Medicare into managed care creates another problem. Some public-health systems have been able to survive on Medicaid money, and provide indigent care to those not in Medicaid. As money is squeezed out of the system, one of the last means of funding indigent care will be lost. (See article below on AB 9, another threat to indigent care in California.)
According to a January 26 statement of the National Association of State and Territorial AIDS Directors, 21 states now have severe budget shortfalls in their ADAP programs. Eleven other states are reporting difficulties in meeting demands for combination therapies. Few have been able to add the new FDA-approved drugs 3TC and saquinavir to their programs. At least two states suspended providing drugs entirely in 1995, almost certainly leading to death or permanent harm to persons with no other way to pay for treatment; in February 1996, Washington D.C. shut down its program for a week. Other states have removed many important drugs, or restricted their programs in other ways.
What Can Be Done?
On the issue of paying for care, a shared interest and natural coalition exists between pharmaceutical companies on one hand, and AIDS patients, physicians, service organizations, and activists on the other. This coalition is potentially powerful, since the two major partners bring different and complementary strengths; for example, different members of Congress, different reporters, etc. will listen to one but not to the other. This strategy of focusing first on getting resources into the pipeline may require postponing or de-emphasizing issues like drug prices, which would divide the coalition.
The following also need attention:
There may be more leverage in asking companies to do their share by improving patient assistance-programs. Unless manufacturing cost is an issue (as with some protease inhibitors), these programs cost the companies little -- either in cash or in lost sales, since their clients are screened and have no way to buy the drug. Also, these programs would be easy for private organizations to monitor, since persons who fall through the cracks are likely to complain, and such cases can easily be brought to public attention.
What is needed are more activist groups to make sure that the public interests is represented. One organization we work with, ACT UP/Golden Gate, is doing this very well. But few cities have any comparable organization or vehicle for people to be involved in this effort.
It would cost relatively little to screen available drugs for antiviral activity in small trials. The problem so far has been lack of political will and social organization.
Traditional grassroots pressure tactics may now need legal advice, however, since the new telecommunications law not only censors computer speech, but may restrict activism by phone and fax as well. It is now a felony, in interstate or foreign communications, if anyone "makes repeated telephone calls or repeatedly initiates communication with a telecommunications device, during which conversation or communication ensues, solely to harass any person at the called number who receives the communication." Does this make it illegal to repeatedly fax an ACT UP leaflet to an insurance or pharmaceutical company? That may depend on authorities' attitudes toward AIDS activists.
Alternative strategies could include organizing a phone bank to go through the telephone book, looking for allies -- who will each call only once to the company and to other appropriate parties. Or we can learn from the new labor union strategies, which bring unsafe or substandard products, facilities, and employers to wide public attention.
Ironically the target corporations would probably prefer the traditional zaps, because the protesting communications stayed in house. Single calls from one or a few individuals are ignored by companies and government agencies alike; zaps have provided a harmless way to get an organization's attention, putting an issue onto the table so that it can be addressed on its merits. But now Congress has spoken, requiring legal research to update activist tactics. It may now be necessary to involve a wider public from the start -- or to walk away from the issues and let people die.
AB 9: California Bill
The California Assembly has passed a bill, AB 9 (Goldsmith, R-Poway), that would end the current requirement that counties provide General Assistance, and medical care of last resort for persons who do not have access to Medi-Cal, private insurance, or any other way of getting medical care. If this bill becomes law, counties could decide to have no such care at all; and if they did provide indigent medical care, it could only be for life-threatening or limb- threatening conditions. There is concern that all counties will close facilities and reduce or eliminate last-resort care, leaving people with no access to treatment when they become ill.
The effect on communicable disease control does not seem to have been thought through. Unless a loophole can be found, the bill prohibits counties from providing last-resort care for communicable diseases which are not life threatening. The law would allow counties to treat life-threatening diseases like tuberculosis if they wanted to; but how would these illnesses be diagnosed if indigent persons could not see a healthcare professional when they get sick?
AB 9 could pass without thought to the consequences, because of the extreme partisanship of the California legislature. Under the Democrats, the bill had no serious chance; under the Republicans -- who achieved control of the Assembly in January 1996, when Assemblyman Willie Brown was forced out by term limits and left to become Mayor of San Francisco -- passage was all but automatic. Since minds were already made up, the bill never needed to build support through the normal political processes of accommodation and improvement.
The bill is now in the California State Senate. AIDS organizations are urging Californians to call their state senator immediately and tell him or her to oppose AB 9, then to follow up the call with a letter.
For more information, contact:
AIDS Project Los Angeles Sacramento office, Sophia Kwong, 916/443-9055;
LIFE AIDS Lobby, 916/444-0424;
ACT UP/Golden Gate, 415/252-9200.
Press Gag Rules at AIDS Conferenceby John S. James
[Although this conference is over, the issues it raised will affect future AIDS research meetings. Especially important is how press restrictions can change the depth of media coverage which AIDS research receives.]
