Subject: BETA (Bulletin/Experimental Treatments/AIDS) Date: Nov 1988 2218 lines &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Bulletin of Experimental Treatments for AIDS &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& This display has 2218 lines. You can't back up, it has to come in sequence. B-E-T-A (Bulletin of Experimental Treatments for AIDS) A publication of the San Francisco AIDS Foundation -- November 1988 Table of Contents Antivirals for HIV Infection How Do Antiviral Drugs Work? What is an "Effective" Antiviral? Which Tests Can Help an Individual Decide Whether or Not to Use an Antiviral? Availability of Antivirals Insurance Dextran Sulfate Iscador AL721 Ribavirin Carrisyn BHT (Butylated hydroxytoluene) CD4 and CD4-Pseudomonas exotoxin Rifabutin Foscarnet (trisodium phosphonoformate) Alpha Interferon Beta Interferon Tumor Necrosis Factor (TNF) and Gamma Interferon Peptide-T Bile Salts ddC (Dideoxycytidine) AZT Update AZT Dosage Rare HIV Rebound Effect Dose Reduction of AZT Acyclovir and AZT AZT and Vitamin B12 AZT and Cryptosporidiosis AZT and Toxoplasmosis AZT and Kaposi's Sarcoma (KS) AZT and Muscle Toxicity AZT and Children A Proposed Prophylactic Treatment for MAI The Polymerase Chain Reaction (PCR) Test Summary Chart of Antivirals AZT Dextran sulfate Iscador AL721 Ribavirin Carrisyn BHT CD4 CD4-Pseudomonas exotoxin Rifabutin Foscarnet (trisodium phosphonoformate) ddC Alpha Interferon Beta Interferon Gamma Interferon & Tumor Necrosis Factor (TNF) Glossary References Community Research Alliance in San Francisco Next Issue Statement of Purpose --------------------------------------------------------------- (Words followed by an asterisk (*) are defined in the Glossary.) --------------------------------------------------------------- NOTICE The information in BETA does not imply a recommendation of any action or treatment by the San Francisco Department of Public Health or the San Francisco AIDS Foundation. Always consult with an AIDS-knowledgeable physician before using any drug. If you are looking for a physician, or want more information about AIDS, call the bilingual English/Spanish AIDS Foundation Hotline: (415-863-AIDS), 800-FOR-AIDS in Northern CA, or 415-864-6606 for TDD service. *************************************************************** ANTIVIRALS FOR HIV INFECTION by Jim Palazzolo and Ron Baker This issue of BETA discusses sixteen possible antiviral treatments for HIV infection and includes an update on AZT studies. We have given special attention to AZT, dextran sulfate, Iscador, AL721, ribavirin, carrisyn and BHT because these substances are currently available to people considering antiviral treatments for HIV. We also review CD4, CD4-Pseudomonas exotoxin, rifabutin, foscarnet, ddC, tumor necrosis factor, the interferons and peptide-T: these antiviral therapies are available only to people enrolled in clinical trials. Before discussing these experimental treatments in detail, we consider some general questions: (1) How do antivirals work against HIV? (2) What are the characteristics of an "effective" antiviral treatment? (3) Which tests can help an individual decide whether or not to start an antiviral therapy? We also discuss the availability of antivirals and insurance issues. How do antiviral drugs work? An antiviral drug interferes with the life cycle of a virus. Antiviral drugs for HIV can work at several points in the life cycle of the virus. An antiviral may prevent HIV from entering a cell by changing the cell membrane* or the envelope of the virus. Others may inhibit viral proteins* such as reverse transcriptase* and stop the production and integration* of viral DNA* into an infected cell. Some antivirals can block this viral DNA from forming new viruses. Others block the budding of new viruses from infected cells. What is an "effective" antiviral? There are several things to look for when considering an antiviral treatment for HIV infection: (1) Does the antiviral treatment cross the blood-brain barrier*? Unless the treatment can inhibit replication of HIV in the brain, HIV-infected individuals may develop dementia*. Several antivirals reviewed in this issue of BETA can cross the blood-brain barrier. However, AZT is the only antiviral proven effective by clinical trials in stopping HIV replication in the brain and in treating AIDS-related dementia. Further research will be necessary to find out whether or not other antivirals can stop HIV replication in the brain. (2) Does the antiviral stop HIV infection between macrophages? A macrophage is a type of white blood cell which appears to be a reservoir for HIV replication. HIV does not kill macrophages, but interferes with their important function as "scavenger" cells for the immune system. Macrophages can carry HIV to other cells throughout the body. HIV-infected macrophages may play a role in AIDS dementia. However Gendelman of Walter Reed Hospital has found that HIV- infected macrophages release a substance that kills brain cells. [1] To be effective, an antiviral must block HIV infection in macrophages. Researchers disagree about whether AZT does this. According to Samuel Broder of the National Cancer Institute, "You cannot necessarily assume a drug [such as AZT] that works against HIV in T-helper cells will work against the virus in macrophages." Carlo Perno (National Cancer Institute) believes AZT is effective in stopping HIV replication in macrophages. [2] In test tube studies, dextran sulfate also blocks HIV infection between macrophages, although it is currently unknown if this occurs in humans taking the drug orally. [3] (3) Does the antiviral block syncytia formation? Syncytia formation is a mass of cells fused together to form one "giant cell. This action causes direct cell-to-cell infection. In laboratory studies AZT does not stop syncytia formation; dextran sulfate, however, does prevent syncytia formation. [4] Which tests can help an individual decide whether or not to use an antiviral? Researchers believe that several tests can be useful in predicting the progression of HIV infection: the p24 antigen test, the total number and percentage of T-helper cells, and the beta-2 microglobulin test. These tests can also help individuals and their physicians decide whether or not to start antiviral therapy. They may also be useful in evaluating the success of a treatment. The p24 antigen test measures the amount of p24 core protein circulating in the blood. A positive p24 test result suggests HIV replication. The test also measures the amount of p24 antigen, but there seems to be no correlation between higher amounts of p24 antigen and faster progression to AIDS. [5] In the S.F. General cohort study, 59% of asymptomatic seropositives testing positive for the p24 antigen developed AIDS within three years and only 7% of those testing negative progressed to AIDS in the same period. Of those testing positive, however, 41% did not develop AIDS in three years. This indicates the p24 antigen test is not 100% accurate in predicting progression to AIDS. Other tests should be used in conjunction with the p24 antigen test to evaluate whether to begin an antiviral therapy for HIV infection. The total number and percentage of T-helper cells is also important in deciding whether to start antiviral therapy. The normal number of T-helper cells is between 480 and 1800. The median in HIV-negative individuals is approximately 850. Rapid rates of decline in T-helper cell numbers in HIV-infected individuals indicate destruction of these cells. T-helper cells should be monitored every few months in individuals infected with HIV. People with a rapidly falling number of T-helper cells or a count below 400 should seriously consider using antiviral therapy. Beta-2 microglobulin is a protein on cell surfaces. Increased amounts of this protein may indicate replication of HIV or CMV*. In one study, the level of this protein was found to be the best predictor of progression to full-blown AIDS in HIV- infected individuals. Beta-2 microglobulin is measured in milligrams per liter of blood. Below 3 mg per liter of blood is considered normal in healthy individuals. When beta-2 microglobulin rises above 3 mg per liter of blood, then there is greater risk of disease progression. The greatest risk for progression is above 5 mg per liter. In one study, 69% of those with greater than 5 developed AIDS in 3 years. Of those with between 3 and 5, 37% developed AIDS in 3 years. Beta-2 microglobulin may also be an indicator of macrophage infection as well as T-helper cell involvement in HIV infection. For this reason, the test "may be a better predictor of progression than the T-helper cell count." [6] Individuals using these tests should not rely on any single one, but instead should have an AIDS-knowledgeable physician monitor several of these indicators at the same time. Many physicians advise HIV-infected individuals to take these tests every three to six months. Individuals and physicians ordering these tests should be aware that test results may vary widely according to the laboratory that performs the tests. Furthermore, because these indicators are not 100% accurate in predicting progression to AIDS, individuals should not feel terrorized by low T-helper counts or a positive p24 antigen test result. Availability of Antivirals AZT is the only FDA-approved antiviral and the only one with demonstrated clinical efficacy for HIV infection. The June 1988 issue of BETA covers AZT in depth. An update on the drug is included in this issue. AZT is readily available for those who can afford it. Other less expensive antivirals are also available. Dextran sulfate can be purchased without a prescription in Japan. One can buy ribavirin without a prescription in Mexico. Iscador is available through the mail from Switzerland with a prescription from a physician. AL721, dextran sulfate, carrisyn and BHT can be purchased through local buyers' clubs, such as The Healing Alternatives Foundation in San Francisco (415-626-2316). Other experimental