Date: Sun, 18 Sep 1994 14:02:53 -0700 From: "John S. James" Subject: AIDS Treatment News #204 /* Written 9:30 PM Aug 4, 1994 by aidsnews in igc:aidstreatment */ /* ---------- "AIDS Treatment News #204" ---------- */ AIDS TREATMENT NEWS Issue #204, August 5, 1994 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: HIV RNA: New Blood Test for Individualized Therapy and Faster Trials Nutrition and AIDS: Interview with Kristin Weaver, Bay Area Nutrition Counseling Center and Clinic (BANC), at San Francisco General Hospital California: MediCal Cut in Monthly Prescription Allowances Starting October 1 Announcements, Notes Kaposi's Sarcoma -- Major Overview Published Interim AIDS Coordinator Announced Medical Marijuana: 89 Percent Support Correction -- Zerit (d4T) Information Number ***** HIV RNA: New Blood Test for Individualized Therapy and Faster Trials by John S. James During the last two years, new blood tests for HIV viral load have increasingly been used in clinical trials and other scientific research. There is great interest among researchers, as the early, preliminary results of major studies are showing that changes in viral load due to change in therapy can predict clinical benefit in patients. Meanwhile, the tests are about to come into use (outside of formal studies) in medical practice for individualizing patient care; the challenge will be learning when to use them and how to interpret the results. But it is widely agreed that a reliable blood test for viral activity in the body -- if it can help predict which drugs will be successful for a particular patient, as these tests do seem to do -- could revolutionize HIV medicine by improving treatment with existing drugs, as well as shortening the time required for new treatments to be proven. We believe that this development is more important than most physicians, treatment activists, or even the scientists working with the tests may realize, for the following reasons: * Existing treatments do seem to work well at certain times for many people. A scientifically validated way to guide each patient to the best treatment for him or her could substantially improve patient care now, without the need to wait for better drugs to become available. * A reliable viral test would enable antiviral drugs -- and even some immune-based and other kinds of therapies to be tested much more rapidly and less expensively than under the current system. This should greatly shorten the time required to make better treatments available. Now it usually takes years, and hundreds (if not thousands) of patients to show that an AIDS treatment improves survival, or reduces the number of opportunistic infections. In contrast, blood tests often show clear results in weeks, and relatively few patients may be enough to produce statistical proof. But first, it must be shown that a decrease in viral load caused by a change in drug therapy indicates a real benefit for the patient. * "Alternative" treatments -- those without a rich, well- connected institution behind them -- could also be tested scientifically, perhaps in small, community-based studies. Those which are worthless can be discarded, and those which are found to be effective can be targeted to the particular patients most likely to benefit. * Similarly, traditional medicines being used around the world in HIV treatment could be screened with these tests, potentially making effective treatment available for the first time for millions of people who cannot obtain high- priced pharmaceuticals. At the same time, validating traditional remedies may provide new options to improve treatment for those who already have access to conventional medical care. * We believe that the biggest obstacle to AIDS treatment development, the major reason it has not been productive, is that the combination of high regulatory hurdles and lack of national will has made it impossible for low-priority treatment ideas, those with only a few champions and little or no industry or government support, to begin to be tested so that they can build credibility if they work. Since most major medical advances start as low-priority ideas, and prove themselves through a series of surprises, the current system -- which limits the field to projects which already have major support -- chokes off the wellspring of innovation, virtually guaranteeing stagnation. This problem does not correct itself, due to peoples' natural tendency to focus on what they already consider important, instead of cultivating development paths for ideas which are currently outside of their understanding and therefore may not appear attractive. Giving the power to determine what works to individual patients and physicians can allow new ideas to proceed, breaking the existing monopoly on drug development and the resulting choke hold on our future. All these benefits depend, of course, on whether what is being measured by the new tests is a useful indicator of how well a treatment is working. It would seem logical that lowering the amount of HIV in the blood would be an improvement. But experts are cautious, because prior viral tests (especially the p24 antigen test) have been too inaccurate to be very useful in drug development. Much remains to be learned; but the information now available is encouraging. Background: What Is HIV RNA? The genetic information for almost all living things is stored in the nucleus of cells, in a chemical called DNA. In the body, the same information in DNA can be transcribed into RNA; then the information in the RNA is translated into proteins, which determine the structure and function of the cell. Retroviruses (such as HIV), however, have their genetic information in RNA. When the virus gets inside a cell, the information is transcribed in reverse into DNA, which then becomes part of the cell's genetic inheritance. The cell can then produce new viruses, or be damaged in