AIDS Treatment News
Fifty Volunteer for Live-Vaccine Trial
by John S. James
More than 50 individuals, 40 of them physicians, have
volunteered for a live-vaccine human safety trial using
weakened HIV, which has its nef gene and other genes deleted.
Vaccines containing live but attenuated viruses are commonly
used to protect against other diseases (polio, for example),
but HIV presents additional problems, because it is a
retrovirus which integrates its genetic information into the
human DNA, and because it causes an infection that is not
ordinarily self-limiting in the body. Some researchers
believe that much more laboratory and animal studies must be
done before a live HIV vaccine is ready for human testing.
A current proposal, put together primarily by Charles Farthing, M.D., medical director of the AIDS Healthcare Foundation in Los Angeles, and Gordon Nary and Jose Zuniga, executive director and deputy executive director of the International Association of Physicians in AIDS Care (IAPAC), calls for a first human safety test on five to ten HIV- negative physician volunteers, which could take place in about two years. The group plans to seek FDA approval, and is discussing its plans with vaccine experts at the U.S. National Institutes of Health.
A similar vaccine has successfully protected rhesus monkeys against SIV, a virus which is very similar to the human virus HIV-2. And about 14 years ago, before there were HIV tests for the blood supply, six people in Australia were given transfusions from a donor with a naturally occurring strain of attenuated HIV; they became infected but remain healthy. No one knows if they have become protected against HIV; but there is no evidence today that anyone has become infected with a second strain of HIV after a first strain has become established.
The current research plan is to conduct the first vaccine trial in several volunteers; if all of them remain well and with a very low viral load for six months, the trial would be expanded to 50. If everything continues to go well after another six months, then placebo-controlled trials could be started in very high risk populations in the U.S. and other countries.
For us the bottom line is that more than 8,000 people become infected with HIV every day -- while vaccine development is largely stalled by the lack of commercial incentives, and the great difficulty of definitively ruling out long-term risk, or of proving efficacy. The only way to know if the proposed approach will work is to try it. The other choice, to wait and proceed cautiously step by step, will almost certainly lead to a far greater worldwide disaster than has occurred already.
The two years from now until the first planned human trial with a live vaccine should be enough to answer many of the safety and scientific questions. By focusing the discussion and research, this project could led to a major advance in HIV vaccine development even before the first human test occurs.
37th ICAAC Conference, Toronto, Sept. 28 - Oct. 1
The Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), an annual meeting in the U.S. or Canada sponsored by the American Society for Microbiology, focuses primarily on new antibiotics, but is also a major forum for reporting AIDS research results -- especially in years like this one when the International Conference on AIDS is not being held. This year's ICAAC will be held in Toronto, Ontario, September 28 through October 1.
AIDS Treatment News decided to cover ICAAC in our next issue, and distribute this issue early, before leaving for Toronto; the alternative would have been to delay this issue and rush our ICAAC coverage. Meanwhile, you can find ICAAC information on the Web, including:
Unused Drugs Sought for Donation Abroad
by John S. James
Several nonprofit organizations are collecting unused AIDS
and other medicines (not including controlled substances like
narcotics) for free distribution abroad to people who
otherwise could not afford them. Here are three organizations
we have heard from recently. All happen to be located in New
York City, but they can receive unused drugs by mail.
Everyone knows that there will never be enough discarded medications to provide access to modern medical care to the 90 percent of the world's people who do not have it now. But these projects can help many people, and also provide a practical way to take the first steps to focusing on the problem.
Clearly there will not be a single answer to medical care in the developing world. But there are many approaches that make sense now. The most important medications are usually inexpensive, because they are old drugs which are no longer patented. Some proprietary drugs are manufactured without permission in developing countries, although under the GATT (Global Agreement on Tariffs and Trade) this is supposed to stop in several years. Often the most cost-effective health measures are not drugs at all, but clean water and improved nutrition. And in some cases it may be most effective to finance the scientific testing and development of inexpensive treatments, including traditional remedies.
One area that needs more attention is institutional obstacles to negotiating lower prices for government health programs that cannot afford U.S./European rates. Unfortunately some companies are setting global prices -- ruling out 90% of the potential users of their drugs -- apparently because they fear development of a black market. But this risk is limited, because most of the expensive drugs are paid for by major government or private health plans, which cannot institutionalize a black-market supply.