antivirals discussed in this issue of BETA are in various stages of pre-clinical and clinical testing. Pre-clinical testing includes test tube studies to prove that a treatment looks promising, and animal studies to establish its safety. After the pre-clinical testing is finished, the results are submitted to the FDA. If the agency has no objections, it gives the drug an Investigational New Drug (IND) status. Following this, testing in humans begins (clinical trials). These trials are conducted in three phases. Phase I tests the safety of a drug. In this phase researchers study the actions of a drug, its safe dosage range (toxicity) and how it is absorbed and distributed in the body. Phase I trials usually take less than a year. Phase II consists of preliminary efficacy studies in 200 to 300 volunteers. This second phase may take 2 to 3 years to complete. In phase III trials, researchers confirm the results of phase II studies in a larger trial, usually 1000 to 3000 people. In the past phase III trials have required 3-7 years. FDA commissioner Frank Young announced in October plans to speed up the review of drugs for life-threatening illnesses such as AIDS. Young said if an analysis of phase II results looks promising, "desperate patients" could receive a drug before phase III testing even begins. This is essentially how the FDA handled AZT. Insurance Although insurance companies will cover the cost of AZT for some individuals, experimental treatments must usually be paid for by individuals themselves. Some charitable organizations, such as Catholic Charities, will cover a portion of the cost for experimental treatments. An insurance company can be convinced to pay for experimental treatments. For instance, AZT is considered an experimental treatment for HIV-positive individuals who have more than 200 T-helper cells. Some insurance companies will pay for AZT for these individuals. One man wrote a letter to his insurer explaining his reasons for deciding to take AL721 and dextran sulfate instead of AZT. He stated that he could not tolerate the side effects of AZT and that his doctor was willing to monitor any possible side effects of AL721 and dextran sulfate. He also pointed out that these two antivirals cost far less than AZT. Both he and his doctor signed the letter. The company eventually agreed to cover the cost for AL721 and dextran sulfate. Dextran Sulfate Dextran sulfate is a sulfated polysaccharide* used in Japan for over 20 years to lower cholesterol levels. Many other sulfated sugars have shown anti-HIV activity in the test tube, including sea algae extract (SAE), heparin and glycyrrhizin sulfate. Dextran sulfate has several mechanisms of antiviral activity against HIV. In cell culture it blocks syncytia formation* (cell- to-cell infection). [7] AZT cannot block cell-to-cell infection. In laboratory studies dextran sulfate blocks HIV from binding and entering T-helper cells. [8] The drug also works to block reverse transcriptase activity* in cell cultures. Recent evidence also indicates that in laboratory experiments it blocks infection between macrophages. It is not known whether dextran sulfate can cross the blood- brain barrier, which is necessary to stop HIV infection of the brain. In animal studies conducted in Japan, dextran sulfate labeled with radioactive markers was present in the liver, lungs, bone marrow, muscles and brain, in that order. This suggests that only a small amount of the drug crosses the blood-brain barrier. In test tube studies, dextran sulfate works synergistically* with AZT [9], which does cross the blood-brain barrier. San Francisco General Hospital will soon begin a clinical trial to test this combination. Dextran sulfate is a low toxicity antiviral. However, people with diseases in which hemorrhaging may occur (such as hemophilia* or ITP*) should NOT take dextran sulfate. All individuals using the drug should have regular coagulation tests. Dextran sulfate can affect partial thromboplastin time (PTT)* and Prothrombin time (PT)*. In a Japanese study of 18 individuals receiving 1800 mg per day, the drug significantly prolonged both PTT and prothrombin time. [10] In the toxicity trial of dextran sulfate at San Francisco General Hospital, no one on doses between 900 and 5400 mg per day experienced coagulation abnormalities. Some PWA* on higher doses were taken off the drug because of liver toxicity, indicated by higher transminase* levels. The package insert that comes with dextran sulfate warns that people with kidney impairment should NOT take dextran sulfate. A severe decrease in white blood counts appeared in some individuals in the toxicity trial. Two of the 20 had to stop the drug, and 3 required a dose reduction because of neutropenia*. Other possible side effects of dextran sulfate include diarrhea, bloating, skin rash and insomnia. Aspirin should NOT be taken while using dextran sulfate because it interferes with the body's blood clotting activity. When taking dextran sulfate alone, use Tylenol instead of aspirin. Individuals taking a combination of AZT and dextran sulfate, however, should NOT take Tylenol because it may increase the toxic side effects of AZT. Advil or most other medications with ibuprofen provide an alternative to both Tylenol and aspirin, although ibuprofen also has some anti-platelet* activity, especially if taken continuously at high doses. Consult your physician regularly when using ibuprofen with dextran sulfate. Check often for signs of bleeding (bleeding gums or blood in the urine or stool). Dark stools or bright red stools also indicate bleeding. The most effective dosage of dextran sulfate for HIV infection is still unknown. At a does of 2700 mg per day, taken 3 times a day, researchers noted only slight increases in T- helper cell counts. [11] Some researchers have questioned whether dextran sulfate is absorbed into the blood. The phase I trial of the drug at San Francisco General Hospital did not study blood levels. Animal studies performed in Japan suggest hat the blood absorbs the drug. In one study, researchers administered oral dextran sulfate labeled with carbon 14 to rats. After one hour, researchers detected the drug in the rats' blood, although the dextran sulfate had broken down to a smaller molecule. [12] This animal study suggests that oral dextran sulfate is absorbed in the human body as well. Taken orally, dextran sulfate breaks down into small fragments of a low molecular weight. It is currently unknown if these fragments of lower molecular weight can produce the same anti-HIV effect as that produced by the molecule before it breaks down. The July 18, 1988 issue of Treatment Issues reported on Dr. Barbara Starrett's informal study of 54 people taking dextran sulfate for 8 weeks. [13] Fifty-four individuals received 600 mg of the drug 3 times a day. Many used other antivirals (24 took AZT, 24 took acyclovir, and 14 used both). Many others took immunomodulators as well as the dextran sulfate (5 were on naltrexone, 21 on antabuse, and 5 on imuthiol). Only 6 took dextran sulfate alone. Results of p24 antigen testing* were not encouraging regarding the ability of dextran sulfate to stop HIV replication. Only 3 of 13 individuals who were p24 antigen positive became p24 negative. Five who were p24 negative became positive. The results of T-helper cell testing were more encouraging. T-helper cell numbers increased in many individuals: 34% of the 26 PWA followed by Dr. Starrett had increases in T-helper cells, as did 50% of the 12 PWARC and 56% of the asymptomatic seropositives. These results may be due to the AZT or other drugs, but, four of the six taking dextran sulfate alone had "significant rises" in T-helper cell numbers. [14] Dextran sulfate is sold without a prescription in Japan, where the price ranges from $120-$260 for 1000 capsules containing 300 mg dextran sulfate. Several brands are available including Kowa (koh-wa) MDS and Bicibon (bi-she-bon). Both of these brands have the molecular weight and sulfur content believed necessary as an antiviral for HIV. The Healing Alternatives Foundation in San Francisco takes orders for dextran sulfate. The current price is $280 for 1000 tablets containing 300 mg dextran sulfate. Iscador Iscador is the brand name of an extract of European mistletoe (Viscum album), a common plant. In Western Europe it has been used as a cancer treatment for over 60 years. Iscador works as an anticancer agent by directly destroying cancer cells and by enhancing the immune system. [15] Up to 37 different components have been isolated in the mistletoe extract, including polysaccharides*, alkaloids* and lectins*. It is not yet known which components are responsible for the drug's anticancer and immune-boosting activities. Only a few of these components have been isolated and separately tested. Iscador is also an antiviral. UCLA recently began tests to determine its anti-HIV activity. Preliminary results indicate "the unfermented form of Iscador has a significant anti-HIV effect," according to Robert Gorter, M.D. [16] Dr. Gorter has applied to AmFAR to support a clinical trial of Iscador at San Francisco General Hospital for people with PGL*, ARC and AIDS. "Iscador significantly decreases syncytia formation -- the ability of one cell to directly infect another cell. It may also decrease or block the reproduction of the virus within the cell," says Dr. Gorter. Whether or not Iscador works in clinical trials to slow the progression of HIV disease, several studies have proven the drug's immunomodulating activity*. Iscador boosts the immune system in several ways. One study documents the drug's ability to increase T-helper cell numbers and to increase T- helper/suppressor ratios among women with breast cancer. After using Iscador, these women had neutrophil numbers increase 2.3 to 3.2 times higher than before Iscador was given. [17] Young neutrophils* increased over 10 times. Natural killer activity and antibody-dependent cell-mediated cytotoxicity activity* (indicators of immune system