various other ways, sometimes producing abnormal cytokines which can cause illness. Each individual HIV virus has two copies of the RNA which specifies its genetic information. The new tests for viral load detect this RNA, and the test results are usually given as number of copies per milliliter of blood plasma. For example, if someone get a test result of 100,000 (a fairly high number), it means they have 100,000 copies of the RNA (or 50,000 virus particles) per milliliter of plasma. What a Blood Test Needs to Do to Be Useful First, of course, any test used in research or in clinical care must be accurate and reliable. Quality assurance is necessary; it can be done by sending known samples to the labs that run the test. The samples are coded so that the labs do not know what is in each; their answers are then compared against the correct values. But also, to be useful for drug development or for individualizing patient care, a test must be validated -- that is, we need to know that what the test measures has clinical usefulness. Different tests are useful for different purposes. For example, the T-helper count (CD4 count) clearly is useful for prognosis -- predicting how an individual patient is likely to do. For example, pneumocystis almost always occurs when the T-helper count is under 200 or 250, and CMV retinitis when the count is under 50. (These numbers are for adults; the numbers for young children are entirely different.) But while the T-helper count clearly provides predictive information, this does not automatically mean that a change in T-helper count caused by a drug will indicate a corresponding change in the prognosis of patients. In fact, the well-known Concorde study of early use of AZT found that those taking the drug had higher average T-helper counts than those who did not, and this difference persisted for the three years of the study; however, for reasons not well understood, it did not make much difference in death rates or other clinical outcomes -- casting doubt on the use of the T- helper count as an early signal of whether a treatment is working. In analyzing a clinical trial where some patients are randomly assigned to one treatment regimen and some to another, it is easy to tell if one treatment raises the T- helper count (or other blood-test result) more than the other. Also, it is statistically straightforward to determine if one treatment group does better than the other. But it takes more complex statistics to tell that the blood test is actually showing that the drug is working -- to rule out the possibility that the drug helps the patient, and also just happens to change the blood test independently. In the latter case, the test could be worthless for indicating in advance whether another drug is also going to work. This means that a trial with clinical endpoints (which may take several years to generate enough deaths or serious illnesses to produce statistical proof that one treatment is better than the other) may be necessary to validate a new blood test. Fortunately, the tests for HIV RNA can be run with frozen blood samples, which have already been saved from past trials, where the outcome for each patient has already been recorded. This retrospective validation is now well underway, and preliminary results from three major trials, presented by different groups at a recent scientific meeting, have suggested that changes in HIV RNA do indeed predict changes in clinical outcome cause by drug treatment. These results are preliminary, and questions remain. [Note: An alternative strategy would be to not wait for the validation step, by making the reasonable presumption that, other things being equal, a low viral load in patients is better than a high viral load. Then a drug which reduced viral load could be considered effective for purposes of approval, unless there was other information which rebutted the presumption; safety, of course, would have to be proven separately, but proof of efficacy, not safety, is the bottleneck in drug development. The benefit of this approach is that small companies would have a chance to develop and market AIDS treatments; and large companies would have the ability and incentive to develop their drugs rapidly. We believe that this strategy would serve the public better than current approaches for discovering and developing better AIDS treatments; but for various reasons it would be difficult to sell politically. What we do unquestionably need is better information on how to use and interpret these tests. There is a danger that future studies will focus too much on definitive academic proof that the tests can be useful -- which we are learning anyway. Instead, they should focus on getting practical information for physicians who are caring for patients.] Testing for HIV RNA -- Two Different Technologies Two completely different methods, quantitative PCR (currently being developed as a standardized test kit by Roche Molecular Systems, Somerville, New Jersey) and branched DNA (developed by Chiron Corporation, Emeryville, California), are now being widely used in research to test for the amount of HIV RNA in blood. A short explanation of how they work appeared in "Better Tests for HIV Activity; Interview with Mark B. Feinberg, M.D., Ph.D., AIDS Treatment News # 186, November 5, 1993. These two different kinds of tests measure the same thing, and usually they give comparable results. But each kind of test has different strengths and weaknesses. At present, the branched DNA test has a cut-off at 10,000 copies of HIV RNA per milliliter; it cannot measure values lower than that. (Soon the cutoff will be reduced to 5,000 copies per milliliter.) The quantitative PCR testing service which is now commercially available through reference laboratories can go down to 200 copies per milliliter. No one yet knows if keeping the counts under 5,000 is good enough for