"Best Price" and "Most Favored Customer" Problems
U.S. government policies may unintentionally create another barrier to treatment access in certain countries -- those with government health plans which could afford to pay more than the cost of manufacturing a drug (allowing for profitable sales), although not enough to cover the full "first world" costs for gold-plated drug development and marketing (and also for gold-plated waste and corruption).
Some government purchasing regulations require discounts based on the lowest price a company charges anyone for its drug (for example, Medicaid requires the "best price," and the Veterans Administration requires "most favored customer" pricing). Large private organizations like HMOs can also have such terms in their contracts. These contractual clauses, sometimes also in government regulations or laws, prevent pharmaceutical companies from giving deeper discounts to others even if they want to, because if they did, the government or other purchasers could demand the same price, and the company would have to sell most or all of its product at a price too low for it to survive.
If these clauses apply abroad as they do within the U.S. -- which is likely, although AIDS Treatment News could not confirm that they do by press time -- they would make it impossible for companies to sell proprietary pharmaceuticals to countries like Costa Rica or Thailand at prices allowing general use there, even when the sales themselves would have been profitable for the companies.
Research and activism are needed to make sure that such acquisition policies -- intended to assure that ostensible discounts to U.S. taxpayers are real -- do not also have an accidental consequence of denying medicine to millions of people around the world.
Pregnant Women Eligible for Single-Dose Nevirapine Study
by John S. James
A government study will test a single dose of nevirapine
(VIRAMUNE(R)) given during labor, and a single dose given to
the infant between 48 and 72 hours after birth, to help
prevent mother-to-infant transmission of HIV. This is a
placebo study, but it allows other antiretrovirals to be used
in addition; therefore it is essential that women not rely on
this trial for treatment to prevent HIV transmission, but
obtain standard medical care as well.
The dose of nevirapine is 200 mg for the women, and 2 mg/kg for the infant. Mothers and infants will be assigned to the same treatment arm (meaning that either both will receive the drug, or both will receive the placebo). There are no CD4 or viral load requirements for entry; women must not have previously used nevirapine or delavirdine, but nucleoside analogs or protease inhibitors are OK. Eight hundred women are being sought for this study, and 100 are already enrolled.
The trial, called ACTG 316, is sponsored by the AIDS Clinical Trials Group of the U.S. National Institute of Allergy and Infectious Diseases, with the drug being donated by Boehringer Ingelheim Pharmaceuticals, Inc. It is being conducted in the following cities: Albany, NY; Birmingham, AL; Bronx, NY; Durham, NC; Jacksonville, FL; Long Beach, CA; Los Angeles, CA; New Orleans, LA (2 sites); New York City, NY; Newark, NJ; San Diego, CA; San Francisco (2 sites); San Juan, PR; Washington DC; Worcester, MA
For more information, call the AIDS Clinical Trials Information Service, 800-TRIALS-A.
Nevirapine is very effective against HIV. In long-term use it must be part of a combination treatment, because otherwise viral resistance develops quickly. This is unlikely to be a problem with a single dose.
If this trial is successful, it could provide an easier, safer, and less expensive treatment than the AZT regimen which is now standard for reducing mother-to-infant transmission. It could also show whether or not the two treatments together are more effective than the AZT treatment alone.
ADAP, Research, and Prevention Funding, and Needle Exchange
Facing Decisions Now in Congress:
As this issue goes to press on September 26, Congress is
about to take final action on AIDS funding for fiscal year
1998, and on a House amendment to ban Federal funding of
needle exchange programs. The decisions will be made by a
Conference Committee, which has been appointed to reconcile
the different provisions of the Senate and House bills. Calls
are important, especially if you live in Pennsylvania, or
anywhere in the following states: Arkansas, Hawaii, Idaho,
Iowa, Mississippi, Missouri, Nevada, New Hampshire, North
Carolina, South Carolina, Texas, Washington, Wisconsin; or in
certain Congressional districts in other states.
Funding for ADAP (AIDS Drug Assistance Program) is especially critical. Arizona announced that it will stop providing protease inhibitors on November 1 due to lack of funds; at least 10 other states have capped enrollment in ADAP (meaning that qualified people cannot enter the program after a certain number have enrolled), or have waiting lists. Many other states have capped access to protease inhibitors, used medical criteria that contradict the Federal guidelines on HIV treatment, or otherwise limited their ADAP programs.