activity) also increased significantly 24 hours after an Iscador injection. These indicators returned to baseline levels 72 hours after injection. [18] The lectin component of mistletoe and its two component parts show various immunomodulating activities: the activation of macrophages, an increase in phagocytic activity* of white blood cells, and the release of lymphokines*. [19] These actions indicate immune system stimulation. Dr. Gorter is convinced Iscador is non-toxic. Initially it can produce a a strong skin reaction, an immune response called a "delayed sensitivity reaction." This response almost always disappears after a few days. This skin reaction is usually the size of a mosquito bite or slightly larger. "If you initially get an extensive reaction," says Dr. Gorter, "and walking becomes painful, then you should reduce the dose. After a while, you can increase the dose again." We spoke with 5 people who are using Iscador. All reported that during the first few weeks the injection sites become painful welts. Later the pain went away. One individual reported a painful swelling at the injection site and a slightly elevated fever. His physician cut the dose in half. When this reaction subsided, the dose was increased again. He reported no further negative reactions. Iscador may be helpful in reducing some of the side effects of AZT, especially neutropenia and anemia. Unlike AZT, which can cause neutropenia, Iscador increases neutrophil counts. In studies with mice, Iscador produced a faster recovery of the hemopoietic tissue* in the bone marrow and spleen after this tissue was subjected to irradiation with x-rays. [20] These results suggest that Iscador may help individuals using AZT to tolerate the drug better and may help them recover from bone marrow suppression. These animals studies also suggest that further studies on combined use of AZT and Iscador are warranted. Unfermented Iscador is the form of the drug that shows the strongest anti-HIV activity. It also exhibits immune-modulating activity. The fermented type does not show significant anti-HIV activity, although it does exhibit immunomodulating and anticancer effects. Dr. Gorter cautions that people who want to use Iscador should consult a physician knowledgeable about the drug because "if you start with too high a dose the individual may get a strong, inflammatory reaction at the injection site and possibly a fever. People using Iscador should start with a low dose and build up to whatever level they can tolerate. Individuals using Iscador usually start at a low dose of 1 mg and build up to doses of 10, 20, 30 and 40 mg." Iscador is available and inexpensive. The weekly cost is $6 ($3 per ampule). It can be purchased by writing to Switzerland (you must include a prescription from your physician): Institut Hischia, CH-4144 Arelesheim, Kirschweg 9, Switzerland. AL721 AL721 is a treatment composed of three types of lipids* in a 7:2:1 ratio. It is a mixture of 70% neutral lipids, 20% phosphatidylcholine and 10% phosphatidylethanolamine. Some researchers theorize that the composition of lipids in AL721 changes either the viral envelope or the cell membrane by removing cholesterol, therefore making it more difficult for HIV to infect cells. Recent clinical trials of AL721 in HIV-infected individuals are inconclusive. Although no individuals in studies of AL721 have shown significant increases in T-helper cell numbers, some people had reductions of p24 antigen levels and reverse transcriptase activity. These results indicate AL721 may have an antiviral effect against HIV. Several studies of AL721 were presented on at the Fourth International Conference on AIDS in Stockholm (June 1988). In one small study [21], thirteen people at varying stages of HIV disease took 10 grams of AL721 in a fat-free breakfast for three months. Before beginning the study, 5 were antigen negative and 8 were antigen positive. P24 antigen levels fell in 5 of the 8 antigen positive individuals. The 3 whose p24 antigen levels did not decrease had full-blown AIDS, leading the researchers to speculate that AL721 may help reduce the p24 antigen level at earlier stages of HIV infection. In another small study presented at Stockholm, ten people were given 30 grams of AL721 for 12 weeks. [22] Viral culture was positive in all 10 at the onset. Viral culture became negative in 3 after four weeks and negative in 4 more after eight weeks. Three became viral culture positive after treatment stopped. This suggests that AL721 reduced viral activity in these individuals. Six of the 10 developed new opportunistic infections, however, and there was no significant change in T- helper cell numbers in any of the patients during the 12-week period. In one small clinical trial [23], three people with LAS* received 10 grams of AL721 mixed in juice one hour after a fat- free breakfast and a second 10 gram dose mixed in juice at least three hours after a low-fat dinner. They took the AL721 for 8 weeks, stopped the treatment for 4 months, and then took it again for 8 weeks. There was no significant change in T-helper cell numbers among these individuals. In 5 of the 7, reverse transcriptase activity decreased during the 8 weeks on AL721. These values returned to pre-treatment levels after they stopped AL721. These individuals also showed improvement in lymphocyte* function when measured by their response to mitogens*. The researchers conclude, "The lack of apparent effect upon CD4 lymphocyte counts and circulating serum HIV p24 antigen values weigh against the potential of this drug." [24] They also concluded that larger clinical trials of AL721 will be necessary to determine its efficacy as an anti-HIV agent. Researchers have used various dosage schedules of AL721. The dosages used in clinical trials range from 10 to 30 grams per day, usually taken in the morning or at night. According to AIDS Treatment News, AL721 should be taken on an empty stomach, and no other fats should be taken at least two hours before and two hours after the dose. For maximum benefit, the lipids should be thoroughly mixed in water or juice with a blender. For more detailed information about AL721, consult AIDS Treatment News, especially issues 42, 43 and 44 (call 415-255-0588 to order). Individuals can buy AL721 from The Healing Alternatives Foundation in San Francisco (415-626-2316). AL721 costs between $145-$180 for 1 kilogram, a 100-day supply for individuals using 10 grams per day. Ribavirin Ribavirin is a broad-spectrum antiviral approved by the FDA in aerosol form for a respiratory viral infection in infants. It is available in Mexico without prescription. For several years many individuals infected with HIV went to Mexico to purchase the drug because of anecdotal reports that it slowed or stopped the progression of HIV disease. Following FDA approval of AZT and the appearance of other, less expensive antivirals, self- medication with ribavirin has dropped off considerably. The original phase II clinical trial of the drug was presented at the 1987 Third International Conference on AIDS in Washington, D.C. In this study of 163 HIV-seropositive individuals with LAS*, none of the 52 individuals receiving 800 mg per day of ribavirin progressed to AIDS, while 6 of 55 individuals receiving 600 mg a day did progress to AIDS. Ten of 56 individuals receiving placebos progressed to AIDS. No changes in T-helper cell numbers were reported in individuals receiving ribavirin. The FDA disputed these findings. They said that healthier individuals had been put on the drug and sicker individuals with lower T-helper cell numbers received the placebo. The FDA concluded that the study was biased. Because of its concerns about the reliability of the study, the agency put trials of ribavirin on hold. Since then, new trials have begun. Another small study suggested that ribavirin has anti-HIV effect. [25] HIV could not be recovered in 5 of 9 individuals in whom it had been isolated at the beginning of the trial. T-cell function also increased in 9 of 14 people. Larger studies are now underway using higher doses of ribavirin (up to 1600 mg per day). Ribavirin crosses the blood-brain barrier. The drug should not be taken with AZT because it competes for the cellular enzymes that make AZT work, causing both drugs to become less effective. The side effects of ribavirin include anemia, insomnia, headaches, and irritability. Project Inform in San Francisco has followed ribavirin for several years and is the best source of information on the drug. They received a grant from ICN Pharmaceuticals to track individuals self-medicating with ribavirin. The published results of this informal poll can be obtained from Project Inform (call 800-334-7422 in California; outside California call 800- 822-7422). Ribavirin costs $23.50 for a box of 12 capsules containing 200 mg each. Doses used in clinical trials range from 400 mg to 1600 mg daily. Carrisyn Carrisyn is extracted from aloe vera gel, which is derived from the aloe barbadenisis plant. Researchers believe that the active ingredient with antiviral activity in aloe is a polysaccharide. Carrisyn shows antiviral activity against the measles virus and herpes viruses. [26] A recent laboratory study presented in Stockholm reported that reductions of reverse transcriptase and p24 antigen in cell cultures infected with HIV were directly proportional to the concentration of carrisyn used. [27] No clinical study of carrisyn has been conducted, although there is anecdotal information on HIV-infected individuals taking aloe vera juice (which may contain carrisyn) and a report on 15 PWA and PWARC by the manufacturer of carrisyn. These individuals took 250 mg of carrisyn 4 times a day for 6 months. There was a mean increase of T-helper cells from 340 to 450, and everyone in the study experienced improvement in symptoms and reduction in p24 antigen levels. [28] Animal studies indicate that carrisyn has no toxic effect at doses many times those used in AIDS studies so far. The most complete coverage of carrisyn