Bulletin of Experimental Treatments for AIDS, No. 2; November 1988
Jim Palazzolo and Ron Baker

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).

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. Proceedings of the AACR, 28(460):1824, 1987.

[48] Carron W, et al. Anti-HIV activity of beta-interferon in combination with zidovidine. Abstract #3633, IV International Conference on AIDS. Stockholm, 1988.

[49] Miles S, et al. Betaseron interferon has in vivo activity against HIV and AIDS-related KS. Abstract #3517, IV International Conference on AIDS. Stockholm, 1988.

[50] AIDS/HIV Experimental Treatment Directory, August, 1988, p. 109.

[51] AIDS/HIV Experimental Treatment Directory, August, 1988, p. 110.

[52] Heseltine P, et al. Phase I study of peptide-TA in AIDS: pharmacology and immune response. Abstract, IV International Conference on AIDS. Stockholm, 1988.

[53] Baron P, et al. Peptide-T does not inhibit HIV-1 infection in an in vitro serum-free system. AIDS (letter), 2:(3), p. 228, 198.

[54] Lloyd G, et al. Effect of bile salts and of fusidic acid on HIV-1 infection of cultured cells. The Lancet, 1:(8600), HIV-1 June 25, 1988, vol. 1, pp. 1418-21.

[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

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