AIDS organizations are seeking the higher of the different funding levels voted by the House and by the Senate -- for ADAP, for other services of the Ryan White program, for prevention, and for AIDS research. (This year the House was more generous than the Senate in funding AIDS overall, but not on all programs; also, the House bill contains the ban on Federal funding of needle exchange, while the Senate bill does not.
AIDS Action Council in Washington D.C. distributed talking points to use in calling your representatives.
"Now is not the time to retreat from our battle against the epidemic. We are just beginning to see real hope in improving the quality and length of life of people living with HIV/AIDS.
"Funding increases are needed for all AIDS programs. Successfully attacking the HIV/AIDS epidemic in our nation requires a commitment to a full-scale approach, which includes funding for prevention, research, housing and care, including the AIDS Drug Assistance Program.
"The medical care, enabling social services, and health care professional training provided through the Ryan White CARE Act are critical to ensuring the success of any new drug therapies.
"Absent a vaccine, our only hope of halting HIV transmission is through comprehensive, community-based, targeted HIV prevention programs funded by CDC [U.S. Centers for Disease Control and Prevention].
"A strong AIDS research effort, coordinated through the Office of AIDS Research, has led to the development of powerful new treatments for HIV and has made significant contributions to other biomedical research.
"Science should drive policy, not politics. Syringe exchange programs reduce HIV transmission and do not increase injection use. Legislation limiting the ability of local agencies to operate syringe exchange programs presents a serious obstacle to containing the virus. The American Medical Association, American Bar Association, and the U.S. Conference of Mayors all support these programs."
You can contact either of your Senators, or your Representative, through the Capitol Switchboard, 202-224- 3121.
For the most recent information, either (1) call the AIDS Action Council, 202-986-1300, press '4' for the Community Outreach department; or (2) call Project Inform, 415-558- 8669, and ask for Ryan Clary of the Treatment Action Network at ext. 225 -- or check the Treatment Action Network section of the Project Inform Web site at http://www.projinf.org
Poppers (Nitrite Inhalants) and HIV: Immunosuppression, Seroconversion, Unsafe Sex, prepared by Hank Wilson of ACT UP/Golden Gate, lists over 50 major references on health effects of nitrite inhalants. The original "poppers" were banned by Federal law, but suppliers substituted new chemicals to get around the law, with unknown health effects -- and still sell bottles in gay bars and sex clubs, for ostensible uses like cleaning video recorder heads.
The references are annotated with short quotes from the published articles.
Copies are available from ACT UP/Golden Gate, 1651 Market St. #303, San Francisco, CA 94103, 415-864-0738. A donation of at least $2 is requested to help with printing and mailing costs.
HMOs and Quality Care for HIV
Interview with Stephen
Part I of this interview (in AIDS Treatment News #278) looked
at managed care and maintaining medical standards for serious
illnesses like HIV. Part II examines the development of the
HIV treatment protocols used by Brown & Toland, the largest
IPA in San Francisco -- and the quality and economic outcomes
of care by HIV-experienced physicians.
Until recently, medical care was usually provided on a fee- for-service basis, with doctors or medical groups being paid separately for each visit or procedure; the more treatment they did, the more they were paid. Managed care uses a different payment system, called capitation, with doctors or medical groups being paid a fixed amount per month per patient, no matter what their care actually costs. Since each treatment prescribed takes money from the bottom line, the incentive to treat more was replaced by an incentive to treat less. Managed care is controlling medical costs; but a central challenge now is how to make it work properly for patients with HIV or other serious and expensive illnesses.
AIDS Treatment News: How did the Brown & Toland HIV treatment program develop?
Dr. Becker: At California Pacific Medical Group (which recently merged to form Brown & Toland), we were looking at a high prevalence of HIV disease in San Francisco, and a high prevalence of HIV-infected individuals in our contracted health plans. So in 1993 we were asking how we would manage what was a growing HMO population of HIV-infected individuals. The issues of quality were very important, the cost was very high, and we were concerned about patient satisfaction and physician burn-out. How were we going to deal with the pressures in a responsible fashion?
