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ICAAC Newspaper Headlines Misleading on Protease Inhibitor Failure
by John S. James
Many who were not at the recent ICAAC meeting (the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, September 28 - October 1) received an erroneous doom-and-gloom impression from the newspapers. Actually, the meeting had both good news and bad -- probably more of the good news, especially indications that there may be more immune recovery after successful antiretroviral treatment than many experts had thought. There was also more information which is likely to help make existing drug treatments work better in the future (for example, on the importance of maintaining adequate trough levels, and of obtaining viral suppression far below the 400 copy limit of the officially approved viral load test).
But only one AIDS story got much media attention -- the report from the University of California San Francisco and the Gladstone Institute that -- in a large urban clinic, often with heavily pretreated patients -- antiretroviral combinations including a protease inhibitor were having only about a 50% long-term success, vs. the much higher rates, usually over 80%, in clinical trials. Some readers took away an impression that the drugs do not work, so why bother? The problem was not in the news reports themselves but in the headlines, which in the newspaper business are seldom written by reporters, but by writers who are not familiar with the story and are aiming to attract attention.
We spoke afterwards with the presenter, Steven Deeks, M.D. "At least in 1996, many people used protease inhibitors suboptimally, so there was much virological failure. But people should not take from our data the impression that the drugs do not work. I was very impressed at how well they did work, given the limitations.
"People should be encouraged to use these drugs in accordance with the current guidelines. But many cannot or will not do this, so for them the drugs may not have a lasting effect. We need to be aggressive in developing better treatments and strategies."
ICAAC: Online Summaries Available
Steven Deeks, M.D., has published a short (1000 word), excellent summary of HIV news at both the IDSA (Infectious Disease Society of America, San Francisco meeting) and ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto meeting), on the HIV Web site of the University of California Medical Center. Topics include early data on switching to other protease inhibitors (after the first one has virologically failed); indinavir long-term results; nelfinavir long-term results; indinavir blood levels and viral resistance; experimental twice-daily use of indinavir; experimental once-daily use of ddI; results with the new saquinavir soft-gel formulation; nevirapine; efavirenz (DMP 266); and protease inhibitors in clinical practice.
This summary is available at: http://hivinsite.ucsf.edu.
Long-Term Strategies: Should Some Patients Wait to Start Protease Inhibitors?
Interview with Keith Henry, M.D.
by John S. James
Keith Henry, M.D., is Director of the HIV program at Regions Hospital, St. Paul, Minnesota. Regions Hospital has an HIV research program and is affiliated with the AIDS Clinical Trials Group (ACTG) at the University of Minnesota. Many patients are indigent and initially uninsured, and many have already had extensive antiretroviral treatment.
AIDS Treatment News: Explain your concern that the new treatment Guidelines (published for comment by the U.S. Department of Health and Human Services in July 1997) are leading doctors to rush into protease inhibitor treatment for some patients who might be better off with less aggressive approaches for now.
Dr. Henry: One of the take-home messages from the ICAAC meeting (September 28 - October 1, in Toronto, Ontario) was that in the real world, up to half of the people who have started on a protease-inhibitor based antiretroviral combination have virologically failed that regimen. In my practice I have also seen that treatment combinations which include a protease inhibitor have failed to durably suppress HIV viral load in about 50% our patients. This is a scary figure; nationally, it would likely mean that every day there are more people becoming resistant to protease inhibitors than people being infected with HIV. Can we feel secure that the impressive reduction in AIDS-related death and illness, which we have seen and are still seeing today, can be maintained?
How can one prevent protease inhibitor resistance? And is there really a need to rush and put everybody with a detectable HIV RNA level onto a protease-inhibitor based regimen?
When working with patients I am often uncertain about what to do -- except in classic situations. For example, when a person is sick due to HIV, and has a high viral level and low CD4 count, I treat them very aggressively, and usually start with four antiretrovirals. On the other end, if somebody feels great and has a very high CD4 count and very low RNA level, I may choose to just follow them and not prescribe antiretroviral drugs at this time.
But it is hard to know how to treat everybody in the middle. With only 50% success in getting durable viral suppression with a protease-inhibitor regimen, I am reluctant to jump into something that perhaps we do not know as much about as we think we do.