as a treatment for HIV infection is found in Treatment Issues, vol. 1, no. 2. Carrisyn is available in "De Veras Beverage." It reportedly contains .15% carrisyn. Twenty ounces of the beverage should yield an equivalent of 1000 mg of the drug, but no laboratory independent of De Veras, Inc. has tested the carrisyn content of the product. "De Veras Beverage" costs about $135 a month if 20 ounces a day is consumed. According to Treatment Issues, adding a teaspoon of clear vinegar increases the potency of the beverage. The beverage can be ordered from De Veras, Inc. (214- 823-4659) or from a buyers' club. BHT (Butylated hydroxytoluene) BHT is a manufactured antioxidant* used in fats and oils as a food preservative. BHT inactivates a variety of viruses with lipids in their envelopes, including cytomegalovirus (CMV)* and the Semiliki Forest virus. [29] BHT also inactivates the herpes simplex virus (HSV). [30] Cytomegalovirus and the herpes virus are two possible cofactors in HIV progression, and both lead to life- threatening illnesses in individuals whose immune systems have been damaged by HIV. Researchers believe the drug inactivates CMV and HSV by affecting their lipid envelopes. Animal studies on BHT show the drug protects against Newcastle disease virus at extremely low doses (100 to 200 parts per million of total diet). [31] The envelope of HIV contains lipids similar to those found in Newcastle disease virus. [32] In a double-blind placebo-controlled study, the topical application of BHT on herpes simplex lesions shortened lesion duration. [33] There was no evidence of toxicity in this trial. In 1986, a researcher at NIH concluded BHT does not inactivate HIV, although his research has not been published. Results of another laboratory study indicate BHT can reduce the viral activity of HIV. [34] Individuals using BHT report they are taking 500-1000 mg/day. Several began with a low dose of 100 mg, building to a higher dose over several weeks in order to avoid the light- headedness associated with starting at a high dosage. These individuals take BHT 2-4 times daily. BHT is absorbed into the body more efficiently when mixed in oils such as olive or sesame. Do not drink alcohol for 3 hours before and after taking BHT, because it significantly increases the intoxicating effect of alcohol. Studies with mice suggest that BHT modifies the toxicity of X-rays. Individuals taking BHT who are undergoing radiation therapy should consult with their physician. The Healing Alternatives Foundation sells 300g of BHT for $7, a 300-600 day supply, depending on the dose used. CD4 and CD4-Pseudomonas exotoxin CD4 is the protein on the surface of T-helper and other white blood cells to which HIV attaches itself. Genentech, Inc. has created a genetically engineered form of CD4 that may act as a decoy that "tricks" HIV into attaching to it instead of the body's white blood cells. In test tube studies, the manufactured CD4 stops HIV from infecting new cells and also "soaks up" free-floating HIV. Researchers say CD4 will not cure AIDS, but may work to slow the progression of HIV disease. Some scientists caution that the human body may respond to the drug by producing antibodies that will attack and destroy T- helper cells. This has not occurred in animal experiments, but in humans the drug may work differently. Only human trials can answer this important question. As of early October, 10 individuals have received CD4 for up to 10 weeks in a clinical trial at San Francisco General Hospital. PWA in the trial began with a low dose of the drug. Their dose has been increased because no side effects have been reported so far, but it may take several months for the body to produce antibodies to CD4. CD4-Pseudomonas exotoxin is a genetically engineered drug developed to seek out and kill cells infected with HIV. CD4 alone may prevent spread of infection between cells, but it does not kill cells already infected with HIV. In laboratory experiments, CD4-Pseudomonas exotoxin can distinguish between uninfected cells. [35] Researchers caution that more test tube studies as well as experiments with animals are necessary before human trials of CD4-Pseudomonas exotoxin can begin. Rifabutin Rifabutin is an antibiotic currently used to treat MAI* and other AIDS-related bacterial infections. The drug crosses the blood-brain barrier and may prove useful in treating AIDS-related neurological disorders*. Three studies of rifabutin were presented at Stockholm. In one test tube study, the anti-HIV effect was greater when rifabutin was used with either heparin or ddC. [36] Another study concluded the drug had no anti-HIV effect when tested on 16 PWARC [37], but the researchers speculated that rifabutin may be useful when used in combination with other antivirals. In the PWARC study, rifabutin was tolerated up to 2400 mg/day. Toxicity reported from this study included joint pain in 7 individuals and elevated levels of the liver enzyme ALT in 4. Rifabutin can also cause neutropenia. These side effects went away when the drug was discontinued. Foscarnet (trisodium phosphonoformate) Foscarnet shows antiviral activity against all human herpes viruses, including CMV. Herpes viruses may be cofactors that stimulate replication of HIV. Foscarnet also shows antiviral activity against HIV. Research indicates that the drug inhibits reverse transcriptase. Laboratory studies at UCSF suggest that this antiviral blocks HIV infection in macrophages. A small trial of nine PWA with CMV retinitis* at UCSF reported clinical improvements in all but one individual. Six individuals showed a 14-89% decrease in p24 antigen levels. Eight had increased numbers of T-helper cells (all had fewer than 50 T-helper cells at the beginning of the trial), but only one individual showed an increase beyond 150. A phase I trial at San Francisco General Hospital will study the usefulness of combining oral AZT and intermittent IV foscarnet therapy. Researchers hypothesize a synergistic* antiviral effect without increased toxicity. Foscarnet may decrease kidney function. [38] Other side effects of the drug include decreases in hemoglobin* concentration, nausea, anorexia* and headaches. These side effects go away when treatment stops. Alpha Interferon Interferons are natural proteins (lymphokines) produced by the body in response to an infection. These substances "interfere" with cell infection. There are three main classes of interferon: alpha, beta, and gamma. Alpha interferon has been studied as a treatment for KS*. Tumor regressions have occurred in some individuals treated with the drug. In a Canadian study 25 people with KS were treated with alpha interferon for seven months. [43] Two (8%) showed a complete regression of tumors, 5 (20%) a partial response, and 8 (32%) had stable disease. Clinical trials of alpha interferon in combination with AZT indicate this therapy can produce significant regression of tumor size. [44] Unfortunately this combination, especially at higher doses, increases the toxic effects of both drugs. The researchers noted that several leukopenia* occurs at significantly lower doses than if each drug were used by itself. The major side effects of alpha interferon when used alone are fatigue, fever, chills, myalgia* and headaches. Several trials of alpha interferon with AZT for asymptomatic HIV-positive individuals, PWA and PWARC are under way. Preliminary results suggest this combination therapy is less toxic to people at earlier stages of HIV infection. A letter to The Lancet describes the possible benefit of oral alpha interferon at a low dose (2-4) units/kg body weight per day). [45] The authors present the case of a PWA who, over an eleven month period. regained his lost appetite, gained weight, and has remained at work since beginning treatment. "His herpes simplex and mouth ulcers have disappeared, and his T-helper cell counts have risen to 210-520 (from 146-218)," according to the authors. Other researchers have also suggested that PWA could benefit from low dose alpha interferon. [46] Beta Interferon Recombinant beta interferon exhibits the same antiviral, immunomodulatory and anti-cancer activity as the beta interferon produced naturally by the body. Like alpha interferon, in laboratory studies beta interferon stops replication of HIV. [47] In a study presented in Stockholm, the combination of AZT and beta interferon worked better than either antiviral alone to stop HIV replication. [48] Larger clinical trials using this combination are presently under way. In another study presented at Stockholm, 33 individuals with KS received beta interferon in either a low dose (90 million units, 20 people) or a high dose (180 million units, 13 people). [49] Five of 10 people on the low dose had a greater than 50% reduction of HIV antigen, 1 remained stable, and 4 had increases in p24 antigen levels. At the higher dose, 4 of 13 people progressed, 6 remained stable and 3 had problems with skin toxicity. Toxicity was generally mild in this study. Side effects included flu-like symptoms (30 individuals), kidney toxicity (3 individuals) and skin toxicity. No one in the study developed opportunistic infections during treatment. Tumor Necrosis Factor (TNF) and Gamma Interferon TNF is a protein produced by macrophages. By itself, TNF destroys cancer cells and studies of TNF for Kaposi's sarcoma are currently under way. In a phase I trial at San Francisco General Hospital, all individuals treated showed a partial response in 1 or 2 lesions injected with TNF. Toxicity included fever, chills, fatigue, headache, and inflammation at the injection site. [50] Test tube studies suggest that TNF and gamma interferon work together to block HIV replication. The combination also destroys cells already infected with HIV. [51] The study reported modest increases in T-helper cells. P24 antigen levels fell in 2 of 5 people who were antigen positive at the beginning of the trial. Larger trials of TNF and gamma interferon for PWARC are now under way. Peptide-T Some researchers argue that