Those who did not attend the 3rd Conference on Retroviruses and Opportunistic Infections, but saw only the media hype, may have visualized reporters crawling over the meeting like ants, packing the press room while they filed the hundreds of stories that were published. Nothing could be further from the truth. The press room was sterile and empty; we have seldom seen fewer reporters at a major AIDS conference (or fewer people with AIDS, either). Look again at the newspaper articles you read, and note the authors, if any. Most of the articles were reprinted from elsewhere, or attributed to unnamed "wire services," meaning that a rookie reporter who never got near the meeting and knew nothing about the subject was assigned to rewrite articles and wire dispatches by others, to avoid the need to pay royalties. The lack of reporters paradoxically contributed to the media feeding frenzy, allowing half-truth and hearsay to soar without reality checks.
The reporters were absent because they were turned away at the door; this conference rigidly imposed advance registration requirements, with press reportedly traveling from as far as Mexico and Europe having to return empty handed. We have no idea how mainstream reporters, especially foreign ones, were expected to learn about these extraordinary requirements, or how to meet them; we were warned by friends and colleagues to apply early. Also, this meeting was not hot until shortly before it started; mainstream reporters had no reason to apply, until after it was too late. Even well-known AIDS publications like AIDS Treatment News, CRITICAL PATH AIDS PROJECT, and the JOURNAL OF THE INTERNATIONAL ASSOCIATION OF PHYSICIANS IN AIDS CARE, had great difficulties being allowed to register; we do not know who was turned away. AIDS Treatment News was not accepted until less than a week before the meeting, even though we started the application process almost two months earlier, on December 1, and pursued it meticulously. Our airfare would have cost us almost a thousand dollars extra, if we had not bought tickets in advance of acceptance, planning to cover the meeting by interviewing people in the aisles if necessary. (A list of 21 "community press" organizations got in without trouble.)
In many past conferences, people with AIDS have been quietly allowed to register as press, with an editor's letter or other showing of a press connection; these activists in fact do report on the conference to many others, although they are not full-time journalists. This meeting went to some trouble to discourage such arrangements. Instead, there were supposed to be scholarships open to people with HIV; ten thousand dollars would be raised from the pharmaceutical industry to finance admission for about 50 people. But, for reasons we do not know, it never happened.
In the conference, an extraordinarily sterile press environment meant that to learn what was going on, reporters had to recognize people in the hallways, or be recognized by them -- a serious disadvantage for reporters new to AIDS. Press rooms usually distribute dozens of press releases, from the conference staff, from pharmaceutical companies, and from others; in this entire conference we saw only a single release ever in the press room -- a government release on Dr. Anthony Fauci's keynote address, a talk which practicing physicians found useless. There was also a list of program highlights distributed by the conference staff; sometimes photocopies of NEW YORK TIMES, WASHINGTON POST, and USA TODAY articles; a few faxes and other private messages for reporters laid out on a table; and some computers, which were useful because Merck & Co had computerized the conference abstracts and made them available on disk. Beyond that, there was nothing. The press room had a bulletin board, but it was empty throughout; we never saw a single notice posted on it in the entire five days. Reporters seldom visited the room, and they did not stay. The reason for this lack of communication was rigid press rules forbidding those registering as press from distributing anything to other press or anyone else at the conference, under threat of being kicked out of this and future meetings. (There was a table labeled "newsletters," and thanks to chance meetings in the hotel hallways, we were able to get permission to leave copies of AIDS Treatment News there.)
We had no such luck on photographing posters. Our request for permission was denied, although we promised in writing that the pictures would never be published or distributed, only used for our own review to assure the accuracy of our reporting. This rule made it unfeasible for us to visit most of the posters, which were available for only one day while competing meetings were going on; our time could be better used elsewhere. Incidentally, we had never once seen such a rule during our first ten years of covering AIDS meetings -- the first no-picture rule was at the ICAAC conference last fall. Until then the rule had been no flash photography during the oral presentations, which makes sense.
(The reason for the no-picture rule is the fear that scientific and medical journals will consider results presented at the conference to be "published," and therefore reject later articles by the researchers which are based on the same data. The organizers of the Retroviruses conference seem to believe that by making it more difficult for press to cover their meeting, they make it less likely that journals will reject work presented there as being previously published. In our ten years of reporting the epidemic, what we have found consistently among almost all high-level researchers is that no matter how much they may want to save lives, publication rules and journal exclusives come first. That is how their successful careers have been built.)
A press conference took place on the first full day of the meeting, and the reporters' main request was for more press conferences so they could question major speakers. The organizers promised more conferences, but they never happened.
There was a Community Liaison Subcommittee of the Scientific Program Committee, the governing body which was ultimately responsible for the rules of the Retroviruses conference. According to former member Mark Harrington, that entire subcommittee "resigned in protest at the conference's mishandling of press and community registration and participation."