Physicians may be lulled into complacency with the new drugs, because the initial viral load drop looks good. But after the viral load goes below the test limit, they probably see people perhaps once every three months to repeat the test; this is a typical recommendation. If suddenly the virus rockets back, three months is a long time and there could be resistance to several kinds of drugs, and then further treatment choices are limited.
The natural history of HIV suggests that a number of people have an excellent prognosis for years, and that we can identify many of them with clinical evaluation and blood tests. If we are trying to keep a person healthy for 20 to 30 years, and almost certainly we will have better and simpler drugs several years away, does one need to commit now to regimens that have a 50% virological failure rate?
ATN: Is that failure rate only for your patients who are heavily pretreated, who therefore are the hardest to treat?
Dr. Henry: Yes. But in the United States today, an estimated three quarters of a million people already have HIV, and 40,000 a year become newly infected, and an increasing percentage of them are pretreated. For any given clinic population, a relatively small percent are treatment-naive. And it will remain that way, if the push is always to start treating almost everybody quickly. If we do not know the best way to start patients and maintain them, even in the ideal patient population where they have never seen drugs before, a high percent may at first achieve viral suppression below the test limit, but then have the virus return.
ATN: Why are we seeing differences between clinical trials and clinical practice?
Dr. Henry: Major clinical trials are reporting that 80% to 90% of treatment-naive volunteers have complete viral suppression that looks like it may last for years. But very few doctors are claiming this high a success rate in their clinics, even with the treatment-naive patients who are easiest to fully suppress.
The reason may be that the resources are not there to provide education and adherence strategies that would equal what happens in a clinical trial. In the trial, you tend to select for adherent patients. And typically there is one study nurse to 20 volunteers; it is the nurse's job to have them come in and take their medicines. In a typical busy practice, the ratio of nurses to patients may run from one nurse per 150, to one per 300 or even 500 patients. What can be accomplished with phone calls, checking up on things, is quite different in this clinic setting.
And the reimbursement for adherence counseling is almost nonexistent. I would be curious if any practitioner in any state is being paid appropriately by coding that task somehow [on insurance forms]. Here in Minnesota we do not get paid anything for it.
It is a big deal for any individual patient to be started on antiretroviral treatment. Bells should ring, cannons should fire; it is a huge step for that person. Yet it has become somewhat trivialized because we do it so often, and with so many different people, and in the clinic we want to spend more time talking about it, but we cannot. I wish I could have a team of pharmacists and clinical educators work with the patient, but that is not available.
Because of the new Guidelines, a doctor who senses that patients could not be adherent to a complex regimen, and does not give protease inhibitors, may feel deficient. I believe this is a problem with the current recommendations. Might it be better, for many patients, to wait several years and use no therapy now, or use a treatment that would basically hold down the fort without lots of resistance -- until we can do a better job with adherence, and have simpler drugs? Or should we go with the Guidelines and go for broke? I do not think there has been enough debate about this. The results from ICAAC shook up people who have only been reading the headlines of the publications in the various journal articles, saying that the results with the aggressive treatments are good.
Even experienced physicians sometimes feel bad when they are not in compliance with the recommendations. What do doctors with less experience feel? I have patients who say they want a certain treatment, but it is clearly not the right thing at that time. Because of my experience I can tell them that, and they believe I am looking out for their best interest. But physicians with less experience may just start protease inhibitors because it is the thing to do. That is not ideal for developing a long-term strategy.
ATN: Ever since the Guidelines came out, many people have thought that they were too aggressive for some patients.
Dr. Henry: I also think they are not aggressive enough for many others. The line is too thin if you may have just one key drug in a combination. So I often go straight from two drugs to four, double protease inhibitors and double nucleosides. I feel more comfortable with the margin of error. And often the twice-daily dosing which the four-drug regimen can allow is an important advantage. For many patients the four-drug combination might be a better, more durable therapy than three drugs with only one protease inhibitor.
ATN: For those who do not need such intensive therapy, what are some of the treatments you use to "hold down the fort" for those who are not very advanced?