peptide-T blocks HIV infection of T-helper cells as well as improving central nervous system function. [52] Others disagree. [53] A trial with 36 PWA has begun in Sweden. Phase I trials with 12 PWA at the NIG and the University of Southern California indicate that the drug is non- toxic. Bile Salts In a recent laboratory study, bile salts (60% sodium cholate and 40% deoxycholate diluted in water) inactivated HIV. [54] The researchers believe this was due to disruption of the HIV envelope. The bile salts also killed HIV-infected T-helper cells without harming uninfected T-helper cells. AIDS Targeted Information Newsletter urges caution in applying these findings in clinical studies because of limited information about toxicity. [55] The researchers suggest two possible courses in HIV-infected individuals treated with bile salts: (1) a drop in T-helper cells infected with the virus could lead to further progression of the disease, or (2) the HIV-infected cells will be replaced by uninfected T-helper cells. Further studies will be necessary to find out which theory is correct. The body quickly eliminates bile salts. In order to maintain an effective therapeutic dose in the blood, they must be administered intravenously or by injection. ddC (Dideoxycytidine) ddC is in the same family of drugs as AZT. Like AZT, ddC prevents viral replication of HIV and it also crosses the blood- brain barrier. [39] Early clinical trials show that ddC decreases p24 antigen levels and temporarily increases T-helper cell numbers in PWARC and PWA. [40] Unfortunately, ddC is toxic for many individuals: 10 of 20 people developed a painful peripheral neuropathy* after 6 to 14 weeks on ddC. Other toxic side effects of ddC include joint pain, fever, malaise and diarrhea. [41] Because the toxicity of ddC is different than that of AZT, alternating the drugs may help people to avoid the bad side effects of both. The combined use of AZT and ddC may alleviate or eliminate the painful neuropathy caused by ddC. This combination may also help avoid the anemia and neutropenia caused by AZT. Several clinical trials using different dosages of both drugs are currently in progress at Stanford and other medical centers. In a study of 17 individuals alternating both drugs weekly, all gained weight, p24 antigen levels decreased, and both the number and function of T-helper cells increased [42] (see also AZT and Children, p. 20). *************************************************************** AZT UPDATE AZT Dosage In the June 1988 issue of BETA we referred to the standard "full dose" of AZT as 200 mg every four hours (1200 mg every day). Recent studies, however, suggest that a half dose of AZT (600 mg every day) may be as effective . [56] In a study presented at Stockholm, researchers found that there was no difference in the antiviral effect of AZT at a half dose (200 mg every four hours). After eight weeks, the rise in T-helper cells was higher in individuals receiving the half dose than in individuals receiving the full dose. The researchers suggested more studies using a half dose regimen because it may limit the toxicity of AZT. Other researchers have noted that more convenient dosage schedules, such as every six or twelve hours, may be just as effective as every four hours. [57] More convenient dosage schedules may give bone marrow time to recover from the effects of AZT. One study reports that a dosage schedule of 250 mg every 6 hours reduced antigen levels in the cerebrospinal fluid (CSF)*. [58] It is currently unknown if a half dose of AZT (600 mg/day) would be effective in producing this same result. Rare HIV Rebound Effect After Dose Reduction of AZT In a study reported in The Lancet, a small number of PWA developed severe meningoencephalitis* after dose reductions of AZT. [59] One hundred and six individuals participated in the study. Twenty-one had their AZT dose reduced because of bone marrow suppression. Within 17 days of the dose reduction, 4 of these individuals developed acute meningoencephalitis episodes, including fever, headache, neck stiffness, and confusion. These symptoms resolved in 3 of the 4 patients within 2-4 weeks. Many physicians, however, have observed no rebound effect when reducing or stopping AZT. According to Marcus Conant, MD [60], "Physicians will be looking for this rebound effect now to see if it is real. Physicians and patients should be aware that this effect has been reported from this group in London. Whether it is real or not is difficult to say." Harry Hollander, MD [61] commented, "Given my own experience taking people off AZT and after speaking to a number of physicians following patients on AZT, I feel if this rebound effect occurs at all, it is rare." Acyclovir and AZT In the June 1988 issue of BETA we discussed the possibility that a combination of acyclovir and AZT may work better than AZT alone. A multi-center trial in Europe reported on using AZT alone and AZT and acyclovir in PWA. [62] For 48 weeks individuals in this study took either 250 mg of AZT alone every 6 hours or 250 mg of AZT with 800 mg of acyclovir every 6 hours. During the first 24 weeks on combined therapy the only observed benefit was a decrease in herpes virus infections (herpes zoster, herpes simplex and cytomegalovirus). In the second 24 weeks, however, the researchers noted "significant improvement in survival and a reduction in the incidence and severity of opportunistic infections in individuals receiving the combination compared with those given AZT alone." AZT and Vitamin B12 The San Francisco County Community Consortium will begin a study this year of vitamin B12 and AZT. This trial will test the hypothesis that vitamin B12 can help reduce the anemia caused by AZT. Vitamin B12 promotes the production of thymidine monophosphate, a substance in the body which is important for red blood cell formation. This substance is also important in the breakdown of AZT. Researchers theorize that when the body is flooded with AZT,the drug competes with the production of red blood cells for thymidine monophosphate. Monthly intramuscular injections of vitamin B12 may help produce enough thymidine monophosphate in the body to break down AZT as well as promote production of red blood cells. Some physicians believe that B12 levels should be closely monitored in individuals using AZT because individuals who have low B12 levels show a greater tendency to develop anemia when they start AZT. Dr. Conant recommends monthly monitoring of B12 levels in individuals using AZT, and he suggests a monthly intramuscular injection of the vitamin for some people. AZT and Cryptosporidiosis Researchers have found that AZT may be an effective therapy for cryptosporidiosis*, a life-threatening infection in PWA. [63] Until now, there has been no effective treatment for this infection. Sixteen PWA with cryptosporidiosis received either 600 or 1200 mg of AZT every day. Five had cryptosporidiosis as their only opportunistic infection, while the others had one or more other opportunistic infections and/or KS. Of 13 individuals for whom testing for cryptosporidium could be performed, 9 were repeatedly negative after therapy with AZT. Before treatment with AZT these individuals experienced diarrhea for an average of 18 weeks. After four months of treatment the diarrhea disappeared in 12 of 16. After seven months on AZT there was a marked improvement in diarrhea (no diarrhea in 6, improvement in 10, stability in 3, and worsening symptoms in 2). The researchers found that the 600 mg/day dose was just as effective in the treatment of cryptosporidiosis as the "full" dose of 1200 mg. AZT and Toxoplasmosis Researchers have reported on the possible benefit of AZT for PWA with toxoplasmosis. [64] Researchers first treated the toxoplasmosis with regiments of pyrimethamine and sulfadiazine. Twenty-five individuals began AZT an average of 19 weeks after their toxoplasmosis diagnosis. Seventeen did not receive AZT; 8% of this group survived for 1 year. Eight received AZT; 41% of this group survived for 1 year. AZT and Kaposi's Sarcoma (KS) Two studies presented at the Stockholm conference suggest AZT therapy may benefit HIV-related Kaposi's sarcoma. In both studies, many individuals experienced either stabilization or regression of their KS lesions. In one study, 20 people with KS took AZT for an average of 6-1/2 months. [65] Thirty percent had their lesions stabilize, and 40% had their lesions shrink at least 50% or disappear. In the second study, 31% had lesion stabilization, and 27.5% experienced regression of lesion size while using AZT. [66] Clinical trials are under way to treat individuals with KS using a combination of AZT and alpha and beta interferon. AZT and Muscle Toxicity There have been reports that AZT has a toxic effect on muscles. Some individuals on AZT develop a weakness or tenderness in muscles due to the release of an enzyme known as creatine phosphokinase (CPK). CPK is a measure of injury to muscles. Some individuals infected with HIV who are not taking AZT, however, experience these same muscle problems. Reacting to this situation, Dr. Hollander commented, "How much the muscle problem relates to the drug and how much relates to HIV is open to debate at this point." AZT and Children Recent studies show that AZT produces improvements in children with AIDS. Twenty-one symptomatic children between the ages of 14 months and 12 years showed significant improvement in their mental function after taking the drug. [67] Thirteen of the 21 with neurological problems showed improvements. The researchers also noted decreases in swollen lymph nodes and increases in T-helper cell numbers. Enlarged livers and spleens subsided. Almost all of the children in the study gained weight. Unfortunately, two-thirds of the children required blood transfusions to offset the bone marrow toxicity caused by AZT. Five died in the year-long study. Researcher Philip Pizzo told the Wall Street Journal he had begun alternating AZT with ddC as a possible means of minimizing the adverse