maintaining health; if not, some patients will need to use PCR to track lower counts. On the other hand, the branched DNA test appears to be more consistent than quantitative PCR in measuring different subtypes of HIV (although Roche points out that what matters is change in time within each patient, so this might not be an issue). Which test is more accurate is in dispute. Branched DNA is much easier than PCR to run in the laboratory, which should help to make it more accepted in widespread use. Eventually one of these testing technologies may prove better overall than the other. But at this time, researchers using the tests in clinical trials are about equally interested in both. Regulatory Issues Anyone using HIV RNA tests now, before they are part of standard medical practice, should understand that, because of how medical tests are regulated, both quantitative PCR and branched DNA tests are becoming available to physicians and patients in a test format that does not require FDA approval. Therefore, the customer must be extra careful about getting a good-quality test. In the U.S., medical tests are traditionally regulated in two different ways. Usually, the test is provided in the form of a standardized kit, which contains all the materials and instructions required so that any qualified laboratory can test samples. The FDA must approve such a kit before it can be widely used in the U.S. -- and therefore it takes longer for the standardized test kit to become available for medical practice. But a company can also set up its own sophisticated laboratory, sometimes called a reference laboratory, which can perform the testing service. To offer this service without a kit is much more difficult than running a kit produced by somebody else, since the lab has to buy or make all of the materials itself, check their purity, etc. In this case, the company can offer the test commercially as a service, not a product, and this testing service is not regulated by the FDA. Because FDA approval can take some time, the availability of the standardized kit can be a year or more behind the availability of the same test through a testing service by a reference laboratory. During this time before FDA approval, how can one be confident that the test is accurate? We suggest purchasing the test through the companies which are experts in this area -- Roche Biomedical Laboratories for quantitative PCR, and Chiron Corporation for branched DNA. Other companies can run these tests through various agreements with the patent holder, setting up their own reference laboratories; but then the patent holder does not run these laboratories and cannot guarantee their quality. Both Roche and Chiron have immense investments in their technologies (which not only can test for HIV, but will also have many other uses in medicine); and both know the technologies at least as well as anyone else. They have the incentive and also the means to make sure to have good quality control before offering their tests to physicians. Also, government and other researchers have done considerable work with their tests and would quickly notice any serious problem. These protections are not available if one selects a "brand X" HIV RNA test. And later, even after the FDA-approved kits become available, there will still be concern that the laboratory personnel who run the tests be properly trained, to avoid significant variation due to lack of quality control. The Challenge: Interpreting Test Results When one has one's blood tested for HIV RNA, the result comes back as a number of copies of viral RNA per milliliter; this number can range from a low of 200 to a high of over a million. Sometimes the result will be that the number of copies was below the cut-off for the test -- 200 copies for PCR, 10,000 copies (soon to be 5,000) for branched DNA. A single number is hard to interpret; it is more important to watch how the number changes over time. HIV RNA is a very sensitive measure, and can change considerably in response to many things. Some persons with HIV can have as much as a three-fold variation in the number from day to day, for no known cause; others have less variability. Immune stimulation -- for example, from a flu shot -- can cause a large temporary increase. Because of this variability, a small change -- even a two-fold or three-fold change -- in a single number might not be meaningful. AZT and other approved AIDS treatments often cause a drop of about one log (ten fold) in HIV RNA level; however, this drop is usually not sustained, probably because the virus develop resistance to the drugs. Saquinavir, the experimental Hoffmann-La Roche proteinase (protease) inhibitor, did about the same -- close to a one-log drop, but not sustained. Many researchers believe that, to be a major advance in AIDS treatment, a new drug, combination, or other treatment regimen should produce at least a two-log (100 fold) drop in HIV RNA levels, and that this drop must be sustained -- for many months, hopefully for years. The experimental protease inhibitor now being tested by Merck & Co. has produced a two- log or greater drop in a few patients, but again the decrease was not sustained; within a few months, the HIV RNA levels went back up. (For a look at indications of clinical benefit from even the temporary drop, see "Antivirals and Immune Recovery: Interview with Michael S. Saag, M.D., AIDS Treatment News #200, June 3, 1994.) Since an ideal treatment will be hard to find, we will have to settle for less at first. Perhaps several treatments which each alone have a smaller effect could be combined to give better results. As HIV RNA tests come into wider use, physicians and patients will be trying all kinds of treatment regimens while watching the viral load. This could lead to important advances in the search for better treatments or cures. Still there are questions. The HIV RNA test