Dr. Henry: The d4T plus ddI regimen is one I am using more and more -- with the ddI once a day, at night, and d4T twice a day. Some people also add hydroxyurea. The virologic response seems good. With d4T it has been very difficult to know when or if someone is resistant. People have criticized this approach, saying there is more cross resistance than we know about; but I have not seen any data suggesting that when this treatment approach is used, people have quickly failed the next regimen.
Did we really need to use protease inhibitors in many of these patients, my own included? Or were we in too much of a rush to do it, without thinking of some of the long-term implications?
ATN: How reversible is the immune damage caused by HIV?
Dr. Henry: One of the strong arguments for starting maximum treatment immediately is that the immune damage is irreversible. I am not sure about that. Most of the clinical data on the high-potency regimens suggest that even people with fairly advanced disease have improvements in their immune function to the extent that they are quite protected from most infections -- with no major holes which would allow particular infections break through. Even in people with advanced disease -- the worst case -- it appears that there is considerable protection. And for those with CD4 counts over 150, it seems that immune damage is quite reversible. Some of the work we have done with Ashley Haase and others, in looking at levels of T-cells in tissues vs. the blood(1), found people whose lymph nodes were shot, with germinal centers you could hardly detect, yet who recovered with therapy. So it is an open debate about reversibility. We have to learn much more about this.
Most people agree there are better, simpler drugs on the horizon. There needs to be more critical discussion of what is the best time to use a complex, highly active regimen.
ATN: Are your more advanced patients still doing well, despite the virologic failure? Are the gains in reduced death, hospitalization, and opportunistic infections still there?
Dr. Henry: Absolutely. I am taking care of about 300 patients, and we have projected for 1997 that we may have about eight patients who will have died this year. But that is down from 40 deaths per year two to three years ago, about an 80% reduction. For people who came into 1997 and did not have a near-terminal condition, and were on antiretroviral therapy, I have only had one new AIDS opportunistic infection that we have diagnosed in 1997 to date. This amazing improvement leaves me puzzled about how much of the prophylaxis to continue.
The people I am now seeing in the hospital are mostly new patients. They have not been treated, they come in with pneumocystis just like the old days.
I consider it excellent advice that it is rarely an emergency to get people started on antiretroviral therapy. Some leading physicians almost never start patients on treatment until it is their fourth or fifth visit. That is probably wise; you get to know the person, and hopefully all of their questions have been answered. Things were urgent when we were under the gun of all those deaths and infections. But now that these consequences have slowed down, we should start to be more thoughtful about when to apply different strategies.
Ultimately we will also need to be more cost effective. If a patient is looking at possibly 50 years of treatment, and each year costs $10,000, that would be half a million dollars. These resources are valuable. Of course we do not want anybody to get sick when it could be prevented, but the clinical community has an obligation to use resources as carefully as possible. Today I am unsure about what is wise and what is not.
Protease Inhibitor Resistance
Dr. Henry: Some people believe that once you are resistant to one protease inhibitor, you will be resistant to all of them, that there is a common pathway for resistance. If that is true, the decision to use a protease inhibitor is a momentous one; and you have to do all you can to use it at the right time, with the right other drugs. I am not sure that we now know how to do that for many people.
On the other hand, some people say you can use one protease inhibitor, and if you get a viral breakthrough, you can switch to a different protease inhibitor. But there is not much data, except that if saquinavir is the initial drug, following that up with indinavir generally does not work very well. Also, there is a lot of cross resistance between ritonavir and indinavir. And for most people it does not look like nelfinavir can rescue people who are highly resistant to other protease inhibitors.
One of the key issues now is whether there is any difference starting with nelfinavir instead of indinavir. There is very little data on that issue. We are very happy to have both drugs available. Both now use three times a day dosing, which is somewhat inconvenient to maintain indefinitely. Both have fairly good data on durable response in ideal situations. Indinavir has impressive clinical data from ACTG 320, and the one and two year data that Roy Gulick presented from their pivotal clinical trial.
But if indinavir fails to keep the virus controlled, how well can you suppress that virus with other treatments? The data from ICAAC overall was worrisome, indicating that this is very difficult to do.