side effects of both drugs. Dr. Pizzo said that so far the 17 children using the AZT/ddC combination show no toxicity. It is difficult to decide whether to treat infants born to seropositive mothers. Only about half these infants are actually infected with the virus. Some may have antibodies from their mothers and may not be infected with HIV. Those infected may not produce antibodies during their first 15 months. It is difficult to tell which infants are actually infected and which are not, and therefore, which to consider treating. The Polymerase Chain Reaction (PCR) test, a new HIV test, may be of great value in this situation (see below). A Proposed Prophylactic Treatment for MAI Mycobacterium avium-intracellularae (MAI) is a serious infection that affects 15-60% of all PWA. The infection can produce a wasting syndrome with symptoms such as fever, fatigue, night sweats, severe diarrhea and weight loss. MAI can go undetected because its symptoms are similar to those of other opportunistic infections and because it may appear in areas of the body that require invasive procedures for diagnosis. MAI organisms are resistant to the antibiotics currently used to treat the infection (rifabutin, clofazamine and amikacin). Unfortunately, the toxicity of the drugs used to treat MAI often outweighs their small benefit, according to Dr. Hollander. "MAI is a very difficult, if not impossible, infection to treat successfully," he says. A two-year clinical trial planned for San Francisco General Hospital will study the possible benefit of a daily dose of clofazamine as a prophylactic* treatment for MAI. Fifteen physicians in the San Francisco County Community Consortium will also conduct a clofazamine trial among individuals in their private practices. Individuals who have had one bout of PCP* will participate in the San Francisco General Hospital study. Half will receive a daily dose (50 mg) of clofazamine and half will take a placebo. According to Dr. Gorter, "We cannot cure MAI at this time. However, if we can suppress it, then this is a relative success because, if we can improve the quality of life, perhaps the individual will survive longer." The side effects of clofazamine include skin discoloration, diarrhea, rash and itching. Body fluids and stools can also become discolored. The Polymerase Chain Reaction (PCR) Test The Polymerase Chain Reaction (PCR) test can detect infection with HIV much earlier than other tests such as the antibody test or viral culture. Some preliminary studies of individuals at high risk for HIV infection indicate that a small but possibly significant number of these people will test positive on the PCR even though they test negative on other tests. Researchers plan more extensive studies to determine the sensitivity and specificity of the PCR in comparison to antibody testing and viral culture. In the future the PCR may have significant clinical applications: it may eventually be possible to estimate how much HIV an individuals carries. [68] People with a large viral load might choose to begin early anti-HIV therapy. The test may also help settle the question of whether some HIV-positive individuals can eliminate the virus from their immune system. [69] One immediate clinical use for the PCR is to enable doctors to discover whether HIV-positive infants are really infected with the virus. Using the antibody test alone, physicians cannot be certain because infants born to seropositive mothers may receive HIV antibodies from their mothers without acquiring the virus itself. Using the PCR can help in deciding whether or not an infant should be given AZT, for instance. Individuals can get the PCR test by prescription from a physician for approximately $150. In the Bay Area, call Pathology Institute (415-540-1638) or Golden Gate Family Medical Clinic (415-626-2212). Individuals should ask their physicians not to record the test result in their medical records. *************************************************************** SUMMARY CHART OF ANTIVIRALS Antiviral - AZT Mechanism of Action Against HIV: Inhibits reverse transcriptase, terminates viral DNA chain Availability and FDA Status New Drug Application approved for AIDS and severe ARC. Available for asymptomatic seropostives with physician's prescription. Phase III trials underway for asymptomatic seropositive and/or PGL, early ARC, and neurological disease. Phase I trial for pediatric AIDS Cost: Approximately $8,000 per year for "full dose" (1200 mg/day) How Administered: Oral or intravenous Toxicity/Side Effects: + Very toxic: anemia, neutropenia, nausea, fatigue, headaches, insomnia + Healthier individuals appear to tolerate the drug better Comments: + Proven to slow disease progression in some people with AIDS and severe ARC + May be beneficial for mild ARC and some asymptomatic seropositives + May be effective for cryptosporidiosis + "Half-dose" (600 mg/day) may be as effective as "full dose" (1200 mg/day) + Do not take with ribavirin -------------------------------------------------------------- Antiviral - Dextran sulfate Mechanism of Action: Blocks syncytia formation, blocks HIV from binding to T-helper cells, and blocks reverse transcriptase activity Availability and FDA Status: In Japan and at local buyers' clubs without prescription Phase I/II clinical trials Cost: $120-$260 in Japan (1000 300 mg tablets) The Healing Alternatives Foundation in SF currently charges $280. Estimated yearly cost: $980 How Administered: Oral or intravenous Toxicity/Side Effects: Some individuals had severe decrease in white blood counts, liver toxicity, diarrhea, insomnia, skin rash Comments: + Hemophiliacs and people with ITP* should not take dextran sulfate + Do not take aspirin with dextran sulfate + May not cross blood-brain barrier + May work synergistically with AZT + Anti-HIV effect shown only in test tube studies --------------------------------------------------------------- Antiviral - Iscador Mechanism of Action Against HIV May block syncytia formation, may block reproduction of virus within cells Availability and FDA Status Write to Switzerland with physician's prescription. Application for Phase I trial submitted Cost: Approximately $6 per week How Administered: Subcutaneous injection Toxicity/Side Effects: Temporary swelling at injection site Fever Comments: + Used as a cancer therapy for 60 years in Europe + Enhances the immune system + Increases neutrophil numbers and may help people better tolerate AZT. -------------------------------------------------------------- Antiviral - AL721 Mechanism of Action Against HIV: Inhibits viral binding Availability and FDA Status: Contact a buyers' club Phase II Cost: $145-$180 per kilogram Estimated yearly cost: $1,120 (20 g/day) How Administered: Oral, well-mixed in water or juice Toxicity/Side Effects: Non-toxic Comments: + Mix thoroughly in juice or water. + Take on empty stomach with no other fats 2 hours before and 2 hours after --------------------------------------------------------------- Antiviral - Ribavirin Mechanism of Action: Unknown Availability and FDA Status: In Mexico without prescription Phase I/II Cost: $23.50 for a box of 12 200 mg capsules Estimated yearly cost: $5,640 (1600 mg/day) How Administered: Oral Toxicity/Side Effects: Mild anemia, insomnia, headache, irritability Comments: + Clinical trials have not shown reductions in HIV antigen levels + Do not take with AZT --------------------------------------------------------------- Antiviral - Carrisyn Mechanism of Action Against HIV: Unknown Availability and FDA Status: Call The Healing Alternatives Foundation in San Francisco Application for Investigational New Drug (IND) submitted Cost: Approximately $140 a month Estimated yearly cost: $1,680 How Administered: Oral Toxicity/Side Effects Non-toxic Comments: + Immunomodulator + Antiviral activity against the herpes virus + Does not cross blood-brain barrier -------------------------------------------------------------- Antiviral - BHT Mechanism of Action Against HIV: Affects lipid envelope Availability and FDA Status: Available from The Healing Alternatives Foundation Cost: Estimated yearly cost: $14 (1 gram per day) How Administered: Oral, dispersed in oil such as olive or sesame Toxicity/Side Effects: Low toxicity Metallic taste Comments: + Studied in test tube only + Affects lipid envelope of CMV and other herpes viruses + Do not drink alcohol for several hours after taking BHT *************************************************************** The following treatments are available o-n-l-y to people enrolled in clinical trials: Antiviral - CD4 Mechanism of Action Against HIV: Inhibits binding FDA Status Phase I trial How administered: Injection Toxicity/Side Effects: Unknown Comments: + Human trials under way --------------------------------------------------------------- Antiviral - CD4-Pseudomonas exotoxin Mechanism of Action Against HIV: Destroys infected cells FDA Status: Phase I How Administered: Injection Toxicity/Side Effects: Unknown Comments: + Studied in test tube only --------------------------------------------------------------- Antiviral - Rifabutin Mechanism of Action Against HIV Blocks reverse transcriptase FDA Status: Phase II trial for ARC How Administered: Oral Toxicity/Side Effects: Elevated liver enzyme, nausea, pain in joints Comments: + May be most useful when combined with other antivirals --------------------------------------------------------------- Antiviral - Foscarnet (trisodium phosphonoformate) Mechanism of Action Against HIV: Inhibits reverse transcriptase FDA Status: Phase I/II How Administered: Oral or intravenous Toxicity/Side Effects: Fatigue, irritability, headache, nausea, loss of appetite Comments: + Antiviral activity against HIV and all human herpes viruses + Blocks HIV infection between macrophages ---------------------------------------------------------------- Antiviral - ddC Mechanism of Action Against HIV: Inhibits reverse transcriptase FDA Status: Phase I/II How Administered: Oral or intravenous Toxicity/Side