only tells how much virus is in the blood; it does not tell how pathogenic that virus is. Also, the blood level of the virus might or might not be a good indicator of what is going on elsewhere in the body. Much remains to be learned; but meanwhile, it does seem reasonable to use the level of HIV RNA in the blood to help guide treatment decisions, with the goal of lowering the viral load and keeping it low. The Future The quantitative PCR test for HIV RNA is now available to physicians; in fact, it has been available since late 1993, although this has not been widely known. Chiron has announced that its branched DNA test will be available to physicians starting August 15. A major scientific meeting on these issues -- Surrogate Markers of HIV: Strategies and Issues for Selection and Use -- will be held October 12-14 near Washington D.C.; it is being organized by Cambridge Healthtech Institute, Waltham, Massachusetts. It's conclusions may soon become obsolete, however, as important new data from ongoing trials will become available in the months after the meeting. These new trials, prospectively designed to include testing for HIV RNA (as compared to previously-run trials which fortunately happened to have some frozen blood in storage) are important for various reasons. For example, the old trials did not process the blood properly for the new HIV RNA tests; the tests can still be run, but some of their sensitivity is lost. HIV RNA testing may work even better in ongoing trials, where this is not a problem. A major future regulatory issue is whether HIV RNA will have to be re-validated for each new class of drugs -- requiring a large, long-lasting trial with "clinical endpoints" (death or major opportunistic infections) before the viral load tests would be accepted as proving efficacy of the new drug class. [For example, if the viral load as measured by HIV RNA is shown to predict patient benefit from nucleoside analog treatments (AZT, ddI, etc.), can it then be used similarly for protease inhibitors, or will another major trial be required to validate it for protease inhibitors first?] If the FDA decides that the answer is yes -- and it may be leaning that way at this time -- then the result could be to add years to the development time of every new class of drugs, and create a multimillion dollar disincentive to the development of new kinds of AIDS treatment. How to Order HIV RNA Tests * Quantitative PCR for HIV RNA: Physicians can order this test through Roche Biomedical Laboratories, Research Triangle Park, North Carolina; the customer service number is 800/533- 0567, 8 a.m. - 6 p.m. Monday through Friday, 8 a.m. - noon Saturday, Eastern time. * Branched DNA for HIV RNA: Chiron Corporation will offer this test to the HIV clinician starting August 15, 1994. Sample collection, shipping, and other client services will be handled by Nichols Institute, a commercial laboratory which can serve clients throughout the U.S. Information about this test can be obtained by calling 800/553-5445. Bibliography Note: Recent preliminary information on the validation of HIV RNA (as an indicator of benefit of drug therapy) is not yet public, so it is not described in the references below. Bagnarelli P, Valenza A, Menzo S, and others. Dynamics of molecular parameters of human immunodeficiency virus type 1 activity in vivo. Journal of Virology. April 1994; pages 2495-2502. Dailey P, Lindquist C, Collins M, and others. Detection and quantitation of HIV RNA from lymph node tissue using a branched DNA (bDNA) signal amplification assay (Chiron Quantiplex* HIV-RNA assay). The First National Conference on Human Retroviruses and Related Infections, December 12-16, 1993, Washington, DC [abstract #313]. Detmer J, Collins M, Zayati C, Irvine B, Kolberg J, and Urdea M. Comparative quantification of gold standard HIV-RNA representing subtypes A-E using the Quantiplex* HIV-RNA assay. The First National Conference on Human Retroviruses and Related Infections, December 12-16, 1993, Washington, D.C. [poster #204]. Gupta P, Kokka R, Neuwald P, Kern D, Rinaldo C, and Mellors J. Expression of HIV-1 RNA in plasma correlates with the development of AIDS: A Multicenter AIDS Cohort Study (MACS). Ninth International Conference on AIDS, June 7-11, 1993, Berlin [abstract #2481] Holodniy M, Eastman PS, Mole L, and others. Reduction of plasma HIV viral load during ddI/ZDV combination therapy in the presence of ZDV resistance. The First National Conference on Human Retroviruses and Related Infections, December 12-16, 1993, Washington, D.C. [abstract #9]. Holodniy M, Mole L, Winters M, and Merigan TC. Diurnal and short-term stability of HIV virus load as measured by gene amplification. Journal of Acquired Immune Deficiency Syndromes. April 1994; volume 7, pages 363-368. Mellors J, Kingsley L, Gupta P, and others. Detection of plasma HIV RNA by branched DNA (bDNA) signal amplification predicts early onset of AIDS after seroconversion. The First National Conference on Human Retroviruses and Related Infections, December 12-16, 1993, Washington, D.C. [abstract #274]. Mulder J, McKinney N, Christopherson C, Sninsky J, Greenfield L, and Kwok S. Rapid and simple PCR assay for quantitation of human immunodeficiency virus type 1 RNA in plasma: Application to acute retroviral infection. Journal of Clinical Microbiology. February 1994; pages 292-300. Pachl C, Saxer M, Elbeik T, and others. Quantitation of HIV-1 RNA in plasma using a branched DNA (bDNA) signal amplification assay: Evaluation of specimen collection and stability. The First National Conference on Human Retroviruses and Related Infections, December 12-16, 1993, Washington, D.C. [abstract #312]. Pachl C, Elbeik T, Saxer M, and others. Quantitation of HIV-1 RNA in plasma using a signal amplification branched (bDNA) assay. 