A number of physicians got together: myself, Robert Bolan, Jeremy Berge, Lawrence Goldyn, and Alison LaVoy. I assembled this group because we were among the more active HIV doctors who had a fair number of HMO or managed-care patients. There was nothing special about the group; it just seemed like a good place to start.
We decided to build an intervention program based on two overall concepts. One, we would insist that care be given by an HIV-expert physician. Two, we were going to include a care manager. "Care manager" is a term we originated, which has now been taken over by the HMO industry, so everybody is called a care manager. It is different from a case manager, which had the implication of somebody saying "No" to you. The care manager is an HIV-experienced field nurse, who has additional training and understands case management, managed care, and home health.
We looked at different models. A couple companies had services like this; the best known was Clinical Partners. We did not like that model, and developed a model with the company then known as Homedco, which later became Apria Health Care. So our medical group went into a joint venture with Homedco-Apria, who provided the care managers; our medical group provided the doctors, and we built an intervention program based around teaming up the care manager and the HIV doc. Patients would be jointly managed in many respects by the care manager and the physician.
In the beginning it was clear how poorly coordinated the HIV services were. For example, case managers; if you were an HIV-infected patient in an HMO, you often had a case manager who would call you up and not do very much. The medical group had a case manager, who also didn't do very much. If you came into the hospital, there was a case manager there. If you went to the skilled nursing facility, there was a case manager there. If you went on to a hospice, there was a case manager there. So there could be five case managers for one patient. They all took one piece of the patient, but nobody took the whole. We said, get rid of all these case managers. We are going to have one manager; they will know the patient from early on, and follow them through the spectrum of their illness, regardless of the site of their care. We teamed the physician and care manager with a social worker, a nutritionist, and a pharmacist.
We built this model around certain protocols we developed; for example, how do you treat CMV disease? How to tell when somebody should be given that second or third round of anti- lymphoma treatment? Are there predictors that a patient will not do well? How did we decide who needed hospice? Why do some physicians throw drugs after drugs after drugs in patients who are dying, and others can pull back and talk to the patient about what is the best quality of life? We analyzed what our approaches were and came to a certain level of consensus.
We talked through these and came up with a series of protocols. We enrolled a hundred patients in a pilot program; we found it worked very well. The doctors were happy, the patients were happy. We found that our quality was much better, and we found that our economic utilization was better. So we expanded the program, and brought in more of the doctors with many HIV patients.
With managed care, it is not enough to be just a good doctor; you must be a good doctor, and also do it in an economical fashion.
In the fee-for-service system, it was to the doctor's or the medical group's advantage to see the patients very frequently; the industry term is "churning." Historically, it does not matter what specialty, when doctors are paid fee for service, they see patients more often. When doctors have procedures to do and they are paid separately to do those procedures, they do more of them -- including, several years ago, HIV-related infusions. Many HIV doctors gave lots of infusions in those years; they would do infusions in their office, where they could charge a lot, instead of doing it at home when it would be safe and more convenient for the patient to do so.
Many patients who are doing well on the current combination regimens do not need to come for visits as often as they did before. I can review their laboratory work -- not T-cells and viral load, but the tests to make sure they are not having adverse effects from the medications. I don't need them here to look at a set of laboratory tests, all of which are OK. I can look at the labs and call the patient. Getting out of the mindset of bringing patients in and churning through visits is part of what managed care brings. You must not push this too much, at the expense of health or safety. But the doctors that didn't get sucked into the churning, doing things just to enrich themselves, are the same good doctors who will not keep patients away because they get more money by doing so.
The Economics of HIV-Experienced Physicians
Dr. Becker: Bed days per thousand is an HMO industry measure. It is the number of hospital bed days per one thousand enrolled patients. For a "commercial" population (people between the age of 1 year and Medicare eligibility), the number of bed days per thousand should be about 150 to 180. In 1994 our program used about 2000 bed days per 1000 enrollees. In 1995 it was 1700; we were beginning to do more treatment out of the hospital. Then starting in late 1995 and into 1996 we had a big decrease, 1700 down to about 1200. Our experience is similar to what Peter Ruane in Los Angeles presented at the Retroviruses conference earlier this year; Gabe Torres published similar data from experience in New York. In the first part of 1997 the figure is down even further, to about 600 to 700 bed days per thousand.