A presentation from St. Vincent's, with a small number of patients, did not show much success in suppressing virus after treatment with nelfinavir had failed. [Abstract LB-5]
In Toronto we presented our data from patients who had been on Agouron-sponsored studies utilizing nelfinavir. We reported, particularly for patients who did not have advanced disease, that even though their virus had broken through to a high level, usually we were able to suppress virus initially with a ritonavir-saquinavir based regimen, and at least some patients look like they are going to have a durable response.
ATN: What are some of the studies needed now?
Dr. Henry: There are appallingly few studies on how to treat people who have developed protease inhibitor resistance. After much hard work the AIDS Clinical Trials Group has a new study, called ACTG 359, for volunteers who have had indinavir failure; this drug is the market leader, and yet this is the first such study looking in an organized manner at people for whom this drug has failed to control the virus.
The data from the Toronto conference (ICAAC) on protease inhibitor failures was largely anecdotal; it is painfully clear that this area has been overlooked for several years now. There has not been enough support from either government or the companies to develop protocols for people whose protease inhibitors have failed, so there is little knowledge on what to recommend for them.
The protease inhibitors are good drugs. But I am not sure that we can tell the average clinician and patient that now is the time to go for broke. We need more studies to look at how to optimize adherence, and we need plans in place for when the recommended therapies fail.
Clinical research in the next several years needs to focus on how we can do better. We need simpler and less expensive medications -- once or twice a day dosing, and a much better safety margin for nonadherence, or for cases of resistance to perhaps one of the drugs. Today that margin is often thin; sometimes you really have just one key drug that you are relying on, a single protease inhibitor or perhaps a non- nucleoside. If something goes wrong with adherence, or if the pharmacokinetics are not ideal, the regimen will likely fail due to viral resistance.
Also, it is hard to know what our absolute target should be for HIV RNA. We have been working with a lab running the Roche Ultrasensitive assay for six months on our patients who are below the limit of the standard Chiron assay. In our clinic population, about 55% of patients at any given time are below the limit of the Chiron test (500 copies). Roughly 25% of our patients are below 50 copies, and maybe 15% are below 20 copies.
Yet our patients are doing very well clinically. So the question is, for all those people who are not at that absolute lower limit, do I need to pour it on? Or should I try basically not to cause damage (with the drugs)? We need studies to address this critical group, people who are doing well clinically, but maybe they are not below a viral cutoff of 20 copies. We would be able to enroll many patients in such studies. Now I do not know the best way to treat them. There are so many unanswered questions. I wish more good studies were available.
1. Haase AT, Henry K, Zupancic M and others, "Quantitative Image Analysis of HIV-1 Infection in Lymphoid Tissue," Science, November 8, 1996, pages 985-989.
Just before the ICAAC conference, Pharmacia & Upjohn completed an interim analysis which showed that the triple combination of delavirdine (Rescriptor®) plus AZT and 3TC more effectively reduced HIV viral load than either AZT plus 3TC, or AZT plus delavirdine.
Following 32 weeks on triple therapy, 50% of patients had a viral load below the detection limit (40 copies, on the research test used in this trial), as compared with 10% of patients on AZT plus 3TC, and none of on AZT plus delavirdine. Patients on triple therapy maintained a 2.0 log drop from baseline after 32 weeks, as compared with 1.3 log drop for patients on AZT/3TC and 0.5 logs for patients on AZT plus delavirdine. The triple combination was significantly better at reducing viral load than either of the two-drug arms, at weeks 8, 12, 16, 24, and 32 (p<.001).
Although patients in the triple therapy arm had a greater increase in CD4 count, this difference was not statistically significant.
The study population consisted of 137 patients per arm, with an average baseline CD4 count of 360 and viral load of 25,000 copies. Participants either were antiretroviral naive (84.7%) or received less than six months of AZT monotherapy. All drugs were given at their standard doses.
Enrollment in the study was ended early due to ethical concerns about the two-drug therapy arms, since current guidelines recommend more intensive antiretrovirals. The study is still ongoing and blinded, but volunteers will be discontinued if their viral load goes over 5,000 copies, or in some cases if it is between 400 and 5000.