The difficulties at this meeting were not accidental; next year's conference could be as bad or worse. The problems stem from a particular vision and goal of the conference, one which seems to be widely shared on the Scientific Program Committee.
This goal -- which we certainly do support -- is for the conference to bring together basic and clinical researchers, who usually do not talk much to each other. The clinical researchers who largely run the meeting seem to believe that if there is much else going on -- such as activism, or press coverage, or pharmaceutical industry activity -- the basic researchers will leave or not come next year. The organizers want to avoid the big-tent model of the international AIDS conferences since 1990, which some see as circus-like, and focus the Retroviruses conference as a scientific meeting only. That may explain the hostility to activists, and the rules which make it difficult for the press to function, such as forbidding pharmaceutical companies and others from distributing press releases.
Other problems stem from limiting the total size of the meeting, which also required limiting press, and therefore turning away reporters and scientists alike because the meeting was full. The organizers say that no hotel in Washington could hold a larger conference -- they would have to move to the convention center, meaning a less convenient and intimate conference, or use more than one hotel. We counted hundreds of empty seats during the keynote address, however, and floor space for hundreds of seats more, while other large meeting rooms available to the conference were empty.
Bringing together basic and clinical researchers would be extraordinarily important, perhaps the best thing that could happen in AIDS research. But we do not believe that discouraging press, activists, and industry is the key to doing so. Both kinds of researchers were at this conference; but they seemed to be living in different worlds, with little reason to talk to each other. Most of the basic research had no visible relevance to treating patients, perhaps because most basic researchers listen to other scientists, not to physicians who see patients, when they decide what scientific problems they will work on.
The fundamental error, we believe, lies in a currently prevailing definition of science. For background, see an extraordinarily insightful commentary, "The Slowing of Treatment Discovery, 1965-1995," by Richard J. Wurtman and Robert L. Bettiker, published in NATURE MEDICINE, November 1995, pages 1122-1125. This article analyzes why modern science has done so well in advancing fundamental biological knowledge, including knowledge about the human body -- while at the same time it has done so poorly in translating this knowledge into new treatments and cures.
If the Scientific Program Committee of the Retroviruses conference is right about what it takes to get basic researchers to come and talk to clinicians -- a comfortable hotel, and suppression of activism, industry, and the press -- then all the rules are worth it. But if they are wrong, they are doing significant damage for nothing. For this meeting has effectively become the U.S. national AIDS meeting, the most important AIDS research meeting in the country every year, the most important in the world during some years. It serves many purposes and publics, not only the single-minded agenda of bringing basic and clinical researchers together. One purpose it is supposed to serve is the effective dissemination of information to the public.
This year's meeting showed that organizers can exclude much of the press without reducing the quantity of press coverage. What was lost instead was quality. Reporters at the meeting did their jobs, but there were not enough of them to cover the news in depth. For example, the important good news about the Abbott protease inhibitor, which has saved many lives already in a clinical trial, went out to the world without notice of its dangerous drug interactions, an omission which could be life-threatening. And what the news means to Mexico and other countries was not reported, and the information is now lost, because their journalists were turned away while CNN blared out sound bites to the world. The same narrow perspectives were endlessly regurgitated in the media -- so if measured by total column inches, the conference media coverage was a success.
The reason this meeting got press is that leading government- certified experts agreed among themselves that the protease- inhibitor news was important -- and a few major companies, mainly Merck & Co., and Abbott Laboratories, built on that consensus in pursuit of their interests. Indeed the news was good. But the exclusion of much of the press replaced depth of coverage with media hype and manipulation, a disservice to the public.
What Should Be Done?
We have two suggestions:
We believe that the best way to correct this problem would be to establish top-quality peer review panels which are not connected to journals or other publications. These panels, which could be organized by professional societies, would review papers or other reports of scientific work independently of publication; they would have no incentive to demand exclusivity or secrecy. The approved papers (and pending or rejected papers, as well) could be distributed through the Internet, through journals which do not demand pre-publication secrecy, in compilations, or otherwise; whatever the format or distribution system, readers would know that the approved articles had been through professional peer review, so the work could get the attention it deserved.
This system would allow scientists and scholars to earn professional recognition for their work without having to keep it secret first, greatly improving scientific communication and thereby accelerating discovery. And the final quality of the published articles would be higher than today, because busy reviewers (usually only two of them) cannot check everything; without secrecy, the entire scientific community would be able to comment on the work as it was being reviewed. Studies of today's "peer reviewed" articles have found many errors which the reviewers should have caught. Such problems could be greatly reduced by open public exposure instead of secrecy during the review.
What motive would professional societies have to review scientific papers if they are not going to publish them? The same motive those societies now have to grant professional awards of various sorts, awards which develop their own credibility over the years and reflect well on the organizations which sponsor them. And most researchers are unhappy with the current system -- although they seldom discuss the issue publicly, as their careers depend on the journals.