Effects: Painful neuropathy, fever, skin rash Comments: + Very toxic to peripheral nerves. This may be reduced by taking alternately with AZT + Phase II trials in combination with AZT are under way --------------------------------------------------------------- Antiviral - Alpha Interferon Mechanism of Action Against HIV: May reduce viral budding FDA Status: Phase I/II How Administered: Subcutaneous injection or oral Toxicity/Side Effects: Fatigue, fever, chills, headache, pain in muscles Comments: + Antiviral and immune-enhancing activity + KS tumor regression in some individuals + Phase II trials in combination with AZT are under way --------------------------------------------------------------- Antiviral - Beta Interferon Mechanism of Action Against HIV: Unknown FDA Status: Phase III How Administered: Intravenous or subcutaneous Toxicity/Side Effects: Flu-like symptoms, skin toxicity, kidney toxicity Comments: + KS tumor regression in some individuals + Synergistic effect when combined with AZT and ganciclovir (DHPG) --------------------------------------------------------------- Antiviral - Gamma Interferon & Tumor Necrosis Factor (TNF) Mechanism of Action Against HIV: Blocks HIV replication; destroys infected cells FDA Status: Phase I How Administered: Intra-muscular injection Toxicity/Side Effects: Fever, chills, muscle pains, headache Comments: + Used alone, gamma interferon appears to produce no clinical improvement in PWA + Combined with TNF, gamma interferon suppresses HIV (test tube studies) + Human trials under way *************************************************************** GLOSSARY ALKALOIDS: A large group of organic bases that most often occurs in seed. AMPULES: Small, sealed glass containers used to hold a solution for hypodermic injection. ANTIGEN-DEPENDENT CELL-MEDIATED CYTOTOXICITY: A condition by which a T-cell destroys a cell coated with an antibody. This is one of the two major mechanisms the immune system uses to destroy tumor cells. ANOREXIA: Prolonged loss of appetite. ANTICOAGULANT: A substance that delays or counteracts blood clotting. ANTIOXIDANT: A substance that prevents oxidation. These are often used in fats, oils and food to keep them from becoming rancid. BLOOD-BRAIN BARRIER: A barrier between the blood and the brain. It only allows some substances to pass from the blood to the brain. This barrier presents a problem in treating HIV infection because treatments must cross it to stop HIV infection in the brain. CELL MEMBRANE: The wall around a cell that separates it from its environment. CEREBROSPINAL FLUID (CSF): A fluid which circulates around the brain and spinal cord> CMV RETINITIS: An infection of cytomegalovirus (CMV) in the retina of the eye which can cause blindness. CREATININE: A compound found in muscle, blood and urine. The excretion of creatinine in urine is used as a measure of kidney function. CRYPTOSPORIDIOSIS: A parasitic infection that causes severe diarrhea. CYTOMEGALOVIRUS (CMV): A herpes virus. CMV infection can occur without causing any symptoms or it can lead to a flu-like syndrome. CMV can also lead to serious, even life-threatening infections, especially in PWA. CYTOTOXICITY: Toxicity to cells. DEMENTIA: A loss of mental capacity. AIDS-related dementia may be caused by HIV or other infections. DNA: Material in the nucleus of a cell which contains the cell's genetic code. HEMOPHILIA: An inherited disease that causes people to bruise easily and to bleed profusely. It can cause severe internal bleeding. HEMOGLOBIN: The protein in red blood cells responsible for oxygen transport. Normal hemoglobin values are 12-15 g/100 ml for women and 14-16.5 g/100ml for men. These values can vary. HEMOPOIETIC TISSUE: The tissue from which blood is produced in the body. IMMUNOMODULATING THERAPY (IMMUNOTHERAPY): A therapy that attempts to reconstruct or enhance a damaged immune system. Examples of immunomodulating therapy for AIDS include DNCB, isoprinosine and Imutiol (DTC). INTEGRATION: The process by which the viral DNA of HIV enters the DNA of the T-helper cell. It can remain in the cell without reproducing until the T-helper cell is stimulated. ITP (IDIOPATHIC THROMBOCYTOPENIC PURPURA): A condition in which the body produces antibodies against its own platelets (the blood cells that cause blood clotting). Symptoms include bruising, slow healing of wounds and bleeding gums. KS: Kaposi's Sarcoma. KS is a tumor of the walls of blood vessels. It usually appears as pink to purple, painless spots on the surface of the skin, but it can also occur internally. KS is one of the major infections found among PWA, especially gay and bi-sexual men. LAS: Lymphadenopathy associated syndrome, a condition in HIV- infected individuals characterized by swollen, sometimes painful lymph glands. LECTINS: A substance derived from plants that produces action resembling immunological reactions. Lectins are commonly used as mitogens. LEUKOPENIA: A lower than normal number of white blood cells in the circulating blood. LIPIDS: Substances extracted from animal or vegetable cells by "fat" solvents. LYMPHOCYTE: A type of white blood cell. LYMPHOKINES: Products of lymphocytes that are responsible for various immune reactions. Lymphokines include the interferons and interleukins. MENINGOENCEPHALITIS: Inflammation of the brain and spinal cord and their membranes. MITOGENS: Substances that cause T-helper cells to multiply. When T-helper cells are infected with HIV they do not respond normally to mitogens. MYALGIA: Pain in one or more muscles. NEUROLOGICAL DISORDERS: Disorders of the nervous system. These disorders are of the central nervous system (brain and spinal cord), such as dementia, or of the peripheral nervous system (the rest of the nervous system), such as neuropathy. NEUROPATHY: An abnormal and usually degenerative state of nerve tissue. NEUTROPENIA: A shortage of neutrophils. NEUTROPHIL: The most common type of white blood cell. They are the immune system's primary defense against bacterial infections. The normal range of neutrophils is from 3000 to 7000. PERIPHERAL NEUROPATHY: A disorder of the nerves, usually involving the arms and legs. PCP (PNEUMOCYSTIS CARINII PNEUMONIA): A type of pneumonia found in immunosuppressed individuals. It is the most common opportunistic infection in AIDS. PHAGOCYTIC ACTIVITY: The activity of certain white blood cells that can engulf and digest foreign bodies or debris such as bacteria or degenerating tissue. PGL (PERSISTENT GENERALIZED LYMPHADENOPATHY): The body's lymph nodes swell during infection. PGL in HIV infection is a condition in which lymph nodes are chronically swollen in at least two areas of the body for three months or more. Enlarged spleens also occur in about one third of people with PGL. PLATELETS: Blood cells that produce blood clotting. POLYSACCHARIDES: A combination of two or more sugar molecules. PROPHYLACTIC: A drug that helps to prevent a disease before it occurs. PROBTHROMBINE TIME (PT): Prothrombin is a protein produced by the liver to produce clotting of blood. PT is one of four tests for blood coagulation that measures the clotting ability of several coagulation factors. PTT (PARTIAL THROMBOPLASTIN TIME): A test for blood clotting disorders. PWA: Person with AIDS or persons with AIDS. p24 ANTIGEN: A protein fragment of HIV. The p24 antigen test measures this fragment. A positive result for the p24 antigen suggests active HIV replication. REVERSE TRANSCRIPTASE: A viral enzyme that transcribes viral RNA into DNA so that the genetic material of the virus can be integrated into the genetic material of the T-helper cell. Many antivirals inhibit the action of this enzyme. SUBCUTANEOUS: This means "beneath the skin." A subcutaneous injection goes beneath the skin, but not into the deeper muscle tissue. SYNCTIA FORMATION: A mass of cells which fuse together to form one "giant cell." In HIV infection this condition leads to direct cell-to-cell infection. SYNERGISTIC: "Working together." When one drug increases the effectiveness of another one it is said to work synergistically with that drug. TOXOPLASMOSIS: An opportunistic infection caused by a parasite found in cat feces and in uncooked meat. TRANSMINASE: An enzyme that is an indication of liver function. VIRAL PROTEINS: The core and the envelope of HIV are composed of viral proteins. The core includes the proteins p24 and p18 and the envelope includes the proteins gp41 and gp120. VIRAL DNA: RNA, the genetic code of HIV, is transcribed by reverse transcriptase into DNA. This viral DNA may exist in the host cell for a prolonged period of time or become integrated into the genetic material of the host cell. *************************************************************** --------------------------------------------------------------- REFERENCES [1] "AIDS and the Macrophage," Cancer Research Institute Symposium, New York City, June 2-3, 1988. Reported in AIDS Targeted Information Newsletter, July, 1988, p. 1. [2] Ibid [3] Current experimental protocols at San Francisco General Hospital, August 1, 1988, p. 2. [4] Ibid [5] Moss A, et al. Seropositivity for HIV and the development of AIDS or AIDS-related condition: three year follow-up of the San Francisco General Hospital cohort, British Medical Journal, March 12, 1988, p. 749. [6] Ibid [7] Mitsuya H, et al. Dextran sulfate suppression of viruses in the HIV family: inhibition of virus binding to CD4+ cells. Science, 1988, 240:648-694. [8] Ibid [9] Ueno R. Dextran sulfate, a potent anti-HIV agent in vitro having synergism with zidovudine. The Lancet, June 13, 1987, p. 1397. [10] Ishii Y. The effects of orally administered MDS on platelet adhesiveness and blood coagulation. Naika Hokan, 1968, 211(2): 55-58. [11] Abrams D, et al. A phase trial of oral UA001 (dextran sulfate) in patients with AIDS and ARC. Abstract #3580, IV International Conference on AIDS. Stockholm, 1988. [12] Japanese Physicians' Desk Reference, p. 641. [13] Treatment Issues. July 18, 1988, p. 2. [14] Ibid [15] Kwaja T, et al. Recent studies on the anticancer