Linezolid, New Antibiotic Studied for MRSA, Available for Compassionate Use
by Sharon Anderson
A new drug, linezolid, is currently being studied for a variety of infections, including methicillin resistant Staphylococcus aureus (MRSA), a serious infection in persons with AIDS. The developer, Pharmacia & Upjohn, is making the drug available on a compassionate use basis.
Linezolid belongs to a new class of antibiotics called oxazolidinones with a unique mechanism of action. Laboratory tests have shown that it is active against gram positive bacteria (streptococci, staphylococci, enterococci), including strains resistant to currently available antibiotics.
Linezolid is currently undergoing a phase II clinical trial for the treatment of MRSA. Two posters presented at the recent ICAAC conference in Vancouver [abstracts A-115 and A- 116] showed that both the oral and intravenous forms were "well tolerated." The most commonly observed side effects were tongue discoloration and skin rash.
For more information about the trial or the compassionate use program, call Pharmacia & Upjohn's Medical and Drug Information unit at 800-253-8600, 8 a.m. to 5 p.m. Eastern time.
The conference objectives are "the generation of a document to include guidelines for creating a standard of care of wasting syndrome in HIV disease," and "to evolve a priority list of future directions in HIV/AIDS wasting related research."
The sponsors are the International Foundation for Alternative Research in AIDS (IFARA), Program for Wellness Restoration (PoWeR), and the Florida AIDS Education and Training Center at the University of Miami. Funding is provided by a U.S. Health and Human Services grant, and by several pharmaceutical and nutritional-product companies.
For more information, contact the conference at 954-566-4414 Monday through Friday 9:00 a.m. to 5:00 p.m. Eastern time, or by fax at 954-566-3557, or email firstname.lastname@example.org.
Telephone Conference on Resistance and Cross- Resistance, Nov. 5, 1997
To join the call, you need to register in advance, by calling 800-707-BETA.
Telephone Conference on HIV Treatment Developments, Oct. 30
To register, fax your name, address and phone number (by 5:00 p.m. Pacific time Monday October 27) to: Dave Razavi, Education Coordinator at California Pacific Medical Center, 415-885-8646.
Money, Foundations, and the Public Agenda: Investigative Articles Available
by John S. James
The October 8 San Francisco Bay Guardian published a 10-article investigative report on the growing influence of secretive foundations on both mainstream and alternative journalism, and on the environmental and energy movements, in the San Francisco area. Although they do not address AIDS, these articles are already important in the San Francisco AIDS community, and they are likely to have lasting influence. While many specifics are different with AIDS, a fundamental issue is the same -- increasing pressures to marginalize community-based, activist, legitimately grassroots organizing, in favor of bureaucracies which often become self-perpetuating, not effectively accountable, and secretive. The end result is ineffective programs, designed by professionals who do not understand the lives of their clients or interact with them as equals, resulting in poor service and loss of public enthusiasm and support.
The Guardian articles describe how many millions of dollars, originally from oil, insurance, and other industries, are funneled secretly to progressive, environmental, or journalist organization which are willing to accept the funders' policy agendas. Those that do not go along are frozen out of access to funding, information, and major media. The basic requirement is that information unfavorable to certain big-business interests is not to be researched or reported in an unbiased manner. Tax-exempt foundations and other organizations are allowed to secretly receive and disburse large amounts of tax-free money, without the public ever knowing where it came from, where it went to, or for what purposes. Unlike traditional foundation giving, this money is used to influence public debate in favor of specific business interests.
The articles are available at: http://www.sfbg.com/News/32/0 2/31anniv.html.
How AIDS Compares
We believe that in AIDS the situation is not as bad, at least not yet. Two important differences:
The danger now is that almost all AIDS treatment information sources receive substantial pharmaceutical-company support. Much good has come from this cooperation; however, its pervasiveness can prevent life-critical issues from gaining the political momentum they otherwise would, when companies which are major financial supporters would be offended.
The bottom line is that the system does not always correct itself. Without an independent activist voice, vital interest of persons with HIV may not be effectively developed or negotiated.
Copyright 1997 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.