93rd General ASM (American Society for Microbiology) Meeting, May 16-20, 1993, Atlanta, GA. Saksela K, Stevens C, Rubinstein P, and Baltimore D. Human immunodeficiency virus type 1 mRNA expression in peripheral blood cells predicts disease progression independently of the numbers of CD4+ lymphocytes. Proceedings of the National Academy of Sciences, USA. February 1994; volume 91, pages 1104-1108. Sninsky JJ and Kwok S. The application of quantitative polymerase chain reaction to therapeutic monitoring. AIDS. 1993; volume 7 (supplement 2), pages 529-534. ***** Nutrition and AIDS: Interview with Kristin Weaver, Bay Area Nutrition Counseling Center and Clinic (BANC), at San Francisco General Hospital by Tadd Tobias and John S. James Kristin Weaver, R.N., M.S.N., C.N.S.N., is the Clinical Research Coordinator and Nursing Director of GI (Gastrointestinal) Nutrition Services at San Francisco General Hospital. We spoke with her recently about the relationship between HIV disease and nutrition. This is part I of the interview. Note: Recently San Francisco General Hospital was rated best in the U.S. for AIDS care, for the fifth year in a row, in a poll of medical professionals conducted by U.S. News and World Report, (published in the July 18, 1994, issue). ATN: You work with both inpatients and outpatients who live with HIV disease. Can you tell us about the GI Services at San Francisco General Hospital and the Bay Area Nutrition Clinic. KW: When I became the Clinical Research Coordinator here at SFGH, the physicians here were doing a lot of procedures for patients with dysphasia, diarrhea and other GI-related symptoms. We did an in-patient chart audit and found approximately 70% of patients had a diet inappropriate for the symptoms they were experiencing. In addition, nutrition was often at the bottom of the list when it came to providing care. We formed a multi-disciplinary team under the auspices of the Division of Gastroenterology, Hepatology, and Clinical Nutrition. The team consists of a GI specialist, pharmacologist, dietitian, and nurse, who work one-on-one with hospitalized patients, to address the specific problems interfering with optimal nutrient intake. But when patients were discharged home, there would be no outpatient followup. It was difficult to have much of an impact in the short time that people were hospitalized; we wanted to expand our work to reach outpatients earlier. That's why we started BANC, which also is a multidisciplinary approach to assessing and addressing the nutritional concerns of people with HIV. In this outpatient clinic, we help to keep people from losing more weight, or help to keep people nutritionally sound and prevent the onset of weight loss. Patients are active participants in their own care at BANC. It's important to reach people early. It is well-documented that during World War II children who were malnourished developed pneumocystis. If you are malnourished, the immune system suffers. If you are sick, your nutritional needs go up overall. Currently 50-60% of all hospital patients are malnourished. Malnutrition leads to increased length of hospitalization due to repeated complications requiring treatment. If almost all HIV-infected people eventually develop malnutrition, one might speculate that malnutrition is a cofactor in increasing health-care costs. ATN: How do you know if people are malnourished? It's subtler than our typical image of an emaciated individual. KW: That's a very good point. One person was admitted to the hospital with cryptococcal meningitis. He looked pretty well buffed -- not like he had missed many meals. But when we looked at his serum albumin and his body composition, he was already mildly malnourished. Many physicians won't address nutrition because, "You look fine -- your weight is stable." But what you can't see from the outside is that there may be changes already occurring with loss of muscle mass; it is being replaced with fat. You may maintain your overall weight, while inside there are changes leading you down the path to malnutrition. In our chart review we found that 34% of patients were already severely malnourished when they were hospitalized with their first AIDS-defining illness, and another 46% were moderately malnourished. It is clear that changes in nutritional status occur during the relatively quiet phase of "just" being HIV- positive. ATN: How can we explain body composition to our readers, and how can people keep an eye on that? Is an expensive test needed, or are there simple ways? KW: Body composition will tell us what lean/fat ratio you have. This reflects your muscle mass and fat pads. Men will have fewer fat pads than women. In simple starvation the body will start breaking down the fat as a source of energy, and then eventually go to the muscle. With AIDS we're seeing the opposite: The body breaks down the muscle and leaves the fat intact until later. So there are metabolic derangements going on that we don't understand well. Eventually in some people, no matter what you do, unless you're on TPN [explained below], the body won't be able to utilize the protein, carbohydrate and fat you're giving it, to put into muscle and fat. ATN: How do health care providers keep an eye on lean body mass? KW: One simple way is to use a small caliper and test 12 different sites on the body--pulling the skin and fat away from the muscle and pinching, and adding all the numbers. Then you look on a chart for age, sex, height, weight, etc., to estimate the percent of body fat for the individual. We use that plus something we call the Futrex, a machine that bounces infrared light off the arm and computes the percent of fat, lean muscle, and water the individual has. ATN: Can you explain more about the nutritional assessment? KW: There are many things to consider. We look at serum albumin -- your protein level. It has many important functions in your body, but the problem of albumin is affected by all kinds of things and may not be