But if you break down our data by physician experience, you can see that for the less experienced physicians, bed days per thousand changed very little from 1995 to 1996. The huge fall in the bed days is actually from the HIV-expert physicians, who had about a two-thirds drop. They had 591 bed days per thousand; but the non-HIV-expert physicians, whose patients were not enrolled in our intervention program, had about 1500 bed-days per thousand. So there is almost a three- fold difference between these two groups. We are preparing these results for publication. It is important to understand that you can do this within managed care, while absolutely maintaining the quality of care.
I believe some of the differences are because we are using opportunistic infection prophylaxis better. We know from a study we did a year before that 100% of our patients who should have been on PCP prophylaxis were on it, while only 50% of patients managed by a non-expert HIV physicians in San Francisco in 1995 were receiving PCP prophylaxis. Ninety six percent of our patients received appropriate MAI prophylaxis, vs. 9% of the patients of the non-expert physicians. We used antiretroviral combinations earlier, we started using protease inhibitors earlier, our knowledge of natural history is better.
And I think we are better about planning for terminal care when necessary. In that 1995 study, we looked at the percentage of patients with CD4 counts below 200, who had a durable power of attorney for health affairs included in their charts. It was one sixth the number with the less experienced physicians than with the experienced physician group. We studied many other differences as well. With the exception of treatments like infusion -- our program's doctors used more infusions, because they had sicker patients -- the less experienced doctors actually used more services.
A number of people have published on the superior quality of care outcomes from the expert vs. the non-expert physician; we found that as well in our analyses at Brown & Toland. But this is the first time to my knowledge that anybody has been able to demonstrate superior resource utilization among an HIV-experienced physician group.
The audience that needs to know this is the managed-care companies, the IPA executives, the people who are in a position to insist that HIV-infected patients be seen by expert doctors. For whatever reasons, there are many patients who do not come to the acknowledged HIV experts -- who stay with their doc of ten or 15 years because they have a good relationship, even when that physician may not know enough about HIV.
Managed care permitted the development of this kind of HIV intervention program; these figures provide an evaluation. We have the evidence now at Brown & Toland, where HIV is acknowledged as an area deserving much attention in managed care. It is an integral part of every contract that Brown & Toland negotiates with every health plan, that there be specific carve-outs, or provisions, for HIV, in some fashion or another.
ATN: That would include expert physicians, and allowing them to do certain things, like double protease?
DR. Becker: Right.
ATN: To what extent has Brown & Toland achieved this with all the insurance companies it is negotiating with?
DR. Becker: Not all, but most of them. Brown & Toland is a big entity -- it is like the elephant that can sit anywhere it wants. It is hard for the insurance companies, if they want to be in the San Francisco market, not to deal with Brown & Toland. Because of its size, it has a lot of weight, and can say that there are certain standards we must have.
It also helped that this is San Francisco, and the advocacy community is as potent as it is. Kaiser has an HIV advisory board, and HealthNet does, and PacifiCare does; that is an acknowledgment of the strength of the community, and the role the community can play in developing policy.
It is not that I am advocate for managed care. Managed care is here, and is not going away. I think that the community, including patients and doctors, have one of two ways they can go with it. They can flail against it, but it will not go away, or they can try to force it to work as responsibly as it possibly can. We have been successful because we have a big medical group, and we have a number of doctors who have been insistent on making sure that the quality is high.
I spoke to Susan Dooha, of Gay Men's Health Crisis -- she was very concerned, because in many parts of the country, where the doctors are not organized into large medical groups, they do not have the negotiating power, the club if you will, to bang the insurance companies. They have not been able to negotiate good contracts, they cannot get the expert doctors on the panels, and the formularies have been restrictive. That has not been our experience here, but it certainly has happened elsewhere.
I hope that the San Francisco experience can be a model for other communities as well. I hope too that success with HIV in managed care can be translated to other serious and chronic illnesses. The strength of a collaborative physician and patient organization, one that at a minimum is created on a regional basis, may be the most effective means of assuring quality care for those with HIV. The national networks of HIV/AIDS providers now forming hold potential to ensure that such quality exists.
ISSN # 1052-4207
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.