activities of mistletoe and its alkaloids. Oncology, no. 43, supplement 1, p. 42, 1986. [16] Clinical Instructor of Medicine, University of California at San Francisco. [17] Ibid [18] Ibid [19] Franz H. Mistletoe lectins and their A and B chains. Oncology 43: supplement 1, pp. 23-24, 1986. [20] Renta, et al. Biologic properties of Iscador. Laboratory Investigation, 1981, vol. 44, no. 2, p. 43. [21] Yust I, et al. Reduction of circulatory HIV antigen in seropositive patients after treatment with AL721. Abstract #3530, IV International Conference on AIDS. Stockholm, 1988. [22] Goebel F. Clinical findings after administration of lipids in AIDS --a pilot study. Abstract #3531, IV International Conference on AIDS. Stockholm, 1988. [23] Grieco M H, et al. Open study of AL721 treatment of HIV- infected subjects with generalized lymphadenopathy syndrome: an 8 week open trial and follow-up. Antiviral Research, no. 9, p. 188, 1988. [24] Ibid [25] Crumpacker C, et al. Ribavirin enters cerebrospinal fluid. The Lancet, 1988, pp. 45-46. [26] McDaniel H, et al. In vitro studies on polymannoacetate (carrisyn) for antiviral effect. American Society of Clinical Pathologists. New Orleans, 1987, p. 121. [27] McAnalley B, et al. Demonstration of in vitro antiviral action of acemannan (ACE-M) against multiple viruses including the HIV virus. Abstract #3567, IV International Conference on AIDs, Stockholm, 1988. [28] AIDS/HIV Experimental Treatment Directory, August, 1988, p. 60. [29] Kim K, et al. Inactivation of cytomegalovirus and semiliki forest virus by butylated hydroxytoluene, Journal of Infectious Diseases, 138:91-94,1978. [30] Snipes W, et al. Butylated hydroxytoluene inactivates lipid-containing virus. Science, vol. 188, April 4, 1975, pp. 64-66. [31] Brugh M. Butylated hyroxytoluene protects chickens exposed to Newcastle disease virus. Science, vol 197, Sep 23, 1977, pp. 1291-1292. [32] Aloia R, et al. Lipid composition and fluidity of the human immunodeficiency virus. Proceedings of the National Academy of Science, USA, Feb. 1988, vol. 85, pp. 900-904. [33] Freeman D. Treatment of recurrent herpes simplex labialis with topical butylated hydroxytoluene. Clinical Pharmacological Therapy, July, 1985, pp. 56-59. [34] Aloia R, et al. p. 904. [35] Chaudhary, et al. Selective killing of HIV-infected cells by recombinant human CD4-pseudomonas exotoxin hybrid protein. Nature, Sep. 22, 1988, pp. 369-372. [36] Weiser B, et al. Combination anti-HIV activity of rifabutin with heparin or 2',3'-dideoxycytidine (ddC), Abstract #3592, IV International Conference on AIDS. Stockholm, 1988. [37] Siegal F, et al. Dose-related tolerance and efficacy in humans of rifabutin, an antimicrobial with antiviral activity against HIV in vitro. Abstract #3591, IV International Conference on AIDS. Stockholm, 1988. [38] AIDS/HIV Experimental Treatment Directory, vol. 2, number 2, August, 1988, p. 79. [39] Yarchoan R, et al. Phase I studies of 2',3'-dideoxycytidine in severe HIV infection as a single agent and alternating with AZT. The Lancet, January 16:76-81, 1988. [40] Ibid [41] Ibid [42] Ibid [43] Kabbash L, et al. AIDS-associated Kaposi's sarcoma: treatment with moderate doses of recombinant interferon alpha-2a. Abstract #3516, IV International Conference on AIDS. Stockholm, 1988. [44] Dexon L, et al. Combination trail (phase I-II) of zidovudine with lymphoblastoid interferon alpha in patients with AIDS and Kaposi's sarcoma. IV International Conference on AIDS. Stockholm, 1988. [45] Hutchinson V and Cummins J. Low-dose oral interferon in patient with AIDS. The Lancet, December 26, 1987, p. 1530. [46] Dolei A, et al. Direct and cell-mediated effects of interferon-a on cells chronically infected with HTLV-III. Journal of Interferon Research, 1986:6 543-49. [47] Michaels, et al. Recombinant human interferon beta reduces human immunodeficiency virus in peripheral blood mononuclear cells. 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[55] AIDS Targeted Information Newsletter, editor's comments, August, 1988, p. 27. [56] Collaborative AZT Study Group. Hopital Claude Bernard, Paris. Abstract #3154, IV International Conference on AIDS. Stockholm, 1988. [57] The Lancet, February 20, 1988, p. 373. [58] de Ganf J. Zidovudine in a simplified dosage schedule reduces CSF HIV antigen levels in AIDS/ARC patients and asymptomatic subjects. Abstract #3144, IV International Conference on AIDS. Stockholm, 1988. [59] Helbert M, et al. Acute meningoencephalitis on dose reduction of zidovudine. The Lancet, June, 1988, pp. 1249-52. [60] Professor of Dermatology, UCSF. [61] Director, AIDS Clinic, UCSF Medical Center. [62] Maeland A, et al. The effect of different dosage regiments of zidovudine/acyclovir on HIV-antigen-aemia. Abstract, IV International Conference on AIDS, Stockholm, 1988. [63] Matheron S, et al. Effects of AZT on AIDS-related cryptosporidiosis. Abstract #3672, IV International Conference on AIDS. Stockholm, 1988. [64] Hermans P. The benefit of zidovudine in the treatment of AIDS patients with cerebral toxoplasmosis. Abstract #3667, IV International Conference on AIDS. Stockholm, 1988. [65] Eeftinck Schattenkerk. Influence of zidovudine on HIV- related KS. Abstract #3638, IV International Conference on AIDS. Stockholm, 1988. [66] Stambuck D. The effect of AZT treatment on KS in HIV- infected patients. Abstract #3639, IV International Conference on AIDS, Stockholm, 1988. [67] Pizzo P, et al. Continuous intravenous administration of AZT to children with symptomatic HIV infection. Abstract #3146, IV International Conference on AIDS. Stockholm, 1988. [68] Marx J. Multiplying genes by leaps and bounds. Science, June 10, 1988, p. 1409. [69] Ibid *************************************************************** COMMUNITY RESEARCH ALLIANCE IN SAN FRANCISCO The San Francisco Community Research Alliance (CRA) is a community-based research effort whose purpose is to test experimental treatments for HIV disease. Modeled on New York's Community Research Initiative, the CRA will design scientific studies of available experimental treatments. The CRA Board of Directors represents an alliance between community organizations, people infected with HIV, treatment advocates and physicians in clinical practice. CRA is currently forming an Institutional Review Board to review the ethics and design of proposed clinical trials. CRA's Scientific Advisory Committee is actively seeking qualified physicians and researchers to develop and evaluate protocols for clinical trials. If you would like to volunteer time, donate money or simply get more information, please call Mike Lipson (415-626-2145) or write to the CRA at 273 Church Street, San Francisco, CA 94114. *************************************************************** NEXT ISSUE The Immunomodulaters, Antiviral Update, AIDS Treatments in Japan *************************************************************** FOR FURTHER INFORMATION: SF AIDS Foundation (English & Spanish)..................(415) 863-AIDS Northern California.....................................(800) FOR-AIDS TDD.....................................................(415) 864-6606 (Monday-Friday 9:00 am - 9:00 pm Sunday & Saturday 11:00 am - 6:00 pm) AIDS and ARC Switchboard................................(415) 861-7309 Staffed by people with AIDS and ARC (Monday-Friday 12:00 pm - 6:00pm and Saturday 2:00 pm - 5:00 pm) For information about possible enrollment in experimental treatment research trials at SF General Hospital call (415) 821-5089. *************************************************************** YOU CAN HELP! BETA is distributed FREE in San Francisco. You can help BETA provide treatment information at no charge to the public by sending a contribution to the San Francisco AIDS Foundation, P.O. Box 6182, San Francisco, CA 94101. Please make checks payable to the San Francisco AIDS Foundation, Attn: BETA. **************************************************************** Editor Ron Baker Senior Research Consultant Jim Palazzolo Consultants for this issue Robert Gorter, MD William Lang, MD Sandra Hernandez, MD Evelyn Rose, Pharm D John James James Campbell, MD Editorial Assistants Isbel Auerbach, Larissa Hull, Anne Goddard, Francis Jue Production Assistants Jamie Mohn, Don Frazell, John V-J Simon Design Larry Stinson BETA is published by the San Francisco AIDS Foundation, P.O. Box 6182, San Francisco, CA 94101. To order a copy, call (415) 863-AIDS 800-FOR-AIDS in northern California or 415-864-6606 for TDD service. Funding for this issue provided by the San Francisco Department of Public Health and by private and corporate donations. *************************************************************** STATEMENT OF PURPOSE The San Francisco Department of Public Health has determined that without an effective intervention 65-100% of all individuals infected with HIV will eventually develop AIDS. Because of this projection, the San Francisco AIDS Foundation urges these individuals to learn more about care for HIV infection, including experimental treatment options. The decision whether or not to start an experimental therapy for HIV infection should be made in consultation with an AIDS-knowledgeable physician. The San Francisco AIDS Foundation publishes BETA as an educational resource for individuals considering experimental treatments for HIV. BETA reviews available scientific data on these experimental treatments as well as anecdotal information provided by physicians, researchers, and individuals infected with HIV. Presentation of information in BETA does not imply an endorsement of any action or treatment by the San Francisco Department of Public Health or the San Francisco AIDS Foundation. Although BETA's primary audience is HIV-infected individuals, physicians and other people affected by the AIDS epidemic may find BETA useful. The San Francisco AIDS Foundation distributes BETA free in San Francisco. To order a copy, call 415-863-AIDS, 800 FOR-AIDS in northern CA, or 415-864-6606 for TDD service. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display