accurate. Also, the albumin level measures your nutritional status from three weeks ago. More sensitive indicators include pre- albumin (which indicates nutritional status about three days ago), and transferin, another protein, which is very sensitive; it indicates where you were hours ago with your nutritional status. We also look at triglycerides, cholesterol and zinc. Other information that helps us determine the level of malnutrition is the amount of weight lost over a period of time, and the person's percentage of usual body weight. Getting Help Early ATN: You've said that early, aggressive nutritional intervention can prevent weight loss, increase the function of the gut, reduce the chance for opportunistic infections, enhance response to therapies and improve a person's quality of life and sense of well-being. Can you define "early, aggressive nutritional intervention" a little more? KW: When somebody is first diagnosed as being HIV-positive, they should sit down with a registered dietitian or someone in the nutrition field and ask, where am I now? They should align themselves with a physician and tell the doctor, I want to maintain my weight, I want to keep an eye on this. Then, as soon as they start losing weight, even if there are no other symptoms or obvious causes, go to the doctor or dietitian and ask, "Where am I with my body composition and what do I do now?" Through each change that goes on the person needs to be in touch with a physician or someone who's going to be able to give them some direction. The earlier we can get that weight back up and keep an eye on body composition, the better off we will be in prolonging nutritional status and quality of life. ATN: What can we say to people at an earlier stage now? KW: Align themselves with a registered dietitian, not a nutritionist. A nutritionist is someone who may have gone to school or read books, but has never taken a test to confirm their knowledge. A registered dietitian has had four years of college, and many of them will go an extra year of training, and there is a standard test they have to pass, so you know their knowledge base is probably stronger. Their experience and exposure to different types of patients is much more structured and solid than the nutritionists. The nutritionist may be good, but to get the total picture you should choose a registered dietitian who is familiar with HIV disease or who has worked with oncology patients, because there are many similarities in certain aspects of the nutritional component. People who are still feeling good when they find out they are HIV-positive should talk with a registered dietitian and ask, where am I now? How is my body composition -- what percent fat? Am I overweight or underweight? Dietitians can help with eating more healthy foods. It is recommended that people come back occasionally, perhaps every three months, to check on how things are going. As soon as someone starts to lose weight, they should see the doctor or the dietitian. There may be other things going on at that point, or perhaps they may need to add a liquid supplement. As with any health care provider, find a dietitian you can communicate well with, whom you feel comfortable with. ATN: How does one find a registered dietitian? KW: If you don't have a referral, the American Dietetic Association has a list; or you can look in the yellow pages for a registered dietitian. ATN: Will insurance pay? KW: At this point it's probably an out-of-pocket expense, unless a physician is also seeing the person in the same clinic. There is legislation underway now, though, to put registered dietitians in the category of being licensed practitioners, to facilitate payment by insurance. ATN: What about people who can't afford a dietitian? KW: It's a difficult situation. However, if somebody is hospitalized for some reason, they can ask for a nutrition consult and assessment from a registered dietitian or nutritional team, and have that during their hospitalization. Nutritional Status in HIV Disease ATN: HIV related complications often occur in the lower gastrointestinal tract. Can you explain why this is the case? KW: Immune globulins in the gut -- a kind of antibody called IgA -- normally act at the mucosal layer to protect against invading organisms. When somebody is immunocompromised, the body doesn't produce enough of the antibodies to be protective. This creates open portals of entry in the gut for bacteria, funguses and viruses. Critical care patients get septic because they are not using their gut and they are malnourished; these problems allow the translocation of bacteria, etc., into a person's system. That's why we want to keep the gut functioning as long as possible -- stimulate it and keep those immune globulins and macrophages working, so there isn't the opportunity for pathogens to enter. ATN: What can be said about nutritional status as an indicator for survival? KW: Kotler's research found that when a person is at 66% of their ideal body weight and 54% of their body cell mass, they die. People maintain a certain weight, then develop an opportunistic infection and drop their weight. They may gain weight back, but not quite up to what it was before. Another opportunistic infection will continue the downward spiral. That's why it is important to keep nutrition under control, especially while you are in the hospital. This is one disease where everybody has to be their own advocate; go to the doctor and ask about this drug or that trial, pushing, pushing, pushing. Most doctors consider weight loss and malnutrition inevitable. That's one of the most frustrating things for us -- getting the doctors to buy into the fact that there is a lot we can do. ATN: Please explain how to meet the specialized nutritional needs of persons with mildly to severely symptomatic HIV disease. KW: There are nutritional formulas specifically designed for altered-gut problems. For supplementation people can use nutritional formulas which you can get over-the-counter at pharmacies; they come in cans and are taken orally. More severe clinical situations may require peripheral parenteral nutrition (PPN), or total parenteral nutrition (TPN). These are formulated for individual patients and administered intravenously into the arm (PPN), or with a catheter in the chest (TPN). ATN: Give us some examples of when intravenous feeding is appropriate. KW: PPN is for short-term use because it will irritate the veins fairly quickly; 7-10 days is usually the maximum. We used it on a patient with CMV esophagitis so bad he couldn't swallow his own saliva. It was used as a "bridge" until the CMV treatment could kick in and the patient could swallow again. Then we worked him into an appropriate diet. In a different instance we used TPN for a patient who couldn't eat because of an obstructing lymphoma of the stomach. We put him on TPN for two weeks while he was getting chemotherapy and radiation. The tumor melted, and then we could feed him normally. In another case, there was relentless, severe cryptosporidium diarrhea -- 20 liters of stool per day. The patient would die in days if we didn't do something to put the gut at rest. In the first couple of weeks we used TPN to give the gut a rest. Then we reintroduced food in the form of pure amino acids; the product was Vivonex, a chemically-defined liquid diet very low in fat, to stimulate the gut and some digestive enzymes. Basically, the body doesn't have to do any work, the nutrients just get absorbed across the gut mucosa. It's an easy, sort of passive way to get food into someone. One thing to consider is that people on TPN tend to gain fat weight, while on tube feeding (see below) they tend to gain more lean weight -- we think this is because it's more physiologic to have food going directly into the gut. In the case of TPN, it is important to discuss the rationale for it, as well as end-points for its use, before it is started. We have seen TPN help people "over the hump" and improve their nutritional status. However, its drawbacks include the possibility of infection, metabolic and technical problems, and great expense. ATN: Where can one get more information to help make these decisions? KW: The American Society for Parenteral and Enteral Nutrition (ASPEN) is a multidisciplinary society of physicians, pharmacists, nurses, and dietitians, who are specifically interested in nutrition. They put out guidelines about when TPN should be used, when it would be helpful, when it's not a good idea. What Is Tube Feeding? Tube feeding is a less expensive and more "normal" method of feeding someone than PPN or TPN, because you use the gastrointestinal tract. Tube feeding would be appropriate for someone with a normal stomach and gut function, but who had either dysphagia (difficulty in swallowing) or odynophagia (pain on swallowing). The feeding could be given continuously, or just at night to allow freedom to move about during the day. There is a wide range of formulas and ingredients for tube feeding, for example: (1) intact protein and high fat and carbohydrate; (2) various other forms of protein such as peptides or pure amino acids for compromised gut function; (3) medium chain triglycerides, a form of fat that is easily absorbed; (4) fiber; (5) fish oils, etc. The registered dietitian, working with the physician, can make the best recommendation for each individual. [Part II of this interview will look at liquid nutritional supplements, oral rehydration salts, vitamins, and other topics.] ***** California: MediCal Cut in Monthly Prescription Allowances Starting Oct. 1 by Rae Trewartha The 1994 California State budget once again reduced the prescription allowance for MediCal patients -- starting October, 1 the limit will be six per month without prior approval. In 1977 the previous limit of two prescriptions per month was changed to allow an unlimited number; however, the 1992 California State budget reduced this allowance to ten. But the limit of ten did not come into force until July 1 of this year, when an on-line billing system for pharmacies was set up by MediCal. The new limits could have a serious effect on people with severe illness, including AIDS. Prescriptions over the limit can be requested through a Treatment Authorization Request (TAR), a one-page form which is otherwise used to allow prescriptions of drugs which are not on the MediCal formulary. A doctor or pharmacist can complete a TAR which, if it is granted by the MediCal Field Office, will allow the patient to acquire the drug in 3-5 days (urgent TARs can be phoned or faxed in and should be processed within 24 hours). However, many doctors and pharmacists will not deal with TARs. If their request is refused by MediCal, it can be resubmitted, but this will take another 3-5 days. If you do not obtain approval for the drug in this way, you can apply to your county AIDS Drug Assistance Program (ADAP). If the drug is not available on that program, or if you are refused it, you might ask your physician whether the company who manufactures it has a patient assistance program; for a partial list of available programs see AIDS Treatment News #186, November 5, 1993. San Francisco is trying to set up a system to automatically refer rejected MediCal requests to the county ADAP program, which could reimburse the pharmacy. However, only certain pharmacies are enrolled in the ADAP program. Also, this San Francisco proposal has not yet been approved by the state. The ADAP requires that the supply of a drug to a MediCal patient be approved on an annual basis, except where the patient has a higher income than the MediCal limit and is thus required to pay a share of the cost of prescription drugs. For these "share of cost" patients, approval must be applied for on a monthly basis and is based on income. TARs can be also be approved for up to 12 months and, according to Len Terra at the MediCal Benefits Branch, this is the usual case for chronic drugs such as AZT. For other drugs, however, the patient may have to submit a TAR each month, and ADAP will never authorize more than a 30-day supply of a drug at any one time. Len Terra says the MediCal field offices have already experienced an increase in TARs as a result of the ten- prescription limit and they are employing more processors to handle the further increase they expect after October 1. The ADAP also expects a large increase in requests but is confident of being able to handle the paperwork involved. Money to fund ADAP, though, is provided by each county and there is concern that there will not be enough funding to cover what is expected to be a large increase in demand for medications. MediCal patients are now faced with a situation which could endanger their health. Many people with AIDS are taking more than six drugs, and it is not certain that they will obtain the necessary TARs to keep up all their treatments. Ed Miller, at Castro Village Pharmacy in San Francisco, suggests that if you are prescribed more than six drugs, you could ask your doctor or pharmacist to apply for TARs for the drugs you are taking chronically, as these are likely to be approved for a year and save you the trouble and worry of having to apply each month. Also, note that MediCal allows medications (apart from three or four abusable-type drugs) to be dispensed in amounts up to 100 days' supply; if your doctor thinks you are likely to need a drug for this length of time, he or she should prescribe it in this amount. Then you could get another drug on your allowance of six, for the next two months. MediCal patients need to make sure their doctors and pharmacists are aware of the new regulations, and that they are willing to help them obtain the medications they need. People we spoke to were still unsure how the regulations would be imposed, and how difficult it will be for patients to get TARs approved. As we went to press, however, the Department of Health Services scheduled a meeting to discuss the possibility of exemptions for people with AIDS. We will inform you of the outcome. ***** Announcements, Notes ** Kaposi's Sarcoma -- Major Overview Published The KS Project Report: Current Issues in Research & Treatment of Kaposi's Sarcoma, an 85-page report by Michael Marco with Marty Majchrowicz, covers all aspects of conventional treatments, experimental treatments, epidemiology, pathogenesis, and research -- what is being done in KS research, and how its funding and organization need to be improved. The authors are treatment activists who had assistance from leading oncologists; they also interviewed 25 oncologists, dermatologists, radiation oncologists, primary care physicians, and laboratory workers who have extensive experience with AIDS-related KS. The information is very current, as the report was completed rapidly and published in late July 1994 by the Treatment Action Group (TAG). Copies are available from TAG, 147 2nd Ave., Suite 601, New York, NY 10003, 212/260-0300. A $10 donation is requested to help cover cost, but no one will be denied the report for lack of funds. ** Interim AIDS Coordinator Announced On August 2, Patricia S. Fleming was appointed interim AIDS coordinator by President Clinton. Ms. Fleming is currently special assistant to Health and Human Services Secretary Donna E. Shalala. She previously served as administrative assistant to the late Ted Weiss (D-NY), specializing in AIDS and public health issues. According to an August 2 press release from the White House, Fleming "said she expects the interim appointment will last less than two months and that she is not a candidate for the permanent appointment." ** Medical Marijuana: 89 Percent Support An informal telephone poll of over 50,000 people, conducted by Parade Magazine and published in the July 31 issue, found that 89 percent believed that marijuana should be legal for medicinal purposes. This was not a scientific poll which selected people randomly, but consisted of callers who responded to the June 12 Parade Magazine cover article, "Should Marijuana Be Legal?" (It may be no less important as a measure of public opinion, however, because it counted people who cared enough about the issue to take the action of calling in.) For more information on medical marijuana, contact the Alliance for Cannabis Therapeutics, P.O. Box 21210, Kalorama Station, Washington, DC 20009, 202/483-8595. ** Correction -- Zerit (d4T) Information Number AIDS Treatment News #203 gave an information number for physicians to call to obtain information about enrolling patients in the parallel track program for access to d4T, which is continuing for a short time, despite approval of the drug, because of a delay in availability of commercial drug supplies. Due to a typographical error, the phone number we published was incorrect. The correct number is 800/842-8036. [Note: The latest information from Bristol-Myers Squibb is that Zerit may be available in pharmacies starting the second week in August. In that case, new enrollment in the parallel- track program will probably close later in August, with those in the program continuing to receive the drug for about one month after new enrollment closes.] ***** AIDS TREATMENT NEWS Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews.igc.apc.org Editor and Publisher: John S. James Reader Services and Business: Thom Fontaine Tadd Tobias Rae Trewartha Statement of Purpose: AIDS Treatment News reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U.S. funds: personal check or bank draft, international postal money order, or travelers checks. VISA, Mastercard, and purchase orders also accepted. ISSN # 1052-4207 Copyright 1994 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.